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Stereotactic radiosurgery (SRS) is an emerging treatment for patients with multiple brain metastases (BM). The present work compares the SRS of multiple brain metastases with whole-brain radiotherapy (WBRT). We performed a matched-pair analysis for 128 patients with multiple BM treated with either SRS or WBRT over a 5-year period. Patients were matched pairwise for seven potential prognostic factors. A mixed Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS). Distant intracranial progression-free survival (icPFS) and local control were assessed using a Fine and Gray subdistribution hazard model and considering death as competing event. Patients undergoing SRS had a median of 4 BM (range 3–16). 1-year local control of individual BM following SRS was 91.7%. Median OS in the SRS subgroup was 15.7 months (IQR 9.7–36.4) versus 8.0 months (interquartile range, IQR 3.8–18.0) in the WBRT subgroup (HR 2.25, 95% CI [1.5; 3.5], p

BACKGROUND Despite advances in the therapy of glioblastomas (GBM) in the last decades, the most common malignancy of glial origin is still associated with poor prognosis. At present, maximal safe resection followed by adjuvant chemoradiotherapy (CRT) with temozolomide (TMZ) is the standard of care. After completion of CRT, patients usually receive 6 maintenance cycles of TMZ that may be complemented by Tumor-Treating Fields (TTFields). Regardless of age and other prognostic factors, the recent EF-14 trial has shown that addition of TTFields to the maintenance therapy significantly increases overall survival in all patient subgroups. In the EF-14 trial, TTFields were used during maintenance therapy, however a potential benefit of concomitant TTFields therapy during CRT remains unclear. In elderly patients aged >65–70 years, depending on performance status, hypofractionated (chemo)radiotherapy with or without TMZ is the recommended treatment.The primary aim of the GERAS trials is to investigate the optimal time point to start TTFields therapy in elderly patients, as well as feasibility and safety of treatment with the TTFields device in elderly patients with newly diagnosed glioblastoma during hypofractionated (chemo)radiotherapy. Secondary endpoints include progression-free survival at 6 months, overall survival and quality of life during combined treatment. MATERIAL AND METHODS The GERAS trial is a single centre, randomized, two-arm, phase I/II trial that will recruit a total of 64 patients. Patients undergo stratified randomization into treatment arm A or control arm B.Patients in arm A start TTFields therapy at the beginning of hypofractionated radiotherapy with or without TMZ and continue treatment during maintenance chemotherapy. Patients in arm B receive hypofractionated radiotherapy with or without TMZ and begin TTFields therapy together with maintenance chemotherapy. Patients in both arms will be trained in using the TTFields device by certified device support specialists. Follow-up includes MRI imaging four weeks after (chemo)radiotherapy and then every 12 weeks as well as regular lab testing according to the current standard of care. Patients will be assessed for neurological status, neurocognitive function, compliance with TTFields therapy and adverse events during, four weeks after (C)RT and then every 12 weeks for up to 52 weeks. RESULTS Not applicable due to ongoing trial. CONCLUSION With TTFields, a new element in the maintenance therapy of glioblastomas has found its way into clinical routine. The GERAS trial aims to determine the optimal time point to start TTFields therapy as well as the safety and feasibility of concomitant TTFields- and hypofractionated (C)RT in elderly patients. This may lead the way for further phase II/III trials that evaluate survival benefits in this subpopulation of elderly patients treated with hypofractionated (C)RT.

Constituting a part of the innate immune system, the complement system consists of over 50 proteins either acting as part of a 3-branch activation cascade, a well-differentiated regulatory system in fluid phase or on each tissue, or as receptors translating the activation signal to multiple cellular effector functions. Complement serves as first line of defence against infections from bacteria, viruses and parasites by orchestrating the immune response through opsonisation, recruitment of immune cells to the site of infection and direct cell lysis. Complement is generally recognised as a protective mechanism against the formation of tumours in humans, but is often limited by various resistance mechanisms interfering with its cytotoxic action, now considered as a great barrier of successful antibody-based immunotherapy. However, recent studies also indicate a pro-tumourigenic potential of complement in certain cancers and under certain conditions. In this review, we present recent findings on the possible dual role of complement in destroying cancer, especially if resistance mechanisms are blocked, but also under certain inflammatory conditions-promoting tumour development.

Complement-dependent cytotoxicity (CDC) is one of the effector mechanisms mediated by therapeutic anticancer monoclonal antibodies (mAbs). However, the efficacy of antibodies is limited by the resistance of malignant cells to complement attack, primarily due to the over-expression of one or more membrane complement regulatory proteins (mCRPs) CD46, CD55, and CD59. CD20-positive Burkitt lymphoma Raji cells and primary CLL cells are resistant to rituximab (RTX)-induced CDC whereas ofatumumab (OFA) proved to be more efficient in cell killing. Primary CLL cells but not CD52-positive acute lymphoblastic leukemia (ALL) REH cells were sensitive to alemtuzumab (ALM)-induced CDC. Upon combined inhibition on Raji and CLL cells by mCRPs-specific siRNAs or neutralizing antibodies, CDC induced by RTX and by OFA was augmented. Similarly, CDC of REH cells was enhanced after mCRPs were inhibited upon treatment with ALM. All mAbs induced C3 opsonization, which was significantly augmented upon blocking mCRPs. C3 opsonization led to enhanced cell-mediated cytotoxicity of leukemia cells exposed to PBLs or macrophages. Furthermore, opsonized CLL cells were efficiently phagocytized by macrophages. Our results provide conclusive evidence that inhibition of mCRPs expression sensitizes leukemic cells to complement attack thereby enhancing the therapeutic effect of mAbs targeting leukemic cells.