tbuckley/cabot-search huggingface dataset:
Genomics, transcriptomics, and proteomics in the clinical setting: Integrating whole genome and RNA sequencing with quantitative proteomics to better inform clinical treatment selection.
Authors: Shahrooz Rabizadeh, Stephen Charles Benz, Jon Burrows, Todd A. Hembrough, John Z Sanborn, Charles Joseph Vaske, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2015)

11093 Background: Genomic panels, limited to a few hundred target mutations, are the current standard to provide therapeutic insights; however, lack of confirmation of expression of mutated genes is a limitation of these targeted genomics approaches. We report the first comprehensive pan-omic approach, overcoming these issues by integrating analysis of whole genome DNA sequencing with RNA data, including pathway analysis to provide predictive and, subsequently, quantitative proteomics to better identify clinically actionable targets in a timely manner. Methods: Over 50 unique tumors from primary and metastatic disease were selected for pan-omic tumor profiling. A cloud-based DNA and RNA supercomputing platform was developed to produce copy-number estimates, somatic variants, rearrangements, and RNA-abundance estimates from FFPE biopsies. Machine-read pathway analysis integrated whole genome DNA sequencing and RNA data to infer proteomics and predict drug targets. Quantitative, multiplexed proteomic analysis by mass-spectrometry validated therapeutic targets at attomoles per μg of tissue. Results: Approximately 80% of tumors had somatic events in previously published “actionable” genes. Multiple cases showed confirmation between predicted actionable genes and quantitatively increased protein expression; however, many mutations showed little or no expression at the transcriptomic level. These findings were confirmed by quantitative proteomic measurements. Also observed were genomic mutations and protein expression for which approved drugs are available, independent of anatomical tumor type. Conclusions: This is the first report of a fully integrated DNA, RNA, and proteomic diagnostic assay to establish a more accurate view of therapeutic interventions for patients, especially in this era of immuno-oncology. We conclude that the molecular signature of a cancer patient is independent of the anatomical tumor type and, given that many gene mutations were not expressed, that an informed clinical treatment decision requires insight into downstream protein expression and not just DNA alterations alone.
Current Progress in Non-viral RNAi-Based Delivery Strategies to Lymphocytes
Authors: Shoshy Mizrahy, Inbal Hazan-Halevy, Niels Dammes, Dalit Landesman-Milo, Dan Peer
Journal: Molecular Therapy (2017)

RNAi-based therapy holds great promise, as it can be utilized for the treatment of multiple conditions in an accurate manner via sequence-specific manipulation of gene expression. To date, RNAi therapeutics have advanced into clinical trials for liver diseases and solid tumors; however, delivery of RNAi to leukocytes in general and to lymphocytes in particular remains a challenge. Lymphocytes are notoriously hard to transduce with RNAi payloads and are disseminated throughout the body, often located in deep tissues; therefore, developing an efficient systemic delivery system directed to lymphocytes is not a trivial task. Successful manipulation of lymphocyte function with RNAi possesses immense therapeutic potential, as it will enable researchers to resolve lymphocyte-implicated diseases such as inflammation, autoimmunity, transplant rejection, viral infections, and blood cancers. This potential has propelled the development of novel targeted delivery systems relying on the accumulating research knowledge from multiple disciplines, including materials science and engineering, immunology, and genetics. Here, we will discuss the recent progress in non-viral delivery strategies of RNAi payloads to lymphocytes. Special emphasis will be made on the challenges and potential opportunities in manipulating lymphocyte function with RNAi. These approaches might ultimately become a novel therapeutic modality to treat leukocyte-related diseases.
Association of the <i>HOXB13 G84E</i> mutation with increased risk for prostate cancer and other malignancies.
Authors: Jennifer Beebe-Dimmer, William B. Isaacs, Stephen N. Thibodeau, Cecilia Yee, Charles Ewing, Linda Okoth, Kathleen A. Cooney
Journal: Journal of Clinical Oncology (2014)

1558 Background: A rare non-conservative substitution (G84E) in the highly conserved MEIS-interacting domain of the homeobox transcription factor gene HOXB13 has been shown to be associated with an increased risk of prostate cancer. The gene is involved in human embryonic development including the prostate gland, but its role in carcinogenesis is unknown. DNA samples from 9,012 male patients included in the Mayo Clinic Biobank (MCB) were genotyped to determine the frequency of the G84E mutation in this population and its association with various reported cancers. Methods: Subjects were genotyped using a custom TaqMan (Applied Biosystems) assay for G84E (rs138213197). In addition to donating a blood specimen, all MCB participants completed a baseline questionnaire to collect information on medical history, family history, and behavioral characteristics. The frequency of the allele was determined according to both self-report of invasive cancer diagnoses and report of cancer history among first-degree relatives. Results: Forty-nine of 9,012 male patients in the MCB were carriers of G84E (0.5%). Analyses were restricted to those patients with information on history of specific cancers based upon either self-report or electronic medical record. Thirty-one percent (n=2,595) of participants had been diagnosed with cancer, including 46.9% of G84E carriers compared to just 28.7% of non-carriers (p=0.006). G84E was most frequently observed among men with prostate cancer with a carrier frequency of 1.3% compared to 0.4% of men with no history of any invasive cancer (p<0.0001). However, the mutation was also more commonly observed in men with bladder cancer (p=0.06) and leukemia (p=0.01). G84E carriers were more likely to have a positive family history of prostate cancer in a first degree relative compared to non-carriers (43.6% v. 18.6%, p=0.0003). Conclusions: Our study confirms the association between the rare HOXB13 G84E variant and prostate cancer. We have also shown novel associations between G84E and both bladder cancer and leukemia. Future investigation is warranted to confirm these associations in a larger data set in order to improve our understanding of the role of germline HOXB13 mutations in human cancer.
An updated meta-analysis of randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC).
Authors: Suneil Kumar Khanna, Roxanne Cosby, Monika K. Krzyzanowska, Kelvin K. Chan, Timothy R. Asmis, Nazik Hammad, Scott R. Berry
Journal: Journal of Clinical Oncology (2015)

e14641 Background: The median life expectancy for unresectable mCRC is now 30 months. Traditionally, CS are used to treat mCRC; however, to reduce treatment-related toxicity, IS have been developed. Our previously published meta-analysis has now been updated with the results from the AIO KRK 07 study. Methods: A systematic review was conducted to identify RCTs comparing CS to IS. The results of identified trials were clinically homogenous, so the data were pooled using RevMan 5.3 software. Overall survival (OS) hazard ratios (HR) were extracted from the most recently presented trial results. Random effects models were used for all pooling. Results: Twelve RCTs are now identified (N=5,381), 9 with available HRs (N evaluable=5,025). In the experimental arm of these trials, the treatment given after induction included none (“chemotherapy free interval” (CFI), 5 trials, N=3,081), or a maintenance treatment: fluoropyrimidine (1 trial, N=620), or biologic (2 trials, N=852). The AIO KRK 07 trial (N=472) had two IS arms: 1 with a CFI and 1 with biologic maintenance. Results are summarized in the table. Sensitivity analyses demonstrated results were robust across induction and maintenance regimens. The sensitivity analysis of the trials with combination Tx induction and a CFI until progression (CAIRO3, OPTIMOX2, COIN, KRK 0207 n=2,706) is no longer statistically significant when the KRK 0207 data is included (HR=1.08, 95% CI 0.99-1.18, p=0.07). QOL (data from 4 trials) was either the same with both strategies (3 trials, n=1384) or improved in the IS arm (1 trial with CFI, n=1,630). Conclusions: IS of delivering systemic Tx for mCRC do not result in a significant reduction in OS compared to a CS of delivery whether or not maintenance therapy is included. QOL is the same or better with an IS. OS HR (95% CI) Test for Overall Effect, p Heterogeneity, Chi2 (df), p Tau2 (%) I2 (%) All Trials (N=9, 4869 pts) 1.03 (0.96-1.10) p=0.43 6.32 (8), p=0.61 0 0 All Trials with CFI (N=6, 3397 pts) 1.03 (0.95-1.12) p=0.46 5.41 (5), p=0.37 0 8 All Trials with Maintenance Tx (N=4, 1786 pts) 0.99 (0.88-1.11) p=0.84 0.94 (3), p=0.82 0 0
Meta-analysis of adjunctive non-NK1 antagonist medications for control of acute and delayed nausea and vomiting induced by moderate and highly emetogenic chemotherapy.
Authors: Thaiana Aragão Santana, Damila Cristina Trufelli, Felipe Melo Cruz, Leandro Luongo Matos, Auro Del Giglio
Journal: Journal of Clinical Oncology (2014)

e20670 Background: Chemotherapy Induced Nausea and Vomiting (CINV) is among the most distressing chemotherapy induced symptoms that may adversely impact cancer patients’ quality of life. Methods: We conducted a systematic search in Pubmed, Bireme and Cochrane databases for randomized clinical trials, published in English, that evaluated the combination of adjunctive non-Neurokinin 1 (NK1) antagonists drugs (ie neuroleptics, anti-convulsivants and benzodiazepines) with 5-Hydroxitriptamine 3 (5-HT3) antagonists for adult cancer patients recruited to recieve moderate or highly emetogenic chemotherapy. We employed the Review Manager (RevMan) Computer program Version 5.2 for statistical calculations. Results: We included 13 studies with 1669 patients. We observed a significant higher complete protection for acute CINV with adjunctive medications (RR = 0.60; 95% CI: 0.43 - 0.85; p = 0.004; I2 47%) but not for the delayed period (RR = 0.87; 95% CI: 0.73 – 1.04, p = 0.14, I2 15%). We also observed adjunctive medications significantly increased complete control of nausea (RR = 0.62; 95% CI 0.56 – 0.70; p < 0.00001, I2 83%) and vomiting (RR = 0.61; 95% CI: 0.54 – 0.68; p < 0.00001; I2 60%). We could not find in subgroup analysis evidence of superiority of any one of the groups of adjunctive medications over another. Conclusions: We conclude that adjunctive non-NK1antagonists medications may be useful for CINV control. Prospective randomized studies incorporating these low cost medications to new regimens combining 5-HT3 and NK1 antagonists may be warranted.
Impact of current “insufficient” clinical nodal staging on treatment decisions and response to neoadjuvant chemoradiotherapy in esophageal cancer patients.
Authors: Willemieke P.M. Dijksterhuis, Jan-Binne Hulshoff, Hendrik M. van Dullemen, Gursah Kats-Ugurlu, Johannes G.M. Burgerhof, Tijmen Korteweg, Veronique E.M. Mul, Geke Hospers, John Theodorus Plukker
Journal: Journal of Clinical Oncology (2017)

111 Background: Although essential in treatment decision making, clinical nodal (cN) staging in esophageal cancer (EC) remains difficult. We assessed the rate of nodal up- and downstaging and its prognostic value on 5-year disease-free survival (DFS) in EC patients treated with surgery-alone or with neoadjuvant chemoradiotherapy (nCRT). Methods: For this retrospective study, we included 395 EC patients who underwent a curative esophagectomy with or without nCRT between 2000 and 2015. The surgery-alone and nCRT group were matched on clinical T-stage (cT), cN-stage, and histopathological type using propensity score matching ( n=270). Staging consisted of PET with CT, or PET/CT, and endoscopic ultrasonography (n = 235). We compared cN and pathological N-stage (pN) and scored correct, down- and upstaging. The prognostic value of nodal up- and downstaging and localization of node metastases on 5-year DFS were assessed with multivariate Cox regression analysis (factors with a P-value &lt;0.1 on univariate analysis). Results: Nodal upstaging (43.0% vs. 16.3%), correct staging (31.9% vs. 28.1%) and downstaging (25.2% vs. 55.6%) differed between the surgery-alone and nCRT group ( P&lt;0.001). Nodal upstaging was commonly present in adenocarcinoma and cT3-4a tumors. Independent prognostic factors for DFS were pN ( P=0.002) and lymph-angioinvasion ( P=0.016) in the surgery and cN metastasis under the diaphragm ( P=0.012) and lymph node ratio ( P=0.034) in the nCRT group. Conclusions: In esophageal cancer, clinical lymph node staging is still insufficient with &gt;25% nodal downstaging. This inaccuracy might impede assessment of true nodal response to nCRT, affording dubious decisions for a ‘wait-and-see’ strategy.
ブタ心房アブレーション損傷に対する病理電気生理学的相関研究-パート2:高周波エネルギーアプリケーションによる不完全(非貫壁性)心房損傷のメカニズム
Authors: Otomo Kiyoshi, Uno Kikuya, Nagata Yasutoshi, Taniguchi Hiroshi, Kamibayashi Takuo, Komatsu Yuuki, Suzuki Asami, Handa Keita, Yonetsu Taishi, Kimura Shigeki, Kakuta Tsunekazu, Fujiwara Hideomi, Iesaka Yoshito
Journal: Circulation (2008)
Trial of Pregabalin for Acute and Chronic Sciatica
Authors: Stephanie Mathieson, Christopher G. Maher, Andrew J. McLachlan, Jane Latimer, Bart W. Koes, Mark J. Hancock, Ian Harris, Richard O. Day, Laurent Billot, Justin Pik, Stephen Jan, C.-W. Christine Lin
Journal: New England Journal of Medicine (2017)

Sciatica can be disabling, and evidence regarding medical treatments is limited. Pregabalin is effective in the treatment of some types of neuropathic pain. This study examined whether pregabalin may reduce the intensity of sciatica.We conducted a randomized, double-blind, placebo-controlled trial of pregabalin in patients with sciatica. Patients were randomly assigned to receive either pregabalin at a dose of 150 mg per day that was adjusted to a maximum dose of 600 mg per day or matching placebo for up to 8 weeks. The primary outcome was the leg-pain intensity score on a 10-point scale (with 0 indicating no pain and 10 the worst possible pain) at week 8; the leg-pain intensity score was also evaluated at week 52, a secondary time point for the primary outcome. Secondary outcomes included the extent of disability, back-pain intensity, and quality-of-life measures at prespecified time points over the course of 1 year.A total of 209 patients underwent randomization, of whom 108 received pregabalin and 101 received placebo; after randomization, 2 patients in the pregabalin group were determined to be ineligible and were excluded from the analyses. At week 8, the mean unadjusted leg-pain intensity score was 3.7 in the pregabalin group and 3.1 in the placebo group (adjusted mean difference, 0.5; 95% confidence interval [CI], -0.2 to 1.2; P=0.19). At week 52, the mean unadjusted leg-pain intensity score was 3.4 in the pregabalin group and 3.0 in the placebo group (adjusted mean difference, 0.3; 95% CI, -0.5 to 1.0; P=0.46). No significant between-group differences were observed with respect to any secondary outcome at either week 8 or week 52. A total of 227 adverse events were reported in the pregabalin group and 124 in the placebo group. Dizziness was more common in the pregabalin group than in the placebo group.Treatment with pregabalin did not significantly reduce the intensity of leg pain associated with sciatica and did not significantly improve other outcomes, as compared with placebo, over the course of 8 weeks. The incidence of adverse events was significantly higher in the pregabalin group than in the placebo group. (Funded by the National Health and Medical Research Council of Australia; PRECISE Australian and New Zealand Clinical Trials Registry number, ACTRN12613000530729 .).
Psychological distress during hospitalization for hematopoietic stem cell transplantation to predict lower quality of life and high post-traumatic stress disorder symptoms at 6 months post-transplant.
Authors: Harry VanDusen, Lara Traeger, Joel Nathan Fishbein, Tanya Keenan, Joseph A. Greer, William F. Pirl, Vicki A. Jackson, Justin Eusebio, Emily R. Gallagher, Timothy A. Graubert, Jeffrey M. Peppercorn, Thomas R. Spitzer, Karen K. Ballen, Steven L. McAfee, Bimalangshu Dey, Yi-Bin Albert Chen, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2015)

9557 Background: Patients undergoinghematopoietic stem cell transplantation (HCT) experience a steep deterioration in quality of life (QOL) and mood during hospitalization for HCT. The impact of this deterioration on patients’ long-term QOL and post-traumatic stress disorder (PTSD) symptoms is unknown. Methods: We conducted a prospective longitudinal study of patients hospitalized for HCT. At baseline (day-6), day+1, day+8, and 6 months post-HCT, we assessed QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]) and mood (Hospital Anxiety and Depression Scale [HADS]). We used the PTSD Checklist to assess for PTSD symptoms at 6 months. We used multivariable linear regression models to identify predictors of QOL and PTSD symptoms at 6 months post-HCT. Results: We enrolled 97% (90/93) of consecutively eligible patients undergoing autologous (n = 30), myeloablative allogeneic (n = 30), or reduced intensity allogeneic (n = 30) HCT. Overall, patients’ QOL at 6 months (mean FACT-BMT: 110, 95%CI [104-116]) recovered to baseline pre-transplant values (mean FACT-BMT: 110, 95% CI [107-115]). At 6 months, 28.4% of participants met provisional diagnostic criteria for PTSD. In multivariable regression analyses, depression and anxiety symptoms during hospitalization for HCT predicted impaired QOL (HADS-depression β = -1.8, P = 0.04; HADS-anxiety β = -1.7, P = 0.05) and PTSD symptoms (HADS-depression β = 1.0, p = 0.05; HADS-anxiety 1.2, P = 0.01) at 6 months post-HCT. Conclusions: While patients’ overall QOL at 6 months post-HCT returned to baseline values, a significant proportion met provisional diagnostic criteria for PTSD. Psychological distress during hospitalization for HCT was the most important predictor of long-term QOL impairment and PTSD symptoms. Future studies should evaluate whether interventions to reduce psychological distress during HCT may improve long-term QOL and reduce the risk of PTSD symptoms.
Screening for Celiac Disease
Authors: Roger Chou, Christina Bougatsos, Ian Blazina, Katherine Mackey, Sara Grusing, Shelley Selph
Journal: JAMA (2017)

<h3>Importance</h3> Silent or subclinical celiac disease may result in potentially avoidable adverse health consequences. <h3>Objective</h3> To review the evidence on benefits and harms of screening for celiac disease in asymptomatic adults, adolescents, and children 3 years and older for the US Preventive Services Task Force. <h3>Data Sources</h3> Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews, searched to June 14, 2016. <h3>Study Selection</h3> Randomized clinical trials and cohort or case-control studies on clinical benefits and harms of screening vs no screening for celiac disease or treatment vs no treatment for screen-detected celiac disease; studies on diagnostic accuracy of serologic tests for celiac disease. <h3>Data Extraction and Synthesis</h3> One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. <h3>Main Outcomes and Measures</h3> Cancer incidence, gastrointestinal outcomes, psychological outcomes, child growth outcomes, health outcomes resulting from nutritional deficiencies, quality of life, mortality, and harms of screening. No meta-analytic pooling was done. <h3>Results</h3> One systematic review and 3 primary studies met inclusion criteria. No trials of screening for celiac disease were identified. One recent, good-quality systematic review of 56 original studies and 12 previous systematic reviews (sample sizes of primary studies ranging from 62 to more than 12 000 participants) found IgA tissue transglutaminase was associated with high accuracy (sensitivity and specificity both &gt;90%) for diagnosing celiac disease. IgA endomysial antibodies tests were associated with high specificity. Only 2 studies of serologic tests for celiac disease involving 62 and 158 patients were conducted in asymptomatic populations and reported lower sensitivity (57% and 71%). One fair-quality, small (n = 40) Finnish treatment trial of asymptomatic adults with screen-detected celiac disease based on positive serologic findings found initiation of a gluten-free diet associated with small improvement in gastrointestinal symptoms compared with no gluten-free diet (difference less than 1 point on a scale of 1 to 7) at 1 year, with no differences on most measures of quality of life. No withdrawals due to adverse events occurred during the trial; no other harms were reported. No studies were identified that addressed the other outcomes. <h3>Conclusions and Relevance</h3> Although some evidence was found regarding diagnostic accuracy of tests for celiac disease, little or no evidence was identified to inform most of the key questions related to benefits and harms of screening for celiac disease in asymptomatic individuals. More research is needed to understand the effectiveness of screening and treatment for celiac disease, accuracy of screening tests in asymptomatic persons, and optimal screening strategies.