Sylvine Cottin

Bilateral stereotactic anterior capsulotomy for obsessive-compulsive disorder: long-term follow-up

Background and purpose Psychosurgery, such as anterior capsulotomy, is a therapeutic option for treatment-resistant obsessive-compulsive disorder (OCD). In this paper, we present a prospective, long-term follow-up study aimed at evaluating both the efficacy and the safety of anterior capsulotomy for the treatment of severe, refractory OCD. Methods Twenty-four patients were surgically treated in our centre between 1997 and 2009, 19 of whom were included in this study. Patients were assessed at 3, 6, 12, and 24 months and last follow-up (mean of 7 years) was carried out by phone. OCD symptom severity was evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A patient with an improvement rate of over 35% in the Y-BOCS score was considered a responder, while a patient with a 25% improvement was considered a partial responder. Results With a mean improvement of 31% in the Y-BOCS score at long-term follow-up, 36.8% of the patients responded fully to the procedure and 10.5% were considered partial responders, for an overall response rate of 47.3% of patients. At the end of the study, 3/19 patients had recovered (Y-BOCS score <8) and 3/19 were in remission (Y-BOCS score <16). No cases of mortality were reported and the overall adverse event rate was 57.9%. Only 2 patients had permanent surgical complications. Conclusions Anterior capsulotomy is an effective and safe technique for the treatment of severe refractory OCD in patients who have no other alternative to improve their symptoms.

Gap junctions in human glioblastomas: implications for suicide gene therapy.

Glioblastoma is a very aggressive astrocytic tumor and most patients have 1-year survival time after diagnosis. A promising therapeutic strategy is the local delivery of the herpes simplex virus thymidine kinase gene in the tumor bed followed by ganciclovir treatment. The presence of functional gap junctions is highly relevant for the success of suicide gene therapy. Connexins are expressed in practically all tissues and form gap junctions that allow intercellular communication. Connexin 43 (Cx43) is the major connexin member being expressed in astrocytes but its status in glioblastoma is not well defined. We have investigated by immunofluorescence the presence of Cx43 in 74 human glioblastoma samples; its expression was detected in 77% of the samples analyzed. We report here that glioblastoma is a heterogenous disease as regards Cx43 expression with presentations, in which Cx43 expression is unaltered, reduced or totally lost. A predominant Cx43 cytoplasmic localization was observed in four out of eight primary glioblastoma cultures that we have established. This aberrant localization reduced gap junctionnal intercellular communication by 50 to 75% as compared with primary cell cultures displaying gap junctional plaques. However, the bystander effect evaluated after lentiviral delivery of the herpes simplex virus thymidine kinase gene and ganciclovir treatment was detected in all Cx43-positive primary cell cultures, and it was independant of the Cx43 localization. These findings may have important clinical implications for the design of anticancer cytotoxic therapies that rely on the gap junction-mediated bystander effect for their success.

Bystander effect in glioblastoma cells with a predominant cytoplasmic localization of connexin43

Herpes simplex virus thymidine kinase (TK) gene transfer followed by ganciclovir (GCV) administration is an approach investigated for glioblastoma treatment. The bystander effect (BE) enhances the cytotoxic effect of this strategy by allowing the diffusion of phosphorylated GCV from TK-expressing cells toward neighboring TK negative cells. This transfer of toxic metabolites is mainly mediated via gap junctions that are composed of connexins. Downregulation and/or cytoplasmic localization of connexins are common in tumors, and should be detrimental to the success of the TK/GCV strategy. In this study, we investigated the level of expression, the localization and the functionality of connexin43 (Cx43) in three glioblastoma cell lines. We showed that Cx43 was predominantly located in lysosomes and late endosomes, with only few gap junctions present at the cell surface. Surprisingly, the gap-junctional intercellular communication (GJIC) and the BE capacity were preserved, and in two of the cell lines analyzed, it was at least twice as high as compared to a control HeLa transfectant that expresses high levels of Cx43 at the cell membrane. Experiments performed in the presence of α-glycyrrhetinic acid or small interfering RNA confirmed that Cx43 was responsible for the GJIC and the BE. Our results indicate for the first time that the very limited numbers of gap junctions present in glioblastoma cells are highly functional. We thus conclude that the TK/GCV strategy is still a valuable therapeutic option to be developed for the treatment of glioblastoma patients.

Characterization of an alternative packaging system derived from the cat RD114 retrovirus for gene delivery.

Retroviral vectors derived from the Moloney murine leukemia virus (MLV) are widely used in gene therapy. Pseudotyping of these vectors with the cat RD114 retrovirus envelope increases their potential for delivering genes into human hematopoietic cells. In the present study, we have further investigated the potential of the RD114 retrovirus in gene therapy. We describe and characterize an alternative retroviral packaging system derived from the RD114 retrovirus.

Severe cerebellar hemorrhage following transverse sinus stenting for idiopathic intracranial hypertension

We report a severe adverse event occurring in the course of a cohort study (ISRCTN13784335) aimed at measuring the efficacy and safety of venous stenting in the treatment of patients with medically refractory idiopathic intracranial hypertension (IIH). The patient was a 41-year-old woman who was not overweight, who presented with severe headache, grade 1 bilateral papilledema and transient tinnitus, refractory to medical treatment. Right transverse sinus stenting was successfully performed. Following surgery, the patient’s state of consciousness decreased acutely with rapid and progressive loss of brainstem reflex. CT scan revealed acute cerebellar and intraventricular hemorrhage with obstructive hydrocephalus. Angioscan revealed normal venous sinus patency and cerebral MRI showed acute mesencephalic ischemia. Mechanical impairment of cerebellar venous drainage by the stent or venous perforation with the large guidewire used in this technique are two logical ways to explain the cerebellar hemorrhage seen in our patient. The risk of such a complication could probably be reduced using alternative tools and technique. However, given the low level of evidence around the safety of transverse sinus stenting in IIH, its formal assessment in clinical trials is required.

AT-40PROGNOSIS FACTORS IN GLIOBLASTOMA MULTIFORME

BACKGROUND: A few factors are known to have an impact on survival for glioblastoma patients, like age, extent of resection and Karnofsky score. However, a lot remains to be understood to optimally treat these patients. The goal of our study was to find out the prognostic factors of patients in a non-clinical trial setting. METHODS: We retrospectively reviewed 355 adult patients who were treated for Glioblastoma Multiforme between 2007 and 2012. We reviewed the known prognosis factors. We estimated the extent of resection using the pre-op versus post-op post-Gadolinium MRI. The patients were classified as: biopsy, partial resection (> 10% remnant on post-op MRI), subtotal resection (< 10% remnant on post-op MRI) or total (no remnant on MRI). We also looked at the number of chemotherapy regimens after the adjuvant temozolomide. RESULTS: We proceeded to two multivariate analyses of all the data collected. The first one included all patients and extrapolated the data that was not available for some patients. The factors that were statistically associated with increased survival were: women sex (p = 0.0484), being treated with one (p < 0.001), two (p < 0.001) or three (p = 0.0016) regimens of chemotherapy, having a right-side tumor (p = 0.0312). In a second multivariate analysis we included only the patients whose data were complete (309/355). The factors that were statistically associated with increased survival were: chemotherapy; one to three regimens (p < 0,001), further regimens were not statistically related to survival. Factors associated with decreased survival were: biopsy alone, (p = 0,0006) partial resection (p = 0,0168), not having radiotherapy (p = 0,0034) and posterior fossa location (p = 0,0135). DISCUSSION AND CONCLUSION: As previously described, survival is increased with maximal safe resection. The use of multiple chemotherapy regimens improves survival, up to the third regimen. Surprisingly, patients with a longer delay before radiotherapy survived longer. This may reflect the fact that patients with biopsy alone were treated first.