Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

L’objectif de ce travail était la recherche de biomarqueurs moléculaires prédictifs de la tolérance et de l’efficacité des chimio– thérapies utilisées dans le colorectal (CCR) métastatique. Nous avons effectué le génotypage de 20 polymorphismes présents au sein de 9 gènes connus ou suspectés d’être impliqués dans la voie du 5FU, de l’oxaliplatine, ou de l’irinotécan, à partir de l’ADN extrait du sang de 346 patients traités dans le cadre d’un essai de phase III. Cet essai comparait une chimiothérapie séquentielle par 5FU (schéma LV5FU2) suivie d’une association 5FU plus oxali– platine (schéma FOLFOX) à une chimiothérapie combinée de type FOLFOX d’emblée en première ligne de traitement. Nous avons trouvé un risque de toxicité hématologique sévère sous FOLFOX significativement augmenté chez les patients porteurs de l’allèle ERCC2-K751QC. La présence de l’allèle TS-5’UTR3RG du gène de la thymidylate synthase était associée à un taux de réponse significativement plus élevé sous LV5FU2. Le taux de réponse au FOLFOX en 2e ligne était significativement supérieur chez les patients porteurs de l’allèle ERCC1-IVS3+74G, et chez ceux ayant au moins un allèle de GSTT1 présent. L’analyse prédictive a montré un effet dépendant du traitement de certains polymorphismes. En effet, une survie sans progression significativement allongée par l’ajout de l’oxaliplatine en 1re ligne a été observée uniquement chez les patients ayant un génotype TS-5’UTR2R/2R ou 2R/3R, suggérant l’absence de bénéfice d’une bithérapie par FOLFOX d’emblée en première ligne chez les patients TS-5’UTR3R/3R. Ces résultats montrent que l’étude des polymorphismes constitutionnels permettent de prédire non seulement la toxicité mais aussi l’efficacité des chimiothérapies antitumorales du cancer colorectal, et ainsi (sous réserve d’une validation sur une population indépendante) d’orienter la stratégie thérapeutique à l’échelle de l’individu

The enigma of multicentric glioblastoma: physiopathogenic hypothesis and discussion about two cases

International audienceTwo men were admitted following generalized seizures. Cerebral MRI-scans showed multiple independent enhancing lesions which were bilateral (first case) and unilateral but disseminated to the brainstem (second case). Whole-body CT-scans showed no primaries. Both cases were diagnosed by biopsy as IDH1 wild-type multicentric glioblastoma. Treatment of both was palliative. The natural history of this entity remains matter of debate but 2 genomic analysis strikingly revealed that foci from the same patient were of monoclonal origin. Consistently, these 2 cases could sustain the hypothesis that an anatomical connectivity exists between the different foci of a multicentric glioblastoma

Typology of Published Randomized Controlled Trials investigating initial ventilation strategy in Critically Ill Patients with Acute Respiratory Failure-A methodological review

International audienceBackground: Randomized controlled trials (RCTs) in patients with hypoxemic acute respiratory failure (ARF) often failed to show survival benefits and resulted in varying clinical end points.Research Question: This methodologic review was conducted of published RCTs on ARF, with a careful attention to whether the study results were positive or negative.Study Design and Methods: MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science were searched for published RCTs in adult patients with ARF between January 1995 and December 2019. The objective was to investigate sources of heterogeneity and factors associated with a positive RCT (ie, with a significant difference on the primary end point). To determine the importance of the primary end point choice, end points were classified as follows: (1) respiratory event end points (corresponding to modification of the ventilation support); (2) physiologic/clinical end points (corresponding to oxygenation or clinical parameters); and (3) mortality. The Cochrane risk-of-bias tool was used to assess study quality.Results: Seventy-four RCTs were included (57% were single-center RCTs) comparing mainly oxygenation/ventilation strategies (95%) in patients with various ARF causes (62%); studies were stopped prematurely in 20% of the trials. A standardized management of ARF was observed in 24 (32%) trials. Twenty-two distinct primary end points have been used, the first of which were those based on respiratory events (44 RCTs [49%]), namely intubation in 76% of the cases. Physiologic/clinical end points have been used in 21 trials (29%) and mortality in nine (12%). Overall, 42 (57%) RCTs were positive, 52% in studies with respiratory event end points, 76% in studies with physiologic/clinical end points, and 33% in studies with mortality end points. Adjusted for study quality (Cochrane risk-of-bias tool), factors associated with a positive RCT included clinically based primary end points (OR, 8.40; 95% CI, 1.35-65.79), the use of standardized ARF management (OR, 4.55; 95% CI, 1.02-22.88), and single-center trials (OR, 3.85; 95% CI, 1.25-13.11).Interpretation: The typology of published RCTs in patients with ARF could be used to frame future trial designs in this field and guide clinicians and researchers toward optimal research transfer to the bedsid

Herpes Simplex Encephalitis Shortly After Surgery for a Secondary Glioblastoma: A Case Report and Review of the Literature

International audienceBackground: Herpes simplex encephalitis (HSE) and glioblastoma multiforme (GBM) co-occurrence has been described in few cases presenting immunocompromised status related to chemotherapy or chemoradiotherapy. Focal encephalitis over surgical edge of resection occurring shortly after GBM resection is rarely reported, and such infection has never been reported in low-grade glioma with secondary malignant transformation (i.e., secondary GBM). Here, we report a case of HSE misdiagnosed in the early postoperative course following a secondary GBM resection. We also provide a review of the literature about HSE occurring after glioma surgery. Case description: We report a case of an acute HSE with a fatal outcome occurring shortly after surgery for a secondary GBM. The patient presented with hyperthermia 12 days after the surgery and was treated with empirical antibiotics. She later suffered from seizure and neurologic deterioration, leading to death despite delayed antiviral administration. Magnetic resonance imaging revealed considerable fluid-attenuated inversion-recovery signal progression at the edge of the surgical resection and polymerase chain reaction amplification of herpes simplex virus (HSV) 1 DNA was positive. Conclusions: Clinicians should be aware of the existing co-occurrence between HSV infections and GBM during the postoperative course. Cerebrospinal fluid analysis with HSV polymerase chain reaction testing should be promptly undertaken, and some keys clinical elements should justify early empirical treatment, including acyclovir administration. The significant prognostic implication of HSE complicating GBM must raise the attention of neurosurgeon and neuro-oncologist about this entity

Endoscopic transsphenoidal surgery for non-functioning pituitary adenoma: Learning curve and surgical results in a prospective series during initial experience

International audienceBackground: To report the initial experience of surgery for non-functioning pituitary adenoma (NFPA) from a neurosurgeon in a dedicated residency training endoscopic transsphenoidal (ETS) program, and detail the surgical and clinical outcomes during this period.Methods: A prospective series of all patients operated for NFPA, using an ETS approach, during the three first years of experience of a newly board-certified neurosurgeon was analysed. Clinical, radiological and peri-operative data were collected. Extent of resection (EOR) was determined by formal volumetric analysis. Impact of the learning curve and predictive factors of gross total resection (GTR) were determined.Results: Fifty-three patients with NFPA were included in this prospective cohort which was divided in two periods of time ("First period": 30 first cases, and "second period": 23 following cases). Baseline characteristics of the patients in the two periods were similar. Overall occurrence of complication was 22% and was not significantly different in the two periods of time. No patient had severe neurological complication. Gross total resection was achieved in 70% of patients. Mean Extent of resection was 96%. In a multiple linear regression model, a higher EOR was positively correlated with experience (p = 0.018) and negatively correlated with Knosp Score equal to 4 (p < 0.001). Predictive factors for GTR were Higher Knosp grade (p = 0,01), higher pre-operative volume (p = 0.03), and second period of time (p = 0.01).Conclusion: NFPA surgery can be safe and efficient during the learning period. Dedicated intensive learning, careful patient selection and multidisciplinary work are key to shorten the learning curve and achieve satisfactory results

Surgeon's and Patient's Radiation Exposure Through Vertebral Body Cement Augmentation Procedures: A Prospective Multicentric Study of 49 Cases

International audienceOBJECTIVE:Vertebral body cement augmentation as a treatment option for osteoporotic or traumatic fractures has become increasingly popular during the past decade. However, these surgical procedures require numerous fluoroscopic examinations, resulting in high radiation exposure for the patient and the surgical team. The aim of this study was to evaluate the level of radiation exposure of the spine surgeon and the patient during these percutaneous procedures.METHODS:Forty-nine patients admitted for single- or 2-level vertebral compression fracture were prospectively included and treated with vertebral body cement augmentation. For each procedure, radiation dose was measured on the surgeon's whole body, lens, and extremities as well as patient irradiation. Each surgeon wore 2 thermoluminescent dosimeters to measure lens and extremities radiation exposure and 1 electronic personal dosimeter. Patient clinical and surgical data, effective dose to patient, and surgeon were analyzed.RESULTS:Mean operative time was 31.5 ± 11.7 minutes. The average fluoroscopic time was 61.0 ± 27.1 seconds. The average whole-body radiation dose per procedure was 1.4 ± 2.1 μSv. The average equivalent dose to lens and extremities were 44 μSv and 59 μSv, respectively.CONCLUSIONS:Values of radiation doses for surgeon and patient were lower than those reported in the previous literature. The recommended annual dose limit is set to 500 mSv for extremities and 150 mSv for lens. According to our results, the exposure dose to the eye exceeds the annual limit after 3500 procedures. However, there is increasing concern among surgeons about radiation exposure, and there is still a need for solutions as preventive measures

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

International audienceNeurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor genebreast cancer susceptibility gene 1(Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion

A Novel Translational Model of Spinal Cord Injury in Nonhuman Primate

International audienceSpinal cord injuries (SCI) lead to major disabilities affecting > 2.5 million people worldwide. Major shortcomings in clinical translation result from multiple factors, including species differences, development of moderately predictive animal models, and differences in methodologies between preclinical and clinical studies. To overcome these obstacles, we first conducted a comparative neuroanatomical analysis of the spinal cord between mice, Microcebus murinus (a nonhuman primate), and humans. Next, we developed and characterized a new model of lateral spinal cord hemisection in M. murinus. Over a 3-month period after SCI, we carried out a detailed, longitudinal, behavioral follow-up associated with in vivo magnetic resonance imaging (1H-MRI) monitoring. Then, we compared lesion extension and tissue alteration using 3 methods: in vivo 1H-MRI, ex vivo 1H-MRI, and classical histology. The general organization and glial cell distribution/morphology in the spinal cord of M. murinus closely resembles that of humans. Animals assessed at different stages following lateral hemisection of the spinal cord presented specific motor deficits and spinal cord tissue alterations. We also found a close correlation between 1H-MRI signal and microglia reactivity and/or associated post-trauma phenomena. Spinal cord hemisection in M. murinus provides a reliable new nonhuman primate model that can be used to promote translational research on SCI and represents a novel and more affordable alternative to larger primates