tbuckley/cabot-search huggingface dataset:
Clinical implications of genomic-directed therapies by comprehensive genomic profiling in breast cancer patients at a large academic cancer center.
Authors: Ricardo Daniel Parrondo, Veronica Mariotti, Miguel Gonzalez Velez, Lori Ann Leslie
Journal: Journal of Clinical Oncology (2017)

e12037 Background: Increased use of comprehensive genomic profiling (CGP) has recently led to improved genomic characterization of tumors, increased access to individualized therapies and increased availability of clinical trials in breast cancer patients. The aim of this study was to evaluate the clinical impact of genomic profiling in breast cancer patients with the use of a CGP assay at a large cancer center. Methods: We retrospectively analyzed 101 consecutive breast cancer patients who received CGP at the John Theurer Cancer Center between 12/2011 and 08/2016. Genomic alterations (GAs) were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA). GAs, number of available genomic-directed therapies and number of available clinical trials were reviewed. The CGP interrogated up to 315 genes and introns of 28 genes. Results: Median age at diagnosis was 58 years (range: 35-83 years). With a median follow-up of 189 months (range 1-189), median survival was 163 months (range 142-184). A total of 560 GAs were found in our population, with a median of 5.0 GAs/sample (range 0-16), a median of 2.0 therapies/patient (range 0-11), and a median of 11.0 clinical trials/patient (range 0-36). The most frequent GAs found were TP53 (47.5%, n = 48), PIK3CA (34.7%, n = 35), MYC (22.8%, n = 23), CCND1 (19.8%, n = 20), FGF3 (16.8%, n = 17), FGF4 (15.8%, n = 16), and ZNF703 (14.9%, n = 15). A significant positive correlation was found between number of GAs and the number of available targeted therapies and clinical trials (r = 0.5 and r = 0.7, p = 0.00, respectively). Increasing age is a predictor of having a PIK3CA mutation (OR = 1.05; CI:1.01-1.09, p = 0.00) while decreasing age is a predictor of having a MYC mutation by logistic regression (OR = 0.95; CI:0.91-0.95, p = 0.03). Conclusions: The systematic use of CGP led to the identification of a high number of GAs, which correlated with a median of 2.0 individualized therapies and a median of 11.0 clinical trials available for breast cancer patients. The clinical impact of genomic-directed individualized therapies needs to be further investigated in prospective, randomized studies.
Characterization of bone only metastasis (BOM) patients (pts) with respect to tumor subtypes (TS).
Authors: Amanda Marie Parkes, Katherine Clifton, Aydah Al Awadhi, Oluchi Oke, Carla L. Warneke, Jennifer Keating Litton, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2017)

1072 Background: Metastatic breast cancer (MBC) pts with BOM are a unique population with limited characterization. Our goal was to characterize the TS of BOM pts, evaluating differences in sites and types of bone metastases (BM), treatment, and survival. Methods: We identified pts followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis (met). TS was assessed by initial biopsy immunohistochemistry (IHC) (Table 1) with hormone receptor (HR) + defined as ER or PR &gt;10%. Results: We identified 1445 pts with BOM, 1049 with initial biopsy IHC available to group into TS (Table 1). Among BOM pts, the majority had multiple BM at diagnosis (1141/79%), most in both the axial (Ax) and appendicular (App) skeleton (53%). Of the 808 pts with BM categorized on imaging at diagnosis, the majority were lytic (389/48%), with 21% sclerotic, 18% mixed, and 12% blastic. Time from breast cancer diagnosis to first met differed significantly by TS, χ 2 (3) = 94.33, P&lt; .0001, with median time to met longer for pts with blastic (3.08 years; 95% CI 2.03, 4.24) versus lytic lesions (1.75 years; 95% CI 1.27, 2.17). Conclusions: BOM patients are a unique MBC subpopulation, more commonly found in luminal TS patients. Our study demonstrates prognostic differences in BOM pts specific to TS and emphasizes the need for further study of BOM patients. [Table: see text]
Molecular Analysis and In Vivo Efficacy Studies on a Novel Chemical-Series of FLT3 Inhibitors in Human FLT3-ITD AML
Authors: Katelyn Melgar, MacKenzie Walker, Jiang-kang Jiang, Kelli Wison, Kwangmin Choi, James C. Mulloy, Craig J Thomas, Daniel T Starczynowski
Journal: Blood (2016)
La coloscopie panoramique détecte davantage d’adénomes coliques que la coloscopie conventionnelle avec rétrovision proximale: une étude randomisée en cross over
Journal: Endoscopy (2017)

Contexte et objectifs de l’étude: la coloscopie panoramique à 330° (Full-spectrum colonoscopy, FSC ), dont le champ de vision est plus large qu’en coloscopie conventionnelle, vise à augmenter la détection des adénomes coliques. Cette étude grecque cherchait à comparer les taux d’adénomes non détectés en FSC et en coloscopie conventionnelle complétée par un examen du colon droit en rétrovision (CC/R). Patients et Méthodes: Les patients consultant dans 2 centres tertiaires d’endoscopie, chez qui une indication de coloscopie était posée pour des symptômes digestifs, un dépistage ou une surveillance de cancer colorectal, étaient inclus dans l’étude afin d’avoir les 2 procédures à la suite par le même opérateur, l’ordre des examens étant décidé lors de la randomisation.
Impact in delay of start of chemotherapy and surgery on pCR and survival in breast cancer: A pooled analysis of individual patient data from six prospectively randomized neoadjuvant trials.
Authors: Sibylle Loibl, Gustavo Werutsky, Valentina Nekljudova, Sabine Seiler, Jens Uwe Blohmer, Carsten Denkert, Claus Hanusch, Jens Bodo Huober, Christian Jackisch, Sherko Kummel, Andreas Schneeweiss, Michael Untch, Kerstin Rhiem, Peter A. Fasching, Gunter Von Minckwitz, Jenny Furlanetto
Journal: Journal of Clinical Oncology (2017)

571 Background: Time interval from diagnostic biopsy to neoadjuvant chemotherapy (NACT) start (TBC) and from last chemotherapy application to surgery (TCS) are influenced by many factors. It is unclear whether a delay of systemic therapy or surgery impacts patients (pts) outcome. Methods: 9127 pts with early BC from 6 German neoadjuvant trials receiving an anthracycline-taxane based NACT were included. pCR (ypT0/is ypN0), disease free survival (DFS) and overall survival (OS) were compared according to TBC and TCS length (cut-off of ≤4 vs &gt;4weeks (w)), overall and in subgroups (BC subtypes [luminal, HER2+, triple-negative breast cancer (TNBC)] and pCR [yes vs no] for survival endpoints) adjusted by study. Results: Data on TBC were available for 8072 pts, on TCS for 6420, on follow-up (FU) for 7889. Median age was 49 yrs, 25.6% had cT3-4, 48.6% N+, 44.1% G3, 46.0% luminal, 26.4% TNBC, 27.6% HER2+ tumors. Median (m) FU-time was 65 months [0-201]. mTBC was 23 days [0-228] (67.5% ≤4w vs 32.5% &gt;4w), mTCS was 28d [0-204] (53.7% ≤4w vs 46.3% &gt;4w), with inter-study variability for mTBC ranging from 14 to 32d and for mTCS ranging from 24 to 29d from the oldest to the most recently conducted study. TBC did not influence the pCR rate, neither in all patients nor in subgroups. At multivariable logistic regression analysis TBC length did not independently predict pCR. TBC did not influence DFS or OS, neither in all patients nor in subgroups. TCS&lt;4w was associated with a trend towards a better DFS in all patients (HR=1.11 95%CI (0.99-1.24), p=0.08) and in pts not achieving pCR (HR=1.12, 95%CI (0.99-1.26), p=0.08). No difference was observed within BC subtypes. OS was not impacted by TCS length. At multivariable Cox regression analysis TBC or TCS≤4 vs &gt;4w did not independently influence DFS or OS. Conclusions: A delay in starting NACT does not impact the pCR rate, DFS or OS and results are independent of the subgroup. However, early surgery after NACT in pts without pCR seems to influence outcome. Our analysis is explorative, but indicates for the first time, that time interval of starting NACT and undergoing surgery might be uncritical. Further research is ongoing.
Targeting Unconscionable Prescription-Drug Prices — Maryland’s Anti–Price-Gouging Law
Authors: Jeremy A. Greene, William V. Padula
Journal: New England Journal of Medicine (2017)

Interview with Dr. Jeremy Greene on a Maryland law that prohibits price gouging on older essential drugs. (13:00)Download A new state law authorizes Maryland's attorney general to prosecute firms that engage in price increases in noncompetitive off-patent–drug markets that are dramatic enough to "shock the conscience" of any reasonable consumer.
Re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776–87
Authors: Isabel Heidegger, Renate Pichler, Andreas Pircher
Journal: European Urology (2017)
Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8-Year Prospective Study of 50,000 Patients With Bipolar Disorder
Authors: Jie Song, Arvid Sjölander, Erik Joas, Sarah E. Bergen, Bo Runeson, Henrik Larsson, Mikael Landén, Paul Lichtenstein
Journal: American Journal of Psychiatry (2017)

Objective: Conclusions regarding lithium’s antisuicidal effect for bipolar disorder have been limited due to nonrepresentative subjects and potential confounding factors, including varying severity of illness. Findings regarding the effect of valproate, the most common alternative to lithium, are inconsistent for suicidal behavior. This study investigated the associations of these two drugs with the risk of suicide-related events, and possible differences between drugs, by using within-individual designs in a register-based longitudinal cohort. Method: Through linkage of multiple Swedish national registers, 51,535 individuals with bipolar disorder were followed from 2005 to 2013 for treatment with lithium and valproate. Stratified Cox regression was used to estimate the hazard ratios of suicide-related events during treated periods compared with untreated periods. For significant associations between medication and suicide-related events, the population attributable fraction was estimated to assess the public health impact for patients with bipolar disorder. Results: During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78–0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89–1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4%−20%) of suicide-related events could have been avoided if patients had taken lithium during the entire follow-up. Conclusions: The results suggest that lithium should be considered for patients with bipolar disorder with suspected suicidal intentions, although risk for suicide is only one of the considerations when providing clinical care.
Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review
Authors: C.A. Riemer, R.A. el-Azhary, K.L. Wu, J.J. Strand, J.S. Lehman
Journal: British Journal of Dermatology (2017)

Calciphylaxis is associated with significant morbidity and mortality. Palliative care (PC) is a subspecialty that treats the pain and stress of serious illness. To assess whether the role of quality of life (QoL) indices, patient‐reported outcome measures and PC have been studied in patients with calciphylaxis, we performed a systematic literature review. Several databases were searched from inception to October 2016 according to modified Preferred Reporting Items for Systematic Reviews and Meta‐Analyses criteria. We searched for papers on calciphylaxis that mentioned the symptoms and supportive needs of patients, QoL or outcome measures to report symptom severity, and the involvement of PC. Twelve papers met the inclusion criteria. Reported patient symptoms included pain, skin lesion resolution and pruritus, with the first being the most frequently reported. Four papers measured pain using a previously verified patient‐reported outcome measure, including the Visual Analogue Scale. One paper used a verified QoL measure, the Dermatology Quality of Life Index. No tool was used consistently. Eight papers reported the use of hospice care or PC in the treatment of calciphylaxis. No outcome measure was used to prompt PC involvement. Overall, QoL indices, patient‐reported outcome measures and PC are underreported in the treatment of calciphylaxis. PC may be a resource to assist in symptom management and adaptive coping strategies for patients from the onset of disease.
Linac-based radiosurgery for multiple brain metastases: A quality assurance and feasibility study.
Authors: Raphael M. Pfeffer, Daphne Levin, Roberto Spiegelmann
Journal: Journal of Clinical Oncology (2017)

2077 Background: The classical treatment for multiple brain metastases is whole brain radiotherapy (WBRT). For patients with 1-3 brain metastases stereotactic radiosurgery (SRS) results in better response, similar survival and less short and long term toxicity such as neurocognitive dysfunction than WBRT. For patients with &gt; 3 metastases there is little prospective data of SRS partly due to the technical and logistic difficulties of delivering SRS to multiple metastases. We present a new SRS planning program (MMM) that allows the planning and delivery of linac-based SRS to up to 10 brain metastases simultaneously in less overall time than for WBRT. Methods: Between August 2014 and August 2016, patients referred for RT with 2 or more brain metastases were offered treatment with MMM. System QA included ArcCheck diode array and film dosimetry and gel dosimetry based on a patient derived phantom. Individual QA included replanting treatment arcs on an independent system. Results: 94 patients with 2-10 (median 5) metastases and a combined volume of 0.01-8.64 cc were treated. Planning time including image fusion, target delineation and RT plan generation required on average 20 minutes minutes. SRS was delivered using 4-5 (is more 7-10 since return arcs do not address the same targets) non-coplanar arcs and a single isocenter at the center of mass of the metastases. Treatment time to deliver 18-24 Gy to all metastases was 25 mins (beam on time ~6 minutes) for a total time of 45 minutes. This is the same as the time for each individual metastasis on earlier planning systems and compares to 20 minutes planning time and 12 mins delivery time for each of 10 fractions for a conventional 2 field WBRT plan WBRT (total 140 minutes). At 6 months follow up, 88% of treated metastases had decreased in size, 10% were stable and 2% grew. Acute toxicity was mild except for one patient with intractable seizures. Conclusions: Linac based SRS for multiple brain metastases is efficient, requiring the same resources as for treatment of a single metastasis and less resources than for WBRT, with a high rate of local control. Appropriate equipment is available in most radiotherapy departments which will allow more prospective studies of SRS for multiple metastases.
Should This Patient Have Weight Loss Surgery?
Authors: Gerald W. Smetana, Daniel B. Jones, Christina C. Wee
Journal: Annals of Internal Medicine (2017)

Obesity is an important public health priority in the United States. One third of U.S. adults are obese and therefore can expect higher rates of diabetes mellitus, other obesity-related comorbidities, and mortality. In 2013, the American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery issued a guideline that recommended weight loss (bariatric) surgery for all patients with a body mass index (BMI) of 40 kg/m2 or higher and for those with a BMI of 35 kg/m2 or greater in the presence of at least 1 obesity-related comorbidity. Among the 3 most commonly performed surgeries, the amount of excess weight reduction ranges from 49% for laparoscopic adjustable gastric banding to 76% for Roux-en-Y gastric bypass. In accredited centers, perioperative mortality averages 0.3%. In this Beyond the Guidelines, 2 experts in obesity management, a bariatric surgeon and a general internist, discuss the role of weight loss surgery versus dietary and lifestyle modification, both in general and for a specific patient who is eligible for surgery. Ethnic and age-related variability in the effects of obesity on mortality, as well as potential long-term benefits and risks of weight loss surgery for patient subgroups, are discussed.
Abstract NTOC-078: ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY IN OVARIAN CANCER
Authors: Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Philip D. Greenberg
Journal: Clinical Cancer Research (2017)

Abstract Over 20,000 women are diagnosed with ovarian cancer annually—more than half will die within 5 years and this rate has changed very little in the last 20 years, highlighting the need for innovative therapies. Reprogramming immune system cells to target and kill cancer cells represents a promising new treatment strategy. Immune T cells have the potential to control tumor growth without toxicity to healthy tissues when engineered to target proteins uniquely overexpressed in tumors. Recent technological advances have helped identify and validate Wilms' Tumor Antigen 1 (WT1) and mesothelin (MSLN) as valid antigen targets for ovarian cancer; these proteins contribute to malignant and invasive phenotypes and have limited expression in healthy cells. In preclinical studies using either patient-derived cell lines or the mouse ID8 ovarian tumor model, we show that T cells engineered to express either a WT1- or MSLN- specific high-affinity T cell receptor (TCR) can kill human and murine ovarian tumor cells in vitro. Moreover, in a disseminated in vivo murine model, adoptively transferred TCRengineered T cells preferentially accumulated within established ID8 tumors, delayed ovarian tumor growth, and prolonged mouse survival. However, our data also reveal that the tumor microenvironment (TME) limits the persistence and killing capacity of the engineered T cells. Cellular and molecular analyses of human tumor specimens show human therapy will face similar obstacles posed by the TME. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function. Citation Format: Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Philip D. Greenberg. ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-078.
Incidence of irritable bowel syndrome and chronic fatigue following GI infection: a population-level study using routinely collected claims data
Authors: Ewan Donnachie, Antonius Schneider, Michael Mehring, Paul Enck
Journal: Gut (2017)

Objectives To investigate the occurrence of postinfectious IBS in routine outpatient care, comparing different types of GI infection and its interaction with psychosomatic comorbidity. Design Retrospective cohort study using routinely collected claims data covering statutorily insured patients in Bavaria, Germany. Cases were defined as patients without prior record of functional intestinal disorder with a first-time diagnosis of GI infection between January 2005 and December 2013 and classed according to the type of infection. Each case was matched by age, sex and district of residence to a patient without history of GI infection. Prior psychological disorder (depression, anxiety or stress reaction disorder) was assessed in the 2 years prior to inclusion. Proportional hazards regression models were used to estimate the HRs for GI infection and psychological disorder. Chronic fatigue syndrome (CFS) was assessed as a comparator outcome. Results A total of 508 278 patients with first diagnosis of GI infection were identified, resulting in a matched cohort of 1 016 556 patients. All infection types were associated with an increased risk of IBS (HR: 2.19–4.25) and CFS (HR 1.35–1.82). Prior psychological disorder was a distinct risk factor for IBS (HR: 1.73) and CFS (HR: 2.08). Female sex was a further risk factor for both conditions. Conclusion Psychological disorder and GI infections are distinct risk factors for IBS. The high incidence of non-specific GI infection suggests that postinfectious IBS is a common clinical occurrence in primary care. Chronic fatigue is a further significant sequela of GI infection.
Inhibition of p38MAPK signalling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis
Authors: D.T. Egu, E. Walter, V. Spindler, J. Waschke
Journal: British Journal of Dermatology (2017)

Pemphigus vulgaris (PV) is a skin blistering disease caused by autoantibodies targeting the desmosomal adhesion proteins desmoglein (Dsg) 3 and 1. The mechanisms underlying pemphigus skin blistering are not fully elucidated but p38 mitogen-activated protein kinase (p38MAPK) activation is one of the signalling events necessary for full loss of cell cohesion. However, it is unclear whether ultrastructural hallmarks of desmosome morphology as observed in patients' lesions are mediated by p38MAPK signalling.In this study, we tested the relevance of p38MAPK for blister formation and the ultrastructural changes induced by PV autoantibodies in human skin.Human skin samples were injected with IgG fractions of one patient suffering from mucocutaneous PV (mcPV-IgG), one from mucosal-dominant PV (mdPV-IgG) or AK23, a pathogenic monoclonal Dsg3 antibody derived from a pemphigus mouse model. Samples were processed for histological and electron microscopy analyses.mcPV-IgG and AK23 but not mdPV-IgG reduced desmosome size, caused interdesmosomal widening and formation of split desmosomes, and altered keratin filament insertion. In contrast, full epidermal blister formation and lower desmosome number were evident in tissue samples exposed to mcPV-IgG only. Pharmacological inhibition of p38MAPK blunted the reduction of desmosome number and size, ameliorated interdesmosomal widening and loss of keratin insertion and prevented mcPV-IgG-induced blister formation.Our data demonstrate that blistering can be prevented by inhibition of p38MAPK in the human epidermis. Moreover, typical morphological alterations induced by mcPV-IgG such as interdesmosomal widening and the reduction of desmosome size at least in part require p38MAPK signalling.