tbuckley/cabot-search huggingface dataset:
FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases (RCSM): Results of the FFCD 1102 phase II trial.
Authors: Jean Baptiste Bachet, Olivier Lucidarme, Julien Taïeb, Emilie Maillard, Charles-Briac Levache, Jean-Luc Raoul, Thierry Lecomte, Mohamed Hebbar, Fabien Brocard, Simon Pernot, Gilles Breysacher, Jean-Paul Lagasse, Frédéric Di Fiore, Pierre-Luc Etienne, Olivier Jean Marie Dupuis, Albert Aleba, Come Lepage, Philippe Rougier
Journal: Journal of Clinical Oncology (2016)

3513 Background: Optimal therapeutic strategy in patients (pts) with RCSM remains discussed and many front line options can be discussed to best treat primary tumor and metastatic disease: surgery (S), radiotherapy (RT), chemoradiotherapy (CRT) or chemotherapy (CT). Upfront aggressive chemotherapy may be particularly interesting in this setting. Methods: Pts with histologically proven RCSM received FOLFIRINOX: oxaliplatin (O) 85 mg/m2 d1 + irinotecan (I) 180 mg/m2 d1 + leucovorin 400 mg/m2 d1 followed by 5FU 400 mg/m2 bolus d1 and 2,400 mg/m246h continuous infusion biweekly ; 8 cycles were mandatory then therapeutic strategy was investigators’ choice. Eligibility included adequate organ function, age ≥ 18 years, PS ≤ 2, no prior RT or CT. CT-scan and MRI were centrally reviewed. The primary endpoint was disease control rate at 4 m (4m DC). With a Simon 2-stage design, a targeted (H1) 4m DC > 75% was defined (unilateral alpha of 5% and power of 90%). Results: 65 pts were enrolled (07/2012 to 02/2015): male 78%; median age 61 years; PS 0-1 99%; liver metastases 92%; ≥ 2 metastatic sites 63%. All pts received at least 1 cycle of CT; 85% of pts received the 8 planned cycles. Median relative dose-intensities of O, I, 5FU bolus and 5FU continuous were 93.5%, 96.5%, 86% and 96%, respectively. The main grade 3-4 toxicities were neutropenia (29%), diarrhea (12%), abdominal pain (9%), fatigue (8%) and nausea (5%). Local symptoms (rectal bleeding, rectal syndrome and/or sub-occlusion), present in 72% of pts at baseline, were, 16% and 10% at 2 and 4 m, respectively. Primary objective was met with a 4m DC of 94% (95% CI, 86.3-97.8). Objective response rate (RECIST) was 86%. After FOLFIRINOX, 36 pts (55%) had a RT or CRT, 28 (43%) had a resection of the rectal tumor and 18 (28%) had a surgery and/or ablation of their metastases. With a median follow-up of 21.5 m (95% CI, 15.4-24.7), median PFS was 10.9 m (95% CI, 8.8-12.3) with rates of PFS at 6 and 12 m of 82% and 41%. Conclusions: Front line aggressive systemic CT with FOLFIRINOX allows a good local and distant control of RCSM, with acceptable toxicities and leaves the opportunity to decide best locoregional treatment and surgery of metastatic lesions on a controlled disease at 4m. Clinical trial information: NCT01674309.
Therapeutic efficacy of epidermal growth factor receptor monoclonal antibody combined with concurrent chemoradiotherapy in treatment of locally advanced cervical cancer.
Authors: Wenli Chen, Tao Li, Wei Zhang, Jialin Yang, Jian Wang, Jinyi Lang
Journal: Journal of Clinical Oncology (2017)

e17012 Background: There are few studies about epidermal growth factor receptor monoclonal antibody nimotuzumab for the treatment of locally advanced cervical cancer. We aimed to assess the therapeutic efficacy and analyse prognostic factors of chemoradiotherapy combined with nimotuzumab in cervical cancer (stage II B -IV A ) . Methods: We retrospectively analyzed 23 patients with locally advanced cervical cancer(stage II B -IV A ) ,who received concurrent chemoradiotherapy combined with nimotuzumab from 2012 to 2014 (the study group) ,and 30 patients with the similar baseline characteristics who received concurrent chemoradiotherapy alone (the control group). The overall response rates, 5-year overall survival rates, progression-free survival and acute adverse events of the two groups were compared .Multivariate prognostic analysis was performed by a Cox proportional hazards model. Results: The median follow-up time were 46 months (IQR 16-60) in the study group and 42 months (2-60) in the control group.The overall response rates were 87% and 73.3% (P = 0.384) . The 5-year overall survival rates were 63.6% and 36.1% (hazard ratio 2.208,95% CI 0.878-5.557,P = 0.092) .The median progression-free survival in the study group was not achieved (95%CI 9-55) versus 27 months (1-60) in the control group (hazard ratio 2.635, 95% CI 1.030-6.737, P= 0.043).Multivariate prognostic analysis indicated that stage and whether to be combined with nimotuzumab were the influential factors for progression-free survival time.Adverse events were similar between groups.The most common grade 3 or 4 adverse events during treatment in the study group versus the control group were leucopenia(9 [39%] vs 11 [36%]),thrombocytopenia (3 [13%] vs 6 [20%]),anaemia (4 [17%] vs 4 [13%]). Conclusions: Concurrent chemoradiotherapy combined with nimotuzumab in the treatment can improve the progression-free survival time of advanced cervical cancer, while not increasing the incidence of adverse reactions.However, because of the small size of sample in this research, these findings suggest that it is necessary to perform a prospective study with expanded sample size.
ATR Is a Therapeutic Target in Synovial Sarcoma
Authors: Samuel E. Jones, Emmy D.G. Fleuren, Jessica Frankum, Asha Konde, Chris T. Williamson, Dragomir B. Krastev, Helen N. Pemberton, James Campbell, Aditi Gulati, Richard Elliott, Malini Menon, Joanna L. Selfe, Rachel Brough, Stephen J. Pettitt, Wojciech Niedzwiedz, Winette T.A. van der Graaf, Janet Shipley, Alan Ashworth, Christopher J. Lord
Journal: Cancer Research (2017)

Abstract Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18–SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in &amp;gt;130 non–SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18–SSX family fusion genes are known to alter the composition of the BAF chromatin–remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18–SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18–SSX1 Δ71–78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res; 77(24); 7014–26. ©2017 AACR.
Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer
Authors: Zhi Ling Teo, Stephanie Versaci, Sathana Dushyanthen, Franco Caramia, Peter Savas, Chris P. Mintoff, Magnus Zethoven, Balaji Virassamy, Stephen J. Luen, Grant A. McArthur, Wayne A. Phillips, Phillip K. Darcy, Sherene Loi
Journal: Cancer Research (2017)

New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wild-type TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell-cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T-cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell-cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC. Cancer Res; 77(22); 6340-52. ©2017 AACR.
Urinary BPA and Phthalate Metabolite Concentrations and Plasma Vitamin D Levels in Pregnant Women: A Repeated Measures Analysis
Authors: Lauren E. Johns, Kelly K. Ferguson, David E. Cantonwine, Thomas F. McElrath, Bhramar Mukherjee, John D. Meeker
Journal: Environmental Health Perspectives (2017)

Background: In addition to its well-established role in maintaining skeletal health, vitamin D has essential regulatory functions in female reproductive and pregnancy outcomes. Phthalates and bisphenol A (BPA) are endocrine disruptors, and previous research has suggested that these chemical agents may disrupt circulating levels of total 25(OH)D in adults. Objectives: We investigated the relationships between repeated measures of urinary phthalate metabolites and BPA and circulating total 25(OH)D in a prospective cohort of pregnant women. Methods: The present study population includes participants (n=477) in a nested case–control study of preterm birth drawn from a prospective birth cohort of pregnant women at Brigham and Women's Hospital in Boston, Massachusetts. Urine and blood samples were collected for biomarker measurements at median 10 wk and 26 wk of gestation. Results: In repeated measures analysis, we observed that an interquartile range (IQR) increase in urinary mono-3-carboxypropyl phthalate (MCPP) was associated with a 4.48% decrease [95% confidence interval (CI): −7.37, −1.58] in total 25(OH)D. We also detected inverse associations for metabolites of di(2-ethylhexyl) phthalate (DEHP) [percent difference (%Δ)=−2.83 to −2.16]. For BPA, we observed a nonsignificant inverse association with total 25(OH)D in the overall population. Our sensitivity analysis revealed that the associations for some metabolites (e.g., MEHP) varied by race/ethnicity, which may reflect potential differences in susceptibility. In agreement with findings from repeated measures analysis, we reported that DEHP metabolites and BPA were significantly associated with an approximate 20% increase in the odds of vitamin D deficiency (≤20 ng/mL) [odds ratio (95% CI): 1.19 (1.06, 1.35) for molar sum of DEHP metabolites and 1.22 (1.01, 1.47) for BPA] at median 10 wk and 26 wk, respectively. Conclusions: Our results provide suggestive evidence of the potential for environmental exposure to phthalates and/or BPA to disrupt circulating vitamin D levels in pregnancy. https://doi.org/10.1289/EHP1178
Abstract 035: Mechanism of Chronic CaMKII Inhibition-Caused Regression of Heart Failure: Beneficial Effects on Neurohormonal Activation, Left Ventricular and Cardiomyocyte Contractile Function, [Ca <sup>2</sup> +]i Regulation and Beta-Adrenergic Modulation
Authors: Che Ping Cheng, Qun Shao, Heng-Jie Cheng, Michael F Callahan
Journal: Circulation Research (2013)

Background: Recent evidence indicates that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is upregulated in heart failure (HF), contributing to electric, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for HF. However, the role and mechanism of chronic CaMKII inhibition (I) in HF is unclear. We assessed the hypothesis that CaMKII I improves cardiomyocyte function, [Ca 2+ ] i regulation, and β-adrenergic reserve, thus limiting HF progression. Methods: We compared left ventricular (LV) and myocyte functional responses and plasma levels of norepinephrine (NE) over a period of 16 weeks (W) in 6 control (C) and 14 rats with HF induced by isoproterenol (ISO) (170 mg/kg sq for 2 days). After ISO for 12 weeks, HF animals were assigned to receive 4 W treatment with: placebo (saline) (n=6), KN-93 (70 µg/kg/day sq via mini pump) (n=6), or KN-92 (70 µg/kg/day sq via pump) (n=2), respectively. Results: Compared with C, ISO-treated rats had HF onset at 4 W after ISO and progressed to severe HF at 16 W with increased plasma NE (1398 vs 342 pg/ml), decreased ejection fraction (EF, 37% vs 62%) and LV contractility (E ES , 0.8 vs 1.3 mmHg/μl). LV time constant of relaxation (τ) (17.8 vs 10.6 ms) increased, accompanied with significant reductions in cell contraction (dL/dt max , 78 vs 151 μm/s), relaxation (dR/dt max , 59 vs 114 μm/s) and [Ca 2+ ] i transient ([Ca 2+ ] iT ) (0.18 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10 -8 M) was attenuated with significantly less increases in dL/dt max (34% vs 79%) and [Ca 2+ ] iT (19% vs 36%). The LV and myocyte dysfunction persisted in KN-92-treated HF group. In contrast, treatment with KN-93 significantly increased E ES (1.2 mmHg/μl) and EF (60%), decreased τ (12.1 ms) and corrected the elevation of plasma NE (319 pg/ml). Importantly, basal myocyte contraction (dL/dt max ,147 μm/s), relaxation (dR/dt max ,107 μm/s), and [Ca 2+ ] iT (0.25) improved. ISO-induced increase in dL/dt max (71%) and [Ca 2+ ] iT (32%) were augmented and close to normal control levels. Conclusion: Chronic CaMKII I prevents HF-induced sympathetic nervous system activation and improves LV and cardiomyocyte basal and β-AR stimulated contraction and relaxation, thus playing a salutary role at later stages of HF.
Obesity surgery achieves long term weight loss and prevents type 2 diabetes, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Gastric bypass surgery achieves long term weight loss and sustained prevention of type 2 diabetes, hypertension, and dyslipidaemia in severely obese patients, a 12 year follow-up study has shown.1

Previous studies have shown significant weight loss and improvements in type 2 diabetes and cardiovascular risk factors with bariatric surgery, but follow-up has been relatively short term. There has been limited evidence on the long term effects.

The new study prospectively followed up 418 severely obese patients undergoing Roux-en-Y gastric bypass at Rocky Mountain Associated Physicians surgical centre, in the US. Data were …
Abstract 18756: Attainment of Low-Density Lipoprotein Cholesterol Treatment Target in Familial Hypercholesterolemia Patients: A Model Exploring Efficacy of Current and Novel Lipid Lowering Therapies
Authors: Merel L Hartgers, Joost Besseling, G. K Hovingh
Journal: Circulation (2016)

Introduction: Current guidelines recommend low-density lipoprotein cholesterol (LDL-C) levels below 1.8 mmol/L and 2.5 mmol/L for heterozygous familial hypercholesterolemia (FH) patients with and w...
Long-term outcomes of patients with Streptococcus suis infection in Viet Nam: A case-control study
Authors: Vu T.L. Huong, Hoang B. Long, Nguyen V. Kinh, Ta T.D. Ngan, Vu T.V. Dung, Behzad Nadjm, H. Rogier van Doorn, Ngo T. Hoa, Peter Horby, Heiman F.L. Wertheim
Journal: Journal of Infection (2017)

ObjectivesStreptococcus suis is a zoonotic cause of severe meningitis and sepsis in humans. We aimed to assess the long-term outcomes in patients who survived S. suis infection, in particular the progress and impact of vestibulocochlear sequelae.MethodsThis case-control study evaluated outcomes of S. suis infection at discharge and 3 and 9 months post-discharge for 47 prospectively enrolled cases and at 11–34 months for 31 retrospectively enrolled cases. Outcomes in patients were compared to 270 controls matched for age, sex and residency.ResultsThe prevalence ratio (PR) of moderate-to-complete hearing loss was 5.0(95%CI 3.6–7.1) in cases at discharge, 3.7(2.5–5.4) at 3 months, 3.2(2.2–4.7) at 9 months, and 3.1(2.1–4.4) in retrospective cases compared to controls. Hearing improvement occurred mostly within the first 3 months with a change in hearing level of 11.1%(95%CI 7.0–15.1%) compared to discharge. The PR of vestibular dysfunction was 2.4(95%CI 1.7–3.3) at discharge, 2.2(1.4–3.1) at 3 months, 1.8(1.1–2.5) at 9 months, and 1.8(1.1–2.6) for retrospective cases compared to controls. Cases also indicated more problems with mobility, self-care and usual activities.ConclusionsBoth hearing and vestibular impairment were common and persist in cases. Appropriate patient management strategies are needed to reduce the incidence and impact of these sequelae.
Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia
Authors: Jae-Yong Kwak, Sung-Hyun Kim, Suk Joong Oh, Dae Young Zang, Hawk Kim, Jeong-A Kim, Young Rok Do, Hyeoung Joon Kim, Joon Seong Park, Chul Won Choi, Won Sik Lee, Yeung-Chul Mun, Jee Hyun Kong, Joo Seop Chung, Ho-Jin Shin, Dae-Young Kim, Jinny Park, Chul Won Jung, Udomsak Bunworasate, Narcisa Sonia Comia, Saengsuree Jootar, Arry Harryanto Reksodiputro, Priscilla B. Caguioa, Sung-Eun Lee, Dong-Wook Kim
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.
Erratum: Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction.(Journal of the American College of Cardiology(2014)64 (1894-904))
Authors: F Cuculi, G L De Maria, P Meier, E Dall'Armellina, A R De Caterina, K M Channon, B D Prendergast, R C Choudhury, J C Forfar, R K Kharbanda, A P Banning
Journal: Journal of the American College of Cardiology (2015)
Clinical characteristics and outcomes for patients with thymic carcinoma: Evaluation of Masaoka staging.
Authors: Anna Maria Litvak, Kaitlin Woo, Sara A. Hayes, Camelia S. Sima, James Huang, Andre L. Moreira, Maria Teresa Ruiz Tsukazan, Gregory J. Riely
Journal: Journal of Clinical Oncology (2014)

7603 Background: Thymic carcinomas (TC) are rare cancers with limited data regarding outcomes, particularly for those patients (pts) with advanced disease. Methods: We identified pts with TC diagnosed between 1993-2012. Pt characteristics, recurrence free survival (RFS) from date of resection, and overall survival (OS) from date of diagnosis were analyzed. Pts were followed until death or last follow up. Time-to-event outcomes were determined using the Kaplan-Meier method. Results: 121 pts with TC were identified with 7 pts (6%) with Masaoka stage I, 13 (11%) with stage II, 25 (21%) with stage III, 13 (11%) with stage IVA, 61 (51%) with stage IVB, and 2 (2%) with unclear staging. Higher Masaoka stage was associated with worse OS and RFS (5-yr OS of 100%, 81%, 51%, 24%, and 17% for stage I, II, III, IV respectively, p<0.001 and 5-yr RFS of 80%, 28%, and 7% for stage I/II, III, and IV respectively, p<0.001). Stage IVB pts with lymph node involvement had a better 5-year OS as compared to stage IVB pts with distant metastasis (24% vs. 7%, p=0.025). Of the 61 pts with stage IVB disease, 22/29 pts (76%) with lymph node involvement underwent curative intent resection vs. 3/32 pts (9%) with visceral metastasis. Of the 29 stage IVB pts with lymph node involvement treated with surgery, chemotherapy, and radiation, 3 (10%) are currently free of disease with long-term follow-up (range: 3.4 years to 6.8 years). Conclusions: This is the largest review of the clinical features of pts with TC in North America. Stage IVB pts with lymph node positive disease have significantly better OS as compared to Stage IVB pts with distant metastasis. Stage IVB pts with lymph node positive disease treated with multi-modality therapies can have long term recurrence free survival. If validated, these data would support a revised Masaoka staging system with subclassification of stage IVB disease into two groups.
Abstract 3253: Dermal Filler Injection: A Novel Approach for Limiting Early Infarct Expansion
Authors: Liam Ryan, Kanji Matsuzaki, Mio Noma, Theodore J Plappert, Martin G St. John-Sutton, Joseph H Gorman, Robert C Gorman
Journal: Circulation (2007)

Objectives Early infarct expansion promotes adverse remodeling and is associated with poor long-term prognosis. We hypothesized that thickening the infarcted territory of the LV wall by means of intramyocardial injection of a clinically available acellular hydroxyapatite-based dermal filler would attenuate infarct expansion and improve long-term remodeling after myocardial infarction. Methods Twenty-five adult male sheep underwent coronary ligations that create an anteroapical MI. Fifteen animals subsequently underwent injection of 1.3 mL of a viscous hydroxyapatite based preparation into the infarcted territory - 10 served as controls. Rt-3DE was performed at baseline, 30 minutes post-MI, 30 minutes post-injection and then at 2, 4 and 8 weeks post-MI. LV volumes and EF were calculated in each case. Cardiac output was measured at 8 weeks with no inotropic stimulation and then during infusions of 2.5 and 5.0 mcg/kg/min of dobutamine after which all animals were sacrificed. Finally, LV wall thickness was measured within the basal and apical regions of the infarct zone, the borderzone (1 cm strip adjacent to the infarct) and the remote myocardium (base). Results All data are presented in the figure . LV remodeling was attenuated in the treatment animals compared with the control group. Treatment animals had thicker infarcts, higher baseline cardiac output and better response to inotropic stimulation than the control group. Conclusions Early post-infarction intramyocardial thickening with an acellular hydroxyapatite gel attenuates LV remodeling and improves contractile function 8 weeks after an anteroapical MI in a clinically relevant large animal model.