tbuckley/cabot-search huggingface dataset:
Annals Consult Guys – Pros and Cons of Therapy to Increase Bone Mineral Density
Authors: Geno J. Merli, Howard H. Weitz
Journal: Annals of Internal Medicine (2018)

Web Exclusives18 September 2018Annals Consult Guys – Pros and Cons of Therapy to Increase Bone Mineral DensityFREEGeno J. Merli, MD and Howard H. Weitz, MDGeno J. Merli, MDThomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Search for more papers by this author and Howard H. Weitz, MDThomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W18-0014 SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Guys (Howard and Geno) take on a tough one: Will calcium supplementation increase the risk for cardiovascular disease, and should it be avoided in a patient with aortic stenosis?For more videos from and information on Annals Consult Guys, visit go.annals.org/ConsultGuys.. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Thomas Jefferson University, Philadelphia, Pennsylvania (G.J.M., H.H.W.)Disclosures: Geno J. Merli, MD, reports the following: Research grants/contracts: Bristol-Myers Squibb, Bayer. Howard H. Weitz, MD, reports that he has no financial relationships or interests to disclose.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 September 2018Volume 169, Issue 6Page: CG1KeywordsBone densityCalciumCardiovascular diseasesDiagnostic techniquesDisclosureResearch grantsResearch reporting guidelinesStenosis ePublished: 18 September 2018 Issue Published: 18 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.Loading ...
ABSOLUTE: A phase 3 trial of nanoparticle albumin-bound paclitaxel (<i>nab</i>-PTX) versus solvent-based paclitaxel (<i>sb</i>-PTX) in patients with pre-treated advanced gastric cancer (AGC)—Efficacy and QOL results.
Authors: Keisuke Koeda, Kohei Shitara, Atsuo Takashima, Kazumasa Fujitani, Hironori Tsujimoto, Akihito Tsuji, Eiji Oki, Akinori Takagane, Masakazu Takagi, Yasuo Hamamoto, Hideo Baba, Yasushi Omuro, Hiroyuki Okuda, Yasuyuki Nakano, Naotoshi Sugimoto, Michio Nakamura, Kazuhiro Imamura, Daisuke Ichikawa, Hiroyuki Kuwano, Wasaburo Koizumi
Journal: Journal of Clinical Oncology (2017)

4010 Background: Sb-PTX is a standard second-line treatment for patients (pts) with AGC. Nab-PTX was developed to avoid the toxicities with use of solvents in sb-PTX and potentially improve efficacy. Based on ABSOLUTE trial, we conducted the additional analysis to evaluate the efficacy and QOL of nab-PTX and sb-PTX. Methods: Pts who were refractory to a fluoropyrimidine-containing first-line treatment were randomly assigned (1:1:1) to receive intravenous q3w nab-PTX (260 mg/m 2 ) on day 1 of a 21-day cycle, and q1w nab-PTX (100 mg/m 2 ) or q1w sb-PTX (80 mg/m 2 ) on days 1, 8, and 15 of a 28-day cycle. The primary objective was to evaluate whether q3w nab-PTX and q1w nab-PTX were non-inferior to q1w sb-PTX in terms of overall survival (OS). Tumor shrinkage at 8 weeks and at the time of the best response were also investigated. For the QOL analysis, EQ-5D score were collected at baseline and every 8 weeks during the first 24 weeks, and thereafter at every 24 weeks. Time to deterioration of EQ-5D score was compared between each arm as a minimally important difference of 0.05. Results: 741 pts were randomly assigned to q3w nab-PTX, q1w nab-PTX, or q1w sb-PTX. Median OS (months) were 10.3, 11.1, and 10.9, respectively. Q1w nab-PTX was non-inferior to q1w sb-PTX (hazard ratio 0.97, 97.5% CI 0.76-1.23; non-inferiority one-sided p = 0.0085), whereas q3w nab-PTX was not non-inferior to q1w sb-PTX (1.06, 95% CI 0.87-1.31; non-inferiority one-sided p = 0.062).The response rate of target lesions at 8 weeks and at the time of the best response (%) were 22.1 and 27.7 for q3w nab-PTX, 28.2 and 34.9 for q1w nab-PTX, and 18.0 and 25.6 for q1w sb-PTX. Median time to deterioration of EQ-5D score (months) were 2.1 in q3w nab-PTX, 3.8 in q1w nab-PTX, and 3.7 in q1w sb-PTX. Conclusions: Q1w nab-PTX was non-inferior to q1w sb-PTX in terms of OS. In addition, q1w nab-PTX showed favorable effect in comparison with q1w sb-PTX in terms of response rate of target lesions and time at best response. QOL was similar between q1w nab-PTX and q1w sb-PTX. These results suggest that q1w nab-PTX is a useful second-line treatment for pts with AGC. Clinical trial information: 132059.
T cell receptor beta immune repertoire sequencing in FFPE preserved samples: Increasing flexibility and applicability for immuno-oncology studies.
Authors: Lauren Miller, Elizabeth Linch, Jianping Zheng, Denise Topacio-Hall, Timothy Looney, Geoffrey Lowman, Fiona Hyland, Mark Andersen
Journal: Journal of Clinical Oncology (2018)

e24121 Background: T cell receptor beta (TCRβ) immune repertoire analysis by next-generation sequencing is a valuable tool for research studies of the tumor microenvironment and potential immune responses to cancer immunotherapy. Here we describe a TCRβ sequencing assay that leverages the low sample input requirements of AmpliSeq library preparation technology to extend the flexibility of immune repertoire sequencing to include FFPE samples which can often be degraded and in short supply. Methods: The assay targets the highly diverse CDR3 region which allows for T cell clone identification and frequency measurement. The assay allows for functionality with either RNA or DNA input, with little modification of the library construction workflow, as well as flexibility in throughput/sample multiplexing on the Ion 530, 540, or 550 chips. Results: To evaluate assay accuracy, we sequenced libraries including known amounts of 30 well-studied T cell lymphoma rearrangements, as well as evaluation of samples comprised of sorted T cells to ensure the absence of false rearrangement reporting. T cell repertoires were evaluated from as low as 5ng of samples of varying repertoire size such as sorted T cells, peripheral blood leukocytes, fresh-frozen tissue, and FFPE tissue from a variety of normal and cancerous tissues containing a wide range of T cell RNA and DNA. In parallel, we have developed a low input qPCR assay which allows for a quantitative measure of the T cell content across all sample types applicable to the TCRβ sequencing assay. This sample quantification test acts to guide optimal sample input ranges for library construction. Finally, we present the CDR3 TCRβ assay with a dual barcoding approach to increase sensitivity of detection of rare clones. Conclusions: We present a T cell immune repertoire sequencing solution for application in a wide range of sample types, in particular, challenging FFPE samples. In addition, we demonstrate use of a qPCR assay for quantification of sample T cell content to guide sample input for sequencing experiments.
The complete genomic landscape of metastatic prostate cancer pinpoints clinically targetable subgroups.
Authors: Lisanne Francisca van Dessel, Job van Riet, Minke Smits, Michiel Simon Van Der Heijden, Paul Hamberg, Emile E. Voest, Johanna M. Zuetenhorst, Neeltje Steeghs, Petronella Witteveen, John W.M. Martens, Mathijs P. Hendriks, Andre M. Bergman, Ronald De Wit, Stefan Sleijfer, Edwin P.J.G. Cuppen, Harmen J.G. van de Werken, Niven Mehra, Martijn P. Lolkema
Journal: Journal of Clinical Oncology (2018)

5014 Background: Recent genome analysis efforts have shown that genomic alterations obtained from primary and metastatic prostate cancer (mPCa) vary widely, stressing the need to obtain comprehensive genomic data from metastatic tissue. Understanding the complete genomic atlas of mPCa will increase our understanding of cancer progression and improve management of these patients. Methods: Fresh-frozen tissue biopsies of 153 patients with mPCa were analyzed by whole-genome sequencing (WGS) to a minimum depth base coverage of 90x for tumor samples and 30x for peripheral blood (reference). Biopsy sites included bone, lymph node and viscera. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and chromosomal rearrangements and their incidence was compared to results reported for primary disease (Fraser et al. Nature 2017). Results: Median tumor cell content of the biopsied lesions was 60% (95% CI: 56-64%). Median SNV burden was 2.6 SNVs per million base pairs (Mbp; 95% CI: 2.44-2.88) compared to 0.53 SNVs per Mbp in primary disease. High SNV and InDel load correlated with microsatellite instability (MSI) mutational signatures (8/153 tumors). Furthermore, we identified a distinct subgroup harboring signature 3 mutations likely to be associated with BRCA deficiency (26/153 tumors; Alexandrov et al. Nature 2013). Median number of inter-chromosomal rearrangements was 58 (95% CI: 49-67) compared to 19 in primary disease. We found a total of 69 and 62 alterations, including SNVs and CNAs, in the genes AR and TP53, respectively, both important drivers in mPCa. We will present additional data on novel and recurrent genomic alterations and mutational signatures. Conclusions: WGS of metastatic tissue from patients with mPCa shows a clear evolution of aberrations compared to primary disease. Increased frequency of alterations in specific driver genes confirms their role in dissemination and/or therapy failure. Using whole-genome sequencing, we were able to stratify patients into clinically relevant groups (MSI, BRCAness, PI3K and RB) advancing towards improved treatment management of patients with mPCa.
The effect of clinical outcome on patient's perception of physician compassion: A randomized clinical trial (RCT).
Authors: Kimberson Tanco, Ahsan Azhar, Wadih Rhondali, Alfredo Rodriguez-Nunez, Diane D Liu, Jimin Wu, Walter F. Baile, Eduardo Bruera
Journal: Journal of Clinical Oncology (2017)

e21694 Background: We previously found in a RCT video study that patients perceived a physician delivering a more optimistic message as more compassionate and professional. The primary objective of this study was to determine if the clinical outcome modifies the patient’s perception of physician compassion. Methods: 128 patients were randomized to observe a standardized video depicting a physician discussing treatment information (more optimistic [MO] vs. less optimistic message [LO]) with a patient with advanced cancer followed by a vignette depicting the clinical outcome of the patient who continued to decline and now under hospice care. Both physicians displayed identical number of empathetic statements (5) and posture. Surveys were completed after the video and repeated after the vignette including the Physician Compassion Questionnaire (0 = best, 50 = worst). Actors and patients were blinded to the purpose of the study. Investigators were blinded to the video observed by the patient. Results: No significant difference was found in change in compassion scores between [p = 0.40] and within each group (MO vs. LO) after the vignette and video [mean difference(SD): MO 1.7(8.74) p = 0.47 vs LO 0.89(10.24) p = 0.12]. There was a significant decrease of impression of the physician within each group [mean difference(SD): MO -0.79(1.62) p &lt; 0.0001 vs LO -1.17(1.91) p &lt; 0.0001]. There was a significant decrease in total professionalism score within each group [mean difference(SD): MO -0.88(2.25) p = 0.0022 vs LO -0.76(2.22) p = 0.0094]. Overall patient preference decreased for the MO group for the physician being their own physician [mean difference(SD) -0.29(0.77) p = 0.0049] and to recommend the physician to their family [mean difference(SD) -0.29(0.71) p = 0.0009]. Conclusions: The perception of physician compassion was not affected by the actual outcome of the patient. However, the physician was considered less professional. Furthermore, there was also worse preference for the more optimistic physician as physician for self and family after the poor outcome (vignette). More research is necessary to understand the association of clinical outcome and patient perception of physician attributes. Clinical trial information: NCT02498899.
Abstract 11969: Survival From Out-of-Hospital Cardiac Arrest: Intravenous Versus Intraosseous Resuscitation
Authors: Bryan A Feinstein, Benjamin Stubbs, Peter J Kudenchuk
Journal: Circulation (2016)

Background: Although administration of drugs by intraosseous vascular access during out-of-hospital cardiac arrest (OHCA) is growing in popularity and prevalence, the actual effectiveness of this treatment approach is uncertain. Hypothesis: We hypothesized that there would be no difference in resuscitation outcome as measured by survival to hospital discharge after OHCA based on the mode of drug delivery. Methods: We performed a retrospective cohort study of emergency medical services (EMS)-treated, non-traumatic OHCA among persons &gt;18 years of age in King County, WA (excluding Seattle) between September 1, 2012 through December 31, 2014. Patients were classified as IV or IO treatment recipients based on the route of first drug administered during OHCA. Study outcomes were analyzed by multivariate logistic regression. The primary outcome investigated was survival to hospital discharge. Secondary outcomes measured were sustained return of spontaneous circulation (ROSC) and survival to hospital admission. Results: Among 1241 adults with OHCA in whom the time to vascular access was known, 1021 were treated via IV and 220 via IO routes. Patients comprising the IO group were younger, included more women, were more likely to have had an unwitnessed OHCA, an arrest of non-cardiac etiology and less likely to have a shockable initial rhythm than IV patients. IO drug recipients were less likely to achieve sustained ROSC, survive to hospital admission or survive to hospital discharge than the IV group. In adjusted analyses, compared to the IV group, recipients of IO medications were less likely to achieve sustained ROSC (odds ratio (95% confidence interval (CI) 0.69 (0.5, 0.95), p = 0.02) with a trend toward a lower likelihood of being admitted alive to hospital (odds ratio (95% CI) 0.72 (0.52, 1.01), p = 0.06), but there were no differences between the two groups in survival to discharge (odds ratio (95% CI) 0.87 (0.54, 1.40), p = 0.56). Conclusion: IO as compared with IV access is independently associated with a lower likelihood of achieving sustained ROSC after OHCA and a trend toward decreased hospital admission, but not survival to hospital discharge.
NGS cfDNA data as a basis for the development of qPCR diagnostic systems
Authors: V. Mileyko, D. Moiseenko, A. Grinchenko, E. Rozhavskaya, A. Kasianov
Journal: Annals of Oncology (2018)

Background: Circulating cell-free DNA (cfDNA) analysis can serve as a powerful diagnostic tool. However, most of the modern techniques used in oncology nowadays are based on expensive NGS procedures on the nuclear DNA. Here we propose a new approach for the development of cheap diagnostic tests based on cfDNA fragmentation profiles. Methods: We used NGS data from cfDNA to obtain the coverage distribution by fragments of different lengths on healthy donors and patients with colorectal cancer. Based on fragments joint positioning we developed a method for selecting the characteristic and reference genome regions. The reference region was chosen as the area where the coverage levels have the greatest positive correlation between cancer samples and controls. The characteristic region is the region with the highest negative correlation between cancer patients and healthy individuals. Characteristic regions were chosen nearby the transcription start site (TSS) of the gene transcripts with the greatest expression difference between colorectal cancer samples and controls. In the end, we evaluated the results of the in silico qPCR in the selected regions to predict the diagnostic value of the characteristic and reference fragments. Results: We found several cfDNA biomarkers in the suppressor genes, among them KIF1B, LPAR1, APC, FN1, SEPT9. The results obtained from in silico qPCR on the selected loci coincided with the expected patterns. Conclusions: The developed model for the detection of the characteristic cancer-specific loci based on the cfDNA analysis can be used as a design tool for the simple qPCR diagnostics systems. Legal entity responsible for the study: Atlas Oncodiagnostics, LLS. Funding: Atlas Oncodiagnostics, LLS. Disclosure: All authors have declared no conflicts of interest.
In silico analysis of non-synonymous SNPs (nsSNPs) and outcomes in non-small cell lung cancer (NSCLC) patients (pts) treated with immunotherapy (IT).
Authors: Kruti Patel, Matthew K Stein, Lindsay Kaye Morris, Kenneth P Byrd, Benny Weksler, Lee Steven Schwartzberg, Moon Jung Fenton, Ari M. Vanderwalde, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

e14563 Background: Role of biomarkers in predicting benefit from IT in NSCLC is still evolving. These drugs are expensive and benefit less than 50% who receive them, despite PD-L1 status. We hypothesized cancers with increased pathogenic mutations would generate a more robust immune response resulting in increased benefit. Methods: We retrospectively identified NSCLC pts who received next-generation sequencing (NGS) from 2013-2015 by Caris. Pts were divided into those who received IT (IT+) during any line of therapy and those who only received conventional chemotherapy (IT-). PDL-1 status was determined by IHC. In silico analysis with PolyPhen-2 (Harvard) was utilized to predict the significance of nsSNPs. The total pathogenic coding changes (SUM) were defined as the sum of the known pathogenic mutations (MUTp) and pathogenic nsSNPs (pnsSNPs). Outcomes were compared for those with a SUM above (SA) and at or below (SB) the median. All p-values were two-sided: survival outcomes were compared by the log-rank test. Results: 149 NSCLC pts were identified, 99 IT- and 50 IT+. Of 99 IT- and 50 IT+, median age was 65 vs 64; 47% vs 40% females; 57% vs 74% white, 39% vs 18% black; 66% vs 60% adenocarcinoma, 21% vs 30% squamous; 13% vs 6% nonsmokers; 15% vs 6% received a TKI. Median nsSNPs for both were 4. In both groups the mutational burden (MB)- MUTp plus nonsynonymous changes without in silico prediction - did not predict survival (p = 0.27 and p = 0.50). 51% and 52% nsSNPs were predicted-damaging in IT+ and IT-. The median SUM in IT+ was 2 (0-7) and IT- was 2 (0-11). SUM did not predict OS in all comers (p = 0.17). SUM did not predict OS in IT- (p = 0.10) nor in IT+ (p = 0.19), though strong trend in opposite directions were seen. In SB pts, IT+ compared with IT- had no impact on OS (p = 0.38). In SA pts, IT+ had superior outcomes compared to IT- (OS 423d v 244, p = 0.01). PDL1 status did not predict OS in pts that received IT. Conclusions: While MB and PDL1 did not predict outcomes with IT, SA predicted improved OS with IT+ over IT- suggesting the combination of pnsSNPs and known pathogenic lesions may predict benefit from IT. These results need to be validated in a prospective trial but may help select pts that should receive IT.
The outcome of patients with non-chemosensitive relapsed and refractory DLBCL salvaged with radiation therapy followed by autologous stem cell transplant.
Authors: Joanna C. Yang, Karen Chau, Michael Scordo, Craig Steven Sauter, Joachim Yahalom
Journal: Journal of Clinical Oncology (2018)

e19507 Background: For patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who respond to salvage chemotherapy (CMT), autologous stem cell transplant (ASCT) is the standard of care. Yet, patients who are unresponsive to salvage CMT have historically dismal outcomes. At our institution, we have attempted to salvage these patients with radiation therapy (RT) to residual sites of disease as determined by functional imaging prior to ASCT. Methods: Eligible patients had rel/ref DLBCL and received salvage chemotherapy followed by RT and ASCT between the years of 2000 and 2015. Only patients with SD or PD by modern functional imaging criteria after salvage chemotherapy were included for analysis. Survival functions were estimated by the Kaplan-Meier method and compared using a log-rank test. Results: Thirty-one patients, 12 with rel and 19 with ref disease, with a median age of 46 years (22-68 years) received salvage CMT with subsequent functional imaging showing SD (n = 27) and PD (n = 4). All patients then went on to receive RT to the residual sites of disease. Median RT dose was 40Gy (30-54Gy). Six patients received TBI as a component of their conditioning regimen prior to ASCT. With a median follow up of 4.9 years (2.0-16.5 years) for survivors, 4-year relapse-free survival (RFS) was 76% and 4-year overall survival (OS) was 83%. There was no difference in RFS for rel versus ref disease (80% v 74%, p = 0.60). Patients with second-line age-adjusted International Prognostic Index (sAAIPI) scores of 0 and 1 had improved 4-year RFS compared to patients with sAAIPI scores of 2 and 3 (86% v 0%, p < 0.0001). For patients with PET imaging after RT and prior to ASCT (n = 18), residual PET-positivity after RT was not correlated with significantly worse RFS (80% v 92%, p = 0.10). Conclusions: Patients who have stable disease (SD) or progressive disease (PD) that is localized after salvage CMT may benefit from salvage RT to the residual PET-avid disease followed by ASCT, especially if their sAAIPI score is 0 or 1. The outcome from this small cohort is superior to historic outcomes for this high-risk population and represents a promising treatment paradigm to further explore.