tbuckley/cabot-search huggingface dataset:
Genetic variants of kinases suppressors of Ras (KSR) to predict tumor response to first-line cetuximab in patients with mCRC: Prospective analysis in the FIRE 3 trial.
Authors: Leonor Benhaim, Wu Zhang, Takeru Wakatsuki, Armin Gerger, Dongyun Yang, David Paez, Yan Ning, Rita Elie El-Khoueiry, Fotios Loupakis, Pierre Oliver Bohanes, Sebastian Stintzing, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2015)

3613 Background: Activation of EGFR pathway in RAS-BRAF wild-type models can be modulated by scaffold proteins kinase suppressor of ras (KSRs) that binds RAS promoting ERK activation. We previously showed in patients with KRAS-BRAF wild-type tumor treated with FOLFIRI-cetuximab that KSR2 rs11068551 TT was associated to significantly longer PFS. On the other hand, among female patients treated with FOLFIRI-bevacizumab the KSR1 rs2241906 CC genotype was associated to significantly shorter PFS. We aimed at validate our finding by investigating the correlation between KSR variants and clinical outcomes in patients enrolled in the FIRE 3 trial. Methods: Genomic DNA was isolated from tissue samples of 592 patients with KRAS exon 2 wild-type enrolled in the randomized phase III, FIRE 3 trial that was designed to compared the efficacy of two targeted agents when associated to FOLFIRI regimen. Patients were randomly assigned to first-line FOLFIRI associated with either bevacizumab (n = 295) or cetuximab (n = 297) (NCT00433927). In both arms, DNA was amplified by PCR and KSR variants were detected by direct sequencing. Results: We confirmed prospectively that KSR2 rs11068551 could predict outcomes in patients receiving cetuximab. 1/Patients with the TT genotype (n = 40) demonstrated a significant lower response rate than patients carrying C (n = 133) in the cetuximab arm (55% vs. 77%, p= 0.008). 2/ Patients with left-sided tumors and TT genotype (n = 32) showed a significant longer PFS (12.9 vs. 10.2 months, log rank p = 0.049) than patients harboring any of the C allele (n = 128) in the cetuximab arm. 3/ No association between KSR2 rs11068551 and outcomes was seen in the bevacizumab arm. We did not confirm the relation between KSR1 rs2241906 and outcomes (response rate, PFS or OS) even when adjusted with gender and location. Conclusions: We prospectively validated the predictive value of KSR2 rs11068551 mCRC pts treated with first-line cetuximab-containing therapy. This predictive value may dependent on tumor location. We could not confirm the predictive value of KSR1 rs2241906 in patients receiving bevacizumab-containing treatment.
Clinical and molecular features associated with long-term survival of elderly patients with glioblastoma.
Authors: Michael Weller, Martin Sill, Bettina Hentschel, Joerg Felsberg, David T. W. Jones, Dorothee Gramatzki, Kerstin Kaulich, Caroline Happold, Joerg Tonn, Ulrich Herrlinger, Gabriele Schackert, Manfred Westphal, David Capper, Rajiv Kumar, Kari Hemminki, Torsten Pietsch, Markus Loeffler, Stefan M. Pfister, Andreas von Deimling, Guido Reifenberger
Journal: Journal of Clinical Oncology (2017)

2013 Background: Glioblastomas in elderly patients are associated with particularly poor outcome, with only few patients demonstrating long-term survival (LTS). Methods: To better characterize clinical and molecular correlates of LTS in elderly glioblastoma patients, we searched the German Glioma Network (GGN) database for patients aged 71 years or more with histological confirmation of glioblastoma and survival of at least two years after diagnosis. Results: Of 2071 glioblastoma patients enrolled in the GGN from 2004-2012, 425 patients were aged 71 years or more; of these, 27 patients (6.4%) survived for 2 years or more (median survival: 37.1 months, 95% confidence interval: 30.0-44.2 months). A comparison of these 27 patients with the 398 patients who survived shorter than 2 years (median survival: 6.2, 95% confidence interval: 5.2-7.2 months) revealed more intensive up-front treatment and a trend towards higher initial Karnofsky performance score as distinguishing clinical factors. Molecular analyses additionally showed more frequent O 6 -methylguanine-DNA methyltransferase ( MGMT) promoter methylation in the LTS patients. Isocitrate dehydrogenase (IDH) mutation was restricted to single patients and the frequency of telomerase reverse transcriptase ( TERT) promoter mutation did not differ between groups. Genome-wide DNA copy number and methylation profiling using 450k microarray analysis performed for 16 LTS patients and 40 control patients revealed limited differential DNA methylation and no specific copy number profiles linked to LTS. Conclusions: Collectively, our findings confirm that LTS is rare in elderly patients with glioblastoma and that clinical and tumor-associated molecular factors linked to LTS resemble those in standard age patients, except for less common IDH mutation.
Margaret McCartney: To the best of humankind, thank you
Authors: Margaret McCartney
Journal: BMJ (2017)

Barra is a tiny outer island of Scotland, a slight comma falling off the end of the landscape of the Outer Hebrides. Its runway is a white stretch of beach, embraced by the sea. The body of 14 year old Eilidh MacLeod was flown onto it, back to her home, after she was murdered in the recent terrorist attack in Manchester. With great dignity and to a pipers’ lament, her friends and family received her body and took her to be buried. It is entirely, utterly, heartbreaking.

And then, Grenfell Tower. Dozens of people killed in a fire in “an accident waiting to happen,” as residents predicted.1 I write this as a minority government now assembles a ragbag non-coalition, in chaos. It’s hard to know how …
Mir Expression Profile of Peripheral Blood Lymphocytes Predicts Relapse in Pediatric Acute Lymphoblastic Leukemia
Authors: Smadar Avigad, Keren Shichrur, Sara Elitzur, Gil Gilad, Shlomit Barzilai, Galia Avrahami, Nir Dotan, Jennifer Yarden, Isaac Yaniv
Journal: Blood (2016)
Outbreak of Salmonella Weltevreden infections in Norway, Denmark and Finland associated with alfalfa sprouts
Authors: K. E. Emberland, S. Ethelberg, M. Kuusi, L. Vold, L. Jensvoll, B. A. Lindstedt, K. Nygard, C. Kjelsø, M. Torpdahl, Gitte Sørensen, T. Jensen, S. Lukinmaa, T. Niskanen, G. Kapperud
Journal: Eurosurveillance (2007)
Prévalence et signification pronostique des lésions jéjunales détectées par vidéocapsule dans la maladie de Crohn
Authors: C Trang, M Flamant, M Le Rhun, S Sacher-Huvelin, O Maillard, JP Galmiche, A Bourreille
Journal: Endoscopy (2009)

Introduction: La vidéocapsule (VCE) permet de voir l'ensemble de l'intestin grêle et d'analyser les lésions endoscopiques au cours de la maladie de Crohn (MC). Aucune donnée n'est disponible concernant spécifiquement les localisations jéjunales des lésions chez les patients atteints de MC.
Investigating novel resistance mechanisms to third generation EGFR TKI osimertinib in non-small cell lung cancer patients using next generation sequencing.
Authors: Qiuxiang Ou, Xue Wu, Hua Bao, Xiaoling Tong, Xiaonan Wang, Xian Zhang, Zhili Chang, Yu Mao, Yang Shao, Caicun Zhou
Journal: Journal of Clinical Oncology (2017)

2572 Background: Third generation epithelial growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has proven effective in Non-small cell lung cancer (NSCLC) patients who have developed EGFR T790M-mediated resistance to other EGFR TKIs. Unfortunately, a majority of patients still undergo progressed disease after receiving osimertinib treatment. Acquired EGFR C797S mutation has been identified as one major mechanism; however, resistance mechanisms of remaining cases are still largely unknown. Methods: Using next generation sequencing (NGS) targeting 416 cancer-relevant genes, we analyzed the mutation profiles of 99 NSCLC patients that were clinically resistant to osimertinib. Results: In addition to the notable EGFR C797 variants (22%), L792 mutations were identified in 10% of patients, and a further 7% cases carry L718 mutations. Further analysis of 14 patients with paired pre-treatment samples confirmed that these EGFR mutations were acquired during treatment. Interestingly, all L792 mutations are in cis with T790M and in trans with C797 mutations (when present in the same patient). 2 out of 10 L792-positive patients and 6 out of 7 L718-positive patients did not have co-existing C797 mutations, suggesting C797-, L792- and L718-mutated cells may represent different resistant clones. In vitro experiments demonstrated that L792 and L718 mutants also increase osimertinib IC50, and therefore confer their resistance. Besides secondary EGFR mutations, alterations in other key genes such as MET, KRAS, ERBB2 and PIK3CA may also contribute to osimertinib resistance. Notably, MET and KRAS amplifications are present only in patients without above EGFR secondary mutations. Conclusions: In this study, we identified secondary mutations on C797, L792 or L718 residues of EGFR in 29% of osimertinib-resistant patients. Combined with in vitro study, our data strongly suggest that L792 and L718 mutations are likely to alternatively cause osimertinib resistance. Furthermore, MET and KRAS amplification may serve as bypass resistance mechanisms in patients who are EGFR C797-, L792- and L718-wild type.
Differential effects of bevacizumab on the risk of hand-foot syndrome associated with cytotoxic chemotherapy: An updated meta-analysis.
Authors: Arun Gopal, Ronald A. Flores, Mario E. Lacouture, Shenhong Wu
Journal: Journal of Clinical Oncology (2013)

9622 Background: Hand-foot syndrome (HFS) is a dose-limiting toxicity of many chemotherapeutic agents. In a prior meta-analysis of published randomized-controlled clinical trials (RCTs) we showed that the risk of HFS increased significantly with the use of bevacizumab, an angiogenesis inhibitor that is widely used for the treatment of many cancers. In this study, we have included more recent trials and updated our findings. Methods: Databases from PUBMED, Cochrane Database, and abstracts presented at the American Society of Clinical Oncology until December, 2012 were searched for the identification of relevant studies. Eligible studies included prospective RCTs in which the addition of bevacizumab to chemotherapy was compared directly to chemotherapy alone in cancer patients. Relative risk (RR), and 95% confidence interval (CI) were calculated using a fixed- or random-effects model based on the heterogeneity of the studies. Results: A total of eight RCTs including 8,150 patients (bevacizumab 4211, control 3939) with a variety of tumors were analyzed. The summary incidence of HFS was 14.3% (95% CI: 4.8-36.0%). The addition of bevacizumab to chemotherapy did not significantly increase the risk of developing all-grade (RR: 1.17, 95% CI: 0.90-1.51, P=0.240) and high-grade HFS (RR: 1.50, 95% CI: 0.92-2.47, P=0.11) as opposed to chemotherapy alone. The risk of HFS did not vary significantly with tumor types (P=0.21) and bevacizumab dose (P=0.28). However, the risk of HFS varied significantly with concurrent chemotherapeutic agents (P=0.004). Bevacizumab significantly increased the risk for 5-FU based agents (RR 1.2, 95% CI 1.08-1.33, P=0.001) but decreased the risk for non-5-FU based agents (RR 0.63, 95% CI: 0.41-0.96, P=0.03). Conclusions: Bevacizumab may enhance or reduce the risk of HFS depending on particular chemotherapeutic agents used in cancer patients. These findings are of importance to direct supportive care efforts.
Initial phase 1 study of WT2725 dosing emulsion in patients with advanced malignancies.
Authors: Siqing Fu, D. E. Piccioni, Hongtao Liu, Rimas Vincas Lukas, Dawit Aregawi, Kenichiro Yamaguchi, Kate Whicher, Yu-Luan Chen, Nagaraju Poola, John Eddy, Ian Zhang, David Blum
Journal: Journal of Clinical Oncology (2017)

2066 Background: WT2725 is a Wilms’ tumor (WT1)-derived-oligopeptide vaccine intended to induce WT1 specific cytotoxic T-lymphocytes against WT1 positive tumors in HLA-A*0201+ or HLA-A*0206+. This first in human study of WT2725 was conducted to evaluate the safety, tolerability, and efficacy. Methods: Subjects with progressive or recurrent glioblastoma (GBM), acute myeloid leukemia (AML) (patients in morphologic remission with minimal residual disease determined by WT1 RT-PCR were allowed), non-small cell lung cancer (NSCLC), or ovarian cancer despite standard therapy were treated with 0.3, 0.9, 3, and 9 mg of WT2725 subcutaneously (s.c.) every week for 4 weeks, then every other week for 6 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 1); and with 18 mg and 27 mg of WT2725 s.c. every week for 8 weeks, then every other week for 10 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 2). Responses were evaluated by Immune-related Response Criteria (irRC) for solid tumors and modified International Working Group (IWG) for AML. Results: 62 subjects were dosed, the most frequent adverse events were grade 1 injection site reactions (no grade 3 injection site reactions or dose limiting toxicities observed). Of the 21 GBM subjects who were dosed, seven survived for ≥ 1 year (33%). Of these seven subjects, three survived for ≥18 months (14%), and two for ≥2 years (both in complete radiologic remission, 9.5%). One of the seven subjects with ≥1 year survival had previous treatment with bevacizumab. Two subjects continue dosing (1 complete response with no measurable disease &gt;3 years and 1 partial response &gt; 13 months on study). Results in subjects with non-GBM tumors (12 subjects with AML, 21 with ovarian CA, 7 with NSCLC, and 1 other cancer) are not presented here. WT1-specific CTLs and tumor burden was monitored. WT1 specific CTLs were associated with decrease of tumor burden in two patients with low tumor burden. Some patients with high disease burden did not respond. Conclusions: Preliminary data suggests WT2725 is well tolerated with potential antitumor activity in GBM patients, supporting future development of WT2725 for treatment of GBM in selected subjects. Clinical trial information: NCT01621542.
Adherence to tamoxifen in Mexican young women with breast cancer.
Authors: Cynthia Mayte Villarreal-Garza, Bertha Alejandra Martinez-Cannon, Andrea Castro-Sanchez, Alejandra Platas, Alan Fonseca, Yoatzin Vega, Regina Barragan-Carrillo, Alejandro Mohar, Enrique Bargallo-Rocha, Karen Bojoquez-Velazquez
Journal: Journal of Clinical Oncology (2017)

e12003 Background: Young age has been associated with significantly increased risk of breast cancer (BC) death among women with luminal BC. One contributing factor might be the low rate of tamoxifen (TMX) adherence previously reported in this young group. Given that in Mexico a disproportionate rate of BC is diagnosed among YW, information regarding TMX adherence is particularly relevant. Our study's aim was to report TMX adherence in Mexican YW and its associated determinants. Methods: Consecutive patients ≤40y at diagnosis at the National Cancer Institute in Mexico City, under TMX treatment, completed a multiple-choice survey regarding the use and attitudes about hormonal therapy and adherence. Data of TMX disposal was collected from the pharmacy’s records, and the medication possession ratio (MPR) was calculated; an MPR ≥80% was considered adherent. Results: 135 YW with a median age at diagnosis of 35.7y (24-40) were included. 77% were undergraduate, 28% unpaired and 33% childless. Median follow-up was 26 months. 95% of patients reported a regular TMX intake: 70% did not miss any doses, while 25% missed 1-6 doses a month. Only 45% considered that the information received regarding TMX therapy was sufficient and for 37% was incomprehensive. 43% thought TMX significantly reduced their recurrence-risk and 60% strongly believed that they needed to be on TMX treatment. 73% of women reported adverse effects, being menopausal symptoms the most frequent, but only 27% were worried about the treatment long-term effects. From the 99 patients with a pharmacy record, 73% had an MPR &gt; 80%. No significant factor was statistically associated with TMX adherence. Conclusions: Although Mexican YW and pharmacy data surprisingly sustained higher rates of TMX adherence compared to previous data, still a significant proportion of patients were non-adherent. Two-thirds of our patients reported having adverse effects, which might contribute to late TMX discontinuation. Since the newer recommendations of double hormonal blockade could lead to higher withdrawal rates of endocrine therapy in YW, adherence should be emphasized and closely monitored. Accordingly, hormonal treatment adherence should be a key component in the medical assessment of young luminal BC patients.
A multi-center, randomized, double-blind phase II study comparing temozolomide (TMZ) plus either veliparib (ABT-888), a PARP inhibitor, or placebo as 2<sup>nd</sup> or 3<sup>rd</sup>-line therapy for patients (Pts) with relapsed small cell lung cancers (SCLCs).
Authors: Maria Catherine Pietanza, Lee M. Krug, Saiama Naheed Waqar, Afshin Dowlati, Christine L. Hann, Alberto Chiappori, Taofeek Kunle Owonikoko, Kaitlin Woo, Yevgeniya Bensman, Brenda Hurtado, Junya Fujimoto, Ignacio Ivan Wistuba, William D. Travis, Alice P. Chen, John Heymach, Mark G. Kris, Martin Fleisher, Charles M. Rudin, Lauren Averett Byers
Journal: Journal of Clinical Oncology (2016)

8512 Background: Preclinical data indicate that the combination of veliparib, an oral PARP-1/2 inhibitor, and TMZ result in synergistic tumor growth delay or regression. We hypothesized that adding veliparib to TMZ will improve outcomes in pts with relapsed sensitive and refractory SCLCs. Methods: Relapsed SCLC pts treated with 1 or 2 prior regimens were randomized 1:1 to receive oral TMZ 150-200mg/m2/day on days 1-5 of a 28-day cycle along with either veliparib or placebo 40mg twice daily, orally, on days 1-7. Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in pts with sensitive disease (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Correlative studies included immunohistochemistry to evaluate MGMT and PARP and circulating tumor cell enumeration. Results: Between Aug 2012 and Feb 2015, 104 pts were enrolled and 100 pts were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. The proportions of pts alive and progression-free at 4-months were similar between the two arms, 36% vs. 27% (p=0.39). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. In the 93 evaluable pts, response rate was significantly higher with veliparib/TMZ compared to TMZ alone (39% vs 14%, p=0.016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Correlative evaluations are ongoing and will be available at the time of presentation. Conclusions: Response rate was significantly higher with veliparib/TMZ compared to TMZ alone, although an improvement in PFS was not noted. Hematologic toxicity of the combination may have impacted PFS by limiting dosing. Characterizing MGMT and PARP expression in responders may allow for better patient selection and the potential to improve outcomes of this combination in SCLCs. Clinical trial information: NCT01638546.
A cost-effectiveness analysis of palbociclib plus letrozole as first-line treatment for estrogen receptor-positive, HER2-negative, metastatic breast cancer.
Authors: Klazien Matter-Walstra, Matthias Schwenkglenks, Peter Brauchli, Dirk Klingbiel, Konstantin J. Dedes
Journal: Journal of Clinical Oncology (2016)

567 Background: Endocrine treatment remains the optimal systemic treatment for metastatic ER-positive, HER2-negative breast cancer. Recent advances in overcoming acquired or intrinsic endocrine resistance by combination treatments targeting the ER pathway have shown significant improvements in progression-free survival. In first line the CDK4/6 inhibitor palbociclib in combination with letrozol significantly increases progression-free survival. The aim of this study is to examine the cost-effectiveness of this regimen for the Swiss healthcare system. Methods: A Markov cohort simulation based on the PALOMA-2 trial (Finn et al. The Lancet 2015) was used for the clinical course of patients. Input parameters were based on the clinical summary data presented in the trial, while direct costs were assessed for the Swiss healthcare system. Results: Adding palbociblib to letrozol (PALLET) compared to letrozol mono-therapy (LET) was estimated to cost additional CHF342’440 with a gain of 1.14 quality adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of CHF301’227 per QALY gained. In univariate sensitivity analyses none of the tested variations in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. Probabilistic sensitivity analyses showed a 0% probability that PALLET would be cost-effective. Lowering the price of PALLET by 75% resulted in an ICER of CHF73‘995/QALY and a probability being cost effectiveness of 73%. PALLET with its current price, would charge the Swiss health care system with an additional 222 million CHF per year. Conclusions: Palbociclib plus letrozol would require a substantial price-cut to be cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system.
Sarcopenia and altered body composition following abiraterone acetate (AA) and corticosteroid (C) treatment in men with castration-refractory prostate cancer (CRPC).
Authors: Deborah Mukherji, Carmel Jo Pezaro, Diletta Bianchini, Nina Tunariu, Amy Mulick Cassidy, Aurelius Gabriel Omlin, Shahneen Kaur Sandhu, Gerhardt Attard, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2012)

e15134 Background: Sarcopenia, or skeletal muscle wasting, is an independent prognostic factor in advanced malignancy (Prado Lancet Onc 2008) . Decreased muscle and increased fat are recognized side effects of androgen deprivation therapy. AA is a CYP17 inhibitor administered with corticosteroids (C), approved for treatment of advanced CRPC. AA reduces circulating androgens to ‘super-castrate’ levels; we hypothesized that AA + C would impact body composition. Methods: We retrospectively evaluated 54 CRPC pts treated on a Phase I/II trial. Pts received AA alone followed by combination AA + C on biochemical progression. CT scans at baseline, on AA alone and on AA + C were analyzed. Cross-sectional areas of fat and muscle were measured on 3 consecutive images at L4 using OsiriX 4.0. Muscle area was used to calculate skeletal muscle index (SMI); sarcopenia was defined as SMI &lt;52.4 cm 2 /m 2 . Data were analyzed using t-tests and Kaplan-Meier analysis with overall survival (OS) measured from day 1 of AA. Results: Median duration on AA alone was 7.4 months (m; range 1.4-37.5); median duration on concurrent AA + C was 7.4m (range 0.9-46.2). Body composition did not change between two pre-treatment scans (n=29; median 3m apart). On AA alone there was a decrease in total fat (-8.5%, p=0.0001), visceral fat (-9.8%, p=0.0015) and muscle mass (-3.9%, p=0.0023) with a significant decrease in mean body mass index (BMI; -3.4 %, p=0.0118). Conversely AA + C was associated with increased total fat (+15.1%, p&lt;0.0001) and visceral fat (+21.4%, p&lt;0.0001) but no further change in muscle mass. Mean BMI significantly increased on the addition of C, returning to baseline levels (p&lt; 0.0001). Overall, 13 pts (24%) were sarcopenic prior to commencing AA compared to 22 (41%) at the end of treatment. Pts who were sarcopenic at baseline had significantly reduced OS: 26.1m (95%CI 16.6 – 41) vs 46.5m (95%CI 28.6 – 57.5, p=0.0253). Conclusions: Treatment with AA alone resulted in decreased fat and muscle. AA + C increased body fat without further alteration in muscle mass. Changes in BMI did not reflect changes in body composition. Sarcopenia at baseline was a negative prognostic factor in this population.