Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21−/− mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. Significance: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.
For the planning of multiple brain lesions to be treated with stereotactic radiosurgery, Multiple Metastases Element planning software produced equivalent conformity, homogeneity, dose falloff, and brain V but required significantly lower monitor units, when compared to RapidArc plans.
Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.
Craniotomy surgical site infections are an inherent risk and dreaded complication for the elective brain tumor patient. Sequelae can include delays in resumption in adjuvant treatments for multiple surgeries if staged cranioplasty is pursued. Here, the authors review their experience in operative debridement of surgical site infections with single-stage reimplantation of the salvaged craniotomy bone flap. A prospectively maintained database of a single surgeon's neuro-oncology patients from 2009 to 2017 (JRF) was queried to identify 11 patients with surgical site infection after craniotomy for tumor resection. All patients underwent a protocol of aggressive operative debridement including drilling the bone edges and intraoperative flap sterilization with single-stage reimplantation, followed by tailored-antibiotic therapy. Ten of the 11 patients with frankly contaminated bone flaps from surgical site infection were able to be salvaged in a single-stage procedure. Five of these patients underwent adjuvant chemotherapy and/or radiation without secondary complication. There was one treatment failure in a delayed fashion which required additional surgery for craniectomy; however, this occurred after adjuvant treatment was administered. Surgical debridement and bone flap salvage is safe and cost-effective in managing acute surgical site infections after craniotomy for tumors. Additionally, this practice is likely beneficial in expediting the resumption of cancer therapy.
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