tbuckley/cabot-search huggingface dataset:
Tako-tsubo syndrome and use of paclitaxel.
Authors: Dana Ionescu, Danielle Stone, James Stone, Jean-Bernard Durand, Gloria Iliescu, Kaveh Karimzad, Juan Lopez-Mattei, Cezar Iliescu
Journal: Journal of Clinical Oncology (2017)

e14012 Background: Vasospasm and arrhythmias are the main cardiac toxic effects of cancer treatment with Paclitaxel. Chemotherapy induced stress cardiomyopathy (SC) (Tako-tsubo syndrome) has been linked to antineoplastic agents associated with abnormal vasoreactivity. We aimed to identify if there is a causal relationship between SC and Paclitaxel administration. Methods: All cancer patients who fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6–year period were included in the study. We selected and retrospectively reviewed the medical records of all the patients who had chemotherapy induced SC. Clinical presentation, ECG, laboratory data, transthoracic echocardiogram and coronary angiography results were reviewed. Results: Out of30 patients who fulfilled the diagnostic criteria for SC, 5 patients (16.6%) had SC triggered by chemotherapy. Three patients (2 females, 1 male, mean age 71.3 yo) had Paclitaxel induced SC (60%); two patients received a combination of Paclitaxel and Carboplatin for ovarian cancer, and one patient had combination of Paclitaxel and Cyclophosphamide for prostate cancer. Two patients had cardiac manifestations in the first day of Paclitaxel administration. All three patients presented with chest pain; T wave inversion was the main finding on the electrocardiography. All patients had changes in the cardiac biomarkers (BNP mean 1459.7 pg/dl, TN I mean 1.36 ng/dl, CK-MB mean 8.6 ng/dl) and significant LV dysfunction (LVEF &lt; 50%). Characteristic apical ballooning pattern was identified in all cases from left ventriculogram. Chemotherapy was interrupted ; aspirin and beta blockers were initiated in all patients. Two patients were rechallenged with chemotherapy after 10 days, respectively 20 days after SC. None of the patients experienced recurrence of SC, nor arrhythmias while on aspirin and beta blockers. Conclusions: To our knowledge there are no published data on the association of Paclitaxel administration and SC. In cancer patients who develop acute chest pain after administration of Paclitaxel, evaluation for SC is important to exclude NSTEMI diagnosis, which can impact further cancer therapy. Cancer patients with SC whom have complete recovery may early resume cancer therapy.
Novel panomic validation of time to next treatment (TNT) as an effective surrogate outcome measure in 4,729 patients.
Authors: John Marshall, Lee Steven Schwartzberg, Gerold Bepler, David Spetzler, Wafik S. El-Deiry, Nianqing Xiao, Sandeep K. Reddy, Edward S. Kim, George H. Poste, Derek Raghavan
Journal: Journal of Clinical Oncology (2016)

11521 Background: The role of genomic and protein biomarkers in the selection of treatments of advanced cancer is limited by the availability of outcome data following biomarker selected treatment. TNT has been used as a clinical endpoint by the FDA and reflects the clinical decision making process integrating efficacy and toxicity components. We hypothesized that TNT is a meaningful surrogate endpoint correlating to overall survival (OS) for biomarker selected treatments. Methods: We studied 4729 unselected patients (2009-2015), heterogeneous in cancer type, stage, and line of therapy, who were referred for panomic testing utilizing IHC, PCR, ISH, NGS and RNAseq technologies. Treatment data were retrospectively obtained from the International Oncology Network database. TNT was defined as the interval between start of first treatment after tissue collection and next line of treatment. An unselected subset of 952 patients OS data was used to validate TNT as a meaningful clinical surrogate endpoint. Patients were considered “matched” (M) when the biomarker and treatment were consistent and “unmatched” (U) when they were not. The first regimen of treatment was often delivered without knowledge of biomarker results, minimizing selection bias between groups. Results: A significant improvement was observed between M (n=3011) and U (n=1718) cohorts [HR 0.85 (CI:(0.78,0.93), p<0.001)]. The median TNT was 15% longer in the M v U cohorts (248 v 215 days). Improved OS (HR of 0.69 (CI: (0.56,0.84), p<0.001)) was observed between M (n= 505) and U (n=447), with a median increase of more than 1 year (M = 1069 and U = 686 days). Conclusions: Concordance of TNT and OS for patients with biomarker-associated therapies validates the clinical utility of TNT as a surrogate endpoint that can be assessed using EMR extracted data. Additionally, this analysis demonstrates that patients receiving therapies that match their biomarker profile achieve a longer time until subsequent therapy is used. TNT reflects results of a therapeutic medical decision and thus should be further evaluated against PFS or DFI to determine the best surrogate for OS.
Memorial Day Reflections—The Invisible Enemy
Authors: Kim Chen
Journal: JAMA Internal Medicine (2018)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Somatic mutations in mismatch repair pathway genes in non-small cell lung cancer.
Authors: Siddhartha Hk Devarakonda, Ashiq Masood, Tanner Michael Johanns, Irena Lanc, Lingling Du, Bharath Ganesh, Leonard B. Maggi, Saiama Naheed Waqar, Daniel Morgensztern, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2016)

11523 Background: Somatic mutations in mismatch repair (MMR) genes MLH1, MLH3, MSH2, MSH3, MSH6, and PMS2, and/or DNA polymerase POLE, are associated with a high mutation burden in cancer genomes. History of smoking, high mutation burden and MMR status, have all been shown to predict for response to immune checkpoint blockade. We examined the frequency of mutations in MMR genes and POLE in NSCLC, and correlated them with tumor mutation burden. Methods: The frequency of somatic mutations in the above-mentionedgenes was determined in lung adenocarcinoma (LUAD) and squamous cell carcinoma (SQCC) samples using the cBioPortal for cancer genomics. Only studies that performed whole-exome sequencing were analyzed. LUADs for which smoking status was unavailable were excluded. Average mutation count (non-synonymous mutations in sequenced genes per sample) was compared between samples with (positive) and without (negative) these mutations using student's t-test and non-parametric Wilcoxon Rank-Sum test. Results: A total of 553 NSCLC samples (LUAD-375, SQCC-178) were analyzed. Somatic mutations affecting at least one MMR gene or POLE were observed in approximately 13% and 19% of LUAD and SQCC samples respectively (Table). Average mutation count was significantly higher among positive samples for both subtypes of NSCLC. Average mutation count also seemed to be higher among positive LUADs obtained from non-smokers [positive (n=4): 244.2 vs. negative tumors (n=56): 62.5]. Conclusions: Somatic mutations in MMR genes and POLE are seen in approximately 12-19% of NSCLCs and associated with a higher mutation count compared to tumors lacking these mutations. Further studies are needed to determine whether these mutations predict for responsiveness to immune checkpoint inhibitor therapy. Study N MLH1% MLH3% MSH2% MSH3% MSH6% PMS2% POLE % Atleast 1 mutation % Average mutation count: positive (95% CI) Average mutation count:negative (95%CI) P-value (t-test) P-value (Wilcoxon Rank-Sum) LUAD (Imielinski,2012) 162 2 2 2 2 1 1 3 12 587.9 (302.4-873.4) 214.3 (172.9-255.9) 0.01 <0.001 LUAD (TCGA, 2014) 213 2 0 0 0 1 2 6 13 389.6 (282.7-496.5) 217.5 (184.0-249.9) 0.003 <0.001 SQCC (TCGA, 2012) 178 3 4 2 2 2 2 6 19 442.5 (347.3-537.8) 267.5 (228.2-306.9) 0.001 <0.001
Value of sequencing-guided treatment for patients with advanced malignancies.
Authors: Casey B. Williams, Robert Goldberg, Kirstin Anne Williams, Pradip De, Luis Rojas, David Starks, Nandini Dey, Jessica Klein, Rachel Elsey, Amanda McMillan, Ping Ye, Bing Xu, Benjamin Maurice Solomon, Amy K. Krie, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2016)

TPS6632 Background: Current approaches in the treatment of advanced cancer are based predominantly upon lessons learned from the cytotoxic era. Recently, treatments that target specific genetic mutations or the cell’s immune system to stop or reverse disease progression have increased cancer survivorship. However, people who develop metastatic disease are still more likely to die and require expensive medical care. Rational combination approaches that are selected based upon computational analysis of multi-platform molecular data, tailored for each patient based upon their past medical history, performance status and unique molecular profile, and curated to prevent the development of resistance represent a possible solution that warrants further exploration. The optimal treatment strategy for patients with advanced cancer is currently unknown. Resistance to standard therapies like anthracyclines and taxanes limit the number of treatment options in many patients to a small number of non-cross-resistant regimens. However, profiling provides a personalized therapeutic option for a majority of patients. Matching therapies to individual patients with advanced cancer and comparing it to standard of care can identify optimal treatment strategies. We hypothesize that genomic and proteomic profiling of tumor samples will identify aberrations that are linked to targeted therapies and that can be combined in treating patients. We also believe that such personalized treatment will be of significantly higher value to the patient compared to a standard of care or population based pathways. Methods: All patients with advanced disease enrolled to the protocol NCT02470715 from June 2014 to April 2016 will be evaluated for three primary outcomes: Aggregate results of the multiplatform sequencing utilized in the trial and any subsequent therapy recommendations if applicable; Whether the recommended therapy was obtained by each patient and any available results from the treatment; Compare the outcomes and cost of the therapy for patients that received all of the recommended treatment, at least one, but not all of the recommended drugs, or only standard of care. Clinical trial information: NCT02470715.
Dynamic variations in gene expressions of circulating tumor cells in metastatic castration-resistant prostate cancer patients in response to androgen receptor signaling inhibitors.
Authors: Yu Jen Jan, Sungyong You, Junhee Yoon, Jie-Fu Chen, Nu Yao, Shirley Cheng, Michael Freeman, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2018)

e17063 Background: Newer transcriptomic profiles of prostate cancer (PCa) such as the prostate cancer classification system (PCS) have been developed that may be useful clinically to predict PCa prognosis and drug response. Circulating tumor cells (CTCs) are blood borne tumor cells shed from disease sites which harbor RNA signatures of the disease. In this study, we used the Thermoresponsive(TR) NanoVelcro CTC purification system to purified CTCs and performed transcriptomic analysis using the Nanostring nCounter system. We modified the tissue-based PCS panel to fit in our CTC-based assay and tested with purified CTCs from metastatic, castration-resistant prostate cancer (mCRPC) patients. In this study, we benchmarked the feasibility of RNA disease profiling in purified CTCs and explored the correlations between dynamic gene expression variations and androgen receptor signaling inhibitors (ARSI) drug response. Methods: TR-NanoVelcro CTC purification system is combined with Nanostring nCounter system to detect PCa RNA signatures in purified CTCs from patients' blood samples. We selected 31 blood samples from 21 mCRPC patients under ARSI treatments and tested with modified PCS panel using our combined system. We performed PCa disease profiling and correlated the results with patients’ clinical drug response. Results: Our combined system showed high sensitivity in detecting PCa-specific RNA transcripts in calibration studies. We tested the selected samples and analyzed the gene expressions of the modified PCS panel. PCS1 score was calculated and we found that the score is correlated to patients’ clinical drug response. We also demonstrated the dynamic change of PCS1 score in continuous blood samples from the same patients is correlated to patients’ clinical drug response. Conclusions: Our non-invasive, blood-based assay have shown the feasibility of RNA disease profiling in purified CTCs. We demonstrated the correlations between PCS1 score and clinical drug response. We also showed the dynamic variations of gene expression in the same patients is correlated to ARSI drug sensitivity.
Applications of liquid biopsies as prognostic markers in patients (pts) with advanced ovarian cancer (AOC) on metronomic cyclophosphamide (MCy) with or without nintedanib (N) (Trans METRO-BIBF).
Authors: Marcia Hall, Dimple Chudasama, Charlotte Roberts, Nick Stone, Martha Vardaki, Howard Urnowitz, Ekkhard Schuetz, Julia Beck, Emmanouil Karteris
Journal: Journal of Clinical Oncology (2018)

e24065 Background: Identifying circulating tumour cells (CTCs) in multiple ways from AOC pts based on EpCAM as the identifiable antigen (Ag), often with others (MUC1/16, CK8/18/19, CA125) has met with very limited success. Here we report a holistic approach interrogating liquid biopsies from AOC pts using CTC enumeration and characterisation, gene expression, presence and integrity of plasma ctDNA, Raman spectroscopy from plasma and CNI score from plasma and tissue. Methods: CTC enumeration from healthy controls and 5 AOC pts (21 samples) in METRO-BIBF trial were correlated with outcome using Imagestream™, a multispectral imaging flow cytometry system. Changes in gene expression from total RNA was assessed (TATAA 79-gene array panel). Plasma ctDNA from 10 pts was used to detect changes in DNA Integrity Index (DII), as calculated by Alu247/115. Copy number instability (CNI) scores, from paired tissue / ctDNA were explored in 2 pts. Plasma of 10 pts was drop dried onto calcium fluoride slides, 20 Raman spectra were measured from the outer ring of each drop. Results: CTCs were seen in all AOC pts, median- 166 CTCs/ml (range 19-850) vs 0 in 16 controls. AOC pts with > 198 CTCs/ml had poorer OS HR: 0.12 (p = 0.07). RNA from all AOC pts showed significant down-regulation of 16 genes including EpCAM and up-regulation of 12 further genes. A significantly higher DII was seen in 10 AOC pts vs 11 controls (AUC 0.69). Changes in DII correlated with numbers CTCs during treatment cycles. A similar CNI was noted in tissue and plasma in 2 pts, higher CNI scores corresponded with poorer outcome. Highly significant changes in Raman spectra were noted in 10 AOC pts (n = 10) compared to controls (n = 5). The clearest difference being a reduction in carotenoid concentrations. Conclusions: CTC enumeration is feasible and very sensitive for pts with AOC. Molecular profiling of CTCs is possible e.g. (demonstrated 5 genes correlating with poor OS). CNI scores and Raman spectra require further investigation. Further work is being undertaken to explore these methods of detection in a larger and less heavily pretreated AOC populations.
Incidence and epigenetic factors associated with endometrial cancer in Appalachian Kentucky.
Authors: Rohini Manda, Naga Praneeth Raja, Uday Shankar, Mark Dignan, Nagapavani Kandagari
Journal: Journal of Clinical Oncology (2017)

e17113 Background: Data from the US Cancer Statistics Working Group shows that the age-adjusted incidence of endometrial cancer was 25.6/100,000, 2009-2013 for the US and 24.9/100,000 for the Commonwealth of Kentucky. However, for the Kentucky River Area Development District (KR) in the Appalachian region, the rate was higher at 34.2/100,000. This investigation was designed to explore epigenetic factors related to the elevated incidence of endometrial cancer in the KR region of Kentucky. Methods: With IRB approval, retrospective data on women with endometrial cancer were abstracted from tumor registry records for the period 2005-2015. Data including age at diagnosis, family history of cancer, smoking, diabetes and demographic characteristics were analyzed using SPSS. Results: Data on 41 cases of endometrial cancer from 2005-2015 were included in the analyses. The age range was 37-87 with mean age 62. Of the 41 cases, 19.5% (8/41) were under age 50 at diagnosis. 2 out of 8 (25%) had family history of Lynch syndrome associated malignancies. 9 (22.0%) had family history of cancer. No significant associations between smoking, age at diagnosis and diabetes were noted. Conclusions: There is an increased incidence of endometrial carcinoma in Appalachian Kentucky in general, and elevated rates in women under age 50 compared to statewide and US rates. We have shown from our previous research that there is a higher incidence of lynch syndrome among young patients with colon cancer in Appalachian Kentucky. Similar findings were observed with endometrial cancer from this analysis. Further evaluation and genetic testing for any association with Lynch syndrome in this age group is needed.
Clinical benefits and risks associated with darbepoetin alfa and epoetin alfa treatment in patients with lung cancer and chemotherapy-induced anemia.
Authors: Angelica Tiotiu, Isabelle Clerc-Urmes, Francois Chabot, Yves Martinet
Journal: Journal of Clinical Oncology (2016)

e21635 Background: Chemotherapy-induced anemia (CIA) is a frequent complication in lung cancer (LC). One option for the management of this anemia is the administration of recombinant human erythropoietin (RHE) which stimulates red blood cell (RBC) formation. Methods: In this prospective observational study we compared the efficacy and safety of two types of RHE currently available: epoetin alfa and darbepoetin alfa in anemic patients with LC. Results: Sixty four patients (mean age 64±9 years) receiving chemotherapy for stage III and IV LC with CIA (hemoglobin level < 11g/dl) not treated by RBC transfusion were included: 32 patients in group 1 treated by epoetin alfa 40000UI/week and 32 patients in group 2 treated by darbepoetin alfa 150 microg/week. A significant hematopoietic response (HR) was defined as an increase in hemoglobin concentration ≥ 2g/dl or hemoglobin (Hb) concentration ≥ 12g/dl at 6 weeks. There was no significant difference between groups in terms of anemia characteristics at inclusion. Mean Hb levels at baseline were identical: 10.1 g/dl in group 1 and 9.9 g/dl in group 2 (p = 0.34). At 6 weeks mean Hb levels were: 11.4 g/dl in group 1 and 10.6 g/dl in group 2 (p = 0.01). A significant HR was observed in 25% of patients in group 1 and 12.5% of patients in group 2. Three patients in group 2 developed thrombotic events and one in group 1.Overall survival was comparable: 215 days IC 95% [165, 290] in group 1 and 201 days IC 95% [83, 298] in group 2 (p = 0.76). Conclusions: Both tested erythropoietic agents increased Hb levels in anemic patients with LC. In this study epoetin alfa was more efficient than darbepoetin alfa.
Characterization and costs of breast conditions at an open access breast clinic in South Africa.
Authors: Grace Rubin, Sarah Rayne, Naomi Lince-Deroche, Cheryl Hendrickson, Kate Shearer, Faith Moyo, Pamela Michelow, Carol Benn, Cindy Finhaber
Journal: Journal of Clinical Oncology (2018)

e13570 Background: While most breast-related research focuses on cancer, presentation of symptomatic persons in non-screened environments requires both understanding the spectrum of breast diseases and the cost of diagnosis, so as to plan services in resource-constrained settings. This study presents the variety of breast disease managed at a government, open-access breast clinic in South Africa. Methods: We performed a retrospective file review using a systematic random sample of patients 18 years and above presenting for breast care over a 14-month period. We collected demographics, clinical characteristics, management and final diagnoses, as well as diagnostic costs per patient over a 12 month period. Results: The final sample contained 365 individuals (97.5% women). Most were black, unmarried and South African citizens with a median age of 43 years (IQR 31–55). Of those reporting their status (24.1%) 38.6% were HIV-positive. A mass (57.0%) and/or pain (28.5%) were the most common symptoms. Imaging and breast biopsies were required in 78 and 25% of individuals, respectively. Nearly half of biopsies identified breast cancer (44.1% of women ≤40 and 57.3% for women > 40). Benign conditions (47.7%) and no abnormality (18.2%) were common final classifications among women. There was no difference between the final classifications of patients who self-referred versus those who were formally referred from another health care provider. Nearly half of the participants (46.6%) travelled 20 km or more to attend the clinic. When mammography was excluded and hypothetically replaced with ultrasound only, cost savings occurred. Conclusions: Benign breast conditions far outweighed cancer diagnoses. As breast cancer awareness increases in resource-limited countries, we require clinical preparation to manage a range of non-cancer related conditions. Careful planning for maximizing utilization of mammogram machines and considering lower cost ultrasound for some settings could contribute to increased access to breast care services for women in low-resource settings.