tbuckley/cabot-search huggingface dataset:
Medical Education Theme Issue 2011
Authors: Robert M. Golub
Journal: JAMA (2011)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cost of Bleeding-Related Episodes (BREs) in Adult Patients with Primary Immune Thrombocytopenia (ITP): A Population-Based Retrospective Cohort Study of Administrative Claims Data for Commercial Payers in the United States
Authors: Junji Lin, Xinke Zhang, Xiaoyan Li, Ivy Altomare, Jeffrey S Wasser, Karynsa Cetin
Journal: Blood (2015)
Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma.
Authors: Alain Patrick Algazi, Adele H. Muthukumar, Kelly O'Brien, Alex Lencioni, Katy K. Tsai, Maha Kadafour, Paul B. Chapman, Adil Daud
Journal: Journal of Clinical Oncology (2015)

9068 Background: There is currently a lack of effective targeted therapies for BRAF wild type (WT) melanoma. We explored the combination of the MEK inhibitor trametinib with the AKT inhibitor GSK2141795 in BRAF/NRAS WT and BRAF WT/NRAS mutant (MT) melanoma. Methods: Study accrual goal was 24 patients (pts) with metastatic BRAF WT/NRAS WT melanoma and 24 pts with BRAF WT/NRAS MT melanoma. Eligibility criteria included: unresectable stage III or IV disease, ECOG status 0-2, stable CNS disease, and adequate cardiac function (LVEF ≥ 50%, QTc > 480). For each cohort, an interim analysis was pre-specified after 10 pts. If no responses were seen, the cohort would be closed. If one or more responses were seen, an additional 14 pts would be accrued. Pts received trametinib (1.5 mg) and GSK 2141795 (50 mg) orally, once daily for each cycle lasting 28 days. ORR was assessed by RECIST 1.1 with restaging performed every 8 weeks (2 cycles). Results: Twenty pts were enrolled from October 2013 to October 2014: 10 pts in each NRAS cohort. Rash (70%) and diarrhea (50%) were the most common drug-related adverse events (AE's) for all grades; mucositis occurred in 40% of pts. The best overall response was stable disease in 65%: 80% of BRAF WT/NRAS WT patients and 50% of BRAF WT/NRAS MT patients. No RECIST-confirmed partial or complete responses were observed. As a result, both cohorts were closed to further accrual. Median progression-free survival was 2.75 months (IQR: 1.7 to 3.7 mos), with no difference between the NRAS cohorts (p = 0.46). Conclusions: The combination of trametinib and GSK2141795 is safe, but at these doses and schedules, is ineffective in the BRAF WT population, regardless of NRAS status. Clinically significant adverse events were common at the doses tested. Pharmacodynamic studies are ongoing to determine the extent of pathway inhibition achieved. Clinical trial information: NCT01941927.
Association of a polymorphism in amphiregulin with worse prognosis in metastatic colorectal cancer patients treated with cetuximab.
Authors: Peter M. D. Wilson, Takeru Wakatsuki, Fotios Loupakis, Wu Zhang, Dongyun Yang, Sebastian Stintzing, Yan Ning, Nico Benjamin Volz, Rita Elie El-Khoueiry, Joseph Ethan Li, Melissa Janae Labonte, Yu Sunakawa, Martin K. H. Maus, Robert D. Ladner, Afsaneh Barzi, Syma Iqbal, Anthony B. El-Khoueiry, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

e14543 Background: Accumulating data suggests that Amphiregulin (AREG) and Epiregulin (EREG), ligands of the EGFR pathway, are potential prognostic and predictive markers in metastatic colorectal cancer (mCRC). Elevated AREG and EREG gene expression levels are predictive of improved response rates in mCRC patients treated with cetuximab and longer overall survival (OS) in patients with mCRC who did not receive cetuximab. Since polymorphisms in AREG and EREG may affect their expression or function, we tested whether AREG and EREG polymorphisms were associated with clinical outcome in mCRC patients treated with cetuximab. Methods: Seventy-three patients (n=73) with histopathologically-confirmed mCRC with Kras/Braf wild type were enrolled in Italy. These patients were treated with cetuximab monotherapy or irinotecan plus cetuximab as second or third line treatment. Genomic DNA was extracted from blood and 4 SNPs in AREG and 5 SNPs in EREG were analyzed by direct DNA-sequencing. Results: The median follow-up period was 13.3 months in this cohort. The median progression-free survival (PFS) and OS were 5.2 and 12.9 months respectively. The results indicate that the intronic AREG polymorphism rs28364983 A/C was associated with shorter PFS and OS. Patients with homozygous C/C (n=2) showed a median PFS of 2.3 months vs. 5.3 months for patients harboring at least one-A allele (n=71) (HR: 4.26 [95%CI: 0.98-18.5], p=0.05). Patients with homozygous C/C showed a median OS of 3.0 months vs. 13.1 months for patients harboring at least one-A allele (HR: 3.98 [95%CI: 0.93-16.9], p=0.062). An independent cohort of thirty-three patients was used to validate these initial findings and showed that patients with homozygous C/C (n=3) had a median PFS of 2.3 months vs. 3.8 months for patients harboring at least one-A allele (n=103) (HR: 3.79 [95%CI: 1.16-12.3], p=0.027) and a median OS of 3.0 months vs. 8.4 months (HR: 3.01 [95%CI: 0.93-9.71], p=0.065), respectively. Conclusions: AREG rs28364983 predicted worse outcome in mCRC patients treated with cetuximab; however, further analyses are necessary to understand the mechanism and further validate the prognostic and/or predictive role of this polymorphism.
Impact of long-term serum platinum on neuro- and ototoxicity, cardiovascular disease, and hypogonadism in testicular cancer survivors.
Authors: Line veronika Hjelle, Roy M. Bremnes, per Ole Gundersen, Mette Sprauten, Marianne Brydoy, Torgrim Tandstad, Tom Wilsgaard, Sophie D. Fossa, Jan Oldenburg, Hege Sagstuen Haugnes
Journal: Journal of Clinical Oncology (2014)

4518 Background: Previous studies have identified several long-term complications following cisplatin-based treatment in testicular cancer survivors (TCS). We evaluated the impact of long-term serum levels of platinum (Pt) on neuro- and ototoxicity (NTX), cardiovascular disease (CVD) and hypogonadism in TCS. Methods: 292 cisplatin-treated TCS (1980-1994) participated in a national follow-up study (2007-2008), including laboratory tests and a questionnaire. Serum Pt was quantified by Inductively Coupled Plasma-Mass Spectrometry. Symptoms of NTX were assessed with Scale for Chemotherapy-Induced Neurotoxicity (SCIN), with each symptom categorized in 4 categories ranging from 0, “not at all” to 3, “very much”. Total SCIN score was the sum of six scores, ranging from 0 to 18, and categorized into quartiles. Information about CVD (validated) and medication were retrieved from the questionnaire. Hypogonadism was defined as using testosterone substitution and/or having testosterone <10nmol/l. Associations between NTX and long-term Pt levels were analyzed with ordinal logistic regression. Cox regression was performed to evaluate the risk for CVD, and logistic regression for hypogonadism according to levels of Pt and cisplatin dose. The results are presented as odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI), and are adjusted for age. Results: Median follow-up was 20 years (range 11-28). Median Pt was 86 ng/L (range 0-725). There was a significant association between the highest Pt quartile (yes/no) and quartiles of total SCIN-score (OR 1.67, 95% CI 1.03-2.70), tinnitus (OR 1.77, 95% CI 1.08-2.89) and hearing impairment (OR 1.79, 95% CI 1.10-2.92). In total 24 (8.2%) TCS had a CVD event during follow-up. Increasing cisplatin dose, per 100 mg, was significantly associated with CVD (HR 1.14, 95% CI 1.01- 1.28) and hypogonadism (OR 1.09, 95% CI 1.00-1.19). No association was found between residual Pt versus CVD and hypogonadism. Conclusions: 20 years after chemotherapy, residual serum Pt was significantly associated with NTX. The risk of CVD and hypogonadism increased with higher cisplatin dose, but was not associated with serum Pt.
Simon J Newell
Authors: Lawrence Miall, Jonathan Darling, Catherine Harrison
Journal: BMJ (2017)

Simon J Newell (“Simon,” as he was universally known by colleagues and patients) was born in Leytonstone, London, in 1956, one of four brothers. He attended the Edmund Campion School in Hornchurch. The only member of his family to pursue a medical career, Simon entered medical school at the University of Leeds in 1975 and graduated in 1980 with the McGill prize for surgery and honours in paediatrics, medicine, and psychiatry.

Simon’s house jobs and early paediatric training took place in Yorkshire and included a spell as senior house officer to Professor Sir Roy Meadow and to Dr Peter Dear, the first neonatologist at St James’s Hospital, Leeds, in 1982. Both of these consultants were to become his mentors. Simon would later join Peter as the second neonatologist, sharing a 1 in 2 rota. Rumour has it that on appointment Simon was told: “It is 11 years on, 11 years off, and you start tonight.”

Simon gained membership of the Royal College of Paediatrics in 1983, the start of a relationship with the college that would last his entire career. He also became a member of the college of Physicians and Surgeons in Manitoba, Canada, where he worked briefly. He moved with his wife, Debra, also a Leeds graduate, to Birmingham, where he started his registrar training in paediatrics, especially in neonatology and gastroenterology. He spent five years as a clinical lecturer in paediatrics, working with Geoff Durbin, Professor Alexander McNeish, and Ian Booth. He published papers on gastro-oesophageal reflux in preterm babies and explored the role of antacids and prokinetics on the neonatal gut. He was awarded the Donald Patterson prize for …
Phase II trial of gemcitabine plus rapamycin as second line in advanced osteosarcoma: A Spanish Group for Sarcoma Research (GEIS) Study.
Authors: Javier Martin Broto, Andrés Redondo, Claudia María Valverde, María Ángeles Vaz Salgado, Jaume Mora, Xavier Garcia del Muro, Maria Pilar Sancho Marquez, Javier Martinez-Trufero, Robert Diaz Beveridge, Antonio Gutierrez, Pilar Blay, Cristina Tous, Pablo Luna Fra, Antonio Lopez-Pousa
Journal: Journal of Clinical Oncology (2015)

10530 Background: There are few reports focusing on systemic treatment in osteosarcoma (OS) patients progressing after most active drugs. Preclinical data showed activity of rapamycin in xenograft murine models of OS and in a phase II trial testing m-TOR inhibitor; 4/5 partial responses were seen in OS patients. Likewise, gemcitabine exhibited some activity in retrospective series in OS. Additionally, our group had conducted a phase I trial with gemcitabine (G) plus rapamycin (R) in sarcomas with biological inhibition of m-TOR at recommended doses. All these together supported the design of a phase II trial in advanced progressing OS with G and R combination. Methods: Main endpoint was progression free survival rate (PFSR) at 4 months, defining P1 as 40% and P0 as 20%. A minimax Simon’s two-stage design was applied with an estimation sample size of 33 evaluable patients. Most relevant inclusion criteria were as follows: Non-resectable locally advanced or metastatic disease; age 2-80 y; ECOG 0-2 and measurable progressing disease after receiving at least cisplatin, doxorubicin and methotrexate. The scheme consisted of G 800 mg/m2 i.v. d1 and 8 every 21 days administered at 10 mg/m2/min and R 5 mg/day p.o. Results: From September 2012 to November 2014, 36 patients were enrolled in 12 hospitals of GEIS network with a median age of 24 y (4-60). Two patients were non-eligible for this analysis (chondrosarcoma and early finish of trial drugs). Male/Female distribution was 21/15 and ECOG distribution was 30%, 58% and 12% for 0, 1 and 2 respectively. Overall, 115 cycles were administered with median follow-up for alive patients of 5 (1-17) months. Hematologic grade 3/4 toxicity was neutropenia 42%, thrombocytopenia 25%, anemia 14%, febrile neutropenia 8% and most relevant non-hematologic toxicity was fatigue 14% and transaminitis 5%. There were 2 (6%) PR, 13 (39%) SD and 18 (54%) PD. Regarding the main endpoint, PFSR at 4 months was 44% (27-61) and at 6 months was 28% (13-44). Median of PFS and OS were 2.3 months and 11.2 months respectively Conclusions: The trial met the PFSR expectations with low to mild toxicity and therefore deserves further investigation. Translational associated research is ongoing. Clinical trial information: 2012-001106-26.
Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens.
Authors: Nandita Khera, Amy Emmert, Barry Storer, Brenda M. Sandmaier, Edwin Alyea, Stephanie Lee
Journal: Journal of Clinical Oncology (2013)

7034 Background: Reduced intensity (RIC) conditioning regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). Methods: We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients who underwent a RIC allogeneic HCT at Fred Hutchinson Cancer Research Center (FHCRC; n=147) and Dana Farber Cancer Institute (DFCI; n=337) from 1/2008 to 12/2010. Costs up to 2 years after HCT were analyzed for DFCI (n=311) as most patients receive their post-transplant care there. Multiple linear regression was used to analyze the association between clinical variables and costs. Results: Disease distribution and transplant characteristics were comparable between the two sites, though significant differences were seen in age distribution (88% FHCRC patients ≥ 50 years vs. 80% at DFCI, p=0.04) and pre-transplant performance scores (63% patients with Karnofsky score≥ 90 at FHCRC vs. 47% at DFCI; p=0.006). Median costs for first 100 days in 2010 $ at FHCRC and DFCI were $129 000 (range 31,000-352,000) and $96,000 (3,000-614,000) respectively, p=0.0002, but differences were not significant in multivariate analysis. Inpatient costs accounted for 42% of early costs at FHCRC and 87% at DFCI.Significant predictors for early costs included a diagnosis of lymphoma/ myeloma (17% decrease in costs; p=0.01), donors other than matched related (50 -100% increase; p&lt;0.001), relapse (17% increase, p=0.04) and ≥ grade II acute GVHD (37% increase; p&lt;0.001). Median costs between d100 and 2 years were $39,000 (0-976,000) at DFCI. 39% of the 2 year costs occurred after first 100 days. There was no association of late costs with pre-transplant variables, and only death was associated with higher costs (138% increase; p=0.005). Conclusions: After adjustment for pre and post HCT variables, the overall costs of the RIC allogeneic transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/ alternative donors, relapse and acute GVHD were predictors for higher early costs while only death was associated with higher late costs.
Flavoperidol as a novel therapeutic agent for bladder cancer.
Authors: Reema Railkar, Thomas Sanford, Spencer Krane, Q. Quentin Li, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2017)

357 Background: Bladder cancer (CaB) is the 4 th most common cancer among men in the US but receives substantially less research resources than many other cancer types. There has been little change to the management of bladder cancer over the past 25 years. Quantitative high throughput screening (qHTS) of representative cancer lines with oncology drugs may identify new treatments or re-purpose already existing therapies for different disease. We utilized this technique to identify new therapies in three primary bladder lines (RT4, T24, and UMUC3) and their metastatic lines (T24T, SLT3 and FL3 for T24 and LUL-2 for UMUC3). Methods: We screened 8 bladder cancer cell lines (including RT4, T24, and UMUC3) against 1,912 oncology drugs using a 48 hour cell proliferation assay with an ATP−based readout to determine activity and potency of compounds in a dose response manner. One of the candidate drugs inhibitory in all cell lines tested is flavopiridol, a pan CDK inhibitor. We further characterized the mechanism of action and in vivo effects of flavopiridol using various cell based assays and mouse xenograft studies. Results: The initial screen identified 95 compounds active in 8 cell lines. The top 50 compounds were further analyzed for molecular size of &gt;200 g/mol and TPSA&lt;90. This identified mitomycin C and 8 novel compounds. Further testing revealed Flavopiridol to be most consistent with qHTS data having IC50 of 100-300nM in all the cell lines tested. Flavopiridol induces G2/M arrest; however, very little apoptosis was seen suggesting a cytostatic rather than a cytotoxic mechanism of flavopiridol action. Flavopiridol showed dose dependent inhibition of migration, invasion and colony formation in all cell lines tested. Xenograft studies in rapidly growing UMUC-3 cells showed slowing of tumor growth but not complete reduction indicating cytostatic mechanism of flavopiridol. Conclusions: A high throughput drug screen can identify novel compounds in bladder cancer. Flavopiridol seems to be a very effective inhibitor both in vitro and in vivo. Physical properties of Flavopiridol are most suited for intravesical use, which may lead to it being an effective inhibitor of CaB in the bladder at higher doses without any/few systemic toxicities.
Identification of genetic markers of resistance to echinocandins, azoles and 5-fluorocytosine in Candida glabrata by next-generation sequencing: a feasibility study
Authors: C. Biswas, S.C.-A. Chen, C. Halliday, K. Kennedy, E.G. Playford, D.J. Marriott, M.A. Slavin, T.C. Sorrell, V. Sintchenko
Journal: Clinical Microbiology and Infection (2017)
Early mortality (EM) for newly diagnosed multiple myeloma (NDMM) in the Connect MM U.S. registry.
Authors: Howard R. Terebelo, Jatin J. Shah, Brian G. Durie, Rafat Abonour, Cristina Gasparetto, Jayesh Mehta, Mohit Narang, Sachdev P. Thomas, Kathleen Toomey, Chris L. Pashos, Arlene S. Swern, Kristen A. Sullivan, Thomas K. Street, Shankar Srinivasan, Ali Nourbakhsh, James W. Hardin, Robert M. Rifkin
Journal: Journal of Clinical Oncology (2013)

8596 Background: EM occurring ≤ 6 mos from diagnosis of MM has been reported in several NDMM studies. Incidence of EM in the pre-novel-therapy era was 10–14% of patients (pts); causes included infection/pneumonia, renal failure, refractory disease, and cardiac events. Identifying risk factors and improving response rates (RR) could lower EM. Established risk factors only have a sensitivity of 61% and specificity of 74%. Introduction of novel therapies is improving RRs and changing the profile of morbidity risk factors. Fewer indwelling catheters, better antibiotics, and bisphosphonates have reduced morbidity and mortality in MM. This analysis aims to better understand the causes of EM in this new era. Methods: Connect MM is a prospective observational registry of NDMM pts. Since 2009, 1494 pts in 228 US centers have been enrolled. Baseline characteristics were compared for pts who died ≤ 6 mos after enrollment vs pts who survived &gt; 6 mos. Multivariate logistic analyses identified significant associations between baseline characteristics and EM. Results: Most pts received novel therapies (91%). In the entire cohort, EM occurred in 103 pts (7%), of which 93 were treated (6.5%). EM associated characteristics by multivariate analyses (P&lt; 0.05) were: age, ISS disease stage, PS, history of hypertension, hypercalcemia, lower clonal bone marrow cells (subject to further study), and platelet count. Venous thromboembolism and cytogenetics were not risk factors. Causes of the 103 early deaths were: MM progression (38%), cardiac failure (13%), infection (7%), pneumonia (6%), renal failure (4%), sudden death (3%), vascular event, bleeding, pulmonary embolism (1% each), other (15%) and unknown (13%). Conclusions: It is important to recognize EM as a distinct entity in MM. Better understanding of the biology and pt characteristics is required to further reduce its incidence. This is the first assessment of EM in a registry where almost all pts received novel agents. Of the 103 early deaths, 38% were due to MM, representing a 2.6% incidence in the total cohort (under further review). Although the 7% EM in Connect MM is encouraging, there is still room for improvement. Additional analyses on improvements and causes of death should be performed.
Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions
Authors: John J. Cole, Neil A. Robertson, Mohammed Iqbal Rather, John P. Thomson, Tony McBryan, Duncan Sproul, Tina Wang, Claire Brock, William Clark, Trey Ideker, Richard R. Meehan, Richard A. Miller, Holly M. Brown-Borg, Peter D. Adams
Journal: Genome biology (2017)

Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin. In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice. Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.
Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia
Authors: Antonio G. Piga, Immacolata Tartaglione, Rita Gamberini, Ersi Voskaridou, Angela Melpignano, Paolo Ricchi, Vincenzo Caruso, Antonello Pietrangelo, Xiaosha Zhang, Dawn M. Wilson, Ashley Leneus, Abderrahmane Laadem, Matthew L. Sherman, Kenneth M. Attie
Journal: Blood (2016)