A B S T R A C T PurposeAdoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and MethodsPatients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8 ϩ -enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4ϩ lymphocytes, and 35 patients received CD8ϩ -enriched TILs with a median of 0.3% CD4 ϩ lymphocytes. One month after TIL infusion, patients who received CD8 ϩ -enriched TILs had significantly fewer CD4 ϩ peripheral blood lymphocytes (P ϭ .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8 ϩ -enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P ϭ .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8ϩ -enriched TILs responded. ConclusionA randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8 ϩ -enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

OBJECTIVE The incidence of thoracic injuries resulting from cardiopulmonary resuscitation (CPR) is not well characterized. We describe a case in which a CPR-associated atrial rupture was identified with ultrasound and successfully managed in the intensive care unit with a bedside thoracotomy and atrial repair. We then describe a systematic review with pooled data analysis of CPR-associated cardiovascular, pulmonary, pleural, and thoracic wall injuries. DATA SOURCES PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, Current Controlled Trials, and Google. STUDY SELECTION Inclusion criteria for the pooled analysis were any clinical or autopsy study in which a) patients underwent cardiopulmonary resuscitation, b) chest compressions were administered either manually or with the assistance of active compression-decompression devices, and c) autopsy or dedicated imaging assessments were conducted to identify complications. Exclusion criteria for the pooled analysis were pre-clinical studies, case reports and abstracts. DATA EXTRACTION Nine-hundred twenty-eight potentially relevant references were identified. Twenty-seven references met inclusion criteria. DATA SYNTHESIS A systematic review of the literature is provided with pooled data analysis. CONCLUSIONS The incidence of reported CPR-associated cardiovascular and thoracic wall injuries varies widely. CPR with active compression-decompression devices has a higher reported incidence of cardiopulmonary injuries. Bedside ultrasound may be a useful adjunct to assess and risk-stratify patients to identify serious or life-threatening CPR-associated injuries.

Purpose Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, therefore, the anti-glioma efficacy of ionizing radiation. Methods and Materials Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-β) or bevacizumab, alone, or in combination with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; tumor vasculature, with immunohistochemical staining; and tumor oxygenation, with hypoxyprobe staining. Results Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percent area of perivascular cell staining while bevacizumab caused a rapid decrease in the percent area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab the effect was transient, being lost by five days. Administration of IFN-β or bevacizumab prior to RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab, or five days after bevacizumab. Conclusions Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the anti-tumor activity of ionizing radiation. Further investigation into the use and timing of these and other agents that modify vascular phenotype, in combination with radiation, is warranted in order to optimize cytotoxic activity.