tbuckley/cabot-search huggingface dataset:
Outcome of octogenarian versus (vs) young patients (pts) with metastatic renal cell carcinoma (mRCC), treated with sunitinib (su).
Authors: Igal Kushnir, Eli Rosenbaum, Avishay Sella, David Sarid, Maya Gottfried, Natalie Maimon, Avivit Peer, Avivit Neumann, Victoria Neiman, Svetlana Kovel, Eliahu Gez, Wilmosh Mermershtain, Keren Rouvinov, Michael Anthony Carducci, Mario A. Eisenberger, Hans J. Hammers, Victoria J. Sinibaldi, Raanan Berger, Daniel Keizman
Journal: Journal of Clinical Oncology (2016)

538 Background: Su is a standard treatment (tx) for mRCC. Octogenarian pts (aged ≥ 80) are often considered to be unfit for su tx, and recommendations for their tx is limited by the paucity of clinical trials data in this population. We aimed to study baseline characteristics and outcome of octogenarian vs young (aged ≤45) pts with mRCC treated with su. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with su in 8 centers across 2 different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and age, and outcome were performed using the entire pt cohort. Results: Between 2004-2013, 36 octogenarian (group 1; median age 83) and 37 young (group 2; median age 42) mRCC were treated with su. The groups were balanced regarding the following baseline clinicopathologic characteristics: gender, HENG risk, past nephrectomy, mRCC histology, ≥ 2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) &gt;3, and sunitinib induced hypertension (HTN). In group 1 vs 2, 53% vs 27% (p=0.006) had dose reduction/treatment interruption d/t side effects. Clinical benefit (partial response + stable disease) in group 1 vs 2 was 76% vs 84%, while 24% vs 16% had disease progression within the first 3 months of tx (p=0.09). Median PFS was 11 vs 8 months (p=0.1). Median OS was 22 vs 20 months (p=0.7). In multivariate analyses of the entire pt cohort (n=73), age was not significantly associated with PFS or OS. Conclusions: Su is active in octogenarian mRCC pts. Vs young pts, a significantly higher proportion of octogenarian pts had dose reduction/treatment interruption d/t side effects.
Comparison of lymph node staging system in gastric cancer using time-dependent ROC analysis with Harrell’s concordance index.
Authors: Etsuro Bando, Norihiko Sugisawa, Masanori Tokunaga, Yutaka Tanizawa, Taiichi Kawamura, Yusuke Kinugasa, Hideyuki Kanemoto, Katsuhiko Uesaka, Masanori Terashima
Journal: Journal of Clinical Oncology (2013)

12 Background: The aim this study was to clarify what the most informative pathologic lymph node staging system in gastric cancer is, by using time-dependent receiver operating characteristic (ROC) analysis with Harrell’s concordance (c) index. Methods: This study enrolled 2747 primary gastric cancer patients, without prior chemotherapy, who underwent R0 or R1 macroscopically curative resection. We calculated concordance indices of different 3 nodal staging systems (anatomical level based on JPN 13th edition vs. numbers of metastatic nodes based upon TNM 7th edition vs. ratio of metastatic nodes; derived from Yu’s definition {Yu et al. Br J Surg;1997,N0:0, N1;0-0.1, N2;0.1-0.25, N3;0.25-}) for survival. Results: (Anatomical level) Harrell’s c-index was 0.754 with 5-year survival rate of N0; 93%, N1; 73%, N2; 51%, N3; 19%. C-index without node-negative patients was 0.628. (Numbers of positive nodes) C-index was 0.767 with 5-year survival rate of N0; 93%, N1; 81%, N2; 68%, N3; 37%. C-index without node-negative patients was 0.669. (Ratio of nodal involvement) C-index was 0.770 with 5-year survival rate of N0; 93%, N1; 80%, N2; 63%, N3; 29%. C-index without node-negative patients was 0.691, which is significantly larger than those in anatomical level or numbers of positive nodes (p&lt;0.001, p=0.014, respectively). (Comparison of Staging System) If combined pT category with ratio grading system without pStage IA, new staging system is the significantly most informative (c-index; 0.760) than JPN 13th (c-index; 0.735) or TNM 7th (c-index; 0.742) (p=0.009, p=0.023, respectively). Conclusions: Lymph node staging system based on the conception of ratio of metastatic nodes is the most informative staging system than those with anatomical location or numbers of metastatic nodes. These results suggested that in gastric cancer pathologic staging system in next TNM classification should include the ratio of metastatic nodes.
Use of negative thyroid transcription factor (TTF-1) status to predict for negative epidermal growth factor receptor (EGFR) mutations (Mts) status with a high negative predictive value (NPV) in patients (pts) with adenocarcinomas (AC) of the lung.
Authors: N. Somaiah, E. Garrett-Mayer, X. Huang, A. E. Wahlquist, K. Danenberg, G. R. Simon
Journal: Journal of Clinical Oncology (2011)

7530 Background: TTF-1 is expressed in about 72% of ACs. EGFR Mts are present in 10-15% of unselected pts with AC. High TTF1 expression and EGFR Mts are associated with female sex, never-smoking status and longer survival. TTF-1 testing is available in most pathology laboratories. However, most clinics depend on commercial laboratories for EGFR Mt testing where it could be 2-4 weeks before results are available. We hypothesized that ACs negative for TTF-1 will also be negative for EGFR Mts. Methods: Microdissected formalin-fixed paraffin-embedded tumors from 693 pts with NSCLC were tested for EGFR Mts by allele-specific PCR. TTF-1 status was determined by examining pts' pathology reports and documented as positive, negative or not reported. Pts whose TTF-1 status was not reported were excluded. Sensitivity (sns)/specificity(spc) were estimated with their 95% credible intervals (CI). NPV for a range of prevalences (1%-50%) were estimated using a joint model based on sns, spc and an assumed prevalence using Beta(1,1) priors on both sns and spc. WinBugs was used for fitting the model for NPV and the mean and 95% CI for NPV per prevalence were plotted. Results: Out of the 693 ACs, TTF-1 status was known in 301, and EGFR Mts were present in 224 specimens (74%). Only 2 of the 224 EGFR Mt positive specimens were TTF-1 negative(sns (95% CI); 99.1% (96.8-99.9%) and 28 of the 77 EGFR wild type pts were TTF-1 negative (spc; 36.4% (25.7-48.1%). The prevalence of EGFR Mts in the general population of ACs is between 13%-15%. For true EGFR Mt rates of 13% and 15%, the estimated NPVs (95% CIs) are 99.5% (98.6%-99.9%) and 99.4% (98.4%-99.9%), respectively. The estimated NPV with the 95% CI for a range of prevalences of EGFR Mts and detailed demographic data will be presented at the meeting. Conclusions: ACs of the lung that are TTF-1 negative have a 99% probability of being negative for EGFR Mts and therefore could be initiated on chemotherapy while the results of their EGFR Mt testing is awaited allowing for the earlier initiation of treatment in 30% of pts.
Feasibility study of irinotecan based on UGT1A1 polymorphisms for metastatic colorectal cancer: Interim report.
Authors: Hideya Kashihara, Mitsuo Shimada, Nobuhiro Kurita, Masanori Nishioka, Takashi Iwata, Hirohiko Sato, Shinya Morimoto, Kozo Yoshikawa, Tomohiko Miyatani, Chie Mikami
Journal: Journal of Clinical Oncology (2012)

505 Background: Although Irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Previously, we showed UGT1A1 polymorphisms in Japanese patients (2011 ASCO-GI). Here, we present the interim report of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC. Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 30 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m 2 irinotecan, and homo group was 100mg/m 2 . The incidences of severe toxicities in each gene type of UGT1A1 and the response rate in FOLFIRI therapy were investigated. Results: In Japanese people, UGT1A1*6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). On the 30 patients with advanced CRC treated with FOLFIRI, the genotypes of UGT1A1*28 were homozygous in 1 (3%) and heterozygous in 6 (20%), *6 were homozygous in 0 and heterozygous in 8 (27%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (38%). In *28 heterozygous patients, 1 patient (17%) showed severe toxicities. There was no decrease of irinotecan doses in each group. The number of course to PD was 7.6 (1-23). Regarding the response rate, PR, SD, PD was observed in 2 (7%), 6 (20%) and 18 patients (60%), respectively. Conclusions: In our interim report, the dosages of irinotecan based on UGT1A1 polymorphisms are safety in FOLFIRI therapy.
Patterns of care for non-small cell lung cancer at an academic institution affiliated with a National Cancer Institute–designated cancer center: Beth Israel Deaconess Medical Center.
Authors: K. H. Nguyen, M. Huberman, M. Goldstein, S. Kobayashi, D. B. Costa
Journal: Journal of Clinical Oncology (2011)

e18034 Background: Evidenced-based data and treatment guidelines for non-small-cell lung cancer (NSCLC) exist to improve the quality and effectiveness of care for these cancer patients. However, how often evidence-based decisions are used for care of NSCLC is poorly understood. Methods: We examined the patterns of care and the rate of adherence to evidenced-based treatment guidelines for NSCLC at an academic center's thoracic oncology clinic. Of the 622 cases of lung cancer, 185 new patients with NSCLC seen between 2007 and 2009 were included in the study. Evidenced-based care status was determined in 150 cases. Results: 81% of the patients were Caucasian, the mean age was 66 years, 49% were women, 11% were never smokers, 83% had an ECOG performance status of 0 or 1, 49.7% of the tumors were adenocarcinomas, 18% of tumors were genotyped (EGFR or ALK or KRAS mutations) with the genotyping rate being 57.1% in never smokers, and only 13.3% of patients were treated on a clinical trial. We found that the rate of evidenced-based treatment adherence was 94.1% (16/17), 100% (21/21) and 100% (36/36) in patients with stages I, II and III NSCLC, respectively. Stage IV disease was correlated with a higher rate of non-adherence to treatment guidelines when compared to stages I-III (OR 21.21, 95% CI 3.99-394). For the subset of stage IV NSCLC, the rate of evidenced-based adherence was 95% (72/76) for first line therapy, 95% (38/40) for second line therapy and only 25% (4/16) for third line therapy (p < 0.0001). In all patients, or only the subset of stage IV patients who received at least three lines of therapy, there was no significant correlation between evidenced-based adherence status and the patient's age, sex, ECOG performance status, smoking history, ethnicity, or the treating physician of record. Conclusions: These data indicate the patterns of NSCLC care for a typical academic medical center in the United States, and point towards need for improved evidenced-based use of resources in the third line setting of stage IV NSCLC.
Association of complete pathologic response after neoadjuvant chemoradiotherapy and esophagectomy with overall survival that is independent of the timing of the surgery.
Authors: Smit Singla, Moshim Kukar, Raed Alnaji, William Du, Kristopher Attwood, Steven N. Hochwald
Journal: Journal of Clinical Oncology (2015)

200 Background: Esophagectomy after neoadjuvant chemoradiation (nCRT) is known to improve survival outcomes, however the timing of esophagectomy is not well defined. We sought to determine if delayed esophagectomy after nCRT would result in increased likelihood of complete pathological response (cPR) and improve outcomes. Methods: A single institution analysis of all patients treated with nCRT followed by esophagectomy between 2004 and 2014. Patients were divided into four groups based on the timing of surgery (&lt;50 days &amp; &gt;50 days) and pathological response (complete and incomplete), and the data was analyzed for association with survival outcomes Results: Amongst 227 patients (M: 211, F: 16; median age, 61 years) included in our study, the most common site of tumor origin was distal esophagus (n=210, 92.5%), and the most common histologic subtype was adenocarcinoma (n=205, 90.7%). Barretts esophagus was seen in 119 (52.7%), while signet cells were identified in 52 patients (22.9%) on pathology. Most patients had performance status of ECOG 0 or 1 (n=213, 93.8%), and majority of esophagectomies were performed using an open technique (n=157, 69.2%). Most esophagectomies (77.1% vs 22.9%) were performed &gt;50 days after completion of nCRT. These patients had higher proportional incidence of anastomotic leak (11.4% vs 5.8%, p=0.302), conduit necrosis (3% vs 0%, p=0.591), need for reoperation (16% vs 9.6%, p=0.369), and pulmonary (29.7% vs 21.2%, p=0.290) and cardiac complications (18.9% vs 13.5%, p=0.415), but these increases were not significant. There was no significant difference in overall survival (OS) between the groups (median, 48.9 vs 42.6 months in &lt;50 days and &gt;50 days, respectively; p=0.726); however when evaluated by PR, patients with tumors with a cPR were found to have better OS compared to non-cPR (NR vs 33 months, p&lt;0.001). When survival outcomes were compared between the timing of surgery and PR, the difference was not significant (p=0.211). Conclusions: Patients with cPR after nCRT and esophagectomy have improved overall and progression free survival, however, this is independent of the timing of the surgery.
A phase 1b study of the anticancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) with or without paclitaxel protein bound particles (nab-paclitaxel) in patients with pancreatic cancer.
Authors: Antonio Cubillo Gracian, Michael B. Jameson, Enrique Grande, Prasad Cooray, Francis Parnis, Peter Grimison, Mark Jeffery, Robert J. Stagg, Jakob Dupont, Niall C. Tebbutt
Journal: Journal of Clinical Oncology (2014)

279 Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway. DEM is a humanized IgG 2 anti-DLL4 antibody that inhibits tumor growth and decreases cancer stem cell (CSC) frequency in minimally passaged human xenograft models. In addition, DEM has been shown to have an antiangiogenic effect and showed synergistic activity when combined with GEM and nab-paclitaxel in human pancreatic tumor-derived xenograft models. Methods: Pts with 1 st line stage pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m 2 7 of 8 wks, then 3 of every 4 wks. The primary objective was to determine the MTD of DEM. Other objectives were safety, efficacy, immunogenicity, PK and biomarkers of Notch signaling and CSCs. Results: Twenty four pts were enrolled; 8 received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks &amp; 8 received 5 mg/kg every 4 wks of DEM. Three (12.5%) and 21 (87.5%) pts had stage III and IV disease, respectively. Related AEs (all grades) in &gt; 15% of pts were: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%) and decreased appetite (21%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts. Four of 16 (25%) pts had a RECIST partial response and 7 had stable disease. The median PFS for the 5 mg/kg cohort was 5.9 months. The PK and immunogenicity data will also be presented. Conclusions: DEM plus GEM were generally well tolerated with fatigue, hypertension, and vomiting being the most common drug related AEs. Encouraging early clinical activity was observed. The duration of DEM is being limited to 70 days and nab-paclitaxel is also being given in subsequent cohorts. The first cohort of pts receiving GEM, nab-paclitaxel, and DEM has been enrolled and &gt; 100 days of follow-up on these pts will be presented. Clinical trial information: NCT01189929.
Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association
Authors: Claudia Gebhard, Mohammed Sadeh, Dagmar Glatz, Lucia Schwarzfischer, Rainer Spang, Gerhard Ehninger, Christian Thiede, Reinhard Andreesen, Michael Rehli
Journal: Blood (2010)
Redefining postprostatectomy biochemical progression: The significance of a PSA cutoff below 0.2 ng/ml—Results from two retrospective series with and without salvage radiotherapy.
Authors: Lars Budäus, Jonas Schiffmann, Pierre Tennstedt, Dirk Bottke, Hans Heinzer, Markus Graefen, Lutz Moser, Detlef Bartkowiak, Thomas Wiegel
Journal: Journal of Clinical Oncology (2015)

153 Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is usually defined at a PSA &gt;0.2 ng/ml. BCR may precede clinical progression by years. Though salvage radiotherapy (SRT) is recommend to be initiated at PSA &lt;0.5 ng/ml, its efficiency at PSA &lt;0.2 ng/ml is not well documented. Methods: We relied on two independent post-RP cohorts. Cohort 1 (n=311, Hamburg) comprised men whose post-RP PSA levels had risen to 0.1-0.2 ng/ml. Further biochemical and clinical progression were recorded during follow-up. Cohort 2 (n=198, Berlin) were patients with BCR who received SRT (66/72 Gy) at a PSA &lt;0.5 ng/ml. The median follow-up was 6.9 years. Post-SRT progression and overall survival were addressed by Kaplan-Meier analysis and Cox regression modelling. Results: In cohort 1, 299 (96%) men experienced further PSA progression (&gt;0.2 ng/ml) within a median time of 7 months. Subsequent PSA rise to &gt;0.3, &gt;0.4, and &gt;0.6 ng/ml was recorded in 174 (58%), 123 (41%), and 24 (8%) men, respectively. Twenty-four (8%) men developed metastases. In cohort 2, 112 men received SRT at PSA between 0.03 and 0.2 ng/ml, and 86 at 0.2-0.499 ng/ml. The latter group, had a poorer 10-years BCR-free Kaplan-Meier rate, 43% vs. 66% (p=0.051). Together with pT&lt;3, Gleason Score &lt;7, and post-RP PSA &lt;0.03 ng/ml, SRT at PSA &lt;0.2 ng/ml was an independent favorable predictor of freedom from BCR (OR=0.60, p&lt;0.05). Ultimately, 14 patients died. However, overall survival did not significantly correlate with the pre-SRT PSA. Conclusions: The vast majority of patients with a PSA &gt;0.1 ng/ml after RP will subsequently progress to PSA &gt;0.2 ng/ml. Improved progression free survival can be achieved, if SRT is administered at a PSA &lt;0.2 ng/ml. Therefore the contemporary PSA threshold for defining BCR after RP needs to be reconsidered and early sRT should be contemplated on a individual basis for optimizing oncological outcomes.
Relationship of CYP2D6 status and toremifene metabolism.
Authors: J. Kim, J. T. Dalton, K. A. Veverka
Journal: Journal of Clinical Oncology (2011)

e13068 Background: Tamoxifen (TAM) is widely used as endocrine therapy for estrogen receptor (ER) positive breast cancer despite a growing controversy regarding its effectiveness in patients with compromised cytochrome P450 2D6 (CYP2D6) activity. Since it is metabolized to active metabolites via CYP2D6, legitimate concerns have been raised over concurrent use of TAM and drugs that are potent inhibitors of CYP2D6 (e.g., SSRI antidepressants). Toremifene (TOR) is a structural analog of TAM that is approved for the treatment of metastatic breast cancer in postmenopausal women with ER positive or unknown tumors. TOR is primarily metabolized by CYP3A4, while CYP2D6 is thought to play a minor role in its metabolism. We examined the role of individual CYP isoforms in the metabolism of TOR and TAM to N-desmethyl (NDM), 4-hydroxy (4-OH) and 4-OH-N-desmethyl (4-OH-NDM) metabolites. Methods: The in vitro metabolism of TOR and TAM was investigated using human liver microsomes and recombinant CYP proteins. Samples were analyzed by LC-MS/MS. Results: N-demethylation is the primary metabolic pathway for both TOR and TAM. Similar levels of N-desmethyl metabolites were formed for both compounds. N-demethylation occurred by CYP2D6, 3A4 and 1A1 but not appreciably by the other six CYP isoforms tested. Specific inhibitors of CYP2D6 and 3A4 activity blocked N-demethylation. The 4‐OH and 4-OH-NDM metabolites of TAM, but not TOR, were observed when the parent drugs were incubated with the CYP2D6 isoenzyme. The formation of both 4-OH-tamoxifen and 4-OH-NDM-tamoxifen (endoxifen) were significantly inhibited by 2D6 inhibitors, including the SSRI antidepressant paroxetine. These results were corroborated by studies using human liver microsomes from poor, intermediate and extensive CYP2D6 metabolizers. Conclusions: Tamoxifen, but not toremifene, is a substrate for 4-hydroxylation by CYP2D6 in human liver microsomes. The metabolism of toremifene is not markedly affected by potent CYP2D6 inhibitors in human liver microsomes. These results suggest that clinical benefit in subjects taking toremifene to treat metastatic breast cancer would not be subject to allelic variation in CYP2D6 status or affected by co-administration of CYP2D6-inhibiting medications.
Prognostic Impact of Interim and Final PET in Primary Mediastinal Large B-Cell Lymphoma Treated with Intensive Etoposide-Based Therapy
Authors: Vít Procházka, Lenka Henzlová, Eva Buriánková, Zuzana Prouzová, Ale Obr, Martin Novák, Jiří Minařík, Karel Indrák, Tomá Papajík
Journal: Blood (2014)