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Find video protocols related to scientific articles indexed in Pubmed.
Robotic System for MRI-Guided Stereotactic Neurosurgery.
IEEE Trans Biomed Eng
PUBLISHED: 11-07-2014
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Stereotaxy is a neurosurgical technique that can take several hours to reach a specific target, typically utilizing a mechanical frame and guided by preoperative imaging. An error in any one of the numerous steps or deviations of the target anatomy from the preoperative plan such as brain shift (up to 20 mm), may affect the targeting accuracy and thus the treatment effectiveness. Moreover, because the procedure is typically performed through a small burr hole opening in the skull that prevents tissue visualization, the intervention is basically "blind" for the operator with limited means of intraoperative confirmation that may result in reduced accuracy and safety. The presented system is intended to address the clinical needs for enhanced efficiency, accuracy, and safety of image-guided stereotactic neurosurgery for Deep Brain Stimulation (DBS) lead placement. The work describes a magnetic resonance imaging (MRI)-guided, robotically actuated stereotactic neural intervention system for deep brain stimulation procedure, which offers the potential of reducing procedure duration while improving targeting accuracy and enhancing safety. This is achieved through simultaneous robotic manipulation of the instrument and interactively updated in situ MRI guidance that enables visualization of the anatomy and interventional instrument. During simultaneous actuation and imaging, the system has demonstrated less than 15% signalto- noise ratio (SNR) variation and less than 0:20% geometric distortion artifact without affecting the imaging usability to visualize and guide the procedure. Optical tracking and MRI phantom experiments streamline the clinical workflow of the prototype system, corroborating targeting accuracy with 3-axis root mean square error 1:38 0:45 mm in tip position and 2:03 0:58 in insertion angle.
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A Recombinant Modified Vaccinia Ankara Vaccine Encoding Epstein-Barr Virus (EBV) Target Antigens: A Phase I Trial in UK Patients with EBV-Positive Cancer.
Clin. Cancer Res.
PUBLISHED: 08-14-2014
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Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
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Treatment-related dysgeusia in head and neck cancer patients.
Cancer Treat. Rev.
PUBLISHED: 05-21-2014
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Head and neck cancer patients treated with radiotherapy and/or chemotherapy agents may develop altered taste acuity. This, together with radiation induced xerostomia and dysphagia, is a major contributory factor to the anorexia and concomitant morbidity often seen in this group of patients. This paper examines the existing literature in order to assess the prevalence of clinician and patient-reported dysgeusia in HNC patients undergoing oncological treatment. We also describe the temporal manifestations of the same and its reported impact on QOL.
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The Profile of Tumor Antigens Which Can be Targeted by Immunotherapy Depends Upon the Tumor's Anatomical Site.
Mol. Ther.
PUBLISHED: 05-13-2014
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Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens-VSV-HIF-2?+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1-from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2?(Hi), SOX-10(Hi), c-myc(Hi), TYRP1, N-RAS(lo)Cytc(lo) antigen profile, which differed significantly from the HIF-2?(lo), SOX-10(lo), c-myc(lo), TYRP1, N-RAS(Hi)Cytc(Hi) phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b(+) cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses.
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Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.
Int. J. Cancer
PUBLISHED: 05-08-2014
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Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-?) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-?, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-?/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-?/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.
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Final long-term results of a phase I/II study of dose-escalated intensity-modulated radiotherapy for locally advanced laryngo-hypopharyngeal cancers.
Oral Oncol.
PUBLISHED: 05-03-2014
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We previously described dose-escalated intensity-modulated radiotherapy (IMRT) in squamous cell cancer of the larynx/hypopharynx (SCCL/H) to offer improved locoregional control with a low incidence of toxicity at 2years. We now present outcome and safety data at 5years.
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Multiple cervical lymph node involvement and extra-capsular extension predict for contralateral nodal recurrence after ipsilateral radiotherapy for squamous cell carcinoma of the tonsil.
Oral Oncol.
PUBLISHED: 04-23-2014
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Ipsilateral radiotherapy is an established technique for treating well-lateralised tonsillar tumours. Concerns exist regarding the risk of contralateral nodal failure, particularly in patients with ipsilateral nodal involvement at presentation. In this study, we retrospectively reviewed the clinical outcomes of patients treated with ipsilateral radiotherapy aiming to identify factors that predispose to a higher risk of contralateral nodal recurrence.
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Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus.
Mol. Ther.
PUBLISHED: 02-06-2014
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Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells--but not from plasma--suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b(+) cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.
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Targeting HOX transcription factors in prostate cancer.
BMC Urol
PUBLISHED: 01-30-2014
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The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function.
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Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence.
Nat. Med.
PUBLISHED: 07-17-2013
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Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
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Live viruses to treat cancer.
J R Soc Med
PUBLISHED: 07-03-2013
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Viruses that selectively replicate in cancer cells, leading to the death of the cell, are being studied for their potential as cancer therapies. Some of these viruses are naturally occurring but cause little if any illness in humans; others have been engineered to make them specifically able to kill cancer cells while sparing normal cells. These oncolytic viruses may be selective for cancer cells because viral receptors are over-expressed on the surface of cancer cells or because antiviral pathways are distorted in cancer cells. Additionally, when oncolytic viruses kill cancer cells, it can stimulate an antitumour immune response from the host that can enhance efficacy. Numerous early phase trials of at least six oncolytic viruses have been reported with no evidence of concerning toxicity either as single agents or in combination with chemotherapies and radiotherapy. Three oncolytic viruses have reached randomized testing in cancer patients; reolysin in head and neck cancer and JX594 in hepatocellular cancers, while results from the first-phase III trial of T-vec in metastatic melanoma are expected shortly.
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Thymoma and radiation therapy: a systematic review of medical treatment.
Expert Rev Anticancer Ther
PUBLISHED: 06-19-2013
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Thymoma is the most common tumor in the anterior mediastinum (50% in adults). This review presents an update of thymoma treatment, commonly based on the Masaoka clinical staging system. The best treatment option is complete resection with no adjuvant approach in early stages and complete response. For incomplete resection, postoperative radiotherapy is recommended (5-year survival: 50-60%). For unresectable disease, concurrent chemoradiotherapy is performed. In conclusion, high technology (3D radiotherapy, 4D radiotherapy, intensity-modulated radiotherapy, image-guided radiotherapy and computed tomography fusion with PET scan) optimizes tumor target definition and provides dose escalation.
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Radiation-induced carotid artery atherosclerosis.
Radiother Oncol
PUBLISHED: 06-05-2013
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Carotid arteries frequently receive significant doses of radiation as collateral structures in the treatment of malignant diseases. Vascular injury following treatment may result in carotid artery stenosis (CAS) and increased risk of stroke and transient ischaemic attack (TIA). This systematic review examines the effect of radiotherapy (RT) on the carotid arteries, looking at the incidence of stroke in patients receiving neck radiotherapy. In addition, we consider possible surrogate endpoints such as CAS and carotid intima-medial thickness (CIMT) and summarise the evidence for radiation-induced carotid atherosclerosis.
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Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition.
Radiother Oncol
PUBLISHED: 05-26-2013
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We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models.
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Multimodal treatment strategies for elderly patients with head and neck cancer.
Cancer Treat. Rev.
PUBLISHED: 05-12-2013
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The population in developed countries is growing older and the number of elderly people annually diagnosed with head and neck cancers is expected to rapidly increase within the following decades, since these types of tumors are age-dependent. The vast majority of older head and neck cancer patients present with locally advanced disease and multimodality treatment, including surgery, radiation and/or chemotherapy, is considered the best therapeutic option for these patients. However, several factors, including comorbidities, disabilities, frailty, and impaired functional status are considered to be more relevant criteria than chronological age per se for treatment planning. Therapeutic decisions are often complicated and demand the participation of many specialists. Advances in surgical and radiation techniques, along with the use of conventional chemotherapy and molecularly targeted agents, have improved treatment outcomes. The best-tailored individualized therapeutic option should be selected for these patients in order to avoid high toxicity and major functional deterioration. Still, more older-specific studies are needed in order to produce more definitive and applicable results. The aim of this review article is to investigate the multimodal treatment approaches for elderly patients with head and neck cancer.
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Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts.
Nat. Cell Biol.
PUBLISHED: 04-12-2013
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To learn more about cancer-associated fibroblasts (CAFs), we have isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffening, cancer cell invasion and angiogenesis. Remodelling of the ECM and promotion of cancer cell invasion requires the actomyosin cytoskeleton. YAP regulates the expression of several cytoskeletal regulators, including ANLN and DIAPH3, and controls the protein levels of MYL9 (also known as MLC2). Matrix stiffening further enhances YAP activation, thus establishing a feed-forward self-reinforcing loop that helps to maintain the CAF phenotype. Actomyosin contractility and Src function are required for YAP activation by stiff matrices. Further, transient ROCK inhibition is able to disrupt the feed-forward loop, leading to a long-lasting reversion of the CAF phenotype.
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Oncolytic virotherapy needs trials, not access programs.
Clin. Cancer Res.
PUBLISHED: 04-02-2013
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Oncolytic virotherapy is a novel treatment for cancer that exerts direct lytic and indirect immune-mediated antitumor effects. A Finnish research team has reported on an advanced therapy access program for oncolytic adenovirus. The strengths and weaknesses of this approach are highlighted with a view to informing future study conduct.
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Long-term outcomes following low-dose radioiodide ablation for differentiated thyroid cancer.
J. Clin. Endocrinol. Metab.
PUBLISHED: 03-14-2013
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Randomized trials show that low-dose (1.1 GBq [30 mCi]) radioiodide (RAI) has efficacy equivalent to high-dose RAI (3.7 GBq [100 mCi]) in thyroid remnant ablation (TRA) for differentiated thyroid cancer. Long-term follow-up is required to ensure detection of late recurrences and to confirm equivalence in terms of survival end points. However, median follow-up duration within randomized trials is currently limited.
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Fatigue during chemoradiotherapy for nasopharyngeal cancer and its relationship to radiation dose distribution in the brain.
Radiother Oncol
PUBLISHED: 03-11-2013
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Fatigue during head and neck radiotherapy may be related to radiation dose to the central nervous system (CNS). The impact of patient, tumour, and dosimetric variables on acute fatigue was assessed in nasopharyngeal cancer patients undergoing chemoradiotherapy.
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Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse.
Mol. Ther.
PUBLISHED: 03-01-2013
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Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-II? (TOPO-II?) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-II? compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.
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The effect of concomitant chemotherapy on parotid gland function following head and neck IMRT.
Radiother Oncol
PUBLISHED: 02-17-2013
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To determine whether concomitant chemotherapy increases the incidence of high grade xerostomia following parotid-sparing intensity-modulated radiotherapy (IMRT) in patients with locally advanced head and neck squamous cell cancer.
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Dose-response analysis of parotid gland function: what is the best measure of xerostomia?
Radiother Oncol
PUBLISHED: 02-12-2013
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To describe the dose-response relationships for the different measures of salivary gland recovery following radical radiotherapy for locally advanced head and neck squamous cell cancers (LA-HNSCC).
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Key molecular mechanisms in lung cancer invasion and metastasis: a comprehensive review.
Crit. Rev. Oncol. Hematol.
PUBLISHED: 01-16-2013
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Lung cancer remains one of the most common and malignant cancers worldwide. It is most often diagnosed at late stages, when it has already presented local invasion and distal metastases. The basic stages of invasion and metastasis involve the detachment of tumor cells from the extracellular matrix, invasion of surrounding tissues and basal lamina, intravasation into the blood stream, survival and transport through the blood stream, migration, arrest and extravasation at a distal site and formation of a metastatic lesion. These steps require fundamental mechanisms such as angiogenesis, degradation of matrix barriers, disruption of cell-cell and cell-matrix adhesion and inducement of cellular motility. Genes that regulate functions like unlimited growth potential, survival, genomic instability, angiogenesis, epithelial to mesenchymal transition and apoptosis evasion, are involved in giving lung cancer tumors invasive and metastatic competence. Improving of understanding of the underlying molecular and cellular mechanisms remains an urgent and essential issue, in order to develop new more effective strategies in preventing and treating lung cancer.
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A novel serum protein signature associated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors in head and neck squamous cell carcinoma.
Eur. J. Cancer
PUBLISHED: 01-15-2013
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BACKGROUND: Acquired resistance to tyrosine kinase inhibitors (TKIs) is becoming a major challenge in the treatment of many cancers. Epidermal growth factor receptor (EGFR) is overexpressed in squamous carcinomas, notably those of the head and neck (HNSCC), and can be targeted with several TKIs. We aimed to identify soluble proteins suitable for development as markers of EGFR TKI resistance in cancer patients to aid in early and minimally invasive assessment of therapeutic responses. METHODS: Resistant HNSCC cell lines were generated by exposure to an EGFR TKI, gefitinib, in vitro. Cell lines were characterised for their biological behaviour in vitro (using growth inhibition assays, flow cytometry, western blots, antibody arrays and/or immunoassays) and in vivo (using subcutaneous tumour xenografts). Sera from EGFR-treated and -untreated HNSCC patients were analysed by immunoassay. RESULTS: Two independent sublines of CAL 27 and a PJ34 subline with acquired resistance to EGFR TKIs (gefitinib, erlotinib and afatinib) were developed. Resistant cells grew as highly aggressive xenografts leading to reduced host survival rates compared with EGFR-TKI sensitive cells. This suggested a link between resistance in vitro and poor prognosis in vivo. A significant upregulation of proteins linked to tumour angiogenesis and invasion was identified in resistant cells. This resistance-associated protein signature (RAPS) was detected in the sera of a small cohort of HNSCC patients and was associated with reduced survival. CONCLUSION: We have identified a protein signature associated with EGFR-TKI resistance that may also be linked to poor prognosis and warrants further investigation as a potential clinical biomarker.
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Assessment and management of dysphagia in patients with head and neck cancer who receive radiotherapy in the United Kingdom - a web-based survey.
Oral Oncol.
PUBLISHED: 09-20-2011
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We undertook a service evaluation to establish how oropharyngeal dysphagia is managed in head and neck cancer patients receiving radiotherapy in the United Kingdom. A web-based survey including 23 open and closed questions was distributed to Speech and Language Therapy (SLT) teams via a national network of Royal College of Speech and Language Therapists (RCSLT) special interest groups with members involved in head and neck cancer care. Forty-six teams responded to the survey and 89% completed the questionnaire fully. Fifty percent (n=21/42) of the SLT teams reported routinely seeing patients prior to commencing radiotherapy. Baseline oromotor assessment (85.7% (n=36/42)), clinical dysphagia assessment (90.5% (n=38/42)) and information provision on the potential treatment effects on swallowing (97.6% (n=41/42)) and communication ability (85.7% (n=36/42)) were the most common components of initial evaluation. In keeping with expert opinion and emerging evidence, prophylactic swallowing exercises were administered by 71.4% (n=30/42) of teams targeting specific aspects of swallowing, although the nature, intensity and duration of programmes varied. A range of measures are used to monitor progress during treatment. Our survey highlighted that resource limitations affect service provision with some teams managing the consequences of treatment rather than proactive multidisciplinary intervention prior to and during treatment. Cancer- and treatment-related dysphagia can impact significantly on a broad range of outcomes following radiotherapy. There is variability in dysphagia service provision to patients before, during and following treatment. Comprehensive evaluation of swallowing function prior to treatment and proactive management can yield benefits for patients, inform multidisciplinary case management and support those involved in clinical trials to accurately determine treatment effects.
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An affordable compact humanoid robot for Autism Spectrum Disorder interventions in children.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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Autism Spectrum Disorder impacts an ever-increasing number of children. The disorder is marked by social functioning that is characterized by impairment in the use of nonverbal behaviors, failure to develop appropriate peer relationships and lack of social and emotional exchanges. Providing early intervention through the modality of play therapy has been effective in improving behavioral and social outcomes for children with autism. Interacting with humanoid robots that provide simple emotional response and interaction has been shown to improve the communication skills of autistic children. In particular, early intervention and continuous care provide significantly better outcomes. Currently, there are no robots capable of meeting these requirements that are both low-cost and available to families of autistic children for in-home use. This paper proposes the piloting the use of robotics as an improved diagnostic and early intervention tool for autistic children that is affordable, non-threatening, durable, and capable of interacting with an autistic child. This robot has the ability to track the child with its 3 degree of freedom (DOF) eyes and 3-DOF head, open and close its 1-DOF beak and 1-DOF each eyelids, raise its 1-DOF each wings, play sound, and record sound. These attributes will give it the ability to be used for the diagnosis and treatment of autism. As part of this project, the robot and the electronic and control software have been developed, and integrating semi-autonomous interaction, teleoperation from a remote healthcare provider and initiating trials with children in a local clinic are in progress.
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Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy.
Mol. Ther.
PUBLISHED: 07-26-2011
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We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses.
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Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer.
BMC Cancer
PUBLISHED: 06-06-2011
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Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication.
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The use of molecular imaging of gene expression by radiotracers in gene therapy.
Expert Opin Biol Ther
PUBLISHED: 06-02-2011
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Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments.
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Bevacizumab-induced hypertension: pathogenesis and management.
BioDrugs
PUBLISHED: 06-02-2011
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Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.
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Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population.
Eur. J. Endocrinol.
PUBLISHED: 05-12-2011
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To evaluate the tolerability and efficacy of sorafenib in patients with thyroid carcinoma.
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Oncolytic viruses in radiation oncology.
Radiother Oncol
PUBLISHED: 05-09-2011
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Oncolytic viruses are investigational cancer treatments. They are currently being assessed as single agents or in combination with standard therapies such as external beam radiotherapy - a DNA damaging agent that is a standard of care for many tumour types. Preclinical data indicate that combinations of oncolytic viruses and radiation therapy are promising, showing additional or synergistic antitumour effects in in vitro and in vivo studies. This interaction has the potential to be multifaceted: viruses may act as radiosensitizing agents, but radiation may also enhance viral oncolysis by increasing viral uptake, replication, gene expression and cell death (apoptosis, autophagy or necrosis) in irradiated cells. Phase I and II clinical trials investigating combinations of viruses and radiation therapy have been completed, paving the way for ongoing phase III studies. The aim of this review is to focus on the therapeutic potential of these combinations and to highlight their mechanistic bases, with particular emphasis on the role of the DNA damage response.
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Evaluation of factors affecting post-treatment quality of life in oral and oropharyngeal cancer patients primarily treated with curative surgery: an exploratory study.
Eur Arch Otorhinolaryngol
PUBLISHED: 04-19-2011
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The aim was to explore the impact of important clinico-demographic factors on the post-treatment quality of life (QOL) in surgically treated oral and oropharyngeal cancer patients. 63 consecutive follow-up oral and oropharyngeal cancer patients treated primarily with surgery were recruited. 55 patients sent the completed questionnaires and finally included in this study. QOL and important sub-domains of the QOL were assessed. Mean QOL scores (SD) were computed, level of significance was set at P < 0.05. The mean composite QOL score and standard deviation (SD) for oral and oropharyngeal cancer patients were 76.6 (15.2) and 73.4 (13.9), respectively. Patients with higher T-stage (T3 and T4) and higher overall-stage (III and IV) had lower mean QOL scores as against early T (T1 and T2) and overall early-stage (I and II); mean scores (SD) 64.3 (13.6) and 72.3 (13.8), and 76.6 (13.6) and 81.7 (14.1), respectively. Younger patients had lower mean scores (SD) than older patients; mean QOL scores (SD) 69.7 (14.0) and 79.6 (SD), respectively. Patients with reconstruction had lower mean QOL scores as compared to those without reconstruction; mean scores (SD) 67.6 (16.0) and 77.4 (12.5), respectively. In conclusion, tumor-stage, overall-stage, age of patients, and reconstruction had a significant direct effect on the post-treatment QOL of oral and oropharyngeal cancer patients.
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An exploratory study of the influence of clinico-demographic variables on swallowing and swallowing-related quality of life in a cohort of oral and oropharyngeal cancer patients treated with primary surgery.
Eur Arch Otorhinolaryngol
PUBLISHED: 04-16-2011
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There are insufficient data on swallowing and the consequences of its dysfunction in patients with cancers of the oral cavity (OC) and oropharynx (OP) that are treated with primary surgery. The study attempts to explore the effect of important clinico-demographic variables on post-treatment swallowing and related quality of life (QOL) in post-surgical OC and OP cancer patients. Sixty-two consecutive OC and OP cancer patients completed the MD Anderson Dysphagia Inventory (MDADI) questionnaire. Mean scores were computed. Comparison of scores based on mean ranks were performed using Mann-Whitney U test or Kruskal-Wallis test. Level of significance was set at P ? 0.02. Adjustments were made for multiple comparisons. Significantly worse mean (SD) QOL scores were observed in late T-stage (T3/T4) versus early T-stage (T1/T2) patients for global domain, physical domain, functional domain and emotional domains [44.4 (21.9) vs. 78.7 (22.7) (P < 0.001); 50.0 (9.4) vs. 75.9 (16.3), (P < 0.0001); 57.8 (20.6) vs. 84.1 (16.7), (P < 0.001) and 55.2 (18.0) vs. 78.5 (16.3), (P < 0.001)], respectively. Patients undergoing reconstruction versus without reconstruction had worse QOL scores; 58.8 (26.9) versus 79.5 (22.8), (P < 0.01); 61.2 (15.1) versus 76.4 (17.5), (P = 0.002); 65.4 (20.5) versus 86.3 (15.9), (P < 0.0001) and 63.3 (18.8) versus 79.8 (16.3), (P < 0.01), respectively, for global, physical, functional and emotional domains. Advanced T-stage, reconstruction, younger age and base of tongue tumours have a negative impact on post-treatment swallow function and related QOL in these patients.
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Development and validation of first-ever speech-specific perceptual speech evaluation tool for patients with head and neck cancer: the London speech evaluation (LSE) scale.
Head Neck
PUBLISHED: 04-05-2011
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The aim of this study was to develop and validate the first ever speech-specific perceptual speech-evaluation tool for patients with head and neck cancer.
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Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization.
Clin. Cancer Res.
PUBLISHED: 03-09-2011
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Dendritic cells (DC) may be the most effective way of delivering oncolytic viruses to patients. Reovirus, a naturally occurring oncolytic virus, is currently undergoing early clinical trials; however, intravenous delivery of the virus is hampered by pre-existing antiviral immunity. Systemic delivery via cell carriage is a novel approach currently under investigation and initial studies have indicated its feasibility by using a variety of cell types and viruses. This study addressed the efficacy of human DC to transport virus in the presence of human neutralizing serum.
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Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-?B mediated and supports innate and adaptive anti-tumour immune priming.
Mol. Cancer
PUBLISHED: 02-21-2011
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As well as inducing direct oncolysis, reovirus treatment of melanoma is associated with activation of innate and adaptive anti-tumour immune responses.
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Implications of understanding cancer stem cell (CSC) biology in head and neck squamous cell cancer.
Oral Oncol.
PUBLISHED: 02-05-2011
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Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of this disease. Efforts are ongoing throughout the world to improve early detection and prevention of HNSCCs. Often, treatment fails to obtain total cancer cure and this is more likely with advanced stage disease. In recent years it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells (CSC) that escape currently available therapies. CSCs form a minute portion of the total tumour burden but may play a disproportionately important role in determining outcomes. Molecular mechanisms which underlie the genesis of CSCs are yet not fully understood and their detection within the total tumour bulk remains a challenge. Specific markers like Aldehyde dehydrogenase 1 (ALDH1), CD44 and Bmi-1 have shown early promising results both in CSC detection and in guiding treatment protocols. CSCs have been shown to be relatively resistant to standard treatment modalities. It is hoped that developing robust in vitro and in vivo experimental models of CSCs might provide a means of devising more effective therapeutic strategies.
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Bronchial washing levels of vascular endothelial growth factor receptor-2 (VEGFR2) correlate with overall survival in NSCLC patients.
Cancer Lett.
PUBLISHED: 01-14-2011
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The aim of this study was to define pre-treatment VEGF, VEGFR1 and VEGFR2 levels in serum and bronchial washing samples of NSCLC patients in order to examine their correlation to survival. Forty patients with histologically confirmed NSCLC were enrolled. The results indicated that circulating VEGF was correlated to T-classification, as were the ratios of VEGF/VEGFR2 in serum and washing. Best chemotherapy response was observed at lower serum and washing VEGF concentrations. Higher VEGF levels in washing were associated with worse overall survival and progression-free survival. Similar were the results at high values of VEGF/VEGFR2 ratio in washing. Multivariate analysis revealed VEGFR2 levels in serum and washing as independent markers for overall survival. In conclusion, washing VEGFR2 levels are correlated to overall survival, whereas serum and washing VEGF levels are predictive of chemotherapy response. These could help recognize NSCLC patients who benefit from an aggressive therapeutic approach.
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Dose-escalated intensity-modulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 01-13-2011
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To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H).
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Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.
Lancet Oncol.
PUBLISHED: 01-12-2011
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Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia.
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From the bench to bedside: biological and methodology considerations for the future of companion diagnostics in nonsmall cell lung cancer.
Patholog Res Int
PUBLISHED: 01-11-2011
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Companion diagnostics are an emerging and exciting field in the care of oncology patients. These tests accompany standard diagnostic investigations in cancer patients and function as an aid in treatment decision making. A great number of new compounds are under clinical and laboratory testing in nonsmall cell lung cancer (NSCLC). As the variety of therapeutic options expands in the various settings of the disease, it becomes apparent that specific and sensitive molecular tests are necessary to define the subsets of patients who are going to derive clinical benefit. Testing for epidermal growth factor receptor (EGFR) somatic mutations for the appropriate administration of tyrosine kinase inhibitors is just the beginning. Anaplastic lymphoma kinase (ALK) fusion protein detection and molecular histology classification are promising candidate predictors for clinical benefit from crizotinib and pemetrexed, respectively. This paper summarizes such diagnostics and discusses unanswered questions concerning underlying biology and standardization issues.
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Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.
Nat. Med.
PUBLISHED: 01-04-2011
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Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.
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A Bayesian hierarchical model for DCE-MRI to evaluate treatment response in a phase II study in advanced squamous cell carcinoma of the head and neck.
MAGMA
PUBLISHED: 01-04-2011
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Pharmacokinetic parameters from dynamic contrast-enhanced MRI (DCE-MRI) were used to assess the perfusion effects due to treatment response using a tyrosine kinase inhibitor. A Bayesian hierarchical model (BHM) is proposed, as an alternative to voxel-wise estimation procedures, to test for a treatment effect while explicitly modeling known sources of variability.
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Cable-driven elastic parallel humanoid head with face tracking for Autism Spectrum Disorder interventions.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 11-25-2010
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This paper presents the development of new prismatic actuation approach and its application in human-safe humanoid head design. To reduce actuator output impedance and mitigate unexpected external shock, the prismatic actuation method uses cables to drive a piston with preloaded spring. By leveraging the advantages of parallel manipulator and cable-driven mechanism, the developed neck has a parallel manipulator embodiment with two cable-driven limbs embedded with preloaded springs and one passive limb. The eye mechanism is adapted for low-cost webcam with succinct "ball-in-socket" structure. Based on human head anatomy and biomimetics, the neck has 3 degree of freedom (DOF) motion: pan, tilt and one decoupled roll while each eye has independent pan and synchronous tilt motion (3 DOF eyes). A Kalman filter based face tracking algorithm is implemented to interact with the human. This neck and eye structure is translatable to other human-safe humanoid robots. The robots appearance reflects a non-threatening image of a penguin, which can be translated into a possible therapeutic intervention for children with Autism Spectrum Disorders.
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A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer.
Clin. Cancer Res.
PUBLISHED: 11-24-2010
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This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.
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Vesicular stomatitis virus-induced immune suppressor cells generate antagonism between intratumoral oncolytic virus and cyclophosphamide.
Mol. Ther.
PUBLISHED: 10-26-2010
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Despite having potent oncolytic activity, in vitro, direct intratumoral injection of oncolytic vesicular stomatitis virus (VSV) into established AE17ova mesothelioma tumors in C57Bl/6 mice had no therapeutic effect. During studies to combine systemic cyclophosphamide (CPA) with VSV to suppress the innate immune reaction against VSV, we observed that CPA alone had highly significant antitumor effects in this model. However, against our expectations, the combination of CPA and VSV consistently reduced therapeutic efficacy compared to CPA alone, despite the fact that the combination increased intratumoral VSV titers. We show here that CPA-mediated therapy against AE17ova tumors was immune-mediated and dependent upon both CD4 T cells and natural killer (NK) cells. However, intratumoral VSV induced a transforming growth factor-? (TGF-?)-dependent suppressive activity, mediated by CD11b(+)GR-1(+) cells that significantly inhibited both antigen-specific T-cell activation, and CPA-activated, NK-dependent killing of AE17ova tumor cells. Overall, our results show that treatment with oncolytic viruses can induce a variety of immune-mediated consequences in vivo with both positive, or negative, effects on antitumor therapy. These underexplored immune consequences of treatment with oncolytic viruses may have significant, and possibly unexpected, impacts on how virotherapy interacts in combination with other agents which modulate antitumor immune effectors.
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REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer.
Clin. Cancer Res.
PUBLISHED: 10-06-2010
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REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer.
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The effect of cell cycle synchronization on tumor sensitivity to reovirus oncolysis.
Mol. Ther.
PUBLISHED: 09-14-2010
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The potential for increased sensitivity of tumor cells to oncolytic reovirus by altering the normal cell cycle using clinically available pharmacological agents was investigated. B16.F10 mouse melanoma cells were partially synchronized with hydroxyurea, thymidine, or by mitotic shake-off. Cell survival was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium)] survival assay and virus yield in tumors by plaque assay. An enhanced sensitivity to reovirus was observed following the removal of either hydroxyurea or thymidine from the culture medium (P < 0.0001). The greatest survival difference compared to normal cycling cells was noted when the majority of cells were in S and G2/M phases, and was associated with increased viral replication. Cells collected by mitotic shake-off were nearly devoid of cells in S phase and were less susceptible to reovirus-induced cell kill than their nonsynchronized counterparts (P < 0.0001). In vivo combination of hydroxyurea followed by intratumoral reovirus resulted in reduced tumor growth and increased survival compared to monotherapy (P = 0.0041) at 15 days. Increased amounts of virus were retrieved from tumors from mice treated with sequential hydroxyurea/reovirus compared to concomitant treatment or reovirus monotherapy. These data justify clinical evaluation of this approach supported by the extensive experience, low cost, simple administration, and availability of hydroxyurea.
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Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck.
Clin. Cancer Res.
PUBLISHED: 07-31-2010
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This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN).
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Evidence-based review: quality of life following head and neck intensity-modulated radiotherapy.
Radiother Oncol
PUBLISHED: 07-07-2010
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Inverse planned Intensity modulated radiotherapy (IMRT) can minimize the dose to normal structures and therefore can reduce long-term radiotherapy-related morbidity and may improve patients long-term quality of life. Despite overwhelming evidence that IMRT can reduce late functional deficits in patients with head and neck cancer, treated with radiotherapy, a review of the published literature produced conflicting results with regard to quality of life outcomes. Following a critical appraisal of the literature, reasons for the discrepant outcomes are proposed.
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Therapeutic effect of sodium iodide symporter gene therapy combined with external beam radiotherapy and targeted drugs that inhibit DNA repair.
Mol. Ther.
PUBLISHED: 06-29-2010
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Adenoviral (AdV) transfer of sodium iodide symporter (NIS) gene has translational potential, but relatively low levels of transduction and subsequent radioisotope uptake limit the efficacy of the approach. In previous studies, we showed that combining NIS gene delivery with external beam radiotherapy (EBRT) and DNA damage repair inhibitors increased viral gene expression and radioiodide uptake. Here, we report the therapeutic efficacy of this strategy. An adenovirus expressing NIS from a telomerase promoter (Ad-hTR-NIS) was cytotoxic combined with relatively high-dose (50 microCi) (131)I therapy and enhanced the efficacy of EBRT combined with low-dose (10 and 25 microCi) (131)I therapy in colorectal and head and neck cancer cells. Combining this approach with ataxia-telangiectasia mutated (ATM) or DNA-dependent protein kinase (DNA-PK) inhibition caused maintenance of double-stranded DNA breaks (DSBs) at 24 hours and increased cytotoxicity on clonogenic assay. When the triplet of NIS-mediated (131)I therapy, EBRT, and DNA-PKi was used in vivo, 90% of mice were tumor-free at 5 weeks. Acute radiation toxicity in the EBRT field was not exacerbated. In contrast, DNA-PKi did not enhance the therapeutic efficacy of EBRT plus adenovirus-mediated HSVtk/ganciclovir (GCV). Therefore, combining NIS gene therapy and EBRT represents an ideal strategy to exploit the therapeutic benefits of novel radiosensitizers.
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Immunoregulatory effects of freeze injured whole tumour cells on human dendritic cells using an in vitro cryotherapy model.
Cryobiology
PUBLISHED: 06-24-2010
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Tumour cryotherapy has been described as both immunostimulatory and immunoinhibitory in previous studies. However, previous studies have not accurately reproduced the precise conditions of current clinical cryotherapy. The objective of this study is to assess the immunological effects of cryotreated whole tumour cells on dendritic cells (DC) maturation and function using an in vitro model. Prostate cancer cells were cooled using Endocare cryo-system to mimic temperatures achieved during clinical cryotherapy. Human DC were prepared from cluster of differentiation (CD) 14 monocytes and matured with lipopolysaccharide (LPS). Cryotreated cancer cells were added to DC on day 3. On day 7, DC were harvested and phenotyped. Cytokine gene expression was assessed using real time quantitative polymerase chain reaction (RT-PCR). Functional activity of DC was assessed in allogenic mixed lymphocyte reaction (MLR) and the molecular changes using gene microarray technology. There was statistically significant upregulation of costimulatory molecules and maturation markers (CD86, CD83, CD80 and CL II) in DC loaded with cryotreated whole tumour cells compared to both control DC and DC matured with LPS (P < 0.001). There was a significant increase in stimulatory cytokines gene expression (IL-2, IL-12, IL-15, IL-18 and IFN-?). However, IL-10 and TGF-? expression reduced significantly. The effect of different freezing temperature was equal. cDNA microarray analysis showed upregulation of interleukin 1 (IL-1) and cycline dependent kinase inhibitor 1A (CDKN1A (p21) and downregulation of Caspase 8 and BCL2. Overall, our findings suggest that the effect of cryotherapy is generally stimulatory to DC which may enhance anti-tumour effects. Therefore, the combination of cryotherapy and DC vaccine may represent a novel method to increase the efficacy of cryotherapy especially at the peripheral zones of the prostate where cells are exposed to sub-lethal temperature.
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Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.
Clin. Cancer Res.
PUBLISHED: 05-18-2010
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To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses.
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Familial nonmedullary thyroid cancer: a review of the genetics.
Thyroid
PUBLISHED: 05-15-2010
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Thyroid cancer, the commonest of endocrine malignancies, continues to increase in incidence with over 19,000 new cases diagnosed in the European Union per year. Although nonmedullary thyroid cancer (NMTC) is mostly sporadic, evidence for a familial form, which is not associated with other Mendelian cancer syndromes (e.g., familial adenomatous polyposis and Cowdens syndrome), is well documented and thought to cause more aggressive disease. Just over a decade ago, the search for a genetic susceptibility locus for familial NMTC (FNMTC) began. This review details the genetic studies conducted thus far in the search for potential genes for FNMTC.
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MAPK and PI3K signalling differentially regulate angiogenic and lymphangiogenic cytokine secretion in squamous cell carcinoma of the head and neck.
Eur. J. Cancer
PUBLISHED: 05-13-2010
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Vascular endothelial growth factors (VEGF-C and VEGF-A) play important roles in tumour-induced lymphangiogenesis and angiogenesis, respectively, key processes implicated in promoting tumour growth and metastatic spread. Previous work from our laboratory has shown that EGFR overexpression in squamous carcinomas of the head and neck (SCCHN) is linked to high levels of VEGF-A and VEGF-C (but low levels of VEGF-D) and is associated with poor prognosis. The present study explored the signalling pathways regulating the induction of VEGF-C and VEGF-A in the SCCHN cell lines CAL 27 and Detroit 562. The addition of exogenous EGF induced the expression of VEGF-C and VEGF-A in a concentration-dependent manner and this was blocked by a selective EGFR inhibitor, gefitinib. In both cell lines stimulated with endogenous or exogenous ligand, inhibition of MEK1/2 (with U0126 or PD98059) or PI3K (with PI-103 or LY294002) resulted in a marked reduction of EGFR-induced VEGF-A expression, whereas exogenous EGF-induced VEGF-C upregulation was blocked by inhibitors of MEK but not PI3K. Inhibition of p38 MAPK suppressed EGF-induced VEGF-C upregulation in CAL 27 cells, but inhibited EGF-induced VEGF-A upregulation in Detroit 562. Taken together, our evidence suggests that both endogenous and exogenous EGFR activation induces VEGF-A expression requiring both PI3K and MAPK signalling whereas VEGF-C expression is dependent on MAPK, but not the PI3K or mTOR pathways in SCCHN cell lines. p38 MAPK appears to be differentially linked to either VEGF-A or VEGF-C regulation in different cellular contexts.
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Swallowing outcomes following Intensity Modulated Radiation Therapy (IMRT) for head & neck cancer - a systematic review.
Oral Oncol.
PUBLISHED: 05-12-2010
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A systematic review to establish what evidence is available for swallowing outcomes following IMRT for head and neck cancer.
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Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy.
Radiother Oncol
PUBLISHED: 04-20-2010
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This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction.
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Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 03-27-2010
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The aim of this study was to investigate prospectively the weekly volume changes in the target volumes and organs at risk and the resulting dosimetric changes during induction chemotherapy followed by chemoradiotherapy with intensity-modulated radiation therapy (C-IMRT) for head-and-neck cancer patients.
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Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.
Nat. Cell Biol.
PUBLISHED: 03-18-2010
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Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and organotypic models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion.
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Targeting HOX and PBX transcription factors in ovarian cancer.
BMC Cancer
PUBLISHED: 03-10-2010
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Ovarian cancer still has a relatively poor prognosis due to the frequent occurrence of drug resistance, making the identification of new therapeutic targets an important goal. We have studied the role of HOX genes in the survival and proliferation of ovarian cancer cells. These are a family of homeodomain-containing transcription factors that determine cell and tissue identity in the early embryo, and have an anti-apoptotic role in a number of malignancies including lung and renal cancer.
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The biology of the sodium iodide symporter and its potential for targeted gene delivery.
Curr Cancer Drug Targets
PUBLISHED: 02-16-2010
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The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I)) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.
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Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 02-06-2010
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In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma.
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Second trimester maternal serum cystatin C levels in preeclamptic and normotensive pregnancies: A small case-control study.
Hypertens Pregnancy
PUBLISHED: 02-06-2010
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Cystatin C (CC) is a marker of glomerular filtration rate (GFR) and is elevated in cases of established preeclampsia (PE). It also has widespread presence in extracellular space and high levels in PE might reflect placental ischemia. The aim of this study was to measure CC levels in the second trimester in women who subsequently develop PE and in those who remained normotensive.
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Validation of the Sydney Swallow Questionnaire (SSQ) in a cohort of head and neck cancer patients.
Oral Oncol.
PUBLISHED: 02-04-2010
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Impairment of swallowing function is a common multidimensional symptom complex seen in 50-75% of head and neck cancer (HNC) survivors. Although there are a number of validated swallowing-specific questionnaires, much of their focus is on the evaluation of swallowing-related quality of life (QOL) rather than swallowing as a specific function. The aim of this study was to validate the Sydney Swallow Questionnaire (SSQ) as a swallowing-specific instrument in HNC patients. Fifty-four consecutive patients in follow-up for oral and oropharyngeal cancer completed the SSQ and MD Anderson Dysphagia Inventory (MDADI). Thirty-one patients completed both questionnaires again four weeks later to address test-retest reliability. Internal consistency and test-retest reliability was assessed using Cronbachs alpha and Spearmans correlation coefficient, respectively. Construct validity (including group validity) and criterion validity were determined using Spearmans correlation coefficient and Mann-Whitney U-test. Internal consistency, test-retest reliability, construct validity, group validity and criterion validity of the SSQ was found to be significant (P<0.01). We were able to demonstrate the reliability and validity of the SSQ in HNC patients. The SSQ is a precise, reliable and valid tool for assessing swallow in this patient group.
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Acceptability of the fetal electrocardiographic (STAN) monitoring system by staff at a high risk maternity unit.
J Perinat Med
PUBLISHED: 02-04-2010
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To assess staff acceptability of STAN monitoring system.
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Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice.
J. Clin. Invest.
PUBLISHED: 01-27-2010
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Clinical trials of oncolytic virotherapy have shown low toxicity and encouraging signs of efficacy. However, it remains critically important to develop methods for systemic viral delivery if such therapies are to be clinically implemented to treat established tumors. In this respect, much effort is being focused on combining oncolytic viruses with standard treatment modalities such as inhibitors of VEGF165 (an alternatively spliced isoform of VEGF-A) signaling, which are widely used to treat several different cancers. Here, we have demonstrated that combining VEGF165 inhibitors with systemic delivery of oncolytic viruses leads to substantial regression and cure of established tumors in immunocompetent mice. We have shown that manipulating VEGF165-mediated signaling by administering VEGF165 to mice harboring mouse melanoma cells that do not express VEGF165 and by administering a VEGF inhibitor and then withdrawing treatment to allow VEGF levels to rebound in mice harboring mouse melanoma cells expressing VEGF165 allows tumor-associated endothelial cells transiently to support viral replication. This approach led to direct tumor cell lysis and triggered innate immune-mediated attack on the tumor vasculature. It also resulted in long-term antitumor effects, even against tumors in which viral replication is poorly supported. Since this combinatorial approach targets the tumor endothelium, we believe these data have direct, wide-ranging, and immediate clinical applicability across a broad range of tumor types.
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The value of magnetic resonance imaging in target volume delineation of base of tongue tumours--a study using flexible surface coils.
Radiother Oncol
PUBLISHED: 01-22-2010
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Magnetic resonance imaging (MRI) provides superior diagnostic accuracy over computed tomography (CT) in oropharyngeal tumours. Precise delineation of the gross tumour volume (GTV) is mandatory in radiotherapy planning when a GTV boost is required. CT volume definition in this regard is poor. We studied the feasibility of using flexible surface (flex-L) coils to obtain MR images for MR-CT fusion to assess the benefit of MRI over CT alone in planning base of tongue tumours.
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Comprehensive review of small bowel metastasis from head and neck squamous cell carcinoma.
Oral Oncol.
PUBLISHED: 01-18-2010
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Secondary tumours of small intestine account for 10% of all small bowel cancers. The most common sites of primary tumour metastasizing to small bowel are uterus, cervix, colon, lung, breast and melanoma. The majority of these metastatic tumours come from adenocarcinoma primaries; squamous cell carcinoma constitutes a very small proportion of all metastatic small intestinal lesions. Metastasis to small bowel by head and neck squamous cell carcinoma is extremely rare and carries an unfavourable prognosis. Owing to the limited number of published studies, its characteristic features, clinical presentation and outcomes are poorly described. This work aims at specifying these characteristics by reviewing, compiling, analysing and reporting all published cases in the published literature on small bowel metastasis secondary to head and neck squamous cell carcinoma. To the best of our knowledge, this is the first comprehensive review article on the small intestinal metastasis from head and neck squamous cell carcinoma.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.