Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods: Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results: Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0-76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69-1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7-82.1) with everolimus and 77.0% (95% CI 72.1-81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions: Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov: NCT00790036.

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). RESULTS: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. CONCLUSIONS: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. CLINICAL TRIAL REGISTRY AND TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00719264.

[Effect of nicardipine on cerebral vasomotor activity in hypocapnia]. / Action de nicardipine sur la vasomotricité cérébrale en présence d'une hypocapnie.

Nicardipine, a calcium channel antagonist derivative of dihydropyridine, is a cerebral vasodilatator used in the treatment of cerebral vasospasms induced by subarachnoid hemorrhage after rupture of intracranial aneurysm. Hypocapnia is a powerful vasoconstrictor of cerebral arteries, and antagonizes in the baboon the cerebral vasodilative effect of nimodipine, another derivative of dihydropyridine. The action of nicardipine in presence of hypocapnia was not yet study in human. The study of the interaction of nicardipine and hypocapnia on the cerebral arteries show that hypocapnia antagonizes the cerebral vasodilatator properties of nicardipine.

Removable, adjustable and reusable implants for stereotactic interstitial radiosurgery of brain tumors.

Sixty primary brain tumors (gliomas) were treated by interstitial radiosurgery using 192Ir according to a protocol based on the size of the tumor. In all cases, the radioactive wires were left in place for periods ranging from 5 to 10 days, according to dosimetry calculations, and then removed, which was made possible by the use of removable implants. The stainless steel tubes are occluded on their inner side and adjustable in length depending on the depth of the tumor, and are introduced through screws inserted into the skull in an array depending on the preliminary dosimetry. The tubes were afterloaded with 192Ir and removed at the end of the calculated time. Forty-six patients (18 low-grade and 28 malignant gliomas) were treated using this method. One small hematoma was evacuated and no sepsis occurred.

Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease.

Stereotactic thalamotomy of the thalamic nucleus ventralis intermedius (VIM) is routinely used for movement disorders. During this procedure, it has been observed that high-frequency (100 Hz) stimulation of VIM was able to stop the extrapyramidal tremor. In patients with bilateral tremor of extrapyramidal origin, who were resistant to drug therapy, the therapeutic protocol associated (1) a radiofrequency VIM thalamotomy for the most disabled side, and (2) a continuous VIM stimulation for the other side using stereotactically implanted electrodes, connected to subcutaneous stimulators. VIM thalamotomy relieved the tremor in all operated cases. Side effects were mild and regressive. VIM stimulation strongly decreased the tremor but failed to suppress it as completely as thalamotomy did. This was due in part to the fact that programmable stimulator frequency rate is limited to 130 Hz, while it appeared that the optimal stimulation frequency was 200 Hz. This therapeutic protocol appears to be of interest for patients with bilateral extrapyramidal movement disorders.

[Segmentation of the lumbar radicular canal]. / La segmentation du défilé radiculaire lombaire.

The lumbar CT horizontal sections identification requires three levels to be defined of each vertebra: The arthropedicular level (upper third) describes an (omega) at the back with its dense bone structures. At each side of the canal is the upper part of the lateral recess, the narrowest and therefore the most threatened part of the nerve root passage. The isthmopedicular level (middle third) describes a complete bone ring around the vertebral canal. On this non articular level, the congenital dysplasia is most clearly observed. The subpedicular level (lower third) with its muscular surrounding, shows a floral outline. A fourth level, intervertebral or discal, is added. It is very similar to the last one and of course is the most common point of disco-radicular conflict. Each level appears to be specific, both by the silhouette outlined by the ligament and bone structures and by the relationship which they have with the meninges. Each of them has its own pathology which precisely directs the surgical approach.