tbuckley/cabot-search huggingface dataset:
Efficacy and safety of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor harboring secondary mutation with exon 17: Interim report of a phase II trial.
Authors: Chun-Nan Yeh
Journal: Journal of Clinical Oncology (2016)

e22511 Background: Metastatic gastrointestinal stromal tumor (GIST) is a life-threatening disease with no suitable therapy after discovering secondary mutations with exon 17. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Previous in-vitro study showed that regorafenib has inhibitory effect on GIST cells harboring exon 17 mutation. Thus, we performed a phase II trial in patients with advanced GIST harboring secondary KIT mutations with exon 17 to examine the clinical benefit and safety of regorafenib treatment (ClinicalTrials.gov identifier: NCT02606097). Methods: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary endpoint was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] for more than 16 weeks). Results: From May 2014 to May 2015, 15 patients were enrolled at four Taiwan centers for this interim report. CBR was 80%. Five patients achieved PR, and 7 exhibited SD for more than 16 weeks. Median progression-free survival (PFS) was not reachable. Adverse events occurred rapidly after treatment initiation and might be managed via dose modification. The most common grade 3 toxicities was hand-foot-skin reaction (HFSR; 8/15; 55.3%), followed by hypertension (5/15; 33.3%). Conclusions: Regorafenib has significant PFS benefit in patients with advanced GIST harboring secondary KIT mutation with exon 17, especially for patient with stable disease status at enrollment. However, higher frequency of grade III toxicity was observed, especially for HFSR. Further investigation of mechanism responsible for grade III toxicity is urgently needed. Clinical trial information: NCT02606097.
The roadmap for allergology in Europe: The subspecialty of allergology as “stop‐over” on the way to a full specialty. An <scp>EAACI</scp> position statement
Authors: R. Gerth van Wijk, I. Eguiluz‐Gracia, J. Gayraud, J. Gutermuth, E. Hamelmann, E. Heffler, T. A. Popov, P. Schmid‐Grendelmeier, P. V. Tomazic, O. Tsilochristou, N. Muelleneisen
Journal: Allergy (2017)

The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.
Ongoing outbreak with well over 4,000 measles cases in Italy from January to end August 2017 − what is making elimination so difficult?
Authors: Antonietta Filia, Antonino Bella, Martina Del Manso, Melissa Baggieri, Fabio Magurano, Maria Cristina Rota
Journal: Eurosurveillance (2017)

We report an ongoing measles outbreak in Italy, with over 4,400 cases reported in 20 Regions from January to August 2017. Median age was 27 years, 88% of the cases were unvaccinated. The highest incidence was in infants below one year of age and 7% of cases occurred among healthcare workers. Three deaths occurred and two cases of encephalitis were reported. Wide immunity gaps and nosocomial transmission are major challenges to measles elimination in Italy.
Low incidence of subsequent bacteraemia or fungaemia after removal of a colonized intravascular catheter tip
Authors: N. Buetti, E. Lo Priore, A. Atkinson, A. Kronenberg, J. Marschall, A. Burnens, A. Cherkaoui, V. Gaia, O. Dubuis, A.G. Viollier, A. Egli, D. Koch, A. Kronenberg, S. Luyet, P. Nordmann, V. Perreten, J.-C. Piffaretti, G. Prod'hom, J. Schrenzel, S. Leib, A.F. Widmer, G. Zanetti, R. Zbinden
Journal: Clinical Microbiology and Infection (2017)
Abstract 1: Abnormal Cardiac Differentiation Underlies Cardiac Hypertrophy in Noonan Syndrome With RAF1 Mutation
Authors: Fabrice Jaffre, Gang Wang, Amy Roberts, William Pu, Andreas Hahn, Maria Kontaridis
Journal: Circulation Research (2016)

Noonan Syndrome (NS), an autosomal dominant RASopathy disorder, is caused by germ-line mutations that affect the canonical RAS-MAPK pathway. &gt;95% of NS patients with an S257L mutation in Raf1 exhibit cardiac hypertrophy (CH) at a very young age. However, the molecular and developmental mechanisms that elicit CH in these patients remain unknown. Hence, we aimed at modeling CH by differentiating human NS Raf1 induced-pluripotent stem cells (iPSCs) towards the cardiomyocyte fate. We generated iPSCs from an NS pediatric patient with the S257L/+ mutation in the Raf1 gene and corrected the mutation using CRISPR-Cas9 double nickase system. Differentiation of the mutant NS line led to a significantly increased number of cardiomyocytes (CMs) as measured by FACS sorting at day 20, as compared to isogenic corrected cells (5.71 million ± 0.38 of cTNT+ cells vs 3.77±0.54, n=6, p&lt;0.01). Differentiation of mutant iPSCs into mesodermal cells was normal; however, differentiation into cardiac progenitor cells was enhanced by the mutation, as demonstrated by the increased number of NKX2.5+ cells in the mutant culture at this stage of development. In addition, differentiated S257L/+ CMs had a significantly increased cell surface area compared to the control CMs (3,331 μm 2 ± 325 vs 1,638 μm 2 ± 97, n=6, p&lt;0.01). To uncover the aberrant signaling pathways underlying these phenotypes, we generated RAF1 S257L/+ knockin and RAF1 null (KO) Hela cell lines using CRISPR-Cas9n technology. Interestingly, we found that ERK1/2 activity was enhanced in KO cells, both at baseline and in response to growth factor (GF) stimulation. At the opposite, ERK1/2 activity was reduced in mutant cells, suggesting that the RAF1 S257L/+ mutant actually suppresses ERK1/2 activation. Finally, we found that AKT activation was upregulated in S257L/+ cells under GF stimulation, due to decreased ERK1/2-dependent p70-S6 kinase activity and subsequent increase in mTORC2 activity (n=6). Similar experiments are underway in S257L/+, corrected and KO RAF1 iPSC-derived CMs. In conclusion, we propose that the S257L/+ mutation modulates development of CH in NS RAF1 patients through a reduction in ERK1/2 activity and overactivation of the AKT/mTOR signaling pathway, leading to both an increased number and size of CMs.
Tumors of the Small Intestine
Authors: R. Clement Darling, Claude E. Welch
Journal: New England Journal of Medicine (1959)

NEOPLASMS of the small intestine are uncommon. Although many individual case reports or studies of a specific tumor or tumor site have been published, comprehensive reviews have usually been derived, either partially or completely, from autopsy material. Relatively few papers have considered tumors of the small intestine purely from a clinical perspective.Though neoplasms of the small bowel were described in the literature as long ago as 1824, according to Pridgen, Mayo and Dockerty,1 little interest in this subject was apparent until the report of Rankin and Mayo2 appeared in 1930 and that of Raiford3 in 1932. In 1934 Sowles . . .
Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous Wound Healing
Authors: Guoming Sun
Journal: Advanced Healthcare Materials (2017)

The transformation of fibrotic healing process to regenerative one has great potential to fully restore wounded skin. The M2 macrophage phenotype promotes constructive tissue remodeling and instructs tissue repair in a regenerative manner. It is hypothesized that hydrogels that can establish robustness of endogenous cells to regulate M2 phenotype will promote constructive dermal remodeling. Toward this end, a series of dextran-based bioabsorbable hydrogels are developed and self-crosslinkable dextran-isocyanatoethyl methacrylate-ethylamine (DexIEME) is identified as the potential scaffold. The initial screening study revealed that DexIEME has superior biocompatibility in varying concentrations. Although DexIEME brings about low proinflammatory responses, it promotes M2 macrophage phenotype. Then the optimized hydrogel formulation is tested for acute skin injuries using both murine and porcine models. Preliminary data demonstrated that the innovative DexIEME hydrogel promotes complete skin regeneration with hair regrowth on pre-existing scars, while untreated scars remain intact. Preclinical studies further demonstrated that the DexIEME hydrogel regenerated perfect skin during deep porcine wound healing. Overall, the approach to investigate immune-modulated hydrogels yields pro-regenerative DexIEME hydrogel, which may lead to greater clinical success in treating deep dermal injury and attenuating scar formation.
Recurrence of epigenetic gene mutations in thymic epithelial carcinomas revealed by targeted exome sequencing of cancer-associated genes.
Authors: Yisong Wang, Paul S. Meltzer, Christopher Lau, Anish Thomas, Arun Rajan, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2014)

7529 Background: Genetic alterations and etiology of thymic epithelial tumors (TET) are largely unknown, hampering development of effective targeted therapies for TET patients. Methods: TET patients enrolled in a clinical trial of molecularly-guided targeted therapies underwent exome capture sequencing of 197 cancer-associated genes. Somatic non-synonymous sequence variations including missense, nonsense, splice site mutations and indels were identified by comparative sequence analyses of tumor/blood paired samples. Results: Targeted exome capture sequencing of 78 advanced stage TETs (46 thymic carcinomas and 32 thymomas)/blood pairs revealed a total of 134 somatic non-synonymous sequence variations in 68 genes. Somatic non-synonymous sequence variations were found in 50% (39/78) of the TETs analyzed. Thymic carcinomas (67%; 31/46) showed higher incidence of somatic non-synonymous mutations than thymomas (25%; 8/32)(p=0.0002). TP53 (n = 13; 17%) was the most frequently mutated gene in TETs, and TP53 mutant patients showed poorer overall survival than TP53 wild-type patients (p < 0.0001). In thymic carcinomas, genes in epigenetic modification machinery [BAP1 (n = 6; 13%), SETD2 (n = 4; 9%), DNMT3A (n = 3; 7%), TET2 (n = 3; 7%), WT1 (n = 2; 4%), SMARCA4 (n = 2; 4%), and ASXL1 (n = 2; 4%)] were found recurrently mutated, whereas in thymomas, a preponderance of epigenetic gene mutations was not observed. Conclusions: Our results highlight the potential importance of epigenetic machinery in thymic carcinoma and indicate that substantial difference in genetic makeup exists between thymic carcinomas and thymomas. Targeting of epigenetic pathways may be of benefit to patients who carry those mutations.
A systematic review of prospective epidemiological research into injury and illness in Olympic combat sport
Authors: Sally J Bromley, Michael K Drew, Scott Talpey, Andrew S McIntosh, Caroline F Finch
Journal: British Journal of Sports Medicine (2017)

Background Combat sports involve body contact through striking, kicking and/or throwing. They are anecdotally referred to as ‘dangerous’, yet long-term investigation into specific injury rates is yet to be explored. Objective To describe incidence and prevalence of injury and illness within Olympic combat sports and to investigate risk of bias of prospective injury and illness research within these sports. Methods We systematically searched literature published up until May 2016. We included prospective studies of injury/illness in elite combat athletes lasting more than 12 weeks. Risk of bias was assessed using a modified version of the Downs and Black checklist for methodological quality. Included studies were mapped to the Oxford Centre for Evidence-Based Medicine levels of evidence. Results Nine studies were included, and most (n=6) had moderate risk of bias. Studies provided level 1/2b evidence that the most frequently injured areas were the head/face (45.8%), wrist (12.0%) and lower back (7.8%) in boxing; the lower back (10.9%), shoulder (10.2%) and knee (9.7%) in judo; the fingers (22.8%) and thigh (9.1%) in taekwondo; and the knee (24.8%), shoulder (17.8%) and head/face (16.6%) in wrestling. Heterogeneity of injury severity classifications and inconsistencies inexposure measures prevented any direct comparisons of injury severity/incidence across combat sports. Conclusions There is currently a lack of consensus in the collection of injury/illness data, limiting the development of prevention programmes for combat sport as a whole. However, sport-specific data that identify body areas with high injury frequency can provide direction to clinicians, enabling them to focus their attention on developing pathologies in these areas. In doing so, clinicians can enhance the practical elements of their role within the integrated combat sport performance team and assist in the regular update of surveillance records.
Characteristics of breast cancer in Ghana and prevalence of aggressive disease and high mortality.
Authors: Evelyn Mawunyo Jiagge, Joseph K. Oppong, Baffour Awuah, Lisa A. Newman, Max Wicha, Sofia Merajver
Journal: Journal of Clinical Oncology (2014)

596 Background: Breast cancer (BC) is now emerging as the most commonly diagnosed cancer among women in sub-Saharan Africa, surpassing cervical cancer. Although its incidence is relatively low in women in western Africa (approximately 28-35/1000,000), it carries 80% mortality, representing a massive public health problem. We hypothesized that the high mortality of BC is due to late diagnosis and to the high prevalence on estrogen receptor (ER) negative BC that is very aggressive and relatively unresponsive to existing therapies. The overarching objective of this work is to help focus research on the most pressing questions regarding the biological determinants contributing to high mortality from BC in sub-Saharan Africa. Methods: All the cancer cases that reported to Komfo Anokye Teaching hospital in Kumasi, Ghana diagnosed or treated at the facility between 2004 and 2011 were compiled and classified by age, stage, and receptor status, if available. The proportion of BC cases was further grouped by histologic type. Results: BC comprises nearly 25% of all cancers with male breast cancer accounting for 10% of BC cases. Of the female breast cancers, 50% are estrogen receptor negative. More than a third of the patients are younger than 45 years. The age specific incidence appears shifted to younger ages, after accounting for the population pyramid. Conclusions: BC in being increasingly diagnosed in Ghana; increased diagnosed burden may be due to increased awareness and/or to slowly increasing true incidence. BC in Ghanaian women exhibits phenotypic characteristics of younger age distribution, high proportion of ER- disease, high proportion of male breast cancer. These characteristics suggest specific early life exposures, hereditary factors, or both. Molecular genetics studies of tumors of differing ancestries may uncover hereditary factors that contribute to this spectrum of characteristics.
Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with <i>BRAF</i> V600–mutant unresectable or metastatic melanoma (MM).
Authors: Georgina V. Long, Zeynep Eroglu, Jeffrey R. Infante, Sapna Pradyuman Patel, Adil Daud, Douglas Buckner Johnson, Rene Gonzalez, Richard Kefford, Omid Hamid, Lynn Mara Schuchter, Jonathan S. Cebon, William Howard Sharfman, Robert R. McWilliams, Mario Sznol, Jeffrey S. Weber, Bijoyesh Mookerjee, Eduard Gasal, Suman Redhu, Keith T. Flaherty
Journal: Journal of Clinical Oncology (2017)

9505 Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in &lt; 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.
Global, regional, and subregional classification of abortions by safety, 2010–14: estimates from a Bayesian hierarchical model
Authors: Bela Ganatra, Caitlin Gerdts, Clémentine Rossier, Brooke Ronald Johnson, Özge Tunçalp, Anisa Assifi, Gilda Sedgh, Susheela Singh, Akinrinola Bankole, Anna Popinchalk, Jonathan Bearak, Zhenning Kang, Leontine Alkema
Journal: The Lancet (2017)

Global estimates of unsafe abortions have been produced for 1995, 2003, and 2008. However, reconceptualisation of the framework and methods for estimating abortion safety is needed owing to the increased availability of simple methods for safe abortion (eg, medical abortion), the increasingly widespread use of misoprostol outside formal health systems in contexts where abortion is legally restricted, and the need to account for the multiple factors that affect abortion safety.We used all available empirical data on abortion methods, providers, and settings, and factors affecting safety as covariates within a Bayesian hierarchical model to estimate the global, regional, and subregional distributions of abortion by safety categories. We used a three-tiered categorisation based on the WHO definition of unsafe abortion and WHO guidelines on safe abortion to categorise abortions as safe or unsafe and to further divide unsafe abortions into two categories of less safe and least safe.Of the 55· 7 million abortions that occurred worldwide each year between 2010-14, we estimated that 30·6 million (54·9%, 90% uncertainty interval 49·9-59·4) were safe, 17·1 million (30·7%, 25·5-35·6) were less safe, and 8·0 million (14·4%, 11·5-18·1) were least safe. Thus, 25·1 million (45·1%, 40·6-50·1) abortions each year between 2010 and 2014 were unsafe, with 24·3 million (97%) of these in developing countries. The proportion of unsafe abortions was significantly higher in developing countries than developed countries (49·5% vs 12·5%). When grouped by the legal status of abortion, the proportion of unsafe abortions was significantly higher in countries with highly restrictive abortion laws than in those with less restrictive laws.Increased efforts are needed, especially in developing countries, to ensure access to safe abortion. The paucity of empirical data is a limitation of these findings. Improved in-country data for health services and innovative research to address these gaps are needed to improve future estimates.UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction; David and Lucile Packard Foundation; UK Aid from the UK Government; Dutch Ministry of Foreign Affairs; Norwegian Agency for Development Cooperation.
Treatment related mortality (TRM) for AML pts managed at a non-transplant, safety net hospital.
Authors: Krishna Goparaju, Timothy E. O'Brien
Journal: Journal of Clinical Oncology (2017)

e18092 Background: Induction treatment for AML is associated with severe, life threatening toxicities. An accepted criterion for TRM is the 4 week mortality rate. A recent 18 yr study of AML pts treated with 3+7 induction regimens at SWOG institutions revealed an overall TRM at 4 weeks of 11%. Management of AML pts at non-transplant centers is controversial due to concerns over lower volumes, possibly leading to excess TRM. Over a 15-year period TRM was evaluated at a safety net, non-transplant center and compared to a national benchmark. Adherence to national guidelines for diagnostic testing was also assessed. Methods: MetroHealth Medical Center is a safety net hospital with a mission statement requiring all pts to be seen regardless of their ability to pay. Using tumor registry data, all cases of AML from 2001- 2016 were identified. Demographic data, 4 week TRM and compliance with standard diagnostic evaluation per NCCN guidelines were assessed.. Results: 67 cases were identified; average age was 59 (25-89), with equal distribution in gender. 73% were Caucasian, 18% African American, 4.5% Asian and 4.5% Hispanic. All but one (who went into hospice) had standard diagnostic tests sent (flow cytometry, cytogenetics and, for those with normal karyotyping, all had molecular testing for FLT-3 ITD, NPM-1, CEPBA and c-kit). Of the 67 patients, 5 received azacitadine, 2 received decitabine and 12 did not get treated due to co-morbidities and/or poor performance status. 48 patients received induction chemotherapy, of which 5 had APL appropriate therapies and the rest (43) received 3+7 induction regimens. For these 48 pts the 4 week mortality was 10%. Of those who received induction chemotherapy, 27% had favorable, 23% intermediate and 50% had poor risk molecular studies. Conclusions: A 15 yr review of outcomes during AML induction at a non-transplant, safety net institution revealed a TRM rate similar to a national benchmark, in spite of a relatively high percentage of poor risk cases. There was also good adherence to national diagnostic standards. Given the potential changes in the US healthcare delivery system which may result in more pts being seen at safety net institutions, these findings may have implications for future allocation of care.