tbuckley/cabot-search huggingface dataset:
Influence of maternal obesity on the association between common pregnancy complications and risk of childhood obesity: an individual participant data meta-analysis
Authors: Bernadeta Patro Golab, Susana Santos, Ellis Voerman, Debbie A Lawlor, Vincent W V Jaddoe, Romy Gaillard, Bernadeta Patro Golab, Susana Santos, Ellis Voerman, Henrique Barros, Anna Bergström, Marie-Aline Charles, Leda Chatzi, Cécile Chevrier, George P Chrousos, Eva Corpeleijn, Nathalie Costet, Sarah Crozier, Graham Devereux, Merete Eggesbø, Sandra Ekström, Maria P Fantini, Sara Farchi, Francesco Forastiere, Vagelis Georgiu, Keith M Godfrey, Davide Gori, Wojciech Hanke, Irva Hertz-Picciotto, Barbara Heude, Daniel Hryhorczuk, Hazel Inskip, Jesus Ibarluzea, Louise C Kenny, Leanne K Küpers, Hanna Lagström, Irina Lehmann, Virissa Lenters, Sabrina Llop Llop, Per Magnus, Renata Majewska, Johanna Mäkelä, Yannis Manios, Fionnuala M McAuliffe, Sheila W McDonald, John Mehegan, Monique Mommers, Camilla S Morgen, George Moschonis, Deirdre Murray, Carol Ní Chaoimh, Ellen A Nøhr, Anne-Marie Nybo Andersen, Emily Oken, Adriëtte JJM Oostvogels, Agnieszka Pac, Eleni Papadopoulou, Costanza Pizzi, Kinga Polanska, Daniela Porta, Lorenzo Richiardi, Sheryl L Rifas-Shiman, Franca Rusconi, Ana C Santos, Henriette A Smit, Thorkild IA Sørensen, Marie Standl, Camilla Stoltenberg, Jordi Sunyer, Michelle Taylor, Elisabeth Thiering, Carel Thijs, Maties Torrent, Suzanne C Tough, Tomas Trnovec, Steve Turner, Lenie van Rossem, Andrea von Berg, Martine Vrijheid, Tanja Vrijkotte, Jane West, John Wright, Oleksandr Zvinchuk, Debbie A Lawlor, Vincent WV Jaddoe, Romy Gaillard
Journal: The Lancet Child & Adolescent Health (2018)
Abstract 18376: Ethanol Induces Prolongation of the Plateau Phase of Acetylcholine-Activated K+ Current in Mouse Atrial Cardiomyocytes
Authors: Tae-joon Cha, Eun Kyoung Choi, Ga-In Yu, Bong Joon Kim, Dong Hyeon Park
Journal: Circulation (2016)

Ethanol exerts biological effects through multiple receptors, including ion channels. Alcohol intoxication may induce atrial fibrillation prone cellular electrophysiological changes and arrhythmias, primarily AF. Modifications of inward rectifier potassium currents have been implicated in the pathogenesis of AF. However, the mechanisms underlying the potential association between acute ethanol exposure and AF remain unclear. Therefore, we hypothesized that alcohol may affect acetylcholine-activated K+ current in atrial cardiomyocytes. Methods: IKACh current was recorded using a nystatin-perforated whole cell patch-clamp technique following activation by ACh. After the measurement of baseline IKACh current, cardiomyocytes were exposed to ethanol (100 mM for 10 min) and IKACh current was re-measured. Current-voltage (I-V) curves were obtained from the current response induced by voltage ramps between –120 and +60 mV from the holding potential of –40 mV. Results: Application of ACh (10 μM) to the bath soluti...
Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA).
Authors: Aref Al-Kali, Devendra Hiwase, Maria R. Baer, Peter Greenberg, Jake Shortt, Robert Collins, David P. Steensma, Amit Verma, Gail J. Roboz, Jamile M. Shammo, Oliver G. Ottmann, John Francis Seymour, Jeffrey Szer, Wolfgang Meyer, Patrick Simon Zbyszewski, Michael E. Petrone, Steven M. Fruchtman, Guillermo Garcia-Manero, Lewis R. Silverman
Journal: Journal of Clinical Oncology (2017)

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.
Ras homolog family member A/Rho-associated protein kinase 1 signaling modulates lineage commitment of mesenchymal stem cells in asthmatic patients through lymphoid enhancer–binding factor 1
Authors: Xia Ke, Danh C. Do, Changjun Li, Yilin Zhao, Marian Kollarik, Qingling Fu, Mei Wan, Peisong Gao
Journal: Journal of Allergy and Clinical Immunology (2018)
Comparison of survival between upfront primary debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomized trial: JCOG0602.
Authors: Takashi ONDA, Toyomi Satoh, Toshiaki Saito, Takahiro Kasamatsu, Toru Nakanishi, Kazuhiro Takehara, Kenichi Miyamoto, Masashi Wakabayashi, Aikou Okamoto, Kimio Ushijima, Hiroaki Kobayashi, Kei Kawana, Harushige Yokota, Masashi Takano, Kohei Omatsu, Yoh Watanabe, Kaichiro Yamamoto, Nobuo Yaegashi, Toshiharu Kamura, Hiroyuki Yoshikawa
Journal: Journal of Clinical Oncology (2018)

5500 Background: We conducted a phase III non-inferiority trial comparing upfront primary debulking surgery (PDS) and neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal and peritoneal cancers (JCOG0602). Two preceding studies, EORTC55971 and CHORUS demonstrated non-inferior overall survival (OS) of patients treated with NAC. We have already reported reduced invasiveness of NAC setting treatment (NACT) compared to PDS setting treatment (PDST) in analysis of short-term outcomes of JCOG0602. This is a final analysis including primary endpoint of OS. Methods: Target cancer was diagnosed by 1) imaging studies (CT and/or MRI), 2) cytology of ascites, pleural effusions or fluids obtained by tumor centesis, and 3) CA125 > 200 U/ml and CEA < 20 ng/ml. Patients were randomized to PDS arm (PDS followed by 8 cycles of paclitaxel and carboplatin, i.e. TC regimen) and NAC arm (4 cycles of TC, interval debulking surgery [IDS], 4 cycles of TC). Planned sample size was 300 with 3-year OS of 25% in PDS arm, 30.3% in NAC arm and non-inferiority margin of hazard ratio (HR) of 1.161 (these corresponds to median OS of 18 months in PDS arm, 20.9 months in NAC arm and non-inferiority margin of 2.5 months), one-sided alpha of 5% and 80% power. Results: From Nov 2006 to Oct 2011, 301 patients (149 PDS arm and 152 NAC arm) were randomized. Median OS was 49.0 months in PDS arm and 44.3 months in NAC arm. HR was 1.052 [90.8%CI 0.835-1.326] and one-sided non-inferior p value was 0.24. Median progression-free survival was 15.1 months for PDS arm and 16.4 months for NAC arm (HR: 0.987 [95%CI 0.774-1.259]). In PDS arm 147/149 underwent PDS. 49 of them and 130/152 in NAC arm underwent IDS. Complete resection was achieved in 12% (17/147) of PDS and 31% (45/147) of PDS ± IDS in PDS arm and in 64% (83/130) of IDS in NAC arm. Optimal surgery (maximum residual tumor < 1cm) was achieved in 37% (55/147) of PDS and 63% (92/147) of PDS ± IDS in PDS arm and in 82% (107/130) of IDS in NAC arm. Conclusions: The non-inferiority of NAC arm was not confirmed and NACT cannot be always a substitute for PDST. Further studies may be necessary to demonstrate a role of NACT for more limited target. Clinical trial information: UMIN000000523.
Rapid drop in blood platelet count and increase in creatinine in non-small cell lung cancer (NSCLC) patients treated with osimertinib.
Authors: Inger Johanne Zwicky Eide, Aslaug Helland, Simon Ekman, Saulius Cicenas, Jussi Koivunen, Bjørn Henning Grønberg, Odd Terje Brustugun
Journal: Journal of Clinical Oncology (2018)

e21026 Background: Osimertinib has recently become standard of care for advanced, EGFR-mutated NSCLC, and usage in frail populations may incur precautions. Methods: The TREM-study is an investigator initiated multi-center, phase 2, single-arm clinical trial conducted in five Northern European countries. 200 patients with EGFR-mutated NSCLC who progressed on or after EGFR-TKI were treated with osimertinib 80 mg daily until radiological progression, no clinical benefit or death. Blood samples including hematology and creatinine were collected at baseline and at each subsequent visit. The primary endpoint was overall response rate. Results: We analyzed platelet counts and creatinine levels at four time points (baseline and on weeks 2, 8 and 16). The mean platelet count at baseline was 310.7*109/L. There was a statistical significant decrease with a mean difference of 88.4*109/L from baseline to week 2 (p < 0.001) whereas there was no significant change from week 2 until week 16. The drop from baseline until week 2 was significantly larger in patients with a baseline count above 300, with a mean 32 % decrease vs mean 18 % decrease in patients with a baseline count below 300, p < 0.001. 3/177 (1.7 %) patients had a platelet count of less than 100 at week 2, 5/149 (3.4 %) at week 8 and 3/119 (2.5 %) at week 16, only one leading to a dose reduction. There was no significant correlation between response and magnitude of decrease. In multivariate analysis, platelet count at baseline was the only baseline factor correlated to a decrease in platelet count during the two first weeks of treatment with osimertinib, p < 0.001. There was a statistical significant increase in creatinine from mean 73.10 µmol/L at baseline to 81.29 µmol/L at week 2, p < 0.001, and no significant change thereafter. The creatinine level increased above ULN in 26/178 (15%) patients at week 2, none leading to dose reductions. Conclusions: Our data suggest that osimertinib causes a decrease in the platelet count. Selected patients should be monitored closely with blood counts after commencing therapy with osimertinib. Creatinine level increases during the first two weeks of treatment and should also be monitored. Clinical trial information: NCT02504346.
Universal germline BRCA testing of ovarian cancer patients and implications for treatment.
Authors: Erica Bednar, Holly D. Oakley, Charlotte C. Sun, Shannon Neville Westin, Karen H. Lu
Journal: Journal of Clinical Oncology (2016)

5539 Background: BRCA testing is recommended by SGO and NCCN for all invasive, high-grade epithelial ovarian cancer (HGOC) pts. However, recent studies have reported genetic counseling (GC), and testing (GT) rates in this population of 14.5% to 48.0%. To improve our GC and GT rates, we developed a novel care delivery model (NCDM), which includes GC services integrated in the Gyn Onc clinic, physician coordinated GT, and assisted GC referrals through screening of clinic schedules. We report the results of universal BRCA testing of HGOC pts presenting to the Gyn Onc clinic. Methods: From 9/1/2012 – 8/31/2015 data were collected retrospectively and prospectively from a consecutive cohort of pts seen at our institution for diagnosis, treatment, and 2nd opinions for HGOC. Tumor registry, medical records, and research databases were used to collect pt demographics, tumor histology, GC uptake, GT uptake, GT outcome, and downstream effects including PARP Inhibitor (PARPi) treatment. Results: A total of 1622 HGOC pts presented to the Gyn Onc clinic, including 455 pts untreated for HGOC and 1167 pts treated for HGOC prior to presentation. Of those untreated, 373 (82.0%) were recommended to have GC/GT, 322 (70.8%) had GT, and 50 (15.5%) had a BRCA mutation identified. Of those previously treated, 971 (83.2%) were recommended to have GC/GT, 808 (69.2%) had GT, and 162 (20.1%) had a BRCA mutation identified. In total, 1344 (82.9%) were recommended to have GC/GT, 1130 (69.7%) had GT, and 212 (18.8%) had a BRCA mutation. Most commonly documented reasons for pts not having GT included: pt deceased, pt elected to pursue elsewhere, and pt declined GC/GT. Of the 212 patients with a BRCA mutation, 37 (17%) have received PARPi treatment for recurrent disease. 18 received PARPi on a research trial basis, and 18 received treatment off study. Conclusions: Using our NCDM, universal GT of HGOC pts yielded 83% recommended for GC/GT, 70% tested, 19% with a BRCA mutation, and 37 received PARPi therapy. Implementation of the NCDM resulted in increased GT and GC rates. Among pts coming to our tertiary care hospital for HGOC, 1/5 will have a BRCA mutation. Universal testing of HGOC pts has implications for treatment, early cancer detection, and prevention in the pt and their family.
In Vivo validation of novel p53-independent therapeutic modalities for small cell lung cancer (SCLC).
Authors: Kai Kang, Nathan Radakovich, Arjun Khunger, David S. Schrump, David MacPherson, Mark P. Rubinstein, John M. Wrangle, Yogen Saunthararajah, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2018)

e24141 Background: Current treatments for SCLC produce transient responses – 2-year survival is 5%. One reason is that the treatments apply stress upstream of p53 to upregulate it (cytotoxicity), but p53 is genetically inactivated in SCLC, enabling ready selection for resistant cells. We are hence developing towards clinical trials new modalities to cytoreduce SCLC by non-cytotoxic, p53-independent mechanisms. Methods: A murine p53-null SCLC cell line (F1339), developed by tracheal infection of Rblox/p53lox mice with Adeno-CMV-Cre, was inoculated into B6/129 mice by tail vein. After documenting engraftment, mice were treated with PBS, etoposide 8 mg/kg 3X/wk + cisplatin 12 mg/kg 1X/wk, THU-Dec/5Aza (10/0.1/1 mg/kg 3X/wk) or anti-PD1 (5 mg/kg q5d) (n = 5/group). Tumor burden, overall survival (OS), drug pharmacodynamics and metabolism, myeloid derived suppressor cells (MDSCs), and T-cells were measured. Results: The SCLC cells were resistant to clinical concentrations of etoposide/cisplatin (ECis), but were sensitive to DNA methyltransferase 1 (DNMT1)-depletion by non-cytotoxic concentrations of the DNMT1-depleting pyrimidine analogue clinical drugs decitabine (Dec 0.5 µM) or 5-azacytidine (5Aza 5 µM). However, the pyrimidine metabolism network in the cells reacted to Dec and 5Aza challenge with shifts in DCK, UCK2 and CDA expression that reflexively dampened drug uptake, causing resistance after 4 weeks in vitro. To outmaneuver these metabolic reflexes, Dec and 5Aza were alternated, and tetrahydrouridine (THU) to inhibit CDA was added. In vivo, THU-Dec/5Aza significantly extended OS ~2-fold (Log rank p < 0.01); decreased tumor burden (PBS 3.53 g, ECis 3.45 g, THU-Dec/5Aza 1.09 g); increased lymphocyte counts (CD4: PBS 0.99, THU-Dec/5Aza 1.81 k/µL, p < 0.01; CD8: PBS 0.8, THU-Dec/5Aza 1.66 k/µL, p < 0.01); and decreased MDSCs (G-MDSC: PBS 0.13, THU-Dec/5Aza 0.03 k/µL, p < 0.01; M-MDSC: PBS 0.28, THU-Dec/5Aza 0.08 k/µL, p < 0.01). Anti-PD1 alone, like ECis, provided minimal benefit in the syngeneic model of SCLC. Conclusions: Pyrimidine metabolism reflexes to Dec/5Aza challenge can be rationally outmaneuvered, for meaningful non-cytotoxic DNMT1-depleting therapy of ECis/anti-PD1-resistant SCLC.
Emergence of RTK/RAS/PI3K pathway alterations in trastuzumab-refractory HER2-positive esophagogastric (EG) tumors.
Authors: Yelena Yuriy Janjigian, Francisco Sanchez-Vega, Yaelle Tuvy, Nancy Bouvier, Jamie Cathleen Riches, Matthew Margolis, Brittanie M Millang, Sasinya N. Scott, Ritika Kundra, Pau Castel, Geoffrey Yuyat Ku, Jaclyn Frances Hechtman, David Paul Kelsen, David H. Ilson, Efsevia Vakiani, Maurizio Scaltriti, David B. Solit, Barry S. Taylor, Michael F. Berger, Nikolaus Schultz
Journal: Journal of Clinical Oncology (2016)

11608 Background: Up to 30% of EG adenocarcinomas harbor ERBB2 (HER2) gene amplification or oncoprotein over-expression. While trastuzumab prolongs survival in patients with Stage IV HER2+ EG tumors, responses are rarely complete and resistance invariably develops, possibly through the emergence of additional genomic alterations. Methods: We reviewed clinical and pathologic data of patients with metastatic HER2+ (IHC 3+ or FISH >2.0) EG adenocarcinoma undergoing trastuzumab/chemotherapy treatment at MSKCC. Archival formalin fixed paraffin embedded (FFPE) samples were analyzed using a cancer-associated gene bait capture, next generation sequencing (NGS) assay (MSK-IMPACT). Results: 80 patients with Stage IV HER2+ EG adenocarcinoma (59 IHC 3+, 20 IHC2+/FISH+, 1 NGS) treated with trastuzumab/chemotherapy. Median progression free survival on 1st line trastuzumab-based therapy 23 mos [95% CI: 17-32 mos], median overall survival 30 mos [95% CI: 25-29 mos]. NGS was completed on 71 pre-trastuzumab, 38 post-trastuzumab samples, including matched samples for 28 of 80 patients. Loss of HER2 was noted in 21% (8 of 38) post-progression samples by IHC/FISH (4 IHC 0/1, 4 FISH-). We also observed an overall increase in alterations in other receptor tyrosine kinases as well as KRAS, PI3-kinase pathway genes, and SMAD4 (Table 1). In paired post-T samples, we observed loss of HER2 amplification in four patients, and new amplifications of MET (n=2), EGFR (n=1), IGF1R (n=1), as well as mutations in ERBB4 (n=4), KRAS (n=3), PIK3CA (n=2), MTOR (n=2), and loss of function of PTEN (n=3). The KRAS and PIK3CA mutations were known activating, the ERBB4 and MTOR mutations were of unknown significance. Conclusions: We identified loss of HER2 and frequent secondary alterations in the RTK/RAS/PI3K pathway in HER+ EG adenocarcinoma treated with trastuzumab, suggesting mechanisms of resistance. These data suggest the need for repeat biopsies to accurately determine appropriate use of second-line HER2 directed therapy. Gene % pre-T % post-T EGFR amp 9.9 13.2 ERBB4 mut 4.2 15.8 IGF1R amp 2.8 13.2 KRAS amp / mut 8.5 18.4 MET amp 2.8 13.2 MTOR mut 2.8 7.9 PIK3CA mut 5.6 10.5 PTEN mut / homdel 1.4 10.5 SMAD4 mut / homdel 9.9 31.6
Ipilimumab combined with stereotactic radiosurgery in melanoma patients with brain metastases: A multicenter, open label, phase 2 trial.
Authors: Laurent Mortier, Philippe Jamme, Jean Philippe Lacour, Caroline Robert, Thierry Lesimple, Luc Thomas, Laurent Machet, Philippe Saiag, Celeste Lebbe, Caroline Dutriaux, Jean-Jacques Grob, Alain Duhamel, Eve Desmedt, Carole Templier, Xavier Mirabel, Nicolas Reyns, Emilie Le Rhun
Journal: Journal of Clinical Oncology (2018)

9520 Background: Brain metastasis commonly occur in patients with metastatic melanoma (MM) and are managed with surgery or stereotactic radiosurgery (SRS) and/or systemic treatment based on BRAF status and prior treatment. After SRS alone, the median survival is poor (5.6 months). Ipilimumab (Anti CTLA-4) was the first checkpoint inhibitor to demonstrate a survival benefit in patients with metastatic melanoma. The median survival was more recently estimated at 6 months after initiation of ipilimumab alone for brain metastasis. No prospective studies have evaluated the use of ipilimumab in combination with stereotactic radiosurgery for the treatment of brain metastasis from MM. Methods: This open-label, multi-center, phase 2 study (NCT02662725) evaluated the efficacy of one administration of ipilimumab (10 mg/kg) followed by SRS and the maintenance ipilimumab in a cohort of patients with MM brain metastases. Inclusion criteria included: patients of 18 years or older, performance status 0-1, fewer than 4 brain metastases on MRI. The primary objective was to show an increase at least 50% of the median overall survival time of patients receiving SRS alone. The secondary endpoints were to determine the safety profile of the combination, the intra- and extra-brain response rate. This study was supported by Bristol-Myers Squibb. Results: 57 patients (32 males) were enrolled. Median age was 54 (47-67). The study met his primary endpoint: median survival time was 13.2 m, higher than the median survival time of 5.6 m in the reference population (HR = 0.29; 95%CI = 0.19 to 0.39; p < 0.0001). The disease control rate was 49% (28/57). The most serious treatment-related adverse events were colitis (10.5%), hepatitis (10.5%), hypophisitis (8.77%) and headhache (8.77%). One radionecrosis was observed. Conclusions: High dose Ipilimumab plus SRS seemed effective with a manageable safety profile in patients with brain MM. Considering that this is the best survival rate ever observed in this setting, these results seem to confirm a synergy in the combination of immunotherapy and radiotherapy and should be confirmed in a randomized trial. Clinical trial information: NCT02662725.
Longitudinal Trajectory and Characterization of Cancer-Related Cognitive Impairment in a Nationwide Cohort Study
Authors: Michelle C. Janelsins, Charles E. Heckler, Luke J. Peppone, Tim A. Ahles, Supriya G. Mohile, Karen M. Mustian, Oxana Palesh, Ann M. O’Mara, Lori M. Minasian, Annalynn M. Williams, Allison Magnuson, Jodi Geer, Shaker R. Dakhil, Judith O. Hopkins, Gary R. Morrow
Journal: Journal of Clinical Oncology (2018)

Cancer-related cognitive impairment (CRCI) is an important clinical problem in patients with breast cancer receiving chemotherapy. Nationwide longitudinal studies are needed to understand the trajectory and severity of CRCI in specific cognitive domains.