bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the PI3K/AKT/mTOR pathway with MLN0128 (mTORC1/2 inh) and MLN1117 (PI3K alpha inh) in bladder cancer: Rational for its testing in clinical trials.
Authors: Martinez Alejandro , Hernandez Anna , Arpi Oriol , Menendez Silvia , Iarchouk Natalia , Gavilan Elena , Bellosillo Beatriz , Arumí Montserrat , Rojo Federico , Mullane Stephanie A. , Choueiri Toni K. , Rovira Ana , Albanell Joan , Brake Rachael , Bellmunt Joaquim 
Published: February 2017

369 Background: PI3K/AKT/mTOR pathway is a promising target for cancer treatment being commonly deregulated in human bladder tumors and resulting in the promotion of tumor cell growth, survival, and resistance to chemotherapy. The aim of this study is to characterize the effects of MLN0128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, and MLN1117, an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha isoform that may be more efficacious and less toxic than pan-PI3K inhibitors as bladder cancer therapies. Methods: We evaluated the effects of MLN0128 and MLN1117 both as single agents and in combination with each other or with a SOC chemotherapy agent (paclitaxel). The effects of the agents alone or in combination were analysed in a panel of six bladder cancer cell lines and in tumor xenografts. These models were selected based on specific genomic alterations that could be considered as potential therapeutic targets (PIK3CA and TSC mutations). Molecular effects of both agents and the combinations on cell-cycle, apoptosis, autophagy and on cell viability were tested in the bladder cancer cell lines. The in vivo effects on tumor growth inhibition were also assessed. Results: Both MLN0128 and MLN1117 inhibit the PI3K/AKT/mTOR pathway and reduce cell proliferation in bladder cancer cell lines with diverse genetic backgrounds. Combination of MLN0128 + MLN1117 produced synergistic antiproliferative effects in cell lines and improved the effect of each drug alone in vitro and in vivo, with no signs of toxicity in these models. Similar effects were observed with the combination of paclitaxel + MLN0128. Conclusions: Our results show that MLN0128 and MLN1117 are promising investigational agents that might be of value for bladder cancer patients. Further investigation as novel anti-cancer agents alone or in combination with chemotherapy in clinical trials in humans is warranted.
Clinical features and outcomes of testicular choriocarcinoma: A single cancer center experience.
Authors: Wang Jue 
Published: February 2017

401 Background: Pure choriocarcinoma (PC) is a very rare entity and the most aggressive subtype of nonseminomatous germ cell tumor. There is limited published data regarding treatment outcomes in this group of patients. In this series, we report our experience of sixteen patients treated at a single cancer center. Methods: The hospital tumor registry was utilized to retrospectively identify patients with the diagnosis of testicular cancer between 1997-2011. Clinical pathological, radiographic, treatment, and outcome data were retrospectively reviewed and descriptive statistical analysis was performed. Results: Sixteen patients were identified containing choriocarcinoma as component in 120 testicular cancer patients. Four patients (3.3%) had PC and twelve (10%) had mixed choriocarcinoma (MC). The median age of entire cohort was 25 years (range 21–41). Patients with PC was younger (p < 0.001); more advanced stage (IIIC stage 100% vs. 41.7%; p < 0.001), higher rate of lung metastasis (100% vs. 12%; p < 0.001), higher rate of brain metastasis (70% vs. 16.7%; p < 0.001), received more aggressive therapies: RPLND (50% vs. 33.3%; p < 0.001); >2 lines chemotherapy (75% vs. 16.7%; p < 0.001); high dose chemotherapy with stem cell transplant (HDCT) (50% vs. 8.3%; p < 0.001); in comparison with patients with MC. All four PC patients (100%) were classified as poor risk group at diagnosis according to the IGCCCG prognostic classification system. One PC patient died before receiving any therapy, three had standard first and second line chemotherapies (BEP and viep). Two PC patients underwent HDCT (one as third and another as fourth line). One PC patient had pulmonary resection of chemo-resistant disease after HDCT with long term survival. At a median follow-up of 40 months (range 0.2 - 189), three PC (75%) and two MC (16.7%) patients have died in last follow-up. Three-year survival was 25% and 80% in PC and MC, respectively. Conclusions: PC is associated with advanced disease and high rate of pulmonary and brain metastases. The prognoses of these patients remain poor despite of receiving more aggressive therapy, in comparison with patients with MC. Novel therapeutic strategies are urgently needed for patients with this rare cancer.
Preclinical development of a docetaxel nanocarrier to enhance prostate cancer radiosensitivity.
Authors: Crehange Gilles , Boudon Julien , Boidot Romain , Chevrier Sandy , Dalban Cecile , Loiseau Alexis , Collin Bertrand , Oudot Alexandra , Gauthier Thomas , Millot Nadine , Mirjolet Celine 
Published: February 2017

41 Background: From 30% to 50% of high risk prostate cancer patients who undergo radiation therapy (RT) will have a biochemical failure. Combining chemotherapy, such as Docetaxel (DXL), with RT can enhance its efficiency. Multidrug resistance mechanisms often limit drug efficacy by decreasing tumor cell intracellular concentration of drugs. There is interest to develop nanocarrier of DXL to maintain drug inside cancer cells by improving its efficacy. The purpose of this study was to develop a titanate-nanotube (TiONt)-DXL nanocarrier (nanohybrid) and to evaluate its in vivobiodistribution as well as its radiosensitizing efficacy in association with RT on a hormone-independent prostate cancer model. Methods: DXL molecules were grafted on TiONts using PEG-3000 molecules to generate the nanohybrid. In vitrocytotoxic activity of the nanohybrid was evaluated on PC-3 cell line using MTS assay. After intratumoral injection, biodistribution analysis was performed by SPEC-CT imaging of mice bearing subcutaneous PC-3 human prostate tumors. To evaluate the benefit of nanohybrid and RT association, tumors were irradiated using 3 fractions of 4Gy administrated after the injection of nanohybrids. Nine groups of 7 mice were used to evaluate nanohybrid and RT association efficacy : untreated, control with buffer IT injection, +/- RT, free DXL, +/- RT, TiONt +/- RT and TiONt-DXL +/- RT. Mice behavior, health status and tumor volume were monitored twice a week until tumor growth recovery. Results: Biodistribution kinetics showed that more than 70% of nanohybrids were localized into the tumor 96 hours after injection. Mice receiving nanohybrid-RT exhibited a significant tumor growth delay to reach a volume of 1,000mm3compared to mice receiving free DXL-RT: 73.7 days (median, [58.9-89]) vs 56 days (median, [31.5-74]) (p=0.0127). Conclusions: TiONt-DXL improves RT efficacy compared to free DXL. These results suggest that local control might be enhanced by TiONt-DXL. TiONt-DXL can be injected as a radiosensitizer in men harboring high risk localized prostate cancer with needles during prostate brachytherapy procedure.
High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the targeted therapy era: Extension of OS benefits beyond complete response (CR) and partial response (PR).
Authors: Aung Sandra , Morse Michael A. , Wong Michael K.K. , Kaufman Howard , Daniels Gregory A. , McDermott David F. 
Published: February 2017

423 Background: HD IL-2 has been reported to have a overall response rate (ORR) for mRCC of 15% and a median OS of 19 months (Fyfe, 1995), however, the studies that led to its regulatory approval are >15 years old and were performed in an era preceding targeted therapies. Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated between 2007 and 2012) informing an ongoing prospective cohort (~600 patients). We report on the retrospective mRCC subjects (n=97, 13 sites) with survival status determined as of November 2013 and a median follow-up of 32 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2. Results: The ORR was 22% (8% CR and 14% PR). Of 97 subjects, 36 were confirmed deceased and 61 were known to be alive, none were lost to follow-up. The median OS was 51 months, compared to a median OS range of 5-35 months for FDA-approved targeted agents (Harrison, 2013). There was significant clinical benefit in patients with CR, PR, and stable disease (SD), none of which reached median OS compared to 37.9 months in patients with progressive disease (PD). There is a significant advantage in PROCLAIM for those patients treated 1st vs. 2nd line HD IL-2; the median OS was 61.8 months (n=82) vs. 15.3 months (n=15), respectively. The clinical benefit of HD IL-2 therapy as front line is consistent with published data (Birkhauser, 2013). No deaths due to IL-2 related toxicity were reported in the retrospective cohort. Conclusions: The PROCLAIM registry documents a vastly improved OS for HD IL-2 compared to historical results during a time interval marked by the advent of targeted therapy for advanced RCC. Response to IL-2 (CR or PR) is associated with prolonged survival, however, stable disease as well as front line use also appears to positively impact survival. Issues including patient selection characteristics and treatment sequencing are hypotheses currently being explored in the prospective database. Clinical trial information: NCT01415167.
Association of genome-wide copy number alterations with metastasis of clear cell renal cell carcinoma.
Authors: Gowrishankar Banumathy , Thodima Venkata Jaganmohan , Molina Ana M. , Ma Charles , Guttapalli Asha , Gold Theresa Margaret , Motzer Robert J. , Chaganti Raju S.K. , Houldsworth Jane 
Published: February 2017

428 Background: About one-third of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and show poor prognosis. The genetic and epigenetic alterations associated with metastasis in ccRCC have variably been studied, and their role in the metastatic process is unclear. The goals of the current study were to identify genomic copy number alterations (CNAs) associated with ccRCC metastasis and examine their clinical utility. Methods: In this IRB-approved study, genome-wide copy number profiling was performed on DNA from 144 ccRCC (81 primary and 63 metastatic lesions). Differential CNAs between primary and metastatic lesions and between different metastatic sites were identified using Fisher’s exact test. Associations between CNAs and overall survival (OS) were tested using the log rank statistic and Kaplan-Meier method. Genomic profiling data of 437 and 240 primary ccRCC (TCGA and PMID: 23797736, respecitively) were used for verification. Results: Between primary and metastatic lesions, 25 CNAs were significantly different (p<0.05). Of the 11 more frequent in metastatic lesions, nine retained significance when comparing stage IV and stage I TCGA ccRCC. For 368 TCGA locally-invasive tumors (stages I, II, and III), three CNAs (loss of 9p24.3-p13.3, 9p12-q11, and 9q21.12-q21.33) were associated with inferior survival (p=0.002). In the second dataset of 214 locally-invasive lesions, loss of 18q11.2-q23 correlated with shorter OS (p=0.025). Across metastatic lesions, nine CNAs were found to be significantly enriched in lung lesions and three in bone. In a subset of 127 ccRCC with known metastatic status at 5 years after diagnosis, two of these CNAs (gain of 7q36.1-36.3 in lung and loss of 22q13.2 in bone) were significantly enriched in the corresponding primary specimens. Conclusions: This study identified CNAs associated with ccRCC metastasis and common sites of metastasis that have the potential to serve as biomarkers to assist in better risk stratification of patients with this disease. Integrated analyses of genes mapping to the loci of genomic imbalance would further our understanding of the biology of metastasis in renal cancer.
Third-line therapy in metastatic renal cell carcinoma: Results from the International mRCC Database Consortium.
Authors: Heng Daniel Yick Chin , Wells Connor , Donskov Frede , Rini Brian I. , Lee Jae-Lyun , Bjarnason Georg A. , Beuselinck Benoit , Smoragiewicz Martin , Alva Ajjai Shivaram , Srinivas Sandy , Wood Lori , Yamamoto Haru , Ernst D. Scott , Pal Sumanta Kumar , Yuasa Takeshi , Broom Reuben James , Kanesvaran Ravindran , Bamias Aristotelis , Knox Jennifer J. , Choueiri Toni K. 
Published: February 2017

430 Background: Third-line targeted therapy efficacy in metastatic renal cell carcinoma (mRCC) is not well characterized and many funding bodies do not provide reimbursement for it. Methods: The International mRCC Database Consortium (IMDC) consists of consecutive patient series from 25 cancer centers. It was queried for specific sequences of targeted therapy and third-line therapy. Kaplan Meier estimates were used for survival. Cox proportional hazards models were used to adjust hazard ratios for confounders. Patients that stopped second-line therapy were divided into two groups: those that went onto third-line therapy and those did not. Results: 4,050 patients were treated with first-line targeted therapy, of which 2,011 (49.6%) had second-line therapy and 879 (21.7%) had third-line targeted therapy. The most common third-line therapies were everolimus 25%, sorafenib 14%, sunitinib 13%, temsirolimus 11%, pazopanib 10%, and axitinib 6%. IMDC prognostic groups at third-line therapy initiation were 6% favorable risk, 67% intermediate risk, and 27% poor risk. Overall response rate for third-line therapy was 10.5% and 50.9% had stable disease in those patients that were evaluable. Median PFS was 5.1 months (95% CI, 4.5-5.7) and median OS from third-line therapy initiation was 12.0 months (95% CI, 10.7-12.9). Patients stopping second-line therapy that move on to third-line therapy vs. those that do not receive third line therapy have a median OS from stopping second-line therapy of 13.1 vs. 2.3 mons (p<0.0001). When adjusted for second-line IMDC prognostic criteria and KPS at second-line treatment cessation, patients who do receive third-line therapy have a HR of death of 0.41 (95% CI, 0.32-0.52; p<0.0001) compared to those that do not receive third-line therapy. This may be in part due to patient selection. To further limit bias, when excluding patients that live less than 3 months after second-line therapy cessation, the adjusted HR was similar. Conclusions: Third-line targeted therapy has demonstrated activity and is prevalent in use. Further studies are required to determine appropriate sequencing.
Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma.
Authors: Bourlon Maria Teresa , Gao Dexiang , Trigero Sara , Clemons Julia Elizabeth , Lam Elaine Tat , Flaig Thomas W. 
Published: February 2017

453 Background: Increases in mean corpuscular volume (MCV) and hypothyroidism have been observed in patients on sunitinib treatment. We characterized tyrosine kinase-associated macrocytosis in metastatic renal cell carcinoma (mRCC) patients and its relationship, along with thyroid dysfunction, to progression-free survival (PFS). Methods: A retrospective chart review was performed on patients treated with sunitinib and/or sorafenib (01/2005-01/2011). Data pertaining to the development of macrocytosis was analyzed in association with our previous data on thyroid dysfunction in these patients. We assessed PFS, as clinically defined by the treating provider. Results: Seventy-four patients with 103 treatment periods for sorafenib (47) and sunitinib (56) were analyzed. Macrocytosis was found in 55% and 8% of sunitinib and sorafenib treatment periods, respectively (p<0.001). Focusing on the sunitinib-treated patients for all further analysis, the median PFS was 11 months (mo) (95% CI, 6-19). Median PFS was 21 mo (95% CI, 11-25) for patients who developed macrocytosis compared to 4 mo (95% CI, 3-8) in normocytic patients (p=0.0001). The time to development of macrocytosis did not affect the degree of macrocytosis observed (p=0.47). Macrocytosis and hypothyroidism were both significant predictors of prolonged PFS in our cohort. The greatest difference in PFS was noted between patients who developed both macrocytosis and hypothyroidism (25 mo) versus those who remained both normocytic and euthyroid (5 mo) (p<0.0001). Conclusions: Sunitinib-related macrocytosis is associated with a prolonged PFS in mRCC. The concurrent development of both hypothyroidism and macrocytosis in this setting was associated longer PFS compared to either alone. Increased MCV may be used as a biomarker for sunitinib response in this setting. [Table: see text]
Risk factors and a model to predict toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with VEGF-targeted therapy: Results from the International Metastatic RCC Database Consortium.
Authors: Kaymakcalan Marina Dusevic , Xie Wanling , Albiges Laurence , North Scott A. , Kollmannsberger Christian K. , Smoragiewicz Martin , Kroeger Nils , Wells Connor , Rha Sun Young , Lee Jae-Lyun , Fay Andre Poisl , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: February 2017

464 Background: VEGF targeted therapy (VEGF-TT) are standard in advanced metastatic renal cell carcinoma (mRCC), however, toxicities that can lead to drug discontinuation can have a significant impact on patient (pt) outcomes. We aimed to identify risk factors for toxicity and develop the first model to predict toxicity-related treatment discontinuation (TrRD) in mRCC pts treated with VEGF-TT. Methods: Baseline characteristics and treatment outcome data were collected on 936 mRCC pts on first-line VEGF-TT from 7 IMDC institutions. TrTD was analyzed using a competing risk regression model for treatment discontinuation. Results: Median follow up was 23 months. Treatment discontinuation occurred in 833 pts (89%), of which 198 (23.8%) were related to drug toxicity. Sunitinib was the most common VEGF-TT (77%) in our series followed by sorafenib (18.4%). Median time on therapy was 7.1 months in all pts and 4.4 months for pts with TrTD. Most common toxicities leading to TrTD included fatigue, diarrhea and mucositis. On multivariate analysis, significant adverse predictors for TrTD (p<0.05) were: age (≥60 years), baseline glomerular filtration rate (GFR) <30 cc/min, number of metastatic sites (>1), and baseline sodium level (<LLN). A model was developed using the number of patient risk factors to predict the risk of TrTD (Table). Conclusions: In the largest series reported to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors that predict toxicity-related treatment discontinuation in mRCC pts treated with VEGF-TT. Based on the number of risk factors present, we built the first model to predict treatment-related drug discontinuation. This model can be used for treatment and frequency of monitoring considerations in clinical practice. [Table: see text]
Bevacizumab monotherapy as salvage therapy for patients with advanced clear cell renal cell carcinoma pretreated with targeted drugs.
Authors: Lee Chung-Han , Hoetker Andreas M , Voss Martin Henner , Feldman Darren Richard , Woo Kaitlin , Patil Sujata , Coskey Devyn Taylor , Akin Oguz , Hsieh James , Motzer Robert J. 
Published: February 2017

468 Background: Bevacizumab targets vascular endothelial growth factor (VEGF) and has showed benefit in first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α (Lancet 370: 2103). This retrospective analysis assessed the efficacy of bevacizumab monotherapy after progression on targeted drugs such as VEGFr tyrosine kinase inhibitors (TKI), and/or mTOR inhibitors. Methods: A retrospective analysis was performed on patients with metastatic ccRCC who received bevacizumab monotherapy at MSKCC after progression on prior targeted therapies. Primary end point is overall survival and secondary endpoints include progression free survival, time on therapy, and toxicity analysis. Results: 71 patients were treated with bevacizumab monotherapy in the salvage setting. Patients were heavily pretreated with 36 (51%) patients receiving bevacizumab as a fourth-line agent or later and 33 (46%) patients received at least 2 prior VEGF targeted agents. Seventeen (24%) patients had a KPS <80% and 20 (28%) patients were in the poor prognosis MSKCC risk group. Overall median OS was 11.5 months (95% CI, 6.4-17.4 months) and overall median PFS was 1.9 months (95% CI, 1.7-4.1). Nine (13%) patients had a prolonged time on therapy of >12 months. At last analysis, 8 (11%) patients remained on therapy. Therapy was discontinued for progression of disease (n=56, 89%), adverse events (n=4, 6%), or unknown/unrelated reasons (n=3, 5%). Univariate analysis showed KPS (<80% vs. ≥80%) and MSKCC Risk Factor Classification (poor vs. favorable) as prognostic for poor outcome with hazard ratios of 3.97 (95% CI, 2.09-7.52, p<0.001) and 2.84 (95% CI, 1.17-6.89, p=0.021), respectively. No significant differences in OS were seen when comparing number of lines of prior therapy or lines of prior VEGF targeted therapy. Conclusions: Bevacizumab monotherapy resulted in prolonged disease control in a subset of patients with few discontinuations for adverse events in patients after progression on other targeted therapies, including those who were heavily pretreated. The number of prior VEGF targeted TKI therapies did not correlate with response to bevacizumab, which may reflect a difference in targeting the receptor vs. ligand.
Preoperative renal parenchymal volumetrics and prediction of renal insufficiency following radical nephrectomy.
Authors: Pruthi Deepak Kumar , Oomah Sasha , Chhibba Ruchi , Kirkpatrick Ian , McGregor Thomas 
Published: February 2017

471 Background: To identify predictors of post-operative renal insufficiency by analyzing pre-operative imaging volumetrics among patients undergoing radical nephrectomy (RN) for renal cell carcinoma (RCC). Methods: A retrospective review of all patients undergoing RN for RCC between January 2011 and August 2013 was performed. Estimated glomerular filtration rate (eGFR) was calculated employing the modified diet in renal disease (MDRD) formula using the pre-operative and one-year serum creatinine values. Pre-operative and 1-year post-operative CT/MRI scans were reviewed. AW Volume Share 5 workstations were utilized to calculate volumes. Statistical analysis using Chi-square and Fisher exact test were employed. Results: Of the 147 patients undergoing RN 65 patients met the inclusion criteria. Patients with smaller tumor volumes (<375 cm3) were more likely to have a greater decline in their post-operative eGFRs (>35%) when compared to patients with larger tumors (58 vs. 21%; p=0.0165). Patients with a pre-operative eGFR >60 ml/min/1.73m2 had a greater (>25%) drop in their 1-year eGFR (81 vs. 47%; p=0.0084). A smaller volume (<150 cm3) of parenchyma of the ipsilateral kidney was associated less compensatory (<25%) hypertrophy (100 vs. 69, p=0.0348). Smaller tumors (<300 cm3) were more likely to have a greater degree (>10%) of compensatory hypertrophy (78 vs. 43% p=0.0234) and less blood loss (<300 cc, 82 vs. 44%, p=0.0082). Older patients and patients with a combined history of diabetes (DM) and hypertension (HTN) were more likely to have compensatory (>25%) hypertrophy (age >65, 100% vs. 31%, p<0.001; DM+HTN, 100% vs. 75%, p=0.0084). The degree of compensatory hypertrophy (>25%) however, did not predict 1-year eGFR (35%) change (p=0.2203). New kidney disease (eGFR<60 ml/min/1.73m2) occurred in 71% patients. Conclusions: Volumetric imaging shows promising potential and may become a valuable tool in predicting post-operative renal insufficiency for patients undergoing nephrectomy and should be investigated further both in RN and partial nephrectomy cohorts.