tbuckley/cabot-search huggingface dataset:
A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia
Authors: Ramiro Garzon, Michael Savona, Rachid Baz, Michael Andreeff, Nashat Gabrail, Martin Gutierrez, Lynn Savoie, Paul Morten Mau-Sorensen, Nina Wagner-Johnston, Karen Yee, Thaddeus J. Unger, Jean-Richard Saint-Martin, Robert Carlson, Tami Rashal, Trinayan Kashyap, Boris Klebanov, Sharon Shacham, Michael Kauffman, Richard Stone
Journal: Blood (2017)
The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis
Authors: Keertan Dheda, Tawanda Gumbo, Gary Maartens, Kelly E Dooley, Ruth McNerney, Megan Murray, Jennifer Furin, Edward A Nardell, Leslie London, Erica Lessem, Grant Theron, Paul van Helden, Stefan Niemann, Matthias Merker, David Dowdy, Annelies Van Rie, Gilman K H Siu, Jotam G Pasipanodya, Camilla Rodrigues, Taane G Clark, Frik A Sirgel, Aliasgar Esmail, Hsien-Ho Lin, Sachin R Atre, H Simon Schaaf, Kwok Chiu Chang, Christoph Lange, Payam Nahid, Zarir F Udwadia, C Robert Horsburgh, Gavin J Churchyard, Dick Menzies, Anneke C Hesseling, Eric Nuermberger, Helen McIlleron, Kevin P Fennelly, Eric Goemaere, Ernesto Jaramillo, Marcus Low, Carolina Morán Jara, Nesri Padayatchi, Robin M Warren
Journal: The Lancet Respiratory Medicine (2017)
Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection
Authors: Oluwaseun Falade-Nwulia, Catalina Suarez-Cuervo, David R. Nelson, Michael W. Fried, Jodi B. Segal, Mark S. Sulkowski
Journal: Annals of Internal Medicine (2017)

Background: Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection. Purpose: To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection. Data Sources: MEDLINE and EMBASE from inception through 1 November 2016. Study Selection: 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently. Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without. Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling. Conclusion: Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis. Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711)
Contribution of Assisted Reproductive Technology to Overall Births by Maternal Age in the United States, 2012-2014
Authors: Aaron D. Levine, Sheree L. Boulet, Dmitry M. Kissin
Journal: JAMA (2017)

This study uses US Centers for Disease Control and Prevention surveillance data to estimate the proportion of live births attributable to assisted reproductive technology by maternal age in the United States between 2012 and 2014.
Phase I study of concomitant chemoradiotherapy with irinotecan, 5-FU, and hydroxyurea for patients with advanced and/or recurrent head and neck cancer: Toxicity and outcome results
Authors: J. K. Salama, D. J. Haraf, K. Stenson, E. E. Vokes
Journal: Journal of Clinical Oncology (2004)

5561 Background: At University of Chicago, concomitant chemoRT for advanced and recurrent head and neck cancer has been studied for 2 decades. We investigated the addition of CPT-11 as a promising new agent to our established regimen of 5-FU, hydroxyurea (HU), and hyperfractionated RT (HF2X). The goal was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of this regimen. Time to progression, patterns of failure, and survival were secondary endpoints. Methods: Between 8/98 and 8/01, 31 pts with advanced and recurrent H&N cancer were enrolled. Previously untreated pts were eligible if unressectable or had an expected 2 year survival <20%. Pts with metastatic disease were included if local radiotherapy to the H&N was required. 19 previously radiated pts were included. The median prior RT dose was 66.4 Gy (range: 45–88.4 Gy). The starting dose of CPT-11 was 5 mg/m2/d delivered with continuous infusion 5-FU (600 mg/m2/d), HU (500 mg PO q 12 hours) and BID RT (1.5 Gy/fraction). All pts were treated on a 14 d cycle with 5 consecutive days of therapy and a 9 day break. Subsequent cohorts had CPT-11 escalated by 5 mg/m2/d. Subsequently, 14 pts were treated at the MTD. Results: CPT-11 was well tolerated at the 5 mg/m2/d and 10 mg/m2/d dose levels. 3/3 pts treated at the 15 mg/m2/d level, experienced neutropenic DLT during cycles 1–2. 8/18 (44%) evaluable pts had a response; 5 (28%) had a CR, 3 (17%) had a PR, 5 had stable disease (28%) and 5 pts progressed. At a median f/u of 24 mos for surviving pts, (range, 16.5–51), 4 pts (13%) are alive and NED. 2 yr overall survival (OS) and disease free survival (DFS) was 31.3% and 24.4%. Re-irradiated pts had a median survival of 9.5 mos (range: 0.7–50.5) and a 2 yr OS of 24.5%. 2 yr DFS of squamous histology re-irradiation pts was 23%. Conclusions: The MTD and recommended phase II dose of CPT-11/ HF2X was 10 mg/m2/d. Neutropenia was dose limiting. Response rates were reasonable. Further investigation of this regimen may be worth additional study. Re-irradiation with concurrent chemotherapy resulted in the survival of a significant fraction of pts. No significant financial relationships to disclose.
Phase III SYNERGY trial: Docetaxel +/- custirsen and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and poor prognosis.
Authors: Kim N. Chi, Celestia S. Higano, Brent A. Blumenstein, James Andrew Reeves, Susan Feyerabend, Gwenaelle Gravis, Jean-Marc Ferrero, Cindy Jacobs, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2015)

5009 Background: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a 2nd-generation antisense that inhibits clusterin production. The SYNERGY trial evaluated docetaxel +/- custirsen as 1st-line therapy in men with mCRPC (N = 1022). Following 509 deaths, median overall survival (OS) was 23.4 months (m) vs. 22.2 m for custirsen and control arms, respectively (hazard ratio [HR] 0.93; P = 0.42). To explore the hypothesis that clusterin inhibition may be more relevant in poor prognosis disease, we evaluated outcomes by prognostic sub-groups retrospectively. Methods: A prognostic scoring system was developed in the control arm using multiple variable modeling. The modeling included evaluation of interactions and used hierarchical step down. Results of the final model included the following main effects: liver mets, opioid use, Karnofsky < 90, PSA, LDH, alk phos, and hemoglobin. The median score dichotomized pts into good and poor prognosis. Outcomes included survival and PSA progression as defined by PCWG1 and PCWG2. Results: The analysis included 984 pts with complete data. Median survival for the poor and good prognosis groups in the control arm was 14.0 m and 30.4 m, respectively (HR = 3.66). The custirsen HR effect differed between poor and good prognosis groups (interaction P = 0.069). The HR estimate for custirsen survival benefit was 0.73 (95% CI: 0.0589 to 0.902) for poor prognosis and 1.02 (95% CI: 0.760 to 1.37) for good prognosis. The poor prognosis group was analyzed separately for treatment effect (n = 492). The median OS was 17.0 m in the custirsen arm vs. 14.0 m in the control arm (stratified HR = 0.72, 95%CI: 0.579 to 0.892, P = 0.0026). PSA progression in the poor prognosis group also favored custirsen with a HR of 0.73 (95% CI: 0.589 to 0.907) for PCWG1 and 0.808 (95% CI: 0.633 to 1.031) for PCWG2. Conclusions: CRPC pts with a poor prognosis appeared to benefit from custirsen when added to docetaxel as 1st-line therapy. This finding underscores the importance of enriching for a study population based on the mechanism of action for targeted agents. Clinical trial information: NCT01188187.
CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment
Authors: Bradley W. Blaser, Jessica L. Moore, Elliott J. Hagedorn, Brian Li, Raquel Riquelme, Asher Lichtig, Song Yang, Yi Zhou, Owen J. Tamplin, Vera Binder, Leonard I. Zon
Journal: The Journal of Experimental Medicine (2017)

The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Recent advances marking fluorescent HSPCs have allowed exquisite visualization of HSPCs in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Here, we show that the chemokine cxcl8 and its receptor, cxcr1, are expressed by zebrafish endothelial cells, and we identify cxcl8/cxcr1 signaling as a positive regulator of HSPC colonization. Single-cell tracking experiments demonstrated that this is a result of increases in HSPC–endothelial cell “cuddling,” HSPC residency time within the CHT, and HSPC mitotic rate. Enhanced cxcl8/cxcr1 signaling was associated with an increase in the volume of the CHT and induction of cxcl12a expression. Finally, using parabiotic zebrafish, we show that cxcr1 acts HSPC nonautonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that cxcl8/cxcr1 signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation.
IS SHOE DROP A KEY FACTOR FOR INJURY PREVENTION IN RUNNING? PART 1: AN RCT ON INJURY RISK
Authors: Laurent Malisoux, Nicolas Chambon, Axel Urhausen, Daniel Theisen
Journal: British Journal of Sports Medicine (2017)

Background Modern running shoes come in variable heel-to-toe drops, but it is currently unknown if this feature plays a role in the prevention of injuries. Objective To determine if the drop of conventional cushioned running shoes influences injury risk and whether running regularity (&gt;6 months of regular practice over the previous year) modifies this association. Design Double-blind randomised controlled trial, with a 6-month follow-up. Setting Leisure-time distance runners. Participants Study participants (n=553) were recruited via advertisements in local newspapers. They were required to report any running activity, sport practice and injury using a dedicated internet platform. Intervention Running shoes with a drop of 10 mm (D10, n=176), 6 mm (D6, n=190) or 0 mm (D0, n=187). Apart from the shoe drop, the 3 versions were strictly identical. A stratified analysis was conducted according to the participants' running regularity. Main Outcome Measurements First running-related injury self-reported by the participants, and systematically verified by email or phone call. Cox regression analyses were used to compare injury risk between exposure groups. Results 136 of the participants (25%) sustained at least one injury. The proportion of injured participants were 21.6%, 27.4% and 24.6% in the D10, D6 and D0 groups, respectively. The overall injury risk was not different among the participants who had received the D6 version (hazard rate ratios – HR=1.30; 95% confidence intervals −95% CI=0.86–1.98) or the D0 version (HR=1.17; 95% CI=0.76–1.80) when compared to the conventional D10 version. The stratified analysis revealed that low drop shoes (D6 and D0 grouped together) were associated with a lower injury risk in occasional runners (HR=0.48; 95% CI=0.23–0.98), and with a higher injury risk in regular runners (HR=1.67; 95% CI=1.07–2.62). Conclusions Overall, injury risk was not influenced by the drop of conventional cushioned running shoes, yet this association may be modified by the runner's profile.
First-line chemotherapy (CT) versus anti-androgen therapy (AT) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Individual patient analysis of the Veterans Health Administration (VHA) dataset.
Authors: Guru Sonpavde, Ahong Huang, Li Wang, Onur Baser, Raymond Miao
Journal: Journal of Clinical Oncology (2017)

156 Background: The outcomes of pts receiving first-line CT vs AT for mCRPC are unclear. Using the VHA dataset, we compared outcomes with first-line CT vs AT in pts with mCRPC and assessed the impact of prior androgen deprivation therapy (ADT) duration and known prognostic factors. Methods: Pts with mCRPC initiating first-line AT (abiraterone, enzalutamide) or CT (taxane) from Oct 2012 to Sept 2014 were identified. The impact of AT vs CT on overall survival (OS) and time to discontinuation (TTD) was assessed using Cox proportional hazard models, adjusting for prior ADT duration, known prognostic factors (hemoglobin [Hb], albumin [alb], alkaline phosphatase [ALP], prostate-specific antigen [PSA]), Charlson Comorbidity Index (CCI) and chronic disease score (CDS). Results: Overall, 1445 pts were evaluable; 1108 received AT (abiraterone 996, enzalutamide 112) and 337 received CT (docetaxel). The overall median duration of prior ADT was 464 days. On multivariable analysis, prior ADT duration, CCI, CDS, Hb, Alb, ALP and PSA were associated with OS, but AT vs CT was not (HR: 1.041 [95% CI: 0.853–1.270], p = 0.6943). PSA levels, prior ADT duration, and ALP was associated with TTD, and TTD was shorter for CT vs AT (HR: 2.339 [95% CI: 1.969–2.779], p &lt; 0.0001). Longer prior ADT duration was associated with longer OS (HR: 0.566, p &lt; 0.0001) and TTD (HR: 0.831, p = 0.0363) in the AT cohort, but not in the CT cohort. Treatment-free interval (TFI) (between first- and second-line treatment) was longer for CT vs AT (mean: 53 vs 39 days; p = 0.0303). Conclusions: To our knowledge, this is one of the largest mCRPC datasets analyzed at the individual pt level comparing first-line CT vs AT. OS was not significantly different for first-line CT vs AT after adjusting for key prognostic factors, despite shorter TTD with CT and longer TFI after first-line CT. Prior ADT duration ≤ 464 days was associated with shorter OS and TTD in the AT cohort, but not the CT cohort, suggesting that such pts may benefit from receiving CT over AT. The results are hypothesis-generating and prospective validation is required. Funding: Sanofi Genzyme
AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling
Authors: Renfang Mao, Shu Meng, Qilin Gu, Raquel Araujo-Gutierrez, Sandeep Kumar, Qing Yan, Felicidad Almazan, Keith A. Youker, Yingbin Fu, Henry J. Pownall, John P. Cooke, Yury I. Miller, Longhou Fang
Journal: Circulation Research (2017)

Angiogenesis improves perfusion to the ischemic tissue after acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that AIBP (apolipoprotein A-I [apoA-I]-binding protein)-regulated cholesterol efflux in endothelial cells controls zebra fish embryonic angiogenesis.This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions and to explore the underlying molecular mechanism.In this article, we report the generation of AIBP knockout (Apoa1bp-/-) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to nonlipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4 (delta-like ligand 4)-stimulated Notch activation in human retinal endothelial cells. Increasing high-density lipoprotein levels in Apoa1bp-/- mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp-/- mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp-/- mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy.Our data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions.
Low-dose gemcitabine doxorubicin and docetaxel combination in patients with advanced/unresectable/metastatic sarcoma who failed prior chemotherapy: Updated analysis.
Authors: Vivek Narasimhan, James Hu, Kamalesh Kumar Sankhala, Doris V. Quon, Lawrence Menendez, Lita Fernandez, Victoria S Chua, Sant P. Chawla
Journal: Journal of Clinical Oncology (2014)

10599 Background: Gemcitabine with Docetaxel is active in soft tissue sarcoma. Doxorubicin is a standard agent for sarcoma with proven efficacy. The combination of Gemcitabine, Docetaxel and Doxorubicin has been studied, and is well tolerated and active in breast cancer and non-small cell lung cancer. This study assesses the safety profile and efficacy of Gemcitabine, Doxorubicin, and Docetaxel regimen in patients with advanced, metastatic and/or unresectable sarcoma. Methods: 31 patients with advanced unresectable/metastatic sarcomas who progressed through standard chemotherapy were enrolled with consent. Patients were treated with Gemcitabine 400 mg/m2, Doxorubicin 20 mg/m2, and Docetaxel 20 mg/m2 on days 1 and 8 of a 21 day cycle. Disease was assessed with RECIST 1.1 and median Progression Free Survival(PFS) and Response rates(RR) were calculated. Toxicity evaluation was done using NCI CTCAE 4.2. Results: All subjects had advanced metastatic disease and were treated with a median of 2 prior regimens(range1-6). The sarcoma subtypes were Leiomyosarcoma(29%), Dedifferentiated Liposarcoma(13%), Myxoid Liposarcoma(13%), Angiosarcoma(6%), Synovial Sarcoma(6%), Pleiomorphic Undifferentiated Sarcoma(6%) and other(27%). 31% patients were treated with prior Gemcitabine and Taxotere and 67% with prior Anthracycline. The median age was 53(range25-72). 31 patients were enrolled and 26 were evaluable for response. A partial response was observed in one patient and stable disease in 24 patients with a median PFS of 3.5 months. Grade 3 or 4 cytopenias were observed in 45% of patients(7neutropenia, 3Anemia, and 5thrombocytopenia). One patient was taken off study due to toxicity and no significant grade 3 or 4 non-hematologic toxicities were seen. Conclusions: The combination of Gemcitabine, Doxorubicin and Docetaxel is well tolerated with manageable toxicity profile. Though response rates were low, this heavily pretreated population demonstrated durable stable disease even when rechallenged with prior used agents. The role of this low dose combination is not well defined but should be considered as an option in the appropriate setting.
Outcome of recurrent osteosarcoma patients enrolled in seven phase II trials through CCG, POG, and COG: Learning from the past to move forward.
Authors: Joanne P. Lagmay, Mark D. Krailo, Ha Dang, AeRang Kim, Douglas S. Hawkins, Orren Beaty, Brigitte C. Widemann, Theodore Zwerdling, Lisa Bomgaars, Anne-Marie Langevin, Holcombe E. Grier, Brenda Weigel, Susan Blaney, Richard Greg Gorlick, Katherine A. Janeway
Journal: Journal of Clinical Oncology (2015)

10042 Background: The use of radiographic response as the primary endpoint in phase II osteosarcoma (OS) trials may limit optimal detection of treatment response due to the calcified tumor matrix. We assessed outcome data for children with recurrent/refractory OS enrolled on single agent Children’s Oncology Group phase II trial to establish this cohort’s baseline expected survival outcome. Methods: We performed a retrospective analysis of outcome for children with recurrent/refractory OS enrolled on one of seven phase II trials with an OS stratum conducted by COG and predecessor groups from 1997-2007. Trials included A09713 (topotecan), ADVL0122 (imatinib), ADVL0421 (oxaliplatin), ADVL0524 (ixabepilone), CCG-0962 (docetaxel), P9761 (irinotecan) and P9963 (rebeccamycin analogue). All trials used RECIST or WHO with primary endpoint as response rate. Event Free Survival (EFS) was correlated with the following potential prognostic factors: age, trial, number of prior chemotherapy regimens, gender and race. To determine the historical disease control rate for patients with fully resected disease, we used the EFS in a Phase II study (AOST0221) of osteosarcoma patients given inhaled GMCSF with first pulmonary recurrence, which had a biological endpoint. Results: In each included trial the OS stratum failed to meet the primary endpoint. Radiographic responses were observed in only 3 trials. The highest response rate was 11% seen in A09713. EFS for 96 subjects with OS and measurable disease was 12% at 4 months (95% CI: 6-19%). There was no impact of age, gender or race on EFSnor was there a significant difference in EFS across trials or by number of prior treatment regimens. The 12-month EFS for the 42 subjects enrolled in AOST0221 was 20% (95% CI: 10-34%). Conclusions: The aggregate outcome for children with recurrent/refractory OS in these previously conducted single arm phase II trials was disappointing. Given the poor EFS for children with recurrent/refractory OS it is unlikely that active agents were missed using traditional RECIST response. Nevertheless, we have now defined baseline EFS outcomes that can be incorporated into future phase II trial design for recurrent osteosarcoma.