Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past five years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90% survival), average (standard) risk (75–90% survival), high risk (50–75% survival) and very high risk (<50% survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.

Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. The key involvement of angiogenesis in tumor growth and metastasis has started to redefine chemotherapy and new protocols have emerged. Metronomic chemotherapy, which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. The potential of metronomic chemotherapy was revealed in animal models a decade ago and the efficacy of this approach has been confirmed in the clinic. In the past 5 years, multiple clinical trials have investigated the safety and efficacy of metronomic chemotherapy in a variety of human cancers. While the results have been variable, clinical studies have shown that these new treatment protocols represent an interesting alternative for either primary systemic therapy or maintenance therapy. We review the latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients. Accumulating evidence suggests that the efficacy of such treatment may not only rely on anti-angiogenic activity. Potential new mechanisms of action, such as restoration of anticancer immune response and induction of tumor dormancy are discussed. Finally, we highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy.

Since its inception in 2000, metronomic chemotherapy has undergone major advances as an antiangiogenic therapy. The discovery of the pro-immune properties of chemotherapy and its direct effects on cancer cells has established the intrinsic multitargeted nature of this therapeutic approach. The past 10 years have seen a marked rise in clinical trials of metronomic chemotherapy, and it is increasingly combined in the clinic with conventional treatments, such as maximum-tolerated dose chemotherapy and radiotherapy, as well as with novel therapeutic strategies, such as drug repositioning, targeted agents and immunotherapy. We review the latest advances in understanding the complex mechanisms of action of metronomic chemotherapy, and the recently identified factors associated with disease resistance. We comprehensively discuss the latest clinical data obtained from studies performed in both adult and paediatric populations, and highlight ongoing clinical trials. In this Review, we foresee the future developments of metronomic chemotherapy and specifically its potential role in the era of personalized medicine.

We have previously reported that anti-tubulin agents induce the release of cytochrome c from isolated mitochondria. In this study, we show that tubulin is present in mitochondria isolated from different human cancerous and non-cancerous cell lines. The absence of polymerized microtubules and cytosolic proteins was checked to ensure that this tubulin is an inherent component of the mitochondria. In addition, a salt wash did not release the tubulin from the mitochondria. By using electron microscopy, we then showed that tubulin is localized in the mitochondrial membranes. As compared with cellular tubulin, mitochondrial tubulin is enriched in acetylated and tyrosinated ␣-tubulin and is also enriched in the class III ␤-tubulin isotype but contains very little of the class IV ␤-tubulin isotype. The mitochondrial tubulin is likely to be organized in ␣/␤ dimers and represents 2.2 ؎ 0.5% of total cellular tubulin. Lastly, we showed by immunoprecipitation experiments that the mitochondrial tubulin is specifically associated with the voltage-dependent anion channel, the main component of the permeability transition pore. Thus, tubulin is an inherent component of mitochondrial membranes, and it could play a role in apoptosis via interaction with the permeability transition pore.

The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.