tbuckley/cabot-search huggingface dataset:
Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018
Authors: Morie A. Gertz
Journal: Blood Cancer Journal (2018)

Immunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure with preserved ejection fraction, non-diabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Algorithms will be provided on how to evaluate patients with suspected AL amyloid as well as how to manage patients referred from other medical specialties with biopsy-proven amyloid. An organized stepwise approach to the treatment of patients with light chain amyloidosis, including established and investigational therapies, will be reviewed.
Mucinous component assessed by magnetic resonance imaging in primary rectal cancer tissue before chemoradiotherapy and tumor response.
Authors: Hiroshi Miyakita, Sotaro Sadahiro, Gota Saito, Kazutake Okada, Akira Tanaka, Toshiyuki Suzuki
Journal: Journal of Clinical Oncology (2018)

768 Background: Mucinous carcinoma has been reported to have a lower survival rate, a poorer histologic response to preoperative chemoradiotherapy (CRT) than non-mucinous differentiated adenocarcinoma. Mucinous carcinoma was difficult to diagnose on biopsy because mucinous components are mainly located inside the tumor. We therefore compared MRI findings before and after CRT with histologic findings of resected specimens to investigate the predictive factor of response to CRT. Methods: The study group comprised 205 patients with locally advanced rectal cancer (LARC) who received CRT (40 to 45 Gy) from January 2006 through December 2014. T2-weighted fast-spin echo MRI was used to show the area ratio of mucin lakes (ML) to the maximum cut surface of the primary tissue. The presence or absence of ML and the area ratio of ML on the maximum cut surface were evaluated. Results: The histologic type on preoperative biopsy was well-differentiated or moderately differentiated adenocarcinomas in 202 patients (98.5%), poorly differentiated adenocarcinoma in 2 patients (1.0%), and mucinous carcinoma in only 1 patient (0.5%). ML area ratio on MRI before treatment was less than 20% in 194 patients (94.6%), 20% to 50% in 4 patients (2.0%), 50% or more in 7 patients (3.4%). In 11 patients with ML area ratio of 50% or more in resected specimen, mucinous carcinoma was diagnosed in only one patient (14.3%). The tumor shrinkage rate was 74% in patients with ML area ratio of less than 20%, 54.5% with ML area ration of 20% to 50%, and 56.4% with ML area ratio of 50% or more. (p = 0.002) The rate of T-downstaging was significantly greater in patients with ML area ratio of less than 20% than those with ML area ratio of 20% or more. (58% vs. 27%, p = 0.047) The rates of pCR were 13% and 0%, however, the difference was not significant. (p = 0.21) Conclusions: Mucinous carcinoma is difficult to diagnose on biopsy before chemoradiotherapy. The diagnosis of mucin lakes on MRI before treatment may be useful for predicting the response to CRT.
Association of adjuvant chemotherapy with overall survival in resected pancreatic adenocarcinoma previously treated with neoadjuvant therapy.
Authors: Douglas S. Swords, Ignacio Garrido-Laguna, Sean J. Mulvihill, Gregory J. Stoddard, Matthew A. Firpo, Courtney L. Scaife
Journal: Journal of Clinical Oncology (2018)

404 Background: Guidelines for adjuvant chemotherapy in patients with resected pancreatic adenocarcinoma (PDAC) who received neoadjuvant chemotherapy are equivocal. A lymph node ratio (LNR) ≥ 0.15 may predict lack of benefit, but conflicting results are reported. Methods: The National Cancer Database was searched to identify patients who were resected after neoadjuvant chemotherapy in 2006-2013. Exclusions: metastases at surgery, 90-day postoperative mortality, adjuvant radiation, and outlier interval from diagnosis to surgery (&lt;2.5 or &gt;10 months). The association between adjuvant chemotherapy and overall survival (OS) from diagnosis was examined using multivariable Cox regression and inverse propensity of treatment weighted (IPTW) Cox regression. An IPTW based estimator of the average treatment effect (ATE) was used to quantify the population average survival benefit of treatment. Outcomes were examined in all patients and in those with LNR &lt; 0.15 and ≥ 0.15. Results: 681/2488 patients (27%) received adjuvant chemotherapy. In multivariable Cox regression, adjuvant chemotherapy was associated with improved OS in the overall cohort and in patients with LNR &lt; 0.15. A trend towards improved OS was also observed for those with LNR ≥ 0.15. After accounting for indication bias using IPTW, a significant survival benefit for was observed only for patients with LNR &lt; 0.15. The ATE among LNR &lt; 0.15 patients was 3.3 (95% CI 1.0, 5.7) months, indicating that the average survival of the population would be 3.3 months longer if all received treatment. Conclusions: Adjuvant chemotherapy in resected PDAC patients who received neoadjuvant therapy appears to be beneficial in patients with negative lymph nodes or minimal nodal burden. High LNR after neoadjuvant therapy may be an indicator of adverse tumor biology that is less likely to derive a therapeutic benefit. [Table: see text]
Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source
Authors: Robert G. Hart, Mukul Sharma, Hardi Mundl, Scott E. Kasner, Shrikant I. Bangdiwala, Scott D. Berkowitz, Balakumar Swaminathan, Pablo Lavados, Yongjun Wang, Yilong Wang, Antonio Davalos, Nikolay Shamalov, Robert Mikulik, Luis Cunha, Arne Lindgren, Antonio Arauz, Wilfried Lang, Anna Czlonkowska, Jens Eckstein, Rubens J. Gagliardi, Pierre Amarenco, Sebastian F. Ameriso, Turgut Tatlisumak, Roland Veltkamp, Graeme J. Hankey, Danilo Toni, Daniel Bereczki, Shinichiro Uchiyama, George Ntaios, Byung-Woo Yoon, Raf Brouns, Matthias Endres, Keith W. Muir, Natan Bornstein, Serefnur Ozturk, Martin J. O’Donnell, Matthys M. De Vries Basson, Guillaume Pare, Calin Pater, Bodo Kirsch, Patrick Sheridan, Gary Peters, Jeffrey I. Weitz, W. Frank Peacock, Ashkan Shoamanesh, Oscar R. Benavente, Campbell Joyner, Ellison Themeles, Stuart J. Connolly
Journal: New England Journal of Medicine (2018)

Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).
#Me_Who Anatomy of Scholastic, Leadership, and Social Isolation of Underrepresented Minority Women in Academic Medicine
Authors: Michelle A. Albert
Journal: Circulation (2018)

The thing to do, it seems to me, is to prepare yourself so you can be a rainbow in somebody else's cloud.Somebody who may not look like you…" -Maya Angelou (1928-2014) In academic medicine, underrepresented minority women physician-scientists (URMWP)* are uncommon, particularly in leadership positions.Data from the American Association of Medical Colleges show that among internal medicine chairs, 12 are Asian men, 10 are black (9 men, 1 woman), 7 are Hispanic (5 men, 2 women), and 137 are white (116 men, 21 women).In the top 40 ranked cardiology programs, there are no female cardiology chiefs, whereas there are at least 10 Asian, 2 black, 1 Hispanic, and 24 white men, respectively.There are more URMWP than URM men, yet URMWP are less likely to be professors and occupy leadership positions in academia.Specifically, among US medical school faculty, relative proportions at assistant, associate, and full professor levels according to race/ethnicity and sex have remained essentially unchanged over the past 20 years.Information from the American Association of Medical Colleges shows that only 11%, 9%, 11%, and 24% of Asian, black, Hispanic, and white women, respectively, are full professors compared with 21%, 18%, 19%, and 36% of Asian, black, Hispanic, and white men, respectively.In addition, although there are representative proportions of women and Asians at the lowest faculty levels, they have not equitably progressed in academic medicine, likely reflecting discrimination and structural/ organizational barriers that are also applicable to black and Hispanic women.
Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease
Authors: Paul M Ridker, Jean G. MacFadyen, Robert J. Glynn, Wolfgang Koenig, Peter Libby, Brendan M. Everett, Martin Lefkowitz, Tom Thuren, Jan H. Cornel
Journal: Journal of the American College of Cardiology (2018)
Impact of angiotensin-converting enzyme inhibitors or receptor blockers on post-ICU discharge outcome in patients with acute kidney injury
Authors: Etienne Gayat, Alexa Hollinger, Alain Cariou, Nicolas Deye, Antoine Vieillard-Baron, Samir Jaber, Benjamin G Chousterman, Qin Lu, Pierre François Laterre, Xavier Monnet, Michael Darmon, Marc Leone, Bertrand Guidet, Romain Sonneville, Jean-Yves Lefrant, Marie-Céline Fournier, Matthieu Resche-Rigon, Alexandre Mebazaa, Matthieu Legrand
Journal: Intensive Care Medicine (2018)
Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy
Authors: Cheyne Kurokawa, Ianko D Iankov, S Keith Anderson, Ileana Aderca, Alexey A Leontovich, Matthew J Maurer, Ann L Oberg, Mark A Schroeder, Caterina Giannini, Suzanne M Greiner, Marc A Becker, E Aubrey Thompson, Paul Haluska, Mark E Jentoft, Ian F Parney, S John Weroha, Jin Jen, Jann N Sarkaria, Evanthia Galanis
Journal: JNCI Journal of the National Cancer Institute (2018)

Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however. We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration–approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided. Constitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = –0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines. These findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.
The construction and validation of the Severe Asthma Questionnaire
Authors: Michael E. Hyland, Rupert C. Jones, Joseph W. Lanario, Matthew Masoli
Journal: European Respiratory Journal (2018)

The US Food and Drug Administration's procedure for scale validation requires a documented stepwise process of qualitative and quantitative data. The aim of this paper is to provide final quantitative validating data for the Severe Asthma Questionnaire (SAQ). The SAQ, Asthma Control Test, Mini Asthma Quality of Life Questionnaire and EQ-5D-5L were completed by 160 patients attending a severe asthma clinic; 51 patients completed the SAQ on two occasions for test–retest reliability analysis. The SAQ produces two scores, a SAQ score based on the average of 16 items and a SAQ-global score from a single 100-point global quality of life scale. Construct validity was demonstrated by factor analysis of the 16 items, convergent validity by correlations of &gt;0.6 between the SAQ, SAQ-global and other questionnaires, and discriminant validity by the ability of the SAQ and SAQ-global to distinguish between different treatment levels. Test–retest reliability (intra-class correlation) was 0.93 for the SAQ and 0.93 for the SAQ-global, and the alpha coefficient for the SAQ was 0.93. The SAQ was developed using recommended qualitative and quantitative procedures for scale development, and can be used to gain insight into patients’ perceptions of how severe asthma and its treatment affects their lives.
siRNA in ovarian cancer – Delivery strategies and targets for therapy
Authors: Dirk van den Brand, Vicky Mertens, Leon F.A.G. Massuger, Roland Brock
Journal: Journal of Controlled Release (2018)

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the sixth leading cause of cancer related death in women overall. Despite improved surgical techniques and advances in chemotherapy, mortality hardly decreased over the last twenty years. The major problem is that (micro)metastases persevere in the abdominal cavity, causing incurable tumor recurrence. Therefore, there is an imminent need for new therapeutic strategies. Oligonucleotide (ON) based therapies such as RNA interference (RNAi) provide the possibility to specifically address disease-related pathways. However, small interfering RNA (siRNA) molecules are unable to enter cells without a drug delivery system. Therefore, nanocarriers have been developed to aid intracellular delivery of siRNA. EOC is, in most cases, confined to the abdominal cavity, providing the possibility for peritoneal drug delivery. As a consequence, EOC should be an ideal candidate for ON therapies as intraperitoneal delivery reduces sequestration of drug formulations in other organs. In this review, we will discuss delivery strategies and siRNA targets that have been tested in EOC. Delivery strategies cover the full range of delivery approaches from polymers to exotic delivery strategies like microbubble based nanoparticles. For siRNA targets, those that aim at re-sensitizing the tumor cells to chemotherapy can be discriminated from those that reduce growth and metastasis of the tumor cells. Despite preclinical successes and the advantage that intraperitoneal delivery holds over systemic delivery, no strategy has made it into the clinic yet. We postulate that confirmatory studies that combine the most promising delivery approaches with the most promising targets are required to reach a consensus on those formulations that should be pursued for further (pre-)clinical research.
The prognostic role of preoperative serum lactate dehydrogenase (LDH) in patients with resected advanced melanoma.
Authors: Neil Majithia, Ana Velazquez Manana, Yiyi Yan, Lisa A. Kottschade, Roxana Stefania Dronca, Matthew Stephen Block, Wendy Kay Nevala, Svetomir Markovic
Journal: Journal of Clinical Oncology (2017)

e21054 Background: Up to 50% of patients undergoing resection for advanced melanoma experience recurrence. Identification of preoperative prognostic biomarkers is needed to ascertain risk of relapse and guide postoperative management. Lactate dehydrogenase (LDH) represents a strong prognostic factor in unresectable metastatic (stage IV) melanoma, but its relevance in patients with resected stage III or IV disease remains unknown. Methods: We retrospectively analyzed data from patients with stage III and IV melanoma who had undergone complete resection of disease and received follow-up treatment at Mayo Clinic, Rochester between January 1, 2000 and January 31, 2012. Clinical data were collected from electronic records. Survival data were estimated using the Kaplan-Meier method. Associations of preoperative LDH with time to relapse and death were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals. Results: A total of 154 subjects with resectable stage III or IV melanoma were included in the study. Median age at the time of resection was 58; 54 (35.1%) were female. One-hundred sixteen (75.3%) patients were classified as stage III and 38 (24.7%) stage IV. Adjuvant systemic treatment was administered in 75 (48.7%) patients and adjuvant radiation in 32 (20.7%). Median duration of follow-up was 4.0 years. Sixteen (10.3%) patients had preoperative LDH above the upper limit of normal. Each 50-unit increase in LDH was associated with a 15% increased risk of relapse (HR 1.15; p = 0.040) and 23% increased risk of death (HR 1.23; p = 0.001). After adjusting for age, gender, stage, number of sites, adjuvant systemic treatment, and adjuvant radiation, preoperative LDH remained associated with time to death (HR 1.25; p = 0.002). Preoperative LDH greater than the upper limit of normal was associated with increased hazard of death, both with univariate (HR 2.44; p = 0.005) and multivariate (HR 2.17; p = 0.017) analyses. Conclusions: This study supports the role of elevated preoperative LDH as a predictor of inferior outcomes in patients with advanced melanoma. Further study to correlate LDH to outcomes in the era of adjuvant immunotherapy is required.
Abstract B32: Targeting WNT signaling in vivo via Tankyrase inhibition
Authors: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Lukas Dow
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 95% of CRCs show hyperactive WNT signaling, yet there are no targeted therapies that effectively suppress the WNT pathway. The majority (~80%) of these tumors harbor a mutation in APC, a scaffold component of the “destruction complex,” which is a critical negative regulator of WNT. Using genetically defined mouse models of CRC, we recently showed that restoring Apc function can induce WNT suppression and rapid and sustained disease regression. While there is no way to restore normal APC protein in human CRCs, it may be possible to restore the function of the APC-associated destruction complex by inhibiting Tankyrase (TNKS) enzymes. Tankyrase inhibitors have been shown to stabilize AXIN, prevent degradation of the destruction complex, and decrease levels of WNT signaling. While in vitro studies have shown promise, it is unclear whether TNKS inhibition could provide a therapeutic benefit in vivo. Some published work reports significant antitumor activity, while others suggest overt dose-limiting toxicity. Thus, while TNKS inhibition holds significant potential, it is not clear whether TNKS enzymes are a viable target for CRC therapy. To circumvent the limitations of drug delivery, potency, and specificity, we generated mice with inducible, fluorescent reporter-linked shRNAs targeting Tnks and its redundant family member Tnks2. Here we show that potent, simultaneous shRNA-mediated knockdown of both genes is sufficient to stabilize Axin in vivo, similar to treatment with a pan-TNKS inhibitor, XAV939. We show that Tnks1/2 knockdown stabilizes Axin and suppresses WNT signaling, but surprisingly, does not disrupt intestinal architecture. Importantly, Tnks1/2 silencing blocks hyperproliferation and tumor development in mice following Apc disruption. In contrast to current studies using small-molecule TNKS inhibitors, our work suggests that there is a viable therapeutic window of TNKS1/2 inhibition in vivo, and that this strategy enables control of hyperactive WNT signaling in CRC and other WNT-associated cancers. Citation Format: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Lukas Dow. Targeting WNT signaling in vivo via Tankyrase inhibition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B32.
Staphylococcus aureus bloodstream infection in patients with ventricular assist devices–Management and outcome in a prospective bicenter cohort
Authors: Insa Joost, Wolfgang Bothe, Christine Pausch, Achim Kaasch, Berit Lange, Gabriele Peyerl-Hoffmann, Greta Flüh, Matthias Müller, Christian Schneider, Harald Seifert, Winfried V. Kern, Friedhelm Beyersdorf, Siegbert Rieg
Journal: Journal of Infection (2018)