[Three-dimensional Conformal Radiotherapy for Extracranial Tumors Using a Stereotactic Body Frame]

Igaku Butsuri : Nihon Igaku Butsuri Gakkai Kikanshi = Japanese Journal of Medical Physics : an Official Journal of Japan Society of Medical Physics. 2001  |  Pubmed ID: 12766310

This paper was reviewed to evaluate the feasibility of three-dimensional (3-D) conformal radiotherapy for extracranial tumors, especially for solitary lung tumors using a stereotactic body frame. To extend the technique of stereotactic irradiation for intracranial tumors, accurate body fixation and regulation of internal target motion are essential. In our study, a stereotactic body frame was used, and daily setup accuracy was verified. As a result, its setup accuracy was maintained within 0-8.5 mm (Ave=2.5mm). In our initial clinical experiences for thirty-two patients with 6-10 non-coplanar static beams, forty or 48 Gy was irradiated. During the follow-up of 4-27 (Average=11) months, twenty-nine (94%) tumors were locally controlled without any symptomatic complications. Recently, respiratory-gated irradiation systems, CT-linac systems, a real-time tumor tracking system, Cyber-knife, and C-arm linac were developed. With all these techniques, stereotactic irradiation for extracranial tumors are future direction of three-dimensional conformal radiotherapy.

Dysregulation of IL-13 Production by Cord Blood CD4+ T Cells is Associated with the Subsequent Development of Atopic Disease in Infants

Pediatric Research. Feb, 2002  |  Pubmed ID: 11809914

Early intervention strategies in allergic diseases will be dependent on identification of newborns at high risk for later development of atopic disease. In this cohort study of 106 neonates, we investigated whether cytokine production property and responsiveness to IL-12 of neonatal CD4(+) T cells were associated with the subsequent development of atopic disease and whether a skewed cytokine production property was intrinsic to helper T cells. To exclude the effects of contaminating cells, highly purified cord blood CD4(+) T cells were stimulated with anti-CD3 MAb and recombinant B7-2 molecule in the presence or absence of IL-12. Production of IL-13 and interferon-gamma was determined by ELISA. The infants were assessed at 12 mo for the development of atopic diseases. CD4(+) T cells of neonates who manifested allergic symptoms (atopic group) produced higher levels of IL-13 compared with those of the nonatopic group in both the presence and absence of IL-12. No significant difference was noted between the two groups with respect to interferon-gamma production. Moreover, higher IL-13 production was also observed in neonates with chronic eczema than those with short-term eczema. Our data suggest that increased production of IL-13 by neonatal CD4(+) T cells is a useful marker of newborns at high risk for subsequent development of atopic diseases and that an intrinsic abnormality of CD4(+) T cell is associated with the pathogeneses of atopic disease, especially atopic dermatitis in infants.

Conserved Domains in the Chicken Homologue of BRCA2

Oncogene. Feb, 2002  |  Pubmed ID: 11850831

Germline mutation of the BRCA2 gene causes a high risk of developing breast and ovarian cancer. Although the BRCA2 protein has been implicated in homologous recombination (HR) of DNA and in transcription, it is still unclear how mutation leads to tumorigenesis. We have identified a non-mammalian homologue of BRCA2 from chicken, which encodes a protein with 3397 amino acids (aa) and shows only 40% identity to human BRCA2. However, comparison of the mammalian and chicken sequences revealed remarkably high homology in several segments. These include a N-terminal region (approximately 100 aa), which was previously shown to possess intrinsic transcriptional activity, and a C-terminal region (aa residue approximately 2480-approximately 3180 in human BRCA2), which has not been clearly assigned any function. In contrast, although the eight BRC repeats of mammalian BRCA2 are believed to play an important role in HR by interacting with Rad51, the BRC3, BRC5, and BRC6 repeats exhibit virtually no similarity to their mammalian counterparts. Among 311 missense mutations listed as unclassified variants in the NIH Breast Cancer Information Core database, only 83 of these sites are identical in chicken BRCA2. Thus, chicken BRCA2 may provide a means to identify domains and residues associated with cancer predisposition.

Antitumor Effect of TAT-oxygen-dependent Degradation-caspase-3 Fusion Protein Specifically Stabilized and Activated in Hypoxic Tumor Cells

Cancer Research. Apr, 2002  |  Pubmed ID: 11929818

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues. These impart resistance to radiotherapy and anticancer chemotherapy, as well as predisposing to increased tumor metastases. To develop a potentially therapeutic protein drug highly specific for solid tumors, we constructed fusion proteins selectively stabilized in hypoxic tumor cells. A model fusion protein, oxygen-dependent degradation (ODD)-beta-galactosidase (beta-Gal), composed of a part of the ODD domain of hypoxia-inducible factor-1alpha fused to beta-Gal, showed increased stability in cultured cells under a hypoxia-mimic condition. When ODD-beta-Gal was further fused to the HIV-TAT protein transduction domain (TAT(47-57)) and i.p. injected to a tumor-bearing mouse, the biologically active fusion protein was specifically stabilized in solid tumors but was hardly detected in the normal tissue. Furthermore, when wild-type (WT) caspase-3 (Casp3(WT)) or its catalytically inactive mutant was fused to TAT-ODD and i.p. injected to a tumor-bearing mouse, the size of tumors was reduced by the administration of TAT-ODD-Casp3(WT) but not by TAT-ODD-mutant Casp3. TAT-ODD-Casp3(WT) did not cause any obvious side effects on tumor-bearing mice, suggesting specific stabilization and activation of the fusion protein in the hypoxic tumor cells. These results suggest that the combination of protein therapy using a cytotoxic TAT-ODD fusion protein with radiotherapy and chemotherapy may provide a new strategy for annihilating solid tumors.

Postoperative Radiotherapy for Intracranial Ependymoma: Analysis of Prognostic Factors and Patterns of Failure

Journal of Neuro-oncology. Jan, 2002  |  Pubmed ID: 11949831

The long-term results of external beam radiotherapy following surgical resection in patients with intracranial ependymomas were evaluated to identify the prognostic factors and the pattern of recurrence. Between June 1961 and January 1999, 48 patients with intracranial ependymoma were treated with external beam irradiation with >40 Gy following surgery. Total doses of 40.5-63.4Gy were delivered to the tumor site in 22-46 fractions over 33-101 days. Six patients with spinal deposit or positive cerebrospinal fluid cytology received whole spinal axis irradiation, and 4 patients received prophylactic spinal irradiation. The median follow-up of surviving patients was 110 months. The 10-year overall and relapse-free survival rates were 47% and 42%, respectively. In multivariate analysis, female gender, lower tumor grade and total resection were found to be associated with better relapse-free survival. Twenty of 26 recurrences developed at the primary tumor site (inside the irradiation field), two at the unirradiated cerebellum and spinal cord, and four at the spinal cord without intracranial failure. Only one of 34 patients with supratentorial tumors developed isolated spinal metastasis, whereas 3 of 14 patients with infratentorial tumors did so. Regarding the late neurotoxicity of radiotherapy, one of the 15 long-term (>4 years) survivors whose psychosocial status could be evaluated showed marked cognitive impairment. It was suggested that the use of new treatment strategies to improve local control would be warranted, and that prophylactic whole spinal axis irradiation appeared to be of more benefit in patients with infratentorial tumors than in those with supratentorial tumors.

Clinical Outcomes of 3D Conformal Hypofractionated Single High-dose Radiotherapy for One or Two Lung Tumors Using a Stereotactic Body Frame

International Journal of Radiation Oncology, Biology, Physics. Mar, 2002  |  Pubmed ID: 11958900

This study was performed to evaluate the clinical outcomes of three-dimensional (3D) conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame.

Renal Aplasia is the Predominant Cause of Congenital Solitary Kidneys

Kidney International. May, 2002  |  Pubmed ID: 11967035

Congenital solitary kidneys, which are susceptible to renal failure, have been considered mostly due to unilateral renal agenesis and partly due to renal aplasia. Risk of familial recurrence and of other associated anomalies is known to be much higher in renal agenesis than in renal aplasia. However, differential diagnosis between the two renal anomalies is difficult, and renal agenesis has been found much less frequently in ultrasound screening studies of fetuses than in autopsy studies.

Two Cases of Anaphylactic Reaction to Gelatin Induced by a Chloral Hydrate Suppository

Pediatrics International : Official Journal of the Japan Pediatric Society. Feb, 2002  |  Pubmed ID: 11982879

Bone Mineral Status in Ambulatory Pediatric Patients on Long-term Anti-epileptic Drug Therapy

Pediatrics International : Official Journal of the Japan Pediatric Society. Jun, 2002  |  Pubmed ID: 11982890

For ambulatory pediatric outpatients,reports of abnormalities of bone metabolism associated with anti-epileptic drugs are inconsistent and may be difficult to interpret.

Infantile Renal Dysfunction Associated with Intrauterine Exposure to Ritodrine and Magnesium Sulfate

Nephron. Jun, 2002  |  Pubmed ID: 12053081

[Assessment of Complications in a Randomized Controlled Study on Multimodality Therapy for Patients Following Breast-conserving Surgery: Kansai Breast Cancer Radiotherapy Research Group (5'-KBR)]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Jul, 2002  |  Pubmed ID: 12145995

PURPOSE: We conducted a randomized controlled study to evaluate the safety and usefulness of a combined treatment of radiotherapy and chemotherapy with doxifluridine (5'-DFUR) plus tamoxifen (TAM) as an adjuvant therapy for breast cancer patients after conservative surgery. The complications observed in this trial are reported herein. METHODS: A total of 550 patients were registered and randomized (based on factors such as T, N, with/without radiotherapy) to groups A and B. Drug regimens were: group A, 5'-DFUR 600 mg/body/day for 6 months and TAM 20 mg/body/day for 2 years; group B, 5'-DFUR 600 mg/body/day for 2 years and TAM 20 mg/body/day for 2 years. Radiotherapy (2 Gy x 5 times/week, for 5 weeks) was administered to 88.6% of evaluable patients (481/543). Radiation-related acute adverse reactions occurred in 28.5% of the 481 patients and moderate to severe reactions occurred in 1.5% of the patients. Delayed radiation-related adverse reactions occurred in 23.8% of the patients but none were severe. Chemo-endocrine therapy-related adverse reactions occurred in 17.9% of group A patients and 25.6% of group B patients. Grade 3 reactions occurred in 6 of the group A patients (2.4%) and in 5 of the group B patients (1.9%); all adverse reactions subsided after dose reduction or discontinuation. These findings suggest that the combination therapy of irradiation and 5'-DFUR with TAM is safe for patients after breast conserving surgery.

Erythromycin in ELBW Infants

The Journal of Pediatrics. Aug, 2002  |  Pubmed ID: 12183739

Adjuvant Radiation Therapy Following Mastectomy for Breast Cancer

Breast Cancer (Tokyo, Japan). 2002  |  Pubmed ID: 12185328

Many randomized clinical trials have been performed to address the effectiveness of postmastectomy radiation therapy (PMRT) to regional lymph nodes with or without chest wall irradiation. Although these studies have confirmed the usefulness of RT to reduce loco-regional recurrence, the benefit of postoperative RT for survival remains controversial. Recent prospective trials of PMRT in combination with systemic chemotherapy clearly demonstrated the benefit of this combined adjuvant therapy for both locoregional recurrence and survival outcomes. Based upon this new evidence, guidelines and recommendations for PMRT in the management of breast cancer have been proposed by the American Society of Clinical Oncology and by the International Consensus Panel at the International Conference on Adjuvant Therapy of Primary Breast Cancer in St. Gallen. PMRT is recognized as a standard adjuvant treatment for patients with more than 4 positive axillary nodes in these guidelines and recommendations. This re-appraisal of PMRT has not attracted much attention in Japan so far. Clinical studies are needed to determine how to best incorporate PMRT in the multimodal treatment of node-positive breast cancer.

Methylenetetrahydrofolate Reductase Polymorphism in Childhood Primary Focal Segmental Glomerulosclerosis

Nephron. Oct, 2002  |  Pubmed ID: 12218328

The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population.

Early Sensitization to House Dust Mite is a Major Risk Factor for Subsequent Development of Bronchial Asthma in Japanese Infants with Atopic Dermatitis: Results of a 4-year Followup Study

Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. Sep, 2002  |  Pubmed ID: 12269646

Bronchial asthma (BA) often develops in children with atopic dermatitis (AD). Identification of factors that could predict the development of asthma in children with AD is useful for early intervention.

Vasoactive and Natriuretic Mediators in Umbilical Cord Blood: a Report of Our Observation and Review of the Literature

Early Human Development. Oct, 2002  |  Pubmed ID: 12324183

The relative potency and interrelationship among vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. However, little is known about their potential roles in the perinatal setting.

Oxidant and Antioxidant Activities in Childhood Meningitis

Life Sciences. Oct, 2002  |  Pubmed ID: 12383885

Animal studies have provided substantial evidence for a key role of reactive oxygen species, nitric oxide and its related compounds in the complex pathophysiology of bacterial meningitis. However, there is little information on changes in the redox status in human meningitis. In the present study, we evaluated the redox status and oxidative stress in the central nervous system of children with meningitis. Oxidant and antioxidant activities were assessed from cerebrospinal fluid levels of acrolein-lysine adducts (a marker of lipid peroxidation), nitrite (a marker of nitric oxide production) and bilirubin derivatives (a marker of antioxidant activity of bilirubin). All these markers were several times higher in children during the early phase of bacterial meningitis compared with those of children without meningitis and patients with aseptic meningitis. In the bacterial meningitis group, the levels of bilirubin derivatives correlated significantly with those of acrolein-lysine adducts and nitrite. Acrolein-lysine adducts and nitrite decreased significantly as the patients started to respond to treatment but bilirubin derivatives remained elevated. In conclusion, our data indicate the enhancement of both oxidant and antioxidant activities in the central nervous system of children with early bacterial meningitis, but not in those with aseptic meningitis. Clinical and laboratory improvement may be associated with a decrease in oxidant activities in the central nervous system.

Meatus Tightly Covered by the Prepuce is Associated with Urinary Infection

Pediatrics International : Official Journal of the Japan Pediatric Society. Dec, 2002  |  Pubmed ID: 12421265

Almost all newborns have phimosis, which is known as one of the risk factors for urinary infection. The present study analyzed which specific prepuce conditions correlated with the development of febrile urinary infection in Japanese male infants.

Is Whole-brain Irradiation Necessary for Primary Central Nervous System Lymphoma? Patterns of Recurrence After Partial-brain Irradiation

Cancer. Jan, 2003  |  Pubmed ID: 12491514

Neurotoxicity after whole-brain irradiation remains a major problem in the treatment of primary central nervous system lymphoma (PCNSL). To clarify whether whole-brain radiation is necessary for PCNSL, the authors retrospectively analyzed the outcome of patients treated with partial-brain irradiation.

[Therapeutic Strategy for Prostate Specific Antigen (PSA) Failure After Radical Prostatectomy]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Jan, 2003  |  Pubmed ID: 12557702

Prostate specific antigen (PSA) failure occurs in 20% to 50% of patients who undergo radical prostatectomy. There is no consensus on how PSA failure should be managed. Recently, salvage radiotherapy is reported to be an effective treatment for PSA failure, and 20%-70% of cases are recurrence-free. The aim of salvage radiotherapy is a cure and this is quite different from other options, for example, endocrine therapy. Salvage radiotherapy is likely to become more important as a treatment for PSA failure after radical prostatectomy.

Early Treatment of Urinary Infection Prevents Renal Damage on Cortical Scintigraphy

Pediatric Nephrology (Berlin, Germany). Feb, 2003  |  Pubmed ID: 12579399

Diagnosis of urinary infection in young children is often delayed, which may result in renal damage. However, it remains to be clarified how soon the treatment should be started to prevent renal changes. The present study prospectively enrolled young children with diagnosis of their first febrile urinary infection who underwent technetium-99m dimercaptosuccinate renal cortical scintigraphy within 120 h of initiation of treatment. Patients with abnormal renoscintigraphy received antibiotics for 2 weeks and scintigraphy was repeated 1 year later. Twenty-two children were enrolled from July 1995 through March 2000. Acute-phase renoscintigraphy identified focal defects in 0 of the 14 children who were treated within 24 h of the disease, 1 of the 3 treated in 24-48 h, and 2 of the 5 treated in 48-72 h. Repeat renoscintigraphy showed disappearance of the focal defects in all 3 children. The present study has shown that early treatment within 24 h of onset of the fever due to urinary infection should deter renal changes. Fever for more than 24 h prior to diagnosis indicates a high risk for renal changes and needs an immediate effective treatment to avoid renal damage.

Logical Checking Function Increases the Accuracy of Data Entry in the Patterns of Care Study

Strahlentherapie Und Onkologie : Organ Der Deutschen Röntgengesellschaft ... [et Al]. Feb, 2003  |  Pubmed ID: 12590321

For clinical studies, the use of a databases combined with a computer is becoming popular for data capturing. Commercially available database software has a logical checking function, which can restrict the type of data and their range. The study presented here quantitatively and prospectively evaluated the effectiveness for data management with this function using the database of Patterns of Care Study (PCS) in Japan.

Oxidative Stress and Altered Antioxidant Defenses in Children with Acute Exacerbation of Atopic Dermatitis

Life Sciences. Apr, 2003  |  Pubmed ID: 12650859

The underlying mechanisms of skin inflammation in atopic dermatitis (AD) are not completely understood. The purpose of the present study was to examine the involvement of oxidative stress and antioxidant defenses in children with acute exacerbation of AD. We studied 13 children who were hospitalized for acute exacerbation of AD with purulent skin infection by Staphylococcal aureus (age, 1.5 to 10.0 years), and 28 age-matched healthy subjects (controls). Urine samples obtained from the patients on admission, on 2nd and 7th-9th hospital days, as well as from the controls were analyzed for 8-hydroxy-2'-deoxyguanosine (8-OHdG) (a marker of oxidative DNA damage), acrolein-lysine adducts (a marker of lipid peroxidation), bilirubin oxidative metabolites (BOM) (a marker of antioxidant activity of bilirubin under oxidative stress) and nitrite/nitrate (NO(x)(-)) (a marker of endogenous nitric oxide production). Of these, urinary concentrations of 8-OHdG, acrolein-lysine adducts and BOM, but not NO(x)(-), were significantly higher in AD children on admission than those in control subjects. Response to treatment was associated with significant falls in the concentrations of 8-OHdG and acrolein-lysine adducts. Urinary concentrations of acrolein-lysine adducts, but not 8-OHdG, were still significantly higher in AD patients on the 7th-9th hospital day relative to the control. Urinary BOM remained almost constant and significantly high in AD children during hospitalization. Our findings indicate that oxidative stress and altered antioxidant defenses are involved in the pathophysiology of acute exacerbation of AD, and that suppression of oxidative stress might be a potentially useful strategy for the treatment of AD.

Gas-phase Disproportionation of Nitric Oxide at Elevated Pressures

Free Radical Research. Feb, 2003  |  Pubmed ID: 12653205

T.P. Melia's chemical kinetics study of the disproportionation of nitric oxide (NO), 3NO --> NO2 + N2O, (Melia, T.P. (1965) J. Inorg. Nucl. Chem., 27, 95-98), which is the most quoted quantitative investigation presently available, revealed a rather strong dependence of the effective rate constant, Kk' of Melia's third-order rate law, -d[NO]/dt = Kk'[NO]3, on the initial pressure of NO. In order to estimate extent of accumulation of NO2 and N2O as a function of time by integration of the rate law, we have evaluated the dependence of the effective rate constant as a function of pressure and thus as a function of time on the basis of the non-ideality of NO gas. Although our approach is crude in that the non-idealities of NO2 and N2O and other NOx products and a probable deviation of the gas mixture from the Dalton's law have not been considered, it provides a means for approximately estimating the rate of accumulation of NO2 and N2O based on Melia's data. According to these calculations, the extent of the disproportionation is generally negligible at low initial pressures, e.g. 5 atm or less, while at 200 atm, the mole fractions of NO2 and N2O can become as high as 12-13% only after 10 days. These values are alarmingly high for handling pressured NO- in N2-mixture in either research or clinical settings. This information must be borne in mind when compressed NO in commercial cylinders is employed in high precision experiments. Disproportionation of NO under pressure also deserves attention in inhalation of low doses of NO in the treatment of diseases characterized by pulmonary hypertension and hypoxemia.

[Breast Cancer]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Mar, 2003  |  Pubmed ID: 12669390

As most of the clinical evidence that has a significant impact on the care of breast cancer is based on studies conducted in Western countries, it is important to understand the differences in the natural history of the disease as well as in the patterns of care before applying that evidence to daily practice in Japan. For example, the EORTC 22881 study demonstrated significant improvement of local control after breast conserving therapy with the additional use of 16 Gy of boost irradiation to the tumor bed after 50 Gy of whole breast irradiation for margin negative patients. However, the extent of the surgery in this study was smaller than that common in Japan, and the criteria for a negative margin was less strict than that in Japan. Therefore, it may be over-treatment to give boost irradiation routinely to margin negative patients in Japan. On the other hand, as it is a universal observation that patients under the age of 40 have greater risk of local recurrence, the result of EORTC 22881 study that the benefit of boost irradiation was greatest in patients younger than age of 40 encourages us to confirm this finding in our own clinical settings. It is desirable to develop clinical evidence of high quality in Japan that are directly applicable to Japanese patients.

Concurrent Chemotherapy and Radiotherapy with Low-dose Cisplatin for Nasopharyngeal Carcinoma

American Journal of Clinical Oncology. Apr, 2003  |  Pubmed ID: 12714887

Eighty-one patients with nondisseminated nasopharyngeal carcinoma consecutively treated between January 1977 and December 1998 were analyzed to evaluate whether a concurrent adjunction of low-dose cisplatin enhances the outcome of definitive radiotherapy. Ninety-eight percent (n = 79) of the cases were ranked as stage III/IV according to the 1987 Union International Contre le Cancer staging criteria. Patients treated before 1987 and treated after 1988 were mainly managed by radiotherapy alone (historical group: n = 48) and concurrent chemoradiotherapy with relatively low-dose cisplatin (CCRT group: n = 33), respectively. The locoregional failure-free survival rate of the CCRT group was significantly better than that of the historical group (72.8% vs. 35.9% at 5 years, p = 0.0041). However, multivariate analysis identified only the total dose and the T-stage as significant independent factors for locoregional control. No difference was observed on overall, disease-specific, and distant failure-free survival between the two groups. The results of the present study suggest that concurrent adjunction of low-dose cisplatin will not improve the outcome of definitive radiotherapy for nasopharyngeal carcinoma. Full-dose concurrent chemoradiotherapy, as well as the appropriate dose escalation for better locoregional control, will be mandatory to achieve better survival.

Late Skin and Subcutaneous Soft Tissue Changes After 10-gy Boost for Breast Conserving Therapy

Breast Cancer (Tokyo, Japan). 2003  |  Pubmed ID: 12736565

To evaluate the influence of boost irradiation for breast conserving therapy on skin and subcutaneous tissue.

Preparation of Ceramic Microspheres for in Situ Radiotherapy of Deep-seated Cancer

Biomaterials. Aug, 2003  |  Pubmed ID: 12742735

Radiotherapy is one of the most effective treatments for cancers. However, external irradiation provides only small doses to deep-seated cancers, and often causes damage to healthy tissues. It has been reported that 20-30 microm diameter 17Y(2)O(3)-19Al(2)O(3)-64SiO(2) (mol%) glass microspheres are useful for the in situ irradiation of cancers. Yttrium-89 (89Y) in this glass can be neutron bombarded to form the beta-emitter 90Y (half-life=64.1h). When injected in the vicinity of the cancer, such activated glass microspheres can provide a large localized dose of beta-radiation. The Y(2)O(3) content of the glass in the microspheres is limited to only 17 mol%. Chemically durable microspheres with a higher Y(2)O(3) content need to be developed. Phosphorus-31 (31P) with 100% natural abundance can also be activated by neutron bombardment to form the beta-emitter 32P (half-life=14.3d). Chemically durable microspheres containing a high phosphorus content are expected to be more effective for cancer treatment. We prepared pure Y(2)O(3) and YPO(4) microspheres using a high-frequency induction thermal plasma melting technique, and investigated the resulting structure and chemical durability. We successfully prepared smooth, highly spherical polycrystalline Y(2)O(3) and YPO(4) microspheres with diameters in the range 20-30 microm. Both the Y(2)O(3) and YPO(4) microspheres showed high chemical durability in saline solutions buffered at pH=6 and 7. These microspheres are expected to be more effective than the conventional glass microspheres for the in situ radiotherapy of cancer.

Clinical Evaluation of Dynamic Arc Conformal Radiotherapy for Paraaortic Lymph Node Metastasis

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Apr, 2003  |  Pubmed ID: 12758247

This study was performed to evaluate the efficacy and safety of dynamic arc conformal radiotherapy, a simple intensity modulated radiation therapy (IMRT), for the treatment of paraaortic lymph node metastases. Materials and

Formation of Advanced Glycosylation End Products and Oxidative Stress in Young Patients with Type 1 Diabetes

Pediatric Research. Sep, 2003  |  Pubmed ID: 12761359

Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type 1 diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. Urine samples of 38 patients with type 1 diabetes [mean age (+/-SD), 12.8 +/- 4.5 y; diabetes duration, 5.7 +/- 4.3 y; HbA1c, 8.0 +/- 1.6%; urinary albumin excretion, 12.6 +/- 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria (> or =15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.

Cholangitis and Liver Abscess After Percutaneous Ablation Therapy for Liver Tumors: Incidence and Risk Factors

Journal of Vascular and Interventional Radiology : JVIR. Dec, 2003  |  Pubmed ID: 14654488

To determine the risk factors of cholangitis and liver abscess occurring after percutaneous ablation therapy for liver tumors.

Tumor Hypoxia: a Target for Selective Cancer Therapy

Cancer Science. Dec, 2003  |  Pubmed ID: 14662015

Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO(2) < 0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties.

Development of Severe Complications Caused by Stent Placement Followed by Definitive Radiation Therapy for T4 Esophageal Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Dec, 2003  |  Pubmed ID: 14663644

Esophageal stenting in previously irradiated patients is known to cause more severe complications than those in patients who were not irradiated. But there are few reports regarding the results of stent placement before radiation therapy. Three patients with stage T4 esophageal cancer with direct invasion to the trachea and/or aorta underwent radiation therapy after stent placement. Two of the three patients had received systemic chemotherapy before radiation therapy. Fifty-one to 66 Gy of radiation therapy was administrated 15 to 66 days after the stent placement. The initial response to radiation therapy was no change (NC) or progressive disease (PD). All patients died of bleeding or pneumonia caused by perforation at the site of the stents 17 to 79 days after the radiation therapy. It is strongly suggested that even in patients with locally advanced esophageal cancer with severe dysphagia, radiation therapy should precede stent placement, because the consequences of radiation therapy after stent placement are devastating, and radiation therapy alone can, potentially, resolve the symptoms.

High Levels of Urinary Pentosidine, an Advanced Glycation End Product, in Children with Acute Exacerbation of Atopic Dermatitis: Relationship with Oxidative Stress

Metabolism: Clinical and Experimental. Dec, 2003  |  Pubmed ID: 14669163

Pentosidine is an advanced glycation end product formed by sequential glycation and oxidation. The formation of pentosidine is increased in diseases associated with oxidative stress, such as inflammatory conditions. The aim of the present study was to determine the urinary concentration of pentosidine in atopic dermatitis (AD) and its relationship to the inflammatory status of AD. Urine samples of 32 children with AD and 30 age-matched healthy control subjects were assayed for pentosidine, pyrraline (another advanced glycation end product formed by nonoxidative glycation), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) (an established marker of oxidative stress). Of these 3 markers, urinary concentrations of pentosidine were significantly higher in patients with acute exacerbation of AD than in healthy controls and patients with stable AD. Urinary concentrations of 8-OHdG were significantly higher in AD patients with and without acute exacerbation than in healthy controls. Urinary pentosidine levels correlated significantly with those of 8-OHdG when all data of healthy controls and AD patients were plotted. In patients with acute exacerbation of AD, both urinary pentosidine and 8-OHdG significantly decreased after 7 to 9 days of treatment. Our findings in patients with acute exacerbation of AD suggest that pentosidine levels are partly determined by the prevailing oxidative stress in these patients.

A Randomized Study of Two Long-course Prednisolone Regimens for Nephrotic Syndrome in Children

American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. Jun, 2003  |  Pubmed ID: 12776266

Long-course prednisolone regimens have been shown to be more effective than short-course regimens in sustaining remission of nephrotic syndrome in children. However, the most beneficial approach among the long-course regimens remains unknown.

Medical Management of Congenital Anomalies of the Kidney and Urinary Tract

Pediatrics International : Official Journal of the Japan Pediatric Society. Oct, 2003  |  Pubmed ID: 14521548

Renal damage in children has been found to be more congenital in origin than was previously thought. Congenital anomalies of the kidney and urinary tract (CAKUT) involve renal dysplasia, renal hypoplasia, urinary tract obstruction and vesicoureteral reflux. CAKUT are sometimes bilateral and different types often coexist. Depending on their types and severity, children with CAKUT often have varying degrees of a reduced number of nephrons at birth. CAKUTare now the leading cause of renal failure in children. Children with renal dysplasia or obstructive uropathy may have abnormal renal tubules, and tend to lose essential water and sodium in urine. This can lead to poor body growth unless they are supplemented with water and sodium. Children with severe ureteric reflux often develop urinary infection and renal scarring. Renal scarring can further increase the risk of renal failure in children who already have other CAKUTand fewer nephrons than normal. Hypertension and proteinuria may develop in children with renal dysplasia and further aggravate renal function unless they are treated. Recent advances in the understanding and management of CAKUT make it possible for children with CAKUT to grow normally, have fewer complications such as urinary infection, have longer renal survival, and survive even with end-stage renal diseases through renal replacement therapy.

Patterns of Care Study in Japan: Analysis of Patients Subjected to Mastectomy Followed by Radiotherapy

Japanese Journal of Clinical Oncology. Sep, 2003  |  Pubmed ID: 14594939

Two prospective studies reported in 1997 demonstrated that postoperative radiotherapy after mastectomy was not only associated with a higher loco-regional control rate but also with a higher overall survival rate. The purpose of this study is to clarify the processes of care for patients undergoing mastectomy and postoperative radiotherapy in Japan.

Patterns of Care Study: Comparison of Process of Post-mastectomy Radiotherapy (PMRT) in Japan and the USA

Japanese Journal of Clinical Oncology. Oct, 2003  |  Pubmed ID: 14623920

The Patterns of Care Study (USPCS) by the American College of Radiology (ACR) has made significant contributions to improvements in the procedures of care for patients with breast cancer in the USA. The purpose of this study was to identify problems associated with the process of care for patients undergoing post-mastectomy radiotherapy (PMRT) in Japan compared with those in the USA.

Radiation Therapy for Brain Metastases from Breast Cancer

Breast Cancer (Tokyo, Japan). 2003  |  Pubmed ID: 14634514

Breast cancer is one of the most common malignancies that metastasize to the brain. Radiation therapy plays a central role in the management of brain metastases.

Evaluation of Lung Injury After Three-dimensional Conformal Stereotactic Radiation Therapy for Solitary Lung Tumors: CT Appearance

Radiology. Jan, 2004  |  Pubmed ID: 14645881

To evaluate the computed tomographic (CT) appearance of tumors and lung injury in patients who have undergone stereotactic radiation therapy (SRT) for solitary lung tumors.

N2O Anesthesia May Exacerbate Hyperhomocysteinemia and Endothelial Dysfunction in Patients with Renal Impairment

Kidney International. Jan, 2004  |  Pubmed ID: 14675071

A Technique for Noninvasive Respiratory Gated Radiation Treatment System Based on a Real Time 3D Ultrasound Image Correlation: a Phantom Study

Medical Physics. Feb, 2004  |  Pubmed ID: 15000610

This paper proposes a new respiratory gated radiation treatment system that allows real-time tumor localization while avoiding invasive operation to a patient. The proposed system employs a three-dimensional (3D) ultrasound device, a 3D digital localizer, and a real-time image processing system. At the planning time, CT and 3D ultrasound reference data are simultaneously acquired under a breath-hold condition. At the treatment time, ultrasound data on three orthogonal planes are acquired and transferred to the image processing system on a real-time basis. Subsequently, normalized image correlation indices using the reference and the real-time ultrasound data are calculated for the three orthogonal planes after performing real-time coordinate transform using the 3D digital localizer attached to an ultrasound probe. Prior to the system execution, the coordinate transform matrices are partially calculated using an ultrasound calibration phantom and the 3D digital localizer. A trigger pulse to a linac can be generated when the normalized image correlation index exceeds a predetermined threshold level. Experiments have been carried out using a moving-target phantom that simulates a patient respiratory motion. We have observed that the variation of the calculated real-time correlation index synchronizes with the periodical motion of the moving-target, suggesting that real-time localization for a moving tumor is feasible with the proposed system.

[Development of Automatic Verification System for Portal Image in Radiotherapy]

Nihon Hoshasen Gijutsu Gakkai Zasshi. Jan, 2004  |  Pubmed ID: 15041912

The current method of verification for external beam radiation therapy visually compares a simulation image with a portal image. However, because this method depends largely upon the observer's experience, it sometimes results in inter-observer differences. In this study, we developed software to measure atomatically the quantitative difference between the simulation image and portal image using an image-analysis method. The feasibility of this software was evaluated on a rectangular field in the pelvic region. We took 12 simulation images of a pelvic phantom, setting 4 different field shapes on each of 3 isocenters. We then obtained 84 portal images setting 7 known distances from each of the 12 simulation images. Using this software, the direction of shift was detected correctly, and the distance of shift was detected correctly to within less than 3 mm. We consider that this software could be a useful method of verification.

Feasibility of Breast-conserving Therapy for Macroscopically Multiple Ipsilateral Breast Cancer

International Journal of Radiation Oncology, Biology, Physics. May, 2004  |  Pubmed ID: 15093910

Macroscopically multiple ipsilateral breast cancer (MMIBC) is generally considered a contraindication for breast-conserving therapy (BCT). The result of BCT for MMIBC is reported and the feasibility discussed.

Oxidative Stress in Neonates: Evaluation Using Specific Biomarkers

Life Sciences. Jul, 2004  |  Pubmed ID: 15193953

Increased oxidative stress has been implicated in pathogenesis of serious diseases in neonates. We measured urinary levels of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative DNA damage), acrolein-lysine adduct (a marker of lipid peroxidation and oxidative protein damage), and nitrite/nitrate (a marker of endogenous nitric oxide formation) in one-month-old neonates to examine the status of oxidative stress and its relationship to the degree of prematurity and clinical condition in neonates. Study subjects comprised three groups: healthy term neonates, clinically stable preterm neonates requiring no supplemental oxygen, and clinically sick preterm neonates requiring supplemental oxygen and ventilator support. Urinary levels of 8-hydroxy-2'-deoxyguanosine and acrolein-lysine adduct were significantly higher in sick preterm neonates than those of stable preterm and healthy term neonates. In the sick preterm group, neonates developing active retinopathy showed significantly higher levels of acrolein-lysine adduct than the other neonates without retinopathy. There were no significant differences in both urinary markers of oxidative stress between stable preterm and healthy term neonates. The urinary nitrite/nitrate levels were not significantly different among the three groups, suggesting no difference in endogenous nitric oxide formation. Collectively, these results provide evidence of augmentation of oxidative damage to DNA, lipids and proteins, especially in clinically sick preterm neonates.

Many Confounding Factors Influencing Urinary Beta(2)-microglobulin Excretion in Premature Newborns

The Journal of Pediatrics. Jun, 2004  |  Pubmed ID: 15212063

Effects of Antioxidants and Nitric Oxide on TNF-alpha-induced Adhesion Molecule Expression and NF-kappaB Activation in Human Dermal Microvascular Endothelial Cells

Life Sciences. Jul, 2004  |  Pubmed ID: 15219804

Cell adhesion molecules expressed on endothelial cells in inflamed skin appear to be controlled by the actions of cytokines and reactive oxygen species. However, molecular mechanisms of the expression of adhesion molecules during skin inflammation are currently not well understood. To evaluate the role of antioxidants and nitric oxide in modulating inflammatory processes in the skin, we examined the effects of pyrrolidine dithiocarbamate (PDTC, 0.1 mM) and spermine NONOate (Sper-NO, 1 mM) on adhesion molecule expression and nuclear factor kappa B (NF-kappaB) activation induced by TNF-alpha (10 ng/ml) in cultured human dermal microvascular endothelial cells (HDMEC). Treatment of cells with TNF-alpha for 4 h significantly induced the surface expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1). Treatment with TNF-alpha for 8 h significantly induced the surface expression of E-selectin, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). The up-regulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-kappaB induced by TNF-alpha for 2 h were significantly decreased by the above two pretreatments. N-acetylcysteine (10 mM) and S-nitroso-N-acetylpenicillamine (1 mM) had no significant inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-alpha. These findings indicate that both cell surface and mRNA expression of adhesion molecules in HDMEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-kappaB. These results suggest a potential therapeutic approach using antioxidant agents or nitric oxide pathway modulators in the treatment of inflammatory skin diseases.

Concurrent Chemoradiotherapy for Esophageal Cancer: Comparison Between Intermittent Standard-dose Cisplatin with 5-fluorouracil and Daily Low-dose Cisplatin with Continuous Infusion of 5-fluorouracil

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Jun, 2004  |  Pubmed ID: 15221597

Although current standard treatment for advanced esophageal cancer is intermittent standard-dose cisplatin with 5-fluorouracil (5-FU) (ISD-FP), daily low-dose cisplatin with continuous infusion of 5-FU (CLD-FP) is advocated for equivalent effectiveness and lower toxicity. The feasibility of these two concurrent chemoradiotherapeutic protocols was retrospectively reviewed for local control rate, overall survival, toxicity, and compliance in a single institutional situation.

Local Hyperthermia Combined with External Irradiation for Regional Recurrent Breast Carcinoma

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Jun, 2004  |  Pubmed ID: 15221602

The purpose of this study was to evaluate the therapeutic effects of hyperthermia in combination with radiotherapy for locoregional recurrence of breast cancer, and to assess the factors related to subsequent local tumor control.

Transcatheter Arterial Embolization for Large Pancreaticoduodenal Artery Aneurysm with Mechanically Detachable Coils

Cardiovascular and Interventional Radiology. Mar-Apr, 2004  |  Pubmed ID: 15259816

Large aneurysms (5.5 and 3.6 cm in diameter) arising from the inferior pancreaticoduodenal artery located just near the main superior mesenteric artery were incidentally diagnosed in two patients. Transcatheter arterial embolization, packing mechanically detachable coils and microcoils into the aneurysms, was performed while the inflated balloon catheter was placed near the neck of the aneurysms. The procedures were successfully performed and no aneurysmal rupture or bowel ischemia was noted during follow-up. Balloon-assisted transcatheter arterial embolization with mechanically detachable coils seems to be an effective and safe treatment for large inferior pancreaticoduodenal aneurysms.

Targeting Hypoxic Cancer Cells with a Protein Prodrug is Effective in Experimental Malignant Ascites

International Journal of Oncology. Sep, 2004  |  Pubmed ID: 15289874

Tumor hypoxia in a solid tumor mass has long been recognized as a cause of resistance to current cancer therapies, and has also been suggested to be a potent driving force towards malignancy. Recent progress in the understanding of the molecular mechanism of the tumor response to hypoxia has increased attention on targeting hypoxia for cancer therapy. We have generated a hypoxia-targeting fusion protein, TOP3, which is composed of a protein transduction domain (PTD) of HIV TAT, an oxygen-dependent degradation domain (ODD) of HIF-1 alpha, and procaspase-3. Here, we examine the effects of TOP3 in a rat ascites model. First, we clarified that the fluid in ascites from MM1 cells, which are derivatives of AH130 rat ascites hepatoma cells, was highly hypoxic. In vitro, MM1 cells retained protein degradation machinery through the ODD domain, and TOP3 effectively impaired MM1 cell growth in culture under hypoxic conditions by inducing apoptosis. Intraperitoneal administration of TOP3 prolonged the life span of rats bearing a significant amount of malignant ascites, and 60% of the treated animals were cured without recurrence of ascites. Thus, TOP3 had a dramatic effect on malignant ascites and, hence, we propose that rodent malignant ascites is an appropriate platform for testing hypoxia-targeted drugs.

Effects of Antioxidant and Nitric Oxide on Chemokine Production in TNF-alpha-stimulated Human Dermal Microvascular Endothelial Cells

Free Radical Research. May, 2004  |  Pubmed ID: 15293554

Chemokines have been implicated convincingly in the driving of leukocyte emigration in different inflammatory reactions. Multiple signaling mechanisms are reported to be involved in intracellular activation of chemokine expression in vascular endothelial cells by various stimuli. Nevertheless, redox-regulated mechanisms of chemokine expression in human dermal microvascular endothelial cells (HDMEC) remain unclear. This study examined the effects of pyrrolidine dithiocarbamate (PDTC, 0.1 mM) and spermine NONOate (Sper-NO, 1 mM) on the secretion and gene expression of chemokines, interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), and eotaxin. This study also addresses PDTC and Sper-NO effects on activation of nuclear factor kappa B (NF-kappaB) induced by TNF-alpha (10 ng/ml). Treatment with TNF-alpha for 8 h significantly increased secretion of IL-8, MCP-1, and RANTES, but not of eotaxin, in cultured HDMEC. Up-regulation of these chemokines was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h, but not by 1 mM 8-bromo-cyclic GMP. The mRNA accumulation of IL-8, MCP-1, RANTES, and eotaxin, and activation of NF-kappaB were induced by TNF-alpha for 2 h; all were suppressed significantly by the above two pretreatments. These findings indicate that both secretion and mRNA accumulation of IL-8, MCP-1, and RANTES in HDMEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly via blocking redox-regulated NF-kappaB activation. These results suggest that restoration of the redox balance using antioxidant agents or nitric oxide pathway modulators may offer new opportunities for therapeutic interventions in inflammatory skin diseases.

Influences of the P53 Status on Hypoxia-induced Gene Expression

Journal of Radiation Research. Jun, 2004  |  Pubmed ID: 15304978

The p53 tumor-suppressor gene is one of the most frequently mutated genes in human cancers, and its genetic alterations may play critical roles in oncogenesis, tumor progression, and angiogenesis. To clarify the influence of the p53 status on hypoxia-inducible gene expression, we first performed transfection assays with a hypoxia-responsive vector carrying 5 hypoxia-responsive elements upstream of the human CMV minimal promoter driving transcription of the luciferase gene in various human tumor cell lines with wild-type (wt) or mutant (mut) p53. As a result, hypoxia responsiveness considerably varied between cell lines, and we could not obtain clear evidence that the hypoxia-inducible factor-1 (HIF-1) mediated gene expression in the wt-p53 cells was lower than that in cells with mut-p53. It is interesting that SaOS2 cells (p53 null) showed the highest luciferase activities under both aerobic and hypoxic conditions among tested cells. Next, to elucidate the effects of endogenous wt- and mut-p53s, a transfection assay and Northern blot analysis for VEGF transcription under hypoxia were performed by using isogenic variants of HT1080 cells differing in their p53 status. The luciferase and the endogenous VEGF mRNA expression were apparently lower in a variant carrying mutations in both p53 alleles than in a parental line harboring wt-p53, implying that some types of mutant p53 constitutively accumulated in cells can decrease both the basal and the hypoxia-induced expressions in addition to wt-p53.

Stereotactic Hypofractionated High-dose Irradiation for Stage I Nonsmall Cell Lung Carcinoma: Clinical Outcomes in 245 Subjects in a Japanese Multiinstitutional Study

Cancer. Oct, 2004  |  Pubmed ID: 15378503

Stereotactic irradiation (STI) has been actively performed using various methods to achieve better local control of Stage I nonsmall cell lung carcinoma (NSCLC) in Japan. The authors retrospectively evaluated results from a Japanese multiinstitutional study.

Concentrations of Pentosidine, an Advanced Glycation End-product, in Umbilical Cord Blood

Free Radical Research. Jul, 2004  |  Pubmed ID: 15453634

Advanced glycation end-products (AGEs) are formed over several weeks to months by non-enzymatic glycation and oxidation ("glycoxidation") reactions between carbohydrate-derived carbonyl groups and protein amino groups, known as the Maillard reaction. Pentosidine is one of the best-characterized AGEs and is accepted as a satisfactory marker for glycoxidation in vivo. The present study was intended to measure pentosidine concentrations in umbilical cord blood from newborns with various gestational ages using our recently established high-performance liquid chromatography method [Tsukahara, H. et al. (2003) Pediatr. Res. 54, 419-424]. Our study demonstrates, for the first time, that pentosidine is detected in most of the umbilical blood samples. This study also shows that the umbilical blood concentrations of pentosidine are considerably lower than normal adult values, but that they increase with gestation progression and fetal growth. Umbilical pentosidine concentrations were significantly elevated in newborns of mothers with preeclampsia compared to those of mothers without preeclampsia. We conclude that accumulation of AGEs and oxidative stress occurs in fetal tissues and organs in utero at the early stage of human life and that their accumulation is augmented in the maternal preeclampsic condition.

Transthoracic Percutaneous Radiofrequency Ablation for Liver Tumors in the Hepatic Dome

Journal of Vascular and Interventional Radiology : JVIR. Nov, 2004  |  Pubmed ID: 15525754

Computed tomography (CT)-guided transthoracic radiofrequency ablation was performed for nine liver tumors of eight patients, which were located in the hepatic dome and undetectable by ultrasound (US). A total 11 sessions of ablation were performed. Complications were noted in five sessions (45%) and no complications were noted in six sessions (55%). Pneumothorax was noted in five sessions (45%), including two sessions (18%) with major pneumothorax requiring a chest tube. Major complications were seen in two sessions (18%), major pneumothorax and both major pneumothorax and moderate pleural effusion, respectively. CT-guided transthoracic radiofrequency ablation may be an alternative for treatments of liver tumor in the hepatic dome.

Stereotactic Body Radiation Therapy for Early-stage Non-small-cell Lung Cancer: the Japanese Experience

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Oct, 2004  |  Pubmed ID: 15549583

Stereotactic body radiation therapy is a new treatment modality for early-stage non-small-cell lung cancer, and is being intensively investigated in the United States, the European Union, and Japan. We started a feasibility study of this therapy in July 1998, using a stereotactic body frame. The eligibility criteria for primary lung cancer were: (1) solitary tumor less than 4 cm; (2) inoperable, or the patient refused operation; (3) histologically confirmed malignancy; (4) no necessity for oxygen support; (5) performance status equal to or less than 2, and (6) the tumor was not close to the spinal cord. A total dose of 48 Gy was delivered in four fractions in 2 weeks in most patients. Lung toxicity was minimal. No grade II toxicities for spinal cord, bronchus, pulmonary artery, or esophagus were observed. Overall survival for 29 patients with stage IA, and 14 patients with stage IB disease was 87 % and 80 %, respectively. No local recurrence was observed in a follow-up of 3-50 months. Regional lymph node recurrence developed in 1 patient, and distant metastases developed in 4 patients. We retrospectively analyzed 241 patients from 13 Japanese institutions. The local recurrence rate was 20% when the biological equivalent dose (BED) was less than 100 Gy, and 6.5% when the BED was over 100 Gy. Overall survival at 3 years was 42% when the BED was less than 100 Gy, and 46% when it was over 100 Gy. In tumors which received a BED of more than 100 Gy, overall survival at 3 years was 91% for operable patients, and 50% for inoperable patients. Long-term results, in terms of local control, regional recurrence, survival, and complications, are not yet evaluated. However, this treatment modality is highly expected to be a standard treatment for inoperable patients, and it may be an alternative to lobectomy for operative patients. A prospective trial, which is now ongoing, will, answer these questions.

[Evaluation of Positioning Reproducibility Using a Re-locatable Head Frame for Stereotactic Radiotherapy]

Nihon Hoshasen Gijutsu Gakkai Zasshi. Oct, 2004  |  Pubmed ID: 15565014

In fractionated stereotactic radiotherapy (SRT), the accuracy of patient relocation is very important. The Gill-Thomas-Cosman (GTC) re-locatable stereotactic frame is used for patient immobilization. A depth helmet and measuring probe are used to check the stability of the patient's head position relative to the GTC frame. However, displacement error caused by rotation of the patient's head is not considered in the depth-helmet measurement. Consequently, displacement of the isocenter position cannot be confirmed by the measurement obtained from the depth helmet. In this study, we evaluated the precision of reproducibility by comparing measurement values of the depth helmet with the displacement of anatomical position on a CT image. We analyzed 21 setups of 8 patients immobilized for SRT using the GTC frame, between June 2001 and June 2003. The reproducibility of the GTC frame was checked at each treatment by comparing it with the treatment planning position. The average discrepancy of the GTC frame set-up measured by the depth helmet was 0.6 mm, with a standard deviation of 0.3 mm. The result measured by CT was 0.7 mm, with a standard deviation of 0.4 mm. When the error of each measurement point was within 1.0 mm, the accuracy of relocation of the patient could be considered clinically acceptable. Displacement error not considered in the measurement of the depth helmet could be evaluated by using CT.

18F-FDG and 11C-methionine PET for Evaluation of Treatment Response of Lung Cancer After Stereotactic Radiotherapy

Annals of Nuclear Medicine. Dec, 2004  |  Pubmed ID: 15682847

This study was performed to investigate the feasibility of FDG- and L-[methyl-11C]methionine (Met)-PET for the follow up of lung cancer after stereotactic radiotherapy (SRT). Nine patients (pt) with solitary lung cancer underwent SRT. Met- and FDG-PET studies were performed one week before SRT and from one week to 8 months after SRT. Responses to SRT were complete in 2 pt and partial in 7 pt. Met- and FDG-PET scan showed high tracer uptake in all tumors before SRT. After SRT, standardized uptake values (SUV) of FDG and Met changed concordantly. Both decreased with time in 5 pt but did not decrease steadily in 4 pt, where 2 pt showed an increase at 1 to 2 weeks after SRT and 2 pt showed an increase at more than 3 months after SRT. The former appears to reflect the acute reaction to SRT and the latter radiation-induced pneumonitis. Although the addition of Met-PET did not provide additional information over FDG-PET, FDG- and Met-PET could be used to evaluate the treatment effect of SRT.

Real-time Imaging of Hypoxia-inducible Factor-1 Activity in Tumor Xenografts

Journal of Radiation Research. Mar, 2005  |  Pubmed ID: 15802864

Hypoxia-inducible factor-1 (HIF-1) is responsible for various gene expressions related to tumor malignancy, such as metastasis, invasion and angiogenesis. Therefore, monitoring HIF-1 activity in solid tumors is becoming increasingly important in clinical and basic studies. To establish a convenient system for visualizing HIF-1 activity in tumor xenografts, we employed a promoter consisting of five copies of hypoxia response elements (5HRE), whose activity depends on HIF-1, and used a derivative of green fluorescence protein (d2EGFP) as a reporter gene. A human melanoma cell line, Be11, which contains the 5HRE-d2EGFP gene, showed fluorescence in response to hypoxia. The fluorescent intensity correlated inversely with the surrounding oxygen tension, and was time-dependent for the hypoxic treatment. Reoxygenation resulted in a rapid decrease in fluorescence due to the signal sequence for protein degradation encoded in d2EGFP, which enabled monitoring of HIF-1 activity in real-time. Heterogeneous fluorescence was observed in the solid tumor of a non-sacrificed tumor-bearing mouse. Immunohistochemical analysis confirmed that d2EGFP-expressing regions overlapped with the ones stained with a hypoxia marker, pimonidazole. These results suggest that the 5HRE-d2EGFP gene is suitable for the real-time imaging of HIF-1-activating cells in vivo, due to the short half-life of the d2EGFP protein as well as the specificity of the 5HRE promoter for HIF-1 activity.

Treatment Planning of Stereotactic Radiotherapy for Solitary Lung Tumor

International Journal of Radiation Oncology, Biology, Physics. Apr, 2005  |  Pubmed ID: 15817363

To analyze the stereotactic radiotherapy (SRT) plans in terms of internal target volume (ITV) and organs at risk (OARs).

Effects of Antioxidants and NO on TNF-alpha-induced Adhesion Molecule Expression in Human Pulmonary Microvascular Endothelial Cells

Respiratory Medicine. May, 2005  |  Pubmed ID: 15823455

Pro-inflammatory cytokines initiate the vascular inflammatory response via upregulation of adhesion molecules on the endothelium. Recent observations suggest that reactive oxygen intermediates may play a pivotal role in TNF-alpha signaling and upregulate gene expression. We therefore evaluated the effects of pyrrolidine dithiocarbamate (PDTC; 0.1 mM) and spermine NONOate (Sper-NO; 1 mM) on adhesion molecule expression and nuclear factor kappa B (NF-kappaB) activation induced by TNF-alpha (10 ng/ml) in cultured human pulmonary microvascular endothelial cells (PMVEC). Treatment of cells with TNF-alpha for 4 h significantly induced the surface expression of E-selectin and ICAM-1. Treatment with TNF-alpha for 8 h significantly induced the surface expression of E-selectin, ICAM-1 and VCAM-1. The upregulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h. 8-Bromo-cyclic GMP (1 mM) had no such effect, suggesting that the NO donor's effect was non-cGMP-dependent. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-kappaB induced by TNF-alpha for 2 h were decreased significantly by the above two pretreatments. N-acetylcysteine (10 mM) and S-nitroso-N-acetylpenicillamine (1 mM) had little inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-alpha. Treatment with TNF-alpha for 4 h enhanced HL-60 leukocyte adhesion to human PMVEC, the effect of which was inhibited significantly by pretreatment with PDTC or Sper-NO. These findings indicate that both cell surface and mRNA expression of adhesion molecules in human PMVEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-kappaB. Although our in vitro results cannot be directly extrapolated to the in vivo situation, they suggest a potential therapeutic approach for intervention in cytokine-mediated inflammatory processes in the human lung.

Treatment Outcome of Breast-conserving Therapy in Patients with Positive or Close Resection Margins: Japanese Multi Institute Survey for Radiation Dose Effect

Breast Cancer (Tokyo, Japan). 2005  |  Pubmed ID: 15858438

The relationship between a positive resection margin and the risk of ipsilateral breast tumor recurrence (IBTR) is controversial. To evaluate the radiation dose and other factors influencing the ipsilateral breast tumor control (IBTC) in patients with positive or close resection margins after breast conserving surgery (BCS), the Japanese Radiation Oncology Study Group (JROSG) S-99-3 study group conducted a multi-institute survey of these patients.

Bilateral Breast-conserving Therapy for Bilateral Breast Cancer: Results and Consideration of Radiation Technique

Breast Cancer (Tokyo, Japan). 2005  |  Pubmed ID: 15858445

Although breast-conserving surgery followed by definitive irradiation is an established treatment for patients with early breast cancer, the role of breast-conserving therapy (BCT) for patients with bilateral breast cancer has not been well studied and the radiation therapy technique is still under investigation. We examined the feasibility of breast-conserving therapy for bilateral breast cancer and present here our radiation therapy technique with CT simulator.

Aminopeptidase N/CD13 Targeting Fluorescent Probes: Synthesis and Application to Tumor Cell Imaging

Peptides. Nov, 2005  |  Pubmed ID: 15885853

A family of fluorescein-peptide conjugates (CNP1-3) for aminopeptidase N (APN/CD13) targeting fluorescent probes were designed and synthesized. Among the three conjugates, CNP1 bearing tumor-homing cyclic peptide CNGRC, could selectively label APN/CD13 over-expressing on the surface of tumor cells of HT-1080, as identified by means of fluorescent microscopic cell imaging. CNP1 was shown to be a promising fluorescent probe applicable to tumor-targeting molecular imaging.

A Tumor-specific Gene Therapy Strategy Targeting Dysregulation of the VHL/HIF Pathway in Renal Cell Carcinomas

Cancer Science. May, 2005  |  Pubmed ID: 15904470

Hypoxia-inducible factors, key transcription factors for hypoxia-dependent gene expression, play important roles in angiogenesis and tumor growth. The VHL protein binds to the alpha subunit of (HIF-alpha) for its oxygen-dependent degradation. VHL mutations are found frequently in sporadic RCC. Disruption of VHL results in an abnormal accumulation of HIF-alpha, leading to the upregulation of downstream genes such as the vascular endothelial growth factor gene. We constructed a luciferase reporter vector driven by hypoxia-responsive elements (5HRE/luc) and a therapeutic vector expressing a herpes simplex virus thymidine kinase gene (5HRE/tk). In the transient transfection assay using VHL-deficient 786-O cells, constitutive luciferase expression was detected under both aerobic and hypoxic conditions. In contrast, 786-O cells transfected with a wild-type VHL showed hypoxia-inducible luciferase activity. In in vitro MTS assay, 50% of growth inhibition of 786-O cells stably transfected with 5HRE/tk was achieved with exposure to 0.2 microg/mL of GCV under both aerobic and hypoxic conditions. Xenografts of the stable clone in SCID mice exhibited a marked regression on daily injections of GCV (50 mg/kg) for 10 days. In conclusion, a hypoxia-responsive vector may have therapeutic potential for RCC with VHL mutations.

Quantification of L-type Fatty Acid Binding Protein in the Urine of Preterm Neonates

Early Human Development. Jul, 2005  |  Pubmed ID: 15970406

We measured urinary excretion of L-type fatty acid binding protein (L-FABP) in preterm neonates on days 1, 5-10, and 25-30 of life. Urinary L-FABP levels (expressed as the ratio to creatinine) in preterm neonates were considerably higher than those of healthy adults. They did not change significantly during the study period. Urinary L-FABP levels showed significant positive correlation with those of urinary N-acetyl-beta-D-glucosaminidase activity on day 1, and with those of 8-hydroxy-2'-deoxyguanosine on days 25-30. These results suggest that L-FABP is expressed in the neonatal kidney. Our results may also point to potential effects of proximal tubular damage and oxidative stress on urinary excretion of L-FABP.

The Patterns of Care Study for Breast-conserving Therapy in Japan: Analysis of Process Survey from 1995 to 1997

International Journal of Radiation Oncology, Biology, Physics. Jul, 2005  |  Pubmed ID: 15990008

To present the results of a process survey on breast-conserving therapy (BCT) in Japan from 1995 to 1997.

Long-term Results of Definitive Radiotherapy for Stage I Esophageal Cancer

International Journal of Radiation Oncology, Biology, Physics. Aug, 2005  |  Pubmed ID: 16029790

To analyze retrospectively the long-term results of external beam radiotherapy (RT) with or without intraluminal brachytherapy (ILBT) for patients with Stage I esophageal cancer.

Thyroid Gland Tumor Diagnosis at US Elastography

Radiology. Oct, 2005  |  Pubmed ID: 16118150

To prospectively evaluate the elastographic appearance of thyroid gland tumors and explore the potential sensitivity and specificity of ultrasonographic (US) elastography for differentiating benign and malignant tumors, with histopathologic analysis as the reference standard.

Clinical Outcomes of a Phase I/II Study of 48 Gy of Stereotactic Body Radiotherapy in 4 Fractions for Primary Lung Cancer Using a Stereotactic Body Frame

International Journal of Radiation Oncology, Biology, Physics. Dec, 2005  |  Pubmed ID: 16169670

To evaluate the clinical outcomes of 48 Gy of three-dimensional stereotactic radiotherapy in four fractions for treating Stage I lung cancer using a stereotactic body frame.

Quantitation of Glutathione S Transferase-pi in the Urine of Preterm Neonates

Pediatrics International : Official Journal of the Japan Pediatric Society. Oct, 2005  |  Pubmed ID: 16190959

Glutathione S transferases (GSTs) are widely distributed enzymes found in highly varying amounts in tissues of the human body. The enzyme GST-pi in urine has been used as a marker of renal distal tubular cell damage. The present study was intended to evaluate urinary excretion of GST-pi and its relationship to other renal markers and to the status of oxidative stress in preterm neonates.

Optical Imaging of Tumor Hypoxia and Evaluation of Efficacy of a Hypoxia-targeting Drug in Living Animals

Molecular Imaging. Jul-Sep, 2005  |  Pubmed ID: 16194450

Solid tumors containing more hypoxic regions show a more malignant phenotype by increasing the expression of genes encoding angiogenic and metastatic factors. Hypoxia-inducible factor-1 (HIF-1) is a master transcriptional activator of such genes, and thus, imaging and targeting hypoxic tumor cells where HIF-1 is active are important in cancer therapy. In the present study, HIF-1 activity was monitored via an optical in vivo imaging system by using a luciferase reporter gene under the regulation of an artificial HIF-1-dependent promoter, 5HRE. To monitor tumor hypoxia, we isolated a stable reporter-transfectant, HeLa/5HRE-Luc, which expressed more than 100-fold luciferase in response to hypoxic stress, and observed bioluminescence from its xenografts. Immunohistochemical analysis of the xenografts with a hypoxia marker, pimonidazole, confirmed that the luciferase-expressing cells were hypoxic. Evaluation of the efficacy of a hypoxia-targeting prodrug, TOP3, using this optical imaging system revealed that hypoxic cells were significantly diminished by TOP3 treatment. Immunohistochemical analysis of the TOP3-treated xenografts confirmed that hypoxic cells underwent apoptosis and were removed after TOP3 treatment. These results demonstrate that this model system using the 5HRE-luciferase reporter construct provides qualitative information (hypoxic status) of solid tumors and enables one to conveniently evaluate the efficacy of cancer therapy on hypoxia in malignant solid tumors.

Recurrence of Osteosarcoma After Intraoperative Radiation Therapy

Orthopedics. Oct, 2005  |  Pubmed ID: 16237885

General Rules for Clinical and Pathological Recording of Breast Cancer 2005

Breast Cancer (Tokyo, Japan). 2005  |  Pubmed ID: 16410755

Marked Renal Damage in a Child with Hydronephrosis Infected by Trichosporon Asahii

Pediatric Nephrology (Berlin, Germany). Feb, 2005  |  Pubmed ID: 15625616

We describe a case of urinary infection caused by Trichosporon asahii, which drastically aggravated renal function in a left hydronephrotic kidney. Previous implantation of a nephrostomy tube and a ureteral J-stent and administration of broad-spectrum antibiotics seemed to have predisposed the non-granulocytopenic child to the urinary fungal infection.

Regional Hyperthermia Combined with Radiotherapy for Uterine Cervical Cancers: a Multi-institutional Prospective Randomized Trial of the International Atomic Energy Agency

International Journal of Radiation Oncology, Biology, Physics. Jan, 2005  |  Pubmed ID: 15629605

Hyperthermia can be used to enhance the effects of radiation, and a combined treatment may, in some circumstances, be an advantage. Uterine cervical cancer is very common in developing countries. The control of locally advanced pelvic tumors is difficult with conventional treatment modalities. Based upon the biologic rationale and in view of the recent advances in heating and thermometry techniques, radiotherapy in combination with hyperthermia was investigated in a multi-institutional prospective randomized trial sponsored by the International Atomic Energy Agency. The primary purpose was to clarify whether the combination of hyperthermia and radiotherapy improves the rate of local control, compared with radiotherapy alone.

Comparison of Three Radiotherapy Treatment Planning Protocols of Definitive External-beam Radiation for Localized Prostate Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Dec, 2005  |  Pubmed ID: 16369743

Three radiotherapy treatment planning (RTTP) protocols for definitive external-beam radiation for localized prostate cancer, designed and clinically applied at Kyoto University, were compared.

Radiofrequency Ablation for Small Hepatocellular Carcinoma: Prospective Comparison of Internally Cooled Electrode and Expandable Electrode

Radiology. Jan, 2006  |  Pubmed ID: 16373776

To prospectively compare the effectiveness of radiofrequency (RF) ablation performed by using an internally cooled electrode and an expandable electrode for the treatment of small (< or = 3.0 cm) hepatocellular carcinomas (HCCs).

Diffusion-tensor Fiber Tractography: Intraindividual Comparison of 3.0-T and 1.5-T MR Imaging

Radiology. Feb, 2006  |  Pubmed ID: 16396839

To prospectively evaluate the depiction of brain fiber tracts at 3.0- versus 1.5-T diffusion-tensor (DT) fiber tractography performed with parallel imaging.

[Impact of Optimization Algorithms on the Intensity Map in IMRT Treatment Planning.]

Igaku Butsuri : Nihon Igaku Butsuri Gakkai Kikanshi = Japanese Journal of Medical Physics : an Official Journal of Japan Society of Medical Physics. 2006  |  Pubmed ID: 17344641

In inverse planning of IMRT, optimum intensity maps are generated using an optimization algorithm. In this paper, impacts of two different optimization algorithms on the intensity map in IMRT treatment planning were evaluated. These were from the steepest descent (SD) and simulated annealing (SA) methods. The following five patterns were compared: [1] SD with calculation time of 5 min; [2] SD with the terminal criterion based on cost function; [3] SA with calculation time of 5 min; [4] SA with the terminal criterion; and [5] SA with the terminal criterion using a smoothing filter. Differences of D(95%) for the planning target volume, V(70Gy) for the rectum wall and the bladder wall were up to 0.5, 1.8 and 3.2 %, respectively in all patterns. The dosimetric impact was negligible. In contrast, generated intensity maps were sensitive to the algorithms. Intensity maps generated by SA tended to have much fluctuation due to numerical artifacts compared to those generated by SD. The difference in the profile was over 7 % between the algorithms. The smoothing filter decreased the fluctuation in intensity maps of SA. In conclusion, it is important to understand impacts of optimization algorithms on the intensity map and the dose distribution.

Influence of Radiation Dose Rate and Lung Dose on Interstitial Pneumonitis After Fractionated Total Body Irradiation: Acute Parotitis May Predict Interstitial Pneumonitis

International Journal of Hematology. Jan, 2006  |  Pubmed ID: 16443559

This study evaluated patients for the influence of the dose rate and lung dose of fractionated total body irradiation (TBI) in preparation for allogeneic bone marrow transplantation (BMT) on the subsequent development of interstitial pneumonitis (IP). Sixty-six patients at our institute were treated with TBI followed by BMT. All of the patients received a total TBI dose of 12 Gy given in 6 fractions over 3 days and were divided into 3 groups according to the radiation dose rate and lung dose: group A, lung dose of 8 Gy (n = 18); group B, lung dose of 12 Gy at 8 cGy/min (n = 25); and group C, lung dose of 12 Gy at 19 cGy/min (n = 23). The overall survival rate, the cumulative incidence of relapse, and the cumulative incidence of IP were evaluated in relation to various potential indicators of future IP. There were no significant differences in survival and relapse rates between patient group A and combined groups B and C. Clinically significant IP occurred in 13 patients. The cumulative incidence of IP was significantly higher in patients who developed acute parotitis as indicated by either an elevation in the serum amylase level or parotid pain of grade 1 to 2. There was no difference in IP incidence among groups A, B, and C. There was no significant difference in IP incidence between lung dose values of 8 Gy (with lung shielding) and 12 Gy (without lung shielding) and between dose rate values of 8 cGy/min and 19 cGy/ min, at least when TBI was given in 6 fractions. The presence of acute parotitis during or just after TBI may be a predictor of IP.

Antitumor Protein Therapy; Application of the Protein Transduction Domain to the Development of a Protein Drug for Cancer Treatment

Breast Cancer (Tokyo, Japan). 2006  |  Pubmed ID: 16518058

The genomic information obtained through the human genome project has been accelerating the analysis of the functions of various disease relevant genes. The high molecular weight biomolecules, including oligonucleotides, antisense nucleotides, small interference RNA and peptides, as well as genes (cDNA) and proteins, are becoming increasingly important for the development of molecular therapies. However, the potential of such information-rich macromolecules for therapeutic use has been limited by the poor permeability across the lipid bilayer of the cellular plasma membrane. Over the past decade, a unique activity of oligopeptides, known as protein transduction domains (PTDs) or cell penetrating peptides (CPPs), has made it possible to transduce biologically active macromolecules into living cells in vitro by conjugating a PTD to the desired macromolecule. Furthermore, this activity has also enabled the systemic delivery of bioactive macromolecules to all tissues in living animals. However, we are now confronted with the next difficulty delivering the macromolecules specifically to the therapeutic targets in vivo. In this review, we focus on the application of PTD to develop antitumor macromolecules and introduce several representative strategies to discriminate between tumor and normal tissue. In addition, we discuss the unique characteristics of breast cancer, which are expected to facilitate the application of PTD to develop novel protein therapy for breast cancer.

[Tumor-specific Gene Therapy Strategy for Renal Cell Carcinomas]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Feb, 2006  |  Pubmed ID: 16523975

Urinary Creatinine Excretion and Protein/creatinine Ratios Vary by Body Size and Gender in Children

Pediatric Nephrology (Berlin, Germany). May, 2006  |  Pubmed ID: 16550362

Urinary protein/creatinine ratio (Up/cr) is a simple measurement for evaluation of proteinuria. However, exact effects of body size and gender on urinary excretion of creatinine and Up/cr remain unknown. We aimed to clarify their effects. Early morning urine samples were collected from 124 children with urinary tract disorders. Urinary hourly excretion of creatinine, Ucr (in milligrams per hour), urinary hourly excretion of protein per body surface area, Up (milligrams per square meter per hour), and Up/cr (milligrams per milligram) were calculated. Effects of gender, age, body height, body weight and body surface area on Ucr and Up/cr were analyzed, respectively, in a multiple linear regression model. Body surface area and gender affected Ucr (r2=0.842, P<0.0001). Ucr adjusted by body surface area increased as body surface area grew with moderate variation. Up/cr showed a close correlation with Up and was affected by body height and gender as well. The regression equation showed that Up/cr values corresponding to the normal upper limit of Up, i.e., 4 mg/m2/h, in boys and girls 170 cm tall were approximately one third of those in children 80 cm tall (0.121 vs 0.043 for boys, 0.132 vs 0.047 for girls). The present study indicates that estimation of Up/cr needs to include consideration of children's body height and gender.

Outcome of Percutaneous Transhepatic Venoplasty for Hepatic Venous Outflow Obstruction After Living Donor Liver Transplantation

Radiology. Apr, 2006  |  Pubmed ID: 16567488

To evaluate retrospectively the outcome of percutaneous transhepatic venoplasty of hepatic venous outflow obstruction after living donor liver transplantation (LDLT).

[Stereotactic Body Radiotherapy (SBRT)]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Apr, 2006  |  Pubmed ID: 16612153

The techniques of three-dimensional conformal radiotherapy (3 D-CRT) and patient immobilization have recently been developed, enabling us to focus high doses on the target with relatively less irradiation of normal tissues. In radiotherapy for solitary lung tumors, the local control may be safely improved by delivering a higher dose at only the target volume using these techniques. Recently, several clinical studies on stereotactic body radiotherapy (SRT) using the 3 D-CRT technique for solitary lung tumors have been reported. The single dose used is 10-15 Gy, and the total sessions are three to five. The local control rate is more than 90% and complication rates are very low. Therefore, this treatment is a promising new non-invasive treatment for early stage lung cancer. A multi-institutional clinical study, JCOG 0403, in now underway.

Characteristics of Patients Who Developed Radiation Pneumonitis Requiring Steroid Therapy After Stereotactic Irradiation for Lung Tumors

Cancer Journal (Sudbury, Mass.). Jan-Feb, 2006  |  Pubmed ID: 16613661

To find possible risk factors for symptomatic radiation pneumonitis (RP) after stereotactic irradiation (STI) for peripheral non-small cell lung cancer (NSCLC), pre-treatment pulmonary function test and dose volume statistics in patients who developed RP requiring steroid intake were retrospectively compared with statistics of those who did not develop RP.

Suppression of VEGF Transcription in Renal Cell Carcinoma Cells by Pyrrole-imidazole Hairpin Polyamides Targeting the Hypoxia Responsive Element

Acta Oncologica (Stockholm, Sweden). 2006  |  Pubmed ID: 16644575

Hypoxia inducible factor (HIF), a master regulator of critical genes for cell survival under hypoxic conditions, is known to be related to tumorigenesis and progression of renal cell carcinoma. N-methylpyrrole (Py)-N-methylimidazole (Im) hairpin polyamides are synthetic organic compounds that recognize and bind to the minor grooves of specific DNA sequences. We synthesized three Py-Im hairpin polyamides targeting the flanking sequences of hypoxia responsive element (HRE; a binding site of HIF) in the promoter region of the vascular endothelial growth factor (VEGF) gene. The effects of the polyamides on HIF-induced transcription were evaluated by a luciferase assay using a reporter plasmid containing a VEGF promoter. Real time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay were performed to examine the effects of the polyamides on the transcription and secretion of VEGF in A498 renal cell carcinoma cells, which have a frame-shift mutation in the von Hippel-Lindau gene. A combination of three Py-Im hairpin polyamides suppressed HIF-induced transcription in reporter assays using 293 cells and successfully suppressed transcription and translation of the VEGF gene in A498 cells. Inhibition of the HIF-HRE interaction was confirmed by an electrophoresis mobility shift assay. An approach using Py-Im hairpin polyamides may be a new strategy for the treatment of renal cell carcinoma.

Enzymatic Preparation of Hollow Magnetite Microspheres for Hyperthermic Treatment of Cancer

Journal of Materials Science. Materials in Medicine. Jul, 2006  |  Pubmed ID: 16770544

Ferrimagnetic materials can be expected to be useful as thermal seeds for hyperthermic treatment of cancer, especially where the cancer is located in deep parts of body, as they can generate heat by magnetic hysteretic loss when they are placed in an alternating magnetic field. In this study, hollow magnetite (Fe(3)O(4)) particles were prepared using an enzymatic reaction of urease. A hollow particle was obtained by using a Pasteur pipette. The particle was 500 microm in size and was composed of Fe(3)O(4). Its saturation magnetization and coercive force were 57 emuxg(-1) and 183 Oe, respectively. Its heat generation under an alternating magnetic field of 300 Oe at 100 kHz was estimated to be 45 Wxg(-1). Microspheres 30 microm in diameter were also successfully obtained by using a spray gun.

Development of a Four-dimensional Image-guided Radiotherapy System with a Gimbaled X-ray Head

International Journal of Radiation Oncology, Biology, Physics. Sep, 2006  |  Pubmed ID: 16820270

To develop and evaluate a new four-dimensional image-guided radiotherapy system, which enables precise setup, real-time tumor tracking, and pursuit irradiation.

Small Cell Lung Carcinoma: Eight Types of Extension and Spread on Computed Tomography

Journal of Computer Assisted Tomography. Jul-Aug, 2006  |  Pubmed ID: 16845299

The aim of this study was to classify the types of tumor extension and spread of small cell lung carcinoma (SCLC) and to recognize the unusual types of spread pattern of SCLC on computed tomography (CT) including multidetector row CT (MDCT) using contrast-enhanced material.

A Case of Metachronous Bilateral Breast Cancer with Bilateral Radiation Pneumonitis After Breast-conserving Therapy

Breast Cancer (Tokyo, Japan). 2006  |  Pubmed ID: 16929127

We report a patient with metachronous bilateral breast cancer who has twice developed radiation pneumonitis after breast-conserving therapy for each breast. The patient was a 48-year-old woman, who presented with Stage I right breast cancer. After wide excision of the right breast tumor and dissection of level I axillary lymph nodes, systemic therapy with oral 5-FU and tamoxifen was started. Subsequently, tangential irradiation with a total dose of 50 Gy in 25 fractions was given. Seven months after irradiation, she developed respiratory symptoms and radiation pneumonitis was diagnosed. The symptoms resolved with oral prednisolone. Thirty months after the right breast cancer treatment, Stage I left breast cancer was diagnosed. After wide excision of the left breast tumor and partial removal of the level I axillary lymph nodes, the same oral systemic chemo-hormonal therapy was initiated. Thereafter, tangential irradiation with a total dose of 50 Gy in 25 fractions was given. Four months after irradiation, she developed respiratory symptoms. A chest X-ray showed an area of increased density in the left lung consistent with radiation pneumonitis. The symptoms were mild and they improved spontaneously without medication. Although there is insufficient evidence to justify or withhold whole breast radiation therapy from patients with a history of contralateral breast cancer and radiation pneumonitis, it is essential to discuss the adequacy of whole breast irradiation and the possibility of alternative approaches, such as breast-conserving surgery without irradiation or partial breast irradiation for this rare condition.

Phase II Study of Nimustine, Carboplatin, Vincristine, and Interferon-beta with Radiotherapy for Glioblastoma Multiforme: Experience of the Kyoto Neuro-Oncology Group

Journal of Neurosurgery. Sep, 2006  |  Pubmed ID: 16961130

This Phase II study was performed to determine the safety, tolerability, and efficacy of combining nimustine (ACNU)-carboplatin-vincristine-Interferon-beta (IFNbeta) chemotherapy.

Mechanism of Hypoxia-specific Cytotoxicity of Procaspase-3 Fused with a VHL-mediated Protein Destruction Motif of HIF-1alpha Containing Pro564

FEBS Letters. Oct, 2006  |  Pubmed ID: 17010341

Under normoxic conditions the alpha-subunit of hypoxia-inducible factor (HIF-1alpha) protein is targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein acting as an E3 ubiquitin ligase. Recently, we developed a hypoxia-targeting protein, TOP3, which consisted of procaspase-3 with the VHL-mediated protein destruction motif of HIF-1alpha. This design enables procaspase-3 to be regulated similarly with HIF-1alpha, being degraded under normoxia while stabilized under hypoxia. Furthermore, stabilized TOP3 was cleaved by the hypoxic stress-induced endogenous caspases and thus the procaspase-3 was converted to active caspase-3 specifically under hypoxic conditions. These data demonstrated that the VHL-mediated protein destruction motif of HIF-1alpha endowed procaspase-3 with hypoxia-specific cytotoxicity.

Vertebrate POLQ and POLbeta Cooperate in Base Excision Repair of Oxidative DNA Damage

Molecular Cell. Oct, 2006  |  Pubmed ID: 17018297

Base excision repair (BER) plays an essential role in protecting cells from mutagenic base damage caused by oxidative stress, hydrolysis, and environmental factors. POLQ is a DNA polymerase, which appears to be involved in translesion DNA synthesis (TLS) past base damage. We disrupted POLQ, and its homologs HEL308 and POLN in chicken DT40 cells, and also created polq/hel308 and polq/poln double mutants. We found that POLQ-deficient mutants exhibit hypersensitivity to oxidative base damage induced by H(2)O(2), but not to UV or cisplatin. Surprisingly, this phenotype was synergistically increased by concomitant deletion of the major BER polymerase, POLbeta. Moreover, extracts from a polq null mutant cell line show reduced BER activity, and POLQ, like POLbeta, accumulated rapidly at sites of base damage. Accordingly, POLQ and POLbeta share an overlapping function in the repair of oxidative base damage. Taken together, these results suggest a role for vertebrate POLQ in BER.

Dosimetric Verification in Participating Institutions in a Stereotactic Body Radiotherapy Trial for Stage I Non-small Cell Lung Cancer: Japan Clinical Oncology Group Trial (JCOG0403)

Physics in Medicine and Biology. Nov, 2006  |  Pubmed ID: 17047260

A multicentre phase II trial of stereotactic body radiotherapy for T1N0M0 non-small cell lung cancer was initiated in Japan as the Japan Clinical Oncology Group trial (JCOG0403). Before starting the trial, a decision was made to evaluate the treatment machine and treatment planning in participating institutions to minimize the variations of the prescription dose between the institutions. We visited the 16 participating institutions and examined the absolute dose at the centre of a simulated spherical tumour of 3.0 cm diameter in the lung using the radiation treatment planning systems in each institution. A lung phantom for stereotactic body radiotherapy (SBRT) was developed and used for the treatment planning and film dosimetry. In the JCOG radiotherapy study group, the no model-based calculation algorithm or the model-based calculation algorithm with a dose kernel unscaled for heterogeneities were selected for use in the initial SBRT trials started in 2004, and the model-based calculation algorithm with a dose kernel scaled for heterogeneities was selected for the coming trial. The findings of this study suggest that the clinical results of lung SBRT trials should be carefully evaluated in comparison with the actual dose given to patients.

Results of Radiation Therapy Combined with Neoadjuvant Hormonal Therapy for Stage III Prostate Cancer: Comparison of Two Different Definitions of PSA Failure

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Oct, 2006  |  Pubmed ID: 17058138

We herein report the clinical outcome of radical radiation therapy combined with neoadjuvant hormonal therapy (NHT) for stage III (International Union Against Cancer [UICC] 1997: UICC 97) prostate cancer. Prostate-specific antigen (PSA) failure-free survival was assessed according to two different definitions, and the appropriateness of each definition is discussed.

Evaluation of Primary Brain Tumors with FLT-PET: Usefulness and Limitations

Clinical Nuclear Medicine. Dec, 2006  |  Pubmed ID: 17117071

The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors.

Avascular Necrosis of Bilateral Femoral Head As a Result of Long-term Steroid Administration for Radiation Pneumonitis After Tangential Irradiation of the Breast

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Dec, 2006  |  Pubmed ID: 17180520

We report a patient with avascular necrosis of the bilateral femoral head resulting from long-term steroid administration for radiation pneumonitis that occurred after tangential irradiation of the breast. The patient was a 50-year-old postmenopausal woman with breast cancer, stage IIIB (T4bN0M0) in the right C area. Following wide excision of right breast carcinoma and level III axillary lymph node dissection, whole-breast X-ray irradiation was given, at a dose of 2 Gy per fraction; the total dose was 50 Gy. On day 84 after the initiation of radiation therapy, she developed radiation pneumonitis. As the lung shadow expanded to the contralateral lung, she received steroid medication. Despite the steroid medication, the symptoms were exacerbated; therefore, she underwent steroid pulse administration with subsequent oral steroid medication. She improved immediately, but subsequently the radiation pneumonitis relapsed three times when the steroid medication was stopped. The period of medication was 423 days and the cumulative amount of steroids was 7365 mg before complete resolution occurred. In the 19 months after she stopped the steroid administration, she developed avascular necrosis (AVN) of the bilateral femoral head. This was regarded as a complication of the steroid treatment. Patients treated with long-term or high-dose steroid administration have been suggested to be at great risk of developing AVN, but this hypothesis remains controversial. The probability of AVN occurrence may be very small, but it should be considered as one of the complications of steroids, which are often used to treat radiation pneumonitis.

Analysis of Gene-expression Profiles After Gamma Irradiation of Normal Human Fibroblasts

International Journal of Radiation Oncology, Biology, Physics. Jan, 2006  |  Pubmed ID: 16257130

To understand comprehensive transcriptional profile of normal human fibroblast in response to irradiation.

Initial Experiences of Palliative Stereotactic Radiosurgery for Recurrent Brain Lymphomas

Journal of Neuro-oncology. Mar, 2006  |  Pubmed ID: 16283435

In Kyoto University Hospital, stereotactic radiosurgery (SRS) has been performed for its rapid palliative effect in patients with recurrent primary central nervous system lymphoma (PCNSL), often in combination with salvage chemotherapy. In the present study, the treatment outcome and toxicity of SRS for recurrent PCNSL was retrospectively evaluated. Between March 1998 and June 2004, 17 histologically proven recurrent PCNSLs in nine patients were treated with linac-based stereotactic radiosurgery. All patients had developed intracranial recurrences after initial treatment including external beam radiation therapy (EBRT). The prescribed dose was 10.0-16.0 (median 12.0) Gy. Seven of nine patients received systemic chemotherapy around the time of SRS. The target volume was 0.4-24.5 ml (median 3.5 ml). Initial tumor response could be evaluated in 15 of 17 lesions. Among them, radiological complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) was observed in 3, 10, 2, and 0 lesions, respectively. One-year overall survival rate and relapse-free survival rate after first SRS was 58% and 22%, respectively. Improvement of symptoms was observed in six patients. The time from SRS to symptomatic relief was 1-57 days (median 3 days). No > or = grade 2 acute toxicities related to SRS were observed. In conclusion, linac-based SRS with a prescription dose of 10-12 Gy for recurrent PCNSL is useful for palliation, especially considering the short time, rapid tumor response, and low treatment toxicity.

Chemoradiotherapy in Patients with Pancreatic Carcinoma: Phase-I Study with a Fixed Radiation Dose and Escalating Doses of Weekly Gemcitabine

Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]. 2006  |  Pubmed ID: 16327288

The aim of this phase-I study is to determine the maximum tolerated dose (MTD) of weekly gemcitabine in concurrent combination with a total radiation dose of 54 Gy in patients with pancreatic cancer.

Cervical Lymph Node Metastases: Diagnosis at Sonoelastography--initial Experience

Radiology. Apr, 2007  |  Pubmed ID: 17293571

To prospectively estimate the accuracy of sonoelastography in the differentiation of benign and metastatic cervical lymph nodes (LNs) in patients suspected of having thyroid or hypopharyngeal cancer, with histologic nodal findings as the reference standard.

Stereotactic Radiosurgery for Atypical and Anaplastic Meningiomas

Journal of Neuro-oncology. Aug, 2007  |  Pubmed ID: 17361335

Atypical and anaplastic meningiomas frequently recur in the relatively short-term after surgery. We have followed such postoperative cases by short-interval repeated MRI and have performed stereotactic radiosurgery (SRS) for progressive tumors as a salvage therapy. The objective of this report was assessment of the degree of tumor control, the risk of complications, and the presence of variables that predict outcome in patients treated with SRS for high-grade meningiomas. We reviewed 12 high-grade meningioma patients with 30 lesions treated by Linac-based SRS at Kyoto University Hospital between 1997 and 2002. They included 10 atypical meningiomas and 2 anaplastic ones according to the WHO classification. A mean tumor volume was 4.40cc and a mean marginal dose of SRS was 18.0 Gy (12-20 Gy). After a mean follow-up period of 43.4 months (6-84 months), 13 lesions had progression tumor within the SRS field and 6 lesions had out of the SRS field. Nine of 14 lesions, which were treated by SRS with a marginal dose of less than 20 Gy, had local recurrence in the SRS field. In contrast, four of 16 lesions, which were treated with marginal dose of 20 Gy, had local recurrence in the SRS field. The marginal dose <20 Gy was a statistically significant factor for a short-term progression in high-grade meningiomas (P = 0.0139). Five-year progression-free survival ratio in lesions treated with SRS below 20 Gy and 20 Gy were 29.4% and 63.1%, respectively. In conclusion, based on our findings, we suggest that recurrent high-grade meningiomas be treated by SRS with a marginal dose exceeding 20 Gy.

Interinstitutional Variations in Planning for Stereotactic Body Radiation Therapy for Lung Cancer

International Journal of Radiation Oncology, Biology, Physics. Jun, 2007  |  Pubmed ID: 17363190

The aim of this study was to assess interinstitutional variations in planning for stereotactic body radiation therapy (SBRT) for lung cancer before the start of the Japan Clinical Oncology Group (JCOG) 0403 trial.

Current Status of Stereotactic Body Radiotherapy for Lung Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Feb, 2007  |  Pubmed ID: 17380434

Stereotactic radiotherapy (SRT) for extracranial tumors has been recently performed to treat lung and liver cancers, and has subsequently been named stereotactic body radiotherapy (SBRT). The advantages of hypofractionated radiotherapy for treating lung tumors are a shortened treatment course that requires fewer trips to the clinic than a conventional program, and the adoption of a smaller irradiated volume allowed by greater setup precision. This treatment is possible because the lung and liver are considered parallel organs at risk. The preliminary clinical results, mostly reported on lung cancer, have been very promising, including a local control rate of more than 90%, and a relatively low complication rate. The final results of a few clinical trials are awaited. SBRT may be useful for the treatment of stage I lung tumors.

[Radiation Therapy for Lung Cancer]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Apr, 2007  |  Pubmed ID: 17431339

Radiation therapy is one of the most important modalities for the treatment of lung cancer. Current progress of radiation therapy in cooperation with the development of physics and biology is remarkable. The techniques of three-dimensional treatment planning and three-dimensional conformal radiotherapy (3D-CRT) have facilitated the use of higher radiation doses. Patients with early-stage non-small cell lung cancer (NSCLC) are candidates for curative surgical resection. However, the number of elderly patients has been increasing, and these patients often have medical contraindications that prevent curative surgery. Recently, several clinical trials on stereotactic body radiotherapy (SBRT) using the 3D-CRT technique for solitary lung tumors have been reported. The local control rate for stage I disease is more than 90%, and survival rates are promising. Now a prospective multi-institutional trial is ongoing to determine whether this modality can become a standard treatment for inoperable patients or an alternative to lobetectomy. For locally advanced NSCLC, unfortunately, recent studies have demonstrated that conventional therapies may have reached a therapeutic plateau. Now several radiation dose escalation studies utilizing conventional fractionation and 3D-CRT techniques are ongoing. The strategies of almost all of these trials are to eliminate elective nodal irradiation and deliver a higher dose of radiation to gross tumor volume while sparing normal tissues. Preliminary experience has resulted in promising survival, but should be developed to integrate into the combined treatment to completely control both local disease and other microscopically involved lesions. The combination of novel chemotherapeutic agents and molecular targeting therapies with radiation therapy is being investigated. Development of molecular imaging techniques is expected to facilitate more selective dose escalation in tumors.

Hypoxia and Hypoxia-inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer

Cancer Research. May, 2007  |  Pubmed ID: 17483326

Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a major regulator of adaptation to hypoxia and is implicated in the malignant progression of cancers. Here, we studied whether hypoxia and HIF-1 expression contribute to the development of bone metastases using a well-characterized animal model of bone metastasis in MDA-MB-231 human breast cancer cells. To study the role of hypoxia in bone metastases, we tested the effects of the fusion protein (TOP3), the oxygen-dependent degradation domain of HIF-1alpha fused with HIV-TAT, and procaspase-3. TOP3 selectively induced apoptosis in hypoxic tumor cells in vitro and significantly reduced bone metastases in vivo. We next examined the role of HIF-1 in bone metastases by establishing MDA-MB-231 cells overexpressing constitutively active or dominant-negative HIF-1alpha (MDA/CA-HIF or MDA/DN-HIF, respectively). Bone metastases of MDA/CA-HIF were significantly increased with elevated number of CD31-positive blood vessels. In contrast, bone metastases were significantly reduced in MDA/DN-HIF. Because the progression of osteolytic bone metastases is due in part to the imbalance between bone formation and bone resorption, we examined the effects of hypoxia and HIF-1 on the differentiation of osteoblasts and osteoclasts. Hypoxia and CA-HIF overexpression markedly inhibited osteoblastic differentiation, whereas hypoxia increased osteoclast-like cell formation. In conclusion, these results suggest that tumor-associated hypoxia and HIF-1 expression promote the progression of bone metastases in breast cancer. Our results also suggest that hypoxia and HIF-1 lead to the development of osteolytic bone metastases by suppressing osteoblast differentiation and promoting osteoclastogenesis.

Development of an Ultrasmall C-band Linear Accelerator Guide for a Four-dimensional Image-guided Radiotherapy System with a Gimbaled X-ray Head

Medical Physics. May, 2007  |  Pubmed ID: 17555261

We are developing a four-dimensional image-guided radiotherapy system with a gimbaled x-ray head. It is capable of pursuing irradiation and delivering irradiation precisely with the help of an agile moving x-ray head on the gimbals. Requirements for the accelerator guide were established, system design was developed, and detailed design was conducted. An accelerator guide was manufactured and basic beam performance and leakage radiation from the accelerator guide were evaluated at a low pulse repetition rate. The accelerator guide including the electron gun is 38 cm long and weighs about 10 kg. The length of the accelerating structure is 24.4 cm. The accelerating structure is a standing wave type and is composed of the axial-coupled injector section and the side-coupled acceleration cavity section. The injector section is composed of one prebuncher cavity, one buncher cavity, one side-coupled half cavity, and two axial coupling cavities. The acceleration cavity section is composed of eight side-coupled nose reentrant cavities and eight coupling cavities. The electron gun is a diode-type gun with a cerium hexaboride (CeB6) direct heating cathode. The accelerator guide can be operated without any magnetic focusing device. Output beam current was 75 mA with a transmission efficiency of 58%, and the average energy was 5.24 MeV. Beam energy was distributed from 4.95 to 5.6 MeV. The beam profile, measured 88 mm from the beam output hole on the axis of the accelerator guide, was 0.7 mm X 0.9 mm full width at half maximum (FWHM) width. The beam loading line was 5.925 (MeV)-Ib (mA) X 0.00808 (MeV/mA), where Ib is output beam current. The maximum radiation leakage of the accelerator guide at 100 cm from the axis of the accelerator guide was calculated as 0.33 cGy/min at the rated x-ray output of 500 cGy/min from the measured value. This leakage requires no radiation shielding for the accelerator guide itself per IEC 60601-2-1.

Regional Hyperthermia Combined with Radiotherapy for Locally Advanced Non-small Cell Lung Cancers: a Multi-institutional Prospective Randomized Trial of the International Atomic Energy Agency

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Jun, 2007  |  Pubmed ID: 17566842

An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone.

Radiotherapy for Erdheim-Chester Disease

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Jun, 2007  |  Pubmed ID: 17566851

A 42-year-old woman suffered from pain in both legs, and fever. She was diagnosed with Erdheim-Chester disease (ECD), based upon bone biopsy. Initially, she received steroid therapy, which led to temporary improvement. However, bone pain in the right femur was so progressive that, as a trial course of radiation therapy, she was given a total dose of 18 Gy in ten fractions to the right distal femur. She showed a gradual response, and the local pain became controllable. Erdheim-Chester disease (ECD) is an uncommon, non-Langerhans form of histiocytosis, which is characterized by radiological and pathological findings, but its treatment is still controversial. We here present a representative case report of radiotherapy for ECD.

A Japan Clinical Oncology Group Trial for Stereotactic Body Radiation Therapy of Non-small Cell Lung Cancer

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. Jul, 2007  |  Pubmed ID: 17603306

Stereotactic body radiation therapy (SBRT) is a new treatment modality. To confirm the safety and efficacy, the Radiation Therapy Study Group of the Japan Clinical Oncology Group (JCOG) has started a phase II study of SBRT for stage IA non-small cell lung cancer (JCOG 0403). This study is ongoing with a strict quality control and quality assurance program, and the results will indicate whether a future phase III trial comparing SBRT with surgery is warranted. In addition, international collaboration will be critical to establish the role of SBRT in the treatment of lung cancer.

Hypofractionated Stereotactic Radiotherapy (HypoFXSRT) for Stage I Non-small Cell Lung Cancer: Updated Results of 257 Patients in a Japanese Multi-institutional Study

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. Jul, 2007  |  Pubmed ID: 17603311

Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study.

Hypoxia Inducible Factor-1 Influences Sensitivity to Paclitaxel of Human Lung Cancer Cell Lines Under Normoxic Conditions

Cancer Science. Sep, 2007  |  Pubmed ID: 17608771

Paclitaxel (PTX) is an anticancer drug that is effective against a wide range of solid tumors. The effect of PTX on two human lung cancer cell lines, PC14PE6 and NCI-H441 cells, was examined in an orthotopically transplanted animal model with an in vivo imaging devise. Although PTX effectively suppressed tumor growth and improved survival rate in NCI-H441, it did not influence these in PC14PE6. In vitro experiments confirmed that PC14PE6 cells are resistant to PTX under normoxic conditions and that both cell lines were resistant to PTX under hypoxic conditions. It was found that the expression level of endogenous hypoxia inducible factor (HIF)-1alpha in PC14PE6 is much higher than that in NCI-H441 cells under normoxic conditions. Furthermore, sensitivity to PTX in these cell lines was reversed when HIF-1alpha expression was decreased by siRNA specific to HIF-1alpha in PC14PE6 and increased by overexpression of the exogenous HIF-1alpha gene in NCI-H441. These results suggest that HIF-1 influences the PTX sensitivity of these cells. The authors further examined beta-tubulin, a target molecule of PTX, with western blotting and immunohistochemical analysis in these cells. The expression level of beta-tubulin was comparable in these cells under both normoxic and hypoxic conditions while the distribution of beta-tubulin and cell morphology were changed according to HIF-1alpha expression levels, suggesting that HIF-1 influences the conformation and dynamics of microtubules. These data support the potential development of HIF-1 targeted approaches in combination with PTX, where drug resistance tends to contribute to treatment failure.

The Combination of Hypoxia-response Enhancers and an Oxygen-dependent Proteolytic Motif Enables Real-time Imaging of Absolute HIF-1 Activity in Tumor Xenografts

Biochemical and Biophysical Research Communications. Sep, 2007  |  Pubmed ID: 17624305

The transcriptional activity of hypoxia-inducible factor-1 (HIF-1) is associated with tumor malignancies; therefore, it is important to comprehend its dynamism in solid tumors. However, a molecular imaging strategy to accurately access it remains to be developed. We constructed here a novel HIF-1-dependent reporter gene, 5HREp-ODD-luc, in which 5 copies of the hypoxia-response element (5HRE) enhance expression of the oxygen-dependent degradation (ODD) domain and luciferase (luc) fusion under hypoxia. Because the ODD domain caused the oxygen-dependent degradation of the ODD-Luc protein, the novel reporter gene showed little leak of luminescence under normoxia. Such a property caused an increase of the hypoxia-responsiveness up to about 4.7 x 10(4) -fold. Moreover, the ODD domain caused rapid degradation of the ODD-Luc protein under normoxia, the luminescence reflected the dynamism of HIF-1 activity in real-time. The superiority of the novel reporter gene will surely accelerate analysis of the intratumoral HIF-1 activity during tumor progression and cancer treatments.

[Current Situation and Prospects for Radiation Therapy in Breast Cancer]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Jun, 2007  |  Pubmed ID: 17682195

Development of a New Concept Automatic Frequency Controller for an Ultrasmall C-band Linear Accelerator Guide

Medical Physics. Aug, 2007  |  Pubmed ID: 17879787

We are developing a four-dimensional, image-guided radiotherapy system with a gimbaled x-ray head. The system has pursuing irradiation capability in addition to precise irradiation capability, owing to its agile x-ray head. The moving x-ray head requires a very small C-band accelerator guide. The heat intensity of the accelerator guide is much higher than that of conventional S-band medical linear accelerators. The resonance frequency varies over almost 1.0 MHz with a thermal time constant of about 30 s. An automatic frequency controller (AFC) is employed to compensate for this variation in resonance frequency. Furthermore, we noted that fast AFC response is important for step-and-shoot intensity modulation radiotherapy (IMRT), in which the beam is turned on and off frequently. Therefore, we invented a digital AFC, based on a new concept, to provide effective compensation for the thermal characteristics of the accelerator guide and to ensure stable and optimized x-ray treatment. An important aspect of the performance of the AFC is the capture-frequency range over which the AFC can seek, lock on to, and track the resonance frequency. The conventional, analog AFC used in S-band medical linear accelerators would have a capture-frequency range of about 0.9 MHz, if applied to our accelerator guide, and would be inappropriate. Conversely, our new AFC has a capture-frequency range of 24 MHz, which is well suited to our accelerator guide. The design concept behind this new AFC has been developed and verified. A full prototype system was constructed and tested on an existing accelerator guide at the rated x-ray output (500 cGy/min) of our radiotherapy system, with a pulse-repetition frequency of 300 Hz. The AFC acquired the resonance frequency of the accelerator guide within 0.15 s after beam-on, and provided stable tracking and adjustment of the frequency of the microwave source to the resonance frequency of the accelerator guide. With a planned improvement of the initialization of the AFC it should be able to acquire the resonance frequency within 33 ms.

Patterns of Care Study of Breast-conserving Therapy in Japan: Comparison of the Treatment Process Between 1995 1997 and 1999 2001 Surveys

Japanese Journal of Clinical Oncology. Oct, 2007  |  Pubmed ID: 17911378

The Japan Patterns of Care Study (JPCS) conducted two national surveys to identify changes associated with the treatment process of care for patients undergoing breast-conserving therapy (BCT). Between the two national surveys, the Japanese Breast Cancer Society published its treatment guideline for BCT.

Evaluation of Mass-like Consolidation After Stereotactic Body Radiation Therapy for Lung Tumors

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Oct, 2007  |  Pubmed ID: 17929117

The purpose of this study was to evaluate the characteristics of mass-like consolidation of the lung on computed tomography (CT) after stereotactic body radiation therapy (SBRT) retrospectively.

Near-infrared Fluorescent Labeled Peptosome for Application to Cancer Imaging

Bioconjugate Chemistry. Jan, 2008  |  Pubmed ID: 18163535

Nonionic amphiphilic copolypeptides, which were composed of hydrophilic poly(sarcosine) and hydrophobic poly(gamma-methyl L-glutamate) blocks, were synthesized with varying chain lengths of the blocks. The polypeptides having a suitable hydrophilic and hydrophobic balance were found to form vesicular assemblies of 100 nm size in buffer, which was evidenced by the TEM observation, the DLS analysis, and the encapsulation experiment. The genuine peptide vesicles, peptosomes, were labeled with a near-infrared fluorescence (NIRF) probe. In vivo retention in blood experiment showed long circulation of the peptosome in rat blood as stable as the PEGylated liposome. NIRF imaging of a small cancer on mouse by using the peptosome as a nanocarrier was successful due to the EPR effect of the peptosome. Peptosome is shown here as a novel excellent nanocarrier for molecular imaging.

Current Status of Accelerated Partial Breast Irradiation

Breast Cancer (Tokyo, Japan). 2008  |  Pubmed ID: 18224403

Accelerated partial breast irradiation (APBI) is a radiotherapy method used in breast-conserving therapy. In APBI, the tumor bed is topically irradiated over a short period after breast-conserving surgery. The fundamental concept underlying APBI is that more than 70% of ipsilateral breast tumor recurrence occurs in the neighborhood of the original tumor, and that hypofractionated radiotherapy can be applied safely when the irradiated volume is small enough. It is expected to reduce the time and cost required for conventional whole breast irradiation while maintaining equivalent local control. Several techniques including multicatheter interstitial brachytherapy, intracavitary brachytherapy, intraoperative radiation therapy, and 3D conformal external beam radiation therapy have been proposed, and each of them has its own advantages and drawbacks. Although APBI is increasingly used in the United States and Europe, and the short-term results are promising, its equivalence with whole breast radiation therapy is not fully established. In addition, because the average breast size in Japan is considerably smaller than in the West world, the application of APBI to Japanese patients is technically more challenging. At this point, APBI is still an investigational treatment in Japan, and the optimal method of radiation delivery as well as its long-term efficacy and safety should be clarified in clinical trials.

Feasibility of Accelerated Partial Breast Irradiation Using Three-dimensional Conformal Radiation Therapy for Japanese Women: a Theoretical Plan Using Six Patients' CT Data

Breast Cancer (Tokyo, Japan). 2008  |  Pubmed ID: 18224404

Several methods have been reported for accelerated partial breast irradiation (APBI), but in Japan, there are few facilities where brachytherapy or intra-operative radiotherapy is available. Japanese women have smaller physiques than American women in general. Thus, we developed external beam plans for APBI using computed tomography (CT) data of Japanese patients, to investigate whether APBI using three-dimensional conformal radiation therapy is safely applicable for Japanese women, while verifying the dose distributions.

Emission Under Hypoxia: One-electron Reduction and Fluorescence Characteristics of an Indolequinone-coumarin Conjugate

Chembiochem : a European Journal of Chemical Biology. Feb, 2008  |  Pubmed ID: 18224643

A characteristic feature of the reactivity of indolequinone derivatives, substituents of which can be removed by one-electron reduction under hypoxic conditions, was applied to the development of a new class of fluorescent probes for disease-relevant hypoxia. A reducing indolequinone parent molecule conjugated with fluorescent coumarin chromophores could suppress efficiently the fluorescence emission of the coumarin moieties by an intramolecular electron-transfer quenching mechanism and a conventional internal-filter effect. Under hypoxic conditions, however, the conjugate, denoted IQ-Cou, underwent a one-electron reduction triggered by X irradiation or the action of a reduction enzyme to release a fluorescent coumarin chromophore, whereupon an intense fluorescence emission with a maximum intensity at 420 nm was observed. The one-electron reduction of IQ-Cou was suppressed by molecular oxygen under aerobic conditions. IQ-Cou also showed intense fluorescence in a hypoxia-selective manner upon incubation with a cell lysate of the human fibrosarcoma cell line HT-1080. The IQ-Cou conjugate has several unique properties that are favorable for a fluorescent probe of hypoxia-specific imaging.

Taip2 is a Novel Cell Death-related Gene Expressed in the Brain During Development

Biochemical and Biophysical Research Communications. May, 2008  |  Pubmed ID: 18291095

TAIP2 was isolated as one of the homologous genes of TAIP3 (TGF-beta-up-regulated apoptosis-inducing-protein chromosome 3). The transcript of the mouse counterpart of TAIP2, designated mTaip2, was detected in several tissue specimens from embryos to adults, while mTaip2 was dominantly expressed in the embryonic brain. The overexpression of the full-length mTaip2 induced cell death in various cell lines. An analysis of mTaip2 deletion mutants revealed that the N-terminal half of mTaip2, but not the C-terminal half, had nuclear localization and cell death-inducing activities. The results indicate that mTaip2 is a novel cell death-related gene dominantly expressed in the embryonic brain, thus suggesting that mTaip2 may play a role in development of the brain.

Comparisons of the Impact of Systematic Uncertainties in Patient Setup and Prostate Motion on Doses to the Target Among Different Plans for Definitive External-beam Radiotherapy for Prostate Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Feb, 2008  |  Pubmed ID: 18307020

We aimed to compare the impact of systematic uncertainties in patient setup and prostate motion on three different external-beam radiotherapy protocols for prostate cancer.

Stereotactic Body Radiotherapy for Oligometastatic Lung Tumors

International Journal of Radiation Oncology, Biology, Physics. Oct, 2008  |  Pubmed ID: 18374506

Since 1998, we have treated primary and oligometastatic lung tumors with stereotactic body radiotherapy (SBRT). The term "oligometastasis" is used to indicate a small number of metastases limited to an organ. We evaluated our clinical experience of SBRT for oligometastatic lung tumors.

Accelerated Fractionation Versus Conventional Fractionation Radiation Therapy for Glottic Cancer of T1-2N0M0 Phase III Study: Japan Clinical Oncology Group Study (JCOG 0701)

Japanese Journal of Clinical Oncology. May, 2008  |  Pubmed ID: 18390558

A randomized Phase III study was started in Japan to demonstrate the non-inferiority of survival of accelerated fractionation radiation therapy (2.4 Gy/fr) with conventional fractionation radiation therapy (2 Gy/fr) in patients with T1-2N0M0 glottic cancer. This study began in September 2007, and a total of 360 patients will be accrued from 22 institutions within 4 years. The primary endpoint is 3-year progression-free survival (PFS). The secondary endpoints are overall survival, local progression-free survival, disease-free survival, survival with preserved voice function, complete response rate, proportion of treatment completion and adverse events.

Development of a Three-dimensionally Movable Phantom System for Dosimetric Verifications

Medical Physics. May, 2008  |  Pubmed ID: 18561639

The authors developed a three-dimensionally movable phantom system (3D movable phantom system) which can reproduce three-dimensional movements to experimentally verify the impact of radiotherapy treatment-related movements on dose distribution. The phantom system consists of three integrated components: a three-dimensional driving mechanism (3D driving mechanism), computer control system, and phantoms for film dosimetry. The 3D driving mechanism is a quintessential part of this system. It is composed of three linear-motion tables (single-axis robots) which are joined orthogonally to each other. This mechanism has a motion range of 100 mm, with a maximum velocity of 200 mm/s in each dimension, and 3D motion ability of arbitrary patterns. These attributes are sufficient to reproduce almost all organ movements. The positional accuracy of this 3D movable phantom system in a state of geostationary is less than 0.1 mm. The maximum error in terms of the absolute position on movement was 0.56 mm. The positional reappearance error on movement was up to 0.23 mm. The observed fluctuation of time was 0.012 s in the cycle of 4.5 s of oscillation. These results suggested that the 3D movable phantom system exhibited a sufficient level of accuracy in terms of geometry and timing to reproduce interfractional organ movement or setup errors in order to assess the influence of these errors on high-precision radiotherapy such as stereotactic irradiation and intensity-modulated radiotherapy. In addition, the authors 3D movable phantom system will also be useful in evaluating the adequacy and efficacy of new treatment techniques such as gating or tracking radiotherapy.

Diameter of Tumor Blood Vessels is a Good Parameter to Estimate HIF-1-active Regions in Solid Tumors

Biochemical and Biophysical Research Communications. Sep, 2008  |  Pubmed ID: 18586004

As the transcriptional activity of hypoxia-inducible factor 1 (HIF-1) is associated with resistance of tumor cells to current antitumor therapies, the spatiotemporal dynamics of HIF-1-active regions has been of great interest as a therapeutic target. In the present study, we established a unique cancer cell line, which changes color HIF-1-dependently, and monitored it during tumor progression. In imaging experiments, HIF-1-active cells appeared over the tumor xenograft, but dramatically decreased in number as blood vessels developed around the tumor. The remaining HIF-1-active cells at the center of the xenograft also disappeared after neovascularization. Thereafter, tumor growth was accelerated and HIF-1-active cells reappeared in different regions. The distance between HIF-1-active cells and the nearest vessels correlated to the diameter of the vessel (r=0.801). These results provide a basic knowledge of how to estimate the spatiotemporal dynamics of HIF-1-active cells using information about the image-guided architecture of tumor blood vessels.

TS-1 Enhances the Effect of Radiotherapy by Suppressing Radiation-induced Hypoxia-inducible Factor-1 Activation and Inducing Endothelial Cell Apoptosis

Cancer Science. Nov, 2008  |  Pubmed ID: 18823375

The therapeutic effect of concurrent chemoradiotherapy with TS-1 has been confirmed in various solid tumors; however, the detailed mechanism of action has not yet been fully elucidated. In the present study, we identified hypoxia-inducible factor-1 (HIF-1) as one of the targets of TS-1 in chemoradiotherapy. In growth delay assays using a tumor xenograft of non-small-cell lung carcinoma, H441, TS-1 treatment enhanced the therapeutic effect of single gamma-ray radiotherapy (14 Gy) and significantly delayed tumor growth by 1.58-fold compared to radiotherapy alone (P < 0.01). An optical in vivo imaging experiment using a HIF-1-dependent 5HRE-luc reporter gene revealed that TS-1 treatment suppressed radiation-induced activation of HIF-1 in the tumor xenografts. The suppression led to apoptosis of endothelial cells resulting in both a significant decrease in microvessel density (P < 0.05; vs radiation therapy alone) and a significant increase in apoptosis of tumor cells (P < 0.01; vs radiation therapy alone) in tumor xenografts. All of these results indicate that TS-1 enhances radiation-induced apoptosis of endothelial cells by suppressing HIF-1 activity, resulting in an increase in radiosensitivity of the tumor cells. Our findings strengthen the importance of both HIF-1 and its downstream gene, such as vascular endothelial cell growth factor, as therapeutic targets to enhance the effect of radiotherapy.

Geometrical Differences in Target Volumes Between Slow CT and 4D CT Imaging in Stereotactic Body Radiotherapy for Lung Tumors in the Upper and Middle Lobe

Medical Physics. Sep, 2008  |  Pubmed ID: 18841867

Since stereotactic body radiotherapy (SBRT) was started for patients with lung tumor in 1998 in our institution, x-ray fluoroscopic examination and slow computed tomography (CT) scan with a rotation time of 4 s have been routinely applied to determine target volumes. When lung tumor motion observed with x-ray fluoroscopy is larger than 8 mm, diaphragm control (DC) is used to reduce tumor motion during respiration. After the installation of a four-dimensional (4D) CT scanner in 2006, 4D CT images have been supplementarily acquired to determine target volumes. It was found that target volumes based on slow CT images were substantially different from those on 4D CT images, even for patients with lung tumor motion no larger than 8 mm. Although slow CT scan might be expected to fare well for lung tumors with motion range of 8 mm or less, the potential limitations of slow CT scan are unknown. The purpose of this study was to evaluate the geometrical differences in target volumes between slow CT and 4D CT imaging for lung tumors with motion range no larger than 8 mm in the upper and middle lobe. Of the patients who underwent SBR between October 2006 and April 2008, 32 patients who had lung tumor with motion range no larger than 8 mm and did not need to use DC were enrolled in this study. Slow CT and 4D CT images were acquired under free breathing for each patient. Target volumes were manually delineated on slow CT images (TV(slow CT)). Gross tumor volumes were also delineated on each of the 4D CT volumes and their union (TV(4D CT)) was constructed. Volumetric and statistical analyses were performed for each patient. The mean +/- standard deviation (S.D.) of TV(slow CT)/TV(4D CT) was 0.75 +/- 0.17 (range, 0.38-1.10). The difference between sizes of TV(slow CT) and TV(4D CT) was not statistically significant (P = 0.096). A mean of 8% volume of TV(slow CT) was not encompassed in TV(4D CT) (mean +/- S.D. = 0.92 +/- 0.07). The patients were separated into two groups to test whether the quality of target delineation on slow CT scans depends on respiratory periods below or above the CT rotation time of 4 s. No significant difference was observed between these groups (P = 0.229). Even lung tumors with motion range no larger than 8 mm might not be accurately depicted on slow CT images. When only a single slow CT scan was used for lung tumors with motion range of 8 mm or less, 95% confidence values for additional margins for TV(slow CT) to encompass TV(4D CT) were 4.0, 5.4, 4.9, 5.1, 1.8, and 1.7 mm for lateral, medial, ventral, dorsal, cranial, and caudal directions, respectively.

IL12RB2 and ABCA1 Genes Are Associated with Susceptibility to Radiation Dermatitis

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Oct, 2008  |  Pubmed ID: 18927311

Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted.

In Vitro Heat Generation by Ferrimagnetic Maghemite Microspheres for Hyperthermic Treatment of Cancer Under an Alternating Magnetic Field

Journal of Materials Science. Materials in Medicine. May, 2008  |  Pubmed ID: 17914614

Ferrimagnetic materials can be expected to be useful as thermo seeds for hyperthermic treatment of cancer, especially where the cancer is located in deep parts of body, as they can generate heat by magnetic hysteretic loss when they are placed in an alternating magnetic field. Recently, it was reported that ferrimagnetic maghemite (gamma-Fe2O3) microspheres 20-30 microm in diameter prepared in aqueous solution can show excellent heat generating ability. However, these microspheres have many cracks on their surfaces. In this study, the preparation conditions for the microspheres was further optimized in order to obtain crack-free ferrimagnetic microspheres, and the in vitro heat generation of the obtained microspheres was measured in an agar phantom under an alternating magnetic field. Crack-free gamma-Fe2O3 microspheres 20-30 microm in diameter were obtained successfully. Their saturation magnetization and coercive force were 68 emu g(-1) and 198 Oe, respectively. Their heat generation under an alternating magnetic field of 300 Oe at 100 kHz was estimated to be 42 W g(-1). The microspheres showed in vitro heat generation when they were dispersed in an agar phantom and placed under an alternating magnetic field. It is believed that these microspheres may be useful for the in situ hyperthermic treatment of cancer.

Survival and Relapse Pattern After Trimodality Therapy for Malignant Pleural Mesothelioma

General Thoracic and Cardiovascular Surgery. Nov, 2009  |  Pubmed ID: 19908112

Multimodality therapy has been applied to resectable malignant pleural mesothelioma, but the tolerability of the treatment and relapse pattern in detail remain unknown. We reviewed our experience of trimodality therapy as a single-institution study in Japan.

New Algorithm to Simulate Organ Movement and Deformation for Four-dimensional Dose Calculation Based on a Three-dimensional CT and Fluoroscopy of the Thorax

Medical Physics. Oct, 2009  |  Pubmed ID: 19928063

The aim of this study was to develop a 4D-modeling algorithm, designated "3D+," to simulate organ movement and deformation for 4D dose calculation without the need for 4D-CT or deformable image registration and to assess the validity of this algorithm.

The Akt/mTOR Pathway Assures the Synthesis of HIF-1alpha Protein in a Glucose- and Reoxygenation-dependent Manner in Irradiated Tumors

The Journal of Biological Chemistry. Feb, 2009  |  Pubmed ID: 19098000

Transcriptional activity of HIF-1 (hypoxia-inducible factor-1) has been reported to be up-regulated in solid tumors after ionizing radiation; however, the molecular mechanism underlying the response remains to be elucidated. In the present study, we performed a series of molecular imaging experiments using a HIF-1-dependent reporter gene, 5HREp-ODD-luc, and found an essential role of the Akt/mTOR pathway. Hypoxic tumor cells distant from blood vessels were dramatically reoxygenated at 24 h postirradiation, and HIF-1 activity increased as HIF-1alpha accumulated in the reoxygenated regions. The accumulation was inhibited with a nonmetabolizable glucose analog, 2-deoxy-d-glucose, through the suppression of radiation-induced phosphorylation of Akt in the reoxygenated regions. Akt knockdown and an mTOR inhibitor revealed the importance of the Akt/mTOR pathway in the postirradiation accumulation of HIF-1alpha. In vitro experiments confirmed that an increase in glucose availability induced Akt phosphorylation under reoxygenated conditions and consequently up-regulated HIF-1alpha translation. Moreover, both the accelerated translation and the previously reported reactive oxygen species-mediated stabilization of HIF-1alpha protein were essential to the activation of HIF-1. All of these results indicate that Akt/mTOR-dependent translation of HIF-1alpha plays a critical role in the postirradiation up-regulation of intratumoral HIF-1 activity in response to radiation-induced alterations of glucose and oxygen availability in a solid tumor.

A Randomized Phase II Study of Cisplatin/5-FU Concurrent Chemoradiotherapy for Esophageal Cancer: Short-term Infusion Versus Protracted Infusion Chemotherapy (KROSG0101/JROSG021)

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Aug, 2009  |  Pubmed ID: 19167122

A randomized phase II study was conducted to compare the toxicity and efficacy of combining short-term chemotherapy (CT) or protracted CT with radiotherapy (RT) for esophageal cancer.

Ring-opening Metathesis Polymerization-based Synthesis of ICG-containing Amphiphilic Triblock Copolymers for in Vivo Tumor Imaging

Bioconjugate Chemistry. Mar, 2009  |  Pubmed ID: 19193062

Water-soluble triblock copolymers consisting of hydrophobic-hydrophilic-dye segments were synthesized by ring-opening metathesis polymerization (ROMP) of norbornadiene monomers, copper-catalyzed click reaction, osmium-catalyzed dihydroxylation, and the following transformations. These polymers in aqueous conditions could form spherical assemblies, whose diameters were 50-60 nm by TEM measurement. From in vivo optical imaging experiments, the spherical assemblies of these copolymers could be efficiently accumulated in tumor cells. In addition, the spherical assemblies of water-soluble polymers accumulated in a tumor cell over two weeks.

Radiolytic Activation of a Cytarabine Prodrug Possessing a 2-oxoalkyl Group: One-electron Reduction and Cytotoxicity Characteristics

Organic & Biomolecular Chemistry. Feb, 2009  |  Pubmed ID: 19194578

An anti-tumour agent of cytarabine (ara-C) was conjugated with a 2-oxopropyl group at the N(4) position to obtain a radiation-activated prodrug (oxo-ara-C) that targeted hypoxic tumour tissues with selective cytotoxicity. The parent anti-tumour agent, ara-C, was confirmed to be released from oxo-ara-Cvia one-electron reduction upon hypoxic X-ray treatment. The prodrug oxo-ara-C had dramatically reduced cytotoxicity against human lung adenocarcinoma A549 cells relative to ara-C because of the effect of 2-oxopropyl substituent. In contrast, X-ray treatment of hypoxic A549 cells containing oxo-ara-C enhanced the cytotoxic effect, indicating that toxic ara-C was preferentially released in hypoxic cells via radiolytic one-electron reduction by hydrated electrons (e(aq)(-)).

Dose-response Relationship and Dose Optimization in Radiotherapy of Postoperative Keloids

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. May, 2009  |  Pubmed ID: 19201502

The treatment dose and fractionation dose that are considered in postoperative keloids had been reported in the previous studies. We performed retrospective analysis to elucidate the factors influencing the treatment outcome.

[Molecular Imaging--diagnosis by Functional Imaging]

Gan to Kagaku Ryoho. Cancer & Chemotherapy. Mar, 2009  |  Pubmed ID: 19295260

In the 20th century, technological innovation in instrumentation has enabled us to noninvasively observe the structural detail of organs and tissues in diagnostic imaging. The 21st century is the era of analyzing the whole body at the molecular level as symbolized by post-genomic studies. In addition to structural information, functional information will be applied to the non-invasive imaging of the human organ functions in the near future. Thus, the era of structural imaging will progress to the era of functional imaging. Recent progress in optical imaging has accelerated the multimodality of instruments for structural imaging such as magnetic resonance imaging(MRI)and computerized tomography( CT), and functional imaging with molecular probes. Although there are many limitations to optical modality for whole body imaging, the multi-functional nature of optics will cause a revolution in diagnostic imaging.

The HIF-1-active Microenvironment: an Environmental Target for Cancer Therapy

Advanced Drug Delivery Reviews. Jul, 2009  |  Pubmed ID: 19409433

Solid tumors possess unique microenvironments that are exposed to chronic hypoxic conditions, so-called tumor hypoxia. Although more than half a century has passed since it was suggested that tumor hypoxia correlated with bad treatment outcomes and contributed to the recurrence of cancer, no fundamental solution to this problem has yet been found. Hypoxia-inducible factor HIF-1 is the main transcription factor that regulates the cellular response to hypoxia. It induces various genes, whose function is strongly associated with the malignant alteration of the entire tumor. The cellular changes induced by HIF-1 are extremely important therapeutic targets of cancer therapy, particularly in the therapy against refractory cancers. Therefore targeting strategies to overcome the HIF-1-active microenvironment are important for cancer therapy.

Selective Killing of Hypoxia-inducible Factor-1-active Cells Improves Survival in a Mouse Model of Invasive and Metastatic Pancreatic Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. May, 2009  |  Pubmed ID: 19417024

Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested.

Impact of Radiation Therapy on Breast-conserving Therapy for Breast Cancer in Japanese Women: a Retrospective Analyses of Multi-institutional Experience. Kansai Breast Cancer Radiation Therapy Study Group

Oncology Reports. Jun, 2009  |  Pubmed ID: 19424624

Whole breast radiation therapy (RT) after breast-conserving surgery is sometimes omitted in Japan; however, its impact on the outcome has not been properly evaluated. A multi-institutional retrospective study was conducted to clarify the impact of RT on local control after breast-conserving therapy (BCT). Data were collected from 3576 patients from 37 participating hospitals, of whom 1763 were eligible for analyses. Five hundred and five patients had ipsilateral breast tumor recurrence (IBTR) and 1258 patients did not. Details of IBTR were available for 245 of 505 patients who had IBTR, the location of IBTR was within or adjacent to the original tumor bed in 168 patients (68.6%). IBTR was salvaged with partial mastectomy in 119 patients (48.6%). Second recurrence in the ipsilateral breast was observed in 27 patients (11.0%). Univariate analyses demonstrated that administration of RT, the resection margin status, hormone responsiveness, T stage, N stage and stage were significantly related to IBTR. Multivariate analysis demonstrated that administration of RT, T stage and N stage were significantly correlated to IBTR. Among them, administration of RT had the largest impact on RT and it decreased the risk of IBTR by 77.3%. Omission of RT had the most significant impact on IBTR. RT should be given as a standard component of BCT.

Imaging of HIF-1-active Tumor Hypoxia Using a Protein Effectively Delivered to and Specifically Stabilized in HIF-1-active Tumor Cells

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Jun, 2009  |  Pubmed ID: 19443598

Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumor progression and in the development of resistance to radiotherapy. We designed a novel fusion protein (PTD-ODD-SAV [POS]) consisting of a protein transduction domain (PTD), streptavidin (SAV), and a portion of the oxygen-dependent degradation domain (ODD) of HIF-1alpha that confers the same oxygen-dependent regulation as HIF-1alpha on POS. (3-(123/125)I-iodobenzoyl)norbiotinamide ((123/125)I-IBB) was conjugated to the SAV moiety of POS to synthesize (123/125)I-IBB-labeled POS ((123/125)I-IPOS). The purpose of this study was to evaluate the feasibility of (123)I-IPOS as an imaging probe for HIF-1-active tumor hypoxia.

Near-infrared Fluorescence Tumor Imaging Using Nanocarrier Composed of Poly(L-lactic Acid)-block-poly(sarcosine) Amphiphilic Polydepsipeptide

Biomaterials. Oct, 2009  |  Pubmed ID: 19525007

A nanocarrier, lactosome, which is composed of poly(L-lactic acid)-block-poly(sarcosine), as a contrast agent for the liver tumor imaging was examined using the near infrared fluorescence (NIRF) optical imaging technique. Lactosome labeled with indocyanine green (ICG) showed a high escape ability from the reticulo-endothelial system (RES). Lactosome was found to be stable in a blood circulation, and gradually accumulated specifically at a model liver tumor site, which was obtained by graft of HepG2/EF-Luc cells at a mouse liver. The high tumor/liver imaging ratio is due to the enhanced permeation and retention (EPR) effect of lactosome. The fluorescence intensity at the tumor site was correlated with the degree of malignancy. Tumor imaging using lactosome as a nanocarrier is therefore a potential candidate for a facile and general tumor imaging technique.

Impact of Motion Velocity on Four-dimensional Target Volumes: a Phantom Study

Medical Physics. May, 2009  |  Pubmed ID: 19544777

This study aims to assess the impact of motion velocity that may cause motion artifacts on target volumes (TVs) using a one-dimensional moving phantom. A 20 mm diameter spherical object embedded in a QUASAR phantom sinusoidally moved with approximately 5.0 or 10.0 mm amplitude (A) along the longitudinal axis of the computed tomography (CT) couch. The motion period was manually set in the range of 2.0-10.0 s at approximately 2.0 s interval. Four-dimensional (4D) CT images were acquired by a four-slice CT scanner (LightSpeed RT; General Electric Medical Systems, Waukesha, WI) with a slice thickness of 1.25 mm in axial cine mode. The minimum gantry rotation of 1.0 s was employed to achieve the maximum in-slice temporal resolution. Projection data over a full gantry rotation (1.0 s) were used for image reconstruction. Reflective marker position was recorded by the real-time positioning management system (Varian Medical Systems, Palo Alto, CA). ADVANTAGE 4D software exported ten respiratory phase volumes and the maximum intensity volume generated from all reconstructed data (MIV). The threshold to obtain static object volume (V0, 4.19 ml) was used to automatically segment TVs on CT images, and then the union of TVs on 4D CT images (TV(4D)) was constructed. TVs on MIV (TV(MIV)) were also segmented by the threshold that can determine the area occupied within the central slice of TV(MIV). The maximum motion velocity for each phase bin was calculated using the actual averaged motion period displayed on ADVANTAGE 4D software (T), the range of phases used to construct the target phase bin (phase range), and a mathematical model of sinusoidal function. Each volume size and the motion range of TV in the cranial-caudal (CC) direction were measured. Subsequently, cross-correlation coefficients between TV size and motion velocity as well as phase range were calculated. Both misalignment and motion-blurring artifacts were caused by high motion velocity, Less than 6% phase range was needed to construct the 4D CT data set, except for T of 2.0 s. While the positional differences between the TV and ideal centroid in the CC direction were within the voxel size for T > or = 6.0 s, the differences were up to 2.43 and 4.15 mm for (A,T) = (5.0 mm, 2.0 s) and (10.0 mm, 2.0 s), respectively. The maximum volumetric deviations between TV sizes and V0 were 43.68% and 91.41% for A of 5.0 and 10.0 mm, respectively. TV(MIV) sizes were slightly larger than TV(4D) sizes. Volumetric deviation between TV size and V0 had a stronger correlation with motion velocity rather than phase range. This phantom study demonstrated that motion artifacts were substantially reduced when the phantom moved longitudinally at low motion velocity during 4D CT image acquisition; therefore, geometrical uncertainties due to motion artifacts should be recognized when determining TVs, especially with a fast period.

Initial Validations for Pursuing Irradiation Using a Gimbals Tracking System

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Oct, 2009  |  Pubmed ID: 19699544

Our newly designed image-guided radiotherapy (IGRT) system enables the dynamic tracking irradiation with a gimbaled X-ray head and a dual on-board kilovolt imaging subsystem for real-time target localization. Examinations using a computer-controlled three-dimensionally movable phantom demonstrated that our gimbals tracking system significantly reduced motion blurring effects in the dose distribution compared to the non-tracking state.

Survey of Stereotactic Body Radiation Therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group

International Journal of Radiation Oncology, Biology, Physics. Oct, 2009  |  Pubmed ID: 19735861

To recognize the current status of stereotactic body radiotherapy (SBRT) in Japan, using a nationwide survey conducted by the Japan 3-D Conformal External Beam Radiotherapy Group.

Usefulness of HIF-1 Imaging for Determining Optimal Timing of Combining Bevacizumab and Radiotherapy

International Journal of Radiation Oncology, Biology, Physics. Oct, 2009  |  Pubmed ID: 19735869

To study the relationship between the hypoxia-inducible factor-1 (HIF-1) activity level after bevacizumab treatment and the antitumor effects of radiation to determine the optimal combination schedule of bevacizumab with radiotherapy.

Measurement of Interfraction Variations in Position and Size of Target Volumes in Stereotactic Body Radiotherapy for Lung Cancer

International Journal of Radiation Oncology, Biology, Physics. Oct, 2009  |  Pubmed ID: 19735879

To investigate the interfraction variations in volume, motion range, and position of the gross tumor volume (GTV) in hypofractionated stereotactic body radiotherapy (SBRT) for lung cancer using four-dimensional computed tomography.

Effect of Audio Coaching on Correlation of Abdominal Displacement with Lung Tumor Motion

International Journal of Radiation Oncology, Biology, Physics. Oct, 2009  |  Pubmed ID: 19735881

To assess the effect of audio coaching on the time-dependent behavior of the correlation between abdominal motion and lung tumor motion and the corresponding lung tumor position mismatches.

Monitoring of Biological One-electron Reduction by (19)F NMR Using Hypoxia Selective Activation of an (19)F-labeled Indolequinone Derivative

Journal of the American Chemical Society. Nov, 2009  |  Pubmed ID: 19842623

Biological reduction of fluorine-labeled indolequinone derivative (IQ-F) was characterized by (19)F NMR for quantitative molecular understanding. The chemical shift change in (19)F NMR allowed monitoring of the enzymatic reduction of IQ-F. Upon hypoxic treatment of IQ-F with NADPH:cytochrome P450 reductase, IQ-F was activated via catalytic one-electron reduction to release nonafluoro-tert-butyl alcohol (F-OH), while the formation of F-OH was significantly suppressed under aerobic conditions. Similar hypoxia-selective reduction of IQ-F occurred within A549 cells, which expresses NADPH:cytochrome P450 reductase. The kinetic analysis was also performed to propose a reaction mechanism. The molecular oxygen slightly prevents the binding of IQ-F to reductase, while the rate of net reaction was decreased due to oxidation of a semiquinone anion radical intermediate generated by one-electron reduction of IQ-F. The disappearance of IQ-F and appearance of F-OH were imaged by (19)F fast spin echo, thus visualizing the hypoxia-selective reduction of IQ-F by means of MR imaging.

Imaging and Targeting of the Hypoxia-inducible Factor 1-active Microenvironment

Journal of Toxicologic Pathology. Jun, 2009  |  Pubmed ID: 22271982

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues. They are refractory to radiotherapy and anticancer chemotherapy. Although more than half a century has passed since it was suggested that tumour hypoxia correlates with poor treatment outcomes and contributes to recurrence of cancer, no fundamental solution to this problem has been found. Hypoxia-inducible factor-1(HIF-1) is the main transcription factor that regulates the cellular response to hypoxia. It induces various genes, whose function is strongly associated with malignant alteration of the entire tumour. The cellular changes induced by HIF-1 are extremely important therapeutic targets of cancer therapy, particularly in therapy against refractory cancers. Therefore, targeting strategies to overcome the HIF-1-active microenvironment are important for cancer therapy. To Target HIF-1-active/ hypoxic tumor cells, we developed a fusion protein drug, PTD-ODD-Procaspase-3 that selectively induces cell death in HIF-1-active/hypoxic cells. The drug consists of the following three functional domains: the protein transduction domain (PTD), which efficiently delivers the fusion protein to hypoxic tumor cells, the ODD domain, which has a VHL-mediated protein destruction motif of human HIF-1α protein and confers hypoxia-dependent stabilization to the fusion proteins, and the human procaspase-3 proenzyme responsible for the cytocidal activity of the protein drug. In vivo imaging systems capable of monitoring HIF-1 activity in transplanted human cancer cells in mice are useful in evaluating the efficiency of these drugs and in study of HIF-1-active tumor cells.

Noninvasive Tracking of Donor Cell Homing by Near-infrared Fluorescence Imaging Shortly After Bone Marrow Transplantation

PloS One. 2010  |  Pubmed ID: 20559437

Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases.

Early Protective Effect of Bone Marrow Mononuclear Cells Against Ischemic White Matter Damage Through Augmentation of Cerebral Blood Flow

Stroke; a Journal of Cerebral Circulation. Dec, 2010  |  Pubmed ID: 20947840

To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain.

Dosimetric Characterization of a Multileaf Collimator for a New Four-dimensional Image-guided Radiotherapy System with a Gimbaled X-ray Head, MHI-TM2000

Medical Physics. Sep, 2010  |  Pubmed ID: 20964187

To present the dosimetric characterization of a multileaf collimator (MLC) for a new four-dimensional image-guided radiotherapy system with a gimbaled x-ray head, MHI-TM2000.

Magnetic SiO2 Gel Microspheres for Arterial Embolization Hyperthermia

Biomedical Materials (Bristol, England). Dec, 2010  |  Pubmed ID: 21060148

We have prepared magnetic SiO(2) microspheres with a diameter of 20-30 µm as thermoseeds for hyperthermia of cancer. These were prepared by directly introducing preformed magnetic iron oxide nanoparticles (IONPs) into microspheres of a SiO(2) gel matrix derived from the hydrolysis of tetramethoxysilane (TMOS) in a water-in-oil (W/O) emulsion. Dimethylformamide (DMF) was used as a stabilizer, methanol (CH(3)OH) as a dispersant and ammonia (NH(4)OH) as the catalyst for the formation of the spherical particles in the aqueous phase of the W/O emulsion. The magnetic IONPs were synthesized hydrochemically in an aqueous system composed of ferrous chloride, sodium nitrate and sodium hydroxide. Mono-dispersed magnetic SiO(2) gel microspheres with a diameter of approximately 20 µm were successfully obtained by adding a determined amount of solution with a molar ratio of TMOS/DMF/CH(3)OH/H(2)O/NH(4)OH = 1:1.4:9:20:0.03 to kerosene with a surfactant (sorbitan monooleate/sorbitan monostearate = 3:1 by weight ratio) that was 30 wt% of the total amount of the oil phase. These were estimated to contain up to 60 wt% of IONPs that consisted mainly of Fe(3)O(4) and showed a higher specific absorption rate (SAR = 27.9-43.8 W g(-1)) than that of the starting IONPs (SAR = 25.3 W g(-1)) under an alternating current magnetic field of 300 Oe and 100 kHz.

Impact of Multileaf Collimator Width on Intraprostatic Dose Painting Plans for Dominant Intraprostatic Lesion of Prostate Cancer

Journal of Applied Clinical Medical Physics / American College of Medical Physics. 2010  |  Pubmed ID: 21081876

The aim of this study was to investigate the impact of multileaf collimator width (MLC-W) on intraprostatic dose painting plans for prostate cancer.Prostate cancer maps based on the histopathological findings were superimposed onto simulation CT images. Clinical target volume (CTV) 1 was defined as the prostate and the base of the seminal vesicles, and CTV2 was defined as the dominant intraprostatic lesions. Planning target volume (PTV) 1 and PTV2 were delineated by adding 5 mm margins to CTV1 and CTV2, respectively. For each case, two dose painting plans were created to deliver 74 Gy to PTV1 and 84 Gy to PTV2 with dynamic multileaf collimator technique using two different MLCs: m3 (MLC-W: 3mm) and Millennium (5 mm). Plans were evaluated by comparing the conformation number (CN), a quantity that defines the degree of conformality.The CNs for plans using the m3 and Millennium were 0.68 and 0.67 for PTV1 and 0.59 and 0.58 for PTV2, respectively. The CNs tended to be higher for a thinner leaf width (p < 0.05).Dosimetric advantages associated with smaller leaves were observed. However, differences between 3 mm and 5 mm leaf width were relatively small, which suggested that 5 mm leaf width would be acceptable in dose painting plans for prostate cancer.

In Vivo Imaging of HIF-active Tumors by an Oxygen-dependent Degradation Protein Probe with an Interchangeable Labeling System

PloS One. 2010  |  Pubmed ID: 21203417

Hypoxia-inducible factor (HIF) functions as a master transcriptional regulator for adaptation to hypoxia by inducing adaptive changes in gene expression for regulation of proliferation, angiogenesis, apoptosis and energy metabolism. Cancers with high expression of the alpha subunit of HIF (HIFα) are often malignant and treatment-resistant. Therefore, the development of a molecular probe that can detect HIF activity has great potential value for monitoring tumor hypoxia. HIF prolyl hydroxylases (HPHDs) act as oxygen sensors that regulate the fate of HIFα protein through its oxygen-dependent degradation (ODD) domain. We constructed a recombinant protein PTD-ODD-HaloTag (POH) that is under the same ODD regulation as HIFα and contains protein transduction domain (PTD) and an interchangeable labeling system. Administration of near-infrared fluorescently labeled POH (POH-N) to mouse models of cancers allowed successful monitoring of HIF-active regions. Immunohistochemical analysis for intratumoral localization of POH probe revealed its specificity to HIF-active cells. Furthermore, lack of the PTD domain or a point mutation in the ODD domain abrogated the specificity of POH-N to HIF-active cells. Overall results indicate that POH is a practical probe specific to HIF-active cell in cancers and suggest its large potential for imaging and targeting of HIF-related diseases.

A Novel Screen Using the Reck Tumor Suppressor Gene Promoter Detects Both Conventional and Metastasis-suppressing Anticancer Drugs

Oncotarget. Aug, 2010  |  Pubmed ID: 21304177

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.

Ring-opening Metathesis Polymerization-based Synthesis of Polymeric Nanoparticles for Enhanced Tumor Imaging in Vivo: Synergistic Effect of Folate-receptor Targeting and PEGylation

Biomaterials. Feb, 2010  |  Pubmed ID: 19853909

We have synthesized amphiphilic copolymers using ring-opening metathesis polymerization (ROMP), a copper-catalyzed dipolar click reaction, and osmium-catalyzed dihydroxylation. The resulting copolymers were easily conjugated with folate and dye (indocyanine green) moieties, using a transamidation method. The copolymers exhibited high water solubility and formed nanometer-sized self-assemblies in aqueous medium. The amphiphilic copolymers modified by dihydroxylation of the polymer backbone exhibited much lower cmc values than the non dihydroxylated copolymer. Copolymers conjugated with folate moieties reduced the fluorescence intensity of aqueous polymer solutions both in vitro and in vivo, but their self-assemblies efficiently accumulated at tumor sites because of folate-receptor recognition at tumor tissue. The PEGylation of copolymers improved the stability of the self-assemblies in aqueous medium as well as the tumor site selectivity in vivo. Furthermore, the fluorescent nanoparticles consisting of PEG- and folate-conjugated ROMP-based copolymers accumulated in tumor tissue selectively and efficiently, whereas accumulation in all other normal organs was reduced. The PEGylation and folate conjugation can synergistically improve the in vivo tumor site selectivity of ROMP-based copolymers.

A Novel Strategy to Tag Matrix Metalloproteinases-positive Cells for in Vivo Imaging of Invasive and Metastatic Activity of Tumor Cells

Journal of Controlled Release : Official Journal of the Controlled Release Society. May, 2010  |  Pubmed ID: 20096316

Matrix metalloproteinases (MMPs) are endopeptidases responsible for degrading the extracellular matrix (ECM) and remodeling tissue in both physiological and pathological processes. MMP2 and membrane-type 1 MMP (MT1-MMP) have been associated with tumor invasion, metastasis and angiogenesis; therefore, a molecular imaging strategy assessing their activity may help to predict the malignancy of tumors. Here, we established a novel method of specifically tagging the surface of MMP2- and MT1-MMP-positive cells, and applied it to the development of an optical imaging probe. We constructed a protein-based probe composed of a glutathione-S-transferase (GST)-tag (Inhibitory [I]-domain), a polypeptide as a specific substrate for both MMP2 and MT1-MMP (Cleaved [C]-domain), a transmembrane domain of the epidermal growth factor receptor (Transmembrane [TM]-domain), and DsRed2 (Fluorescent [F]-domain). In vitro experiments clearly demonstrated that, after the probe was cleaved at the C-domain by the MMPs, the resultant TM-F-domain was inserted into the cellular membrane. Optical imaging experiments in vivo demonstrated that the probe was cleaved and specifically remained in tumor xenografts in a MMP-dependent manner. These results indicate that the release of the I-C-domain through the proteolytic cleavage of the C-domain by MMP2 and MT1-MMP triggers the tagging of cellular membranes with the TM-F-domain. The present feasibility study opens the door to the development of a novel imaging probe for tumor malignancy using positron emission tomography as well as an optical imaging device.

A Consensus-based Guideline Defining the Clinical Target Volume for Pelvic Lymph Nodes in External Beam Radiotherapy for Uterine Cervical Cancer

Japanese Journal of Clinical Oncology. May, 2010  |  Pubmed ID: 20133334

To develop a consensus-based guideline as well as an atlas defining pelvic nodal clinical target volumes in external beam radiotherapy for uterine cervical cancer.

Rapid Detection of Hypoxia-inducible Factor-1-active Tumours: Pretargeted Imaging with a Protein Degrading in a Mechanism Similar to Hypoxia-inducible Factor-1alpha

European Journal of Nuclear Medicine and Molecular Imaging. Aug, 2010  |  Pubmed ID: 20428865

Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-(123)I-iodobenzoyl)norbiotinamide ((123)I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and (123)I-IBB for rapid imaging of HIF-1-active tumours.

Characterization of FDG-PET Images After Stereotactic Body Radiation Therapy for Lung Cancer

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Nov, 2010  |  Pubmed ID: 20430463

The purpose was to characterize (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) findings after stereotactic body radiation therapy (SBRT) for lung cancer.

Long-term Outcomes of Three-dimensional Conformal Radiation Therapy Combined with Neoadjuvant Hormonal Therapy in Japanese Patients with Locally Advanced Prostate Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Dec, 2010  |  Pubmed ID: 20652347

The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with locally advanced prostate cancer who initiated salvage hormonal therapy (SHT) at a relatively early phase were evaluated.

Stereotactic Body Radiation Therapy for Lung Cancer: Achievements and Perspectives

Japanese Journal of Clinical Oncology. Sep, 2010  |  Pubmed ID: 20670962

Stereotactic body radiation therapy is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. This technique basically derived from that of radiosurgery for intracranial lesions allows us to deliver high dose to the target leading to high control of the tumor without causing significant cytotoxicities associated with the treatment. Early-stage non-small cell lung cancers are regarded as most appropriate malignancies for this modality and accordingly have most intensively been investigated. With many encouraging outcomes in retrospective studies, several prospective clinical trials have been started world-wide. Japan Clinical Oncology Group protocol 0403 is a phase II trial of stereotactic body radiation therapy for T1N0M0 non-small cell lung cancer including both inoperable and operable patients. The results for operable patients are to be disclosed this year after 3 years of follow-up. It is highly probable that stereotactic body radiation therapy can be a standard treatment modality for inoperable patients for early-stage non-small cell lung cancer. The role of stereotactic body radiation therapy for operable patients is expected to be clarified by the outcomes of coming clinical trials. Tremendous advance in stereotactic body radiation therapy is expected when four-dimensional radiation therapy coping with tumor movement is realized. Among several approaches, tumor tracking appears most ideal. The new image-guided radiotherapy system which has the capability of tumor tracking has been developed in Japan.

Hypofractionated Stereotactic Radiotherapy for Acoustic Neuromas: Safety and Effectiveness over 8 Years of Experience

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Feb, 2011  |  Pubmed ID: 20830603

Little information is available about long-term outcomes of hypofractionated stereotactic radiotherapy (hypo-FSRT) for acoustic neuromas. In this study, the safety and effectiveness of hypo-FSRT for unilateral acoustic neuroma were reviewed over 8 years of experience at our institution.

Positional Reproducibility of Pancreatic Tumors Under End-exhalation Breath-hold Conditions Using a Visual Feedback Technique

International Journal of Radiation Oncology, Biology, Physics. Apr, 2011  |  Pubmed ID: 20832187

To assess positional reproducibility of pancreatic tumors under end-exhalation (EE) breath-hold (BH) conditions with a visual feedback technique based on computed tomography (CT) images.

PET Imaging of Hypoxia-inducible Factor-1-active Tumor Cells with Pretargeted Oxygen-dependent Degradable Streptavidin and a Novel 18F-labeled Biotin Derivative

Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging. Oct, 2011  |  Pubmed ID: 20838908

We aimed to evaluate the feasibility of using streptavidin-biotin-based pretargeting for positron emission tomography (PET) imaging of hypoxia-inducible factor (HIF)-1-active tumors.

Impact of Double-balloon Rectal Catheter Use in External-beam Radiotherapy for Prostate Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Feb, 2011  |  Pubmed ID: 20922449

Prostate motion and rectal sparing are important treatment strategy issues in external-beam radiotherapy for localized prostate cancer. To address these issues, we prospectively investigated the feasibility of using a double-balloon rectal catheter.

Prognostic Factors in Stereotactic Body Radiotherapy for Non-small-cell Lung Cancer

International Journal of Radiation Oncology, Biology, Physics. Mar, 2011  |  Pubmed ID: 20472343

To investigate the factors that influence clinical outcomes after stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC).

Preparation of Magnetic Iron Oxide Nanoparticles for Hyperthermia of Cancer in a FeCl₂-NaNO₃-NaOH Aqueous System

Journal of Biomaterials Applications. Mar, 2011  |  Pubmed ID: 20207773

Magnetic iron oxide nanoparticles (MIONPs) were synthesized in a FeCl₂-NaNO₃-NaOH aqueous system under various initial Fe(2+)/NO⁻₃ molar ratios (α) and Fe(2+)/OH- molar ratios (β) in order to clarify the effects of the initial molar ratio of reactants on the reaction mechanism. The Fe(2+)/NO⁻₃ /OH(-) molar ratio of 3 : 1 : 5 led to the formation of magnetic nanoparticles mainly composed of magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃). The 36 nm sized γ-Fe₂O₃ and 413 nm sized Fe₃O₄ were obtained by changing the order in which NaNO₃ was added to a NaOH solution. The in vitro heat generations of the resulting MIONPs in an agar phantom were measured under an alternating magnetic field (100 kHz, 23.9 kA/m). The temperature rise (ΔT) of the agar phantom for the 36 nm sized γ-Fe₂O₃ was 55°C in the first 140 s, with a concentration of 58 mg Fe/mL. Our results showed that it is possible to prepare MIONPs with high heating efficiencies under optimal conditions using the present method.

Phase II Study of Radiation Therapy Combined with Weekly Low-dose Gemcitabine for Locally Advanced, Unresectable Pancreatic Cancer

American Journal of Clinical Oncology. Apr, 2011  |  Pubmed ID: 20065850

Through a phase I study with a fixed radiation dose of 54 Gy and escalating doses of weekly gemcitabine, we established a recommended dose of gemcitabine at 250 mg/m in combination with radiation therapy for patients with unresectable pancreatic cancer.

Effective Encapsulation of a New Cationic Gadolinium Chelate into Apoferritin and Its Evaluation As an MRI Contrast Agent

Nanomedicine : Nanotechnology, Biology, and Medicine. Oct, 2011  |  Pubmed ID: 21333752

Gd-Me(2)DO2A with a T(1) proton relaxivity twice as high as that of commercial Gd-DOTA was newly designed and synthesized. Me(2)DO2A kept its high association property with gadolinium ions (Gd(3+)), and the Gd-Me(2)DO2A was efficiently encapsulated into the apoferritin cavity to further enhance the T(1) relaxivity as much as 10-fold higher than Gd-DOTA on a Gd basis. The high T(1) relaxivity was attained by (i) increased accessibility of water molecules to Gd(3+) ions in the chelate and (ii) macromolecular effect of the encapsulation. By the surface modification of apoferritin with dextran, in vivo blood clearance time of apoferritin could be prolonged. Magnetic resonance imaging of tumor-bearing mice showed that the apoferritin contrast agent accomplished tumor detection effectively as a bright signal as a result of the enhanced permeation and retention effect. Single-dose toxicity test showed no serious side effects. The apoferritin-encapsulated Gd is therefore a possible candidate for a new magnetic resonance imaging contrast agent.

Simulation for Improvement of System Sensitivity of Radiochromic Film Dosimetry with Different Band-pass Filters and Scanner Light Intensities

Radiological Physics and Technology. Jul, 2011  |  Pubmed ID: 21409612

The delivered dose of high-energy photon beams is measured with radiochromic film. Previous studies sought to improve the system sensitivity of radiochromic film dosimetry by use of band-pass filters. However, band-pass filters reduce the scanning light intensity. To avoid a reduction of the signal-to-noise ratio, one must increase the scanner light intensity. Our purposes in this study were to develop an optical system model of GAFCHROMIC EBT2 radiochromic film dosimetry, and to estimate the system sensitivity characteristics by employing a combination of band-pass filters and scanner light intensities. The spectra of the scanner light source, band-pass filter, and irradiated EBT2 films were measured with a spectrometer. Meanwhile, the intensity of a light path from the scanner light source to the scanner detector was simulated. Then, the dose-response curves were computed with six simulated virtual band-pass filters of varying bandwidth. The simulated dose-response curves were in good agreement with the experimental values. The slope of the simulated dose-response curve was steeper when a filter of narrower bandwidth was used; however, at the same time, saturation was observed at a lower dose. For achieving the same dose response as was observed without a band-pass filter, it was necessary to increase the scanner light intensity. We proved that our proposed optical system model was valid, suggesting that a realistic simulation may be feasible with the proposed model. For improvement of the system sensitivity of radiochromic film dosimetry, it is necessary to select a well-balanced combination of band-pass filter and scanner light intensity.

Identification of Transcription Factor E3 (TFE3) As a Receptor-independent Activator of Gα16: Gene Regulation by Nuclear Gα Subunit and Its Activator

The Journal of Biological Chemistry. May, 2011  |  Pubmed ID: 21454667

Receptor-independent G-protein regulators provide diverse mechanisms for signal input to G-protein-based signaling systems, revealing unexpected functional roles for G-proteins. As part of a broader effort to identify disease-specific regulators for heterotrimeric G-proteins, we screened for such proteins in cardiac hypertrophy using a yeast-based functional screen of mammalian cDNAs as a discovery platform. We report the identification of three transcription factors belonging to the same family, transcription factor E3 (TFE3), microphthalmia-associated transcription factor, and transcription factor EB, as novel receptor-independent activators of G-protein signaling selective for Gα(16). TFE3 and Gα(16) were both up-regulated in cardiac hypertrophy initiated by transverse aortic constriction. In protein interaction studies in vitro, TFE3 formed a complex with Gα(16) but not with Gα(i3) or Gα(s). Although increased expression of TFE3 in heterologous systems had no influence on receptor-mediated Gα(16) signaling at the plasma membrane, TFE3 actually translocated Gα(16) to the nucleus, leading to the induction of claudin 14 expression, a key component of membrane structure in cardiomyocytes. The induction of claudin 14 was dependent on both the accumulation and activation of Gα(16) by TFE3 in the nucleus. These findings indicate that TFE3 and Gα(16) are up-regulated under pathologic conditions and are involved in a novel mechanism of transcriptional regulation via the relocalization and activation of Gα(16).

High-contrast Fluorescence Imaging of Tumors in Vivo Using Nanoparticles of Amphiphilic Brush-like Copolymers Produced by ROMP

Angewandte Chemie (International Ed. in English). Jul, 2011  |  Pubmed ID: 21656616

Positioning Accuracy of a New Image-guided Radiotherapy System

Medical Physics. May, 2011  |  Pubmed ID: 21776788

To evaluate the accuracy of the patient-positioning function of a newly developed image-guided radiotherapy system, the MHI-TM2000 (Mitsubishi Heavy Industries, Ltd., Japan).

Evaluation of [125I]IPOS As a Molecular Imaging Probe for Hypoxia-inducible Factor-1-active Regions in a Tumor: Comparison Among Single-photon Emission Computed Tomography/X-ray Computed Tomography Imaging, Autoradiography, and Immunohistochemistry

Cancer Science. Nov, 2011  |  Pubmed ID: 21824221

To image hypoxia-inducible factor-1 (HIF-1)-active tumors, we previously developed a chimeric protein probe ([(123/125) I]IPOS) that is degraded in the same manner as HIF-1α under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF-1. In vivo single-photon emission computed tomography (SPECT)/X-ray CT (CT) imaging, autoradiography, and double-fluorescent immunostaining for HIF-1α and pimonidazole (PIMO) were carried out 24 h after the injection of [(125) I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi-pinhole, high-resolution SPECT/CT imaging with [(125) I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [(125) I]IPOS in the tumors. Immunohistochemistry revealed that the HIF-1α-positive areas and PIMO-positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [(125) I]IPOS accumulation were positively and significantly correlated with the HIF-1α-positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [(125) I]IPOS-accumulated areas and HIF-1α-positive areas was significantly greater than that between the [(125) I]IPOS-accumulated areas and the PIMO-positive areas (P < 0.01). These findings indicate that [(125) I]IPOS accumulation reflects HIF-1 expression. Thus, [(123/125) I]IPOS can serve as a useful probe for the molecular imaging of HIF-1-active tumors.

A Consensus-based Guideline Defining Clinical Target Volume for Primary Disease in External Beam Radiotherapy for Intact Uterine Cervical Cancer

Japanese Journal of Clinical Oncology. Sep, 2011  |  Pubmed ID: 21875938

To develop a consensus-based guideline to define clinical target volume for primary disease (clinical target volume primary) in external beam radiotherapy for intact uterine cervical cancer.

Detailed Dosimetric Evaluation of Intensity-modulated Radiation Therapy Plans Created for Stage C Prostate Cancer Based on a Planning Protocol

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Sep, 2011  |  Pubmed ID: 21960356

BACKGROUND: Intensity-modulated radiation therapy (IMRT) has been employed as a precision radiation therapy with higher conformity to the target. Although clinical outcomes have been reported for many investigations, detailed treatment planning results have not been mentioned to date. The aim of this study was to evaluate the dose specifications of our IMRT treatment plans for locally advanced prostate cancer. METHODS: Seventy-seven clinically applied IMRT plans treated between September 2003 and December 2005, in which patients were irradiated with 78 Gy in the prone position, were retrospectively analyzed. Dosimetric data output from dose volume histograms were evaluated in detail. RESULTS: The mean dose ± standard deviation, homogeneity index, and conformity index to the planning target volume (PTV) were 78.3 ± 0.7 Gy (100.4 ± 0.9%), 13.7 ± 3.0, and 0.83 ± 0.04, respectively. For the clinical target volume, the mean dose was 80.3 ± 0.7 Gy (102.9 ± 0.9%).The V40, V60, and V70 Gy of the rectal wall were 58.3 ± 2.8, 29.6 ± 2.7, and 15.2 ± 3.0%, respectively. Planning difficulties were encountered in patients whose bowels were displaced downward, as constraints imposed by the bowel position altered the dose index of the PTV. In many cases, additional bowel optimization parameters were required to satisfy constraints for organs at risk. However, major deviation could be avoided by inverse planning with computer optimization. CONCLUSION: IMRT allowed the creation of acceptable and practical treatment plans for locally advanced prostate cancer. Reports regarding detailed dosimetric evaluations are mandatory for interpreting clinical outcomes in the future.

Long-term Outcomes of Three-dimensional Conformal Radiation Therapy Combined with Neoadjuvant Hormonal Therapy for Japanese Patients with T1c-T2N0M0 Prostate Cancer

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Oct, 2011  |  Pubmed ID: 21968911

BACKGROUND: The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with T1c-T2N0M0 prostate cancer, with initiation of salvage hormonal therapy (SHT) at a relatively early phase, were analyzed. METHODS: Fifty-nine Japanese patients with T1c-T2N0M0 prostate cancer who received radical 3D-CRT between January 1999 and January 2003 were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were: 72 years, 9.4 ng/ml, and 6 months, respectively. Seventy Gy was given in 35 fractions confined to the prostate ± seminal vesicles. AHT was not administered after 3D-CRT in any patients. RESULTS: The median follow-up period was 89 months. The median PSA value at the time of initiation of SHT was 4.7 ng/ml (range 0.1-21.6 ng/ml). The overall, disease-specific, PSA failure-free (based on the Phoenix definition), and SHT-free survival rates at 8 years were 82.8% (95% confidence interval [CI] 72.4-93.2), 100%, 62.4% (47.1-77.8), and 82.6% (71.3-94.0), respectively. Only one patient developed grade 3 late toxicity. CONCLUSIONS: The PSA control rates in our series of Japanese patients with stage T1c-T2N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed at least comparable to those reported from Western countries; as well, the patients had excellent outcomes. The present outcomes can be used as basic data for evaluating the impact of dose escalation with intensity-modulated radiation therapy for Japanese patients with prostate cancer in the future.

JCOG Radiation Therapy Study Group: History and Achievements

Japanese Journal of Clinical Oncology. Nov, 2011  |  Pubmed ID: 21980050

The Radiation Therapy Study Group (RTSG) of the Japan Clinical Oncology Group (JCOG) was established in 2003. The missions of this group are to develop new standards of care with innovative, advanced technology radiation therapy, both for single- and multi-modality cancer treatment, and to improve radiation therapy quality and outcomes of JCOG trials conducted by other organ-oriented groups. In 2004, the first RTSG trial, a Phase II study of stereotactic body radiation therapy for Stage IA non-small cell lung cancer (JCOG 0403), was initiated. Four other trials are currently open for accrual. JCOG 0702 is a Phase I study of stereotactic body radiation therapy in patients with T2N0M0 non-small cell lung cancer. JCOG 0701 is a Phase III study comparing accelerated fractionation with conventional fractionation radiation therapy for T1-2N0M0 glottic cancer. JCOG 0906 is a multicenter safety trial of hypofractionated radiation therapy after breast-conserving surgery in patients with margin-negative invasive breast cancer. JCOG 1015 is a Phase II study of intensity-modulated radiation therapy with chemotherapy for loco-regionally advanced nasopharyngeal cancer. Other RTSG activities include a medical physics working group responsible for dosimetry audits; a genetic analysis working group involved in accompanying research to analyze single-nucleotide polymorphisms to identify predictors of radiation toxicities; a working group that has developed atlases of clinical target volumes for uterine cervical cancer; and participation in the Harmonisation Group to promote global harmonization of radiotherapy and radiotherapy quality assurance among trial groups. Further efforts to improve radiation therapy quality and outcomes of cancer treatment are necessary.

Influence of Side Chain Length on Fluorescence Intensity of ROMP-based Polymeric Nanoparticles and Their Tumor Specificity in In-vivo Tumor Imaging

Small (Weinheim an Der Bergstrasse, Germany). Dec, 2011  |  Pubmed ID: 22038685

In this study, amphiphilic brush-like copolymers conjugated with short alkyl or long polymeric chains of various lengths are synthesized using ring-opening metathesis polymerization (ROMP) of substituted norbornadiene monomers followed by chemical transformations. These amphiphilic copolymers form spherical self-assemblies in aqueous media with diameters of 132-244 nm. The low critical aggregation concentration of these assemblies (2.5 × 10(-3) -1.4 × 10(-5) g/L) indicates that they are quite stable in dilute conditions. An appropriate length of polymer side chain that conjugates the polymer backbone with a hydrophobic ICG (indocyanine green) moiety enhanced the fluorescence intensities of these self-assemblies in aqueous solution as well as in tumor-bearing mice. A longer side chain conjugated with tumor targeting agents could significantly affect the tumor specificity of self-assemblies to a greater extent. The self-assemblies bearing hydrophilic tumor targeting agents, such as a glucosamine molecule and a cyclic RGD (arginine-glycine-asparatic acid) peptide, accumulated in tumor tissues with high selectivity, while those having a hydrophobic targeting agent, such as folate moieties, accumulated in tumor sites with low selectivity. The results demonstrated here unambiguously indicate that the fluorescence intensity and tumor specificity of self-assemblies are strongly affected by the length of side chains that conjugate with dyes and targeting agents.

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-inducible Transcription Factor-based in Vivo Bioluminescence Imaging

PloS One. 2011  |  Pubmed ID: 22102864

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.

Stereotactic Body Radiotherapy (SBRT) for Operable Stage I Non-small-cell Lung Cancer: Can SBRT Be Comparable to Surgery?

International Journal of Radiation Oncology, Biology, Physics. Dec, 2011  |  Pubmed ID: 20638194

To review treatment outcomes for stereotactic body radiotherapy (SBRT) in medically operable patients with Stage I non-small-cell lung cancer (NSCLC), using a Japanese multi-institutional database.

Interfractional Dose Variations in Intensity-Modulated Radiotherapy With Breath-Hold for Pancreatic Cancer

International Journal of Radiation Oncology, Biology, Physics. Apr, 2011  |  Pubmed ID: 21477941

PURPOSE: To investigate the interfractional dose variations for intensity-modulated radiotherapy (RT) combined with breath-hold (BH) at end-exhalation (EE) for pancreatic cancer. METHODS AND MATERIALS: A total of 10 consecutive patients with pancreatic cancer were enrolled. Each patient was fixed in the supine position on an individualized vacuum pillow with both arms raised. Computed tomography (CT) scans were performed before RT, and three additional scans were performed during the course of chemoradiotherapy using a conventional RT technique. The CT data were acquired under EE-BH conditions (BH-CT) using a visual feedback technique. The intensity-modulated RT plan, which used five 15-MV coplanar ports, was designed on the initial BH-CT set with a prescription dose of 39 Gy at 2.6 Gy/fraction. After rigid image registration between the initial and subsequent BH-CT scans, the dose distributions were recalculated on the subsequent BH-CT images under the same conditions as in planning. Changes in the dose-volume metrics of the gross tumor volume (GTV), clinical target volume (CTV = GTV + 5 mm), stomach, and duodenum were evaluated. RESULTS: For the GTV and clinical target volume (CTV), the 95th percentile of the interfractional variations in the maximal dose, mean dose, dose covering 95% volume of the region of structure, and percentage of the volume covered by the 90% isodose line were within ±3%. Although the volume covered by the 39 Gy isodose line for the stomach and duodenum did not exceed 0.1 mL at planning, the volume covered by the 39 Gy isodose line for these structures was up to 11.4 cm(3) and 1.8 cm(3), respectively. CONCLUSIONS: Despite variations in the gastrointestinal state and abdominal wall position at EE, the GTV and CTV were mostly ensured at the planned dose, with the exception of 1 patient. Compared with the duodenum, large variations in the stomach volume receiving high-dose radiation were observed, which might be beyond the negligible range in achieving dose escalation with intensity-modulated RT combined with BH at EE.

Interfractional Reproducibility in Pancreatic Position Based on Four-dimensional Computed Tomography

International Journal of Radiation Oncology, Biology, Physics. Aug, 2011  |  Pubmed ID: 21493016

To assess the interfractional positional variation of the pancreas using four-dimensional computed tomography (4D-CT) and to determine the suitable phase of respiration for dose delivery methods to account for pancreatic tumor motion.

Delayed Initial Radioactive Iodine Therapy Resulted in Poor Survival in Patients with Metastatic Differentiated Thyroid Carcinoma: a Retrospective Statistical Analysis of 198 Cases

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. May, 2011  |  Pubmed ID: 21498534

To elucidate the prognostic role of (131)I radioactive iodine therapy (RIT), we conducted a retrospective cohort study analyzing the clinical factors that affect survival of postoperative patients with differentiated thyroid carcinoma (DTC).

[Current Situation and Perspectives of Radiation Oncology]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Jun, 2011  |  Pubmed ID: 22208011

Dosimetric Investigation of Breath-hold Intensity-modulated Radiotherapy for Pancreatic Cancer

Medical Physics. Jan, 2012  |  Pubmed ID: 22225274

Purpose: To experimentally investigate the effects of variations in respiratory motion during breath-holding (BH) at end-exhalation (EE) on intensity-modulated radiotherapy (BH-IMRT) dose distribution using a motor-driven base, films, and an ionization chamber.Methods: Measurements were performed on a linear accelerator, which has a 120-leaf independently moving multileaf collimator with 5-mm leaf width at the isocenter for the 20-cm central field. Polystyrene phantoms with dimensions of 40 × 40 × 10 cm were set on a motor-driven base. All gantry angles of seven IMRT plans (a total of 35 fields) were changed to zero, and doses were then delivered to a film placed at a depth of 4 cm and an ionization chamber at a depth of 5 cm in the phantom with a dose rate of 600 MU/min under the following conditions: pulsation from the abdominal aorta and baseline drift with speeds of 0.2 mm/s (BD(0.2mm/s)) and 0.4 mm/s (BD(0.4mm/s)). As a reference for comparison, doses were also delivered to the chamber and film under stationary conditions.Results: In chamber measurements, means ± standard deviations of the dose deviations between stationary and moving conditions were -0.52% ± 1.03% (range: -3.41-1.05%), -0.07% ± 1.21% (range: -1.88-4.31%), and 0.03% ± 1.70% (range: -2.70-6.41%) for pulsation, BD(0.2mm/s), and BD(0.4mm/s), respectively. The γ passing rate ranged from 99.5% to 100.0%, even with the criterion of 2%/1 mm for pulsation pattern. In the case of BD(0.4mm/s), the γ passing rate for four of 35 fields (11.4%) did not reach 90% with a criterion of 3%/3 mm. The differences in γ passing rate between BD(0.2mm/s) and BD(0.4mm/s) were statistically significant for each criterion. Taking γ passing rates of > 90% as acceptable with a criterion of 3%/3 mm, large differences were observed in the γ passing rate between the baseline drift of ≤5 mm and that of >5 mm (minimum γ passing rate: 92.0% vs 82.7%; p < 0.01).Conclusions: This study suggested that the baseline drift of >5 mm should be avoided in the BH-IMRT.

Preliminary Report of Late Recurrences, at 5 Years or More, After Stereotactic Body Radiation Therapy for Non-small Cell Lung Cancer

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. Feb, 2012  |  Pubmed ID: 22252562

: Long-term outcomes remain unknown after stereotactic body radiation therapy (SBRT). We observed a few patients who developed disease progression late, at 5 years or more, after SBRT. In this report, we describe the characteristics of those patients with late recurrence after SBRT.

Dosimetric Advantage of Intensity-modulated Radiotherapy for Whole Ventricles in the Treatment of Localized Intracranial Germinoma

International Journal of Radiation Oncology, Biology, Physics. Feb, 2012  |  Pubmed ID: 21640515

To investigate the dosimetric advantage of intensity-modulated radiotherapy (IMRT) for whole ventricles (WV) in patients with a localized intracranial germinoma receiving induction chemotherapy.

Experimental Validation of Heterogeneity-corrected Dose-volume Prescription on Respiratory-averaged CT Images in Stereotactic Body Radiotherapy for Moving Tumors

Medical Dosimetry : Official Journal of the American Association of Medical Dosimetrists. 2012  |  Pubmed ID: 21497502

The purpose of this study was to experimentally assess the validity of heterogeneity-corrected dose-volume prescription on respiratory-averaged computed tomography (RACT) images in stereotactic body radiotherapy (SBRT) for moving tumors. Four-dimensional computed tomography (CT) data were acquired while a dynamic anthropomorphic thorax phantom with a solitary target moved. Motion pattern was based on cos(6) (t) with a constant respiration period of 4.0 sec along the longitudinal axis of the CT couch. The extent of motion (A(1)) was set in the range of 0.0-12.0 mm at 3.0-mm intervals. Treatment planning with the heterogeneity-corrected dose-volume prescription was designed on RACT images. A new commercially available Monte Carlo algorithm of well-commissioned 6-MV photon beam was used for dose calculation. Dosimetric effects of intrafractional tumor motion were then investigated experimentally under the same conditions as 4D CT simulation using the dynamic anthropomorphic thorax phantom, films, and an ionization chamber. The passing rate of γ index was 98.18%, with the criteria of 3 mm/3%. The dose error between the planned and the measured isocenter dose in moving condition was within ± 0.7%. From the dose area histograms on the film, the mean ± standard deviation of the dose covering 100% of the cross section of the target was 102.32 ± 1.20% (range, 100.59-103.49%). By contrast, the irradiated areas receiving more than 95% dose for A(1) = 12 mm were 1.46 and 1.33 times larger than those for A(1) = 0 mm in the coronal and sagittal planes, respectively. This phantom study demonstrated that the cross section of the target received 100% dose under moving conditions in both the coronal and sagittal planes, suggesting that the heterogeneity-corrected dose-volume prescription on RACT images is acceptable in SBRT for moving tumors.

Trends in Local Therapy Application for Early Breast Cancer Patients in the Japanese Breast Cancer Society Breast Cancer Registry During 2004-2009

Breast Cancer (Tokyo, Japan). Jan, 2012  |  Pubmed ID: 22124993

Prospective Multi-institutional Study of Definitive Radiotherapy with High-dose-rate Intracavitary Brachytherapy in Patients with Nonbulky (<4-cm) Stage I and II Uterine Cervical Cancer (JAROG0401/JROSG04-2)

International Journal of Radiation Oncology, Biology, Physics. Jan, 2012  |  Pubmed ID: 21470794

To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study.