Chronic Voluntary Binge Ethanol Consumption Causes Sex-Specific Differences in Microglial Signaling Pathways and Withdrawal-associated Behaviors in Mice.

BACKGROUND: Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward. However, the microglial molecular and cellular pathways associated with EtOH binge consumption remain poorly understood. METHOD: In this study, adult C57BL/6J male and female mice were subjected daily to a gelatin-based drinking-in-the-dark voluntary EtOH consumption paradigm (3 h/d for 4 months) to characterize EtOH consumption and withdrawal-associated and anxiety-like behaviors. Brain microglia were isolated at the end and analyzed for protein expression profile changes using unbiased mass spectrometry-based proteomic analysis. RESULTS: Both male and female mice consistently consumed binge quantities of EtOH daily, resulting in blood EtOH levels > 80 mg/dl measured at the end of the 3-hour daily consumption period. Although female mice consumed a significantly greater amount of EtOH than male mice, EtOH withdrawal-associated anxiety-like behaviors measured by marble-burying, light-dark box, and elevated plus maze tests were predominantly observed in male mice. Proteomic analysis of microglia isolated from the brains of animals at the end of the 4-month binge EtOH consumption identified 117 and 37 proteins that were significantly up- or downregulated in EtOH-exposed male and female mice, respectively, compared to their pair-fed controls. Protein expression profile-based pathway analysis identified several cellular pathways that may underlie the sex-specific and EtOH withdrawal-associated behavioral abnormalities. CONCLUSION: Taken together, our findings revealed sex-specific changes in EtOH withdrawal-associated behaviors and signaling pathways in the mouse brain microglia and may help advance our understanding of the molecular, cellular, and behavioral changes related to human binge EtOH consumption.

Prognostic and therapeutic factors of gliosarcoma from a multi-institutional series.

The aims of this multicentre retrospective study were to identify prognostic or therapeutic factors impacting on overall survival in patients with gliosarcoma. The analysis included all patients treated for gliosarcoma between 1998 and 2014 in seven French academic centres. Seventy-five patients with a median age of 60 years (range from 23 to 79 years) were treated with a combination of surgery (n = 66), radiotherapy (adjuvant for 64 patients and exclusive for 8 patients) and temozolomide based chemotherapy (n = 58). Median follow-up was 12 months (range from 2 to 71 months). Two-year overall survival (OS) and disease free survival rates were 12 % (95 % CI 4-20 %) and 2 % (95 % CI 0-6 %), respectively. The median OS was 13 months. Treatment at recurrence consisted of chemotherapy (n = 38) (bevazicumab for 18 patients, repeat temozolomide for 10 patients), salvage surgery (n = 8) and radiochemotherapy (n = 1). In univariate analysis, younger age, higher total dose of radiotherapy, longer time to recurrence and treatment at recurrence significantly increased OS. In multivariate analysis, high total dose of radiotherapy (HR = 0.97, p = 0.007) and treatment at recurrence (HR = 0.28, p < 0.001) were favourable prognostic factors of OS. Radiotherapy at a minimum dose of 54 Gy and salvage treatment increased OS of gliosarcoma. Unlike glioblastoma, in our analysis, TMZ based chemotherapy was not associated with an improvement in OS compared to patients who received radiation therapy only.

Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation.

OBJECTIVE: To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. METHODS: Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was tend; MR acquisitions performed at tend-2M, tend-4M and tend-6M (respectively 2, 4 and 6 months before tend) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from tend-4M to tend-2M and ∆B from tend-6M to tend-4M. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. RESULTS: The fraction of hypoperfused tumor volume (F_hPg) was a relevant biomarker. A ratio R(F_hPg) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at tend compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). CONCLUSION: Iterative analysis of F_hPg from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. KEY POINTS: • Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. • Biomarkers were assessed through their patterns of variation during the follow-up. • The fraction of hypoperfused tumour volume (F_hP g ) seemed to be a relevant biomarker. • An innovative ratio R(F_hP g ) could be an early surrogate marker of relapse. • A significant time gain could be achieved in the management of GBM patients.

[Management of patients with metastatic cutaneous melanoma: French national guidelines. French National Cancer Institute]. / Prise en charge thérapeutique des patients atteints d'un mélanome cutané métastatique : recommandations nationales françaises. L'Institut national du cancer.

BACKGROUND: Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy. AIMS: Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. RESULTS: This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.

Management of Graves' ophthalmopathy by radiotherapy: A literature review.

Orbital radiotherapy for Graves' ophthalmopathy is an example of non-oncological radiotherapy. First introduced in the 1930s, this treatment has become widely used since the 1980s with several studies showing proof of both effectiveness and safety: a decrease of soft tissue involvement in 70 to 80% of patients and an improvement of ocular mobility in 30 to 80% of patients. Nowadays, it's one of the second line treatment options recognized by the European Group on Graves' orbitopathy in the management of a moderate to severe and active disease after failure of glucocorticoids. In that setting, orbital radiotherapy should be combined with glucocorticoids. To our knowledge, there are no practical recommendations on how orbital radiotherapy should be planned and conducted for Graves' ophthalmopathy. Optimal dose is not defined however the most frequent regimen consists of 20Gy in ten fractions of 2Gy, though other options may yield better results. Lastly, the use of modern technique of radiotherapy such as intensity-modulated radiation therapy may allow a better sparing of organs at risk compared to three-dimensional radiotherapy using lateral opposing fields.

[Abscopal effect: Myth or reality?] / Effet abscopal : mythe ou réalité ?

The abscopal effect has been mentioned since 1953. The increase in knowledge about the immune system and the development of immunotherapies support its potential therapeutic interest. While it is accepted that radiotherapy induces an immune response, demonstrating its systemic impact is not easy. The preclinical basis is solid but its clinical validation pending. Radiotherapy rarely induces tumor reduction at a distance from the beams, probably due to its immunosuppressive effect. This is why a synergy between radiotherapy and systemic treatments targeting these immunosuppressive mechanisms was observed. Several parameters can modulate the induction of the abscopal effect. Among these, the fractionation of the dose seems to be determining with currently a pre-eminence of hypofractionated stereotaxis. On the other hand, even if the choice of more immunogenic targets (liver, lung) should be favoured, the optimal number of lesions to be irradiated remains to be defined as well as the minimum volume allowing sufficient release of tumor antigens. The impact of radiation-induced lymphopenia on radiotherapy/immunotherapy efficacy needs to be assessed more precisely, as does the effect of radiotherapy techniques on them. Finally, the choice of immunotherapy(ies) and the combination regimen with radiotherapy remain under discussion. A sequential scheme appears to provide less toxicities but the concomitant would lead to a better response. The study of these different parameters should allow us to deliver optimized radiotherapy/immunotherapy(ies) combinations to our metastatic patients in order to benefit as many people as possible from this abscopal effect.

[Role of radiotherapy in haematology]. / Place de la radiothérapie en hématologie.

The management of myeloid and lymphoid disease is essentially based on chemotherapy and targeted therapies. Since radiotherapy could be responsible for severe late toxicities, essentially due to conventional bidimensional irradiation techniques, many trials have attempted to omit radiotherapy or to scale down the dose in their therapeutic strategy. Nevertheless, radiotherapy still plays a role for curative or symptomatic purposes.

[Extreme hypofractionated radiation therapy for pancreatic cancer]. / Radiothérapie hypofractionnée extrême du cancer du pancréas.

Pancreatic cancer has poor prognosis and a continuously growing incidence. By 2030, it should become the second cause of death by cancer worldwide and in France. The only curative treatment is surgery that is achievable in only 20% of patients at the time of initial diagnosis, with a high rate of incomplete resection. Neoadjuvant treatments using chemotherapy with or without radiotherapy are more often admitted to play an important role by selecting non-progressing cases who will benefit from surgery, by increasing the number of complete resection, and by making locally advanced and borderline tumours accessible to resection. However, the role of radiotherapy is still debated. Because of its dosimetric advantages, its short total duration, and its good tolerance with reduced volumes of irradiation, stereotactic radiotherapy has been largely studied. Compared to chemoradiotherapy, this technique could improve the therapeutic index helping to preserve the general status of patients in order to give them access to secondary surgery. It remains a promising technique still under evaluation, to be delivered ideally, as part of a clinical trial, or within an experimented team.

[Seeking colleagues' advice when facing complex clinical situations]. / Savoir « passer la main ¼ devant une situation complexe.

Seeking a second medical advice as a medical practitioner is a frequent situation that should be facilitated to best suit patients' expectations, while maintaining medical confidentiality. The patient and his relatives need to be involved with diagnostic and therapeutic procedures. The radiation oncologist should accept and help a patient who seeks a second advice, and patients will always appreciate when the physician helps them to seek such an advice. Examples that each practitioner should know include tertiary centers tumor boards, centers with access to innovation or clinical research, or with special teams to take care of specific populations such as adolescents and young adults. In some situations, no treatment can also be the best treatment, and it takes time to explain and discuss such watchful waiting strategies to patients. In case of recurrent disease after radiotherapy, salvage reirradiation must be discussed at a tertiary tumor board and weighed against other options, especially for rare and complex cases. Radiation oncology has gained multiple options with technological advances, such as proton therapy, brachytherapy, stereotactic body radiotherapy with respiratory tracking or contact therapy. Radiation oncologists must know the benefits associated with each option in terms of survival, local control or organ preservation in order to address patients to the best practitioner.

[Total skin electron beam therapy for early-stage mycosis fungoides: immediate results and long-term follow-up in 68 patients]. / Electronthérapie corporelle totale du mycosis fongoïde aux stades précoces: 68 cas.

BACKGROUND: Our aim was to evaluate the efficacy of total skin electron beam therapy (TSEB) in the management of early-stage mycosis fungoides in order to assess its position in relation to other skin-directed therapies. PATIENTS AND METHODS: A retrospective study of 68 patients (30 in stage T1 and 38 in stage T2). RESULTS: The median treatment duration was 6 weeks. Three months after the end of TSEB, a complete clinical response occurred in 66 patients (97%). The most marked effects of acute toxicity included localized ulcerations in 13 patients (13.2%) not requiring hospitalization. Mean follow-up was 6.5 years (1.6 to 28.7). The overall survival rates at 5 and 10 years were 86% and 71%, respectively. Thirty-nine patients (57.4%) experienced relapse with a mean disease-free interval of 1.8 years. The disease-free survival rates at 5 and 10 years were 41% and 31%, respectively. This rate was higher when TSEB was performed early (p=0.031). Twenty-one years after TSEB, only one case of cutaneous malignancy (basal cell carcinoma) was noted. DISCUSSION: Because of its high response rates and rapidity of action, TSEB should be considered as first-line therapy in the management of early-stage mycosis fungoides.

RILA blood biomarker as a predictor of radiation-induced sarcoma in a matched cohort study.

PURPOSE: Radiation-induced sarcoma (RIS) is a rare but serious event. Its occurrence has been discussed during the implementation of new radiation techniques and justified appropriate radioprotection requirements. New approaches targeting intrinsic radio-sensitivity have been described, such as radiation-induced CD8 T-lymphocyte apoptosis (RILA) able to predict late radio-induced toxicities. We studied the role of RILA as a predisposing factor for RIS as a late adverse event following radiation therapy (RT). PATIENTS AND METHODS: In this prospective biological study, a total of 120 patients diagnosed with RIS were matched with 240 control patients with cancer other than sarcoma, for age, sex, primary tumor location and delay after radiation. RILA was prospectively assessed from blood samples using flow cytometry. RESULTS: Three hundred and forty-seven patients were analyzed (118 RIS patients and 229 matched control patients). A majority (74%) were initially treated by RT for breast cancer. The mean RT dose was comparable with a similar mean (± standard deviation) for RIS (53.7 ±â€¯16.0 Gy) and control patients (57.1 ±â€¯15.1 Gy) (p = .053). Median RILA values were significantly lower in RIS than in control patients with respectively 18.5% [5.5-55.7] and 22.3% [3.8-52.2] (p = .0008). Thus, patients with a RILA >21.3% are less likely to develop RIS (p < .0001, OR: 0.358, 95%CI [0.221-0.599]. CONCLUSION: RILA is a promising indicator to predict an individual risk of developing RIS. Our results should be followed up and compared with molecular and genomic testing in order to better identify patients at risk. A dedicated strategy could be developed to define and inform high-risk patients who require a specific approach for primary tumor treatment and long term follow-up.

[Potential combination of target therapy and radiation therapy in GI tract cancers]. / Place potentielle des thérapies ciblées en association avec la radiothérapie dans les cancers digestifs.

At cellular level, signalization pathway activated by ErbB receptors participate to the proliferation, migration and differenciation of many cellular types. Observed alterations are mutations, overexpressions with or without gene amplification or abnormal stimulation by their ligands. The most frequently observed mutation is an extracellular deletion aiming to activate tyrosine kinase activity without ligand. Strategies to target the EGFr receptor include antisens oligonucleotids, antibodies directed to extracellular component of tyrosine kinase receptor. Only monoclonal antibodies and TKI have been developed in clinical research, mainly for oesophageal and rectal carcinomas. Solid tumor proliferation is under control of tumoral mechanisms and the interaction between tumor and microenvironment. In particular, angiogenesis is important during invasive and metastasis phases. The major role of Vasculoendothelial Growth Factor (VEGF) in angiogenesis is useful for tumor growth, which has been demonstrated by many convergent studies. Radiosensitivation or reversion of radioresistance could be obtained by inhibition of VEGF pathway. Antibodies directed against this molecule have been introduced in GI tract malignancies for the treatment of pancreatic and colic carcinomas.

[Stage I endometrial carcinoma]. / Cancer de l'endomètre de stade I.

Most endometrial cancers are diagnosed at stage I (disease limited to the uterine corpus). The definitive treatment for endometrial carcinoma consists in total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy. The decision of adjuvant treatment depends on risk factors. Postoperative radiotherapy plays a major role in the management of stage I endometrial cancer but the respective place of external radiotherapy and vaginal brachytherapy remains controversial. Adjuvant external beam radiotherapy reduces locoregional recurrences, but carries a risk of toxicity without overall survival benefits. Recent data suggest that vaginal brachytherapy is effective in preventing vaginal recurrence with lower toxicity and should be the treatment of choice for intermediate risk endometrial cancer.

Salvage brachytherapy as a modern reirradiation technique for local cancer failure: The Phoenix is reborn from its ashes.

The treatment of local recurrence of a previously irradiated cancer or a second cancer arising in-field remains challenging. Ultimately, the objective of salvage therapy is to control disease while ensuring minimal collateral damage, thereby optimizing both cancer and toxicity outcomes. Reirradiation has historically been associated with unacceptable toxicity and a limited benefit. Brachytherapy offers the best dose distribution and a high radiation dose to the target volume while better protecting surrounding previously irradiated healthy tissues. The management of local cancer recurrence in irradiated areas should be planned through multidisciplinary discussions and patients should be selected carefully. This overview of the literature describes brachytherapy as a reirradiation treatment in local recurrences of previously irradiated prostate, breast, head and neck and rectal cancers, or second primary cancers occurring in-field. For these cancers, the prognosis and therapeutic challenges are quite different and depend on the type of primary cancer. However, current data confirm that brachytherapy reirradiation is feasible and has acceptable toxicity.

[Is a linac able to do better than tomotherapy or Cyberknife?]. / Un accélérateur linéaire peut-il faire aussi bien qu'un appareil de tomothérapie ou un Cyberknife?

Tomotherapy is a new external beam radiation therapy technique using helicoidal intensity modulated radiation principle. It is able to avoid multiple isocenters requested to irradiate large volumes. This machine integrates image acquisition, treatment planning, positioning of the patient and irradiation into a sole engine. Six degrees of freedom robot coupled with a 6 MV linear accelerator, InCA has installed the Cyberknife in France in 3 sites chosen. The last generation of linac is a multifunction machine able to deliver conformal irradiations with or without intensity modulated radiation therapy, cranial or extracranial stereotactic irradiation with or without arctherapy or modulation. Performances of each machine have to be measured and compared in a medical and economical procedure.

Safety and efficacy of intensity-modulated radiotherapy in the management of spermatic cord sarcoma.

PURPOSE: Spermatic cord sarcoma is a rare disease, which management remains controversial due to the lack of guidelines. The standard therapeutic approach is surgical: wide soft-tissue resection with radical inguinal orchidectomy, The diagnosis is made during the analysis of the specimen. The high rate of local recurrence indicates adjuvant radiotherapy of the tumor bed. The aim of this series is to determine the efficacy and safety of postoperative intensity-modulated radiotherapy for spermatic cord sarcomas. PATIENTS AND METHODS: Our series included five consecutive cases of spermatic cord sarcoma treated between 2011 and 2014. The indications for radiotherapy were: R1 status after initial surgery, R1 status after wide en bloc resection and orchiectomy, high French federation of cancer centers (FNCLCC) grade, tumor size over 5cm, tumor resection during surgery. RESULTS: Median age at diagnosis was 66years (range 46-84years). Median follow-up was 18months (range 6-28months). Four patients had repeat surgery after incomplete removal. All surgeries were orchidectomy with primary ligation of testicular vessels. One patient did not have an in sano margin after the second surgical procedure. The median tumor size was 60mm (range 30-150mm). No recurrence was observed during the follow-up. CONCLUSION: No grade 4 toxicities were reported and the most frequent acute toxicity was dermatitis. No recurrence was reported after adjuvant intensity-modulated radiotherapy. The treatment is feasible and well tolerated and seems to provide encouraging results regarding locoregional control of the disease. Dynamic or rotational intensity-modulated radiotherapy is now recommended to decrease acute toxicities while improving the efficacy of this approach.

[High precision radiotherapy with ultrasonic imaging guidance]. / Radiothérapie de haute précision guidée par échographie.

Conformal radiation therapy with or without intensity modulation is the standard treatment of localized prostate cancer and facilitates dose escalation. The implementation of three-dimensional conformal radiotherapy necessitates focusing on target volume delineation, dosimetry, reproducibility of treatment and quality control. Recently, ultrasound systems that allow direct daily visualization of the prostate have become available. This non-invasive technique can be used to correct both prostate organ motion and set-up error and leads to increase treatment accuracy.

[Implementation of transabdominal ultrasound image guided conformal intensity modulated radiotherapy]. / Mise en oeuvre de la radiothérapie conformationnelle par modulation d'intensité guidée par échographie transabdominale.

PURPOSE: Optically guided ultrasound imaging has been used in our department since 2003 in order to implement an on line correction scheme in intensity modulated radiation therapy of prostate carcinoma. PATIENTS AND METHODS: The corrections observed during the initial time period of the system (17 patients) are compared to those observed more recently (10 patients). Treatment margins are calculated. RESULTS: Overall systematic errors decreased between 2003 and 2006, and are presently statistically not different from zero. Random errors remain the same (max 4.3 mm). Proposed margins are 7 mm both in lateral and longitudinal direction and 8.4 mm in anteroposterior. CONCLUSION: Ultrasound can be used for on line correction of both positioning and internal organs motion errors and allows reduction of the margins between clinical and planning volume.

[Radiotherapy for brain metastases]. / Radiothérapie des métastases cérébrales.

Radiotherapy for brain metastases has become more multifaceted. Indeed, with the improvement of the patient's life expectancy, side effects must be undeniably avoided and the retreatments or multiple treatments are common. The cognitive side effects should be warned and the most modern techniques of radiation therapy are used regularly to reach this goal. The new classifications of patients with brain metastases help guiding treatment more appropriately. Stereotactic radiotherapy has supplanted whole brain radiation therapy both for patients with metastases in place and for those who underwent surgery. Hippocampus protection is possible with intensity-modulated radiotherapy. Its relevance in terms of cognitive functioning should be more clearly demonstrated but the requirement, for using it, is increasingly strong. While addressing patients in palliative phase, the treatment of brain metastases is one of the localisations where technical thinking is the most challenging.

[Guidelines for the radiotherapy of gliomas]. / Référentiels d'irradiation des gliomes.

Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy.