Discerning the survival advantage among patients with prostate cancer who undergo radical prostatectomy or radiotherapy: The limitations of cancer registry data.

BACKGROUND: The objective of this study was to compare the overall survival of patients who undergo radical prostatectomy or radiotherapy versus noncancer controls to discern whether there is a survival advantage according to prostate cancer treatment and the impact of selection bias on these results. METHODS: A matched cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. In total, 34,473 patients ages 66 to 75 years were identified who were without significant comorbidity, were diagnosed with localized prostate cancer, and received treatment treated with surgery or radiotherapy between 2004 and 2011. These patients were matched to a noncancer control cohort. The rates of all-cause mortality that occurred within the study period were compared. Cox proportional hazards regression analysis was used to identify determinants associated with overall survival. RESULTS: Of 34,473 patients who were included in the analysis, 21,740 (63%) received radiation therapy, and 12,733 (37%) underwent surgery. There was improved survival in patients who underwent surgery (hazard ratio, 0.35; 95% confidence interval, 0.32-0.38) and in those who received radiotherapy (hazard ratio, 0.72; 95% confidence interval, 0.68-0.75) compared with noncancer controls. Overall survival improved significantly in both treatment groups, with the greatest benefit observed among patients who underwent surgery (log rank P < .001). CONCLUSIONS: Population-based data indicated that patients with prostate cancer who received treatment with either surgery or radiotherapy had improved overall survival compared with a cohort of matched noncancer controls. Surgery produce longer survival compared with radiation therapy. These results suggest an inherent selection-bias because of unmeasured confounding variables. Cancer 2017;123:1617-1624. © 2017 American Cancer Society.

Preoperative predictors of pathological lymph node metastasis in patients with renal cell carcinoma undergoing retroperitoneal lymph node dissection.

PURPOSE: Patients with locally advanced renal cell carcinoma represent a subset that may benefit from retroperitoneal lymph node dissection. We identified preoperative clinical predictors of positive lymph nodes in patients with renal cell carcinoma without distant metastasis who underwent retroperitoneal lymph node dissection. MATERIALS AND METHODS: We retrospectively analyzed data on a consecutive cohort of 1,270 patients with cTany Nany M0 renal cell carcinoma who were treated at a single institution from 1993 to 2012. Multivariate analysis was performed to determine preoperative predictors of pathologically positive lymph nodes in patients who underwent retroperitoneal lymph node dissection. A nomogram was developed to predict the probability of lymph node metastasis. Overall, cancer specific and recurrence-free survival was estimated using the Kaplan-Meier Method. RESULTS: We identified 1,270 patients with renal cell carcinoma without distant metastasis who had (564) or did not have (706) retroperitoneal lymph node dissection performed. Of the 564 patients 131 (23%) and 433 (77%) had pN1 and pN0 disease, and 60 (37%) and 29 (7.2%) had cN1pN0 and cN0pN1 disease, respectively. ECOG PS, cN stage, local symptoms and lactate dehydrogenase were associated with nodal metastasis on multivariable analysis. A nomogram was developed with a C-index of 0.89 that demonstrated excellent calibration. Differences in overall, cancer specific and recurrence-free survival among pNx, pN0 and pN1 cases were statistically significant (p <0.001). CONCLUSIONS: Local symptoms, ECOG PS, cN stage and lactate dehydrogenase were independent predictors of lymph node metastasis in patients who underwent retroperitoneal lymph node dissection. Our predictive nomogram using these factors showed excellent discrimination and calibration.

The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo.

The discovery of RNAi has revolutionized loss-of-function genetic studies in mammalian systems. However, significant challenges still remain to fully exploit RNAi for mammalian genetics. For instance, genetic screens and in vivo studies could be broadly improved by methods that allow inducible and uniform gene expression control. To achieve this, we built the lentiviral pINDUCER series of expression vehicles for inducible RNAi in vivo. Using a multicistronic design, pINDUCER vehicles enable tracking of viral transduction and shRNA or cDNA induction in a broad spectrum of mammalian cell types in vivo. They achieve this uniform temporal, dose-dependent, and reversible control of gene expression across heterogenous cell populations via fluorescence-based quantification of reverse tet-transactivator expression. This feature allows isolation of cell populations that exhibit a potent, inducible target knockdown in vitro and in vivo that can be used in human xenotransplantation models to examine cancer drug targets.

Preoperative pulmonary embolism does not predict poor postoperative outcomes in patients with renal cell carcinoma and venous thrombus.

PURPOSE: Patients with renal cell carcinoma who present with pulmonary embolism and venous thrombus may not be offered surgery because of presumed poor postoperative outcomes. In this multicenter study we evaluated perioperative mortality, recurrence and cancer specific survival in patients with renal cell carcinoma and venous thrombus diagnosed with preoperative pulmonary embolism. MATERIALS AND METHODS: We reviewed consecutive patient records from our 3 tertiary hospitals to identify patients with renal cell carcinoma and venous thrombus treated with surgery from 2000 to 2011. Univariate and multivariate Cox proportional hazards analysis was used to evaluate whether preoperative pulmonary embolism or other clinical variables were associated with postoperative disease recurrence or cancer specific survival. RESULTS: Pulmonary embolism was identified preoperatively in 35 of 782 patients (4.4%) with renal cell carcinoma. Those with pulmonary embolism preoperatively were more likely to have higher level thrombus and higher T stage (p <0.01). No differences were found in other clinical or pathological features between the groups. There was no difference in 90-day mortality in patients diagnosed with pulmonary embolism preoperatively. Of 395 patients without metastasis preoperatively 147 (37.2%) showed metastatic renal cell carcinoma at a median followup of 22 months. There was no difference in the recurrence rate of renal cell carcinoma in patients with pulmonary embolism (p = 0.36). Recurrence in the lung was not more common in patients with vs without pulmonary embolism preoperatively (p = 0.71). Also, preoperative pulmonary embolism was not predictive of worse cancer specific survival (p = 0.58). CONCLUSIONS: Preoperative pulmonary embolism is not associated with worse early mortality, recurrence or cancer specific survival in patients with renal cell carcinoma and tumor thrombus.

The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase ßTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis.

Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype.