tbuckley/cabot-search huggingface dataset:
A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab and pertuzumab in HR-positive, Her2-positive metastatic breast cancer.
Authors: Krystal Pauline Cascetta, Poulikos Poulikakos, Charles L. Shapiro, Aarti Sonia Bhardwaj, Julie Fasano, Hanna Irie, Paula Klein, Anupama Goel, Kevin Kalinsky, Sylvia Adams, Eleni Andreopoulou, Shabnam Jaffer, Meng Ru, Amy Tiersten
Journal: Journal of Clinical Oncology (2018)

TPS1103 Background: Overexpression or amplification of HER2 occurs in approximately 15 – 20% of patients and about half of these tumors are hormone receptor (HR) positive. Studies suggest that this 10% of all breast cancer cases may derive less benefit from endocrine therapy than those with HR+ disease without HER2 overexpression. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. To date, no studies have examined the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in this patient population. Trial Design: Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, Her2-positive Metastatic Breast Cancer. Eligibility Criteria: Stage IV HR+, HER2+ breast cancer patients. Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including expression of cyclin D1, cyclin E1 and E2, retinoblastoma, phosphorylated retinoblastoma, and p16 levels. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to assess for correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance. Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. If ≥ 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or, if the highest level has been reached and < 33% of patients have experienced DLT, that will be considered the MTD. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients. Accrual: Maximum of 36 subjects. Clinical trial information: NCT03304080.
Paternal use of antidepressants and offspring outcomes in Sweden: nationwide prospective cohort study
Authors: Alexander Viktorin, Stephen Z Levine, Margret Altemus, Abraham Reichenberg, Sven Sandin
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine the association between paternal antidepressant use at conception and offspring preterm birth, malformations, autism spectrum disorder, and intellectual disability. <h3>Design</h3> Observational prospective cohort study with regression methods, and negative control comparison. <h3>Setting</h3> Sweden nationwide. <h3>Participants</h3> 170 508 children conceived from 29 July 2005 and born in 2006-07, followed up to 2014 at age 8-9 years. This cohort included 3983 children born to fathers receiving antidepressant treatment during the conception period (that is, from four weeks before conception to four weeks after), a control group of 164 492 children not exposed to paternal antidepressant use, and a negative control comparison group of 2033 children born to fathers who did not use antidepressants during the conception period but began antidepressant treatment later during the pregnancy period (that is, from four weeks after conception to childbirth). <h3>Main outcome measure</h3> Offspring preterm birth, malformation diagnosed at birth, diagnosis of autism spectrum disorder, and diagnosis of intellectual disability. <h3>Results</h3> Paternal antidepressant use during conception was not associated with preterm birth (adjusted odds ratio 0.91 (95% confidence interval 0.79 to 1.04)) or malformations (1.06 (0.90 to 1.26)) using logistic regression, compared with offspring born to unexposed fathers. No association was seen between antidepressant use during conception and autism (adjusted hazard ratio 1.13 (0.84 to 1.53)) or intellectual disability (0.82 (0.51 to 1.31)) using Cox regression. In children whose fathers initiated antidepressant treatment during pregnancy, results were similar for all outcomes apart from intellectual disability, which had an increased adjusted hazard ratio (1.66 (1.06 to 2.59)). Compared with the 2033 children whose fathers initiated antidepressant treatment during pregnancy, the 3983 children exposed to paternal use of antidepressants at conception had no differences in preterm birth, malformation, and autism, but a reduced risk of intellectual disability (adjusted hazard ratio 0.49 (0.26 to 0.93)). <h3>Conclusion</h3> Paternal intake of antidepressants during the period around conception is safe with respect to the risk of the four major adverse outcomes in offspring—preterm birth, malformation, autism, or intellectual disability.
Barriers to Follow-up Colonoscopies for Patients With Positive Results From Fecal Immunochemical Tests During Colorectal Cancer Screening
Authors: Folasade P. May, Elizabeth M. Yano, Dawn Provenzale, Julian Brunner, Christine Yu, Jennifer Phan, Purnima Bharath, Elizabeth Aby, Doantrang Dinh, Dean S. Ehrlich, Tina R. Storage, Lisa D. Lin, Nimah N. Jamaluddin, Donna L. Washington
Journal: Clinical Gastroenterology and Hepatology (2018)
A Better Medical Regimen for the Management of Miscarriage
Authors: Carolyn L. Westhoff
Journal: New England Journal of Medicine (2018)

Data from the National Survey of Family Growth suggest that at least 600,000 cases of early pregnancy loss, often called miscarriage, occur before 12 weeks of gestation each year in the United States.1 The treatment options for a woman with a miscarriage include observation until spontaneous resolution, vacuum aspiration, or medical management with misoprostol.2 Observation is often slow and always unpredictable, and aspiration is quick and predictable but invasive; the time frame, predictability, and invasiveness of medical management fall somewhere between those of observation and aspiration. The rate of success with a single dose of 800 μg of misoprostol administered . . .
Clinical and biological features and response to preoperative chemotherapy in Russian women with breast cancer stage T1-3N0-1 according to genetic status.
Authors: Irina Vladimirovna Kolyadina, Vahan Yurikovich Bokhian, Olga Pavlikova, Dmitry Komov, I. Ganshina, Lyudmila Zhukova, Liudmila Lyubchenko, Nikolay Kozlov, Irina Poddubnaya
Journal: Journal of Clinical Oncology (2018)

e12651 Background: clinical and biological features and response to preoperative chemotherapy in genetic breast cancer (BC) stage T1-3N0-1 are poorly understood. Methods: Our study included 213 women (age 24-76, median - 47 years) with BC stage T1-3N0-1 treated in NCRC in 2004-2016. After neoadjuvant chemotherapy (anthracycline ± taxanes ± platinum regimes; in HER2+ BC with trastuzumab ± pertuzumab) patients had radical surgery. Tumor size distribution was: T1- 3,3%, T2- 63,4%, T3- 33,3; lymph node status was: N0 -25,8%, N1-74,2%. Biological subtype was luminal A (7,8%), luminal B HER2-negative (42,2%), luminal HER2+ (16,1%), triple negative (20,3%) and non-luminal HER2+ (13,5%). Genetic test of BRCA1/2 and CHEK-2 status was made in 82 women; clinically relevant genetic mutations (GM) were found in 16 cases, 19,5% (BRCA1- in 13,4%; CHEK2- in 3,7%; both BRCA1 and CHEK2- 2,4%). We studied the clinical and biological features and the rate of complete pathological response (pCR) in women with or without GM, analyze was made by SPSS 20,0. Results: We did not find any differences (p > 0,05) in histological type, grade, tumor size and lymph node status in group with or without GM. But median age of women with GM was significantly younger than without GM (33 vs 49 years, p < 0,01). Luminal A subtype was absent in group with GM in contrast to patients without GM (10,6%), but triple negative BC was in 50% women with GM and in 15% - without GM, р = 0,03. BRCA1 mutation associated with triple-negative BC (64%), but CHEK2 mutation - with HER2+ BC (60%), p < 0,01. The preoperative chemotherapy in group without GM included platinum regimes in 22% only, but in women with GM - in 62,5% cases. The rate of pCR was high (70,3% - in women with GM; 56,2% - in group without GM, р = 0,283). But the rate of pCR in non-genetic group did not depend from platinum incorporation in chemotherapy in contrast to women with GM who had the highest rate of pCR in platinum-containing chemotherapy (83%) and significantly lower rate of pCR (40%) in platinum-free regimes, p = 0,01. Conclusions: Genetic BC in Russian women was associated with young age and aggressive biology, but high response to preoperative platinum-containing chemotherapy
High Rate of Drug-Free Remission After Induction Therapy With Golimumab in Early Peripheral Spondyloarthritis
Authors: Philippe Carron, Gaëlle Varkas, Thomas Renson, Roos Colman, Dirk Elewaut, Filip Van den Bosch
Journal: Arthritis & Rheumatology (2018)

New treatment algorithms using tumor necrosis factor (TNF) blockers in early stages of spondyloarthritis (SpA) induce high rates of clinical remission or low disease activity. It could be anticipated that such early intervention strategies in peripheral SpA may induce drug-free remission. We undertook this study to evaluate drug-free clinical remission after induction therapy with golimumab in patients with very early active peripheral SpA, and to identify patient characteristics that predict sustained drug-free remission.Eligible patients were age ≥18 years and fulfilled the Assessment of SpondyloArthritis international Society criteria for peripheral SpA. All patients had symptom duration of <12 weeks. Sustained clinical remission was defined as the absence of arthritis, enthesitis, and dactylitis at 2 consecutive major visits, after which treatment was withdrawn. Patients were prospectively followed up to assess the rate of sustained drug-free clinical remission and clinical relapse.Eighty-two percent of patients (49 of 60) fulfilled sustained clinical remission criteria after a regimen of induction therapy with golimumab. The majority of patients already reached this status at week 24 (n = 30), with an additional 11 and 8 patients at weeks 36 and 48, respectively. All patients had a follow-up period of at least 18 months after drug withdrawal. Fifty-three percent of patients (26 of 49) still have drug-free remission of their disease. Inability to sustain drug-free remission was associated with the presence of psoriasis and polyarticular disease (swollen joint count >5).Anti-TNF treatment in very early peripheral SpA results in a remarkably high rate of sustained clinical remission. More than 50% of patients continue to have remission of their disease after withdrawal of therapy, which highlights a defined window of opportunity permitting induction of drug-free remission.
NHS England failed to disclose full amount of lost clinical correspondence, say MPs
Authors: Gareth Iacobucci
Journal: BMJ (2018)

NHS England did not disclose the full extent of a serious administrative failure that saw hundreds of thousands of items of medical correspondence lost and put patients at risk, a damning report by MPs has concluded.1

The report by the Public Accounts Committee said that the NHS wasted nearly £2.5m reviewing the mishandling and that NHS England had not communicated effectively with general practices about how they should handle misdirected clinical correspondence.

The problems surfaced in March 2016 when NHS Shared Business Services, an agency co-owned by the Department of Health and the IT company Sopra Steria, revealed that 709 000 …
A Disintegrin and Metalloproteinase Domain-9: A Novel Proteinase Culprit with Multifarious Contributions to Chronic Obstructive Pulmonary Disease
Authors: Xiaoyun Wang, Francesca Polverino, Joselyn Rojas-Quintero, Duo Zhang, José Sánchez, Ilyas Yambayev, Eva Lindqvist, Robert Virtala, Ratko Djukanovic, Donna E. Davies, Susan Wilson, Rory O’Donnell, Danen Cunoosamy, Petra Hazon, Andrew Higham, Dave Singh, Henric Olsson, Caroline A. Owen
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Proteinases with a disintegrin and a metalloproteinase domain (ADAMs) have not been well studied in COPD. We investigated whether ADAM9 is linked to COPD in humans and mice.
Fertility and cancer: Understanding the barriers to accessing information and resources.
Authors: Aditi Narayan, Carla Bann, Katherine Treiman, Cindy Soloe
Journal: Journal of Clinical Oncology (2018)

116 Background: Some cancer treatments may lead to infertility in individuals diagnosed during their reproductive years. Infertility can affect a cancer survivor’s long-term quality of life by causing depression as well as reduced life satisfaction and increased anxiety. Addressing fertility concerns is a major component of survivorship care. Methods: In 2017 LIVESTRONG launched a national survey to assess whether patients are being informed about potential fertility risks due to a cancer diagnosis and/or related treatments; whether they are receiving necessary education and access to resources to make informed decisions about fertility preservation; and the financial burden of fertility preservation. A total of 1,064 people diagnosed with cancer between ages of 15-39 during 2006 to 2017 responded to the survey. Results: Seventy-nine percent of respondents said a health professional had discussed fertility issues with them, but only 51% were referred to a fertility specialist. Respondents diagnosed between 2011 and 2017 were more likely to report fertility discussions compared to those diagnosed between 2006 and 2010 (84% vs. 69%; p&lt;.001), and to be referred to a fertility specialist (58% vs. 33%, p &lt;.0001). More educated respondents and those with health insurance at time of diagnosis were more likely to report fertility discussions than those who did not (96% vs. 85%; p=.04). The most frequently discussed topics were possible risks to fertility (89%), methods of fertility preservation (70%), whether the respondent wanted any/or more children (64%), and timing for fertility preservation (50%). Insurance and financial issues were less frequently discussed: costs of fertility preservation (37%), insurance coverage (26%), and financial assistance (30%). Forty-four percent did not take steps to preserve their fertility. Conclusions: Many respondents reported not preserving fertility before treatment because they were not referred to a fertility specialist (30%) or insurance did not cover the costs (20%). All patients diagnosed in their reproductive years should be informed of infertility risks and receive information/resources on preservation options, regardless of education, income level, and insurance status.
A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors.
Authors: Paul James Wood, Robyn Strong, Grant A. McArthur, Michael Michael, Elizabeth Algar, Andrea Muscat, Lin Rigby, David M. Ashley
Journal: Journal of Clinical Oncology (2014)

10061 Background: Deregulated acetylation of histones plays a key role in the pathogenesis of haematological and solid tumors by changing the transcription of genes involved in cell cycle control, differentiation or apoptosis. Thus, there is considerable interest in HDAC inhibition as a potential therapeutic modality in the treatment of hematological and solid tumor malignancies, including pediatric malignancies. Methods: This is an open label, Phase I, multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumours. Primary endpoints were to define and describe associated toxicities, and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and also to assess its biologic activity by measuring the histone acetylation status in peripheral blood mononuclear cells (PBMNC). Results: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15mg/m2. Three patients were removed from study prior to completion of course one due to tumour progression. A dose of 15mg/m2 was tolerated with one dose limiting toxicity (DLT) observed in the six patients evaluated for DLT. Two (22%) patients experienced grade 3-4 thrombocytopenia, 1 (11%) experienced grade 3 anemia, and 2 (22%) experienced grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (22%) of patients studied. Vomiting (44%), nausea (33%) and hypokalaemia (22%) were also common adverse events. Two (22%) of patients experienced a Grade II QTcF change (0.478 +/- 0.006 msec). One cardiac DLT (T wave changes) was reported. PK values for 15mg/m2 (n=9) dosing were: Tmax 0.8 hours, Cmax 235.2 ng/ml, AUC0-t 346.8h.ng/ml and t1/2 7.3 hours. Pooled flow cytometry results of all nine patient samples confirm that panobinostat significantly induced acetylation of histone H3 and H4 at 6 hours (p< 0.001), 24 hours (P<0.01) and 28-70 hours (p<0.05) post dose. Conclusions: A significant, sustained, biological effect of panobinostat, as measured by acetylation status of histone H3 and H4, was achieved at a dosing level of 15mg/m2. PK data and drug tolerability at 15mg/m2 was very similar to that seen in adults at an equivalent dosing level. Clinical trial information: ACTRN12609000978268.
Community-level changes in condom use and uptake of HIV pre-exposure prophylaxis by gay and bisexual men in Melbourne and Sydney, Australia: results of repeated behavioural surveillance in 2013–17
Authors: Martin Holt, Toby Lea, Limin Mao, Johann Kolstee, Iryna Zablotska, Tim Duck, Brent Allan, Michael West, Evelyn Lee, Peter Hull, Andrew Grulich, John De Wit, Garrett Prestage
Journal: The Lancet HIV (2018)
Decision aids and health information technology: One size does not fit all.
Authors: Katia Noyes, Christina Crabtree-Ide, David Holub, Michelle Shayne, Jennifer Rodriguez, Irfan Rizvi, Fergal J. Fleming, Varsha Sharda, Pradeep Sharda, Patricia Bellohusen, Nancy K. Termer, Louis S. Constine
Journal: Journal of Clinical Oncology (2018)

74 Background: Nearly 3 million cancer survivors in the US reside in rural areas. Existing survivorship care models were developed mainly at large academic centers, and thus require adaption to meet the challenging needs of the rural community. Rural cancer survivors (RCS) face issues with coordination of care, decision-making, access to specialty services, supportive care resources, and time and resources required for travel. RCS are at greater risk for social isolation and inadequate emotional support. To address these challenges, many studies propose information technology (IT), mobile, and video solutions. We assessed the potential of online and mobile video technology applications to reduce barriers to survivorship care for RCS, families, and caregivers. Methods: We conducted 2 in-person focus groups with rural care managers, providers, and public health professionals, and one virtual cross-disciplinary focus group of patients, caregivers, and provider stakeholders to evaluate acceptability of video modules. Using a Community-Based Participatory Research approach, we worked with community partners to design and develop materials that adequately addressed their needs. Results: Focus group results indicate that video modules added little value for RCS due to sporadic internet access, limited patient IT literacy, vision and memory problems, and patient difficulty interpreting information. Therefore, we designed and piloted a paper RCS Checklist to be taken to appointments, available in waiting areas or through care managers, and to serve as a guide for shared patient-provider decision-making. The resulting checklist includes evidence-based information about survivorship care goals and approaches, care coordination strategies, information about local cancer supportive services, health insurance reimbursement, state disability policies, psychosocial support, and stress-reduction tips. Conclusions: In some special patient populations like RCS, use of health IT for patient empowerment and care coordination may be a poor choice. Engaging relevant stakeholders in the development of location-specific communication and decision aid materials is paramount to successful engagement of patients and caregivers.
Ultrasound targeting of Q-starch/miR-197 complexes for topical treatment of psoriasis
Authors: Rinat Lifshiz Zimon, Galya Lerman, Einat Elharrar, Tal Meningher, Aviv Barzilai, Moamen Masalha, Ramesh Chintakunta, Etili Hollander, Riki Goldbart, Tamar Traitel, Moti Harats, Yechezkel Sidi, Dror Avni, Joseph Kost
Journal: Journal of Controlled Release (2018)
Pan-cancer microsatellite instability to predict for presence of Lynch syndrome.
Authors: Alicia Latham Schwark, Preethi Srinivasan, Yelena Kemel, Jinru Shia, Chaitanya Bandlamudi, Diana Mandelker, Marianne Dubard-Gault, Christina Tran, Sumit Middha, Jaclyn Frances Hechtman, Alexander Penson, Anna M. Varghese, Liying Zhang, Mark E. Robson, David B. Solit, Luis A. Diaz, Barry S. Taylor, Kenneth Offit, Michael F. Berger, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2018)

LBA1509 Background: The success of immunotherapy in microsatellite unstable (MSI-H) and/or DNA mismatch repair deficient (MMR-D) tumors has resulted in routine MSI-H/MMR-D testing in advanced solid tumors. Unlike colorectal (CRC) and endometrial cancer (EC), where this has long been undertaken, the characterization of Lynch syndrome (LS) across heterogeneous MSI-H/MMR-D tumors is unknown. Methods: Through a targeted NGS panel, MSI status was determined via MSIsensor. Scores of &lt; 3, ≥3 to &lt; 10, or ≥10 designated Microsatellite stable (MSS), MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. Immunohistochemical staining (IHC) for MMR-D and tumor signatures in LS patients were assessed. Clinical variables were correlated with MSI and compared via Chi square or T-test. Results: Of 15,045 tumors spanning &gt; 50 cancers , 93.2% were MSS, 4.6% MSI-I, and 2.2% MSI-H. Germline mutations were identified in 0.3% (37/14,020), 1.9% (13/699), and 16.3% (53/326) in the MSS, MSI-I, and MSI-H groups, respectively (p-value &lt; 0.001). 25% of 1,025 MSI-H/MSI-I tumors were CRC/EC, but 50% (33/66) of LS patients had MSI-H/MSI-I tumors less commonly or not previously associated with LS (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell). LS pts with MSI-H/MSI-I non-CRC/EC tumors only met testing criteria in 63.6% of cases, had lower MSIsensor scores, and were more likely to be MSI-I (MSI-I: non-CRC/EC, 30.3% (10/33) vs CRC/EC 9.1% (3/33); p-value = 0.03). IHC was completed in 86.4% (57/66) of LS MSI-H/MSI-I tumors, with 98.3% MMR-D-concordance. Of LS pts with MSS tumors, 78% had MSH6/PMS2 mutations, but 71% of LS pts with MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations(p-value &lt; 0.001). 89% (33/37) of MSS tumors of LS pts had non-MMR-D signatures. Conclusions: MSI-H/MMR-D is predictive of LS across tumor types and suggests a more heterogeneous spectrum of LS-associated cancers than previously appreciated. Nearly 40% of LS pts with MSI-H/MMR-D non-CRC/EC tumors did not meet clinical criteria for genetic testing, suggesting that MSI-H/MMR-D tumors, regardless of cancer type or family history, should prompt germline testing for the evaluation of LS.