Prognostic Value of Sarcopenia and Albumin in the Surgical Management of Localized Renal Cell Carcinoma.

INTRODUCTION: A universally accepted model for preoperative surgical risk stratification in localized RCC patients undergoing nephrectomy is currently lacking. Both the evaluation of body composition and nutritional status has demonstrated prognostic value for patients with cancer. This study aims to investigate the potential associations between sarcopenia and hypoalbuminemia and survival outcomes in patients with localized kidney cancer treated with partial or radical nephrectomy. MATERIALS AND METHODS: We retrospectively analyzed 473 patients with localized RCC managed with radical and partial nephrectomy. Skeletal muscle index (SMI) was measured from preoperative CT and MRI. Sarcopenic criteria were created using BMI- and sex-stratified thresholds. Relationships between sarcopenia and hypoalbuminemia (Albumin <3.5 g/dL) with overall (OS), recurrence-free (RFS), and cancer-specific survival (CSS) were determined using multivariable and Kaplan-Meier analysis. RESULTS: Of the 473 patients, 42.5% were sarcopenic and 24.5% had hypoalbuminemia. Sarcopenia was significantly associated with shorter OS (HR=1.51, 95% CI 1.07-2.13), however, was nonsignificant in the RFS (HR = 1.33, 95% CI 0.88-2.03) and CSS (HR=1.66, 95% CI 0.96-2.87) models. Hypoalbuminemia predicted shorter OS (HR=1.76, 95% CI 1.22-2.55), RFS (HR=1.86, 95% CI 1.19-2.89), and CSS (HR=1.82, 95% CI 1.03-3.22). Patients were then stratified into low, medium, and high-risk groups based on the severity of sarcopenia and hypoalbuminemia. Risk groups demonstrated an increasing association with shorter OS (all p<0.05). Reduced RFS was observed in the medium risk-hypoalbuminemia (HR=2.18, 95% CI 1.16-4.09) and high-risk groups (HR=2.42, 95% CI 1.34-4.39). Shorter CSS was observed in the medium risk-hypoalbuminemia (HR=2.31, 95% CI 1.00-5.30) and high-risk groups (HR=2.98, 95% CI 1.34-6.61). CONCLUSION: Localized RCC patients with combined preoperative sarcopenia and hypoalbuminemia displayed a two to a three-fold reduction in OS, RFS, and CSS after nephrectomy. These data have implications for guiding prognostication and treatment election in localized RCC patients undergoing extirpative surgery.

Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity.

Individuals homozygous for the "Z" mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

Data regarding covariates significantly associated with sarcopenia and varying albumin statuses in patients with renal cell carcinoma.

Poor functional, nutritional, and muscle status is a significant negative predictor for surgical and survival outcomes in patients with cancer, including renal cell carcinoma. This dataset displays results from preoperative muscle composition analysis and albumin levels in a large cohort (n = 473) of patients undergoing surgery for renal cell carcinoma. Data was obtained from retrospective review of prospectively maintained databases and retrospective image analysis. The optimal cut-point for skeletal muscle index (sarcopenia) was determined by a receiver operatic characteristic analysis to optimally stratify cohort, adjusting for BMI and sex. A threshold value of 3.5 g/dL was used to categorize normal versus low serum albumin. Patients were stratified into low risk (non-sarcopenic and normal albumin), medium risk (non-sarcopenic and low albumin, or sarcopenic and normal albumin), and high risk (sarcopenic and low albumin) groups. This data could potentially be used in future studies to determine other relationships between nutrition and musculature in renal cell carcinoma patients.

Machine Learning in Body Composition Analysis.

Body composition analysis (BCA) generates objective anthropometric data that can inform prognostication and treatment decisions across a wide variety of urologic conditions. A patient's body composition, specifically muscle and adipose tissue mass, may be characterized via segmentation of cross-sectional images (computed tomography, magnetic resonance imaging) obtained as part of routine clinical care. Unfortunately, conventional semi-automated segmentation techniques are time- and resource-intensive, precluding translation into clinical practice. Machine learning (ML) offers the potential to automate and scale rapid and accurate BCA. To date, ML for BCA has relied on algorithms called convolutional neural networks designed to detect and analyze images in ways similar to human neuronal connections. This mini review provides a clinically oriented overview of ML and its use in BCA. We address current limitations and future directions for translating ML and BCA into clinical practice. PATIENT SUMMARY: Body composition analysis is the measurement of muscle and fat in your body based on analysis of computed tomography or magnetic resonance imaging scans. We discuss the use of machine learning to automate body composition analysis. The information provided can be used to guide shared decision-making and to help in identifying the best therapy option.

Sarcopenia and modified Glasgow Prognostic Score predict postsurgical outcomes in localized renal cell carcinoma.

BACKGROUND: Body composition and inflammation are gaining importance for prognostication in cancer. This study investigated the individual and combined utility of the preoperative skeletal muscle index (SMI) and the modified Glasgow Prognostic Score (mGPS) for estimating postoperative outcomes in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy. METHODS: The authors performed a retrospective review of 352 patients with localized RCC. SMI was measured via computed tomography or magnetic resonance imaging. Patients met the criteria for sarcopenia by body mass index- and sex-stratified thresholds. Multivariable and Kaplan-Meier analyses of associations of sarcopenia and mGPS with overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) were performed. Variables were analyzed independently and combined into risk groups: low risk (nonsarcopenic, low mGPS), medium risk (sarcopenia only), medium risk (inflammation only), and high risk (sarcopenic, high mGPS). Receiver operating characteristic (ROC) curves were used to analyze risk groups in comparison with the Stage, Size, Grade, and Necrosis (SSIGN) score and the modified International Metastatic RCC Database Consortium (IMDC) score. RESULTS: The majority of the patients were at stage pT3 (63%), 39.5% of the patients were sarcopenic, and 19.3% had an elevated mGPS at the baseline. The median follow-up time was 30.4 months. Sarcopenia and mGPS were independently associated with worse OS (hazard ratio for sarcopenia, 1.64; P = .006; hazard ratio for mGPS, 1.72; P = .012), CSS, and RFS. Risk groups had an increasing association with worse RFS (P = .015) and CSS (P = .004) but not OS (P = .087). ROC analyses demonstrated a higher area under the curve for risk groups in comparison with the SSIGN and IMDC scores at 5 years. CONCLUSIONS: Sarcopenia and an elevated mGPS were associated with worse clinical outcomes in this study of patients with localized RCC. This has implications for preoperative prognostication and treatment decision-making. LAY SUMMARY: Kidney cancer is a disease with a wide variety of outcomes. Among patients undergoing surgical removal of the kidney for cancer that has not spread beyond the kidney, many are cured, but some experience recurrence. Physicians are seeking ways to better predict who is at risk for recurrence or death from kidney cancer. This study has evaluated body composition and markers of inflammation before surgery to predict the risk of recurrence or death after surgery. Specifically, low muscle mass and an elevated inflammation score (the modified Glasgow Prognostic Score) have been associated with an increased likelihood of recurrence of kidney cancer and death.

Overlapping Urological Surgeries at a Tertiary Academic Center.

OBJECTIVE: To evaluate whether the practice of procedure-time overlapping surgery (OS) is associated with inferior outcomes compared to nonoverlapping surgery (NOS) in urology, to address the paucity of data surrounding urologic surgeries to support or refute this practice. MATERIALS AND METHODS: We performed a retrospective review of all urological surgeries at a single tertiary-level academic center, Emory University Hospital, from July 2016 to July 2018. Patients who received OS were matched 1:2 to patients who had NOS. The primary outcomes were perioperative and postoperative complications and mortality. RESULTS: We reviewed 8535 urological surgeries. In-room time overlap was seen in 50.5% of cases and procedure-time overlap in 7.4%. Eleven out of the 13 attending urologists performed OS. The average time in the operating room was greater for OS by an average of 14 minutes. The average operative time was greater for OS than NOS by 11 minutes, but this did not reach statistical significance. There was no significant difference between the cohorts for rate of blood transfusions, ICU stay, need for postoperative invasive procedures, length of postoperative hospital stay, discharge location, Emergency Room visits, hospital readmission rate, 30 and 90-day rates of postoperative complications, and mortality. CONCLUSION: Procedure-time overlapping surgeries constituted a minority of urological cases. OS were associated with greater in-room time. We found no increased risk of perioperative or postoperative adverse outcomes in OS compared to matched NOS.

A Strategy for Undergraduate Medical Education in Urology During the COVID-19 Pandemic.

OBJECTIVE: To provide a framework for a virtual curriculum during the COVID-19 pandemic for medical student educators that introduces and teaches clinical concepts important in urology and surgical specialties in general. METHODS: We created a 1-week virtual urology course utilizing interactive lectures, case-based exercises, and faculty-proctored surgical video reviews. Students were assigned self-study modules and participated in case-based discussions and presentations on a topic of their choice. Students' perceptions of urology as a specialty and the utility of the course was evaluated through pre- and postcourse surveys. Understanding of urologic content was evaluated with a multiple-choice exam. RESULTS: A total of nine students were enrolled in the course. All students reported increased understanding of the common urologic diagnoses and of urology as a specialty by an average of 2.5 points on a 10-point Likert scale (Cohen's measure of effect size: 3.2). Additionally, 56% of students reported increased interest, 22% reported no change and 22% reported a decreased interest in pursuing urology as a specialty following the course. Students self-reported increased knowledge of a variety of urologic topics on a 10-point Likert scale. The average exam score on the multiple-choice exam improved from 50% before the course to 89% after the course. CONCLUSIONS: Various teaching techniques can be employed through a virtual platform to introduce medical students to the specialty of urology and increase clinical knowledge surrounding common urologic conditions. As the longevity of the COVID-19 pandemic becomes increasingly apparent and virtual teaching is normalized, these techniques can have far-reaching utility within the traditional medical student surgical curriculum.

Quantification of body composition in renal cell carcinoma patients: Comparing computed tomography and magnetic resonance imaging measurements.

PURPOSE: Body composition measures provide valuable information for prognostication and treatment election in cancer patients. We investigated the novel use of magnetic resonance imaging (MRI) for skeletal muscle and adipose tissue cross-sectional area measurements in preoperative renal cell carcinoma (RCC) patients. MATERIALS AND METHODS: RCC patients with pre-operative CT and MRI abdominal imaging were identified. Semi-automatic segmentation measurement of skeletal muscle area (SMA), intramuscular fat area (IMFA), visceral fat area (VFA), subcutaneous fat area (SFA), linear measurements of psoas, paraspinal muscles were performed. Pearson correlation coefficients, Bland-Altman plot analyses were done. Multivariable regression analysis examined the relationship between patient characteristics and skeletal muscle. RESULTS: Image analysis was performed on 58 RCC patients with preoperative CT and MRI imaging. For segmentation measures, r = 0.99, 0.99, 0.99, and 0.98 for SMA, IMFA, VFA, SFA, respectively, and 0.96 for linear measures of skeletal muscle. Bland-Altman analysis revealed a bias toward larger CT value for SMA (1.35 %), linear muscle measures (2.79 %), and SFA (10.34 %), and toward larger MRI values for IMFA (0.75 %) and VFA (5.81 %). ECOG ≥ 1 was associated with lower skeletal muscle than ECOG 0 for all measurements. CONCLUSIONS: Strong correlation of CT and MRI cross sectional measurements of skeletal muscle and adipose tissues supports the use of axial MRI images for comprehensive measurement of body composition. This has widespread implications for body composition research and cancer patient care.

A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells.

Individuals with the genetic disorder alpha-1 antitrypsin deficiency (AATD) are at risk of developing lung and liver disease. Patient induced pluripotent stem cells (iPSCs) have been found to model features of AATD pathogenesis but only a handful of AATD patient iPSC lines have been published. To capture the significant phenotypic diversity of the patient population, we describe here the establishment and characterization of a curated repository of AATD iPSCs with associated disease-relevant clinical data. To highlight the utility of the repository, we selected a subset of iPSC lines for functional characterization. Selected lines were differentiated to generate both hepatic and lung cell lineages and analyzed by RNA sequencing. In addition, two iPSC lines were targeted using CRISPR/Cas9 editing to accomplish scarless repair. Repository iPSCs are available to investigators for studies of disease pathogenesis and therapeutic discovery.

Multilineage transduction of resident lung cells in vivo by AAV2/8 for α1-antitrypsin gene therapy.

In vivo gene delivery has long represented an appealing potential treatment approach for monogenic diseases such as α1-antitrypsin deficiency (AATD) but has proven challenging to achieve in practice. Alternate pseudotyping of recombinant adeno-associated virus (AAV) vectors is producing vectors with increasingly heterogeneous tropic specificity, giving researchers the ability to target numerous end-organs affected by disease. Herein, we describe sustained pulmonary transgene expression for at least 52 weeks after a single intratracheal instillation of AAV2/8 and characterize the multiple cell types transduced within the lung utilizing this approach. We demonstrate that lung-directed AAV2/8 is able to achieve therapeutic α-1 antitrypsin (AAT) protein levels within the lung epithelial lining fluid and that AAT gene delivery ameliorates the severity of experimental emphysema in mice. We find that AAV2/8 efficiently transduces hepatocytes in vivo after intratracheal administration, a finding that may have significance for AAV-based human gene therapy studies. These results support direct transgene delivery to the lung as a potential alternative approach to achieve the goal of developing a gene therapy for AATD.