Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK-/- and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK-/- mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK-/- mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK-/- mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK-/- mice; however, survival was similar between septic MLCK-/- mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

Predictive Nomogram for Recurrence following Surgery for Nonmetastatic Renal Cell Cancer with Tumor Thrombus.

PURPOSE: Following surgery for nonmetastatic renal cell carcinoma with tumor thrombus the risk of recurrence is significant but variable among patients. The purpose of this study was to develop and validate a predictive nomogram for individual estimation of recurrence risk following surgery for renal cell carcinoma with venous tumor thrombus. MATERIALS AND METHODS: Comprehensive data were collected on patients with nonmetastatic renal cell carcinoma and thrombus treated at a total of 5 institutions from 2000 to 2013. Independent predictors of recurrent renal cell carcinoma from a competing risks analysis were developed into a nomogram. Predictive accuracy was compared between the development and validation cohorts, and between the nomogram and the UISS (UCLA Integrated Staging System, SSIGN (Stage, Size, Grade and Necrosis) and Sorbellini models. RESULTS: A total of 636 patients were analyzed, including the development cohort of 465 and the validation cohort of 171. Independent predictors, including tumor diameter, body mass index, preoperative hemoglobin less than the lower limit of normal, thrombus level, perinephric fat invasion and nonclear cell histology, were developed into a nomogram. Estimated 5-year recurrence-free survival was 49% overall. Five-year recurrence-free survival in patients with 0, 1, 2 and more than 2 risk factors was 77%, 53%, 47% and 20%, respectively. Predictive accuracy was similar in the development and validation cohorts (AUC 0.726 and 0.724, respectively). Predictive accuracy of the thrombus nomogram was higher than that of the UISS (AUC 0.726 vs 0.595, p = 0.001), SSIGN (AUC 0.713 vs 0.612, p = 0.04) and Sorbellini models (AUC 0.709 vs 0.638, p = 0.02). CONCLUSIONS: We present a predictive nomogram for postoperative recurrence in patients with nonmetastatic renal cell carcinoma with venous thrombus. Improving individual postoperative risk assessment may allow for better design and analysis of future adjuvant clinical trials.

Predicting Length of Stay Following Radical Nephrectomy Using the National Surgical Quality Improvement Program Database.

PURPOSE: Length of stay is frequently used to measure the quality of health care, although its predictors are not well studied in urology. We created a predictive model of length of stay after nephrectomy, focusing on preoperative variables. MATERIALS AND METHODS: We used the NSQIP database to evaluate patients older than 18 years who underwent nephrectomy without concomitant procedures from 2007 to 2011. Preoperative factors analyzed for univariate significance in relation to actual length of stay were then included in a multivariable linear regression model. Backward elimination of nonsignificant variables resulted in a final model that was validated in an institutional external patient cohort. RESULTS: Of the 1,527 patients in the NSQIP database 864 were included in the training cohort after exclusions for concomitant procedures or lack of data. Median length of stay was 3 days in the training and validation sets. Univariate analysis revealed 27 significant variables. Backward selection left a final model including the variables age, laparoscopic vs open approach, and preoperative hematocrit and albumin. For every additional year in age, point decrease in hematocrit and point decrease in albumin the length of stay lengthened by a factor of 0.7%, 2.5% and 17.7%, respectively. If an open approach was performed, length of stay increased by 61%. The R(2) value was 0.256. The model was validated in a 427 patient external cohort, which yielded an R(2) value of 0.214. CONCLUSIONS: Age, preoperative hematocrit, preoperative albumin and approach have significant effects on length of stay for patients undergoing nephrectomy. Similar predictive models could prove useful in patient education as well as quality assessment.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PURPOSE: Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. MATERIALS AND METHODS: The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. RESULTS: Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. CONCLUSIONS: In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

Risk of Readmission After Uncomplicated Hospitalization After Radical Cystectomy.

BACKGROUND: Enhanced recovery pathways after radical cystectomy attempt to decrease length of hospitalization, but might increase risk of readmission after discharge. We evaluated the relationship between length of stay and readmission after uncomplicated hospitalization for bladder cancer patients treated with radical cystectomy. PATIENTS AND METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we identified bladder cancer patients who were treated with radical cystectomy from 2011 to 2015. We limited this cohort to those who did not have complications captured while in-hospital, and assessed the proportion readmitted within 30 days of surgery on the basis of length of stay (ie, < 7, 7-9, ≥ 10 days). We fit multivariable logistic regression models to estimate odds of readmission after adjusting for potential confounding factors. RESULTS: Among 4624 patients treated with radical cystectomy, 1003 (21.7%) were readmitted within 30 days of surgery. Of 1,003 readmitted patients, 503 (50%) experienced a major complication after discharge. Factors associated with an increased risk of readmission included diversion with neobladder, diabetes, prolonged surgical time, and obesity (all P < .01). Patients with hospitalization < 7 days were not at increased risk of readmission compared with those with prolonged stays (354/1769, 20.0% < 7 days vs. 201/968, 20.8% ≥ 10 days, adjusted odds ratio, 1.04; 95% confidence interval, 0.90-1.21). CONCLUSION: In the absence of in-hospital complications after radical cystectomy, shorter hospitalizations were not associated with an increased risk of readmission. These findings emphasize the safety and potential cost savings of enhanced recovery pathways after these complex operations.

Impact of histologic subtype on cancer-specific survival in patients with renal cell carcinoma and tumor thrombus.

BACKGROUND: Although different prognostic factors for patients with renal cell carcinoma (RCC) and vena cava tumor thrombus (TT) have been studied, the prognostic value of histologic subtype in these patients remains unclear. OBJECTIVE: We analyzed the impact of histologic subtype on cancer-specific survival (CSS). DESIGN, SETTINGS, AND PARTICIPANTS: We retrospectively analyzed the records of 1774 patients with RCC and TT who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 US and European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable ordered logistic and Cox regression models were used to quantify the impact of tumor histology on CSS. RESULTS AND LIMITATIONS: Overall 5-yr CSS was 53.4% (confidence interval [CI], 50.5-56.2) in the entire group. TT level (according to the Mayo classification of macroscopic venous invasion in RCC) was I in 38.5% of patients, II in 30.6%, III in 17.3%, and IV in 13.5%. Histologic subtypes were clear cell renal cell carcinoma (cRCC) in 89.9% of patients, papillary renal cell carcinoma (pRCC) in 8.5%, and chromophobe RCC in 1.6%. In univariable analysis, pRCC was associated with a significantly worse CSS (p<0.001) compared with cRCC. In multivariable analysis, the presence of pRCC was independently associated with CSS (hazard ratio: 1.62; CI, 1.01-2.61; p<0.05). Higher TT level, positive lymph node status, distant metastasis, and fat invasion were also independently associated with CSS. CONCLUSIONS: In our multi-institutional series, we found that patients with pRCC and vena cava TT who underwent radical nephrectomy and tumor thrombectomy had significantly worse cancer-specific outcomes when compared with patients with other histologic subtypes of RCC. We confirmed that higher TT level and fat invasion were independently associated with reduced CSS.