Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study

Abstract

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001–2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.

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Primary spinal myxopapillary ependymoma in the pediatric population: a study from the Surveillance, Epidemiology, and End Results (SEER) database

Abstract

Primary spinal myxopapillary ependymomas (MPE) in children are extremely rare. We examined the patient demographics, treatment modalities, and the associated outcomes of children with MPE using the Surveillance, Epidemiology, and End Results (SEER) national cancer database to gain a better understanding of these tumors. The SEER database (1973–2012) was used to analyze patients 21 years of age and younger with histologically confirmed MPE localized to the spinal cord or cauda equina. We analyzed patient demographics, extent of surgical resection, and radiation treatment. Overall survival was calculated using the Kaplan–Meier method. Statistical significance was defined as p < 0.05, with all data analyzed in IBM SPSS Statistics 21. 122 pediatric patients met inclusion criteria. The median age was 16 years (range 0–21) with 63 % male and 87 % Caucasian. The mean follow-up time was 4.5 years (95 % CI 3.93–5.07). Overall survival at 5 and 10 years was 97 and 95 %, respectively. We found 37 % underwent gross-total resection (GTR), 36 % subtotal resection (STR), and 27 % biopsy only. Patients who received GTR alone (n = 37) had a statistically significant increase in overall survival compared to those who received STR plus adjuvant radiation (n = 20) (Χ² = 5.9, p < 0.05). To our knowledge, this is the largest survival analysis of pediatric patients with MPE. Overall survival is excellent at the 5 and 10-year time points; however, GTR should be the goal of treatment when possible. For patients with MPE, future studies should focus on longer follow-up, the role of radiation, and the therapeutic approach at tumor recurrence.

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Evaluation of assays for drug efficacy in a three-dimensional model of the lung

Abstract

Background

The focus of the outlined work is the establishment of a three-dimensional lung model for various drug-screening applications.

Methods

The non-small cell lung cancer (NSCLC) cell line Colo699 was cultivated as monolayer (2D) on plates for 5 days or as microtissues (3D) using a hanging-drop system for 5 and 10 days. Cells and microtissues were treated with afatinib (10–80 µM), cisplatin (100–800 µM) or vinorelbine (25–200 µM) for 24 or 48 hours (h). Cell proliferation and viability were analysed by intra-cellular adenosine triphosphate (ATP) and lactate dehydrogenase release (LDH) assays, annexin V/propidium iodide (PI) staining, and cell cycle determination. Microtissue morphology and size, as well as cell death were evaluated via phase contrast microscopy.

Results

Our results demonstrate the valid determination of viability and cell death using established assays in the 3D system for drug testing. The comparison of ATP, LDH and cytometry data showed moderate (0.40) to very strong (0.99) correlations. Thereby, we observed partially significant differences in drug efficacy between microtissues and 2D cultures dependent from the applied treatment and read-out method. Altogether, microtissues developed resistance to cisplatin and vinorelbine; but remained more vulnerable to afatinib. These findings were confirmed with microscopy.

Conclusion

In summary, we established an NSCLC 3D test system with multiple assays compatible for drug-testing applications of substances with different mechanisms of action. In addition, our data support the usage of microtissues as more accurate tools for drug-efficacy testing with the possibility of long-term cultivation and treatment.

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Distinct functional domains of PNMA5 mediate protein–protein interaction, nuclear localization, and apoptosis signaling in human cancer cells

Abstract

Purpose

Members of paraneoplastic Ma (PNMA) family have been identified as onconeuronal antigens, which aberrant expressions in cancer cells of patients with paraneoplastic disorder (PND) are closely linked to manifestation of auto-immunity, neuro-degeneration, and cancer. The purpose of present study was to determine the role of PNMA5 and its functional relationship to MOAP-1 (PNMA4) in human cancer cells.

Methods

PNMA5 mutants were generated through deletion or site-directed mutagenesis and transiently expressed in human cancer cell lines to investigate their role in apoptosis, subcellular localization, and potential interaction with MOAP-1 through apoptosis assays, fluorescence microscopy, and co-immunoprecipitation studies, respectively.

Results

Over-expressed human PNMA5 exhibited nuclear localization pattern in both MCF-7 and HeLa cells. Deletion mapping and mutagenesis studies showed that C-terminus of PNMA5 is responsible for nuclear localization, while the amino acid residues (₃₉₁KRRR) within the C-terminus of PNMA5 are required for nuclear targeting. Deletion mapping and co-immunoprecipitation studies showed that PNMA5 interacts with MOAP-1 and N-terminal domain of PNMA5 is required for interaction with MOAP-1. Furthermore, co-expression of PNMA5 and MOAP-1 in MCF-7 cells significantly enhanced chemo-sensitivity of MCF-7 to Etoposide treatment, indicating that PNMA5 and MOAP-1 interact synergistically to promote apoptotic signaling in MCF-7 cells.

Conclusions

Our results show that PNMA5 promotes apoptosis signaling in HeLa and MCF-7 cells and interacts synergistically with MOAP-1 through its N-terminal domain to promote apoptosis and chemo-sensitivity in human cancer cells. The C-terminal domain of PNMA5 is required for nuclear localization; however, both N-and C-terminal domains of PNMA5 appear to be required for pro-apoptotic function.

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Limited Stage Aggressive Non-Hodgkin Lymphoma: What Is Optimal Therapy?

Opinion Statement

The seminal SWOG trial S8736 trial established the success of a short course of chemotherapy followed by involved field radiation in treating limited stage aggressive NHL lymphoma. Addition of rituximab offered a surprisingly modest improvement in this disease subset. Radioimmunotherapy could hold a slight advantage over rituximab, but that should be investigated in a randomized trial setting. The role of radiation therapy continues to be widely debated, with interpretation complicated by different trial populations, methods of assessing risk, as well as by differences in timing and dose of radiation. Prolonged course of chemotherapy followed by radiation is certainly not justified in all patients with limited stage disease. Three to four cycles of R-CHOP followed closely by IFRT/ISRT, or six cycles of R-CHOP chemoimmunotherapy (based on the MInT trial) are acceptable options. PET/CT scans may further limit radiation to minority of patients who have residual PET-positive masses. PET/CT-directed treatment strategy is being tested in a US intergroup trial. There is evidence that localized DLBCL has a different biology as compared to advanced stage disease. This relates to propensity of limited stage disease to be proportionately more germinal center B-cell like (GCB) and to have late relapses beyond 5 years. Both biology and imaging need to be integrated in the study of limited stage disease without presumption that it should be approached the same as advanced stage disease.

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A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors

Summary

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg–80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60–125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF^V600E mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF^V600E mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

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Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours

Abstract

Purpose

This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed.

Methods

In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation.

Results

Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response.

Conclusions

Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies.

Clinical trial registration number

NCT01813474.

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