Kelly L. Stratton

Preoperative Nutritional Status Is an Important Predictor of Survival in Patients Undergoing Surgery for Renal Cell Carcinoma

BACKGROUND The role of malnutrition has not been well studied in patients undergoing surgery for renal cell carcinoma (RCC). OBJECTIVE Our aim was to evaluate whether nutritional deficiency (ND) is an important determinant of survival following surgery for RCC. DESIGN, SETTING, AND PARTICIPANTS A total of 369 consecutive patients underwent surgery for locoregional RCC from 2003 to 2008. ND was defined as meeting one of the following criteria: body mass index <18.5 kg/m(2), albumin <3.5 g/dl, or preoperative weight loss ≥ 5% of body weight. INTERVENTION All patients underwent radical or partial nephrectomy. MEASUREMENTS Primary outcomes were overall and disease-specific mortality. Covariates included age, Charlson comorbidity index (CCI), preoperative anemia, tumor stage, Fuhrman grade, and lymph node status. Multivariate analysis was performed using a Cox proportional hazards model. Mortality rates were estimated using the Kaplan-Meier product-limit method. RESULTS AND LIMITATIONS Eighty-five patients (23%) were categorized as ND. Three-year overall and disease-specific survival were 58.5% and 80.4% in the ND cohort compared with 85.4% and 94.7% in controls, respectively (p<0.001). ND remained a significant predictor of overall mortality (hazard ratio [HR]: 2.41, 95% confidence interval [CI], 1.40-4.18) and disease-specific mortality (HR: 2.76; 95% CI, 1.17-6.50) after correcting for age, CCI, preoperative anemia, stage, grade, and nodal status. This study is limited by its retrospective nature. CONCLUSIONS ND is associated with higher mortality in patients undergoing surgery for locoregional RCC, independent of key clinical and pathologic factors. Given this mortality risk, it may be important to address nutritional status preoperatively and counsel patients appropriately.

A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

pH-induced conformational changes of AcrA, the membrane fusion protein of Escherichia coli multidrug efflux system.

The multidrug efflux system AcrA-AcrB-TolC of Escherichia coli expels a wide range of drugs directly into the external medium from the bacterial cell. The mechanism of the efflux process is not fully understood. Of an elongated shape, AcrA is thought to span the periplasmic space coordinating the concerted operation of the inner and outer membrane proteins AcrB and TolC. In this study, we used site-directed spin labeling (SDSL) EPR (electron paramagnetic resonance) spectroscopy to investigate the molecular conformations of AcrA in solution. Ten AcrA mutants, each with an alanine to cysteine substitution, were engineered, purified, and labeled with a nitroxide spin label. EPR analysis of spin-labeled AcrA variants indicates that the side chain mobilities are consistent with the predicted secondary structure of AcrA. We further demonstrated that acidic pH induces oligomerization and conformational change of AcrA, and that the structural changes are reversible. These results suggest that the mechanism of action of AcrA in drug efflux is similar to the viral membrane fusion proteins, and that AcrA actively mediates the efflux of substrates.

ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma

Study Type – Prognosis (cohort series)

Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma.

PURPOSE To determine whether statin use at time of surgery is associated with survival following nephrectomy or partial nephrectomy for renal cell carcinoma (RCC). Statins are thought to exhibit a protective effect on cancer incidence and possibly cancer survival in a number of malignancies. To date, no studies have shown an independent association between statin use and mortality in RCC. METHODS A retrospective cohort study of 916 patients who underwent radical or partial nephrectomy for RCC from 2000 to 2010 at a single institution was performed. Primary outcomes were overall (OS) and disease-specific survival (DSS). Univariable survival analyses were performed using the Kaplan-Meier and the log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model. The predictive discrimination of the models was assessed using the Harrell c-index. RESULTS The median follow-up of the entire cohort was 42.5 months. The 3-year OS estimate was 83.1% (95% CI: 77.6%-87.3%) for statin users and 77.3% (95% CI: 73.7%-80.6%) for nonstatin users (P = 0.53). The 3-year DSS was 90.9% (95% CI: 86.3%-94.0%) for statin users and 83.5% (95% CI: 80.1%-86.3%) for nonstatin users (P = 0.015). After controlling for age, American Society of Anesthesiology class, pT category, pN category, metastatic status, preoperative anemia and corrected hypercalcemia, and blood type, statin use at time of surgery was independently associated with improved OS (hazard ratio = 0.62; 95% CI: 0.43-0.90; P = 0.011) and DSS (hazard ratio = 0.48; 95% CI: 0.28-0.83; P = 0.009). The multivariable model for DSS had excellent predictive discrimination with a c-index of 0.91. CONCLUSIONS These data suggest that statin usage at time of surgery is independently associated with improved OS and DSS in patients undergoing surgery for RCC.

Locally advanced prostate cancer: the role of surgical management

Among the heterogeneous population of patients with prostate cancer, a high‐risk group with locally advanced prostate cancer (LAPC) present a diagnostic and therapeutic dilemma. Although the incidence of LAPC has decreased with screening since the introduction of prostate‐specific antigen (PSA) testing, significantly many patients are still diagnosed with LAPC. These patients are by definition at higher risk of metastatic disease and worse outcomes. The role of radical prostatectomy (RP) in this population has been debated, as the combination of radiotherapy and hormonal therapy is becoming used more frequently for LAPC. Unfortunately, the clinical staging and evaluation of LAPC is a challenge that results in possibly understaging or overstaging these patients. This further complicates therapeutic decision‐making, and as a result no established standard treatment has been proposed. Like other patients with prostate cancer, individualized therapeutic choices are essential and depend on a multitude of factors. Herein we examine the role of RP for managing LAPC and attempt to emphasize how the risk of distant disease and difficulty with clinical staging might favour incorporating a surgical approach as part of the therapy for patients with LAPC.

Urinary collecting system invasion is a predictor for overall and disease-specific survival in locally invasive renal cell carcinoma

OBJECTIVE To examine the impact of urinary collecting system invasion (UCSI) on survival in patients with pathologic stage T3 renal cell carcinoma (RCC). MATERIALS AND METHODS We identified 1420 patients who underwent nephrectomy at a single institution between 1988 and 2008. Patients with pT3 RCC and data on UCSI were examined (n=303). Clinicopathologic variables were compared using chi-square tests, and a multivariate analysis using the Cox proportional hazards method was used to evaluate the relationship between UCSI and survival. RESULTS Of 303 patients with pT3 RCC, 67 (22.1%) had UCSI. UCSI was associated with higher T3 substage, tumor size, lymph node metastasis, and sarcomatoid features, as well as a shorter 5-year overall (51.9% vs 30.4%; P=.003) and disease-specific survival (59% vs 33.9%; P<.001) compared with those without USCI. On multivariate analysis, UCSI was independently associated with overall (HR 1.49; 95% CI, 1.02-2.17) and disease-specific survival (HR 1.76; 95% CI, 1.15-2.68). CONCLUSIONS The presence of UCSI is independently associated with higher overall and disease-specific mortality in patients undergoing nephrectomy for pT3 RCC. Locally advanced tumors crossing an additional anatomic boundary into the urinary collecting system appear to represent a particularly aggressive form of disease. These data suggest consideration for including UCSI in the next TNM staging system for RCC.

Mechanism of antibiotic efflux in Gram-negative bacteria.

Active efflux of antibiotics mediated by multidrug transporters is a mechanistic basis of multidrug resistance in bacteria. The most versatile multidrug transporters are those found in Gram-negative bacteria. They have a high level of constitutive expression and provide an immediate response to structurally diverse antimicrobial agents including clinically important antibiotics. The versatility and efficiency of multidrug transporters in Gram-negative bacteria heavily depend on coupling of drug efflux with the transport across the outer membrane. The coupling is achieved through the assembly of multi-component protein complexes that span both the inner and the outer membranes of Gram-negative bacteria. In this review we discuss the mechanistic and structural features of multidrug efflux complexes with the major focus on the tight coupling of drug efflux with transport across the outer membrane.

Transurethral Photoacoustic Endoscopy for Prostate Cancer: A Simulation Study

The purpose of this study was to optimize the configuration of a photoacoustic endoscope (PAE) for prostate cancer detection and therapy monitoring. The placement of optical fiber bundles and ultrasound detectors was chosen to maximize the photoacoustic imaging penetration depth. We performed both theoretical calculations and simulations of this optimized PAE configuration on a prostate-sized phantom containing tumor and various photosensitizer concentrations. The optimized configuration of PAE with transurethral light delivery simultaneously increases the imaging penetration depth and improves image quality. Thermal safety, investigated via COMSOL Multiphysics, shows that there is only a 4 mK temperature rise in the urethra during photoacoustic imaging, which will cause no thermal damage. One application of this PAE has been demonstrated for quasi-quantifying photosensitizer concentrations during photodynamic therapy. The sensitivity of the photoacoustic detection for TOOKAD was 0.18 ng/mg at a 763 nm laser wavelength. Results of this study will greatly enhance the potential of prostate PAE for in vivo monitoring of drug delivery and guidance of the laser-induced therapy for future clinical use.

Blood loss associated with radical cystectomy: a prospective, randomized study comparing Impact LigaSure vs. stapling device.

OBJECTIVES Radical cystectomy (RC) is associated with significant blood loss and transfusion requirement. We performed a prospective, randomized trial to compare blood loss, operative time, and cost using 2 different and commonly employed approaches to tissue ligation and division during RC: mechanical (stapler device) and electrosurgical (heat-sealing device). METHODS AND MATERIALS Eighty patients undergoing RC for urothelial bladder carcinoma were randomized to use of either an Endo GIA Stapler or Impact LigaSure device for tissue ligation and division. Primary outcomes were blood loss, operative time, and device costs. Data were analyzed with Wilcoxon rank sum test and Welch 2-sample t test. RESULTS There were no significant demographic or preoperative differences between the cohorts. Mean estimated blood loss was similar between the electrosurgical (687 ml) and stapler (708 ml) arms (P = 0.850). There were no significant differences between cohorts when comparing operative times or transfusion requirement. There was a significant increase in the mean number of adjunctive suture ligatures used in the stapling device arm (3.0 vs. 1.5, P = 0.047). Total device costs were significantly lower with the LigaSure compared with the GIA Stapler (