tbuckley/cabot-search huggingface dataset:
Predictors of In-Hospital Mortality in Patients With Metastatic Cancer Receiving Specific Critical Care Therapies
Authors: Kah Poh Loh, Ankit Kansagra, Meng-Shiou Shieh, Penelope Pekow, Peter Lindenauer, Mihaela Stefan, Tara Lagu
Journal: Journal of the National Comprehensive Cancer Network (2016)

In-hospital mortality is high for critically ill patients with metastatic cancer. To help patients, families, and clinicians make an informed decision about invasive medical treatments, we examined predictors of in-hospital mortality among patients with metastatic cancer who received critical care therapies (CCTs).We used the 2010 California Healthcare Cost and Utilization Project: State Inpatient Databases to identify admissions of patients with metastatic cancer (age ≥18 years) who received CCTs, including invasive mechanical ventilation (IMV), tracheostomy, percutaneous endoscopic gastrostomy (PEG) tube, acute use of dialysis, and total parenteral nutrition (TPN). We first described the characteristics and outcomes of patients who received any CCTs. We then used multivariable logistic regression models with generalized estimating equations (to account for clustering within hospitals) to identify predictors of in-hospital mortality among patients who received any CCTs.For 2010, we identified 99,085 admissions among patients with metastatic cancer. Of these, 9,348 (9.4%) received any CCT during hospitalization; 50% received IMV, 15% PEG tube, 8% tracheostomy, 40% TPN, and 8% acute dialysis. Inpatient mortality was 30%. Of patients who received any CCT and survived to discharge, 27% were discharged to a skilled nursing facility. Compared with patients who died, costs of care were $3,019 higher for admissions in which patients survived the hospitalization. Predictors of in-hospital mortality included non-white race (vs whites), lack of insurance (vs Medicare), unscheduled admissions, principal diagnosis of infections (vs cancer-related), greater burden of comorbidities, end-stage renal disease, liver disease and lung cancer (vs other cancers).Although more studies are needed to better understand risks and benefits of specific treatments in the setting of specific cancer types, these data will help to inform decision-making for patients with metastatic cancer who become critically ill.
Case 45-1977
Authors: H. Joachim Burhenne, James J. Galdabini
Journal: New England Journal of Medicine (1977)

Presentation of CaseA 39-year-old man was admitted to the hospital because of jaundice.He was well until three months previously, when he began to have heartburn and frequent belching; he reduced his food intake and lost 7 kg in weight. Six weeks before admission he entered another hospital, where bilateral inguinal herniorrhaphy was performed under nitrous oxide — halothane anesthesia. Pruritus occurred almost immediately after the operation, with anorexia, nausea and occasional vomiting. One week later jaundice developed, and his stools were tan, malodorous and floating; his urine was dark, and he noticed a distaste for cigarettes. The jaundice . . .
Abstract 877: Evolution of resistance to EGFR inhibition from drug tolerant cancer cells
Authors: Aaron N. Hata, Yotam Drier, Maria Gomez-Caraballo, Faria Siddiqui, Lecia Sequist, Bradley Bernstein, Jeffrey Engelman
Journal: Cancer Research (2016)

Abstract Acquired drug resistance to targeted cancer therapies remains a significant clinical problem. Although mechanisms of acquired resistance of EGFR mutant non-small cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. We demonstrate that acquired resistance caused by the T790M gatekeeper mutation can occur either by selection of pre-existing T790M clones or via evolution of T790M-negative drug tolerant cells that develop the mutation during drug treatment. Additionally, the path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells have a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR. To characterize drug tolerant cells in patients undergoing EGFR inhibitor therapy, we performed single-cell RNA-Seq on EGFR mutant NSCLC samples prior to and after initiation of EGFR inhibitor. These results offer novel insights into the evolution of acquired resistance to EGFR inhibitors and point to new therapeutic opportunities to prevent or overcome resistance in the clinic. Citation Format: Aaron N. Hata, Yotam Drier, Maria Gomez-Caraballo, Faria Siddiqui, Lecia Sequist, Bradley Bernstein, Jeffrey Engelman. Evolution of resistance to EGFR inhibition from drug tolerant cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 877.
TP53 Mutations Detected By Next-Generation Deep-Sequencing In Patients With Myelodysplastic Syndrome and Isolated Deletion (5q): Results From a German Multicenter Trial
Authors: Maximilian Mossner, Johann-Christoph Jann, Evi Lauinger-Lörsch, Daniel Nowak, Uwe Platzbecker, Aristoteles Giagounidis, Katharina S. Götze, Anne Letsch, Detlef Haase, Katayoon Shirneshan, Richard F. Schlenk, Alexander Kohlmann, Torsten Haferlach, Gesine Bug, Michael Lübbert, Arnold Ganser, Julia Obländer, Stephanie Fey, Wolf-Karsten Hofmann, Ulrich Germing, Florian Nolte
Journal: Blood (2013)
Enrollment of and toxicity in patients 70 years and older on CTEP/NCI-sponsored, single-agent phase I studies from 1980 to 2005.
Authors: S. L. Chow, Y. Lin, N. K. LoConte, R. B. Royds, T. G. Nekrassova, S. P. Ivy, J. Mauer, G. Wilding, R. Stoller, M. J. Egorin
Journal: Journal of Clinical Oncology (2010)

9119 Background: It is unknown if patients (pts) ≥ 70 years old (y.o.) are underrepresented in Cancer Therapy Evaluation Program (CTEP/NCI)-sponsored phase I studies, and if they have more drug-related toxicity. We performed a retrospective review of the CTEP/NCI-sponsored phase I data base maintained by Theradex to evaluate the relationship between age and toxicity in single-agent phase I clinical trials. Methods: 12,535 pts were enrolled, and 218 different antineoplastic agents were evaluated between 1980 and 2005. Pts were separated into 4 age groups (<30 y.o.; 30-49 y.o.; 50-69 y.o.; and ≥70 y.o.), and age distribution was calculated for 5-year enrollment periods. We also calculated the percentage of pts experiencing grade 3-4 hematologic and/or nonhematologic toxicity and used a 2-sided Z-test to compare the rates of grade 3-4 hematologic and nonhematologic toxicity between pts ≥ 70 y.o. and < 70 y.o. Results: The mean (± SD) age was 55 ± 13 y.o., and 13.4% of pts enrolled were ≥70 y.o. Accrual of pts ≥ 70 y.o. increased over time: 9.5% (1980-1985); 10.7% (1986-1990); 14.1% (1996-2000); and 19.3% (2001-2005). There was a small, but statistically significant, increased incidence of grade 3-4 hematologic (2%, p = 0.05, 95% CI [0.1%, 3%]) and nonhematologic (2.4%, p = 0.03, 95% CI [0.6%, 4.2%]) toxicity in pts ≥70 y.o. compared to younger age groups. Conclusions: Pts ≥70 y.o., who represent ∼30% of pts with cancer, have been underenrolled by investigators performing CTEP/NCI-sponsored, single-agent phase I studies. Enrollment of pts ≥70 y.o. has increased progressively over time, possibly reflecting investigator willingness to enroll such pts and the increasing age of the U.S. population. The lack of large increases in grade 3-4 hematologic and nonhematologic toxicity in pts ≥70 y.o. implies that such pts are not likely to bias the maximum tolerated dose defined by single-agent phase I studies. Grade/toxicity < 30 y.o. (n = 516) 30-49 y.o. (n = 3294) 50- 69 y.o. (n = 7048) ≥ 70 y.o. (n = 1677) Grade 3 hematologic 5.8% 6.0% 6.0% 6.9% Grade 4 hematologic 12.0% 7.6% 6.9% 8.1% Grade 3 nonhematologic 11.6% 11.0% 9.9% 11.6% Grade 4 nonhematologic 2.9% 2.6% 2.4% 3.5% No significant financial relationships to disclose.
Abstract 2619: Novel biomarkers and molecular alterations for breast cancer initiation and susceptibility
Authors: Natascia Marino, Mariah L. Johnson, Hiromi Tanaka, Xi Wu, Theresa Mathieson, Jill E. Henry, Mircea Ivan, Yunlong Liu, Connie Rufenbarger, Anna Maria V. Storniolo.
Journal: Cancer Research (2016)

Abstract Background: Despite significant advances in diagnosis and treatment, breast cancer remains the leading cause of cancer-related death in women worldwide. Therefore, there is a critical need to identify molecular mechanisms responsible for cancer initiation and progression. To date, there have been attempts to identify biomarkers that can predict progression of pre-malignant lesions (i.e. DCIS) to invasive carcinoma. Our study aims to identify earliest markers of breast cancer initiation. Methods: We evaluated local (breast tissue) and systemic (serum/plasma) molecular alterations associated with breast cancer susceptibility using the unique resources available at the Komen Normal Tissue Bank at IUSCC. Human specimens (serum/plasma and breast tissue) donated by women before their cancer was clinically detectable were used to identify circulating biomarkers that are associated with breast cancer risk. Specimens from age-matched controls were used for comparison. Sera/plasma were analyzed for circulating miRNAs and telomeric level in the cell-free circulating DNA (cfDNA). We employed next generation sequencing to obtain transcriptome in the “normal” breast of women who eventually developed breast cancer and age-matched control normal breast. Results/Discussion: Serum/plasma of women who developed breast cancer showed variation in circulating miRNAs as well as telomeric cfDNA levels as compared to the healthy control group. Among 385 microRNAs detected in circulation, 10 miRNAs were present at different levels in the susceptible group. In addition, susceptible group displayed reduced levels of plasma telomeric cfDNA and telomere shortening in breast epithelium. Transcriptome analysis of microdissected breast epithelium and stroma revealed molecular alterations in the “normal” breast tissue associated with cancer development. Pathway analyses of these differentially expressed genes are underway to determine the mechanisms associated with breast cancer initiation. Conclusion/Impact: Functional analysis of biomarkers identified in this study may help in cancer risk assessment and improvement of preventive therapy. Citation Format: Natascia Marino, Mariah L. Johnson, Hiromi Tanaka, Xi Wu, Theresa Mathieson, Jill E. Henry, Mircea Ivan, Yunlong Liu, Connie Rufenbarger, Anna Maria V. Storniolo. Novel biomarkers and molecular alterations for breast cancer initiation and susceptibility. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2619.
Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With <i>ALK</i>-Rearranged Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2
Authors: Lucio Crinò, Myung-Ju Ahn, Filippo De Marinis, Harry J.M. Groen, Heather Wakelee, Toyoaki Hida, Tony Mok, David Spigel, Enriqueta Felip, Makoto Nishio, Giorgio Scagliotti, Fabrice Branle, Chetachi Emeremni, Massimiliano Quadrigli, Jie Zhang, Alice T. Shaw
Journal: Journal of Clinical Oncology (2016)

Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.
Lenalidomide Related Diarrhea Correlates With Survival In Multiple Myeloma
Authors: Beth Faiman, Surbhi Sidana, Paul Elson, Kellie Bruening, Hien K. Duong, Robert M Dean, Jason Valent, Christy Samaras, Debbie Hastings, Mitchell R Smith, Frederic J. Reu
Journal: Blood (2013)
Coronary Revascularization in Patients with CKD Stage 5D: Pragmatic Considerations
Authors: Gautam R. Shroff, Charles A. Herzog
Journal: Journal of the American Society of Nephrology (2016)

Coronary revascularization decisions for patients with CKD stage 5D present a dilemma for clinicians because of high baseline risks of mortality and future cardiovascular events. This population differs from the general population regarding characteristics of coronary plaque composition and behavior, accuracy of noninvasive testing, and response to surgical and percutaneous revascularization, such that findings from the general population cannot be automatically extrapolated. However, this high-risk population has been excluded from all randomized trials evaluating outcomes of revascularization. Observational studies have attempted to address long-term outcomes after surgical versus percutaneous revascularization strategies, but inherent selection bias may limit accuracy. Compared with percutaneous strategies, surgical revascularization seems to have long–term survival benefit on the basis of observational data but associates with substantially higher short–term mortality rates. Percutaneous revascularization with drug-eluting and bare metal stents associates with a high risk of in-stent restenosis and need for future revascularization, perhaps contributing to the higher long–term mortality hazard. Off–pump coronary bypass surgery and the newest generation of drug–eluting stent platforms offer no definitive benefits. In this review, we address the nuances, complexities, and tradeoffs that clinicians face in determining the optimal method of coronary revascularization for this high-risk population.
A phase II study of daily afatinib (BIBW 2992) with or without temozolomide (21/28 days) in the treatment of patients with recurrent glioblastoma.
Authors: D. D. Eisenstat, L. B. Nabors, W. P. Mason, J. R. Perry, W. R. Shapiro, P. Kavan, S. Phuphanich, Y. Fu, X. J. Cong, M. Shahidi, D. A. Reardon
Journal: Journal of Clinical Oncology (2011)

2010 Background: Epidermal growth factor receptor (EGFR) is over-expressed in ~50% of glioblastoma (GBM); approximately half express the constitutively active mutant receptor EGFRvIII. Afatinib (A), an irreversible erbB family blocker (including EGFRvIII), has high levels of in vitro activity in tumor cell lines resistant to reversible EGFR inhibitors.Temozolomide (T) can overcome O6-methylguanine methyltransferase (MGMT) resistance. We hypothesized that daily A or daily A+T (AT, 21/28 days) may be an effective treatment for recurrent GBM. Methods: The trial's primary objectives were to evaluate efficacy and safety of A and AT compared to T in recurrent GBM, and to assess molecular determinants of response to A. Patients (pts) with histologically-confirmed GBM at first recurrence after prior combined chemoradiotherapy were randomized 1:1:1 to receive A, AT or T. Randomization was stratified by age (≤50 vs. >50 years) and Karnofsky Performance Status (KPS; 70, 80 vs. 90, 100). A was dosed daily at 40 mg; T was dosed at 75 mg/m2 for 21/28 days. The primary endpoint was 6-month progression-free survival rate (PFS-6). Independent imaging and pharmacokinetic assessments were obtained. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and MGMT. Patients were treated until undue toxicity or disease progression. Results: Enrolment was completed in June 2010. 119 pts were randomized (median age 58 years [range 22–81]) and 54% had a KPS of 70–80. The most frequent AEs in pts A-treated pts were diarrhea (70% and 68% in A and AT, respectively) and rash (80% and 69%). PFS-6 by investigator assessment was 3%, 17% and 22% in the A, AT and T arms, respectively. A was statistically worse compared to T (p=0.008); AT was comparable to T (p =0.59). Best overall response included partial response in one, five and six pts and SD in 22, 20 and 21 pts in A, AT and T, respectively. Preliminary biomarker data in 54 pts suggested durable disease control in EGFRvIII-positive pts treated with A/AT. Updated biomarker data will be presented. Conclusions: Afatinib has limited single-agent activity in recurrent GBM; however, potential activity in biomarker-selected pts warrants further evaluation.
The Yale Open Data Access (YODA) Project — A Mechanism for Data Sharing
Authors: Harlan M. Krumholz, Joanne Waldstreicher
Journal: New England Journal of Medicine (2016)

Dr. Harlan Krumholz on the movement toward broader, responsible, productive sharing of data from clinical trials. (14:09)Download As medical research moves toward the more open approach to data sharing from which physics, astronomy, and genetics currently benefit, the YODA Project offers one of several pioneering data-sharing mechanisms that are already in use.
Abstract 2265: An integrated analysis of gene mutations and gene sets for predicting paclitaxel response in lung adenocarcinoma
Authors: Chia-Yu Huang, Yu-Chiao Chiu, Tzu-Pin Lu, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Hung Hsiao, Eric Y. Chuang
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer death worldwide. A prevalent histological subtype of lung cancer is adenocarcinoma. Chemotherapies and targeted therapies have been developed to treat such malignancy. However, due to the heterogeneity of cancer genomes, drug responses vary considerably among patients and the average survival rate remains quite unsatisfactory. Therefore, integrated biomarkers for predicting drug responses are greatly needed. Addressing this, in the present study we aimed to develop a prediction model based on an integrated analysis of gene mutations and gene sets. Briefly, the two-tailed Student's t-test was performed to identify the gene mutations and gene sets of which activities were associated with drug sensitivity, and classification trees were derived from these genomic features. We applied the analysis to genomic datasets and drug sensitivity data from the Cancer Cell Line Encyclopedia (CCLE) and gene sets defined in the Molecular Signatures Database (MSigDB), and constructed a prediction model for response to paclitaxel, a widely used drug for cancers, in lung adenocarcinoma. Taking KRAS mutation as an example, we identified 20 and 15 drug response-associated gene sets in KRAS-mutant and KRAS-wild type cell lines, respectively. The two lists of gene sets were mutually exclusive, suggesting the need of building individual prediction models for groups of cancer subtypes. We then built a classification tree for each of the two groups and tested their prediction performance by leave one out cross-validation tests; ∼64% and ∼81% accuracy was achieved for KRAS-mutant and KRAS-wild type cell lines, respectively. Gene sets of “SIG_CHEMOTAXIS” and “PID_ERB_GENOMIC_PATHWAY” served as crucial nodes for the trees of KRAS-mutant and KRAS-wild type cells, respectively. In conclusion, we developed a novel method that integrates gene mutations and gene sets for predicting drug responses and demonstrated its high performance in lung adenocarcinoma. Our model is widely applicable to identify potent biomarkers for anticancer drugs in cancers and accelerate the realization of precision medicine. Citation Format: Chia-Yu Huang, Yu-Chiao Chiu, Tzu-Pin Lu, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Hung Hsiao, Eric Y. Chuang. An integrated analysis of gene mutations and gene sets for predicting paclitaxel response in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2265.
Case 29-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, William Silen, Benjamin Castleman
Journal: New England Journal of Medicine (1973)

Presentation of Case*A 15-year-old girl was admitted to the hospital because of abdominal pain and vomiting.She was well until four years previously, when increasing depression developed after her father died of myocardial infarction. Nineteen months before admission she began to complain of vague abdominal pain. Three months later her appetite decreased, with a loss of 18 kg in weight. Severe episodic vomiting and abdominal pain occurred, and there were a few bouts of diarrhea. Thirteen months before entry a gastrointestinal series (Fig. 1) revealed antral and duodenal narrowing and a possible duodenal ulcer: the esophagus appeared normal. Physical . . .