bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors of neuroendocrine tumors (NETs) in a Mexican cohort.
Authors: Camargo Vanessa Rosas , Huitzil-Melendez Fidel David , Gamboa-Dominguez Armando , Cano Garia Fernando , Galvan Salazar Gabriel , Leon-Rodriguez Eucario
Published: March 2020

e15186

Background: NETs comprise a heterogeneous group of neoplasms regarding clinical behavior. Our aim was to identify clinical and pathological variables associated with survival in a mexican cohort. Methods: We retrospectively reviewed the medical records of all gastroenteropancreatic(GEP)-NETs with histopathological confirmation evaluated at our Institution from January 2000 to December 2011. Relevant clinical and histopatholocical features were recorded. Overall survival (OS) was estimated using Kaplan Meier method and survival distributions were compared using the Log rank test. Results: 175 patients with GEP-NETs were identified in the study period. We excluded 35 patients with insulinomas and 40 patients with lesions amenable to endoscopic resection given 100% cancer specific survival. Therefore, 100 patients with GEP-NETs (61% gastrointestinal / 39% pancreatic) with malignant potential were analyzed: median age 53 y/o, 55% were male, 39% were localized, 4% had regional spread and 57% were metastatic at presentation. 35% of patients harbored functional tumors. 32% of patients showed isolated liver metastasis while 24% of patients showed hepatic and extrahepatic metastatic disease. 37% were NETs grade 1/2, 56% were neuroendocrine carcinomas and 6% were mixed neuroendocrine carcinoma / adenocarcinoma. Median OS was 79.6 months. Univariate analysis identified clinical stage (P=0.002), weight loss (P=0.000), jaundice at presentation (P=0.036), ECOG performance status (P=0.000), resection of primary tumor (P=0.000) and resection of metástasis (P=0.001) as significantly associated with survival. Multivariate analysis excluded resection of primary tumor only. Conclusions: In this mexican cohort, clinical factors were the most important determinants of prognosis.
Survival following initiation of everolimus for second-line treatment of metastatic renal cell carcinoma: Prognostic factors in clinical practice and comparison to clinical trials.
Authors: Wong Michael K.K. , Jonasch Eric , Pal Sumanta Kumar , Signorovitch James E. , Lin Peggy L. , Liu Zhimei , Wang Xufang , Culver Kenneth W. , Scott Jeffrey A. , George Daniel J. , Vogelzang Nicholas J.
Published: March 2020

e15500

Background: Current overall survival (OS) for metastatic renal cell carcinoma (mRCC) patients in clinical practice may differ from clinical trials. We aimed to identify and validate prognostic factors for OS in practice-based patients receiving 2nd-line everolimus (EVE), and to compare their OS vs. the RECORD-1 trial of EVE for mRCC. Methods: Two separate samples of oncologists/hematologists reviewed charts for patients initiating 2nd-line EVE between 2009 and 2011 following a 1st-line tyrosine kinase inhibitor (TKI). OS was defined as time from EVE initiation to death (censored at last follow-up). In the 1st sample of charts (the study sample), prognostic factors were identified via multivariable Cox proportional hazards models with stepwise selection. Prognostic factors considered included age, duration of mRCC and 1st-line treatment, metastatic sites, diabetes, histological subtype, ECOG and KPS score, and progression during 1st-line treatment. Model performance was assessed in the 2nd sample (the validation sample). Kaplan-Meier (KM) estimates for OS were compared between chart data and RECORD-1. Results: The study and validation samples included 220 and 97 patients, respectively. Significant prognostic factors were clear cell histology (hazard ratio (HR) = 2.9), KPS score <80% (HR = 2.9), duration of mRCC <1 year (HR = 2.7), progression on 1st-line TKI (HR = 2.2), and liver metastasis (HR = 1.9) (all P <.05). In the validation sample, KM estimates for 1-year OS were 90% for patients with 0-2 risk factors, 62% for patients with 3 risk factors, and 20% for patients with 4-5 risk factors (log-rank P <.001). OS estimates were consistent between both chart samples with 1-year OS probabilities of 67% and 68% and median OS of 19 and 23 months. In RECORD-1 1-year OS was 60% and median OS was 14.8 months (Motzer et al., 2010, Cancer). Conclusions: Prognostic factors for OS following 2nd-line EVE for mRCC in clinical practice were consistent with those previously identified in trial data. However, OS with 2nd-line EVE in clinical practice was longer than observed in trial data, and was not associated with type of 1st-line TKI.
Effect of sunitinib and pazopanib on necrosis and autophagic cell death in cancer cells: Role of cathepsin B.
Authors: Santoni Matteo , Amantini Consuelo , Morelli Maria Beatrice , Farfariello Valerio , Nabissi Massimo , Liberati Sonia , Bonfili Laura , Eleuteri Anna Maria , Mozzicafreddo Matteo , Burattini Luciano , Berardi Rossana , Cascinu Stefano , Santoni Giorgio
Published: March 2020

e15513

Background: Tyrosine kinase inhibitors (TKI), such as sunitinib, sorafenib and pazopanib, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). However, their use in sequential or combined strategies is limited by the lack of evidences on TKI-induced cell death in cancer cells. Aim of our study was to evaluate the different mechanisms responsible of the anti-proliferative and cytotoxic effects induced in vitro by µM doses of sunitinib, sorafenib and pazopanib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Necrotic cell death was evaluated by Annexin-V/PI staining and FACS analysis. The cathepsin B activation was evaluated by western blot using an anti-cathepsin B antibody; the cathepsin B proteolytic activity was determined using the fluorogenic Z-Arg-Arg-AMC peptide and the fluorescence of the hydrolyzed 7-amino-4-methyl-coumarin was detected by a SpectraMax Gemini XPS microplate reader. Results: We found that sunitinib and pazopanib markedly reduced at mM dose the viability of BC cells. Treatment for 24h with 20µM of sunitinib, by triggering “Incomplete autophagy”, induced necrosis of BC cells. In addition, sunitinib as a lysosomotropic agent, entered free within the lysosomes, where by increasing lysosomal pH and impairing cathepsin B activity, induced lysosomal-dependent necrosis. By contrast, treatment of BC cells for 72h with 20µM of pazopanib induced autophagic cell death, which was markedly reversed in a dose-dependent manner by the autophagic inhibitor 3-MA. The pazopanib-induced autophagic cell death was associated with increased procathepsin B cleavage and enhanced cathepsin B activity. Conclusions: Overall, our results show different cathepsin B-dependent cancer cell death mechanisms induced by sunitinib or pazopanib, providing the biological basis for novel molecularly targeted approaches.
Retrospective analysis of sorafenib as first or second target therapy in mRCC patients in Italian centers: An update.
Authors: Derosa Lisa , Gernone Angela , Morelli Franco , Sava Teodoro , Zustovich Fable , Rossi Lorena , Ferrari Vittorio D. , Sabbatini Roberto , Gasparro Donatello , Felici Alessandra , Cascinu Stefano , Calvani Nicola , Lo Re Giovanni , Rizzo Mimma , Iacovelli Roberto , Bracarda Sergio , Porta Camillo , Galligioni Enzo , Cogoni Alessio Aligi , Procopio Giuseppe ,   RESET Study Group
Published: March 2020

e15524

Background: With several agents available for the treatment of metastatic renal cell carcinoma (mRCC) a better understanding of their use in daily clinical practice is fundamental in the decision-making process. Methods: The REtrospective analysis of Sorafenib (So) as 1st or 2nd targET therapy (RESET) in mRCC was a retrospective, observational field study that assessed the use and safety of So in clinical practice in Italian centers. Treatments were determined by physicians per local prescribing guidelines. Patients (pts) treated with So single agent as 1st or 2nd target therapy (TT) for mRCC between 1st Jan 2008 and 31st Dec 2010 were eligible for inclusion. Endpoints included safety, overall survival (OS), progression-free survival, response rate and treatment duration. Subgroup analyses included age, ECOG performance status, prior therapy, number of metastases and line of TT with So. Results: From Feb to Jul 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.7%), rash (2.2%), hypertension, fatigue and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.4 – 19.6 mos) and median PFS was 5.9 mos (95% CI 4.9-6.7 mos). Median duration of treatment with So was 5.03 mos. Disease control (complete response + partial response + stable disease) was observed in 198(56%) pts. In pts receiving So as first or as second TT median OS was 19.9 mos (95% CI 15.9-25.3 mos) and 16.3 mos (95% CI 13.0-18.2 mos) respectively. In the subgroup of pts treated with So 1st TT followed by sunitinib (Su) 2nd TT (44 pts) and Su 1st TT followed by So 2nd TT (173 pts), median OS was 30.4 mos (95% CI 22.0-34.8 mos) and 16.6 mos (95% CI 13.1-18.2 mos) respectively. There were 269(76%) pts that received a total of 2 lines of therapy for mRCC, 133(38%) pts 3 lines and 43(12%) pts 4 lines of therapy. Conclusions: The efficacy and safety profile of So in the setting of Italian community-based daily clinical practice was similar to data reported in prospective clinical trials. The efficacy of So was observed in both the subgroups of pts receiving So as either the first or second TT for mRCC, with intriguing OS data in first line.
Epithelial-mesenchymal transition markers in metastatic transitional cell carcinoma (mTCC) patients under vinflunine treatment.
Authors: Sacristan Felipe , Aparicio Guadalupe , Grande Enrique , Haz-Conde Mar , Medina Villaamil Vanessa , Figueroa Angelica , Valladares Ayerbes Manuel , Antón Aparicio Luis M.
Published: March 2020

e15532

Background: Vinflunine (VFL) demonstrated in vitro antiproliferative effects in human tumour cell lines, and in vitro antitumor activities against subcutaneous tumour xenografts. Recently, we demonstrated that VFL causes these effects through tubulin instability, which is one of the leading intracellular molecular process that drives epithelial-mesenchymal transition (EMT). In addition, VFL may induce up-regulation in expression levels of E-cadherin/N-cadherin cocient. Methods: The study included a retrospective analysis of 18 patients with mTCC treated with carboplatin-based chemotherapy. The patients who demonstrated objective response (38.8%) continued with vinflunine 320 mg/m2 one day every three weeks until progression. EMT protein expression (E-cadherin, beta-catenin, vimentin, CK18) was evaluated by Western blotting and also by immunohistochemistry (IHQ). Results: Overall mean age of patients was 71 years. The median overall survival was 3.5 years for the carboplatin-based chemotherapy (95% CI, 0.377-3.623). In patients treated with VFL, it was demonstrated a correlation of performance status and overall response with the histological type and age. We also found a relationship between different EMT markers in patients that received VFL. Conclusions: The above data provide evidence for an intrincate mechanism by which VFL could stop the transition from epithelial cells to the invasive mesenchymal phenotype. Molecular mechanism of Snail, Slug, Twist and Hakai will be reported.
Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.
Authors: Gardner Faithlore Patrice , Joseph Richard Wayne , Serie Daniel , Hilton Tracy W. , Parasramka Mansi , Eckel-Passow Jeanette , Cheville John , Leibovich Bradley C. , Parker Alexander S.
Published: March 2020

e15539

Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 1,380 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/16/1990 and 4/14/2009. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features we employed Kruskal-Wallis tests and for associations with cancer-specific survival we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher MayoSSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001), and this association remained strong after after multivariate adjustment for well-known predictors of RCC aggressiveness. Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.62 95% CI 1.95-3.54; p<0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.48 95% CI 1.56-7.76; p =0.002). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.
Differences of protein expression of renal cell carcinoma (RCC) by tumor location and treatment.
Authors: Gonzalez Anneliese , Said Rabih , Brown Robert E , Zhang Yufeng , Amato Robert J.
Published: March 2020

e15556

Background: Resistance to targeted therapy in RCC is primarily related to tumor and environmental changes. We assessed the difference of morphology and protein analyte expression by metastatic site and treatment types. Methods: Archival tissues from primary and metastatic RCC biopsies were studied. Immunohistochemical probes included antibodies for the protein analytes: phospholipase D2; fatty acid synthase; phosphorylated (p)-Akt (Ser 473); p-mTOR [Ser 2448]); p-p70S6K (Thr 389); p-extracellular signal-regulated kinase (ERK) 1/2 (Thr 202/Tyr 204); p-signal transducer and activator of transcription (STAT)3 (Tyr 705); vascular endothelial growth factor (VEGF)-A; stem cell markers CD44 and CD56; and intratumoral FOXP3 vs. CD8 lymphocytes. Results: A total of 66 patients with available tissue biopsies were assessed. Fourteen patients had additional biopsy at progression. Morphoproteomics was assessed on a total of 81 specimens. The nuclear distribution of phospholipase D2 was statistically significant different by biopsy site (p=0.0046) with highest expression in bone and lung. Similarly, the cytoplasmic expression fatty acid synthase was significantly different by biopsy site (p=0.0167) with highest expression in lymph node and adrenal. More importantly, nuclear mTOR activity was different by tumor biopsy site (p=0.001) with predominant expression in lung, lymph nodes and brain. Compared to mTORC1, which was more expressed in primary tumors, mTORC2 is more expressed in lung and bone metastasis. None of the other protein analytes expression was different based on tumor location. Further analysis on patients with multiple biopsies showed that the plasmalemmal CD56 expression increased with therapy but none of the other protein expression. Conclusions: This analysis emphasized the role of the microenvironment in tumor biology. Prospective treatment trial is underway based on the different molecular fingerprints.
Predictive markers in metastatic transitional cell carcinoma (mTCC) patients treated with carboplatin plus pemetrexed regimen.
Authors: Aparicio Guadalupe , Medina Villaamil Vanessa , Taron Miquel , Rosell Rafael , Antón Aparicio Luis M.
Published: March 2020

e15558

Background: Treatment with platinum derivatives plus pemetrexed has shown a benefit in metastatic transitional cell bladder carcinoma (mTCC); however, the subset of patients most likely to benefit has not yet been identified. Predictive markers of pemetrexed response can be inferred from its mechanism of action in inhibiting nucleotide synthesis. In the present study we evaluated the predictive role of BRCA1, RAP80, TS, REV3 and AEG1 mRNA levels in a series of mTCC samples from patients treated with carboplatin plus pemetrexed (CP) and correlated with pathological response to chemotherapy and median survival. Methods: We retrospectively analyzed 18 patients with mTCC. Eligible patients received pemetrexed 500 mg/m2 in combination with carboplatin at an area under the concentration curve of 5. Total treatment dose was given on day 1 of each cycle and repeated every 21 days for 6 cycles. Gene expression levels were quantified by real-time quantitative PCR from paraffin-embedded pre-treatment tumor samples obtained by transurethral resection. Results: Patients were male, mean age 71 years (range 51-83). Median overall survival was 3.5 years (95% CI, 0.377-3.623). Non-responders had average survival of 2.2 years (SE=0.436) compared to an average of 5.5 years for responders (SE=0.661) (Pearson X2=4.667, p=0.031). We found an association between non-responders and elevated RAP80 expression (paired t (df)=-2.69, p=0.028) (paired t (df)=2.372, p=0.039). In the multivariate analysis elevated TS level was the variable most predictive of shorter survival (OR=1.158, p=0.047). Conclusions: CP regimen demonstrated moderate activity in patients with mTCC. Our data indicates that RAP80 and TS could be predictors of poor outcome. Also, RAP80 expression may predict efficacy of CP as first-line treatment and could be a useful tool to customize therapy in bladder cancer patients. A prospective study is warranted to validate these observations.
Association of methylation of genes in the taurine/hypotaurine pathway with worse prognosis in renal cell carcinoma.
Authors: Gross Andrew , Choueiri Michel , Shen John P. , Randall James Michael , Ideker Trey , Hofree Matan
Published: March 2020

e15562

Background: Epigenetic silencing of genes associated with the taurine/hypotaurine pathway has been associated with worse outcome in several tumors such as CDO1 in breast cancer, and GAD1 in prostate cancer. Our objective was to assess the prognostic value of methylation status of genes in the taurine/hypotaurine pathway in patients with renal cell carcinoma (RCC). Methods: We performed an analysis of 283 RCC samples using data from The Cancer Genome Atlas (TCGA). Ten genes belonging to the taurine/hypotaurine metabolic were analyzed using principal component analysis to determine a composite methylation profile of the pathway. A Cox proportional-hazards regression model was then used to determine the association of the composite methylation profile with patient survival. Results: CDO1, GAD2, and GAD1 influenced the outcome of the composite gene the most. Increasing degree of methylation correlated with more advanced tumor stage, and was an independent predictor of overall patient survival. Among patients with localized and locally advanced disease (stages 1-3), high levels of methylation correlated with significantly worse OS (Table). No difference in outcome was noted in patients with metastatic disease. Conclusions: Silencing of genes in the taurine/hypotaurine pathway through methylation is predictive of poorer outcomes in patients with localized RCC. Increasing degree of methylation correlates with tumor stage. Among patients with localized disease and belonging to the same stage, higher degree of methylation correlated with with worse prognosis. Interestingly, this effect is not observed in patients with metastatic disease, indicating the possible activation of other pathways that override the role of the taurine/hypotaurine pathway. [Table: see text]
Can neoadjuvant gemcitabine plus carboplatin followed by immediate cystectomy improve survival in patients with cisplatin-ineligible muscle-invasive bladder cancer?
Authors: Koie Takuya , Suzuki Yuichiro , Tobisawa Yuki , Yoneyama Tohru , Mori Kazuyuki , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2020

e15565

Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin based chemotherapy. In the present study, we conducted a propensity score analysis to elucidate the clinical significance of neoadjuvant gemcitabine and carboplatin chemotherapy (GCarbo) for cisplatin-ineligible patients with MIBC. Methods: The cohort of the neoadjuvant group consisted of 51 patients with MIBC, treated between March 2005 and June 2011, who were ineligible for cisplatin. Patients received 2 courses of GCarbo consisting of 800 mg/m2gemcitabine on days 1, 8, and 15, and carboplatin with an AUC of 4 on day 2. After GCarbo, radical cystectomy (RC) and bilateral pelvic lymph node dissection (PLND) were performed at an interval of 1 month. The cohort of RC alone included 59 cisplatin-ineligible MIBC patients treated with RC and bilateral PLND between June 1998 and February 2010. Propensity score matching was used to adjust for potential selection biases associated with treatment type. The endpoints were overall (OS) and disease-free survival (DFS). Results: Of the 51 patients who received GCarbo and RC, 6 (11.8%) RC specimens were found to be cancer free. Grade 3/4 neutropenia occurred in 17 patients (33.3%) and thrombocytopenia in 11 patients (21.6%). There were no patients who experienced grade3/4 nephrotoxicity or nausea. Propensity score-matched analysis indicated 45 matched pairs from both groups. The median follow-up period was 35.3 months. The 3-year OS rate was 86.5% for neoadjuvant GCarbo vs. 50.6% for the RC alone group (P < 0.0001). The DFS rate was 78.8% for neoadjuvant GCarbo vs. 44.8% for RC alone (P= 0.001). Multivariate analysis revealed that the neoadjuvant GCarbo regimen was an extremely strong and independent predictor of the longer OS and DFS. Conclusions: Although the present study is non-randomized, neoadjuvant GCarbo chemotherapy followed by immediate RC achieved significantly longer OS and DFS than cystectomy alone. The clinical usefulness of the present treatment for cisplatin-ineligible patients with MIBC should be verified by further trials.
Clinical and prognostic implications of delta-like ligand 4 and hypoxia-inducible factors in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib as first-line therapy.
Authors: Xie Mian , He Chao sheng , He Zhao hui , Lin Qi zhan
Published: March 2020

e15567

Background: Sunitinib is recommended as the first line treatment of patients with metastatic renal cell carcinoma (mRCC). Delta-like ligand 4 (DLL4) is a Notch ligand that is upregulated by hypoxia and has a role in tumor angiogenesis. The aim of this study was to evaluate clinical and prognostic implications of DLL4 and markers of hypoxia in mRCC patients treated with sunitinib as first-line therapy. Methods: Treated-naïve, clear cell mRCC patients were received sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2). We prospectively collected plasma samples before treatment and the expressions of DLL4, Notch1, HIF-1α, HIF-2α were measured using enzyme-linked immunosorbent (ELISA). Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The log-rank test was used to assess the significance of univariate survival analysis. Multivariate analysis using Cox Regression model was performed to identify independent prognostic factors. Results: Between Aug 2008 and Sep 2010, consecutive 86 patients with mRCC were enrolled. Median follow up period was 35 months. The objective response rate (ORR) was 29.3% (95% confidence interval [CI], 13.5% to 37.7%), median PFS was 10.1 months (95% CI, 8.7 to 12.1 months), and median OS was 23.6 months (95% CI, 16.8 to 26.5 months). Most treatment-related side effect were mild to moderate, including hypertension, fatigue, thrombocytopenia and hand-foot syndrome. Both high DLL4 and low HIF-1α levels significantly correlated with lower ORR (DLL4: 19.8% versus 31.7%, P < 0.001; HIF-1α: 16.8% versus 33.5%, P = 0.002) and shorter PFS (DLL4: 8.6 versus 12.1 months, P = 0.01; HIF-1α: 8.3 versus 11.9 months, P = 0.01), but this was not predictive of OS. Neither survival nor ORR was associated with expressions of Notch1 and HIF-2α. Conclusions: Sunitinib has shown effective anti-tumor activity in treatment-naïve mRCC patients. High expression of DLL4 and low expression of HIF-1α may mediate resistance to sunitinib. Baseline levels of DLL4 and HIF-1α have prognostic impact on PFS for patients treated with sunitinib.
Is there any prognostic importance of pretreatment serum M30 and serum M65 levels on progression-free survival of patients with metastatic renal cell carcinoma treated with first-line sunitinib?
Authors: Basaran Mert , Yildiz Ibrahim , Sen Fatma , Kilic Leyla , Keskin Serkan , Darendeliler Emin , Bavbek Sevil E.
Published: March 2020

e15569

Background: Effective cancer biomarkers for early detection, prognosis, or prediction of therapy response are urgently need in metastatic renal cell cancer (RCC). Soluble cytokeratin 18 fragments (M30, M65) are released from human cancer cells during epitelial cell death. Specific enzyme-linked immunosorbent assays (ELISA) using related antibodies distinguish between apoptotic (M30) or apoptotic and necrotic (M65) tumor cell death in serum samples. The aim of this study was to determine the prognostic value of plasma M30 and M65 levels in predicting survival rates of patients with metastatic RCC treated with first-line sunitinib. Methods: Thirty-nine patients with metastatic RCC and 39 healthy controls were included in this study. The patients’ samples were collected prior to the first cycle of sunitinib therapy and serum M30 and M65 levels were measured by ELISA. Results: The median ages of the patients and controls were 60 and 58 years, respectively. No difference was detected in the median serum M30 level between the patients and controls (53.7 vs. 49.1 U/l, P = 0.31). The median serum M65 level was significantly higher in patients than in controls (334.0 vs. 179.1 U/l, P<0.001). Receiver operating characteristic (ROC) analysis revealed that the best cut-off value for serum M65 level for predicting progression-free survival (PFS) was 313.6 U/l. The median PFS of patients whose M65 levels were lower than or equal to 313.6 U/l was better than that of patients whose M65 levels were greater than 313.6 U/l (P = 0.03) in univariate analysis. But serum M65 levels in patient group were not found to be an important prognostic factor for PFS in the multivariate analysis. Conclusions: Serum M65 levels were significantly elevated in patients with metastatic RCC compared to healthy individuals. Future prospective studies with large sample sizes are needed to address the possible impact of M30 and M65 levels on the treatment responses of patients and whether these markers may be prognostic factors for PFS or OS in patients with RCC.
Carcinoma of the unrivaled bilharzial urinary bladder of Egyptians: Expanding radiotherapy and decline of obligate cystectomy—Historic perspective and a demonstration study of 34 patients.
Authors: Saied Gamal Moustafa , Moustafa Karim G
Published: March 2020

e15571

Background: The objective is to validate the new clinicopathological features involving carcinoma of the unrivaled urinary bladder of Egyptian patients, alongside studying their reflection on management. Methods: Timely contributions of leading Egyptian experts in bladder cancer in the last 4 decades were reviewed. Additionally, 34 patients were studied in 2 subsets based on planned treatment modality: group A (12 cases) treated by cystectomy and group B (22 cases) treated by transurethral resection plus stipulated radiotherapy. Treatment results were evaluated. Results: An overview of studies published in the last 4 decades is given, demonstrating a striking change in the characteristic features of bladder carcinoma in this country, more obvious in 2007 and after. Present work revealed 44.1% of patients had their tumor erupting in a bilharzial bladder where walls demonstrated classical cystoscopic features of the disease. Histologically 86.7 % of them were squamous cell carcinoma. Almost 60% of patients had had their tumors in a non-bilharzial bladder, 94.7% of them were transitional cell carcinoma. Thirteen out of 15 patients in group A were treated by cystectomy carrying 7.7 % perioperative mortality, whereas 11 out of 12 patients in group B received radiotherapy preceded by transurethral resection. Distribution of clinicopathological findings and treatment modalities is tabulated. Conclusions: Bladder cancer in Egyptian patients has lost its weird features imposed by bilharzial cystitis. It is shifting towards alien types making it suitable for organ preserving management.
Prediction of a potential lethal phenotype in testicular nonseminomatous germ cell tumor.
Authors: Bilen Mehmet Asim , Lin Sue-Hwa , General Rosale , Pagliaro Lance C. , Logothetis Christopher , Gorlov Ivan , Tu Shi-Ming
Published: March 2020

e15575

Background: Cancer is a heterogeneous disease. The nature of heterogeneity provides clues about the biologic origin of cancer. Studying cancer heterogeneity may enable us to elucidate the various subtypes of a particular cancer, and improve the diagnosis, prognostication, and therapy of cancer. Nonseminomatous germ cell tumor (NSGCT) is a prime example of a heterogeneous disease. We determined the lethality of NSGCT by characterizing the histological makeup of primary testicular tumors (proportion of embryonal carcinoma [EC], choriocarcinoma, seminoma, yolk sac tumor [YST], and teratoma) and their tumor burden. Methods: From November 1997 to October 2012, 142 consecutive patients diagnosed with a NSGCT were included for this study. Predictors significant in univariate analysis: tumor stage, tumor size, percentage of YST component, and percentage of EC component were used as predictors of cancer specific death or incurability in a multivariate binary logistic regression model. The outcome of the model is probability of death or incurability. Results: Patient characteristics: age, median (range) – 25 (12-53); race – Caucasians 65%, Hispanics 28%; pathology – embryonal carcinoma 15%, teratoma 6%, mixed NSGCT 79%; stage – I 43%, II 33%, III 24%; size of primary tumor, median (range) – 3.8 cm (0.9-27); HCG<5,000 95%, >5,000 4%; AFP<1,000 85%, >1,000 13%; therapy – salvage chemotherapy 15%, RPLND 34%, HD chemotherapy w/ SCT 1%, WBRT 1%. Univariate analysis showed that clinical stage (p=.0001), presence of YST (p<.005), size of primary tumor (p=.005), and absence of EC (<.01) have prognostic significance. We developed a nomogram to identify patients who are most likely to succumb to their NSGCT based on the histologic makeup of their primary tumor, size of the primary tumor, initial tumor markers, and appropriate surgeries after chemotherapy. Conclusions: Presence of YST in advanced NSGCT predicts chemotherapy resistance in a potentially lethal phenotype. Early diagnosis and timely treatment with chemotherapy and surgery may improve the clinical outcome of these patients. Results of this study need to be validated in another data base or a prospective clinical trial.
Three lines of targeted therapy for metastatic renal cell carcinoma (mRCC): A viable strategy?
Authors: Buchler Tomas , Bortlicek Zbynek , Poprach Alexandr , Kubackova Katerina , Kiss Igor , Zemanova Milada , Fiala Ondrej , Abrahamova Jitka , Melichar Bohuslav ,   Czech Renal Cancer Cooperative Group
Published: March 2020

e15581

Background: Sequential therapy with tyrosine kinase inhibitors (TKIs) and the mTOR inhibitor everolimus has been proposed for mRCC. The aim of the present retrospective analysis was to compare the efficacy of everolimus used after one versus two prior TKIs and to assess the progress of a defined cohort of patients (pts) through sequential lines of therapy. Methods: In the national database of mRCC pts treated with targeted agents 368 pts received everolimus as the 2nd (N=269) or 3rd (N=99) targeted agents following TKIs sunitinib or sorafenib. Survival was calculated using the Kaplan-Meier method, and the differences were assessed using the Log-rank test. Furthermore, the treatment course was evaluated in 331 mRCC pts starting 1st line therapy with sunitinib or sorafenib in 2010. The data cut-off date was October 8, 2012. Results: Progression-free survival (PFS) for everolimus in the 2nd versus the 3rd line of targeted therapy was 6.5 months (95% confidence interval [95% CI] 5.3-7.7 months) versus 6.1 months (95% CI 4.0-8.3 months), respectively (P=0.159). The incidence and profile of adverse events were similar in both lines. PFS from the start of the first targeted agent to progression on the third targeted agent was similar for pts receiving three lines of therapy using the TKI-TKI-mTOR (N=99) and TKI-mTOR-TKI (N=17) sequence: 28.5 months (95% CI 25.2-31.7 months) versus 27.2 months (95% CI 24.0-30.4 months), respectively (P=0.281). The median follow-up for the initial cohort of 331 pts treated with sunitinib or sorafenib was 20.1 months. 152 pts (46%) subsequently received a 2nd line therapy, and 82 pts (25%) died before reaching the 2nd line. Of the 152 pts receiving the 2nd line therapy, only 38 pts (11%) went on to the 3rd line, and 46 pts (14%) died before reaching the 3rd line of therapy. The remaining pts still continued on 1st line (N=50; 15%) or 2nd line therapy (N=34; 10%), were lost to follow-up (N=30; 9%), or were alive but not receiving antineoplastic treatment (N=51; 15%). Conclusions: Everolimus has similar efficacy and toxicity whether used in the 2nd or the 3rd line of targeted therapy for mRCC. A minority of mRCC pts starting the 1st line targeted treatment can be expected to reach the 3rd line therapy.
Are there geographic differences in the outcome of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (su)?
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Boursi Ben , Weitzen Rony , Hayat Henry , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Carducci Michael Anthony
Published: March 2020

e15598

Background: Geographic differences in the outcome of pts have been described in various cancers. The VEGFR inhibitor su is a standard treatment (tx) for mRCC. The effect of geographic differences on the outcome of su tx in mRCC is poorly defined. Aims: To study the effect of geographic differences on outcome of su tx in mRCC. Methods: We performed an international multicentre retrospective study of unselected cohort of 275 mRCC pts, who were treated with su from 2004 to 2012 in 7 centers across the US and Middle East (ME; Israel). Clinicopathologic and prognostic factors, and tx outcome were compared between US (n=133) and ME (n=142) pts. Chi-square and Fisher's exact tests were used to compare categorical variables, and two-sample t-test was used to compare continuous endpoints. Progression free survival (PFS) and overall survival (OS) were determined by Cox regression. Results: Median age was 61 (US) vs 65 (ME, p=0.01). The groups were balanced regarding gender, Heng risk, past nephrectomy, RCC histology, presence of ≥ 2 metastatic sites, lung/liver/bone metastasis, use of angiotensin system inhibitors (ASI), prior cytokines/ targeted txt, su induced HTN, and su dose reduction/tx interruption secondary to side effects. The incidence of active smokers (28% vs 15%, p=0.01), bisphosphonates users (23% vs 13%, p=0.03) and pts with pre-tx neutrophil to lymphocyte ratio (NLR) ≤ 3 (63% vs 49%, p=0.04) was higher among ME pts. In US vs ME pts, objective response was partial response/stable disease 77% (n=102) vs 79% (n=112), and progressive disease at first imaging evaluation within the first 3 months (mos) 23% (n=31) vs 21% (n=30) (p=0.77, OR 1.1). Median PFS was 8 vs 12 mos (HR=1.8, p<0.0001), and median OS 21 vs 22 mos (HR=0.94, p=0.9) in US vs ME pts. Factors associated with PFS in multivariate analysis of the entire cohort (n=275) were geographic location (US vs ME), Heng risk, RCC histology, su induced HTN, ASI use, pre-tx NLR, and smoking status. Conclusions: Geographic differences in clinicopathologic factors and PFS of pts with mRCC treated with su may exist. This should be further investigated, and if validated, applied in clinical practice and clinical trials.
Clinical effectiveness of modified method of laparoscopic partial nephrectomy.
Authors: Dimitriadi Sergey N , Kit Oleg Ivanovich
Published: March 2020

e15602

Background: Warm ischemia time (WIT) is the most important factor predicting postoperative renal function condition after laparoscopic partial nephrectomy (LPN). Methods: During 1 year (2012) 22 LPN was performed on T1 stage renal cell carcinoma (RCC) patients. Our current laparoscopic technique involves transperitoneal approach, atraumatic hilar clamping (in all patients), tumor excision by cold endoshears. In 12 cases (54.5%) pelvicaliceal system (PCS) of the kidney was opened. These patients underwent LPN modification, which consists of excluding of separate PCS suture repair of the kidney after tumor excision. This technique allowed reducing WIT. Tumor bed excision was sutured using “sliding clip” technique without using any addition hemostatic materials. Control group consist of 10 (45.5%) patients whose PCS were not opened during LPN. Results: Mean age in the main and control groups was 59.3±10.6 years (range 42-77) and 52.5±11.7 years (range 33-68), mean tumor size – 39.3±7.5 mm (range 29-57) and 39.5±7.5 mm (range 25-52), mean RENAL nephrometry sum - 7.6±1.2 (range 6-10) and 6.8±0.9 (range 5-8), mean WIT – 12.6±2.3 min.(range 9-16) and 11.3±3.1 (range 6-15), mean blood loss – 207.5±237.9 ml (range 50-800) and 97±32.7 ml (range 50-150) respectively. In all 12 cases PCS defect was up to 2 cm. Conversion was performed in one case with RENAL nephrometry sum 10 and one kidney lost due to complexity of resection. Mean follow up was 5.4±3.1 month (range 1-10). Intraoperative hemorrhage was in 2 main group patients. Delayed hemorrhage, urine leak, postoperative renal failure did not occur. All patients confirmed RCC, and all of them had negative inked surgical margins for cancer. Conclusions: Thus, use of modified technique of LPN allowed carrying out difficult partial nephrectomies (up to 10 RENAL nephrometry sum) with no significant deference of WIT (p=0.334 Mann Whithitney U-test) from more simple LPN (without opening PCS). This explains absence of kidney injury in the postoperative period. We suppose, that meticulous suture repair of a tumor bed using “sliding clip” technique with defects of PCS up to 2 cm is safe, considered urine leak development. This approach will allow to expand indications to LPN.
Outcomes associated with sunitinib alternative schedule compared to traditional schedule: a single-center experience.
Authors: Atkinson Bradley J. , Kalra Sarathi , Wang Xuemei , Bathala Tharakeswara , Perpich John , Corn Paul Gettys , Tannir Nizar M. , Jonasch Eric
Published: March 2020

e15611

Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify 1) common AEs, 2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and 3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from 1/26/06 to 3/1/11. Pts > 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p < 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS > 2 (HR 3.9), elevated LDH (HR 2.04), and > 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p < 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged time on treatment and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.
Inactivation of the nuclear receptor TR3 as an important new drug target for treating RCC.
Authors: Abdelrahim Maen , Safe Stephen , Abudayyeh Ala
Published: March 2020

e15618

Background: The high mortality of patients with RCC is due to poor performance of most chemotherapy. There is a critical need for development of new mechanism-based drugs.The nuclear orphan receptor NR4A1 (TR3, Nur77) are immediate early genes activated by various stressors. NR4A is highly expressed in multiple tumors. TR3 knockdown studies show that TR3 plays an important role in cancer cell growth and angiogenesis. The pro-oncogenic activity of this receptor is an excellent example of “non-oncogene addiction” which is essential for maintaining the cancer cell/tumor phenotype. Methods: Multiple RCC cell lines have been used. Several different classes of C-substituted DIMs summarized in Fig1 has been screened for TR3 deactivation in RCC cell lines using GAL4-TR3/UAS-luc constructs (Fig1). Effects of the C-DIM compounds on cancer cell growth and expression of Sp-regulated genes has been determined by cell counting, the MTT assay, western blot and activation of caspases 3 and 9 and directly compared to knockdown of TR3 by RNAi. Results: Knockdown of TR3 by RNAi has confirmed that TR3 is pro-oncogenic and we have focused on structure-activity relations (SARs) of C-DIM analogs to identify compounds that inactivate TR3. Renal cancer cells were treated with c-DIM TR3 inactivators and this significantly inhibited cell proliferation (Figs 2 and 3). Expression of TR3 in RCC cell lines has not previously been reported. Fig. 4 presents a western blot of cell lysates showing that TR3 is expressed in these cell lines. TR3 inactivators decreased expression of survivin and bcl-2 and this was accompanied by several apoptotic markers. These results show that RCC cells not only express TR3 but TR3 inactivators decrease the pro-survival genes and induce apoptosis which confirm that TR3 is also a target for renal cancer therapy. TR3 pro-oncogenic activity is due, in part, to the role of TR3 in constitutive expression of survivin and other Sp-regulated genes (VEGF, c-MET..). TR3 also involves in formation of a complex with p53 which inactivates the tumor suppressor gene. Thus inactivation of TR3 activates p53 pathway (Fig 5). Conclusions: TR3 is overexpressed in RCC. We have shown for the first time that TR3 is an important new drug target for treating RCC.
Clinical implications of a prostate cancer risk SNP profile in two treatment cohorts.
Authors: Goh Chee Leng , Saunders Ed , Leongamornlert Daniel , Dadaev Tokhir , Tymrakiewicz Malgorzata , Thomas Karen , Selvadurai Elizabeth , Woode-Amissah Ruth , Mahmud Nadiya , Castro Elena , Olmos David , Guy Michelle , Govindasami Koveela , Wilkinson Rosemary , Sawyer Emma , Amin Al Olama Ali , Easton Douglas , Kote-Jarai Zsofia , Parker Chris , Eeles Ros A.
Published: March 2020

e16000

Background: Prostate cancer (PCa) has a heritable risk and genome-wide association studies (GWAS) have so far identified 76 single nucleotide polymorphisms (SNPs) associated with PCa risk. Currently these SNPs have only been evaluated against overall PCa risk and several disease parameters. Their clinical utility remains undefined. We explore the potential prognostic role of the risk SNP profile in 2 PCa cohorts; Active Surveillance (AS) and androgen deprivation therapy (ADT). Methods: PCa patients at the Royal Marsden Hospital who consented for DNA analyses were eligible. 2 separate cohorts were identified; those undergoing AS and those receiving ADT. The risk SNPs were genotyped using Sequenom or Fluidigm platforms. The cumulative SNP risk scores for each patient were calculated by summing risk alleles for each loci using the weighted effect as estimated in previous studies (log-additive model). For the AS group, the risk scores were analysed against defined adverse outcomes in AS, including adverse histology on repeat biopsy and time to treatment, to determine their prognostic value. For the ADT group, the risk scores were assessed against time to relapse, defined by either biochemical relapse or evidence of progression on imaging. Results: In the AS group, 391 patients’ DNA were studied. 31% of those have since undergone treatment and 30% have histological upgrade on repeat biopsies. On univariate analysis, there was no significant relationship between the risk scores and biopsy upgrade or time to treatment (p>0.05). When analysing differences in outcomes between the higher and lower risk groups (top 25% and lowest 25% of the genetic risk distribution), there was again no relationship (p>0.05). In the ADT group, 567 patients’ DNA were studied. The mean duration of response was 30 months. No significant associations were found when risk scores were analysed as a continuous variable against time to relapse on ADT, or when analysing difference between the top and bottom 25% of the risk distribution (p>0.05). Conclusions: PCa SNP risk scores have not been shown to be prognostic factors in either AS or ADT. This is the first study analysing the potential prognostic role of the latest GWAS risk SNPs in PCa treatment cohorts.