Development and validation of a multicenter Cox regression model to predict all-cause mortality in patients with renal masses suspicious for renal cancer.

OBJECTIVE: Life expectancy models are useful tools to support clinical decision-making. Prior models have not been used widely in clinical practice for patients with renal masses. We sought to develop and validate a model to predict life expectancy following the detection of a localized renal mass suspicious for renal cell carcinoma. MATERIALS AND METHODS: Using retrospective data from 2 large centers, we identified patients diagnosed with clinically localized renal parenchymal masses from 1998 to 2018. After 2:1 random sampling into a derivation and validation cohort stratified by site, we used age, sex, log-transformed tumor size, simplified cardiovascular index and planned treatment to fit a Cox regression model to predict all-cause mortality from the time of diagnosis. The model's discrimination was evaluated using a C-statistic, and calibration was evaluated visually at 1, 5, and 10 years. RESULTS: We identified 2,667 patients (1,386 at Corewell Health and 1,281 at Johns Hopkins) with renal masses. Of these, 420 (16%) died with a median follow-up of 5.2 years (interquartile range 2.2-8.3). Statistically significant predictors in the multivariable Cox regression model were age (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.03-1.05); male sex (HR 1.40; 95% CI 1.08-1.81); log-transformed tumor size (HR 1.71; 95% CI 1.30-2.24); cardiovascular index (HR 1.48; 95% CI 1.32-1.67), and planned treatment (HR: 0.10, 95% CI: 0.06-0.18 for kidney-sparing intervention and HR: 0.20, 95% CI: 0.11-0.35 for radical nephrectomy vs. no intervention). The model achieved a C-statistic of 0.74 in the derivation cohort and 0.73 in the validation cohort. The model was well-calibrated at 1, 5, and 10 years of follow-up. CONCLUSIONS: For patients with localized renal masses, accurate determination of life expectancy is essential for decision-making regarding intervention vs. active surveillance as a primary treatment modality. We have made available a simple tool for this purpose.

Incidental discovery of metastatic renal cell carcinoma at the vaginal wall: A case report.

Metastasis of renal cell carcinoma (RCC) to the vaginal wall has rarely been reported in the literature. We present a case of a 48-year-old who was found to have a solitary RCC metastasis at the vaginal wall, five years following radical nephrectomy. This case is noteworthy because this late presentation is unique, with prior reports of synchronous metastasis or metastasis within two years of nephrectomy, highlighting the need to consider metastatic RCC to the vagina a possibility even many years after treatment.

Simplified cardiovascular index may be the best comorbidity index for clinical use in prediction of mortality for renal cancer patients.

OBJECTIVE: Understanding the relationship between comorbidities and life expectancy is important in cancer patients who carry risks of cancer and noncancer-related mortality. Comorbidity indices (CI) are tools to provide an objective measure of competing risks of death. We sought to determine which CI might be best incorporated into clinical practice for patients with suspected renal cancer. MATERIALS AND METHODS: 1572 patients diagnosed with renal masses (stage I-IV) between 1998 and 2016 were analyzed for this study. Patient data were gathered from a community-based health center. Comorbidities were evaluated individually, and with 1 of 4 CI: Charlson (CCI), updated CCI (uCCI), age-adjusted CCI (aCCI), and simplified cardiovascular index (CVI). Cox-proportional hazard analysis of all-cause mortality was performed using the four CI, adjusting for the 4 CI, adjusting for age, gender, race, tumor size, and tumor stage. RESULTS: Univariable analyses revealed the four CI were significant predictors of mortality (P < 0.05), as were age, gender, tumor size, and stage. Comorbid conditions at diagnosis included hypertension (47.8%), diabetes mellitus (47.2%), coronary artery disease (41.1%), chronic kidney disease (31.8%), peripheral vascular disease (8.0%), congestive heart failure (5.7%), chronic obstructive pulmonary disease (5.7%), and cerebrovascular disease (2.0%). When analyzing the 4 CI in multivariable survival analyses accounting for factors available at diagnosis, and analyses incorporating pathologic and recurrence data, only CVI score and uCCI remained statistically significant (P < 0.05). Limitations of this work are the retrospective nature of data collection and data from a single institution, limiting the generalizability. CONCLUSION: Increasing comorbidity, age, tumor size, and cM stage are predictors of ACM for suspected renal cancer patients. CVI appears to provide comparable information to various iterations of CCI (uCCI, aCCI) while being the simplest to use. Utilization of CVI may assist clinicians and patients when considering between interventional and noninterventional approaches for suspected renal cancer.

Incidence and clinical relevance of paraneoplastic syndromes in patients with renal cell carcinoma.

BACKGROUND: Paraneoplastic syndromes (PNS) are defined as the signs and symptoms attributed to cytokines or hormones released from a tumor or a patient's immune system. PNS have been reported with many cancers for decades and data supporting their relevance in renal cell carcinoma (RCC) are largely historical. The widespread use of electronic medical record (EMR) systems provides a more robust method to capture data. The objective of this study was to establish contemporary data regarding the incidence and relevance of PNS in patients undergoing nephrectomy for suspected RCC. METHODS: In this retrospective single-institution study, 851 patients undergoing nephrectomy for suspected RCC between 2011 and 2018 were assessed for the presence or absence of PNS as defined by laboratory abnormalities. Factors associated with PNS and with all-cause mortality were examined. RESULTS: The incidence of PNS was 33.1% among 851 patients prior to nephrectomy. The most prevalent PNS were anemia (22.4%), thrombocytosis (7.5%), and elevated C-reactive protein (CRP) (7.4%). PNS were more common in women (39.2% vs. 29.4%, p = 0.0032) and higher stage RCC (31.1% of stage I vs. 54.2% of stage IV, p = 0.0036). Factors associated with the presence of PNS in multivariable analysis included female gender, high comorbidity, and stage IV RCC. Prenephrectomy PNS were associated with poorer survival in multivariable analysis (HR: 2.12, p = 0.0002). Resolution of PNS occurred in 52.1% of patients after nephrectomy, including 55.2% with stage I to III and 38.5% with stage IV RCC (p = 0.10). CONCLUSIONS: Using EMR data, laboratory evidence of PNS was present in one-third of a contemporary cohort of patients undergoing nephrectomy, with >50% of PNS resolving after surgery. Consistent with prior reports, PNS are more common in higher-stage RCC and are associated with poorer survival in RCC patients.

Metastatic renal cell carcinoma in the bladder following complex partial nephrectomy: A case report.

Metastasis of renal cell carcinoma (RCC) to the bladder is rare. We present a case of a 74-year-old patient with a metachronous, solitary metastasis of RCC to the bladder twenty months after partial nephrectomy and JJ-stent placement for a complex renal tumor. The mechanism of RCC metastasis to the bladder remains controversial, and we believe this case adds support to the drop metastasis theory.

Lysosomal targetomics of ghr KO mice shows chaperone-mediated autophagy degrades nucleocytosolic acetyl-coA enzymes.

Mice deficient in GHR (growth hormone receptor; ghr KO) have a dramatic lifespan extension and elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in ghr KO mice downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Following up on these initial proteomics findings, we used a cell culture approach to show that CMA is necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Inhibition of CMA in NIH3T3 cells has been shown to lead to aberrant accumulation of lipid droplets. We show that this lipid droplet phenotype is rescued by knocking down ACLY or ACSS2, suggesting that CMA regulates lipid droplet formation by controlling ACLY and ACSS2. This evidence leads to a model of how constitutive activation of CMA can shape specific metabolic pathways in long-lived endocrine mutant mice.Abbreviations: CMA: chaperone-mediated autophagy; DIA: data-independent acquisition; ghr KO: growth hormone receptor knockout; GO: gene ontology; I-WAT: inguinal white adipose tissue; KFERQ: a consensus sequence resembling Lys-Phe-Glu-Arg-Gln; LAMP2A: lysosomal-associated membrane protein 2A; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; PBS: phosphate-buffered saline; PI3K: phosphoinositide 3-kinase.

Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in ad libitum-fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. We have previously reported that long-lived Pou1f1/Pit1 mutant (Snell) mice and ghr (growth hormone receptor) knockout mice (ghr KO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and ghr KO mice have decreased GFAP phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and ghr KO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA in vivo. Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and ghr KO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in Cip2a mRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling.Abbreviations: CMA: chaperone-mediated autophagy; GH: growth hormone; ghr KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of Lamp2 transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li-ghr KO: liver-specific ghr knockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.

Inhibition of class I PI3K enhances chaperone-mediated autophagy.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.