tbuckley/cabot-search huggingface dataset:
Predictors and Association With Clinical Outcomes of the Changes in Exercise Capacity After Transcatheter Aortic Valve Replacement
Authors: Omar Abdul-Jawad Altisent, Rishi Puri, Ander Regueiro, Chekrallah Chamandi, Tania Rodriguez-Gabella, Maria del Trigo, Francisco Campelo-Parada, Thomas Couture, Josep Ramon Marsal, Mélanie Côté, Jean-Michel Paradis, Robert DeLarochellière, Daniel Doyle, Siamak Mohammadi, Eric Dumont, Josep Rodés-Cabau
Journal: Circulation (2017)

At present, there are no objective data specifically examining the clinical impact of variations in exercise capacity post-transcatheter aortic valve replacement (TAVR). We describe the changes in exercise capacity between baseline and 6 months post-TAVR, and ascertain factors associated with and clinical implications of a lack of improvement in exercise capacity post-TAVR.A total of 305 patients (mean age, 79±9 years; 44% men; Society of Thoracic Surgeons predicted risk mortality score, 6.7±4.2%) undergoing TAVR completed both baseline and follow-up exercise capacity assessments at 6 months post-TAVR. Exercise capacity was evaluated by the 6-minute walk test (6MWT). Clinical outcomes were compared between patients displaying greater than (n=152; improving group) versus less than (n=153; nonimproving group) the median percentage change in distance walked between baseline and 6-month follow-up examinations. The primary outcome measure was clinical event rates, measured from the 6-month post-TAVR period onward. Further dichotomization according to baseline 6MWT distance (less than versus more than median walking distance, or slow walker versus fast walker) was also assessed.The mean overall distances walked pre- and post-TAVR (6 months post-TAVR) were 204±119 and 263±116 m, respectively (Δ6MWT=60±106 m), with 219 (72%) patients demonstrating an increase in their walking distance (median percentage increase of the entire population was 20% [interquartile range, 0%-80%]). Factors independently correlated with reduced exercise capacity improvement included a range of baseline clinical characteristics (older age, female sex, chronic obstructive pulmonary disease; P<0.05 for all), periprocedural major or life-threatening bleeding (P=0.009) and new-onset anemia at 6 months post-TAVR (P=0.009). Failure to improve the 6MWT distance by at least 20% was independently associated with all-cause mortality (P=0.002) and cardiovascular death or rehospitalization for cardiovascular causes (P=0.001). Baseline slow walkers who were able to improve the 6MWT distance presented with significantly better outcomes than nonimprovers (P=0.01 for all-cause mortality; P=0.001 for cardiovascular end point).Approximately one-third of patients undergoing TAVR did not improve their exercise capacity postprocedure. The lack of functional improvement post-TAVR was predicted by a mix of baseline and periprocedural factors translating into poorer clinical outcomes. These results suggest that systematically implementing exercise capacity assessment pre- and post-TAVR may help to improve patient risk stratification.
Abstract AP31: TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER
Authors: Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R. Rutkowski, Benjamin G. Bitler, Michael J. Allegrezza, Yuhki Yokoyama, James E. Bradner, Jose R. Conejo-Garcia, Rugang Zhang
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: Expression of programmed death ligand 1 (PD-L1) is up-regulated in many cancers and has been found to suppress antitumor immunity through binding to its receptor programmed death 1 (PD-1). Blockade of PD-1/PD-L1 signaling axis enhances antitumor immunity in many cancers including epithelial ovarian cancer (EOC). Despite the importance of PD-L1 in tumor immunity, the epigenetic regulation of PD-L1 expression remains poorly understood. AIMS: To determine the roles of epigenetic components in regulating PD-L1 gene expression and modulating antitumor immunity. METHODS: Toward this goal, I screened a small molecule library of epigenetic inhibitors and examined their inhibition on PD-L1 expression in EOC cells to identify the positive hits. To further confirm PD-L1 inhibition in vivo, C57BL/6 mice are injected with luciferase expressing mouse ovarian cancer ID8 cells and treated with or without epigenetic inhibitors, PD-L1 expression in both tumor cells and immune cells are examined, tumor growth and survival are also monitored. RESULTS: BET inhibitors suppresses both constitutive and IFNγ induced PD-L1 expression in EOC cells through targeting BRD4. Further ChIP-seq and ChIP assay demonstrate that BRD4 directly binds to PD-L1 gene promoter and regulated its transcription. BET inhibitor JQ1 suppresses PD-L1 expression in both tumor cells and immune cells including dendritic cells and macrophages in mice bearing ID8 mouse ovarian cancer cells. Moreover, the BET inhibitor suppresses the tumor growth and improves the survival of EOC bearing mice through activating antitumor T cells. CONCLUSION: Taken together, we demonstrated that BRD4 can directly regulate PD-L1 expression in EOC cells by binding to the promoter of PD-L1 encoding gene, suppressing PD-L1 expression with BET inhibitors blocks PD1/PD-L1 signaling and enhances antitumor immunity in vivo. These findings indicate that pharmacological inhibition of BET proteins represent a new therapeutic strategy for EOC by targeting PD-L1 expression. Citation Format: Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R. Rutkowski, Benjamin G. Bitler, Michael J. Allegrezza, Yuhki Yokoyama, James E. Bradner, Jose R. Conejo-Garcia, Rugang Zhang. TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP31.
The Protective Effect of Pregnancy on Risk for Drug Abuse: A Population, Co-Relative, Co-Spouse, and Within-Individual Analysis
Authors: Kenneth S. Kendler, Henrik Ohlsson, Dace S. Svikis, Kristina Sundquist, Jan Sundquist
Journal: American Journal of Psychiatry (2017)

Objective: The authors sought to determine whether pregnancy is an intrinsic motivator for cessation of drug abuse. Method: The authors conducted prospective cohort, co-relative, co-spouse, and within-person analyses of registration for drug abuse during pregnancy among Swedish women born between 1980 and 1990 who gave birth between ages 20 and 35 (N=149,512). Drug abuse was assessed from medical, criminal, and pharmacy registries. Results: In the population, rates of drug abuse were lower during pregnancy (unadjusted odds ratio=0.67, 95% CI=0.60, 0.74). Compared with population results, the negative association between pregnancy and drug abuse was moderately stronger in cousins (odds ratio=0.49, 95% CI=0.39, 0.62) and substantially stronger in siblings (odds ratio=0.35, 95% CI=0.24, 0.51) discordant for pregnancy. The estimated odds ratio for drug abuse in pregnancy-discordant monozygotic twins was even stronger, at 0.17 (95% CI=0.10, 0.31). Within individuals, the odds ratio for drug abuse while pregnant compared with an equivalent prepregnancy interval was similar to that seen in pregnancy-discordant monozygotic twins, at 0.22 (95% CI=0.19, 0.26). Compared with cohabiting fathers, mothers had a greater reduction in risk for drug abuse during pregnancy (odds ratio=0.40, 95% CI=0.34, 0.47). Pregnancy was more protective in women with low parental education and without a cohabiting, actively drug-abusing father. Compared with prepregnancy baseline, within-individual analyses indicate that risk for drug abuse is also substantially reduced in the postpartum period, for example, the odds ratio for postpartum days 0–242 was 0.13 (95% CI=0.11, 0.16). Conclusions: Risk for drug abuse in women is substantially reduced during pregnancy. Multiple analyses suggest that this association is largely causal, suggesting that pregnancy is indeed a strong intrinsic motivator for drug abuse cessation. Similar strong protective effects may be present in the immediate postpartum period. Our results have implications for our etiologic models of drug abuse and especially for contingency management programs seeking to reduce drug abuse risk.
Durable Overall Survival Benefit in Patients ≥ 60 Years with Relapsed or Refractory AML Treated with Vosaroxin/Cytarabine Vs Placebo/Cytarabine: Updated Results from the Valor Trial
Authors: Farhad Ravandi, Ellen K. Ritchie, Hamid Sayar, Jeffrey E. Lancet, Michael Craig, Norbert Vey, Stephen A. Strickland, Gary J. Schiller, Elias J. Jabbour, Harry P. Erba, Arnaud Pigneux, Heinz-August Horst, Christian Recher, Virginia M. Klimek, Jorge E. Cortes, Gail J. Roboz, Adam R. Craig, Renee Ward, Jennifer Smith, Hagop M. Kantarjian, Robert K. Stuart
Journal: Blood (2016)
Phase II study of apatinib plus vinorelbine, a novel combination of all-oral regimen in heavily pretreated patients with metastatic HER2-negative breast cancer.
Authors: Anjie Zhu, Peng Yuan, Jiayu Wang, Fei Ma, Yang Luo, Ying Fan, Qing LI, Pin Zhang, Binghe Xu
Journal: Journal of Clinical Oncology (2017)

TPS1123 Background: Antiangiogenic therapy in combination with chemotherapy is effective in control advanced breast cancer(ABC). Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Phase II clinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated, metastatic breast cancer. The median progression free survival (PFS) and median overall survival (OS) of single agent in both triple-negative and non-triple-negative breast cancer were 3.3-4.0 months and 10.3-10.6 months, respectively. The overall response rate and disease control rate (DCR) reached 16.7% and 66.7%, respectively. This all-oral phase II study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer(MBC). Methods: This single arm prospective study enrolled patients with HER2(Human epidermal growth factor receptor-2 ) negative advanced breast cancer, pretreated with anthracycline and taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimen. The estimated Enrollment was 40 patients.The primary end point of this study was PFS. Secondary end points included objective response rate (ORR), DCR, OS and safety. Patients were treated with apatinib 500/425mg daily plus oral vinorelbine 60-80 mg/m2 day1,8,15 every 3 weeks/cycle. Starting doses of Apatinib were chosen according to age, weight and patient status. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (6 weeks) there after until disease progressed. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs, version 4.0. Clinical trial information: NCT02768415.
Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination
Authors: Rafał J. Mostowy, Nicholas J. Croucher, Nicola De Maio, Claire Chewapreecha, Susannah J. Salter, Paul Turner, David M. Aanensen, Stephen D. Bentley, Xavier Didelot, Christophe Fraser
Journal: Molecular Biology and Evolution (2017)

Diversity of the polysaccharide capsule in Streptococcus pneumoniae-main surface antigen and the target of the currently used pneumococcal vaccines-constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium's ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination.
Effects of age, immune landscape, and response to trastuzumab (H) in HER-2 positive (HER2+) breast cancer in NCCTG (Alliance)-N9831.
Authors: Aixa Elena Soyano, Daniel Serie, Afshin Mashadi-Hossein, Sarah Warren, Gerardo Colon-Otero, Keith L. Knutson, Edith A. Perez, Alvaro Moreno-Aspitia, E Aubrey Thompson, Saranya Chumsri
Journal: Journal of Clinical Oncology (2017)

530 Background: Therapeutic efficacy of H involves activation of the immune system.Age-dependent progressive deterioration of the immune response is referred as immunosenescence. In HER2+ breast cancer, the effects of aging and the ability of H to activate endogenous anti-tumor immunity is unknown. A previous report from HERA trial showed no significant increase in risk of early recurrence with age (≤ or &gt; 40). We evaluated the long-term outcome of HER2+ patients (pt) related to age and immune landscape. Methods: 1,392 pt from N9831 trial were evaluated. Stromal tumor infiltrating lymphocytes (sTIL) were evaluated in H&amp;E slides. Lymphocyte predominant breast cancer (LPBC) was defined as sTIL ≥ 50%. Molecular TIL (mTIL) and immune subset signatures were evaluated using NanoString research CodeSets. Cox proportional hazard ratio (HR) was used for analysis. Results: There were 1,111 (79.8%) pt &gt; 40 years old (yo) and 281 (20.2%) pt ≤ 40 yo. Younger age was significantly associated with hormone receptor positivity (p 0.00011) and luminal B subtype (p 0.011). With a median follow up of 10.6 years, there was no significant difference in long-term outcome among pt ≤ 40 vs. &gt; 40 yo who received H (HR = 0.88 (0.62-1.24), p = 0.45). Similar findings were observed when age was dichotomized at 50 and 60 yo. While there was no association between sTIL and age, a small but significant increase in mTIL CD45 expression with age (p 0.003) was observed. Similar small increases in cytotoxic cell (p 0.007) and T cell (p 0.015) immune scores were also observed with increasing age. Among pt who received chemotherapy alone, pt &gt; 40 yo with LPBC (n 55) had excellent outcome with 92.4% recurrence free survival (RFS) at 10 years. However, there was no significant difference in RFS among pt ≤ 40 yo with or without LPBC. Conclusions: Among pt treated with H, there was no significant difference in outcome related to age. In contrast to a decline expected from immunosenescence, we observed small but significant increases in mTIL signatures for total lymphocytes, cytotoxic, and T cell subsets. Among patients who received chemotherapy alone, our data suggested that pt &gt; 40 yo with LPBC had excellent prognosis, compared to pt &gt; 40 yo without LPBC.
Periareolar zigzag incision in breast conserving surgery.
Authors: Beom Seok Ko, hee Jeong Kim, Jisun Kim, Sae Byul Lee, jong Won Lee, Byung Ho Sohn, Sung-Bae Kim, Sei-Hyun Ahn
Journal: Journal of Clinical Oncology (2017)

e12093 Background: Breast conserving surgery (BCS) followed by radiation therapy is today standard therapy for early breast cancer. Avoiding scars on the breast is women’s desire. Numerous minimal approaches have evolved due to this concern. The periareolar incision is often used to remove relatively small tumors located near the nipple. But periareolar incision has a disadvantages include limited exposure of the surgical field. Periareolar zigzag incision has the advantage of not only good surgical field but also contributed to better surgical scars. The purpose of this study was to evaluate the usefulness of periaroar zigzag incision and oncological safety. Methods: We retrospectively reviewed breast cancer patients who performed breast conserving surgery with periareolar zigzag incision by one surgeon from January 2016 to December 2016. In this study, patients with bilateral breast cancer or other diseases who underwent cooperative surgery were excluded. Intraoperative frozen section margin was evaluated in all patients and additional resection was performed when positive margin was present. Final margin status was determined by examination of the permanent paraffin-embedded sections. Patients characteristics, tumor characteristics, operative time, size of specimen and the distance from the tumor to nipple were evaluated. Results: A total of 193 patients were reviewed. The median age of the patients was 50 years (range: 25-79 years), median tumor size was 1.7 cm (range: 0-8.8 cm), median tumor distance from the nipple was 3.0 cm (range: 0.5-8.0 cm) and median specimen sized was 5.0 cm (range: 2.0-15.0 cm). The median operation time was 70 minutes (range: 32-138 min) in patients without axillary dissection, and 91 minutes (range: 60-171 min) in patients who underwent axillary dissection. In 13 patients (6.7%), tumor was found in intraoperative frozen biopsy and re-excision was performed. There were no major complications associated with surgery. There were no reoperations due to bleeding or other reasons. Conclusions: In breast conservation surgery, the periareolar zigzag incision technique has good cosmetic effect and a enough operative field can be obtained, so it may be applied oncological safely even when relatively large tumors are removed.
Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial
Authors: Charles T. Quinn, Santosh L. Saraf, Victor R. Gordeuk, Courtney D. Fitzhugh, Susan E. Creary, Prasad Bodas, Alex George, Ashok B. Raj, Alecia C. Nero, Catherine E. Terrell, Lisa McCord, Adam Lane, Hans C. Ackerman, Yu Yang, Omar Niss, Michael D. Taylor, Prasad Devarajan, Punam Malik
Journal: American Journal of Hematology (2017)

Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin-II-receptor-1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase-2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a ≥25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold-change in UACR was -0.74 for MacroA and -0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142➝104 mL/minute/1.73 m2 ), N = 1; rise in serum creatinine >50% (0.2➝0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase-3, randomized, placebo-controlled trial of losartan for the nephropathy of SCA.
Comparing outcomes of neoadjuvant endocrine therapy versus chemotherapy in ER-positive breast cancer: Results from a prospective institutional database.
Authors: Nathalie LeVasseur, Walter Yip, Huaqi Li, Kaylie Willems, Caroline Illmann, Miranda McDermott, Christine E. Simmons
Journal: Journal of Clinical Oncology (2017)

581 Background: While neoadjuvant chemotherapy (NACT) has been established as the standard of care for medically fit patients, there has been renewed interest in utilizing neoadjuvant endocrine therapy (NET) for the treatment of women with estrogen-receptor (ER) positive, HER-2 negative breast cancer. Rates of pCR are known to be low in this population, but there is inconsistent data regarding downstaging and long-term outcomes in a non-trial setting with NET vs NACT. Methods: A prospective institutional databaseof breast cancer patients treated with neoadjuvant therapy at the British Columbia Cancer Agency from 2012-2016 was analyzed to identify all medically fit patients with ER positive, HER2 negative breast cancer. Patients were then divided into two groups: those who received NET or NACT. Baseline characteristics were compared between groups. A matched analysis (age, stage and grade) was then performed to compare rates of downstaging, pCR and scores from a validated neoadjuvant therapy outcomes calculator (CPS+EG). Results: A total of 154 patients met eligibility criteria for this study. One hundred and six patients (69%) received NACT and 48 (31%) received NET. Women offered NACT were significantly younger (51 vs 64y, p &lt; 0.001) than those offered endocrine therapy and presented with a higher clinical stage (LR 27.93, p = 0.002). According to multiple linear regression for downstaging, clinical stage followed by NACT were the most important predictors of downstaging. When matched for age, stage and grade, downstaging was significantly higher with NACT (31/48, 65%) as compared to NET (12/48, 25%), p &lt; 0.001. Of these, 12.5% achieved pCR with NACT as compared to 2.1% with NET, LR 4.243, p = 0.039. No significant differences in CPS+EG scores were identified when comparing NACT to NET. Conclusions: Significantly higher rates of downstaging were achieved with NACT as compared to NET when patients were matched for age, stage and grade. Rates of pCR remain low for ER-positive breast cancer patients. Although not validated with the use of NET, CPS+EG scores predicting long-term outcomes were not significantly different with NET compared to NACT.