Training of radiotherapy professionals: status, content, satisfaction and improvement suggestions in the Greater Region.

BACKGROUND: The initial training of Radiation Oncology professionals can vary widely across Europe. The aim of this study was to assess the status and content of the initial training programs currently implemented in the Greater Region: Lorraine (Nancy, France), Saarland (Homburg, Germany), Luxembourg, and Liège (Wallonia, Belgium). METHODS: A survey was developed to investigate (1) the overall satisfaction, learning objectives, and teaching methods used during initial training programs and (2) the perceptions of the importance of key professional competencies as described by the CanMEDS (a framework that identifies and describes the abilities physicians require to effectively meet the health care needs of the people they serve). In addition, open-ended questions were used to elicit opinions on room for improvement. Participants (N = 38) were physicians (radiation oncologists (RO) seniors and residents) and radiation therapists (RTTs). RESULTS: Only 21.1% of the respondents declared having acquired all the competencies required for their professional practice during their initial training. Heterogeneity in teaching methods was noted within professional programs but there is no difference between those from RO and RTT in the teaching of technical and relational skills. Relational skills were not addressed in a range of 39.5-57.9% of respondent's curricula. More practical lessons were deemed necessary to improve radiotherapy (RT) training programs. CONCLUSIONS: Radiation oncology professionals expressed the need for more practical teaching, especially in the training of non-technical skills. Regarding the perceived importance of professional aptitudes, radiation oncology professionals highlighted medical and relational skills as the most important competencies.

Prospective validation of stringent dose constraints for prostatic stereotactic radiation monotherapy: results of a single-arm phase II toxicity-oriented trial.

PURPOSE: There are no safety-focused trials on stereotactic body radiotherapy (SBRT) for localized prostate cancer. This prospective 3­year phase II trial used binomial law to validate the safety and efficacy of SBRT with stringent organ at risk dose constraints that nevertheless permitted high planning target volume doses. METHODS: All consecutive ≥ 70-year-old patients with localized prostate adenocarcinoma who underwent SBRT between 2014 and 2018 at the National Radiotherapy Center in Luxembourg were included. Patients with low Cancer of Prostate Risk Assessment (CAPRA) scores (0-2) and intermediate scores (3-5) received 36.25 Gy. High-risk (6-10) patients received 37.5 Gy. Radiation was delivered in 5 fractions over 9 days with Cyberknife-M6™ (Accuray, Sunnyvale, CA, USA). Primary study outcome was Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) genitourinary and rectal toxicity scores at last follow-up. Based on binomial law, SRBT was considered safe in this cohort of 110 patients if there were ≤ 2 severe toxicity (CTCAEv4 grade ≥ 3) cases. Secondary outcomes were biochemical progression-free survival (bPFS) and patient quality of life (QOL), as determined by the IPPS and the Urinary Incontinence QOL questionnaire. RESULTS: The first 110 patients who were accrued in a total cohort of 150 patients were included in this study and had a median follow-up of 36 months. Acute grade ≥ 3 toxicity never occurred. One transient late grade 3 case was observed. Thus, our SBRT program had an estimated severe toxicity rate of < 5% and was safe at the p < 0.05 level. Overall bPFS was 90%. QOL did not change relative to baseline. CONCLUSION: The trial validated our SBRT regimen since it was both safe and effective.

Assessing the neuroanatomy knowledge and spatial ability of radiotherapy technologist undergraduates using an interactive volumetric simulation tool-the RadioLOG project.

OBJECTIVE: To assess the use of a volumetric image display simulation tool (VDST) for the evaluation of applied radiological neuroanatomy knowledge and spatial understanding of radiotherapy technologist (RTT) undergraduates. METHODS: Ninety-two third-year RTT students from three French RTT schools took an examination using software that allows visualization of multiple volumetric image series. To serve as a reference, 77 first- and second-year undergraduates, as well as ten senior neuroradiologists, took the same examination. The test included 13 very-short-answer questions (VSAQ) and 21 exercises in which examinees positioned markers onto preloaded brain MR images from a healthy volunteer. The response time was limited. Each correct answer scored 100 points, with a maximum possible test score of 3,400 (VSAQ = 1,300; marker exercise = 2,100). Answers were marked automatically for the marker positioning exercise and semi-automatically for the VSAQs against prerecorded expected answers. RESULTS: Overall, the mean test score was 1,787 (150-3,300) and the standard deviation was 781. Scores were highly significantly different between all evaluated groups (p < 0.001). The interoperator reproducibility was 0.90. All the evaluated groups could be discriminated by VSAQ, marker, and overall total scores independently (p ≤ 0.0001 to 0.001). The test was able to discriminate between the three schools either by VSAQ scores (p < 0.001 to 0.02) or by overall total score (p < 0.001 to 0.05). CONCLUSION: This software is a high-quality evaluation tool for the assessment of radiological neuroanatomy knowledge and spatial understanding in RTT undergraduates. KEY POINTS: • This VDST allows volumetric image analysis of MR studies. • A high reliability test could be created with this tool. • Test scores were strongly associated with the examinee expertise level.

Well-Differentiated Papillary Mesothelioma of the Peritoneum: A Retrospective Study from the RENAPE Observational Registry.

BACKGROUND: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature. OBJECTIVE: We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry. PATIENTS AND METHODS: All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed. RESULTS: We report on 56 patients with a mean age of 52 years (range 21-74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0-33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified. CONCLUSIONS: Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE).

BACKGROUND: Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity - including second malignancies - reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively. METHODS/DESIGN: ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (γH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease...) will be reported. DISCUSSION: ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology. TRIAL REGISTRATION: ID-RCB number: 2015-A00975-44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016.

Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.

Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.

Hematopoietic stem cells develop in the absence of endothelial cadherin 5 expression.

Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from cadherin 5 (Cdh5; vascular endothelial-cadherin)(+) endothelial precursors, and isolated populations of Cdh5(+) cells from mouse embryos and embryonic stem cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Because Cdh5(-/-) mice embryos die before the first HSCs emerge, it is unknown whether Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlb(bw306)), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Using time-lapse confocal imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5(-/-)green fluorescent protein (GFP)(+/+) cells in chimeric mice, we demonstrated that Cdh5(-/-)GFP(+/+) HSCs emerging from embryonic day 10.5 and 11.5 (E10.5 and E11.5) AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multilineage adult blood. We also developed a conditional mouse Cdh5 knockout (Cdh5(flox/flox):Scl-Cre-ER(T)) and demonstrated that multipotent hematopoietic colonies form despite the absence of Cdh5. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs.

A HELLP syndrome complicates a gestational trophoblastic neoplasia in a perimenopausal woman: a case report.

BACKGROUND: HELLP syndrome is a combination of symptoms described as hemolysis, elevated liver enzymes and low platelets, that complicates 0.01-0.6 % of pregnancies. HELLP syndrome has been scarcely reported associated with partial moles, another rare complication of pregnancy. This manuscript describes the only reported case of HELLP syndrome associated with a complete invasive hydatiform mole. CASE PRESENTATION: We report a perimenopausal patient in prolonged remission from an uncommon high-risk invasive complete mole. The diagnosis was set in a context of early onset preeclampsia and HELLP syndrome. The development of life-threatening complications required primary hysterectomy. Postoperative hCG quickly returned to normal with EMA/CO multi-agent chemotherapy. CONCLUSION: Our patient is in prolonged remission from a complete mole complicated with EOP and HELLP syndrome. This exceptional case of complicated gestational trophoblastic neoplasia reflects a very rare condition in which several risk factors for placental ischemia are associated. Emergency hysterectomy should be considered as salvage initial treatment in such life-threatening situations.

Evaluation of the Prognostic Value of Pretherapeutic Magnetic Resonance Imaging in Predicting Soft Tissue Sarcoma Radiation Response: A Retrospective Study from a Large Institutional Sarcoma Imaging Database.

Background: RT-induced hyalinization/fibrosis was recently evidenced as a significant independent predictor for complete response to neoadjuvant radiotherapy (RT) and survival in patients with soft tissue sarcoma (STS). Purpose: Non-invasive predictive markers of histologic response after neoadjuvant RT of STS are expected. Materials and Methods: From May 2010 to April 2017, patients with a diagnosis of STS who underwent neoadjuvant RT for limb STS were retrieved from a single center prospective clinical imaging database. Tumor Apparent Diffusion Coefficients (ADC) and areas under the time-intensity perfusion curve (AUC) were compared with the histologic necrosis ratio, fibrosis, and cellularity in post-surgical specimens. Results: We retrieved 29 patients. The median ADC value was 134.3 × 10-3 mm2/s. ADC values positively correlated with the post-treatment tumor necrosis ratio (p = 0.013). Median ADC values were lower in patients with less than 50% necrosis and higher in those with more than 50% (120.3 × 10-3 mm2/s and 202.0 × 10-3 mm2/s, respectively (p = 0.020). ADC values higher than 161 × 10-3 mm2/s presented a 95% sensitivity and a 55% specificity for the identification of tumors with more than 50% tumor necrosis ratio. Tumor-to-muscle AUC ratios were associated with histologic fibrosis (p = 0.036). Conclusions: ADC and perfusion AUC correlated, respectively, with radiation-induced tumor necrosis and fibrosis.

Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

A single formula to describe radiation-induced protein relocalization: towards a mathematical definition of individual radiosensitivity.

Immunofluorescence with antibodies against DNA damage repair and signaling protein is revolutionarising the estimation of the genotoxic risk. Indeed, a number of stress response proteins relocalize in nucleus as identifiable foci whose number, pattern and appearance/disappearance rate depend on several parameters such as the stress nature, dose, time and individual factor. Few authors proposed biomathematical tools to describe them in a unified formula that would be relevant for all the relocalizable proteins. Based on our two previous reports in this Journal (Foray et al., 2005; Gastaldo et al., 2008), we considered that foci response to stress is composed of a recognition and a repair phase, both described by an inverse power function provided from a Euler's Gamma distribution. The resulting unified formula called "Bodgi's function" is able to describe appearance/disappearance kinetics of nuclear foci after any condition of genotoxic stress. By applying the Bodgi's formula to DNA damage repair data from 45 patients treated with radiotherapy, we deduced a classification of human radiosensitivity based on objective molecular criteria, notably like the number of unrepaired DNA double-strand breaks and the radiation-induced nucleo-shuttling of the ATM kinase.

Lighting Up the Fire in the Microenvironment of Cold Tumors: A Major Challenge to Improve Cancer Immunotherapy.

Immunotherapy includes immune checkpoint inhibitors (ICI) such as antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death protein/programmed death ligand 1 (PD-1/PD-L1) axis. Experimental and clinical evidence show that immunotherapy based on immune checkpoint inhibitors (ICI) provides long-term survival benefits to cancer patients in whom other conventional therapies have failed. However, only a minority of patients show high clinical benefits via the use of ICI alone. One of the major factors limiting the clinical benefits to ICI can be attributed to the lack of immune cell infiltration within the tumor microenvironment. Such tumors are classified as "cold/warm" or an immune "desert"; those displaying significant infiltration are considered "hot" or inflamed. This review will provide a brief summary of different tumor properties contributing to the establishment of cold tumors and describe major strategies that could reprogram non-inflamed cold tumors into inflamed hot tumors. More particularly, we will describe how targeting hypoxia can induce metabolic reprogramming that results in improving and extending the benefit of ICI.

Stereotactic focal radiotherapy as an alternative treatment for low-risk prostate cancer: Results of a single-arm monocenter Phase-II trial.

Introduction: Since radical treatments in low risk prostate cancer do not improve overall survival in comparison to active surveillance, preserving quality of life (QOL) remains the key objective. Active surveillance of indolent prostate cancer avoids curative treatment side-effects but necessitates repeated biopsies. Focal stereotactic body radiation therapy (focal SBRT) may be an alternative. This non-randomized Phase-II trial examined the feasibility and safety of focal SBRT for low and favorable intermediate-risk prostate cancer. Methods: Patients were recruited in 2016-2019 if they had: localized CAPRA ≤ 3 prostate adenocarcinoma; an isolated PIRADS≥4 macroscopic tumor on MRI; WHO Performance Status 0-1; and no major urinary symptoms. 36.25 Gy (80% isodose prescription) were delivered in 5 fractions every other day. Primary outcome was delay between focal SBRT and salvage-treatment initiation. Secondary outcomes were: acute/late genitourinary/rectal toxicity; biological, clinical and MRI local control; and change in QOL measures. Results: Over a median follow-up of 36 months, salvage prostatectomy in the 24 eligible patients was never required. Three-year biochemical progression-free survival was 96%. The single biochemical recurrence was a small (2-mm) Gleason 6 (3 + 3) lesion in the non-irradiated lobe. All 19 patients with ≥1 post-treatment MRI evaluations demonstrated complete radiological response. Acute/late grade ≥3 toxicities did not occur: all acute toxicities were grade-1 genitourinary (38% patients), grade-2 genitourinary (8%), or grade-1 rectal (13%) toxicities. There was one (4%) late grade-1 genitourinary toxicity. QOL was unchanged at last follow-up, as shown by IPSS (2.86 to 3.29, p>0.05), U-QOL (0.71 to 0.67, p>0.05), and IIEF5 (the 14 initially potent patients maintained potency (IIEF5 > 16)). Conclusion: Focal SBRT is feasible, well-tolerated, and preserves QOL. This innovative robotized approach challenges active surveillance.

Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline.

PURPOSE: Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). MATERIALS AND METHODS: A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. RESULTS: Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. CONCLUSION: New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

The Normal, the Radiosensitive, and the Ataxic in the Era of Precision Radiotherapy: A Narrative Review.

(1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tumoricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume constraints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we conducted a critical review of the current state of the knowledge on individual determinants of cellular/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large translational studies implement various tests and enriched NTCP models designed to improve the prediction of toxicities. iRS testing could better support informed radiotherapy decisions for individuals with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy's risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radiotherapy protocols relying on extended NTCP models integrating iRS.

Initial PCV Chemotherapy Followed by Radiotherapy Is Associated With a Prolonged Response But Late Neurotoxicity in 20 Diffuse Low-Grade Glioma Patients.

Background: Study RTOG 9802 in high-risk diffuse low-grade gliomas (DLGGs) showed the potential synergistic effect on survival of the procarbazine, CCNU, and vincristine (PCV) radiotherapy (RT) combination. Limited data on long-term neurocognitive impact and quality of life (QoL) have yet been reported. Patients and Methods: We described a monocentric series of patients treated at first line by the combination of PCV immediately followed by RT between January 01, 1982 and January 01, 2017. Radiological data were collected and included volume, velocity of diametric expansion (VDE), and MRI aspects. Long-term neurocognitive and QoL were analyzed. Results: Twenty patients fulfilled the eligibility criteria. The median response rate was 65.1% (range, 9.6%-99%) at the time of maximal VDE decrease corresponding to a median volume reduction of 79.7 cm3 (range, 3.1 to 174.2 cm3), which occurred after a median period of 7.2 years (range, 0.3-21.9) after the end of RT. An ongoing negative VDE was measured in 13/16 patients after the end of RT, with a median duration of 6.7 years (range, 9 months-21.9 years). The median follow-up since radiological diagnosis was 17.5 years (range, 4.8 to 29.5). Estimated median survival was 17.4 years (95% CI: 12; NR). After a long-term follow-up, substantial neurotoxicity was noticed with dementia in six progression-free patients (30%), leading to ventriculo-peritoneal shunt procedures in three, and premature death in five. Thirteen patients (65%) were unable to work with disability status. Successive longitudinal neurocognitive assessments for living patients showed verbal episodic memory deterioration. Conclusions: PCV-RT combination seems to have not only an oncological synergy but also a long-term neurotoxic synergy to consider before initial therapeutic decision.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies.

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

Cranial organs at risk delineation: heterogenous practices in radiotherapy planning.

BACKGROUND: Segmentation is a crucial step in treatment planning that directly impacts dose distribution and optimization. The aim of this study was to evaluate the inter-individual variability of common cranial organs at risk (OAR) delineation in neurooncology practice. METHODS: Anonymized simulation contrast-enhanced CT and MR scans of one patient with a solitary brain metastasis was used for delineation and analysis. Expert professionals from 16 radiotherapy centers involved in brain structures delineation were asked to segment 9 OAR on their own treatment planning system. As reference, two experts in neurooncology, produced a unique consensual contour set according to guidelines. Overlap ratio, Kappa index (KI), volumetric ratio, Commonly Contoured Volume, Supplementary Contoured Volume were evaluated using Artiview™ v 2.8.2-according to occupation, seniority and level of expertise of all participants. RESULTS: For the most frequently delineated and largest OAR, the mean KI are often good (0.8 for the parotid and the brainstem); however, for the smaller OAR, KI degrade (0.3 for the optic chiasm, 0.5% for the cochlea), with a significant discrimination (p < 0.01). The radiation oncologists, members of Association des Neuro-Oncologue d'Expression Française society performed better in all indicators compared to non-members (p < 0.01). Our exercise was effective in separating the different participating centers with 3 of the reported indicators (p < 0.01). CONCLUSION: Our study illustrates the heterogeneity in normal structures contouring between professionals. We emphasize the need for cerebral OAR delineation harmonization-that is a major determinant of therapeutic ratio and clinical trials evaluation.

Proof of Concept of a Binary Blood Assay for Predicting Radiosensitivity.

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.