tbuckley/cabot-search huggingface dataset:
A phase II study of the PI3K inhibitor taselisib (GDC-0032) combined with fulvestrant (F) in patients (pts) with HER2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (BC).
Authors: Maura N. Dickler, Cristina Saura, Donald A. Richards, Ian E. Krop, Andres Cervantes, Philippe L. Bedard, Manish R. Patel, Lajos Pusztai, Mafalda Oliveira, Joseph A. Ware, Huan Jin, Timothy R. Wilson, Thomas Stout, Michael C. Wei, Jerry Y. Hsu, Jose Baselga
Journal: Journal of Clinical Oncology (2016)

520 Background: The PI3K pathway is activated in HR+ BC, often via gain-of-function mutations in PIK3CA that occur in ~40% of HR+ BC. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant PI3Kα isoforms than wild type (WT) PI3Kα. Phase Ib data demonstrated good tolerability and preliminary efficacy for taselisib + F in HR+ BC. Methods: This Phase II, open-label, single-arm study enrolled post-menopausal pts with HER2-, HR+ locally advanced or metastatic BC (mBC) who had progression or non-response to ≥ 1 prior endocrine therapy in adjuvant or mBC settings. Pts received taselisib (6 mg capsule PO qd) plus F (500 mg IM on Cycle 1 Day 1, Cycle 1 Day 15, then q4w Day 1 of each cycle) until progressive disease or unacceptable toxicity. PIK3CA mutation status was centrally confirmed retrospectively on archival tumor tissue by 'cobas' PIK3CA Mutation Test. Primary endpoints were objective response rate (RECIST version 1.1) and clinical benefit rate (CBR; confirmed CR and PR, or stable disease for > 180 days) in all pts and pts with PIK3CA mutations. Secondary endpoints include additional measures of safety, efficacy and pharmacokinetics. Results: 60 pts were enrolled; 17 had PIK3CA mutations, 27 had WT PIK3CA and 16 had unknown PIK3CA mutation status. Among pts with baseline measurable disease, confirmed response rates were: PIK3CA mutations (n = 12) 41.7%, WT (n = 21) 14.3%, unknown (n = 11) 9.1%; all confirmed responses were PRs. CBRs were: PIK3CA mutations 41.7%, WT 23.8%, unknown 27.3%. Common Grade ≥ 3 adverse events (AE) were colitis (13.3%), diarrhoea (11.7%), hyperglycaemia (6.7%), and pneumonia (5%). 18.3% of patients discontinued taselisib treatment due to an AE. More detailed safety and efficacy data will be presented. Conclusions: The combination of taselisib plus F had an acceptable side effect profile and clinical activity in pts with HER2-, HR+ advanced BC, with a numerically higher response and CBR in patients with PIK3CA mutations compared with WT pts. Taselisib is currently being tested with F in a randomized Phase III study (SANDPIPER, NCT02340221). Clinical trial information: NCT02340221.
Phase I imaging study of the HER3 antibody RG7116 using <sup>89</sup>Zr-RG7116-PET in patients with metastatic or locally advanced HER3-positive solid tumors.
Authors: Frederike Bensch, Laetitia E. Lamberts, Marjolijn N. Lub-de Hooge, Anton G.T. Terwisscha van Scheltinga, Johan R. de Jong, Jourik A. Gietema, Carolien P. Schroder, Michiel M. Smeenk, Wolfgang Jacob, Keelara Abiraj, Michaela Wolf, Celine Adessi, Georgina Meneses-Lorente, Magdalena Zajac, Martin Weisser, Adrienne H. Brouwers, Elisabeth De Vries
Journal: Journal of Clinical Oncology (2014)

11095 Background: Human epidermal growth factor receptor 3 (HER3) can play a critical role in tumor growth, proliferation and progression. The glycoengineered humanized monoclonal HER3-targeting antibody RG7116 is currently in phase I development (NCT01482377). Knowledge about whole body target expression, drug biodistribution and organ pharmacokinetics is lacking from many phase I designs. The aim of this imaging study is to determine in vivo biodistribution and tumor targeting characteristics of RG7116 by means of immunoPET using 89Zr-RG7116. Methods: Patients with HER3-positive metastatic or locally advanced solid tumors underwent 89Zr-RG7116-PET before treatment with RG7116. To determine optimal tracer dose and imaging schedule patients received 89Zr-RG7116 with increasing doses of unlabeled RG7116 followed by up to 3 PET scans until 7 days post injection (pi). Tracer uptake in organs of interest and tumor lesions was quantified as standardized uptake value (SUV) and tumor-to-background ratios (TBR) were calculated. Results: 13 patients participated without experiencing major safety issues. Initially, 7 patients received 37 MBq 89Zr-RG7116 containing 10, 50 or 100 mg unlabeled RG7116. The optimal dose was 100 mg and PET 2 days pi did not add valuable information. Subsequent patients (n=6) were evaluated at the 100 mg dose with PET scans 4 and 7 days pi. In all 13 patients tracer uptake in tumor lesions was seen, including in 12/13 biopsied HER3-positive lesions. In 3 of the 13 patients previously unknown brain and bone metastases were also detected. At the 100 mg dose 37 tumor lesions (9 patients) were quantifiable, with mean SUVmax 4 days pi of 4.2 (±1.8 SD). Normal antibody tissue distribution was seen with mean SUVmax 4 days pi for liver 8.1, intestine 6.5, blood pool 6.2, kidney 5.0, spleen 4.9, and low uptake in the vertebrae 2.7, lung 1.4, muscle 1.1 and brain 0.5, resulting in mean TBR of 3.60 (range 1.10-9.53). Conclusions: With 89Zr-RG7116-PET biodistribution of RG7116 was determined and tumor specific uptake of 89Zr-RG7116 was shown in patients with HER3-positive metastatic cancer. Analysis of HER3 saturation by repeated 89Zr-RG7116-PET scanning is ongoing. Clinical trial information: NCT01482377.
Association between Reperfusion Renal Allograft Biopsy Findings and Transplant Outcomes
Authors: Sumit Mohan, Eric Campenot, Mariana C. Chiles, Dominick Santoriello, Eric Bland, R. John Crew, Paul Rosenstiel, Geoffrey Dube, Ibrahim Batal, Jai Radhakrishnan, P. Rodrigo Sandoval, James Guarrera, M. Barry Stokes, Vivette D’Agati, David J. Cohen, Lloyd E. Ratner, Glen Markowitz
Journal: Journal of the American Society of Nephrology (2017)

Biopsy findings at the time of procurement of deceased donor kidneys remain the most common reason cited for kidney discard. To determine the value of renal allograft histology in predicting outcomes, we evaluated the significance of histologic findings, read by experienced renal pathologists, in 975 postreperfusion biopsy specimens collected from 2005 to 2009 after living donor ( n =427) or deceased donor ( n =548) renal transplant. We evaluated specimens for the degree of glomerulosclerosis, interstitial fibrosis and tubular atrophy, and vascular disease; specimens with a score of 0 or 1 (scale, 0–3) for each parameter were considered optimal. Overall, 66.3% of living donor kidneys and 50.7% of deceased donor kidneys received an optimal histology score ( P &lt;0.001). Irrespective of donor status, suboptimal kidneys came from older donors with a higher incidence of diabetes mellitus, hypertension, and obesity and a higher mean kidney donor risk index (all P &lt;0.001). Death-censored outcomes after transplant differed significantly between optimal and suboptimal kidneys only in the deceased donor transplants ( P =0.02). Regardless of histologic classification, outcomes with deceased donor kidneys were inferior to outcomes with living donor kidneys. However, 73.2% of deceased donor kidneys with suboptimal histology remained functional at 5 years. Our findings suggest that histologic findings on postreperfusion biopsy associate with outcomes after deceased donor but not living donor renal transplants, thus donor death and organ preservation–related factors may be of greater prognostic importance. Discarding donated kidneys on the basis of histologic factors may be inappropriate and merits further study.
Trifluridine/Tipiracil combined to oxaliplatin sensitizes microsatellite stable colorectal cancer to anti-PD-1 blockade
Authors: Emeric Limagne, Lisa Nuttin, Aodrenn Spill, Marion Thibaudin, Valentin Derangere, Valerie Cattan, Alain Bruno, Nadia Amellal, Francois Ghiringhelli
Journal: Annals of Oncology (2017)
A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma
Authors: A K Mitra, T Harding, U K Mukherjee, J S Jang, Y Li, R HongZheng, J Jen, P Sonneveld, S Kumar, W M Kuehl, V Rajkumar, B Van Ness
Journal: Blood Cancer Journal (2017)

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options.
Bad Clade Deletion Supertrees: A Fast and Accurate Supertree Algorithm
Authors: Markus Fleischauer, Sebastian Böcker
Journal: Molecular Biology and Evolution (2017)

Supertree methods merge a set of overlapping phylogenetic trees into a supertree containing all taxa of the input trees. The challenge in supertree reconstruction is the way of dealing with conflicting information in the input trees. Many different algorithms for different objective functions have been suggested to resolve these conflicts. In particular, there exist methods based on encoding the source trees in a matrix, where the supertree is constructed applying a local search heuristic to optimize the respective objective function. We present a novel heuristic supertree algorithm called Bad Clade Deletion (BCD) supertrees. It uses minimum cuts to delete a locally minimal number of columns from such a matrix representation so that it is compatible. This is the complement problem to Matrix Representation with Compatibility (Maximum Split Fit). Our algorithm has guaranteed polynomial worst-case running time and performs swiftly in practice. Different from local search heuristics, it guarantees to return the directed perfect phylogeny for the input matrix, corresponding to the parent tree of the input trees, if one exists. Comparing supertrees to model trees for simulated data, BCD shows a better accuracy (F1 score) than the state-of-the-art algorithms SuperFine (up to 3%) and Matrix Representation with Parsimony (up to 7%); at the same time, BCD is up to 7 times faster than SuperFine, and up to 600 times faster than Matrix Representation with Parsimony. Finally, using the BCD supertree as a starting tree for a combined Maximum Likelihood analysis using RAxML, we reach significantly improved accuracy (1% higher F1 score) and running time (1.7-fold speedup).
A pilot study of the effects of androgen deprivation therapy on physical function and comprehensive geriatric health in older men with prostate cancer.
Authors: Elizabeth Riley Kessler, Thomas W. Flaig, Elaine Tat Lam, Kathryn M. Breaker, Michael Wacker, Catherine Jankowski
Journal: Journal of Clinical Oncology (2017)

e16510 Background: Alteration of the androgen axis through androgen deprivation therapy (ADT) is the mainstay of prostate cancer (PCa) treatment. Unfortunately, the resultant hypogonadal state has detrimental effects on muscle and bone and may impair physical function (PF). Older patients may be more vulnerable to PF changes while on ADT. We conducted a pilot study to evaluate the changes in PF and geriatric health in older men initiating ADT using tests easily employed in routine clinical practice. Methods: Men with PCa initiating ADT were enrolled and were assessed every 3 months (mos) for up to 12 mos. PF was measured using the short physical performance battery (SPPB) and geriatric health was screened using the Vulnerable Elders Survey (VES13) which predicts potential death or decline over 2 years. The primary endpoint was change in SPPB and VES13 at 3 mos. Results: We enrolled 17 patients with a median age of 75 years (range 67-85) beginning ADT therapy. Fourteen patients had metastasis, 2 had locally advanced disease, and 1 had biochemical recurrence. The majority had Gleason score (GS) 7 cancer (9/17), 7/17 GS 8-10, and 1/17 with GS 6. Eight patients had normal SPPB baseline scores and 9 had moderate impairment (moderate frailty risk) (Mean 10, SD 1.71). Seven had a clinically significant decline in the SPPB at 3 mos, with 1 patient testing as severely impaired. The VES13 screening tool identified 6/17 patients as vulnerable at baseline (Mean 3, SD 3.92). At 3 months, 3/17 patients had a decline in VES13 and 6/17 with an improvement. Of the 10 patients who were followed for at least 6 months, 5 had worsening of the VES13 and 2 had a worsening in SPPB. Conclusions: Older patients initiating ADT have baseline vulnerabilities in geriatric health with little immediate detriment after treatment initiation, perhaps due to overall health improvement with treatment initiation. Changes in PF, however, are seen within the first 3 months of ADT in nearly half of our patients, warranting further investigation into early rehabilitation of men even on short-term ADT. The SPPB is easily employed in clinic and important as reliance on VES13 alone is likely to miss patients with PF impairments.
Perfluoroalkyl Substances during Pregnancy and Offspring Weight and Adiposity at Birth: Examining Mediation by Maternal Fasting Glucose in the Healthy Start Study
Authors: Anne P. Starling, John L. Adgate, Richard F. Hamman, Katerina Kechris, Antonia M. Calafat, Xiaoyun Ye, Dana Dabelea
Journal: Environmental Health Perspectives (2017)

Background: Certain perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widespread, persistent environmental contaminants. Prenatal PFAS exposure has been associated with lower birth weight; however, impacts on body composition and factors responsible for this association are unknown. Objectives: We aimed to estimate associations between maternal PFAS concentrations and offspring weight and adiposity at birth, and secondarily to estimate associations between PFAS concentrations and maternal glucose and lipids, and to evaluate the potential for these nutrients to mediate associations between PFAS and neonatal outcomes. Methods: Within the Healthy Start prospective cohort, concentrations of 11 PFAS, fasting glucose, and lipids were measured in maternal mid-pregnancy serum (n=628). Infant body composition was measured using air displacement plethysmography. Associations between PFAS and birth weight and adiposity, and between PFAS and maternal glucose and lipids, were estimated via linear regression. Associations were decomposed into direct and indirect effects. Results: Five PFAS were detectable in >50% of participants. Maternal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) concentrations were inversely associated with birth weight. Adiposity at birth was approximately 10% lower in the highest categories of PFOA, PFNA, and perfluorohexane sulfonate (PFHxS) compared to the lowest categories. PFOA, PFNA, perfluorodecanoate (PFDeA), and PFHxS were inversely associated with maternal glucose. Up to 11.6% of the effect of PFAS on neonatal adiposity was mediated by maternal glucose concentrations. Perfluorooctane sulfonate (PFOS) was not significantly associated with any outcomes studied. Conclusions: Follow-up of offspring will determine the potential long-term consequences of lower weight and adiposity at birth associated with prenatal PFAS exposure. https://doi.org/10.1289/EHP641
Abstract 258: Pitx2 Promotes Murine Myocardial Regeneration after Myocardial Injury
Authors: GE TAO, Elzbieta Klysik, Yuka Morikawa, James F Martin
Journal: Circulation Research (2014)

Myocardial infarction is the leading cause of morbidity and mortality in the United States. Compromised myocardial function, due to the lack of self-renewal capacity in mature hearts, is a major reason for heart failure. Available therapies can only ameliorate, but not reverse the loss of functional myocardium. With heart transplantation as the only available cure, design of an effective regenerative therapy has become imperative for cardiovascular research. To repopulate the heart with de novo cardiomyocytes, most attempts have been based on the transplantation of cardiac, non-cardiac stem cells or their derivatives, however a more profound knowledge of stem cells is required for achieving significant progress. Meanwhile, triggering endogenous regenerative capacity is a compelling strategy for cardiac repair. It has been reported that proliferation of pre-existing cardiomyocytes strongly contributes to regeneration. Thus, efforts have been made to reintroduce mature cardiomyocytes into mitotic cycle. The mechanisms underlying the proliferation of cardiomyocytes during development and their homeostasis during adulthood are not fully understood, but likely require tight regulation of transcription factors in specific cell types. We have previously shown that the mouse Hippo kinase cascade is a major heart-size control pathway during development. In addition, activation of Yap, a transcriptional cofactor inhibited by Hippo, by genetically disrupting Hippo signaling is sufficient to induce juvenile and adult myocardial regeneration after surgery-induced myocardial infarction. Here we identified the paired-like homeodomain transcription factor 2 (pitx2) as a potential downstream target and cofactor of Yap in mouse heart. Our data indicates that Pitx2 expression is induced by myocardial injury, and is required for neonatal myocardial regeneration in a postnatal day 1 (P1) apex resection model. Further studies show that over-expression of pitx2 in adult cardiomyocytes is sufficient to promote the restoration of myocardial structure and function after myocardial infarction. Together, we show that pitx2 is a new manipulator of myocardial regeneration and could serve as a novel therapeutic target in cardiac regenerative therapy.
Hepatectomy after down-staging of hepatocellular carcinoma with portal vein tumor thrombus using chemoradiotherapy: A retrospective cohort study
Authors: Michinori Hamaoka, Tsuyoshi Kobayashi, Shintaro Kuroda, Hiroshi Iwako, Sho Okimoto, Tomoki Kimura, Hiroshi Aikata, Yasushi Nagata, Kazuaki Chayama, Hideki Ohdan
Journal: International Journal of Surgery (2017)
Post-Approval Safety Study (PASS) of Lenalidomide Compared with Other Treatments in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Michele Cavo, Luciano Masini, Igor W. Blau, Miguel T. Hernandez, Renato Zambello, Paolo de Fabritiis, Christian Berthou, Argiris Symeonidis, Jennifer Bird, Javier De La Rubia, Pamela Bacon, Barbara Rosettani, Elisabeth Kueenburg, Neil Minton
Journal: Blood (2011)
Breast cancer in "young" women: Age cutoff and clinicopathologic features.
Authors: Gang Nie, Haibo Wang, Yuhua Song, Yan Mao, Weihong Cao, Haiyan Hu
Journal: Journal of Clinical Oncology (2017)

e12019 Background: Age of patients play a key role in outcome of breast cancer, and therefore influences choice of treatment. In most studies, "young" is defined as being below 40 or 35 years. However, there are conflicts concerning definition of younger and older patients. In this study, we aim to establish a more appropriate age cut-off between “younger” and “older” breast cancer patients. Methods: A total of 5984 female breast cancer patients recruited in the Breast Cancer Registry of the Affiliated Hospital of Qingdao University during 2008 to 2014 were enrolled. Patients were divided into 11 groups by every 5 years’ age difference. The clinical characteristics and overall survival (OS) were compared among these age groups. Results: Among the five groups under age 45 (n = 1771, 30.0%), larger proportion of patients underwent breast conservation surgery in the “30-34” group (p = .027), and more patients were found with family history in the “25-29” group than in other groups (p = .029). No significant difference was found in OS (p = .059), clinicopathological stage, lymph node status, ER/PR status, HER2 status, or Ki-67 status among those five groups. For patients above 45 (n = 4813, 70.0%), differences were found in OS (p = .001) and significant differences with clinicopathological features (lymph node status, ER/PR status, HER2 status and Ki-67 status) were shown between younger and the older age groups (p = .001) among the six groups, except for family history (p = .066). Conclusions: Clinicopathological characteristics and survival status are similar among breast cancer patients under 45 years and vitiate among older patients. Age 45 is an appropriate cut-off for clinical grouping of breast cancer patients by age .
Short Circuit Currents of Normal and Crohn's Diseased Human Colonic Mucosa
Authors: A Patel, DL Bovell, AD Corbett, RJ Holdsworth
Journal: Endoscopy (2006)

Aims: Inflammatory Bowel Disease (IBD) is a condition of unknown aetiology that causes chronic gut dysfunction and comprises two pathologically different forms, Crohn's Disease (CD) and Ulcerative Colitis (UC). Both conditions are characterised by a marked disturbance in the equilibrium between absorptive and secretory electrolyte transport in inflamed colonic mucosa but the underlying mechanisms are not known.