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Tumor immunoscoring is rapidly becoming a universal parameter of prognosis, and T-cells isolated from tumor masses are used for ex vivo amplification and readministration to patients to facilitate an antitumor immune response. We recently exploited the cancer genome atlas (TCGA) RNASeq data to assess T-cell receptor (TcR) expression and, in particular, discovered strong correlations between major histocompatibility class II (MHCII) and TcR-α constant region expression levels. In this article, we describe the results of searching TCGA exome files for TcR-α V-regions, followed by searching the V-region datasets for TcR-α-J regions. Both primary and metastatic breast cancer sample files contained recombined TcR-α V-J regions, ranging in read counts from 16–39, at the higher level. Among four such V-J rearrangements, three were productive rearrangements. Rearranged TcR-α V–J regions were also detected in TCGA–bladder cancer, -lung cancer, and -ovarian cancer datasets, as well as exome files representing bladder cancer, in Moffitt Cancer Center patients. These results suggest that a direct search of commonly available, conventional exome files for rearranged TcR segments could play a role in more sophisticated immunoscoring or in identifying particular T-cell clones and TcRs directed against tumor antigens.

Approximately 10%‐20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5‐year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty‐one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies. Our study identified nine genes as prognostic biomarkers of ccRCC survival. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets.

Introduction Solid testis tumors in post‐pubertal males usually represent germ cell malignancies; however, other uncommon or rare histologies must be considered. Case presentation We present a case of an 18‐year‐old male undergoing attempted bilateral partial orchiectomies for suspected germ cell tumors. Tumor pathology, laboratory results, radiographic studies, and post‐surgical elevated adrenocorticotropic hormone levels supported the diagnosis of testicular adrenal rest tumors secondary to previously undiagnosed nonclassical congenital adrenal hyperplasia. Conclusion Testicular adrenal rest tumors are rare in patients with nonclassical congenital adrenal hyperplasia and may be accompanied by adrenal insufficiency and hypogonadism, which can be treated with glucocorticoid therapy and testosterone replacement. Differential diagnosis of tumors is challenging but necessary for proper symptom‐based management.

Background The perioperative period can be a critical period with long-term implications on cancer-related outcomes. In this study, we evaluate the influence of regional anesthesia on cancer-specific outcomes in a radical cystectomy (RC) cohort of patients. Methods We performed a retrospective analysis of patients with clinically-nonmetastatic urothelial carcinoma of the bladder who underwent RC at our institution from 2008 to 2012. Patients were retrospectively registered and stratified based on two anesthetic techniques: perioperative epidural analgesia with general anesthesia (epidural) versus general anesthesia alone (GA). Epidural patients received a sufentanil-based regimen (median intraoperative sufentanil dose 50 mcg (45,85). Propensity-score was used to make 1:1 case-control matching. Cumulative risk of recurrence with competing risks was calculated based on anesthetic technique. Kaplan-Meier curves were used to compare recurrence-free (RFS) and cancer-specific survival (CSS). Univariable and multivariable analyses were performed with Cox proportional hazard regression models for RFS and CSS. Results Only patients with complete data on anesthetic technique were included. Out of 439 patients, 215-pair samples with complete follow-up were included in the analysis. Median follow-up was 41.4 months (range: 0.20–101). Patients with epidurals received higher median total intravenous morphine equivalents (ivMEQ) versus those in the GA group (75 (11–235) vs. 50 ivMEQ (7–277), p  < 0.0001). Cumulative risk of recurrence at two years was 25.2% (19.6, 31.2) for epidural patients vs. 20.0% (15.0, 25.7) for GA patients (Gray test p  = 0.0508). Epidural analgesic technique was a significant predictor of worse RFS (adjusted HR = 1.67, 1.14–2.45; p  = 0.009) and CSS (HR = 1.53, 1.04–2.25; p  = 0.030) on multivariable analyses. Conclusions Epidural anesthesia using sufentanil was associated with worse recurrence and disease-free survival in bladder cancer patients treated with surgery. This may be due use of epidural sufentanil or due to the increased total morphine equivalents patient received as a consequence of this drug.

Purpose Lymphadenectomy (LND) is part of the surgical management of penile cancer but causes significant perioperative morbidity. We determined whether sarcopenia, a novel marker of nutritional status, is a predictor of postoperative complications after LND. Materials and methods Seventy-nine patients underwent LND for penile cancer from 1999 to 2014, and 43 had available preoperative abdominal imaging. Skeletal muscle index (SMI) was calculated on axial computed tomography images at the third lumbar vertebrae, and an SMI of 55 cm 2 /m 2 was used to classify patients as sarcopenic versus not. This classification was then correlated with postoperative complications and survival. Results Median lumbar SMI was 54.7 cm 2 /m 2 with 22 (51.2 %) patients categorized as sarcopenic versus 21 (48.8 %) who were not. Twenty-seven postoperative complications occurred in 20 patients within 30 days, of which 11 (40.7 %) were major (Clavien score ≥IIIa) and 16 (59.3 %) were minor. The most common complications were wound dehiscence (25.9 %), wound infection (18.5 %), lymphocele (18.5 %), and flap necrosis (14.8 %). On univariate analysis, the presence of sarcopenia, nodal disease, and lymphovascular invasion were predictors of postoperative complications. On multivariate analysis, only sarcopenia was an independent predictor of 30-day complications [ p  = 0.038; 95 % confidence interval (CI) 1.1–21.1]. Although sarcopenia was not statistically associated with worse overall survival (OS), there was a trend toward poorer outcomes in these patients. Conclusions Sarcopenia can be a useful prognostic tool to predict the likelihood of postoperative complications after LND for penile cancer. Preoperative nutritional supplementation may help reduce complication rates in the future.

Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (110 [18%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Introduction: The choice of approach for partial nephrectomy often depends on surgical complexity. We aimed to determine if surgeon intuition was equivalent to markers of operative complexity, such as RENAL nephrometry and Mayo adhesive probability (MAP) score, in determining the surgical approach for partial nephrectomy (PN). Materials and Methods: We retrospectively identified 119 masses removed for suspected renal cell carcinoma from January 2012 to September 2014 by a single surgeon who intuitively chose treatment with one of three surgical approaches: Open PN (OPN), robotic-assisted transperitoneal PN (RATPN), or robotic-assisted retroperitoneal PN (RARPN). Clinicodemographic characteristics, pathological features, and postoperative outcomes were compared for each approach. Logistic regression was performed to identify independent predictors of open surgical resection, our primary endpoint. Results: Fifty-four tumors (45%) were resected via OPN, 40 (34%) via RATPN, and 25 (21%) via RARPN. OPN was performed in patients with more comorbidities (P = 0.02), lower baseline renal function (P < 0.01), more solitary kidneys (P < 0.01), and more multifocal disease (P < 0.01). Patients undergoing OPN had higher median nephrometry scores compared to RATPN and RARPN patients (8 vs. 7 vs. 7, respectively; P = 0.03), but MAP scores were no different among all three groups (P = 0.36). On multivariate analysis, higher nephrometry scores (odds ratio: 1.41, 95% confidence interval: 1.10-1.81; P = 0.007) were independently associated with open surgical resection. Nephrometry score was predictive of OPN (area under curve = 0.64, P = 0.01) with a score of 6.5 having the highest sensitivity and specificity (76% and 42%, respectively). Conclusions: RENAL nephrometry score was associated with surgical approach intuitively chosen by an experienced surgeon, but the presence of adherent perinephric fat did not correlate with decision-making.

Background Forty years ago the actin cytoskeleton was determined to be disrupted in fibroblasts from persons with DNA repair-defective, hereditary colon cancer, with no clear connection between the cytoskeleton and DNA repair defects at that time. Recently, the large number of sequenced genomes has indicated that mammalian mutagenesis has a large stochastic component. As a result, large coding regions are large mutagen targets. Cytoskeletal protein-related coding regions (CPCRs), including extra-cellular matrix proteins, are among the largest coding regions in the genome and are indeed very commonly mutated in cancer. Methods To determine whether mutagen sensitivity of the actin cytoskeleton could be assessed experimentally, we treated tissue culture cells with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and quantified overall cytoskeleton integrity with rhodamine-phalloidin stains for F-actin. Results The above approach indicated cytoskeletal degradation with increasing mutagen exposure, consistent with increased mutagenesis of CPCRs in TCGA, smoker samples, where overall mutation rates correlate with CPCR mutation rates (R 2  = 0.8694; p < 0.00001). In addition, mutagen exposure correlated with a decreasing cell perimeter to area ratio, raising questions about potential decreasing, intracellular diffusion and concentrations of chemotherapy drugs, with increasing mutagenesis and decreasing cytoskeleton integrity. Conclusion Determination of cytoskeletal integrity may provide the opportunity to assess mutation burdens in nonclonal cell populations, such as in intact tissues, where DNA sequencing for heterogeneous mutation burdens can be challenging.

Objectives: Accurate pathologic interpretation of testicular germ cell tumors (GCTs) can be problematic due to low incidence and variation in histologic patterns. By analyzing changes in the diagnosis of testicular specimens after secondary review, we hoped to determine how these can affect prognosis and treatment. Methods: From 1999 to 2013, a total of 235 patients underwent radical orchiectomy at a referring facility and had pathology specimens reanalyzed by our center’s pathologists with expertise in genitourinary malignancies. We identified discrepancies in pathologic reporting. Results: Fifty (21.3%) patients had variations in interpretation of their orchiectomy specimens. A clinically significant alteration was identified in 16 (6.8%) patients, most commonly due to recognition (or misrecognition) of lymphovascular invasion (LVI) associated with nonseminomatous germ cell tumors (NSGCTs). Changes in LVI status resulted in upstaging or downstaging from clinical stage 1A to stage 1B or vice versa in six patients with NSGCTs, with a subsequent change in therapeutic strategy. In addition, one patient with stage 1 pure seminoma had been misclassified with nonseminoma. Conclusions: Inaccurate interpretation of orchiectomy specimens is not uncommon and may lead to incorrect tumor staging, imprecise assignment of progression risk, and inappropriate management recommendations. Secondary opinions of primary GCT orchiectomy specimens potentially facilitate appropriate counseling and therapeutic strategies.

PurposeTo describe the perioperative safety, functional and immediate post-operative oncological outcomes of minimally invasive RPLND (miRPLND) for testis cancer.MethodsWe performed a retrospective multi-centre cohort study on testis cancer patients treated with miRPLND from 16 institutions in eight countries. We measured clinician-reported outcomes stratified by indication. We performed logistic regression to identify predictors for maintained postoperative ejaculatory function.ResultsData for 457 men undergoing miRPLND were studied. miRPLND comprised laparoscopic (n = 56) or robotic (n = 401) miRPLND. Indications included pre-chemotherapy in 305 and post-chemotherapy in 152 men. The median retroperitoneal mass size was 32 mm and operative time 270 min. Intraoperative complications occurred in 20 (4%) and postoperative complications in 26 (6%). In multivariable regression, nerve sparing, and template resection improved ejaculatory function significantly (template vs bilateral resection [odds ratio (OR) 19.4, 95% confidence interval (CI) 6.5–75.6], nerve sparing vs non-nerve sparing [OR 5.9, 95% CI 2.3–16.1]). In 91 men treated with primary RPLND, nerve sparing and template resection, normal postoperative ejaculation was reported in 96%. During a median follow-up of 33 months, relapse was detected in 39 (9%) of which one with port site (< 1%), one with peritoneal recurrence and 10 (2%) with retroperitoneum recurrences.ConclusionThe low proportion of complications or peritoneal recurrences and high proportion of men with normal postoperative ejaculatory function supports further miRPLND studies.