Chirag G. Patil

BACKGROUND: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). METHODS: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. RESULTS: Twenty-one patients were enrolled with 17 newly diagnosed (ND-GBM) and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33 % responders. TAA expression by qRT-PCR from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. CONCLUSIONS: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumors.

CONTEXT: Few studies have systematically analyzed the long-term recurrence rates of Cushing's disease after initial successful transsphenoidal surgery. SETTING: This was a retrospective review of patients treated at the University of Virginia Medical Center. PATIENTS: A total of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006 were included. MAIN OUTCOME MEASURES: Remission and recurrence rates of Cushing's disease were examined. Recurrence was defined as an elevated 24-h urine free cortisol with clinical symptoms consistent with Cushing's disease. RESULTS: Of the 215 patients who underwent transsphenoidal surgery for Cushing's disease, surgical remission was achieved in 184 (85.6%). The mean length of follow-up was 45 months. Actuarial recurrence rates of Cushing's disease after initially successful transsphenoidal surgery at 1, 2, 3, and 5 yr were 0.5, 6.7, 10.8, and 25.5%, respectively. Among the 184 patients who achieved remission, 32 (17.4%) patients followed for more than 6 months ultimately had a recurrence of Cushing's disease. The median time to recurrence was 39 months. Immediate postoperative hypocortisolemia (serum cortisol < or = 2 microg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 microg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 microg/dl (odds ratio = 2.5; 95% confidence interval 1.12-5.52; P = 0.022). CONCLUSIONS: A quarter of the patients with Cushing's disease who achieve surgical remission after transsphenoidal surgery, recur with long-term follow-up. This finding emphasizes the need for continued biochemical and clinical follow-up to ensure remission after surgery.

STUDY DESIGN: This is a multivariate analysis of a prospectively collected database. OBJECTIVE: To determine preoperative, intraoperative, and patient characteristics that contribute to an increased risk of postoperative wound infection in patients undergoing spinal surgery. SUMMARY OF BACKGROUND DATA: Current literature sites a postoperative infection rate of approximately 4%; however, few have completed multivariate analysis to determine factors which contribute to risk of infection. METHODS: Our study identified patients who underwent a spinal decompression and fusion between 1997 and 2006 from the Veterans Affairs' National Surgical Quality Improvement Program database. Multivariate logistic regression analysis was used to determine the effect of various preoperative variables on postoperative infection. RESULTS: Data on 24,774 patients were analyzed. Wound infection was present in 752 (3.04%) patients, 287 (1.16%) deep, and 468 (1.89%) superficial. Postoperative infection was associated with longer hospital stay (7.12 vs. 4.20 days), higher 30-day mortality (1.06% vs. 0.5%), higher complication rates (1.24% vs. 0.05%), and higher return to the operating room rates (37% vs. 2.45%). Multivariate logistic regression identified insulin dependent diabetes (odds ratios [OR] = 1.50), current smoking (OR = 1.19) ASA class of 3 (OR = 1.45) or 4 to 5 (OR = 1.66), weight loss (OR = 2.14), dependent functional status (1.36) preoperative HCT <36 (1.37), disseminated cancer (1.83), fusion (OR = 1.24) and an operative duration of 3 to 6 hours (OR = 1.33) or >6 hours (OR = 1.40) as statistically significant predictors of postoperative infection. CONCLUSION: Using multivariate analysis of a large prospectively collected data from the National Surgical Quality Improvement Program database, we identified the most important risk factors for increased postoperative spinal wound infection. We have demonstrated the high mortality, morbidity, and hospitalization costs associated with postoperative spinal wound infections. The information provided should help alert clinicians to presence of these risks factors and the likelihood of higher postoperative infections and morbidity in spinal surgery patients.

BACKGROUND: Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012. OBJECTIVES: To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases. SEARCH METHODS: For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review. SELECTION CRITERIA: We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. DATA COLLECTION AND ANALYSIS: We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis. MAIN RESULTS: We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. AUTHORS' CONCLUSIONS: Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.