bluuebunny/crossref_metadata_2025_split huggingface dataset:
A predictive model to identify patients at risk of local recurrence following glansectomy for penile squamous cell cancer (SCC).
Authors: Albersen Maarten , Parnham Arie , Freeman Alex , Nigam Raj , Malone Peter , Muneer Asif 
Published: March 2017

427 Background: Penile preserving surgery for penile cancer is associated with a higher risk of local recurrence (LR). This study developed a predictive model for LR following glansectomy and split skin graft reconstruction . Methods: Retrospective review performed of 177 patients undergoing glansectomy over a 10 year period. The clinicopathological features, LR patterns and cancer-specific survival (CSS) were recorded. Univariate and multivariate logistic regression was used to identify prognostic indicators for LR. The hazard ratio (HR) for LR was estimated using a KM analysis and based on these data we designed a postoperative model for the prediction of LR. Results: The median follow-up period following surgery was 41.4 (1.9-155) months. In total, 9.3 % of the patients developed a LR. Univariate, but not multivariate logistic regression identified perineural invasion (PNI), carcinoma in situ and high grade disease, but not basaloid variant, T stage, lymphovascular invasion and positive resection margins on the specimen to be predictors of LR. A risk model was designed using PNI, CIS and high grade disease in the resected specimen. KM analysis and log rank test revealed no significant differences in LR-free survival between patients with 0 vs 1 or 2 vs 3 risk factors whereas the chance of having local recurrence with 2 risk factors was significantly higher (HR = 5,75; 95% CI 1,43 to 23,15) than with 1 risk factor. A risk stratification model based on a cut-off score of > 1 out of 3 risk factors discriminated well between patients with a high vs low chance of recurrence in a Kaplan-Meier analysis (HR 9.18, 95% CI 3.29 to 25.65 P < 0.001). Indeed, ROC-curve analysis showed an optimal cut-off point of > 1 risk factors with an AUC of 0.77 (P < 0.001, specificity 63%, specificity of 85%) for prediction of LR. Conclusions: Although,LR after glansectomy does not affect the CSS, patients at risk of local recurrence can be identified when > 1 of the factors PNI, CIS and high grade are found on histopathological analysis of the glans. These findings can define the frequency of follow-up and -if validated on pre-op biopsy- potentially be helpful in planning the margins of surgical resection in patients with penile SCC.
Comprehensive genomic profiling of urethral cancer to reveal distinctive features compared to bladder cancer.
Authors: Dorff Tanya B. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Fisher Hugh A.G. , Mian Badar , Nazeer Tipu , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Phil , Gay Laurie M. , Ross Jeffrey S. , Pal Sumanta K. 
Published: March 2017

429 Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p<0.0001 for all comparisons) In addition, mUrethC featured as significantly lower frequency of TMB > 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. [Table: see text]
Index lesion tumor volume on MRI to predict adverse pathologic outcomes following radical prostatectomy.
Authors: Sugano Dordaneh , Sidana Abhinav , Calio Brian P. , Gaur Sonia , Jain Amit L , Maruf Mahir , Merino Maria J , Choyke Peter L. , Turkbey Baris , Wood Bradford J. , Pinto Peter A. 
Published: March 2017

43 Background: Tumor volume measured on postoperative pathology has been shown to be associated with adverse pathologic and oncologic outcomes. Advances in imaging technology may facilitate the prediction of these outcomes prior to surgery. In this study, we evaluated the predictive value of tumor volume of the index lesion (ILTV) calculated from prostate MRI in analyzing adverse pathologic outcomes following radical prostatectomy (RARP). Methods: Clinical and pathologic data from a prospectively maintained, single-institution database was analyzed for patients who underwent 3T MRI prior to RARP (without prior therapy) between 2007 and 2016. ILTV was calculated from T2W MRI by multiplying length by width by depth by 0.52. Adverse pathologic outcomes were determined on whole mount prostatectomy specimens, and defined as positive margins (PM), extracapsular extension (ECE), positive lymph nodes (LNI), and seminal vesicle invasion (SVI). Logistic regression was used to assess associations of clinical, imaging, and histopathological variables with adverse pathologic features. Results: From the 501 patients who underwent RARP, 490 received MRI prior to surgery. The median age of our cohort of was 60 years (IQR 10), and median PSA was 6.21 ng/ml (IQR 6). There were 74/480 patients (15.4%) with PM, 112/474 (23.6%) with ECE, 30/478 (6.4%) with LNI, and 32/482 (6.7%) with SVI. Patients with adverse outcomes had larger ILTV compared to those without (PM: 1.038cc vs 0.807cc, p=0.041; ECE: 1.388cc vs 0.765cc, p<0.001; LNI: 2.970cc vs 0.797cc, p<0.001; SVI: 2.269cc vs 0.798cc, p<0.001). On multivariate analysis, ILTV was found to be an independent predictor of PM (OR: 1.149, p=0.036), ECE (OR: 1.269, p=0.001), LNI (OR: 1.387, p<0.001), and SVI (OR: 1.341, p<0.001). Conclusions: We demonstrate that Index Lesion Tumor Volume measured on T2W MRI is an independent predictor of PM, ECE, LNI, and SVI following RARP, and serves as a preoperative marker that may facilitate and inform patient counseling and decision making.
Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC).
Authors: Pal Sumanta K. , Sonpavde Guru , Agarwal Neeraj , Vogelzang Nicholas J. , Srinivas Sandy , Haas Naomi B. , Signoretti Sabina , Lanman Richard B. , Banks Kimberly , Choueiri Toni K. 
Published: March 2017

434 Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.
Correlation of insulin-receptor expression with efficacy of axitinib in patients with advanced renal cell carcinoma.
Authors: Takahashi Masayuki , Daizumoto Kei , Tsuda Megumi , Kusuhara Yoshito , Mori Hidehisa , Shintani Terumichi , Fukawa Tomoya , Yamamoto Yasuyo , Yamaguchi Kunihisa , Fukumori Tomoharu , Kanayama Hiroomi 
Published: March 2017

442 Background: Axitinib has demonstrated high efficacy with well-controlled adverse events (AEs) for advanced renal cell carcinoma (RCC). Recently, nivolumab has been approved for advanced RCC. However, it is very expensive in Japan and may cause severe immune-related AEs. There is no clue to choose axitinib or nivolumab as the second-line for advanced RCC. Previously we identified the gene set which may predict poor prognosis of RCC patients (Takahashi m et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001) and have sought to elucidate whether insulin receptor (INSR) expression in the gene set may predict the resistance for axitinib as a biomarker. Methods: Axitinib was administered in 36 patients in our department between January 2008 and April 2015. Median age was 70 (36-84) years old with 22 males and 14 females. Histological subtype included clear cell RCC (n=27, 75.0%), clear cell + sarcomatoid component (n=3), collecting duct carcinoma (n=2), papillary, sarcomatoid, mucinous tubular and spindle cell carcinoma (MTSCC), and unknown in each one. Axitinib was administered in two patients as the first line, 21 patients as the second line, and 13 patients as ≥ the third line. Tissue of primary tumor was available in 20/36 patients, including 16 clear cell RCC and 4 other subtypes. Immunohistochemical INSR expression was examined and correlated with survival of the patients with axitinib. Results: Objective response rate was 27.6%, progression-free survival (PFS) was 16.3 months, and overall survival (OS) was 41.9 months in clear cell RCC patients. Patients with low INSR expression (n=7) had significantly shorter PFS (68 vs. 586 days, p<0.001) and OS (169 vs. 1027 days, p=0.004) compared with those with high INSR expression (n=13). If only clear cell RCC was evaluated, patients with low INSR expression (n=3) had significantly shorter PFS (77 vs. 586 days, p=0.008) and OS (294 vs. 1027 days, p=0.016) compared with those with high INSR expression (n=13). Conclusions: Axitinib was highly effective for advanced clear cell RCC. However, immunohistochemically low expression of INSR in the primary tumor may predict the resistance for axitinib and those patients may be more suitable for immune checkpoint inhibitors.
Intra-individual genomic diversity between circulating tumor cell-free DNA (cfDNA) and tumor tissue testing in metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W. , Gill David Michael , Streeter Jessica , Bailey Erin B. , Carroll Emma , Aryal Lubina , Batten Julia A. , Gupta Sumati , Agarwal Neeraj , Maughan Benjamin Louis 
Published: March 2017

444 Background: Multiple approved targeted therapies are available for treatment of mRCC. Though some clinical trials guide treatment selection, there are many gaps without high-level evidence. Both tumor tissue and cfDNA based next-generation sequencing (NGS) testing are frequently performed to help guide treatment. Our objective was to assess type and number of genomic aberrations among tumor tissue and cfDNA. Methods: 14 sequential pts with both tissue and cfDNA NGS testing were selected and genomic profiles were compared. The total number of aberrations detected was statistically evaluated using comparison of the means. The Mann-Whitney test was used to compare the incidence of mutations in identified mutation pathways. Results: There was a discordance in the genetic aberrations detected among tumor versus cfDNA NGS tests, confirming intra-individual genetic diversity. Specifically, alterations in the DNA repair, PI3K, and epigenetic pathways were more common in tissue based testing (Table). Additionally, the median number of mutations identified was significantly lower for cfDNA based NGS testing (median 1.5) compared to tissue based NSG testing (median 10.0) (p < 0.0001). Conclusions: Discordance in the type of genomic aberrations in tissue versus cfDNA testing suggests intra-individual genetic diversity and may have implications in treatment selection when using these tests. Lower number of aberrations detected by the cfDNA testing may have occurred due to lower sensitivity of NGS by cfDNA compared to the tissue based NGS. The higher frequency of aberrations on tissue based testing suggests that tissue based testing should be used preferentially in clinical trials and practice. This data is hypothesis generating and needs further investigation in a larger cohort. [Table: see text]
Development of a novel patient-derived preclinical model from malignant effusions in patients with tyrosine kinase inhibitor resistant clear cell renal cell carcinoma.
Authors: Kang Jung Hun , Heo Mi Hwa , Kim Hee Kyung , Cho Jinhyun , Kim Youjin , Lee Hansang , Lee Sang-Cheol , Park Se Hoon 
Published: March 2017

445 Background: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood and there is a need to develop new therapeutic options overcoming them. Methods: To develop a preclinical model that predicts clinical activity of novel agents.We established patient-derived cell (PDC) and xenograft (PDX) models from malignant effusions (n = 15) or surgical specimen (n = 4).Genomic features of the PDX model were compared with those of the primary tumor. Drug effects of cell viability were then tested with PDC and PDX models. Results: Successful PDCs, defined as cells that maintained growth following 2 passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. Conclusions: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations. We show that novel preclinical models are developed using malignant effusions derived from patients with kidney cancer. The preclinical models can be used to test anti-tumor activity of novel therapeutics. The preclinical model we developed can be used to interrogate sensitivity to targeted agents based on genomic alterations. The PDC model from malignant effusions of patients was successfully converted to a PDX model, and represents an important and feasible platform for future cancer research.
The impact of UGT1A1 and SLCO1B1 genetic polymorphisms and pharmacokinetics of axitinib on clinical safety and efficacy in patients with metastatic renal cell carcinoma.
Authors: Narita Shintaro , Igarashi Ryoma , Tsuchiya Norihiko , Inoue Takamitsu , Fujiyama Nobuhiro , Numakura Kazuyuki , Tsuruta Hiroshi , Kagaya Hideaki , Saito Mitsuru , Niioka Takenori , Miura Masatomo , Satoh Shigeru , Habuchi Tomonori 
Published: March 2017

448 Background: We investigated the impact of genetic polymorphisms and pharmacokinetics of axitinib on adverse events, objective responses, and survival in patients with metastatic renal cell carcinoma (mRCC). Methods: In total, 53 patients with mRCC treated with axitinib were analyzed. Patient was classified as favorable (n = 5), intermediate (n = 36), and poor (n = 12) using the MSKCC risk classification system. High-performance liquid chromatography was used to measure serum axitinib levels. AUC0–12 (ng∙h/mL) was calculated using various serum levels at 0 to 12 h (C0–C12) following administration on day 7 of treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RFLP analysis. Results: The most frequently reported ≥ G3 adverse events were hypertension (43.3%), proteinuria (30.2%), and anorexia (20.1%). The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. Patients with axitinib C0 ≥ 10 ng/mL had a significantly higher rate of hand-foot syndrome ≥ G2 and hypothyroidism ≥ G2 than those with axitinib C0 < 10 ng/mL (p = 0.013, p = 0.005). The overall survival in patients with axitinib C0 ≥ 5 ng/mL was significantly better than that in those with axitinib C0 < 5 ng/mL (p = 0.022). The mean C0 and AUC0–12 values in patients with a poor metabolizer (*6/*6, *6/*28, and *28/*28) of UGT1A1 polymorphism were significantly higher than those in patients with an extensive metabolizer (p = 0.045, p = 0.035, respectively). The mean AUC0–12 value in patients with the SLCO1B1 *15 was significantly higher than that in those without the SLCO1B1 *15 (p = 0.038). Conclusions: Serum axitinib levels were associated with adverse events and overall survival of patients with mRCC. The genetic polymorphisms in UGT1A1 and SLCO1B1 may affect serum axitinib levels in patients with mRCC. Pharmacokinetics and genetic polymorphisms play important roles in the outcomes of patients with mRCC treated with axitinib.
Impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox.
Authors: Narita Shintaro , Ito Ryuichi , Huang Mingguo , Numakura Kazuyuki , Tsuruta Hiroshi , Maeno Atsushi , Saito Mitsuru , Inoue Takamitsu , Tsuchiya Norihiko , Satoh Shigeru , Habuchi Tomonori 
Published: March 2017

449 Background: Obesity increases the risk of renal cell carcinoma (RCC); however, obese patients experience longer survival than non-obese patients. The mechanism of this “obesity paradox” is unknown. We examined the impact of obesity, total adiponectin (AD) level, and intratumoral AD receptors expression on RCC aggressiveness and survival, and also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells with exogenous adiponectin stimulation. Methods: A total of 129 RCC patients treated with surgery were included in the analyses. Preoperative BMI, serum total adiponectin (AD) level, total AD secretion from perinephric adipose tissue, and intratumoral AD receptors mRNA and protein expression were analyzed. Caki-2 and 786- cells were used for in vitro functional analyses. Results: Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003, and p = 0.027, respectively). Cancer-specific survival in overweight and obese patients was significantly better than in normal patients in all patients (p = 0.035). A weak inverse correlation existed between serum AD level and BMI in RCC patients (r = −0.344). Tumor size was slightly correlated with serum AD level, and high serum AD was significantly associated with poor overall survival in patients without metastasis (p = 0.035). The AD level of perinephric adipose tissue and intratumoral AdipoR1/R2 expression in tumors did not correlate with RCC aggressiveness and survival. Exogenous AD significantly enhanced proliferation, but not invasion or migration in 786-O and Caki-2 cells. Exogenous AD significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL in these cells. Conclusions: Low BMI and high AD level are associated with cancer aggressive and poor survival in RCC patients treated surgically. AD modulates proliferation and apoptosis, which may underlie the “obesity paradox” of RCC.
Combined inhibition of autophagy with mTOR inhibitor to enhance cell death in renal cell carcinoma.
Authors: Chen Hua , Potts Kyle , Murray Allan , Hitt Mary , Moore Ron 
Published: March 2017

450 Background: mTOR (mammalian target of rapamycin) and autophagy are increasingly recognized as being a central cellular and pathological process for numerous human diseases, including renal cell carcinoma (RCC). Depending on the cellular context, autophagy may promote cancer cell survival or cell death. However, little is known about the mechanisms of regulating mTOR activity and autophagic function in RCC. We hypothesize that autophagy promotes cell survival via mTOR mediated-phosphatidylinositol 3-kinase (PI3K)/AKT pathway and is regulated by the von Hippel-Lindau (VHL) tumor suppressor. Methods: RCC cells were stably lentiviral transduced with expression of VHL or mCherry-EGFP tandemfluorescent-tagged LC3B for studying autophagic flux. Cell viability was evaluated by cytotoxic XTT and clonogenic assays and flow cytometry. The efficacy of PI3K/AKT/mTOR pathway inhibition by RAD001, PI-103, MK2206, AZD8055, and/or lysosomotropic inhibitors were evaluated by immunoblots and immunofluorescence for autophagy process of autophagosome and lysosome. Results: We show that mTOR is hyperactive in VHL-deficient cells compared to cells with wild-type VHL or VHL-expressing cells. AZD8055-induced toxicity occurs in a VHL-independent manner via cell cycle arrest and clonogenic senescent cell death, but results in significantly increased expression of autophagic marker LC3-II and the formation of autophagic vacuoles. Pharmacologic inhibition or siRNA silencing of autophagy pathway components promotes AZD8055-induced cell death in VHL-deficient cells. Interestingly, defective autophagy marked by the presence of sustained p62 expression in VHL-deficient cells appears to contribute to cell survival via mTOR signaling, which in turn influences autophagosome-lysosome fusion, and thus controls autophagic flux by acting at the termination stage of the process. Conclusions: These results support mTOR and autophagy pathways as potential targets of anticancer drugs and reveal VHL in control of the autophagic program in RCC. Further, this work suggests that combined inhibition of autophagy along with mTOR inhibitors could be a novel therapeutic strategy for the treatment of RCC.