tbuckley/cabot-search huggingface dataset:
Preventing skeletal related events in veterans on bisphosphonates for bone metastases.
Authors: Sheetal Malhotra, Kosana Simeunovic, Ekkawit Chanchorn, Marianna Strakhan, Yeun-Hee Anna Park
Journal: Journal of Clinical Oncology (2014)

e17654 Background: Multiple myeloma and solid tumor metastases can cause bone disease leading to skeletal-related events (SREs) such as bone pain, fractures and spinal cord compression. Intravenous bisphosphonate therapy which is indicated in such cases can lead to osteonecrosis of the jaw and hypocalcemia putting patients at risk for SREs. To decrease these risks, patients require dental evaluation prior to start of bisphosphonate therapy and should be initiated on calcium and vitamin D supplementation. Even with these practice recommendations in place, there is paucity of data on compliance with these recommendations. Our study of veterans with bone metastases or multiple myeloma aimed to 1) Identify those treated with intravenous bisphosphonates. 2) Assess screening dental evaluation prior to treatment. 3) Measure effectiveness of calcium and vitamin D supplementation on bone health. Methods: We performed a retrospective chart review at a Veterans Affairs Medical Center of 118 veterans with multiple myeloma or bone metastases who received intravenous bisphosphonate therapy between January 2008 and November 2013. Patients undergoing dental clearance prior to initiation of intravenous bisphosphonate therapy, and supplementation of vitamin D and calcium were assessed. Data on SREs were also obtained. Results: Of the 118 patients included in the study, 50 (42%) had prostate cancer, 22 (18%) had multiple myeloma and 15 (13%) had lung cancer. All patients receiving bisphosphonates for bone metastases had undergone a dental evaluation prior to starting therapy. However, only 67% had a vitamin D level checked before therapy; 42% of these were vitamin D deficient – 69% received vitamin D supplementation. Overall, rates of calcium and vitamin D supplementation were very low (24% and 27% respectively). 64% of the patients reported an SRE; 41% with bone pain, 11% with pathological fractures, 5% with traumatic fractures, and 6% with nerve root compression. Vitamin D supplementation significantly reduced the odds of an SRE for our patients (OR 0.29, 95% CI = 0.11- 0.80, P< 0.05). Conclusions: Adequate prevention practices can improve bone health and decrease SREs among veterans with multiple myeloma or bone metastases.
Impact of hepatitis C virus polymorphisms on direct‐acting antiviral treatment efficacy: Regulatory analyses and perspectives
Authors: Patrick R. Harrington, Takashi E. Komatsu, Damon J. Deming, Eric F. Donaldson, Julian J. O'Rear, Lisa K. Naeger
Journal: Hepatology (2017)

Several highly effective, interferon‐free, direct‐acting antiviral (DAA)‐based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance‐associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)‐approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously naïve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug‐selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next‐generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance‐related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA‐approved DAA regimens. Conclusion: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA‐based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (H epatology 2018;67:2430‐2448).
Somatic CLL mutations occur at multiple distinct hematopoietic maturation stages: documentation and cautionary note regarding cell fraction purity
Authors: S Marsilio, H Khiabanian, G Fabbri, S Vergani, C Scuoppo, E Montserrat, E J Shpall, M Hadigol, P Marin, K R Rai, R Rabadan, S Devereux, L Pasqualucci, N Chiorazzi
Journal: Leukemia (2017)

Somatic CLL mutations occur at multiple distinct hematopoietic maturation stages: documentation and cautionary note regarding cell fraction purity
Abstract 19661: Ultra High Frequency Ultrasound in Detection of Intimal and Medial Changes in Pediatric Kidney Disease
Authors: Frida Dangardt, Marietta Charakida, Devina Bhowruth, Daniela Thurn, Alicja Rapala, Franz Schaefer, John Deanfield, Rukshana Shroff
Journal: Circulation (2016)

Introduction:  Premature arterial disease has been reported in chronic kidney disease (CKD) patients. However, using conventional methods it is not possible to determine whether these are driven by metabolic (medial) abnormalities rather than traditional cardiovascular (intimal) risk factors.   Hypothesis:  Using an ultra high-resolution ultrasound (UHRUS) technique to measure medial and intimal arterial changes will allow assessment of their determinants and progression in predialysis, dialysis and renal transplanted children.   Methods:  Intimal (IT) and medial (MT) thickness of the carotid, radial and dorsal pedal arteries were measured by UHRUS (40-750MHz) in 54 children (19 pre-dialysis CKD, 20 on dialysis and 15 post-transplant) at baseline and compared to 20 matched healthy controls. One year follow up measurements were performed in 24 children (11 pre-dialysis CKD and 15 post-transplant). Conventional ultrasound (CUS) for carotid IMT was measured for comparison.   Results:  All CKD patients had higher radial IT compared to controls (p=0.05). CUS measurements were similar between patient groups.  CKD children on dialysis for >1year had greater carotid and dorsal pedal MT compared to those on dialysis for   At 1-year follow-up transplanted children had a decrease in carotid and radial MT (p = 0.01 for both), but an increase in dorsal pedal IT (p=0.04). Increased dorsal pedal IT in transplanted patients was associated with a higher systolic BP z- score (p = 0.2, r = 0.22). Children with pre-dialysis CKD (n=6) had a decrease in radial MT (p=0.04), but no other significant changes.   Conclusions:  UHRUS assessment in CKD patients identified modifiable risk factors for intimal and medial vascular disease, which were not detected by CUS. Our findings suggest vascular remodeling in response to a changing cardiovascular risk factor profile after renal transplantation and provide important information for effective CV stratification and treatment of these patients.
Safety and Efficacy of Single-Dose Intravenous Fosaprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients with Hematooncological Malignancies after Moderate and High Emetogenic Chemotherapy
Authors: Semjon Willier, Karin Melanie Cabanillas Stanchi, Martha von Have, Vera Binder, Franziska Blaeschke, Tobias F. Feuchtinger, Michaela Döring
Journal: Blood (2017)
Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study
Authors: Beate Kampmann, James A. Seddon, James Paton, Zohreh Nademi, Denis Keane, Bhanu Williams, Amanda Williams, Sue Liebeschutz, Anna Riddell, Jolanta Bernatoniene, Sanjay Patel, Nuria Martinez, Paddy McMaster, Robindra Basu-Roy, Steven B. Welch
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

To identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of IFN-γ release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children who screened TST-positive but IGRA-negative.We performed a cohort study to evaluate the risk of TB disease in this group.Children exposed to an infectious case of TB in their household were recruited from 11 pediatric TB clinics. TST and IGRA were performed at baseline, with IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months.Of 431 recruited children, 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection, and 239 (60.9%) without TB infection or disease. Eighteen children aged 2 years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. Ninety (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016.In this low-prevalence setting we saw no incident cases of TB disease in children who were TST-positive but IGRA-negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.
An NF-κB signature predicts low-grade glioma prognosis: a precision medicine approach based on patient-derived stem cells
Authors: Tamara Ius, Yari Ciani, Maria Elisabetta Ruaro, Miriam Isola, Marisa Sorrentino, Michela Bulfoni, Veronica Candotti, Cecilia Correcig, Evgenia Bourkoula, Ivana Manini, Enrico Pegolo, Damiano Mangoni, Stefania Marzinotto, Slobodanka Radovic, Barbara Toffoletto, Federica Caponnetto, Andrea Zanello, Laura Mariuzzi, Carla Di Loreto, Antonio Paolo Beltrami, Silvano Piazza, Miran Skrap, Daniela Cesselli
Journal: Neuro-Oncology (2017)

While recent genome-wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived and representative of the glioma microenvironment.By next-generation sequencing, we analyzed the transcriptional profile of GASC derived from patients who underwent anaplastic transformation either within 48 months (GASC-BAD) or ≥7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of a nuclear factor-kappaB (NF-κB) signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-κB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGGs.The key elements differentiating the transcriptome of GASC isolated from LGG with different prognoses were mostly related to hallmarks of cancer (eg, inflammatory/immune process, NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the dataset of TCGA. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression-free survival in 146 grade II LGGs.This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG and outlines the role of patient-based stem cell models as a tool for precision medicine approaches.
A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia
Authors: Eytan M. Stein, Roland B. Walter, Harry P. Erba, Amir T. Fathi, Anjali S. Advani, Jeffrey E. Lancet, Farhad Ravandi, Tibor Kovacsovics, Daniel J. DeAngelo, Dale Bixby, Stefan Faderl, Anand P. Jillella, Phoenix A. Ho, Megan M. O’Meara, Baiteng Zhao, Charles Biddle-Snead, Anthony S. Stein
Journal: Blood (2017)
Small molecule inhibition of stat3 enhances survival in mice with intracerebral melanoma
Authors: Ling-Yuan Kong, Mohamed Abou-Ghazal, Arup Chakraborty, Greg Fuller, Timothy Madden, Wei Qiao, Elizabeth Grimm, Waldemar Priebe, Amy Heimberger
Journal: Cancer Research (2008)

4873  Melanoma is a common and deadly tumor that upon metastasis to the brain, survival is less than one year. Development of new, effective therapies for metastatic melanoma that target novel pathways associated with the genesis of metastatic disease is a major unmet clinical need. Constitutive activation of STAT3 has been demonstrated in a variety of human malignancies, including melanoma. We have designed and synthesized a series of potential inhibitors of the JAK2/STAT3 pathway and identified a lead compound displaying high activity within in vivo models. In the study described here, we tested that in mouse models WP1066, a novel STAT3 pathway blockade agent, has marked in vitro and in vivo activity, even with metastasis to the brain, a site typically refractory to therapies. WP1066 achieved an IC50 of 1.6 μM, 2.3 μM, and 1.5 μM against the human melanoma cell line A375, murine melanoma cell line B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of JAK2 and phosphorylation (Tyr705) of STAT3 in all three melanoma cell lines. In addition, WP1066 decreased the level of c-Myc and survivin in melanoma cells in a dose- and time-dependent manner. Subcutaneous tumor growth of B16EGFRvIII and B16 in a syngeneic murine model in the C57BL/6J background was markedly inhibited by WP1066 compared to those in the vehicle control group (P
Efficacy of PEGylated human IL-10 (AM0010) in combination with anti-PD-1 blockade in patients (pts) with metastatic renal cell carcinoma (mRCC): A phase 1b trial
Authors: A. Naing, J. Infante, D. Wong, W.M. Korn, R. Aljumaily, K. Papadopoulos, K. Autio, S. Pant, T. Bauer, A. Drakaki, N. Daver, A. Hung, P. Van Vlasselaer, M. Oft, N. Tannir
Journal: Annals of Oncology (2017)
Potent long-term cardioprotective effects of single low dose insulin-like growth factor-1 (LD-IGF-1) treatment post myocardial infarction
Authors: J. O'sullivan, A. Leblond, G. Kelly, A. Kumar, Pat Metharom, C. Buneker, N. Alizadeh-Vikali, B. Hynes, R. O'connor, N. Caplice
Journal: Cardiovascular Research (2012)
The full moon and motorcycle related mortality: population based double control study
Authors: Donald A Redelmeier, Eldar Shafir
Journal: BMJ (2017)

<h3>Abstract</h3> <h3>Objective</h3> To test whether a full moon contributes to motorcycle related deaths. <h3>Design</h3> Population based, individual level, double control, cross sectional analysis. <h3>Setting</h3> Nighttime (4 pm to 8 am), United States. <h3>Participants</h3> 13 029 motorcycle fatalities throughout the United States, 1975 to 2014 (40 years). <h3>Main outcome measure</h3> Motorcycle fatalities during a full moon. <h3>Results</h3> 13 029 motorcyclists were in fatal crashes during 1482 relevant nights. The typical motorcyclist was a middle aged man (mean age 32 years) riding a street motorcycle with a large engine in a rural location who experienced a head-on frontal impact and was not wearing a helmet. 4494 fatal crashes occurred on the 494 nights with a full moon (9.10/night) and 8535 on the 988 control nights without a full moon (8.64/night). Comparisons yielded a relative risk of 1.05 associated with the full moon (95% confidence interval 1.02 to 1.09, P=0.005), a conditional odds ratio of 1.26 (95% confidence interval 1.17 to 1.37, P&lt;0.001), and an absolute increase of 226 additional deaths over the study interval. The increase extended to diverse types of motorcyclists, vehicles, and crashes; was accentuated during a supermoon; and replicated in analyses from the United Kingdom, Canada, and Australia. <h3>Conclusion</h3> The full moon is associated with an increased risk of fatal motorcycle crashes, although potential confounders cannot be excluded. An awareness of the risk might encourage motorcyclists to ride with extra care during a full moon and, more generally, to appreciate the power of seemingly minor distractions at all times.
De novo and secondary anaplastic meningiomas: a study of clinical and histomolecular prognostic factors
Authors: Matthieu Peyre, Guillaume Gauchotte, Marine Giry, Sébastien Froehlich, Johan Pallud, Thomas Graillon, Franck Bielle, Dominique Cazals-Hatem, Pascale Varlet, Dominique Figarella-Branger, Hugues Loiseau, Michel Kalamarides
Journal: Neuro-Oncology (2017)

Following recent studies underlining the differences between de novo and secondary anaplastic meningiomas and the prognostic value of telomerase reverse transcriptase (TERT) promoter mutation, we decided to conduct a multicenter retrospective study to address these questions and determine specific prognostic factors in each of these 2 anaplastic meningioma subgroups.Among the 68 meningioma cases initially selected, only 57 were confirmed as anaplastic meningiomas after centralized pathological review. TERT promoter mutation analysis was performed in all cases.Median overall survival was 2.6 years and 5-year survival rate was 10%. This study confirmed the better prognosis of de novo anaplastic meningiomas (28 tumors) compared with secondary anaplastic meningiomas (29 tumors) (P = 0.02). In the "de novo" group, meningiomas diagnosed on histological anaplasia alone had a better prognosis than those in patients with a high number of mitoses with or without anaplasia (P = 0.01). In the "secondary" group, tumors demonstrate very heterogeneous clinical courses leading to malignant transformation, and time to first relapse as a low-grade tumor was a strong predictor of overall survival (P = 0.0007). TERT promoter mutation in anaplastic meningiomas was rare (14%) and did not influence overall survival but was associated with a shorter recurrence-free survival in the secondary anaplastic meningioma subgroup (P = 0.02). The absence of TERT promoter methylation, although rare (3/33 cases), may be associated with prolonged overall survival (P = 0.02).This study highlights the different prognoses of de novo and secondary anaplastic meningiomas with specific prognostic factors in each subgroup. The analysis of TERT mutation and methylation could provide additional prognostic insights.
Encouraging New Uses for Old Drugs
Authors: Rachel E. Sachs, Paul B. Ginsburg, Dana P. Goldman
Journal: JAMA (2017)

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Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines
Authors: Hirofumi Nishikawa, Yoshinori Taniguchi, Tatsuki Matsumoto, Naoki Arima, Mamoru Masaki, Yoshiko Shimamura, Kosuke Inoue, Taro Horino, Shimpei Fujimoto, Kentaro Ohko, Toshihiro Komatsu, Keiko Udaka, Shigetoshi Sano, Yoshio Terada
Journal: Kidney International (2017)
Introduction of Inactivated Poliovirus Vaccine and Impact on Vaccine-Associated Paralytic Poliomyelitis — Beijing, China, 2014–2016
Authors: Dan Zhao, Rui Ma, Tao Zhou, Fan Yang, Jin Wu, Hao Sun, Fang Liu, Li Lu, Xiaomei Li, Shuyan Zuo, Wei Yao, Jian Yin
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

When included in a sequential polio vaccination schedule, inactivated polio vaccine (IPV) reduces the risk for vaccine-associated paralytic poliomyelitis (VAPP), a rare adverse event associated with receipt of oral poliovirus vaccine (OPV). During January 2014, the World Health Organization (WHO) recommended introduction of at least 1 IPV dose into routine immunization schedules in OPV-using countries (1). The Polio Eradication and Endgame Strategic Plan 2013-2018 recommended completion of IPV introduction in 2015 and globally synchronized withdrawal of OPV type 2 in 2016 (2). Introduction of 1 dose of IPV into Beijing's Expanded Program on Immunization (EPI) on December 5, 2014 represented China's first province-wide IPV introduction. Coverage with the first dose of polio vaccine was maintained from 96.2% to 96.9%, similar to coverage with the first dose of diphtheria and tetanus toxoids and pertussis vaccine (DTP) (96.5%-97.2%); the polio vaccine dropout rate (the percentage of children who received the first dose of polio vaccine but failed to complete the series) was 1.0% in 2015 and 0.4% in 2016. The use of 3 doses of private-sector IPV per child decreased from 18.1% in 2014, to 17.4% in 2015, and to 14.8% in 2016. No cases of VAPP were identified during 2014-2016. Successful introduction of IPV into the public sector EPI program was attributed to comprehensive planning, preparation, implementation, robust surveillance for adverse events after immunization (AEFI), and monitoring of vaccination coverage. This evaluation provided information that helped contribute to the expansion of IPV use in China and in other OPV-using countries.