Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol.

BACKGROUND: Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. METHODS: The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. DISCUSSION: Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. TRIAL REGISTRATION: NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Comparative mid-term anatomical and functional outcomes following laparoscopic sacrocolpopexy in women under and over 65: results from a prospective study.

PURPOSE: To compare mid-term anatomical and functional outcomes following laparoscopic sacrocolpopexy (LS) between women under and over 65. METHODS: Prospective and observational study involving patients with symptomatic pelvic organ prolapse (POP) undergoing LS. Study population was stratified according to patients' age at the time of surgery. POP symptoms and impact on quality of life were assessed by PFIQ-7 and PFDI-20 questionnaires at baseline and during follow-up. RESULTS: Among our study population (n = 72), 26 women were over 65 and 46 under 65. Mean follow-up duration was 17.6 months, and complete follow-up was available in 90% of patients. No differences between study groups were observed regarding surgery duration, length of stay, and peri-operative complications. Recurrence rate was 1.4% at 18 months of follow-up. Questionnaires analysis revealed a significant improvement in PFIQ-7 and PFDI-20 scores. We found no differences in post-operative scores between control and elderly groups. Sixteen patients experienced de novo stress urinary incontinence (22.2%), with no difference between groups (p = 0.7). Among them, seven required surgical management. CONCLUSIONS: LS was associated with high anatomical success rate and good functional outcomes, regardless of age at the time of surgery. LS should thus be considered in women over 65. Beyond age, the route of surgery should be driven by patient's choice and medical condition.

Vaginal evisceration: an unexpected complication of conization.

Background. Large loop excision of the transformation zone (LLETZ) is routinely performed for the management of high grade intracervical neoplasia (CIN). Several uncommon complications have been described, including postoperative peritonitis, pseudoaneurysm of uterine artery, and bowel fistula. We report a unique case of postoperative vaginal evisceration and the subsequent management. Case. A 73-years-old woman underwent LLETZ for high grade CIN. On postoperative day 3, she was admitted for small bowel evisceration through the vagina. Surgical management was based on combined laparoscopic and transvaginal approach and consisted in bowel inspection and reinstatement, peritoneal washing, and dehiscence repair. Conclusions. Vaginal evisceration is a rare but potentially serious complication of pelvic surgery. This case report is to make clinicians aware of such complication following LLETZ and its management.

Allergy to multiple local anesthetics.

Real allergy to local anesthetic (LA) is very rare. This study was performed to report a case of anaphylaxis to multiple "caine." A 25-years-old atopic nurse developed a very severe anaphylactic reaction on her third infiltration for low back pain with bupivacaine, lidocaine, and methylprednisolone: she developed a vagal reaction, followed during the next 30 minutes by a pruriginous skin rash, followed by a tongue edema and a severe bronchospasm. Adrenalin was injected with a poor response. She was intubated and transferred to the intensive care unit for a few days and, finally, she recuperated completely. Skin-prick tests were done on two occasions. In the first session, no reactions were observed with triamcinolone and methylprednisolone at 1 mg/cc, but a rapid extending maculopapular erythema developed with a final diameter of 50 mm with lidocaine 0.1% (group 2) and 25 mm with procaine 2% (group 1): control 0 mm, histamine, 3 mm. She also complained of itchiness in the neck and shoulder, which resolved in the next 90 minutes. In the second session, a test with bupivacaine 0.0005% (group 2) gave a papule with a diameter of >5 mm, and a test with mepivacaine 0.001% (group 2) was negative: control, histamine, 3 mm; no subsequent tests with mepivacaine were done because she developed a cough and throat pruritus, voice modification, and a sensation of throat narrowing, that resolved with treatment. We reported a case of anaphylaxis to multiple LA (groups 1 and 2), possibly via an IgE-mediated mechanism.