tbuckley/cabot-search huggingface dataset:
Importance of performance status, corrected calcium, and microvascular invasion in predicting overall survival in patients with metastatic renal cell carcinoma at the era of molecular targeted therapy.
Authors: Masatoshi Eto, Tomomi Kamba, Hideaki Miyake, Masato Fujisawa, Takao Kamai, Hirotsugu Uemura, Taiji Tsukamoto, Haruhito Azuma, Akio Matsubara, Kazuo Nishimura, Tsuyoshi Nakamura, Osamu Ogawa, Seiji Naito
Journal: Journal of Clinical Oncology (2013)

e15588 Background: We have recently reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene are significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC) in our prospective trail (Eur Urol 2012, Epub ahead). In the present study, we further evaluated which clinical and pathological factors correlated with overall survival (OS) in the trial. Methods: In the multicenter, prospective study, patients with histologically confirmed RCC that was metastatic, measurable disease, age &gt; 20 years, ECOG performance status (PS) 0-1 and adequate organ function received 3 dosages of 5 million U per week of IFN-α treatment. After the failure of IFN-α, molecular targeted drugs were used. We followed the patients for 2 years to define the date of death or loss to follow-up to calculate OS. Association between OS and clinical, pathological factors, such as age, PS, TNM classification, grade, infiltrating type, sarcomatoid component, microvascular invasion, lactate dehydrogenase (LDH), corrected Calcium (Ca), hemoglobin (Hb), C-reactive protein (CRP), platelet (Plt), etc, was analyzed using the Log-rank test. For multivariate analysis, the Stepwise test was used. Results: Two hundreds three eligible pts were enrolled between December 2006 and October 2009. All pts had prior nephrectomy, and 88.7% had ECOG PS 0. Ninety-four percent of patients had clear cell RCC, and 5% had papillary RCC. The response rate of IFN-α was 13.8% (28/203, 9 CR, 19 PR). Median OS was 42.8 months in mRCC patients initially treated with IFN-α. In univariate analysis, PS, TNM classification, grade, infiltrating type, microvascular invasion, corrected Ca, Hb, CRP, and Plt were significantly associated with OS. Among them, PS, microvascular invasion, and corrected Ca were significantly correlated with OS in multivariate analysis. Conclusions: This prospective study demonstrates that PS, corrected Ca, and microvascular invasion are important in predicting OS in mRCC patients initially treated with IFN-α at the era of molecular targeted therapy. Clinical trial information: UMIN000000731.
Biomarker patterns of metastatic melanoma with implications for therapy.
Authors: Lee D. Cranmer, Sherif S. Morgan, Rebecca Feldman, Omid Hamid
Journal: Journal of Clinical Oncology (2014)

e20050 Background: Annually, metastatic melanoma (MM) is responsible for approximately 10,000 deaths in the United States and 48,000 deaths worldwide. Prognosis worsens dramatically once disease metastasizes distantly. Targeting molecular changes involved in metastasis may be an effective strategy to slow disease progression. In this study, we investigated changes in theranostic biomarkers that may be important for MM, which may provide insight into new therapeutic strategies. Methods: 1,369 cutaneous melanoma cases referred to Caris Life Sciences between 2009 and 2013 were evaluated. Biomarker profiling included a combination of sequencing (Sanger, NGS), protein expression (IHC), and gene amplification (CISH or FISH). Results: We examined profiling data from 1,369 cutaneous melanomas (355 primary skin and 1014 skin metastases). Differential expression between primary and MM using IHC included loss of expression of cKIT, ERCC1, PTEN, SPARC, TOPO1, and TUBB3 (p-values range <0.001 to 0.02) in MM, compared to primary skin specimens. Conversely, MET, MRP1, and TOP2A were overexpressed (p-values: 0.006, 0.01 and <0.001) in MM. MET overexpression was observed in 15% of BRAF-mutated MM in our series. EGFR is amplified by ISH in 35% of the MM set vs. 6% in primary specimens (p<0.001). NGS revealed increased BRAF, PTEN, and PIK3CA mutation rates in MM (p-values: 0.02, 0.02, 0.09), implicating PTEN/PIK3CA in disease progression. Of interest, PTEN mutations co-occurred with BRAF mutations in 13% of patients. Conclusions: Molecular changes observed in MM, as detected by IHC, ISH, and sequencing may provide actionable targets that are important for disease progression. Using a multiplatform approach, we identified subgroups of BRAF-mutated patients that exhibit MET overexpression, EGFR amplification, and PTEN mutations. Since MET and EGFR have been implicated in resistance to BRAFi, our data support using a dual-targeted treatment strategy. Since prognosis varies based on dissemination site, further investigation to determine site-specific metastases would be of high interest.
Dasatinib phase I/II study of patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib: Results of the CA180031 study in Japan
Authors: H. Sakamaki, K. Ishizawa, M. Taniwaki, S. Fujisawa, Y. Morishima, K. Tobinai, M. Okada, K. Ando, K. Ueda, R. Ohno
Journal: Journal of Clinical Oncology (2007)

17515 Background: Dasatinib is a potent, orally active, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. Studies outside Japan have shown dasatinib to be highly effective in overcoming resistance and intolerance to imatinib, inducing durable cytogenetic (CyR) and hematologic responses (HR) in this population. The maximum tolerated dose was not reached in the Phase-I trial outside Japan and a 70-mg BID dose was determined to provide the optimal benefit-risk profile. Methods: This Phase-I/-II study was designed to assess the safety and efficacy of dasatinib in Japanese patients with imatinib-resistant or -intolerant CML or Ph+ALL. In the 4-week Phase-I portion in patients with chronic-phase (CP) CML, three dose levels were evaluated: 50 mg, 70 mg, and 90 mg BID. The Phase-II portion is currently evaluating the CyR of dasatinib in patients with CP-CML at 24 weeks, and the HR rate in accelerated- (AP) or blast-phase (BP) CML and Ph+ ALL at 12 weeks. Results: As of December 2006, 17 eligible patients have been treated in Phase I. Six patients (4F, 2M; median age 43 y [range 27–56]) were treated with 50 mg BID and 1 dose-limiting toxicity (DLT) was observed (Grade 4 thrombocytopenia). Two patients experienced transient Grade 3 ALT elevations but as treatment was uninterrupted, these were not considered DLTs. Six patients (6M; median age 42 y [range 27–55]) were treated with 70 mg BID and again 1 DLT was observed (Grade 4 thrombocytopenia). No DLT has been observed among 4 patients (3M, 1F; median age 41 y [range 27–64]) at the 90-mg BID dose. Major CyRs have been achieved in all three cohorts in the Phase-I segment of the trial. Thirty six patients were enrolled and treated in the Phase-II part of the trial (12 CP-CML, 7 AP- CML, 4 BP-CML, and 13 Ph+ALL). Efficacy and safety data as well as the baseline BCR-ABL mutation data are currently being assessed and will be presented. Conclusions: Dasatinib can be safely administered at doses of up to 90 mg BID to Japanese patients with imatinib-resistant or -intolerant CP-CML. No significant financial relationships to disclose.
Tumor profiles of brain metastases from NSCLC, breast cancer, and melanoma.
Authors: Santosh Kesari, Joanne Xiu, Jethro Lisien Hu, Michael E. Salacz, David Eric Piccioni, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2015)

2060 Background: An estimated 70,000 diagnoses of brain metastases (BM) occur each year in the U.S., with an incidence of 5-7% in breast and melanoma and 20% in lung cancer. Despite its prominence, the biology of BM remains poorly understood. Several theories of BM development exist, including the linear progression model, which suggests that the metastatic capabilities of tumor cells develop at primary sites following the accumulation of alterations. The parallel progression model argues that tumor cells disseminate early and accumulate changes independently at the secondary site. We compare the tumor profiles of BM from common cancers to understand the biology and to identify differential treatment strategies. Methods: Tumor samples were profiled using a multiplatform service (Caris Life Sciences, Phoenix, AZ), including sequencing (Sanger, NGS), protein expression (IHC) and amplification (ISH). Results: 5,391 NSCLC (293 BM, 5,098 lung), 3,595 breast cancer (99 BM, 3496 breast) and 761 melanoma (101 BM, 660 skin) unpaired samples were included. No significant differences were found in 48 genes between BM and the primary tumor sites, with the exception of PIK3CA in breast cancer, which was mutated less in BM vs. the breast samples (10% vs. 26%, p=0.02). In contrast, expression of TOP2A, TOPO1 and TS, and amplification of EGFR, were more prevalent in BM as compared to the primary sites (Table). Conclusions: A similar genetic landscape with limited differences was seen in BM of NSCLC, melanoma and breast cancer compared to primary tumors. The limited differences are more consistent with a linear progression model of cancer metastasis. Additionally ,this suggests that both primary tumor and BM would respond to similar chemotherapeutics with the consideration of effective blood-brain barrier-penetrant drugs. Small molecule inhibitors of EGFR could be considered due to increased EGFR amplification and the higher TOP2A, TOPO1 expression prompts consideration of topoisomerase inhibitors like etoposide or irinotecan. Brain met % Primary met% P NSCLC TOPO2A 75 55 <0.01 TOPO1 64 55 0.02 TS 35 22 <0.01 EGFR FISH 36 28 ns Breast TOPO2A 78 50 <0.01 TOPO1 78 63 <0.01 TS 39 28 0.04 EGFR FISH 31 14 <0.01 Melanoma TOPO2A 76 46 <0.01 TOPO1 61 57 ns TS 56 45 ns EGFR FISH 50 6 <0.01
Randomized double-blind placebo-controlled trial of celecoxib for radiation-induced oral mucositis.
Authors: Rajesh V. Lalla, Linda E. Choquette, Kathleen F. Curley, Robert J. Dowsett, Richard S. Feinn, Upendra P. Hegde, Carol C. Pilbeam, Andrew L. Salner, Stephen T. Sonis, Douglas E. Peterson
Journal: Journal of Clinical Oncology (2013)

9620 Background: Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck (H&amp;N) cancer. OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to treatment interruptions. Due to the role of inflammatory pathways in the pathogenesis of OM, this study investigated the effect of inhibition of cyclooxygenase-2 (COX-2) on severity and morbidity of OM. Methods: In this randomized double-blind placebo-controlled trial,40 H&amp;N cancer patients were randomized to daily use of 200 mg celecoxib or matched placebo, for the duration of RT. Eligibility criteria included planned RT dose of ≥ 5000 cGy to 2+ areas of the mouth and no contraindication for celecoxib use. The planned sample size of 20 per arm provided 80% power to detect a 1 point difference in mean Oral Mucositis Assessment Scale (OMAS) score (range 0-5) at 5000 cGy RT (primary endpoint), applying a two-tailed, two-sample t-test at the 5% level of significance. Clinical OM, normalcy of diet, pain scores and analgesic use were assessed 2-3 times a week by blinded investigators during the 6-7 week period of RT, using validated scales. Results: Twenty subjects were randomized to each arm, which were similar with respect to tumor location, radiation dose, and concomitant chemotherapy. In both arms, mucositis and pain scores increased over the course of RT. Intent-to-treat analyses demonstrated no significant difference in mean (SD) OMAS scores at 5000 cGy [celecoxib 1.32 (0.71), placebo 1.27 (0.86), p = 0.83, two sample t-test]. There was also no difference between the celecoxib and placebo arms respectively, in mean OMAS scores over the period of RT (SD) [0.98(0.77) &amp; 0.97 (0.86), p = 0.84], mean worst pain scores [3.38 (3.07) &amp; 3.31 (3.32), p = 0.83], mean normalcy of diet scores [5.43 (3.86) &amp; 5.11(3.94), p = 0.65], or mean daily opioid medication use in IV morphine equivalents [19.08 (16.57) &amp; 20.48 (19.07), p = 0.48], all by linear mixed model fixed effects regression analysis. There were no SAEs attributed to celecoxib use. Conclusions: Daily use of a selective COX-2 inhibitor, during the period of RT for H&amp;N cancer, did not reduce the severity of clinical OM, pain, dietary compromise or use of opioid analgesics. Clinical trial information: NCT00698204.
Abstract 6: Novel Tools for Generation, Purification, and Analysis of Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Dominik Eckardt, Kristin Noack, Andreas Bosio
Journal: Circulation Research (2015)

Pure and well-characterized cardiac cells derived from human pluripotent stem cells (hPSCs) are of high interest for cardiovascular disease modeling, drug safety studies and development of cell replacement strategies. Although several protocols for cardiac differentiation of hPSCs have been developed, major limitations are clone-to-clone variations in differentiation efficacy as well as heterogeneity of generated cardiomyocyte populations. Therefore, we have developed novel tools for cardiomyocyte differentiation, magnetic cell sorting-based purification and cell analysis using new antibody-conjugates enabling for flow cytometry- and immunofluorescence-based identification of cardiomyocytes and subtypes. hPSCs were maintained under xeno-free conditions in our recently developed StemMACS iPS-Brew XF medium to keep pluripotency for more than &gt;20 passages and enable for efficient cardiac differentiation. We chose a monolayer differentiation protocol based on the timely regulated activation and inhibition of Wnt signaling by small molecules. In order to identify antibodies suitable for cardiomyocyte enrichment or depletion of non-myocytes, we performed a surface marker screen with more than 400 antibodies between days 10-20 of differentiation. Besides identification of new surface markers, our screen confirmed expression of recently published markers like CD172a and CD106. In order to evaluate kinetics of their expression and correlation with intracellular markers of cardiomyocytes and subtypes, we performed a flow cytometry-based analysis of marker expression. Our data indicate a dynamic expression pattern for both CD172a and CD106, either completely or partially overlapping with intracellular cardiomyocyte marker expression. Based on these data we developed magnetic cell separation procedures for the isolation of cardiomyocytes. Magnetically enriched cardiomyocytes initiated contractions after replating and could be stably maintained in culture. Taken together, we have developed novel tools supporting the workflow for efficient generation of PSC-derived cardiomyocytes, magnetic purification and flow cytometry or immunofluorecence-based characterization of cardiomyocytes.
A phase II clinical trial examining the impact of neoadjuvant axitinib on primary tumor response in patients with locally advanced clear cell renal cell carcinoma.
Authors: Jose A. Karam, Catherine E Devine, Marisa Lozano, Nizar M. Tannir, Kamran Ahrar, Pheroze Tamboli, Christopher G. Wood
Journal: Journal of Clinical Oncology (2013)

4516 Background: Previous studies have shown minimal impact of TKIs on primary renal tumor downsizing. Axitinib is a VEGFR TKI that has been recently approved for use in patients with metastatic clear cell renal cell carcinoma (RCC). In this prospective phase II trial, we sought to investigate the safety and role of axitinib in downsizing tumors in patients with non-metastatic renal cell carcinoma, prior to undergoing surgical resection. Methods: Patients with locally advanced (clinical stage T2-T3b N0 M0) biopsy-proven clear cell RCC were eligible for this phase II clinical trial. The primary outcome was objective response rate (using RECIST) following the administration of axitinib for 12 weeks prior to undergoing radical nephrectomy. Secondary outcomes included safety, tolerability, and feasibility of administration of axitinib in this patient population. Patients were given axitinib 5mg PO BID, and dose titration was allowed. Axitinib was continued until 36 hours prior to surgery. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: The study goal of enrolling 24 patients has been recently reached. At present, nineteen patients have completed the studies required for assessment of the primary outcome and are hereby reported. Fifteen patients were males, and four were females. Median age was 61 years (range 42-83 years). All patients had biopsy-proven clear cell RCC. All 19 patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. Adverse events of any grade were: arthralgia in 6, hypothyroidism in 14, fatigue in 15, and hypertension in 16 patients. No wound complications occurred after surgery. Nine patients (47%) experienced a partial response by RECIST, and 10 patients had stable disease. There was no progression of disease while on axitinib. Conclusions: Axitinib is well tolerated in the neoadjuvant setting in patients with planned surgery for locally advanced non-metastatic clear cell RCC. The drug showed tumor downsizing activity when given for 12 weeks prior to surgery. Adverse events of any grade were common and easily manageable with routine care. Clinical trial information: NCT01263769.
Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma
Authors: James R. Perry, Normand Laperriere, Christopher J. O’Callaghan, Alba A. Brandes, Johan Menten, Claire Phillips, Michael Fay, Ryo Nishikawa, J. Gregory Cairncross, Wilson Roa, David Osoba, John P. Rossiter, Arjun Sahgal, Hal Hirte, Florence Laigle-Donadey, Enrico Franceschi, Olivier Chinot, Vassilis Golfinopoulos, Laura Fariselli, Antje Wick, Loic Feuvret, Michael Back, Michael Tills, Chad Winch, Brigitta G. Baumert, Wolfgang Wick, Keyue Ding, Warren P. Mason
Journal: New England Journal of Medicine (2017)

Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown.We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide.A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O6-methylguanine-DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups.In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677 .).
The association between age-related macular degeneration (AMD) and renal cell carcinoma (RCC): A nested case-control study.
Authors: Daniel Keizman, Keren Rouvinov, Avivit Neumann, Yu-Xiao Yang, Maya Gottfried, Hadas Dresler, Ilan Leibovitch, Kevin Haynes, Ronac Mamtani, Shimon Ben Boursi
Journal: Journal of Clinical Oncology (2017)

443 Background: Overexpression of vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of both RCC and AMD. To date, there are no data on an association between AMD and RCC. In the present nested case control study, we aimed to evaluated the association between age-related macular degeneration and RCC risk. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of RCC. For every case, four eligible controls were matched on age, sex, practice site, time, and duration of follow-up. Exposure of interest was diagnosis of AMD prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for RCC were estimated using conditional logistic regression. Adjustment was performed for confounders associated with both AMD and RCC such as smoking, obesity, hypertension, and diabetes. Furthermore, in a secondary analysis, we evaluated the association between other non-VEGF associated retinopathies and RCC, and between AMD and pancreatic cancer, a malignancy characterized by hypovascularity in contrast to the hypervascularity of RCC. Results: The study population included 1,547 patients with RCC and 6,066 matched controls. Median follow-up time was 6 years (IQR 3-9). AMD diagnosis was associated with a significantly increased RCC risk (OR 1.89, 95% CI 1.09-3.29). In contrast, there was no association between other retinopathies and RCC risk (OR 0.8, 95% CI 0.56-1.15). AMD was associated with a lower risk for pancreatic cancer (OR 0.47, 95% CI 0.35-0.64). Conclusions: Patients with AMD may be at higher risk for RCC. Providers should consider screening for RCC within this population.
TP53 Mutation in Waldenstrom Macroglobulinemia
Authors: Stephanie Poulain, Christophe Roumier, Elisabeth Bertrand, Aline Renneville, Sabine Tricot, Aurelie Caillault Venet, Sandrine Geffroy, Morgan Nudel, Charles Herbaux, Stéphanie Guidez, Claude Preudhomme, Xavier Leleu
Journal: Blood (2016)