bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.