tbuckley/cabot-search huggingface dataset:
Correlation of hypertension and proteinuria with outcomes in elderly bevacizumab (BEV)-treated patients with metastatic colorectal cancer (mCRC): Analysis of the BECOX and BECA studies.
Authors: Antonieta Salud Salvia, Jaime Feliu, Maria Jose Safont, Carlos García-Girón, Jorge Aparicio, Ferran Losa, Carlos Bosch, Pilar Escudero, Enrique Casado, Mónica Jorge Fernández, Uriel Bohn Sarmiento, Ramon Pérez-Carrión, Alberto Carmona Bayonas, Ana B. Custodio, Juan Maurel
Journal: Journal of Clinical Oncology (2013)

3589 Background: Studies suggest a relationship between hypertension, which is common in older patients, and outcome in BEV-treated patients with mCRC. We performed a retrospective analysis of two studies – BECA [Feliu et al BJC 2010; EudraCT 2005-002808-42] and BECOX [NCT01067053] – to determine if hypertension and proteinuria predict outcome in elderly BEV-treated patients. Methods: Patients ≥70 years received capecitabine 1250 mg/m 2 bid po on days 1–14 + BEV 7.5 mg/kg on day 1 every 21 days in the BECA study; BECOX patients received capecitabine 1000 mg/m 2 bid po on days 1–14 with BEV 7.5 mg/kg and oxaliplatin 130 mg/m 2 on day 1 (oxaliplatin discontinued after cycle 6). Primary endpoints were overall response rate (ORR) in BECA and time to progression (TTP) in BECOX. Correlations were investigated for hypertension and proteinuria with ORR, disease control rate (DCR), overall survival (OS) and TTP. Logistic regression was performed to identify factors associated with hypertension and proteinuria. Results: 127 patients were included (BECA n=59; BECOX n=68; 61% male, median age 76 years; ECOG PS 0/1/2 45%/52%/2%). During the study 16% of patients had hypertension and 61% had proteinuria as an adverse event. Hypertension correlated with DCR, OS and TTP but not ORR; proteinuria correlated with ORR and DCR (Table). Development of proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors associated with development of hypertension were female gender (odds ratio [OR] 0.241; p=0.011) and greater no. of BEV cycles (OR 1.112; p=0.002); factors associated with proteinuria were diabetes (OR 3.869; p=0.006) and greater no. of BEV cycles (OR 1.181; p&lt;0.0001). Conclusions: This analysis of the BECOX and BECA studies suggests that hypertension and proteinuria are associated with outcome in BEV-treated elderly patients with mCRC. Clinical trial information: NCT01067053. [Table: see text]
Does metformin use affect transporter, hormone receptor and mTOR pathway target expression in endometrial cancers of women with Type II diabetes mellitus?
Authors: Dario R. Roque, A. Mitch Dizon, Brooke S. Rambally, Siobhan O'Connor, Paola A. Gehrig, Sheri Denslow, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2015)

5594 Background: Metformin, has been found to decrease proliferation and inhibit downstream targets of the mTOR pathway in a phase 0 trial in endometrial cancer (EC) patients. Given this, we aimed to determine molecular differences between ECs from patients with Type II diabetes (T2DM) taking metformin versus those not on metformin. Methods: Patients with T2DM who underwent surgical staging for EC were divided into two cohorts based on whether or not they were on metformin. The use of insulin and other anti-diabetic agents was recorded. Tissue microarrays (triplicate cores) were constructed from formalin-fixed, paraffin-embedded hysterectomy specimens. Expression of the estrogen receptor (ER), progesterone receptor (PR), PTEN, LKB1, phosphorylated (p)-AKT, p-4EBP-1, p-S6, p-insulin growth factor-1 receptor (pIGF1R), p-insulin receptor substrate-1 (P-IRS1), PMAT, MATE1 and MATE2 was measured by immunohistochemistry. Results: Of 162 EC patients with T2DM, 102 (63%) were taking metformin and 60 (37%) were not on metformin. There was no significant difference in tumor stage, grade or histology between the two groups. Expression of transporters, hormone receptors, and mTOR pathway targets was similar between the two groups. However, when adjusting for age, BMI, race, tumor grade and stage, there was a trend towards decreased p-AKT expression in metformin users (0.7, 95% CI 0.4-1.1). In addition, BMI > 30 was associated with increased expression of p-S6 (2.8, 95% CI 1.2-6.7) and a trend towards higher p-4EBP-1 expression (2.0, 95% CI 1.0-4.1). Conclusions: We did not find a strong relationship between metformin use and transporters, hormone receptors or mTOR pathway targets in EC patients with T2DM. However, metformin use trended towards decreased p-AKT expression, which is consistent with its ability to inhibit the mTOR pathway. Obesity is known to activate the mTOR pathway, and was associated with increased expression of p-S6 and p-4EBP-1 in ECs. Further studies should focus on identifying molecular biomarkers in patients with T2DM that may predict response to metformin as an anti-tumorigenic agent.
A nomogram to individually predict the presence of chemotherapy-induced nausea and vomiting (CINV) in cancer patients.
Authors: Zhihuang Hu, Wenhua Liang, Li Zhang, Yuxiang Ma, Likun Chen, Yan Huang, Hongyun Zhao, Ting Zhou, Wenfeng Fang
Journal: Journal of Clinical Oncology (2014)

e20680 Background: Chemotherapy-induced nausea and vomiting (CINV) remains one common side effect of cancer treatment, whose presence depends on multiple factors. Prophylactic management of CINV is far more important than the rescue therapy after it happens. Here, we aimed to build a model-based nomogram to predict the individual probability of CINV, which is crucial to guide treatment decisions regarding the use of antiemetic. Methods: Patients from eight clinical trials of antiemetic agents in China from 1985 to 2013 were used to screen eligible subjects, who should have received highly, moderately, or lowly emetogenic chemotherapy (HEC/MEC/LEC) and be evaluable for the outcome of CINV. Complete response during overall phase (0~120 hours after chemotherapy) was used to assess the efficacy of antiemetics. Information on demographics, performance status (PS), alcohol use, motion sickness, history of pregnancy vomiting (PV), antiemetic regimen and other potential risk factors of CINV were examined. Multivariate logistic regression model were used to identify significant variables and integrate them into the nomogram. Bootstraps with 1000 resample were used for calibration and calculating the concordance index (C-index). Results: A total of 993 patients were eligible for analysis. Sex/PV group (male/ female without PV history/female with PV history, P<0.001), age (P=0.059), emetogenic level of chemotherapy (HEC/MEC/LEC, P<0.001), and antiemetic regimen (Metoclopramide/5HT3RA/ 5HT3RA+ DXM/5HT3RA+ DXM+ NK-1RA, P<0.001) were independent factors in multivariate model and were built into the nomogram. The C-index of the nomogram was 0.71 (0.68, 0.74), which was higher than any prediction using single factor above (Sex/PV group 0.56, age 0.54, emetogenic level 0.54, antiemetic regimen 0.62). Alcohol use failed to enter the model due to much value missing (59.2%), although it was an independent factor of CINV in patients with this information (P=0.046). Conclusions: Factors of female, pregnancy vomiting history, age, emetogenic level of chemotherapy and earlier antiemetic regimen indicated high risk of CINV presence. A nomogram could optimize the prediction and patient stratification.
NRAS and KRAS testing by a new diagnostic method to detect point mutations in colorectal cancer specimens: Clart-NRAS iKRAS.
Authors: Maria Luisa Villahermosa, Juan Moscoso del Prado, Nuria Manjon, Ana Isabel Moraga, Maria Jesus Sanz, Javier Hernandez-Losa, Javier Gomez-Roman, Jesper Bonde, Jose Luis Rodriguez-Peralto, Rosario Cospedal
Journal: Journal of Clinical Oncology (2014)

e22159 Background: RAS family mutation status is an important potential clinical variable for treatment visitation in metastatic colon cancer (mCRC). Around 40% of colorectal tumors carry mutations in KRAS exon 2 (codons 12 and 13) which is a negative predictor of response to anti-EGFR therapies. Recent studies extend the range of mutations to include KRAS exons 3 and 4 or NRAS exons 2, 3 as negative response outcome predictors to anti-EGFR-containing therapy. Here, we present a novel diagnostic assay based upon multiplex ARMS-PCR and microarray detection system (CLART technology) to identify infrequent KRAS and NRAS mutations in formalin fixed paraffin embedded CRC specimens. Methods: We designed specific ARMS-primers and hybridization probes for detecting Q61H (183 A>C), K117N (351 A>C), K117N (351 A>T), A146T and A146V mutations in KRAS; and G12D, Q61H (183 A>T), Q61L, Q61N and Q61R mutations in NRAS. Clinical testing was performed using 33 clinical samples which contained the targets of this assay. Moreover, clinical specimens with wild type alleles and with known mutations in KRAS (codons 12, 13) and BRAF were tested to show that no cross reactivity to these targets were detected. The results were cross checked by comparison to Sanger sequencing methodology. Results: Analytical sensitivity was done using recombinant plasmids, results ranged between 100 - 1000 copies/µl for all point mutations excepting three of them (KRAS Q61H -183 A>C-, KRAS K117N -351 A>T- and NRAS Q61L) that were 10000 copies /µl. NRAS Q61R, Q61L, Q61H, Q61L and KRAS A146T mutations were analyzed using specific cell lines, the sensitivity was between 1-5ng. Diagnostic Sensitivity and Specificity data was over 90% and 98% for all mutations respectively. Concordance between present assay and Sanger sequencing were ≥95%. Conclusions: CLART NRAS iKRAS simultaneously detects the most prevalent mutations of NRAS and infrequent KRAS mutations with sensitivity and reproducibility ≥95%, being capable of detecting mutations in samples with less than 5% mutated alleles. Our data supports the use of this technology for clinical testing prior to anti-EGFR treatment, for both KRAS and NRAS status in human colorectal cancer samples.
DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis
Authors: Felix Sahm, Daniel Schrimpf, Damian Stichel, David T W Jones, Thomas Hielscher, Sebastian Schefzyk, Konstantin Okonechnikov, Christian Koelsche, David E Reuss, David Capper, Dominik Sturm, Hans-Georg Wirsching, Anna Sophie Berghoff, Peter Baumgarten, Annekathrin Kratz, Kristin Huang, Annika K Wefers, Volker Hovestadt, Martin Sill, Hayley P Ellis, Kathreena M Kurian, Ali Fuat Okuducu, Christine Jungk, Katharina Drueschler, Matthias Schick, Melanie Bewerunge-Hudler, Christian Mawrin, Marcel Seiz-Rosenhagen, Ralf Ketter, Matthias Simon, Manfred Westphal, Katrin Lamszus, Albert Becker, Arend Koch, Jens Schittenhelm, Elisabeth J Rushing, V Peter Collins, Stefanie Brehmer, Lukas Chavez, Michael Platten, Daniel Hänggi, Andreas Unterberg, Werner Paulus, Wolfgang Wick, Stefan M Pfister, Michel Mittelbronn, Matthias Preusser, Christel Herold-Mende, Michael Weller, Andreas von Deimling
Journal: The Lancet Oncology (2017)
Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): Final results of the TAMRAD trial translational study.
Authors: Isabelle Treilleux, Monica Arnedos, Claire Cropet, Jean-Marc Ferrero, Sophie Abadie Lacourtoisie, Dominique Spaeth, Christelle Levy, Eric Legouffe, Eric Pujade-Lauraine, Quing WANG, Thomas Bachelot
Journal: Journal of Clinical Oncology (2013)

510 Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR+ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM+E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM+E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n=12, HR=0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n= 28, HR=0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n=22, HR=0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n=25, HR=0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n=27, HR=0.37; 95%CI 0.15-0.90) or low 4EBP1 (n=21, HR=0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.
Phase II trial of the combination of subcutaneous bortezomib (Bortez) and pegylated liposomal doxorubicin (PLD) for the treatment of patients with acute myelogenous leukemia (AML).
Authors: Ben Kent Tomlinson, Joseph M. Tuscano, Mehrdad Abedi, Jeanna Welborn, Robert O'Donnell, Mili Arora, Radha Verman, Kelly Jones, Brian Andrew Jonas
Journal: Journal of Clinical Oncology (2015)

7081 Background: The proteasome inhibitor Bortez has activity in AML, both as a single agent and in combination with standard induction. Bortez inhibits NF-κB signaling, and NF-κB activity promotes anthracycline resistance. The combination of Bortez and PLD was well tolerated in trials for multiple myeloma. Methods: We performed a phase II trial of Bortez and PLD in subjects at least 18 years old with relapsed/refractory AML or treatment naïve AML unfit for or who refused standard therapy. Bortez 1.5mg/m2 was given subcutaneously on days 1, 4, 8, and 11, and PLD 40mg/m2was given IV on day 4. Cycles were 21 days long. The primary endpoint was objective response rate (ORR), defined as complete remission (CR) plus partial remission (PR). Results: Fifteen subjects (53% male) were enrolled. Median age was 70 years (range 32-83). Four had relapsed, five had refractory, and six had untreated AML. Subjects had a median of two prior lines of therapy (range 0-7), including two with prior allogeneic transplantation. No subjects achieved a CR and three achieved a PR for an ORR of 20%. Two of the subjects achieving PR were treatment naïve. There were 12 patients that did not meet response criteria, and all three subjects with a PR progressed after cycle 2. The median number of completed cycles was 1 (range 0-2). Of 14 subjects with circulating blasts, eleven (79%) had a decrease in circulating blasts after the first cycle. Four subjects died from disease-related complications during cycle 1. The most common grade 3-4 adverse events were hematologic and infectious, occurring in 93% and 60% of subjects respectively. Two subjects (13%) had grade 3 peripheral sensory neuropathy. Conclusions: The combination of Bortez and PLD demonstrates modest anti-AML activity in a cohort of AML patients that includes heavily pretreated patients. The combination was well tolerated. Given the modest response rate and short duration of response, outcomes could be improved with modification of the current dosing schedule and/or inclusion of additional agent(s). Responses seen in older treatment naïve subjects suggest that this regimen should be studied further in this patient population. Clinical trial information: NCT01736943.
Excellent long-term control in locoregionally recurrent radioactive iodine-refractory papillary thyroid cancer with the addition of external beam radiation therapy to maximal surgical resection.
Authors: William A. Wilson, Joseph Valentino, Thomas Gal, David Sloan, Kenneth B. Ain, Susanne M. Arnold, Yolanda Brill, Mahesh R. Kudrimoti
Journal: Journal of Clinical Oncology (2012)

e16035 Background: Locoregionally recurrent radioactive iodine (RAI) refractory papillary thyroid cancer represents a small percentage of papillary thyroid cancers but is an aggressive disease with significantly lower survival rates. This retrospective review is our experience with these cancers treated with maximal surgical resection followed by external beam radiotherapy. Methods: 26 patients treated from 2001-2011 were eligible for review. After obtaining IRB approval, medical records were reviewed for clinical outcome. All patients had histologically proven recurrences that were negative on I-131 scans. All patients were maximally resected. All patients received external radiotherapy to the thyroid bed, bilateral cervical lymph node levels II-IV, level VI, and superior mediastinal nodes. 15/26 patients received intensity modulated, 9/26 patients received 3-D conformal, and 2/26 patients received Tomotherapy radiation treatment. The mean dose was 5790 cGy (range 5280-6800 cGy). Results: All histologies were papillary thyroid cancer with 4/26 exhibiting tall cell features and 1/26 diffuse sclerosing features. All patients had locoregional relapse in the cervical nodes (16/26) or in the mediastinum (5/26) or both areas (5/26). The mean pre-treatment thyroglobulin was 5.2 (range &lt;0.1 to 599.1). The mean post-treatment thyroglobulin was 1.0 (range &lt;0.1-5.2). Median follow-up was 55 months (range 7-123 months). 0/26 patients failed locoregionally. 2/26 patients failed distantly (lungs). 20/26 patients (77%) of patients had undetectable thyroglobulin at last follow-up. 4/26 patients had detectable thyroglobulin (2.5-16.9), but had not recurred on imaging. 2/26 required PEG placement during treatment, but 0/26 patients were PEG-dependent on long-term follow-up. 1/26 patients experienced grade III osteoradionecrosis of the mandible. Conclusions: External beam radiotherapy provides excellent locoregional control for locoregionally recurrent radioactive iodine-refractory papillary thyroid cancers. Long-term grade III and IV toxicities are uncommon.
Single-nucleotide polymorphism (SNP) of excision repair cross complementation group 1 (ERCC1) in nasopharynx cancer (NPC): A companion biomarker study to Hong Kong NPC Study Group 0502 trial.
Authors: Edwin Pun Hui, Brigette Ma, KC Allen Chan, Charles ML Chan, Cesar SC Wong, Ka Fai To, Anthony WH Chan, Stewart Yuk Tung, Wai Tong Ng, Ashley Chi Kin Cheng, Victor HF Lee, Stephen Lam Chan, Herbert H. F. Loong, Michael KM Kam, Sing Fai Leung, Rosalie Ho, Frankie Mo, YM Dennis Lo, Roger K.C. Ngan, Anthony T. C. Chan
Journal: Journal of Clinical Oncology (2014)

6029 Background: Polymorphisms at ERCC1 has been linked to platinum sensitivity and treatment outcome. We hypothesized that ERCC1 SNP at codon 118 and C8092A is predictive of relapse free survival (RFS) in NPC, and correlates with ERCC1 protein/mRNA in paired tumor samples. Methods: 0502 is a multi-center prospective clinical trial to assess adjuvant chemotherapy in NPC pts with detectable plasma EBV-DNA (pEBV) following primary radiotherapy (RT) or cisplatin-RT (CRT) (NCT00370890). Eligible pts with biopsy proven NPC, AJCC stage IIB-IVB, no persistent locoregional disease or distant metastasis, ECOG 0-1, adequate organ function, were screened by pEBV at 6-8 weeks after completing RT/CRT. Post-RT pEBV -ve pts received no further treatment. pEBV +ve pts underwent work-up and randomization to adjuvant chemotherapy or observation. We tested our hypothesis using samples collected in the 0502 screening cohort. Primary endpoint is relapse free survival (RFS). ERCC1 genotyping was by TaqMan real time PCR. 450 pts is planned to detect a hazard ratio (HR) of 1.5 for the weaker ERCC1 SNP at 80% power and 2-side 5% alpha level. In subset with available tumor biopsies, we quantified ERCC1 protein expression by immunohistochemistry (IHC) or Western blot (WB) with mouse monoclonal antibody (clone 8F1), and ERCC1 mRNA by quantitative RT-PCR. Results: ERCC1 SNP was analyzed in peripheral blood lymphocytes from 478 pts. Median follow up was 3.61 years (90% C.I. 3.36-3.88). 31% pEBV +ve, 17% randomized. ERCC1 genotype distribution at codon 118: 54% CC, 39% CT, 7% TT; C8092A: 38% CC, 50% CA, 12% AA. There was no significant association of ERCC1 SNP with 3-year RFS or overall survival. No significant correlation was observed in ERCC1 SNP and tumor ERCC1 expression by IHC, WB or mRNA. In subset evaluated by ERCC1 IHC (n=79), pts with ERCC1+ve tumor (H-score > median) had worse RFS (HR 2.34, 95% C.I. 1.06-5.16, p=0.036). Multivariate analysis showed pEBV was the most significant adverse prognosticator for all clinical endpoints. Conclusions: We found no association of ERCC1 SNP with NPC survival. pEBV remained the most significant prognostic biomarker in NPC.
Gastric cancer: Clinical differences among Hispanic and non-Hispanic whites at the John Theurer Cancer Center (JTCC), Hackensack University Medical Center.
Authors: Narjust Perez-Florez, Larysa Jessica Gromko, Andrew Jennis, Zubin M. Bamboat, Donald A. McCain, Martin Gutierrez
Journal: Journal of Clinical Oncology (2014)

1613 Background: Gastric cancer is a leading cause of cancer death worldwide and has significant geographical, ethnic, and socioeconomic differences in distribution. The aim of this study was to compare clinicopathological characteristics and survival between Hispanics and non-Hispanic whites with gastric cancer. Methods: We reviewed the records of all patients diagnosed with gastric cancer between January 1999 and March 2013 at the JTCC. A total of 638 patients were studied. Demographics, histology, anatomic site, recurrence and survival rate among both Hispanics and non-Hispanic whites were analyzed. Chi-square test was used to estimate differences in categorical data; Kaplan-Meier and Wilcoxon methods were used for the survival analysis. Results: There were 101 Hispanics (H) and 537 non-Hispanic whites (NHW). The mean age at diagnosis was 63 years (21-88) in H and 69 years (39-95) in NHW. A significant difference in age at diagnosis was found in the Stage IV subgroup, with a mean of 54 years for H and 67 years for NHW. At diagnosis, 48 (47.5%) of H patients had stage IV disease compared with 195 (36.3%) of NHW (p<0.003). H were more likely to have distal cancers and poorly differentiated tumors compared to NHW (43.8% vs. 15.4%, p<0.0001; 70.8% vs. 50.1%, p<0.0001, respectively). H had a higher recurrence rate than NHW (17.8% vs 8.7%, p<0.003). There was a significant difference in median survival between the two groups, being 51 months for H (95% CI: 34.6-66.9) and 99 months for NHW (95% CI: 77.3-120.7) p<0.0001. Gastric cancer was the primary cause of death in 66.2% of H vs. 33.0% of NHW (p<0.0001). From the entire cohort, 17.8% of H vs. 33.0% of NHW were free of disease at the time of death (p<0.007). Conclusions: In our cohort, Hispanic patients were diagnosed with gastric cancer at a younger age, were more likely to have distally located and poorly differentiated tumors, to present with advanced disease at diagnosis, and had shorter overall survival when compared to non-Hispanic whites. Further research should aim to elucidate the basis of these differences, as this could potentially impact management and improve survival.