Other articles by Mark De Ridder on PubMed

• Lipid a Radiosensitizes Hypoxic EMT-6 Tumor Cells: Role of the NF-kappaB Signaling Pathway International Journal of Radiation Oncology, Biology, Physics. Nov, 2003  |   Pubmed ID: 14529784 Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-kappaB (NF-kappaB) signaling.
• Metastases to the Thyroid Gland-a Report of Six Cases European Journal of Internal Medicine. Oct, 2003  |   Pubmed ID: 14769497 The association of an asymptomatic mass, normal thyroid function, and a cold nodule can occur months to years after a primary cancer. Work-up should include ruling out other metastases and fine-needle aspiration cytology. We report six cases of secondary thyroid cancer. Two of the patients in our series presented with hyperthyroidism, which may be due to invasion and disruption of thyroid follicles.
• Macrophages Enhance the Radiosensitizing Activity of Lipid A: a Novel Role for Immune Cells in Tumor Cell Radioresponse International Journal of Radiation Oncology, Biology, Physics. Oct, 2004  |   Pubmed ID: 15380597 This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators.
• Role of the Hypoxic Bone Marrow Microenvironment in 5T2MM Murine Myeloma Tumor Progression Haematologica. Jun, 2005  |   Pubmed ID: 15951294 Unlike most other tumors, multiple myeloma (MM) cells have to survive and to grow in a bone marrow (BM) microenvironment which is already hypoxic by nature. BM hypoxia is crucial for normal hematopoiesis. However, how BM hypoxia and MM affect each other is unknown. We addressed this topic in the 5T2MM mouse model.
• The Role of Chemotherapy in the Treatment of Low-grade Glioma. A Review of the Literature Acta Neurologica Belgica. Sep, 2005  |   Pubmed ID: 16255151 Low-grade gliomas (LGG) are a group of uncommon neuroglial tumors of the central nervous system. They are characterized by a grade I or II according to the WHO classification. Grade I tumors are non-invasive and amenable to surgical resection with curative intent. Diffuse infiltrating LGG (WHO grade II) are tumors with a highly variable prognosis. Curative resection can only rarely be achieved and progression is characterized by transformation into a high-grade glioma (WHO grade III-IV). There are only limited evidence-based treatment recommendations for the management of progressive LGG because of a lack of data from prospective randomized trials. Most often radiotherapy is offered to patients with symptomatic and/or progressive disease. Three randomized trials have failed to demonstrate a survival improvement with either early versus delayed radiation or with a higher dose of radiation. The potential role of chemotherapy for the treatment of LGG has only been addressed in phase II trials. The PCV-chemotherapy regimen is associated with considerable toxicity that limits its applicability. The results with temozolomide (TMZ) chemotherapy have been more promising. Patients with chemosensitive LGG as predicted by heterozygotic loss of chromosomal arms Ip and 19q or methylation of the promoter of the MGMT-gene in the genome of the glioma cells respond to TMZ. Radiotherapy will be compared to chemotherapy asfirst line treatment for LGG in two phase III studies that are planned for by the brain tumor group of the European Organization for Research and Treatment of Cancer (BTG-EORTC) and Radiation Therapy Oncology Group (RTOG).
• The Radiosensitizing Effect of Immunoadjuvant OM-174 Requires Cooperation Between Immune and Tumor Cells Through Interferon-gamma and Inducible Nitric Oxide Synthase International Journal of Radiation Oncology, Biology, Physics. Dec, 2006  |   Pubmed ID: 17056198 To explore whether antitumor immunoadjuvant OM-174 can stimulate immune cells to produce interferon-gamma (IFN-gamma) and thereby radiosensitize tumor cells.
• Prognostic Value of Histopathology and Trends in Cervical Cancer: a SEER Population Study BMC Cancer. 2007  |   Pubmed ID: 17718897 Histopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial.
• Innovations in Image-guided Radiotherapy Nature Reviews. Cancer. Dec, 2007  |   Pubmed ID: 18034185 The limited ability to control for the location of a tumour compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiotherapy (IGRT) these volumes can be optimized and tumoricidal doses can be delivered, achieving maximal tumour control with minimal complications. Moreover, with the ability of high-precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications for radiotherapy, some of which were previously considered infeasible.
• Phase II Study of Preoperative Helical Tomotherapy for Rectal Cancer International Journal of Radiation Oncology, Biology, Physics. Mar, 2008  |   Pubmed ID: 17904302 To explore the efficacy and toxicity profile of helical tomotherapy in the preoperative treatment of patients with rectal cancer.
• A (short) History of Image-guided Radiotherapy Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Jan, 2008  |   Pubmed ID: 18083259 Progress in radiotherapy is guided by the need to realize improved dose distributions, i.e. the ability to reduce the treatment volume toward the target volume and still ensuring coverage of that target volume in all dimensions. Poor ability to control the tumour's location limits the accuracy with which radiation can be delivered to tumour-bearing tissue. Image-guided radiation therapy (IGRT) aims at in-room imaging guiding the radiation delivery based on instant knowledge of the target location and changes in tumour volume during treatment. Advancements are usually not to be attributed to a single event, but rather a combination of many small improvements that together enable a superior result. Image-guidance is an important link in the treatment chain and as such a major factor in this synergetic process. A historic review shows that many of the so-called new developments are not so new at all, but did not make it into mainstream radiotherapy practice at that time. Recent developments in improved IT infrastructures, novel irradiation techniques, and better knowledge of functional and morphologic information may have created the need and optimal environment to revive the interest in IGRT.
• Hypoxic Tumor Cell Radiosensitization: Role of the INOS/NO Pathway Bulletin Du Cancer. Mar, 2008  |   Pubmed ID: 18390408 Hypoxia is a common feature of the tumor microenvironment and a major cause of clinical radioresistance. During the last decades, several strategies to improve tumor oxygenation were developed such as breathing high oxygen content gas under hyperbaric conditions (3 atmosphere) and improving tumor perfusion by nicotinamide, in combination with carbogen breathing and accelerated radiotherapy to counteract tumor repopulation (ARCON). Other strategies to overcome hypoxia induced radioresistance are the use of hypoxic cell radiosensitizers, which mimic oxygen and enhance thereby radiation damage (e.g. the nitroimidazoles) and bioreductive drugs, which undergo intracellular reduction to form active cytotoxic species under low oxygen tension (e.g. mitomycin C and tirapazamine). A meta-analysis of all randomized trials in which some form of hypoxic modification was performed, showed an improved local control and survival, especially in cervix and head-and-neck cancer. Nevertheless, none of the discussed strategies are used in clinical routine because of feasibility and toxicity issues. We developed an alternative strategy that takes advantage of the microenvironment of solid tumors for tumor specific radiosensitization. The inducible isoform of nitric oxide synthase (iNOS) may be induced by bacterial LPS or its derivate lipid A, is expressed by a variety of solid tumors and generates NO at high rates inside tumor cells. This local production of NO results in efficient hypoxic tumor cell radiosensitization, at non-toxic extracellular concentrations of NO. In addition, iNOS is transcriptionally upregulated by hypoxia and proinflammatory cytokines such as interferon-gamma. Hence, we proposed the pro-inflammatory tumor infiltrate as a new target for radiosensitizing strategies and identified two mechanisms: First, tumor associated immune cells (macrophages, T/NK-cells) are a source of mediators that may induce the iNOS/NO pathway inside tumor cells. Second, tumor associated macrophages can produce high levels of NO that may radiosensitize bystander tumor cells. Our ongoing research is focused on combining immunostimulatory and radiosensitizing strategies.
• Hypoxic Tumor Cell Radiosensitization Through Nitric Oxide Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. Sep, 2008  |   Pubmed ID: 18474256 Hypoxia is a principal signature of the tumor microenvironment and is considered to be the most important cause of clinical radioresistance and local failure. Oxygen is so far the best radiosensitizer, but tumor oxygenation protocols are compromised by its metabolic consumption and therefore limited diffusion inside tumors. Many chemical radiosensitizers can selectively target hypoxic tumor cells, but their systemic toxicity compromises their adequate clinical use. NO is an efficient hypoxic radiosensitizer, as it may mimic the effects of oxygen on fixation of radiation-induced DNA damage, but the required levels cannot be obtained in vivo because of vasoactive complications. Our laboratory explored whether this problem may be overcome by endogenous production of NO inside tumors. We demonstrated that iNOS, activated by pro-inflammatory cytokines, is capable of radiosensitizing tumor cells through endogenous production of NO, at non-toxic extracellular concentrations. We observed that this radiosensitizing effect is transcriptionally controlled by hypoxia and by NF-kappaB. Tumor-associated immune cells may contribute to the iNOS-mediated radiosensitization by the generation of pro-inflammatory cytokines and NO, which may diffuse towards bystander tumor cells. Our findings indicate a rationale for combining immunostimulatory and radiosensitizing strategies in the future.
• IFN-gamma+ CD8+ T Lymphocytes: Possible Link Between Immune and Radiation Responses in Tumor-relevant Hypoxia International Journal of Radiation Oncology, Biology, Physics. Jul, 2008  |   Pubmed ID: 18514774 Activated T lymphocytes are known to kill tumor cells by triggering cytolytic mechanisms; however, their ability to enhance radiation responses remains unclear. This study examined the radiosensitizing potential of mouse CD8+ T cells, obtained by T-cell-tailored expansion and immunomagnetic purification. Activated CD8+ T cells displayed an interferon (IFN)-gamma+ phenotype and enhanced by 1.8-fold the radiosensitivity of EMT-6 tumor cells in 1% oxygen, which modeled tumor-relevant hypoxia. Radiosensitization was counteracted by neutralizing IFN-gamma or by blocking the inducible isoform of nitric oxide synthase, thus delineating the immune-tumor cell interaction through the IFN-gamma secretion pathway. Reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorter data in agreement detected downregulation of the IFN-gamma gene by hypoxia, which caused IFN-gamma deficiency next to radioresistance. Therefore, immune and radiation responses are likely to be allied in the hypoxic tumor microenvironment, and CD8+ T cells may bridge immunostimulatory and radiosensitizing strategies.
• Assessment of Intrafractional Movement and Internal Motion in Radiotherapy of Rectal Cancer Using Megavoltage Computed Tomography International Journal of Radiation Oncology, Biology, Physics. Jul, 2008  |   Pubmed ID: 18514785 The aim of this study was to provide estimates of setup and internal margins of patients treated for rectal carcinoma using helical tomotherapy and to assess possible margin adaptations. Using helical tomotherapy, highly conformal dose distributions can be created, and the integrated megavoltage computed tomography (MVCT) modality allows very precise daily patient positioning. In clinical protocols, however, margins originating from traditional setup procedures are still being applied. This work investigates whether this modality can aid in redefining treatment margins.
• Cetuximab with Hepatic Arterial Infusion of Chemotherapy for the Treatment of Colorectal Cancer Liver Metastases Anticancer Research. Jul-Aug, 2008  |   Pubmed ID: 18751435 Both hepatic arterial infusion (HAI) of chemotherapy and cetuximab (CET) have interesting activity for the treatment of colorectal cancer liver metastases (CRC-LM).
• Pseudoprogression After Radiotherapy with Concurrent Temozolomide for High-grade Glioma: Clinical Observations and Working Recommendations Surgical Neurology. Oct, 2009  |   Pubmed ID: 19150114 Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression.
• Preoperative Helical Tomotherapy and Megavoltage Computed Tomography for Rectal Cancer: Impact on the Irradiated Volume of Small Bowel International Journal of Radiation Oncology, Biology, Physics. Aug, 2009  |   Pubmed ID: 19231097 Preoperative (chemo)radiotherapy is considered to be standard of care in locally advanced rectal cancer, but is associated with significant small-bowel toxicity. The aim of this study was to explore to what extent helical tomotherapy and daily megavolt (MV) CT imaging may reduce the irradiated volume of small bowel.
• Volumetric Response Analysis During Chemoradiation As Predictive Tool for Optimizing Treatment Strategy in Locally Advanced Unresectable NSCLC Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Jun, 2009  |   Pubmed ID: 19368985 To study the feasibility of measuring volumetric changes in the primary tumor on megavoltage-computed tomography (MVCT) during chemoradiation and to examine the correlation with local response.
• Toxicity Report of a Phase 1/2 Dose-escalation Study in Patients with Inoperable, Locally Advanced Nonsmall Cell Lung Cancer with Helical Tomotherapy and Concurrent Chemotherapy Cancer. Jan, 2010  |   Pubmed ID: 19918925 The objective of the current study was to evaluate the feasibility and toxicity of radiation dose escalation with concurrent chemotherapy using helical tomotherapy (HT) in patients with inoperable, locally advanced, stage III nonsmall cell lung cancer (LANSCLC) (grading determined according to the American Joint Committee on Cancer 6th edition grading system).
• Toxicity and Outcome Results of a Class Solution with Moderately Hypofractionated Radiotherapy in Inoperable Stage III Non-small Cell Lung Cancer Using Helical Tomotherapy International Journal of Radiation Oncology, Biology, Physics. Aug, 2010  |   Pubmed ID: 20056350 To prospectively assess the feasibility, toxicity, and local control of a class solution protocol of moderately hypofractionated tomotherapy in Stage III, inoperable, locally advanced non-small-cell lung cancer patients.
• An In-house Developed Resettable MOSFET Dosimeter for Radiotherapy Physics in Medicine and Biology. Feb, 2010  |   Pubmed ID: 20090184 The purpose of this note is to report the feasibility and clinical validation of an in-house developed MOSFET dosimetry system and describe an integrated non-destructive reset procedure. Off-the-shelf MOSFETs are connected to a common PC using an 18 bit/analogue-input and 16 bit/output data acquisition card. A reading algorithm was developed defining the zero-temperature-coefficient point (ZTC) to determine the threshold voltage. A wireless interface was established for ease of use. The reset procedure consists of an internal circuit generating a local heating induced by an electrical current. Sensitivity has been investigated as a function of bias voltage (0-9 V) to the gate. Dosimetric properties have been evaluated for 6 MV and 15 MV clinical photon beams and in vivo benchmarking was performed against thermoluminescence dosimeters (TLD) for conventional treatments (two groups of ten patients for each energy) and total body irradiation (TBI). MOSFETS were pre-irradiated with 20 Gy. Sensitivity of 0.08 mV cGy(-1) can be obtained for 200 cGy irradiations at 5 V bias voltage. Ten consecutive measurements at 200 cGy yield a SD of 2.08 cGy (1.05%). Increasing the dose in steps from 5 cGy to 1000 cGy yields a 1.00 Pearson correlation coefficient and agreement within 2.0%. Dose rate dependence (160-800 cGy min(-1)) was within 2.5%, temperature dependence within 2.0% (25-37 degrees C). A strong angular dependence has been observed for gantry incidences exceeding +/-30 degrees C. Dose response is stable up to 50 Gy (saturation occurs at approximately 90 Gy), which is used as threshold dose before resetting the MOSFET. An average measured-over-calculated dose ratio within 1.05 (SD: 0.04) has been obtained in vivo. TBI midplane-dose assessed by entrance and exit dose measurements agreed within 1.9% with ionization chamber in phantom, and within 1.0% with TLD in vivo. An in-house developed resettable MOSFET-based dosimetry system is proposed. The system has been validated and is currently used for in vivo entrance dose measurement in clinical routine for simple (open field) treatment configurations.
• Activated Macrophages As a Novel Determinant of Tumor Cell Radioresponse: the Role of Nitric Oxide-mediated Inhibition of Cellular Respiration and Oxygen Sparing International Journal of Radiation Oncology, Biology, Physics. Apr, 2010  |   Pubmed ID: 20338478 Nitric oxide (NO), synthesized by the inducible nitric oxide synthase (iNOS), is known to inhibit metabolic oxygen consumption because of interference with mitochondrial respiratory activity. This study examined whether activation of iNOS (a) directly in tumor cells or (b) in bystander macrophages may improve radioresponse through sparing of oxygen.
• Volumetric Imaging by Megavoltage Computed Tomography for Assessment of Internal Organ Motion During Radiotherapy for Cervical Cancer International Journal of Radiation Oncology, Biology, Physics. Aug, 2010  |   Pubmed ID: 20378265 To assess the internal organ motion of the cervix and uterus by megavoltage computed tomography (MVCT) during intensity-modulated radiotherapy (IMRT).
• Prediction of Response to Neoadjuvant Radiotherapy in Patients with Locally Advanced Rectal Cancer by Means of Sequential 18FDG-PET International Journal of Radiation Oncology, Biology, Physics. May, 2011  |   Pubmed ID: 20605358 Morphologic imaging techniques perform poorly in assessing the response to preoperative radiotherapy (RT), mainly because of desmoplastic reactions. The aim of this study was to investigate the potential of sequential 18-fluoro-2-deoxy-d-glucose (18FDG-PET) in assessing the response of rectal cancer to neoadjuvant RT and to determine which parameters can be used as surrogate markers for histopathologic response.
• Daily Megavoltage Computed Tomography in Lung Cancer Radiotherapy: Correlation Between Volumetric Changes and Local Outcome International Journal of Radiation Oncology, Biology, Physics. Aug, 2011  |   Pubmed ID: 20638192 To assess the predictive or comparative value of volumetric changes, measured on daily megavoltage computed tomography during radiotherapy for lung cancer.
• Prospective, Risk-adapted Strategy of Stereotactic Body Radiotherapy for Early-stage Non-small-cell Lung Cancer: Results of a Phase II Trial International Journal of Radiation Oncology, Biology, Physics. Aug, 2011  |   Pubmed ID: 20708849 Validation of a prospective, risk-adapted strategy for early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT).
• Geometric Accuracy of a Novel Gimbals Based Radiation Therapy Tumor Tracking System Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Mar, 2011  |   Pubmed ID: 21316786 VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study determines the geometric accuracy of the tracking.
• Single Fraction Versus Fractionated Linac-based Stereotactic Radiotherapy for Vestibular Schwannoma: a Single-institution Experience International Journal of Radiation Oncology, Biology, Physics. Nov, 2011  |   Pubmed ID: 21665381 To evaluate and compare outcomes for patients with vestibular schwannoma (VS) treated in a single institution with linac-based stereotactic radiosurgery (SRS) or by fractionated stereotactic radiotherapy (SRT).
• Delivering Affordable Cancer Care in High-income Countries The Lancet. Oncology. Sep, 2011  |   Pubmed ID: 21958503 The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.
• Setup Accuracy of the Novalis ExacTrac 6DOF System for Frameless Radiosurgery International Journal of Radiation Oncology, Biology, Physics. Apr, 2012  |   Pubmed ID: 21477937 Stereotactic radiosurgery using frame-based positioning is a well-established technique for the treatment of benign and malignant lesions. By contrast, a new trend toward frameless systems using image-guided positioning techniques is gaining mainstream acceptance. This study was designed to measure the detection and positioning accuracy of the ExacTrac/Novalis Body (ET/NB) for rotations and to compare the accuracy of the frameless with the frame-based radiosurgery technique.
• Clinical Evaluation of a Robotic 6-degree of Freedom Treatment Couch for Frameless Radiosurgery International Journal of Radiation Oncology, Biology, Physics. May, 2012  |   Pubmed ID: 21945110 To evaluate the added value of 6-degree of freedom (DOF) patient positioning with a robotic couch compared with 4DOF positioning for intracranial lesions and to estimate the immobilization characteristics of the BrainLAB frameless mask (BrainLAB AG, Feldkirchen, Germany), more specifically, the setup errors and intrafraction motion.
• Phase II Study of Preoperative Helical Tomotherapy with a Simultaneous Integrated Boost for Rectal Cancer International Journal of Radiation Oncology, Biology, Physics. May, 2012  |   Pubmed ID: 22014952 The addition of concomitant chemotherapy to preoperative radiotherapy is considered the standard of care for patients with cT3-4 rectal cancer. The combined treatment modality increases the complete response rate and local control (LC), but has no impact on survival or the incidence of distant metastases. In addition, it is associated with considerable toxicity. As an alternative strategy, we explored prospectively, preoperative helical tomotherapy with a simultaneous integrated boost (SIB).
• Phase II Study of Helical Tomotherapy in the Multidisciplinary Treatment of Oligometastatic Colorectal Cancer Radiation Oncology (London, England). 2012  |   Pubmed ID: 22423615 Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For inoperable patients, we evaluated in this study intensity-modulated and image-guided radiotherapy (IMRT-IGRT) by helical tomotherapy.
• Computer-aided Analysis of Star Shot Films for High-accuracy Radiation Therapy Treatment Units Physics in Medicine and Biology. May, 2012  |   Pubmed ID: 22538289 As mechanical stability of radiation therapy treatment devices has gone beyond sub-millimeter levels, there is a rising demand for simple yet highly accurate measurement techniques to support the routine quality control of these devices. A combination of using high-resolution radiosensitive film and computer-aided analysis could provide an answer. One generally known technique is the acquisition of star shot films to determine the mechanical stability of rotations of gantries and the therapeutic beam. With computer-aided analysis, mechanical performance can be quantified as a radiation isocenter radius size. In this work, computer-aided analysis of star shot film is further refined by applying an analytical solution for the smallest intersecting circle problem, in contrast to the gradient optimization approaches used until today. An algorithm is presented and subjected to a performance test using two different types of radiosensitive film, the Kodak EDR2 radiographic film and the ISP EBT2 radiochromic film. Artificial star shots with a priori known radiation isocenter size are used to determine the systematic errors introduced by the digitization of the film and the computer analysis. The estimated uncertainty on the isocenter size measurement with the presented technique was 0.04 mm (2σ) and 0.06 mm (2σ) for radiographic and radiochromic films, respectively. As an application of the technique, a study was conducted to compare the mechanical stability of O-ring gantry systems with C-arm-based gantries. In total ten systems of five different institutions were included in this study and star shots were acquired for gantry, collimator, ring, couch rotations and gantry wobble. It was not possible to draw general conclusions about differences in mechanical performance between O-ring and C-arm gantry systems, mainly due to differences in the beam-MLC alignment procedure accuracy. Nevertheless, the best performing O-ring system in this study, a BrainLab/MHI Vero system, and the best performing C-arm system, a Varian Truebeam system, showed comparable mechanical performance: gantry isocenter radius of 0.12 and 0.09 mm, respectively, ring/couch rotation of below 0.10 mm for both systems and a wobble of 0.06 and 0.18 mm, respectively. The methodology described in this work can be used to monitor mechanical performance constancy of high-accuracy treatment devices, with means available in a clinical radiation therapy environment.
• Scapula Alata in Early Breast Cancer Patients Enrolled in a Randomized Clinical Trial of Post-surgery Short-course Image-guided Radiotherapy World Journal of Surgical Oncology. 2012  |   Pubmed ID: 22591589 Scapula alata (SA) is a known complication of breast surgery associated with palsy of the serratus anterior, but it is seldom mentioned. We evaluated the risk factors associated with SA and the relationship of SA with ipsilateral shoulder/arm morbidity in a series of patients enrolled in a trial of post-surgery radiotherapy (RT).
• Current Status of Intensified Neo-adjuvant Systemic Therapy in Locally Advanced Rectal Cancer Frontiers in Oncology. 2012  |   Pubmed ID: 22655273 The addition of 5-fluorouracil (5-FU) or its prodrug capecitabine to radiotherapy (RT) is a standard approach in the neo-adjuvant treatment of patients with rectal tumors extending beyond the muscularis propria (stage II) and/or with clinical evidence of regional lymph node metastases (stage III). According to European randomized trials, the combined treatment modality resulted in favorable local control rates as compared with radiotherapy (RT) alone, but no improvement was found regarding the occurrence of distant metastases or overall survival. In an effort to further enhance the response rates and to decrease the high incidence of distant metastases in locally advanced rectal cancer patients, the addition of other chemotherapeutical drugs and biologic agents as radiation sensitizers to neo-adjuvant 5-FU based chemoradiotherapy (CRT) has been recently investigated. The role of those agents is however questionable as first results from phase III data do not show improvement on pathologic complete remission and circumferential resection margin negative resection rates as compared to 5-FU based CRT, nevertheless an increased toxicity.
• Short Course Radiotherapy with Simultaneous Integrated Boost for Stage I-II Breast Cancer, Early Toxicities of a Randomized Clinical Trial Radiation Oncology (London, England). 2012  |   Pubmed ID: 22656865 TomoBreast is a unicenter, non-blinded randomized trial comparing conventional radiotherapy (CR) vs. hypofractionated Tomotherapy (TT) for post-operative treatment of breast cancer. The purpose of the trial is to compare whether TT can reduce heart and pulmonary toxicity. We evaluate early toxicities.
• Radiation Necrosis of the Brain in Melanoma Patients Successfully Treated with Ipilimumab, Three Case Studies European Journal of Cancer (Oxford, England : 1990). Nov, 2012  |   Pubmed ID: 22727601 Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.
• Diagnostic and Prognostic Correlates of Preoperative FDG PET for Breast Cancer European Journal of Nuclear Medicine and Molecular Imaging. Oct, 2012  |   Pubmed ID: 22777335 To explore the preoperative utility of FDG PET for the diagnosis and prognosis in a retrospective breast cancer case series.
• Parotid Gland Sparing with Helical Tomotherapy in Head-and-neck Cancer International Journal of Radiation Oncology, Biology, Physics. Oct, 2012  |   Pubmed ID: 22836056 This study evaluated the ability of helical tomotherapy to spare the function of the parotid glands in patients with head-and-neck cancer by analyzing dose-volume histograms, salivary gland scintigraphy, and quality of life assessment.
• Implementation of HybridArc Treatment Technique in Preoperative Radiotherapy of Rectal Cancer: Dose Patterns in Target Lesions and Organs at Risk As Compared to Helical Tomotherapy and RapidArc Radiation Oncology (London, England). 2012  |   Pubmed ID: 22849723 HybridArc is a novel treatment technique blending aperture-enhanced optimized arcs with discrete IMRT-elements, allowing selection of arcs with a set of static IMRT-beams. This study compared this new technique to helical Tomotherapy, and RapidArc, in preoperative radiotherapy of rectal cancer.
• Early Contralateral Shoulder-arm Morbidity in Breast Cancer Patients Enrolled in a Randomized Trial of Post-surgery Radiation Therapy Breast Cancer : Basic and Clinical Research. 2012  |   Pubmed ID: 22904635 Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity.
• Small Airways Function in Breast Cancer Patients Before and After Radiotherapy Breast Cancer Research and Treatment. Oct, 2012  |   Pubmed ID: 22910929 Radiotherapy treatments for early stage breast cancer patients potentially affect the lung in its most distal air spaces, and previous studies have indicated consistently low baseline values for diffusing capacity in breast cancer patients. We aimed to quantitatively assess baseline small airway function and the acute effects of radiotherapy in breast cancer patients with no confounding effects from respiratory disease or considerable smoking history. In 60 breast cancer patients selected from an ongoing randomized controlled trial, the small airways function was assessed at baseline and 3 months later, after having received either conventional radiotherapy (CR; n = 26) or hypofractionated tomotherapy (TT; n = 34). All indices of small airway function in breast cancer patients were found to be indistinguishable from healthy controls. The total lung capacity was significantly decreased and ventilation heterogeneity was significantly increased 3 months after baseline in the CR arm, but not in the TT arm. When corrected for hemoglobin and lung volume, pulmonary diffusing capacity was not affected by radiotherapy in either treatment arm. Alternatively, discarding patients receiving chemotherapy or loco-regional treatment did not affect these results. We conclude that middle-aged women with breast cancer, but no history of respiratory disease, have normal baseline small airways function. Conventional radiotherapy induces a restrictive pattern and increases heterogeneity of ventilation, the latter most likely resulting from differential expansion between locally irradiated peripheral lung zones and the remainder of the lung. The TT modality did not lead to any such changes.
• Health-related Quality of Life in Survivors of Stage I-II Breast Cancer: Randomized Trial of Post-operative Conventional Radiotherapy and Hypofractionated Tomotherapy BMC Cancer. 2012  |   Pubmed ID: 23098579 Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials. However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionated tomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy.
• Dosimetric Comparison of Different Treatment Modalities for Stereotactic Radiosurgery of Arteriovenous Malformations and Acoustic Neuromas Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Feb, 2013  |   Pubmed ID: 22884842 We investigated the influence of beam modulation on treatment planning by comparing four available stereotactic radiosurgery (SRS) modalities: Gamma-Knife-Perfexion, Novalis-Tx Dynamic-Conformal-Arc (DCA) and Dynamic-Multileaf-Collimation-Intensity-Modulated-radiotherapy (DMLC-IMRT), and Cyberknife.
• Hepatocytes Determine the Hypoxic Microenvironment and Radiosensitivity of Colorectal Cancer Cells Through Production of Nitric Oxide That Targets Mitochondrial Respiration International Journal of Radiation Oncology, Biology, Physics. Mar, 2013  |   Pubmed ID: 22975619 To determine whether host hepatocytes may reverse hypoxic radioresistance through nitric oxide (NO)-induced oxygen sparing, in a model relevant to colorectal cancer (CRC) liver metastases.
• Initial Assessment of Tumor Tracking with a Gimbaled Linac System in Clinical Circumstances: a Patient Simulation Study Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Feb, 2013  |   Pubmed ID: 23398905 To have an initial assessment of the Vero Dynamic Tracking workflow in clinical circumstances and quantify the performance of the tracking system, a simulation study was set up on 5 lung and liver patients.
• Evaluation of the Clinical Usefulness for Using Verification Images During Frameless Radiosurgery Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Jul, 2013  |   Pubmed ID: 23714654 Our previous studies showed that intrafraction motion needs to be corrected for in frameless radiosurgery. This study was designed to evaluate if verification images can correct for mechanical inaccuracy and intrafraction motion. With proper immobilization and verification images on a regular basis during treatment, mechanical (table-) inaccuracies and intrafraction motion can be corrected for and the absence of PTV-margins warranted.
• A Randomized Hypofractionation Dose Escalation Trial for High Risk Prostate Cancer Patients: Interim Analysis of Acute Toxicity and Quality of Life in 124 Patients Radiation Oncology (London, England). 2013  |   Pubmed ID: 24007322 The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. To do so, we carried out a randomized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy (IG-IMRT) in high-risk prostate cancer. Here, we report on acute toxicity and quality of life (QOL) for the first 124 randomized patients.
• Hypoxia Integration in the Serological Proteome Analysis Unmasks Tumor Antigens and Fosters the Identification of Anti-phospho-eEF2 Antibodies As Potential Cancer Biomarkers PloS One. 2013  |   Pubmed ID: 24130777 The expression by tumor cells of proteins with aberrant structure, expression or distribution accounts for the development of a humoral immune response. Autoantibodies (aAb) directed against tumor-associated antigens (TAA) may thus be particularly relevant for early detection of cancer. Serological proteome analysis (SERPA) aims to identify such circulating aAb through the immunoblotting of 2D-separated tumor cell proteins with cancer patient serum and the consecutive MS identification of proteins in reactive spots. This method has the advantage to use post-translationally modified proteins as a source of potential TAA. Here, we applied this strategy by using colorectal tumor cells pre-exposed to hypoxia in order to promote the expression of a pattern of TAA more likely to represent in vivo conditions. We used two human HCT116 and HT29 colorectal cancer cell lines exposed for 48 hours to 1% O2. Spots positive after immunoblotting of 2D-separated lysates of hypoxic cells with the sera of tumor-bearing mice, were collected and analysed by MS for protein identification. Among the hypoxia-specific immunogenic proteins, we identified a phosphorylated form of eukaryotic translation elongation factor 2 (phospho-Thr56 eEF2). We confirmed the increased phosphorylation of this protein in hypoxic colorectal tumor cells as well as in mouse tumors. Using a specific immunoassay, we could detect the presence of corresponding anti-phospho-Thr56 eEF2 aAb in the serum of tumor-bearing mice (vs healthy mice). We further documented that the detection of these aAb preceded the detection of a palpable tumor mass in mice and validated the presence of anti-phospho-Thr56 eEF2 aAb in the serum of patients with adenomatous polyps and colorectal carcinoma. In conclusion, this study validates a phosphorylated form of eEF2 as a new TAA and more generally, provides evidence that integrating hypoxia upstream of SERPA offers a more relevant repertoire of TAA able to unmask the presence of circulating aAb.
• A Complementary Dual-modality Verification for Tumor Tracking on a Gimbaled Linac System Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Dec, 2013  |   Pubmed ID: 24238982 For dynamic tracking of moving tumors, robust intra-fraction verification was required, to assure that tumor motion was properly managed during the course of radiotherapy. A dual-modality verification system, consisting of an on-board orthogonal kV and planar MV imaging device, was validated and applied retrospectively to patient data.
• Preoperative Intensity-modulated and Image-guided Radiotherapy with a Simultaneous Integrated Boost in Locally Advanced Rectal Cancer: Report on Late Toxicity and Outcome Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Jan, 2014  |   Pubmed ID: 24239243 The addition of chemotherapy to preoperative radiotherapy has been established as the standard of care for patients with cT3-4 rectal cancer. As an alternative strategy, we explored intensity-modulated and image-guided radiotherapy (IMRT-IGRT) with a simultaneous integrated boost (SIB) in a prospective phase II study. Here, we report outcome and late toxicity after a median follow-up of 54 months.
• Advances in Radiotherapy and Targeted Therapies for Rectal Cancer World Journal of Gastroenterology : WJG. Jan, 2014  |   Pubmed ID: 24415852 The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy. The stepwise implementation of intensity-modulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery, reducing treatment related toxicity. In addition, the administration of a simultaneous integrated boost offers excellent local control rates. The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches. However, distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread. The expected benefit of targeted therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals, hence hardly justifying rather modest improvements in patient outcomes. On the other hand, the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape. Both N2 neutrophils and myeloid-derived suppressor cells (MDSC) emerge as useful clinical biomarkers of poor prognosis, while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings. Therefore, integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.
• Feasibility of Using the Vero SBRT System for Intracranial SRS Journal of Applied Clinical Medical Physics / American College of Medical Physics. 2014  |   Pubmed ID: 24423838 The Vero SBRT system was benchmarked in a planning study against the Novalis SRS system for quality of delivered dose distributions to intracranial lesions and assessing the Vero system's capacity for SRS. A total of 27 patients with one brain lesion treated on the Novalis system, with 3 mm leaf width MLC and C-arm gantry, were replanned for Vero, with a 5 mm leaf width MLC mounted on an O-ring gantry allowing rotations around both the horizontal and vertical axis. The Novalis dynamic conformal arc (DCA) planning included vertex arcs, using 90° couch rotation. These vertex arcs cannot be reproduced with Vero due to the mechanical limitations of the O-ring gantry. Alternative class solutions were investigated for the Vero. Additionally, to distinguish between the effect of MLC leaf width and different beam arrangements on dose distributions, the Vero class solutions were also applied for Novalis. In addition, the added value of noncoplanar IMRT was investigated in this study. Quality of the achieved dose distributions was expressed in the conformity index (CI) and gradient index (GI), and compared using a paired Student's t-test with statistical significance for p-values ≤ 0.05. For lesions larger than 5 cm3, no statistical significant difference in conformity was observed between Vero and Novalis, but for smaller lesions, the dose distributions showed a significantly better conformity for the Novalis (ΔCI = 13.74%, p = 0.0002) mainly due to the smaller MLC leaf width. Using IMRT on Vero reduces this conformity difference to nonsignificant levels. The cutoff for achieving a GI around 3, characterizing a sharp dose falloff outside the target volume was 4 cm3 for Novalis and 7 cm3 for Vero using DCA technique. Using noncoplanar IMRT, this threshold was reduced to 3 cm3 for the Vero system. The smaller MLC and the presence of the vertex fields allow the Novalis system to better conform the dose around the lesion and to obtain steeper dose falloff outside the lesion. Comparable dosimetric characteristics can be achieved with Vero for lesions larger than 3 cm3 and using IMRT.
• Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Different Non-invasive Techniques for Additional Boost Delivery Radiation Oncology (London, England). 2014  |   Pubmed ID: 24467916 Today it is unclear which technique for delivery of an additional boost after whole breast radiotherapy for breast conserved patients should be state of the art. We present a dosimetric comparison of different non-invasive treatment techniques for additional boost delivery.
• Impact of Planning Target Volume Margins and Rectal Distention on Biochemical Failure in Image-guided Radiotherapy of Prostate Cancer Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Apr, 2014  |   Pubmed ID: 24631146 A previous study in our department demonstrated the negative impact on freedom from biochemical failure (FFBF) of using too narrow planning target volume (PTV) margins during prostate image-guided radiotherapy (IGRT). Here, we investigated the impact of appropriate PTV margins and rectal distention on FFBF.
• Treating Patients with Real-time Tumor Tracking Using the Vero Gimbaled Linac System: Implementation and First Review Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Sep, 2014  |   Pubmed ID: 25049177 To report on the first clinical application of a real-time tumor tracking (RTTT) solution based on the Vero SBRT gimbaled linac system for treatment of moving tumors.
• Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Sequential Versus Simultaneous Integrated Photon Boost BioMed Research International. 2014  |   Pubmed ID: 25162031 Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast.
• Fiducial Marker and Marker-less Soft-tissue Detection Using Fast MV Fluoroscopy on a New Generation EPID: Investigating the Influence of Pulsing Artifacts and Artifact Suppression Techniques Medical Physics. Oct, 2014  |   Pubmed ID: 25281963 Because frame rates on current clinical available electronic portal imaging devices (EPID's) are limited to 7.5 Hz, a new commercially available PerkinElmer EPID (XRD 1642 AP19) with a maximum frame rate of 30 Hz and a new scintillator (Kyokko PI200) with improved sensitivity (light output) for megavolt (MV) irradiation was evaluated. In this work, the influence of MV pulse artifacts and pulsing artifact suppression techniques on fiducial marker and marker-less detection of a lung lesion was investigated, because target localization is an important component of uncertainty in geometrical verification of real-time tumor tracking.
• Impact of Inadequate Respiratory Motion Management in SBRT for Oligometastatic Colorectal Cancer Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Nov, 2014  |   Pubmed ID: 25441611 Stereotactic body radiotherapy (SBRT) in oligometastatic colorectal cancer (CRC) resulted in a disappointing 1-year local control rate of 54% in our experience. We aimed to determine the root cause(s).
• Improving the Intra-fraction Update Efficiency of a Correlation Model Used for Internal Motion Estimation During Real-time Tumor Tracking for SBRT Patients: Fast Update or No Update? Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Sep, 2014  |   Pubmed ID: 25443498 For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated.
• Analysis of the Targeting Uncertainty of a Stereotactic Frameless Radiosurgery Technique for Arteriovenous Malformation Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. Dec, 2014  |   Pubmed ID: 25454170 In order to target arteriovenous malformations (AVM) in a frameless approach, registration of two-dimensional (2D) digital-subtracted-angiographs (DSA) with three-dimensional (3D) computed tomography (CT) is required. Targeting accuracy and delineation of a frameless 2D-DSA and 3D-CT image registration tool based on bony anatomy of the skull was evaluated. This frameless approach assures accurate target localization and can be used in a clinical setting.
• Anti-melanoma Vaccines Engineered to Simultaneously Modulate Cytokine Priming and Silence PD-L1 Characterized Using Ex Vivo Myeloid-derived Suppressor Cells As a Readout of Therapeutic Efficacy Oncoimmunology. 2014  |   Pubmed ID: 25954597 Efficacious antitumor vaccines strongly stimulate cancer-specific effector T cells and counteract the activity of tumor-infiltrating immunosuppressive cells. We hypothesised that combining cytokine expression with silencing programmed cell death ligand 1 (PD-L1) could potentiate anticancer immune responses of lentivector vaccines. Thus, we engineered a collection of lentivectors that simultaneously co-expressed an antigen, a PD-L1-silencing shRNA, and various T cell-polarising cytokines, including interferon γ (IFNγ), transforming growth factor β (TGFβ) or interleukins (IL12, IL15, IL23, IL17A, IL6, IL10, IL4). In a syngeneic B16F0 melanoma model and using tyrosinase related protein 1 (TRP1) as a vaccine antigen, we found that simultaneous delivery of IL12 and a PD-L1-silencing shRNA was the only combination that exhibited therapeutically relevant anti-melanoma activities. Mechanistically, we found that delivery of the PD-L1 silencing construct boosted T cell numbers, inhibited in vivo tumor growth and strongly cooperated with IL12 cytokine priming and antitumor activities. Finally, we tested the capacities of our vaccines to counteract tumor-infiltrating myeloid-derived suppressor cell (MDSC) activities ex vivo. Interestingly, the lentivector co-expressing IL12 and the PD-L1 silencing shRNA was the only one that counteracted MDSC suppressive activities, potentially underlying the observed anti-melanoma therapeutic benefit. We conclude that (1) evaluation of vaccines in healthy mice has no significant predictive value for the selection of anticancer treatments; (2) B16 cells expressing xenoantigens as a tumor model are of limited value; and (3) vaccines which inhibit the suppressive effect of MDSC on T cells in our ex vivo assay show promising and relevant antitumor activities.
• Quality Assurance of a 50-kV Radiotherapy Unit Using EBT3 GafChromic Film: A Feasibility Study Technology in Cancer Research & Treatment. Jan, 2015  |   Pubmed ID: 25575576 Radiochromic EBT3 film is gaining acceptance as a valuable dosimetry system for high-energy photon beams. The advantages of these films over other dosimetry systems are low spectral sensitivity and high spatial resolution. The aim of this study was to validate EBT3 film as a dosimeter for machine and treatment quality assurance (QA) of a 50-kV radiotherapy unit.
• Advances in Radiotherapy Delivery for Rectal Cancer: a European Perspective Expert Review of Gastroenterology & Hepatology. Apr, 2015  |   Pubmed ID: 25644307 Preoperative chemoradiotherapy and radiotherapy with an integrated boost offer excellent local control rates in patients with rectal cancer. The introduction of intensity-modulated radiotherapy and image-guided radiotherapy has drastically improved the tolerance of these treatments. The new challenge is developing organ-preserving strategies and curative treatments for medically inoperable patients. Contact radiotherapy seems efficient for small tumors. Tumor hypoxia limits the success of radiotherapy for locally advanced cancers. Modulation of the L-arginine/iNOS pathway and implementation of hypoxia imaging in radiotherapy planning may overcome this hurdle.
• Stromal Contribution to the Colorectal Cancer Transcriptome Nature Genetics. Apr, 2015  |   Pubmed ID: 25706627 Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.
• Ex Vivo Generation of Myeloid-derived Suppressor Cells That Model the Tumor Immunosuppressive Environment in Colorectal Cancer Oncotarget. Mar, 2015  |   Pubmed ID: 25869209 Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in tumor-bearing subjects and which strongly inhibit anti-cancer immune responses. To study the biology of MDSC in colorectal cancer (CRC), we cultured bone marrow cells in conditioned medium from CT26 cells, which are genetically modified to secrete high levels of granulocyte-macrophage colony-stimulating factor. This resulted in the generation of high numbers of CD11b+ Ly6G+ granulocytic and CD11b+ Ly6C+ monocytic MDSC, which closely resemble those found within the tumor but not the spleen of CT26 tumor-bearing mice. Such MDSC potently inhibited T-cell responses in vitro, a process that could be reversed upon blocking of arginase-1 or inducible nitric oxide synthase (iNOS). We confirmed that inhibition of arginase-1 or iNOS in vivo resulted in the stimulation of cytotoxic T-cell responses. A delay in tumor growth was observed upon functional repression of both enzymes. These data confirm the role of MDSC as inhibitors of T-cell-mediated immune responses in CRC. Moreover, MDSC differentiated in vitro from bone marrow cells using conditioned medium of GM-CSF-secreting CT26 cells, represent a valuable platform to study/identify drugs that counteract MDSC activities.
• Geometric Verification of Dynamic Wave Arc Delivery With the Vero System Using Orthogonal X-ray Fluoroscopic Imaging International Journal of Radiation Oncology, Biology, Physics. Mar, 2015  |   Pubmed ID: 25962626 The purpose of this study was to define an independent verification method based on on-board orthogonal fluoroscopy to determine the geometric accuracy of synchronized gantry-ring (G/R) rotations during dynamic wave arc (DWA) delivery available on the Vero system.
• A Comparison of Two Clinical Correlation Models Used for Real-time Tumor Tracking of Semi-periodic Motion: A Focus on Geometrical Accuracy in Lung and Liver Cancer Patients Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. May, 2015  |   Pubmed ID: 25981054 A head-to-head comparison of two clinical correlation models with a focus on geometrical accuracy for internal tumor motion estimation during real-time tumor tracking (RTTT).
• Tangential IMRT Versus TomoTherapy with and Without Breath-hold in Left-sided Whole Breast Irradiation Acta Oncologica (Stockholm, Sweden). May, 2015  |   Pubmed ID: 25997704
• A Multi-centre Analysis of Treatment Procedures and Error Components in Dynamic Tumour Tracking Radiotherapy Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. May, 2015  |   Pubmed ID: 25998806 This study aimed to compare procedures for dynamic tumour tracking (DTT) using a gimbal-mounted linac between centres in Japan (KU-IBRI) and Belgium (UZB), to quantify tracking error (TE), and to estimate tumour-fiducial uncertainties and PTV margins.