(Folia Morphol 2015; 74, 3: 365-371)

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Despite recent advances in high-risk neuroblastoma therapy, the prognosis for patients remains poor. In addition, many patients suffer from complications related to available therapies that are highly detrimental to their quality of life. New treatment modalities are, thus, urgently needed to further improve the efficacy and reduce the toxicity of existing therapies. Since antibodies specific for O-acetyl GD2 ganglioside display pro-apoptotic activity against neuroblastoma cells, we hypothesized that combination of immunotherapy could enhance tumor efficacy of neuroblastoma chemotherapy. We demonstrate here that combination of anti-O-acetyl GD2 monoclonal antibody 8B6 with topotecan synergistically inhibited neuroblastoma cell proliferation, as shown by the combination index values. Mechanistically, we evidence that mAb 8B6 induced plasma cell membrane lesions, consistent with oncosis. Neuroblastoma tumour cells treated with mAb 8B6 indeed showed an increased uptake of topotecan by the tumor cells and a more profound tumor cell death evidenced by increased caspase-3 activation. We also found that the combination with topotecan plus monoclonal antibody 8B6 showed a more potent anti-tumor efficacy than either agent alone. Importantly, we used low-doses of topotecan with no noticeable side effect. Our data suggest that chemo-immunotherapy combinations may improve the clinical efficacy and safety profile of current chemotherapeutic modalities of neuroblastoma.

Stem cell chemoresistance remains challenging the efficacy of the front‐line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti‐O‐acetyl‐GD2 adjuvant immunotherapy controls glioma stem‐like cell‐driven chemoresistance. Using patient‐derived glioblastoma cells, we found that glioma stem‐like cells overexpressed O‐acetyl‐GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem‐like cell markers CD133 and Nestin and compromised glioma stem‐like cell self‐renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide‐resistant glioma stem‐like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti‐O‐acetyl‐GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide‐resistance driven by glioma stem‐like cells. Together our results offer a proof of concept for using anti‐O‐acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas.

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Introduction The success of modern pediatric surgery (PS) management has led to the recommendation of regional organization and coordination of PS departments. Although small units may obtain excellent results, there is evidence that a concentration to larger units is advantageous. In France, the centralization of PS has been discussed for the past 15 years. A new organization was finally achieved in 2010. The intent was to assure children prompt access to the level of care appropriate to the degree of their pathologies to improve the outcomes and reduce morbidity and mortality. Methods One of the first pertinent governmental measures was an attempt to centralize the PS departments and encourage the development of connection between specialized PS care and routine PS unit. In this review, we report this coordination through the analysis inside two regional French areas. Results Paris is the first example that illustrates the network between four specialized PS departments and eight local hospitals. The aim of this connection was to improve the safety and quality of pediatric surgical management during the night for emergency issues and in the case of neonatology. The second example is the network that coexists in the west part of France through monthly video conferencing sessions and subspecialization (pediatric urology, pediatric oncology, and pediatric liver surgery). Moreover, a national program aimed at improving the management of patients with rare diseases since 2005. For instance, biliary atresia and anorectal malformation centers are located in two academic centers in Paris and the esophageal atresia center is in Lille. These expert centers allowed performing numerous studies along with international publications, thereby offering a better vision of the natural story of diseases to improve care. Finally, this network is emphasized during medical education from PS residency to the fellowship when trainees have to spend at least 1 year in a local hospital. Conclusion The European legislation calls for multidisciplinary centers treating children with rare diseases and proposes clear and demanding quality criteria. The French experience illustrates some interesting and encouraging aspects of the current trends in PS care. Our results strongly suggest that centralization, specialization, and connections between specialized and routine PS departments can greatly improve management of and outcomes in children treated in our units.

10% of the cases featured the variations of popliteal artery terminal branches. Three most commonly seen variations are the trifurcation, anterior tibial-peroneal trunk, and high terminal division of the popliteal artery. The most common course of the superior muscular branches is that there are two large branches which are distributed from the popliteal artery at the height of the knee joint cavity and they do not distribute cutaneous branches. Sural branches are also present as two large vessels without cutaneous branches. The genicular anastomosis branches that run on their own are a typical topographic system of these branches.