Hypoxia-inducible factor pathway genes predict survival in metastatic clear cell renal cell carcinoma

PurposeHypoxia inducible factor (HIF) pathway alterations drive progression of clear cell renal cell carcinoma (ccRCC). We aim to evaluate genes within the canonical and non-canonical HIF pathways as predictors of survival in metastatic ccRCC.Materials and MethodsGene expression was determined from 324 archival pretreatment nephrectomy specimens from CALGB90206, a phase III trial of patients treated with interferon alpha (INF-α) vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed using RNA from tumors macrodissected based on review by genitourinary pathology.ResultsA total of 35 HIF-related genes were assessed by Cox regression analysis. After adjusting for sex and Memorial Sloan Kettering Cancer Center risk score (MSKCC-RS), 11 genes predicted OS: HIF2A (HR 1.059, P = 0.012), EGLN3 (HR 1.089, P = 0.012), VEGFC (HR 0.904, P = 0.039), VEGFD (HR 1.085, P = 0.016), FLT4 (HR 1.093, P = 0.038), CCND1 (HR 1.077, P = 0.026), TGFA (HR 1.127, P = 0.003), EGFR (HR 1.151, P = 0.028), VHL (HR 0.764, P = 0.002), HSP90AA1 (HR 0.845, P = 0.002), and PTEN (HR 1.163, P = 0.050); 7 genes predicted PFS: HIF2A (HR 1.060, P = 0.011), CCND1 (HR 1.082, P = 0.016), TGFA (HR 1.096, P = 0.026), EP300 (HR 1.171, P = 0.031), VHL (HR 0.775, P = 0.007), HSP90AA1 (HR 0.871, P = 0.015), and TP53 (HR 1.119, P = 0.050). Most of these genes validated as significant predictors of survival in the external, TCGA dataset. In multivariate analysis of all externally validated genes, VEGFC (HR 0.906, P = 0.043), TGFA (HR 1.122, P = 0.003), CITED2 (HR 1.113, P = 0.035) and EP300 (HR 1.136, P = 0.049) predicted OS; and HIF2A (HR 1.049, P = 0.036) and EP300 (HR 1.199, P = 0.010) predicted PFS. EGLN3 (HR 1.156, P = 0.045) and BNIP3 (HR 1.254, P = 0.049) significantly interacted with treatment status and predicted PFS in patients treated with IFN-α and IFN-α+bevacizumab, respectively.ConclusionsWe identified specific gene isoforms in both the canonical and non-canonical HIF pathways associated with metastatic RCC survival. EGLN3 and BNIP3 showed significant interaction with treatment arm and may be predictive of treatment response. We have identified genes for future prospective investigation as predictive biomarkers and novel drug targets.     

Paraneoplastic symptoms: Cachexia,polycythemia, and hypercalcemia are,respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma

ObjectivesTo evaluate whether there is a relation between expression of vascular endothelial growth factor (VEGF) and any of the paraneoplastic syndromes (PNS) in clear cell renal cell carcinoma (ccRCC) patients.Materials and methodsA total of 667 patients with ccRCC and at least one PNS were included. Thorough history taking, physical examinations, and laboratory tests were used to diagnose PNS. Immunohistochemistry was performed for VEGF evaluation.ResultsThere were 10 different PNS identified in the population. Sixty patients had a single paraneoplastic presentation. In all patients, presence of cachexia (n = 267, P < 0.0001), polycythemia (n = 40, P = 0.0014), and hypercalcemia (n = 48, P = 0.0006) was correlated to VEGF expression. Correlation was neither acquired in Stauffer's syndrome, pyrexia, elevated erythrocyte sedimentation rate (ESR), anemia, thrombocytosis, hypertension, neuromyopathy nor obtained within patients with single PNS.ConclusionsRelations between PNS and VEGF expression in renal cell carcinoma (RCC) has not been studied yet. The results we gained hereby can help us further understand the mechanistic of PNS in RCC.     

Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients

BackgroundHepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide. Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified.MethodsA total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27–78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high.ResultsA total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0–28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A, and FGF19. SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III–IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 µmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III–IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 µmg/L) (P=0.009, OR =3.414).ConclusionsThe most frequently mutated genes of HCC patients in China were TP53, TERT, and CTNNB1, which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III–IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I–II grade, AFP <25 µmg/L, and a non-hepatitis B background. Also, the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients.     

Prognostic impact of metastasectomy in renal cell carcinoma in the postcytokine therapy era

ObjectivesTo explore the real-world data regarding survival following metastasectomy (MS) for renal cell carcinoma (RCC) in the postcytokine therapy era.Patients and MethodsPatients diagnosed with metastatic renal cell carcinoma (mRCC) between January 2008 and December 2018 at our institutions were retrospectively evaluated. The patients were classified into three groups according to their MS status: (1) complete MS (cMS), (2) incomplete MS (icMS), and (3) without MS (nonMS). Factors for overall survival (OS) after diagnosis were analyzed.ResultsOverall, 314 patients were evaluated. During the follow-up period (median: 25.3 months), a total of 98 patients (31.2%) underwent at least one MS. The cMS group (n = 45, 14.3%) had a significantly longer OS (median: not reached [N.R.]) than the icMS (n = 53, 16.9%) (81.5 months, P= 0.0042) and nonMS groups (28.1 months, P< 0.0001). The icMS group had a significantly longer OS than the nonMS group did (P= 0.0010). Multivariate analysis showed that the MS status was an independent factor for OS (cMS vs. nonMS: P= 0.0004; icMS vs. nonMS: P= 0.0176), together with histopathological type, International Metastatic Renal Cell Carcinoma Database Consortium risk, liver metastasis status, and prior nephrectomy status (all, P< 0.05). In addition, the OS was comparable throughout the eras of systemic therapy (early molecular-targeted therapy, late molecular-targeted therapy, and immune checkpoint inhibitor eras) in the MS group (median: 121.9 vs. N.R. vs. N.R. months, P= 0.948).ConclusionsMS, especially cMS improved survival in selected patients with mRCC in the postcytokine therapy era. In addition, MS still plays a significant role in the current systemic therapy.     

Genomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy

Purpose

To establish prognostic genomic biomarkers for patients with metastatic clear cell renal cell carcinoma (ccRCC).

Brain metastasis from renal cell carcinoma

BackgroundPatients with brain metastasis (BM) from renal cell carcinoma (RCC) have a poorly known prognosis due to the rarity of this disease. The aim of our study was to assess the outcome of patients with a BM due to RCC, and to determine the predictive factors for survival.MethodsConsecutive patients who underwent treatment between 1997 and 2012 were identified retrospectively from a database (n = 28, median age of 57.8 years, sex ratio M/F: 3.7). Main criteria collected concerned survival time. Other data collected were relative to initial histology, clinical findings at the time of BM diagnosis (diagnosis circumstances, KPS), radiological findings and BM characteristics (number, size and localization), treatment of BM (including surgery, stereotactic radiosurgery [SRS], systemic treatments, whole brain radiotherapy [WBRT]) and the outcome of surgery if performed. Statistical analysis of survival was performed using the Kaplan-Meier method.ResultsMedian survival was 13.3 months, 1-year survival was 60.2%, 2-year survival was 16.4%. Univariate analysis showed the existence of intracranial hypertension (P = 0.01), other systemic metastasis (P = 0.049), the absence of deep metastasis (P = 0.03) which are all linked to shorter survival. Age, KPS, initial histology of RCC, number, size, localization, and hemorrhage in BM were not correlated to survival. The median survival in the surgical resection group was 25.3 months versus 8.6 months (P = 0.02). The main criteria for the selection of the surgical group were a single BM (P = 0.04), and superficial metastasis (P = 0.02).ConclusionsThree predictive factors for longer survival in BMRCC were the absence of intracranial hypertension, the absence of acute metastasis and the absence of extracranial metastasis. Surgical removal, when possible, seems to benefit patient survival.     

Clinicopathological and prognostic impact of somatic mutations in Chinese patients with clear cell renal cell carcinoma

BackgroundThe study of the genomic landscape of Chinese clear cell renal cell carcinoma (ccRCC) entered its nascence in recent years, and the clinical relevance of individual genes in Chinese ccRCC has not yet been researched. The study aimed to explore the relationships between somatic mutations and clinical behaviors in Chinese ccRCC.MethodsTumor tissue samples were obtained from 105 Chinese patients with ccRCC and deep sequencing targeting 556 cancer genes was performed. Correlation analysis, receiver operator characteristic (ROC) analysis and survival analysis were carried out using SPSS software.ResultsA total of 41 genes were used to investigate the relationship between genes and clinical behaviors. We found that different clinical indices were mutually correlated, and there were 12 genes associated with clinical indices. The Kaplan-Meier curves showed that high Fuhrman grade and metastatic disease at diagnosis were significantly associated with poor prognosis. Mutations in BAP1, PTEN, ERBB2, TP53, CDK8, TSC1, SETD2, or SPEN were significantly associated with poor prognosis, consistent with the results of The Cancer Genome Atlas (TCGA) cohort. Mutation of BTG1 occurred much more frequently in Chinese ccRCC (10.5%) than in the TCGA cohort (0.60%), and it was associated with a better prognosis.ConclusionsA total of 8 genes (BAP1, PTEN, ERBB2, TP53, CDK8, TSC1, SETD2, and SPEN) were found to be associated with poor prognosis of ccRCC, and a new gene (BTG1) was possibly associated with the good prognosis of Chinese ccRCC.     

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

Comprehensive Assessment of Immuno-oncology Biomarkers in Adenocarcinoma,Urothelial Carcinoma,and Squamous-cell Carcinoma of the Bladder

BackgroundIn patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need.ObjectiveIn this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed.Design, setting, and participantsWithin the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer.InterventionCGP using a hybrid capture–based assay and immunohistochemistry (IHC).Outcome measurements and statistical analysisTumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive.Results and limitationsPure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0–1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation.ConclusionsDeep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials.Patient summaryTumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.     

Preoperative decision making for renal cell carcinoma: Cystic morphology in cross-sectional imaging might predict lower malignant potential

ObjectivesSeveral histologic studies showed more favorable oncologic outcome for renal cell carcinoma (RCC) with cystic change. However, there is no prognostic tool to judge on cystic RCC preoperatively. We hypothesized, that cystic morphology in cross-sectional imaging predicts lower malignant potential.Materials and methodsFrom our prospectively conducted oncologic database, we identified 825 patients who underwent surgery for malignant renal tumors between 2001 and 2010. In 348 cases (42%), adequate imaging was available for an independent review by 2 radiologists. We excluded recurrent and synchronous bilateral RCC, familial syndromes, collecting duct carcinoma, and metastases of other origin. For the resulting 319 patients, we compared clinical, pathologic, and survival outcomes.ResultsMedian age was 63 (19–88) years and 220 (69%) patients were male. Median follow-up was 1.7 (0–9.8) years. Of 319 renal masses, 277 (86.8%) were solid and 42 (13.2%) were cystic. In cystic RCC, median tumor diameter was lower (3 cm vs. 4 cm, P = 0.002) and nephron-sparing surgery was more frequent (69% vs. 41.5%, P = 0.002). None of the patients with cystic RCC and 56 (20.2%) with solid RCC had synchronous systemic disease (P = 0.001). The nuclear grade of cystic RCC was more favorable (P = 0.002). Patients with cystic RCC showed better overall (P = 0.049) and cancer-specific survival (P = 0.027). In a multivariate model, only synchronous metastases, positive R status, and greater tumor diameter were independent risk factors (P≤ 0.03).ConclusionsWe report the first study to show that cystic morphology in cross-sectional imaging might predict RCC with a lower malignant potential. This insight could allow less invasive treatment strategies in selected patients.     

Multi-institutional analysis of renal function outcomes following radical nephroureterectomy and partial ureterectomy for upper tract urothelial carcinoma

PurposeTo compare renal function outcomes in patients undergoing radical nephroureterectomy (RNU) or partial (distal) ureterectomy (PU) for upper tract urothelial carcinoma (UTUC).MethodsClinicopathologic data of patients undergoing RNU or PU for UTUC from 1998 to 2012 were compiled. Glomerular filtration rate was calculated preoperatively and postoperatively using the Modification of Diet in Renal Disease equation. We defined “event” as new-onset stage III chronic kidney disease (CKD) or worsening of CKD stage with preexisting CKD. Event-free survival was assessed with Kaplan-Meier methods. Cox regression analyses were performed to identify predictors of events.ResultsIn total, 193 patients underwent RNU (n = 143) or PU (n = 50) over a median follow-up of 25.9 months. Overall, 15% of patients died of UTUC. High tumor grade (85.9% vs. 66.0%, P = 0.003) and locally advanced stage (>pT2, 37.8% vs. 18.0%, P = 0.014) were significantly more frequent in the RNU cohort. Stage III or higher CKD was present in 61% of RNU patients vs. 48% of PU patients (P = 0.135) at baseline. Although total event rate was higher in the PU cohort (66% vs. 43.4%, P = 0.008), event rates within the first 3 months of surgery were similar between the groups (P = 0.572). Adjuvant chemotherapy was the only predictor of events on Cox regression.ConclusionsRates of new-onset CKD or worsening of CKD stage were similar in patients treated with RNU and PU. Adjuvant chemotherapy may have a more significant effect on renal outcomes than surgical approach, warranting further investigation. Consideration should be given to preoperative chemotherapy, as adjuvant chemotherapy is limited by decreased renal function following surgery.     

Prognostic relevance of ABO blood group system in non-metastatic renal cell carcinoma: An analysis of two independent European cohorts with long-term follow-up

BackgroundThe ABO blood group system has been previously discussed as a risk factor to develop, as well as a prognostic factor in non-metastatic renal cell carcinoma (RCC). Controversial findings have been reported in different populations of RCC patients with rather short follow-up periods. In this study, we aimed to clarify the distribution and prognostic role of ABO blood groups upon 15 years of median follow-up in non-metastatic RCC patients.Materials and methodsWe evaluated the distribution and prognostic significance of ABO blood group system in two independent cohorts (n = 405 and n = 1473) of non-metastatic RCC patients, who underwent curative (partial or total) nephrectomy between 1998 and 2012 at two tertiary academic centers. Cancer-specific survival, metastasis-free survival, as well as overall survival (OS) were assessed using the Kaplan-Meier method, univariable- and multivariable Cox regression models were applied, respectively.ResultsIn the two cohorts, blood groups were not associated with any clinical endpoints (for cohort 2: Cancer-specific survival (HR = 1.233; 95%CI 0.998–1.523, P = 0.052), metastasis-free survival (HR = 1.161; 95%CI 0.952–1.416, P = 0.142) and OS (HR = 1.037; 95%CI 0.890–1.208, P = 0.641), respectively). Compared to 250.298 healthy blood-donors of the Styrian state, the distribution of blood groups was (624 (42.4%) versus 106.861 (42.7%) in group A, 191 (13%) vs. 34.164 (13.7%) in group B, 575 (39%) versus 93.579 (37.4%) in group O and 83 (5.6%) vs. 15.694 (6.3%), P = 0.467).ConclusionIn this large study with the longest period of follow-up reported to date, the ABO blood group system could not be validated as a prognostic factor in predicting important clinical endpoints in non-metastatic RCC patients.     

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations

Introduction

Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance.

Immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma

PurposeTo analyze the immunohistochemical expression of ezrin and moesin in clear cell renal cell carcinoma (ccRCC). These proteins, as part of the ezrin-radixin-moesin complex link the cell membrane to the actin cytoskeleton, affecting such processes as cell adhesion, cell survival, cell motility, and signal transduction. Our aim was to examine the impact of their expression on clinical outcomes and survival rates.Patients and methodsFive hundred seventy-five consecutive patients who had been treated surgically for ccRCC in a single center between 1985 and 2016 were selected. A single pathologist reviewed all cases to perform a uniform reclassification and determined the most representative tumor areas for construction of a tissue microarray.ResultsOf all ccRCC specimens, 106 (18.3%) were negative for ezrin, and 469 (81.7%) had positive ezrin expression; 16 (2.8%) were negative and 559 (97.2%) were positive for moesin, respectively. Ezrin expression was associated with pT stage (P < 0.001), clinical stage (P = 0.012), synchronic metastasis (P < 0.001), incidental tumors (P = 0.007), and International Society of Urological Pathology histological grade (P = 0.025). There was a correlation between moesin expression and clinical stage (P = 0.027), pT stage (P = 0.025), and pN stage (P = 0.007). Ezrin expression significantly influenced tumor-related deaths. By multivariate analysis, negative ezrin expression was an independent risk factor for disease-specific survival (HR 1.89; 95% CI 1.11–3.20).ConclusionsNegativity for ezrin in ccRCC patients significantly impacts survival rates. We encourage further prospective studies to analyze ezrin analysis to evaluate its significance in the prognosis of ccRCC.     

Actionable genomic landscapes from a real-world cohort of urothelial carcinoma patients

BackgroundRecent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we utilized a large, real-world cohort to comprehensively investigate the incidence of genetic alterations with potential therapeutic implications at all stages of bladder cancer.Materials and MethodsWe retrospectively analyzed next-generation sequencing (NGS) data from 1,562 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay. Incidence of genetic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were assessed and stratified by bladder cancer stage. For patients with tumor-normal match sequencing (n=966), incidental germline alterations in 50 genes were assessed.ResultsThe cohort was composed of 165 stage I-II, 211 stage III, and 1,186 stage IV tumors. TMB-high, PD-L1 positive, and MSI-high status were noted in 14%, 33%, and 0.7% of tumors, respectively, and were similar across stages. Alterations in fibroblast growth factor receptor (FGFR)2/3, homologous recombination repair genes, additional DNA repair gene mutations (ERCC2, RB1, FANCC), and NTRK fusions were detected at similar frequencies across disease stages. We identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%).ConclusionsImportant subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways at all stages. This analysis found minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.     

The association between metformin use and oncologic outcomes among surgically treated diabetic patients with localized renal cell carcinoma

IntroductionMetformin inhibits renal cell carcinoma (RCC) cell proliferation both in vitro and in vivo; however, clinical data regarding the effect of metformin in patients with RCC are lacking. We evaluated the association of metformin use with outcomes among patients with surgically treated localized RCC.Materials and methodsWe identified 283 consecutive diabetic patients treated surgically for localized RCC between January 1, 1994 and December 31, 2008. Clinicopathologic features were compared between patients exposed to metformin (n = 83, 29%) and those who were not (n = 200, 71%). Progression-free, cancer-specific, and overall survival rates were estimated with the Kaplan-Meier analysis, and Cox models were used to evaluate the association of metformin use with outcomes.Results and conclusionsPatients receiving metformin had a better renal function (median estimated glomerular filtration rate = 65 vs. 55 ml/min/1.73 m², P<0.001), performance status (Eastern Cooperative Oncology Group<1: 89% vs. 71%, P = 0.001), and lower Charlson comorbidity index (median = 2 vs. 3, P = 0.02) compared with those who did not, but were otherwise similar across other clinicopathologic features (P>0.05 for all). At a median postoperative follow-up of 8.1 years, patients exposed to metformin had similar 5-year progression-free (80% vs. 75%, P = 0.6) and cancer-specific survival rates (91% vs. 81%, P = 0.16), but significantly improved overall survival rate (79% vs. 62%, P = 0.01). However, metformin was not independently associated with the risks of progression, RCC-specific mortality, or all-cause mortality on multivariable analyses. In this surgical cohort of diabetic patients with M0 RCC, preoperative metformin exposure was associated with improved overall survival on unadjusted analysis. Although metformin was not independently associated with oncologic or survival outcomes, future studies appear warranted.     

JAK3 in clear cell renal cell carcinoma: Mutational screening and clinical implications

ObjectivesJanus Kinase 3 (JAK3) mediates cytokine signaling and T-cell activation. We hypothesized that JAK3 mutations may contribute to the development and progression of clear cell renal cell carcinoma (ccRCC). To test this hypothesis, we performed mutational screening and functional studies.Patients and methodsThis hospital-based case-control study included 50 patients with ccRCC and 100 age- and gender-matched controls. Both genomic and tumor DNA were extracted. All 23 JAK3 exons were amplified by PCR and analyzed by denaturing high-performance liquid chromatography and automatic sequencing. Effects of JAK3 mutations on interleukin-2-stimulated peripheral T-cells were analyzed by confocal laser-scanning microscopy and immunoprecipitation.ResultsFour different JAK3 germline missense mutations (p.Gln13Lys; p.Arg925Ser; p.Ala677Thr, p.Val722Ile) were found in a total of 7 ccRCC patients (14%), but in none of the controls (P = 0.0006). All germline mutations were similarly detected in the tumors. An additional somatic missense mutation (p.Tyr238Cys) was found in a patient who had a germline mutation. Four of the mutations have not been previously described (p.Gln13Lys; p.Arg925Ser; p.Ala677Thr, p.Tyr238Cys). Patients with JAK3 mutations more frequently presented with metastases (3 out of 4 [75%] vs. 4 out of 46 [9%]; P = 0.004) and had poorer survival (P = 0.049). In p.Arg925Ser and p.Ala677Thr/p.Val722Ile, functional analyses showed abnormal JAK3 and STAT5 tyrosine phosphorylation and a reduction of JAK3/STAT5 interaction.ConclusionsJAK3 mutations are found in a subset of ccRCC patients and may be associated with ccRCC development and a greater risk of metastases. JAK3 function is compromised in p.Arg925Ser and p.Ala677Thr/p.Val722Ile. Future studies with a larger number of patients need to confirm these findings.     

Anal squamous cell carcinoma incidentally found at hemorrhoidectomy

BackgroundAnal squamous cell carcinoma incidence is increasing nationally and, more so, in Kentucky. Squamous cell carcinoma of the anus unexpectedly identified at hemorrhoidectomy pathologic evaluation is not uncommon. We hypothesized this is occurring more frequently and sought to evaluate its impact on outcomes.MethodsThe Kentucky Cancer Registry, a premier population database, was queried for all squamous cell carcinoma of the anus cases between 2007 and 2016. Hemorrhoidal squamous cell carcinoma of the anus patients were compared with nonhemorrhoidal squamous cell carcinomas of the anus. Patient demographics, treatments, and outcomes were analyzed.ResultsOf the 722 squamous cell carcinoma of the anus cases identified, 3.05% (n = 22) were within hemorrhoidectomy specimens. Demographics were similar between hemorrhoidal squamous cell carcinoma of the anus versus nonhemorrhoidal squamous cell carcinoma of the anus. Chemoradiation was the most common treatment strategy among all patients, and there were similar rates of disease, persistence, recurrence, and survival between hemorrhoidal and nonhemorrhoidal squamous cell carcinoma. Stage I disease was more common in the hemorrhoid group compared with the nonhemorrhoid group (63% vs 27%, P < .01).ConclusionHemorrhoidal squamous cell carcinoma of the anus comprised 3.05% of our population-based cohort. Hemorrhoidal squamous cell carcinomas of the anus were more likely to receive chemoradiation compared with local excision, but there were similar oncologic outcomes. We postulate that some individuals may receive overtreatment with chemoradiation owing to imprecise labeling of hemorrhoid specimens. For this reason, we advocate for separate submission of each hemorrhoid specimen.     

Identification and validation of TGFBI as a promising prognosis marker of clear cell renal cell carcinoma

ObjectiveTo identify prognostic biomarkers in clear cell renal cell carcinoma (ccRCC) using a proteomic approach.Material and methodsWe performed a comparative proteomic profiling of ccRCC and normal renal tissues from 9 different human specimens. We assessed differential protein expression by iTRAQ (isobaric tagging reagent for absolute quantify) labeling with regard to tumor aggressiveness according to the stage, size, grade, and necrosis (SSIGN) score and confirmed our results using Western blot (9 patients) and immunohistochemistry (135 patients) analysis.ResultsAfter proteomic analysis, 928 constitutive proteins were identified. Among these proteins, 346 had a modified expression in tumor compared with that of normal tissue. Pathway and integrated analyses indicated the presence of an up-regulation of the pentose phosphate pathway in aggressive tumors. In total, 14 proteins were excreted and could potentially become biomarkers. Overexpression of transforming growth factor, beta-induced (TGFBI) in ccRCC was confirmed using Western blot and immunohistochemistry analysis. A significant association was found between the presence of TGFBI expression with tumor category T3–4 (P<0.0001), Fuhrman grades III and IV (P<0.0001), tumor size>4 cm (P<0.0001), presence of tumor necrosis (P<0.0001), nodal involvement (n = 0.009), metastasis (P = 0.012), SSIGN score≥5 (P<0.0001), cancer progression (P<0.0001), and cancer-specific death (P<0.0001). Cancer-specific survival was significantly better for patients with no cytoplasmic TGFBI expression (1-, 3-, 5-y cancer-specific survival of 94.7%, 87.8%, and 73.4% vs. 92.9%, 71.2%, and 49.8%, respectively; P<0.0001).ConclusionWe identified 346 proteins involved in renal carcinogenesis and confirmed the presence of a metabolic shift in aggressive tumors. TGFBI was overexpressed in tumors with high SSIGN scores and was significantly associated with oncologic outcomes.