What does a non-response to induction chemotherapy imply in high-risk medulloblastomas?

PURPOSE: High-risk medulloblastomas (HR-MB) may not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). There is no consensus regarding their optimal management. METHODS: A retrospective, multicentre study investigated patients with non-responder HR-MB treated according to the PNET HR + 5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin (induction), patients with SD or PD were analyzed. Upon clinician's decision, the PNET HR + 5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group). RESULTS: Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were better for the SD group: the 5-y PFS and OS were 52% (95% CI 35-67) and 70% (95% CI 51-83), respectively, in the SD group while the 2-y PFS and OS were 17% (95% CI 3-41) and 25% (95% CI 6-50), respectively, in the PD group (p < 0.0001). The PNET HR + 5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24/37 patients whereas 13 patients received miscellaneous treatments including a 36 Gy CSI in 12 cases. Despite that continuation and switched group were well-balanced for factors impacting the outcomes, the latter were better in the continuation group than in the switched group: the 5-y PFS were 78% (95% CI 54-90) versus 0% (p < 0.001), and the 5-y OS were 78% (95% CI 54-90) versus 56% (95% CI 23-79) (p = 0.0618) respectively. In the SD group, multivariate analysis revealed that MYC amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression. CONCLUSION: Patients with post-induction SD may benefit from HDCT and CSI, whereas patients with early PD will require new therapeutic approaches.

MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation.

BACKGROUND: Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma. METHODS: TMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon's 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I. RESULTS: A total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD. CONCLUSION: The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.

[Adolescent and Young Adults (AYAS) brain tumor national Web conference. On behalf of ANOCEF, GO-AJA and SFCE societies]. / La neuro-oncologie des adolescents et adultes jeunes (AJAS) : place d'une RCP nationale. Au nom de l'ANOCEF, GO-AJA et de la SFCE.

The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro-oncologists are warranted to share expertise. Since 2008, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma. RESULTS: Attendance during the year 2015 was as follows: 42 meetings were held; the median number of cases discussed at each meeting was 4 (1 to 8); the mean number of attendants was 7 (2 to 12). One hundred and sixty-eight cases concerning 121 patients were discussed. Mean age was 30 years old (7 to 67). Forty-eight percent were discussed at diagnosis. The patients had mostly medulloblastomas (40%), germ cell tumors (11%), ependymomas (11%), pineal tumors (7%) and embryonal tumors (8%). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols. CONCLUSION: Multidisciplinary Web conference for AYAs is feasible and increases the inclusion rate in protocols. It should be developed further.

Expression of the onconeural CV2/CRMP5 antigen in thymus and thymoma.

Anti-CV2 antibodies (AB) react with the developmentally regulated neural proteins CRMPs and particularly with CRMP5. They occur with small cell lung cancer (SCLC) and thymoma. SCLCs universally express CRMP5. We investigated the expression of CRMPs in thymoma and thymus. In thymoma, none of the CRMPs were detected by immunohistochemistry in tumorous epithelial cells with specific antibodies including CRMP5 but an antibody reacting with a peptide common to the CRMPs labeled a 66-kDa protein in Western blot of rat brain, thymus, and thymoma extracts. Thus, the normal CRMP5 is probably not expressed by tumorous epithelial cells. These results indicate that the mechanisms leading to CRMP5 autoimmunization are different in SCLC and thymoma.

Quantitative study of nerves of the human left atrium.

OBJECTIVES: To quantify and study the distribution of innervation of the left atrium and the pulmonary veins in humans. BACKGROUND: Damage to cardiac nerves has been hypothesized as the explanation for successful radiofrequency ablation of atrial fibrillation. METHODS: From January 2003 to September 2003, histologic and quantitative studies of innervation of the left atrium and the pulmonary veins was performed in 43 consecutive necropsied adult hearts (30 men and 3 women; mean age 45.5 +/- 12.4 years). The left atrium was sectioned in 1-cm slices from left to right, with the plane of section perpendicular to the long axis of the heart. Sections of the pulmonary veins at their ostia and sections 1 cm away of this structure also were obtained. Nerve fiber density was counted manually for each case and expressed as the mean number per slice. RESULTS: Numerous epicardial nerve fibers and ganglia having distinct patterns of distribution in the left atrium were found. Nerve density was significantly higher at the ostia of the four pulmonary veins than in their distal part (7.1 +/- 2.1 vs 5.2 +/- 1.3 for left upper pulmonary vein; 6.3 +/- 1.5 vs 5.2 +/- 1.7 for right upper pulmonary vein; 7.4 +/- 2 vs 5.9 +/- 2 for left lower pulmonary vein; 6.7 +/- 1.8 vs 3.9 +/- 1.3 for right lower pulmonary vein). The left superior vein was significantly more innervated than the right inferior vein (12.3 +/- 3 vs 10.6 +/- 1.4). Gradients of innervation were found from right to left (9.8 +/- 4.6 vs 18.5 +/- 6.6, P < .05) and from the front to the rear of the atrium (17.2 +/- 6.4 vs 20.7 +/- 6.5, P < .05). The same heterogeneous distribution was observed at the myocardial level but with thinner nerve fibers, making quantification difficult. Only very thin nerve fibers were present in the endocardium. CONCLUSIONS: The human left atrium exhibits several gradients of innervation at discrete sites. These findings may have clinical implications for radiofrequency ablation of atrial fibrillation.