tbuckley/cabot-search huggingface dataset:
RAD001-carboplatin combination in triple-negative metastatic breast cancer (TNMBC): A phase II trial.
Authors: Jasmeet Chadha Singh, Stacy Stein, Matthew Volm, Julia Anne Smith, Sylvia Adams, Marlene Meyers, James L. Speyer, Yelena Novik, Robert Schneider, Sylvia Formenti, Franco Muggia, Komal L. Jhaveri, Judith D. Goldberg, Scott Heese, Xiaochun Li, Samantha Davis, Amy Tiersten
Journal: Journal of Clinical Oncology (2013)

1042 Background: Triple negative breast cancer cells often show genetic instability and inability to repair DNA damage rendering them sensitive to platinum agents. Rapamycin enhances platinum- induced apoptosis in breast cancer cell lines. We sought to explore the activity/toxicity of the of carboplatin with RAD001 in TNMBC. Methods: The primary objective of this study was to estimate clinical benefit rate/CBR (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting &gt;6 months) and the toxicity of this combination in women with TNMBC who have had 0-3 prior chemoregimens for MBC. 25 subjects were recruited. This design had &gt; 80% power to test the null hypothesis that the CBR is ≤10% vs. alternative hypothesis that CBR is ≥ 30% (≥6 would need to achieve a clinical benefit). Prior Carboplatin was allowed. Women with treated brain metastasis were eligible. Originally, Carboplatin AUC 6 was administered q3 weeks with daily 5mg of RAD001 with a 3 patient run-in, then 10 mg daily. Due to excessive thrombocytopenia, the dose of Carboplatin was first amended to AUC 5 and then to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). Results: All 25 patients have been recruited. Median age is 58.There have been 1 CR, 6 PR’s, 2 SD's lasting &gt;6 months and 6 PD’s. 3 patients were not evaluable. One SD achieved in a patient progressing on single agent Carboplatin. The estimated CBR is 36% (95% C.I.: 17%-55%). Median PFS is 3.3 months (95% C.I.: 2.4-7.7 months) from start of treatment. 7 patients (28%) had grade 3 or 4 thrombocytopenia and 3 (12%) had grade 3 neutropenia (no bleeding/ febrile neutropenia). Since amendment of Carboplatin to AUC 4 the regimen has been very well tolerated with only 11% grade 3 hemetoxicity. The grade 3 non-heme toxicities included nausea/ vomiting (n=1), mucositis (n=1) and dehydration (n=1). Grade 3 insomnia (n=1) and dyspnea (n=1) were thought to be unrelated to the treatment (no grade 3 fatigue/ interstitial lung disease). Conclusions: The study has achieved the primary end point of demonstrating clinical benefit in TNMBC. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Clinical trial information: NCT01127763.
Methotrexate and cetuximab for metastatic advanced head and neck squamous cell carcinoma.
Authors: Bassel Atassi, George H. Yoo, Natasha Robinette, Khaled Sibai, Ammar Sukari
Journal: Journal of Clinical Oncology (2013)

e17033 Background: After the failure of first-line palliative chemotherapy in recurrent non-resectable or metastatic head and neck squamous-cell carcinoma (HNSCC), there is no standard of care second-line treatment that is proven to improve quality of life or prolong survival. Both methotrexate and cetuximab has shown a single-agent activity in advanced HNSCC. We are presenting our institutional experience in using unique combination chemotherapy with methotrexate plus cetuximab (MC). Methods: Retrospectively, single institution’s charts were reviewed from 2004-2010, all patients have documented recurrent non-resectable or metastatic HNSCC. After failing at least one line of palliative chemotherapy, patients received weekly IV methotrexate 25 mg/m 2 plus IV cetuximab 400 mg/m 2 loading dose at week one followed by 250 mg/m 2 maintenance dose weekly. Each cycle is 4 weeks treatments. Patients who completed at least 2 cycles were included in the study. Patients can receive MC as first line if they have poor performance status. Treatment was continued until progression. Results: Total of 34 patients were included in the study, 26 male and 8 female, 18 African American and 16 Caucasian. Median patient age was 60 years old. 18, 6 and 6 patients received MC as second, third and fourth line therapy, respectively. 4 patients received MC as first line because there were not candidates for more aggressive chemotherapeutic regimens. The average received number of weekly treatments was 25 (8-69) and average number of cycles was 6 (2-17). Prior chemotherapy regimens include taxanes, platinum, 5-flurouracil, and gemcitabin. Median progression free survival was 4.9 months and overall survival was 10.7 months. Overall survival based on race was 9.9 months for Caucasians and 10.7 months for African Americans (P=0.0391). Grade I and II skin rash was observed in 41% of patients, no grade III/IV toxicities were noticed. Conclusions: Methotrexate plus cetuximab is a well tolerated regimen with a significant survival benefit. Prospective studies are warranted in order to evaluate this regimen as a second line palliative therapy for patients with advanced non-curable head and neck squamous cell carcinoma.
Whole-genome bisulfite sequencing of a complex karyotype AML and identification of regulatory aberrations distinct from normal karyotype AML.
Authors: Stephen Capone, Timothy J. Triche, Gino In, Daniel J Weisenberger, Benjamin P Berman, Giridharan Ramsingh
Journal: Journal of Clinical Oncology (2014)

11075 Background: We characterized the methylome and transcriptome of blasts from a 20 year old man with a metastatic mediastinal immature teratoma who developed a complex karyotype acute myeloid leukemia (CK-AML) while on treatment. We performed low-input whole genome bisulfite sequencing (WGBS), RNA sequencing (RNAseq), and HumanMethylation450 (HM450) assays. RNAseq and (when present) matching HM450 results from normal CD34+ cells (N=6), normal karyotype (NK-AML, N=10) and CK-AML blasts (N=10) were compared. Methods: We purified patient bone marrow blasts and CD34+ cells from healthy volunteers (N=6) by fluorescence assisted cell sorting (FACS). We prepared 200ng (HM450) and 50ng (WGBS) of DNA, the latter by EpiGnome Methyl-Seq Kit (Epicentre). Sequencing on a HiSeq 2,000 yielded ~60 million mapped 50bp reads per sample. WGBS alignment and SNP calls were by BWA and Bis-SNP. 5ng RNA generated ~30 million mapped reads per sample, which we aligned with STAR. HM450 and RNAseq data from McNerney's (Blood, 2013) and TCGA NK- and CK-AML samples were also reprocessed. Results: The patient's blasts homozygously expressed mutant TP53 (R282W), TP53INP1, NCKAP1L, UBR4, and IL17RB. HM450 data revealed copy number aberrations and a signature common to TCGA CK-AMLs. Focal hypermethylation overlapped Polycomb repressor complex binding sites in CD34+ cells and, in contrast to NK-AML, affected HOXA and HOXB clusters. Megabase-scale blocks of hypomethylation overlapped those seen in B-cell immortalization (Hansen, 2013) and IMR90 senescence (Cruickshanks, 2013). Non-coding RNAs (e.g. HOTAIRM1) distinguished CK-AML from NK-AML and normal CD34+ cells. Conclusions: This is the first characterization of an AML methylome using WGBS. The methylome of the CK-AML patient shows changes associated with senescence and transformed cells: genome-scale hypomethylation, focal hypermethylation, and promiscuous transcription. Genome-wide DNA methylation changes in the patient’s blasts broadly parallel those seen with immortalization and senescence in other cell types. The genetic and epigenetic heterogeneity observed in CK-AML may nonetheless contribute to its malignant evolution and poor outcomes.
Transcatheter alcohol septal ablation for hypertrophic obstructive cardiomyopathy [5] (multiple letters)
Authors: T. O. Cheng, W. H. Spencer, N. M. Lakkis, Sherif Nagueh, Neal Kleiman, D. Killip, Z. X. He, M. S. Verani, R. Roberts
Journal: Circulation (1999)
An NGS assay strategy with FFPE and cfDNA to determine primary and secondary mutations across the initial diagnosis and subsequent recurrence/progression of patients with localized, recurrent and metastatic GIST.
Authors: Nagavalli Somasundaram, Rebecca Lim, Jermain Chng, Dan Liang Ho, Anna Gan, Clarinda Wei Ling Chua, Mohamad Farid, Sarah B Ng, Iain B. Tan, Richard Hong Hui Quek
Journal: Journal of Clinical Oncology (2015)

10519 Background: Primary and secondary mutations in GIST affect prognosis and treatment response and impacts treatment decision making. A single driver mutation (primary) is found amongst exons of KIT, PDGFRA and less commonly BRAF, KRAS and NRAS. Sequencing multiple genes may be required to determine the primary mutation and the amount of FFPE diagnostic biopsy material can be limiting. Upon disease progression on Imatinib, 1 or more secondary mutations in exons 13,14,15,17 or 18 in KIT can simultaneously develop, affecting response to subsequent therapy. Determining the secondary mutations at progression is limited by the need to test several possible mutations, small sample amount and sampling error from inter and intra-lesional heterogeneity. Methods: We developed a strategy employing next generation sequencing (NGS) tools on FFPE and cfDNA. Tumor FFPE and blood (plasma) samples from GIST patients and subjects without GIST were obtained, the latter as negative controls and serial spike-in analytical titrations. DNA from Fresh Frozen Tumor samples, where available were also obtained. Results: Initial FFPE samples and subsequent blood (plasma) samples were obtained from a cohort of 96 patients with localized or metastatic GIST and 24 control (non-GIST) patients. Primary mutations are determined from FFPE material and secondary mutations from plasma material. From 100ng of DNA in a multiplexed targeted NGS panel, we can determine the primary mutations from exons 9 and 11 of KIT and exons 12,14 and 18 of PDGFRA, exon 15 of BRAF and exons 2,3,4 of KRAS and NRAS simultaneously. From plasma, using just 10 ng of cfDNA, we are able to simultaneously determine the presence or absence of secondary mutations across exons 13,14,15,17 and 18 of KIT down to a variant allele frequency of 0.1%. Conclusions: We have developed a clinically deployable NGS assay strategy to determine primary and secondary mutations across the initial diagnosis and subsequent recurrence/progression of patients with localized, recurrent and metastatic GIST.
New Score Prognostic System for Patients with MDS and Intermediate IPSS-R: Novel Algorithm to Distinguish Between Low and High Risk in This Subset of Patients. Results from the Spanish Group of MDS (GESMD). Gesmdi Score
Authors: Alba Redondo, Mercedes Sánchez Barba, Guillermo Sanz, Teresa Bernal, Montserrat Arnan Sangerman, Fernando Ramos, Carmen Pedro, Mª Luz Amigo Lozano, Victor Marco, David Valcárcel, Mª Teresa Ardanaz, Salut Brunet, Joan Bargay, María Pedreño, Ana I Vicente, María Teresa Cedena, Mar Tormo, Beatriz Arrizabalaga, Blanca Xicoy, Meritxell Nomdedeu, Félix López Cadenas, Carlos Fernández, Juan Carlos Caballero, Guillermo Martín, María Consuelo Del Cañizo, María Díez Campelo
Journal: Blood (2016)
The estimation of life-time for the patients who acquired resistance to standard chemotherapies.
Authors: Tomoko Taniyama, Kenji Hashimoto, Akihiro Hirakawa, Noriyuki Katsumata, Makoto Kodaira, Kan Yonemori, Mayu Yunokawa, Chikako Shimizu, Kenji Tamura, Masashi Ando, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2012)

e19535 Background: Prognostication is important for the advanced cancer patients to make the most for the rest of their life. We examined the accuracy of oncologists’ clinical predictions of survival (CPS) and the factors that oncologists referred to in cancer patients who acquired resistance to standard chemotherapies. We also examined how oncologists share the information about the survival with patients and their family. Methods: Fourteen oncologists treating major adult solid malignancies (breast, lung, gastrointestinal, pancreatic, gynecologic cancer and sarcoma) participated in this observational prospective cohort study between Oct 2010 and Oct 2011. The oncologists were asked to fill in the questionnaire about CPS when patients acquired resistance to standard chemotherapies. Results: The data of 52 patients were available for analysis. The median CPS was 92 days (Interquartile range [IQR], 61 - 168), and the median actual survival (AS) was 80 days (IQR, 35 to 148). The median difference between CPS and AS (|CPS-AS|) was 21 (IQR, -26 to 50) days. According to Pearson correlation between CPS and AS (r = 0.55, p &lt; 0.001), log(CPS) and log(AS) (r = 0.69, p &lt; 0.001) and spearman correlation between CPS and AS (r = 0.66, p &lt; 0.001), it was statistically considered CPS corresponded to AS. The proportion of patients with |CPS-AS| were as follows; within a week, 6%; within 2 weeks, 14%; and within 4weeks, 42%. Concordance rate between CPS and AS was more accurate in gastric and ovarian cancer while it depended on the oncologists. Although, age, oral intake, the number of chemotherapy regimens and the prognostic factors that oncologists referred to were not related with |CPS-AS|. Eighteen patients (35 %) were informed about the prognosis and thirty-seven patients (71 %) were provided with information about palliative care unit. Thirty-three patients (64 %) received best supportive care alone and eighteen patients (35 %) received further chemotherapies. Conclusions: Oncologists’ predictions generally correlated with AS. As long as the prediction of survival is based on the prognostic factors that oncologists referred to, CPS can be correct to within as least 4 weeks.
Cross-sectional evaluation of long-term bowel issues after radical cystectomy.
Authors: Marie C Hupe, Winfried Vahlensieck, Martin Jp Hennig, Tomasz Ozimek, Julian Struck, Hossein Tezval, Axel Stuart Merseburger, Markus A Kuczyk, Mario W Kramer
Journal: Journal of Clinical Oncology (2017)

318 Background: We had previously shown that a significant number of patients after radical cystectomy (RC) suffer from changes in bowel habits and defecation. Reports addressing long-term bowel disorders following RC are rare. This cross sectional study evaluates long-term bowel issues in a large cohort with the help of an issue-tailored questionnaire. Methods: For this purpose a questionnaire assessing changes in bowel function and its impact on daily life was developed and distributed among members of the German bladder cancer self-help group. A total of 431 patients after RC were evaluated. Symptoms such as diarrhea, constipation, urge to defecate, sensation of incomplete defecation, flatulence, and impact on quality of life (QoL) were assessed. Results: A total of 324 patients were followed ≥1 year, 43% patients of those reported current bowel disorders, 40% life restriction and 60% dissatisfaction. Most frequent bowel symptoms were flatulence (49%), followed by diarrhea (30%) and the sensation of incomplete defecation (23%). The highest prevalence rate of diarrhea is reported in year 3 after surgery: &lt;3 months after surgery 14%, 3-11 months 21%, 12-23 months 18%, 24-35 months 44%, 36-59 months 36%, ≥60 months 27% (p&lt;0.01). Also flatulence is a long-term bowel symptom with a prevalence of 50% ≥1 year vs 37% &lt;1 year after surgery (p=0.0334), while the prevalence of other bowel symptoms did not change over time. After 12 months, diarrhea significantly correlated with flatulence, uncontrolled stool loss, urge to defecate, younger age at time of surgery, and the size of bowel segment for urinary diversion (all p&lt;0.01). Patients suffering from diarrhea report a higher defecation frequency, a lower QoL, a higher dissatisfaction level, a lower energy level (all p&lt;0.01), and a lower health state (p=0.0488). Conclusions: Diarrhea is a prominent long-term bowel symptom after RC. A better understanding of long-term bowel symptoms might lead to optimized surgical procedures, post-operative medication and patient education.
Validation of a scoring system to improve life expectancy prediction in advanced cancer patients
Authors: S. Pourchet, V. Montheil, S. Ropert, J. Alexandre, F. Goldwasser, J. P. Durand
Journal: Journal of Clinical Oncology (2009)

e20507 Background: Oncologists accurately estimates survival in 20% of cases for advanced cancer patients (J Clin Oncol 2005 23:6240–48), leading to prescribe chemotherapy until last weeks of life. This study aimed to develop a validated scoring system to prevent futility. Methods: Between January 2004 and November 2008, 500 evaluable out of 546 consecutive pts with uncurable metastatic solid tumors were entered in a prospective study. On a randomly selected derivation set, independent factors assessable at inclusion predicting 2-weeks survival by a multiple logistic regression, were assigned integer weights to develop a risk-index score, which was subsequently tested on a validation set. Results: On the derivation set (334 pts), predictive factors were: urea &gt; 12 mmol/L (weight = 5; odds ratio (OR) = 3.72; 95% confidence interval (CI) = [1.59; 8.71], p = .002), Karnofsky Performance Status ≤ 30% (weight = 4; OR = 3.28; 95% CI = [1.80; 6.01], p &lt; .001), leucocytes &gt; 15 G/L (weight = 3; OR = 2.49; 95% CI = [1.18; 5.25], p = .017), pre-albumin ≤ 0.05 (weight = 3; OR = 2.42; 95% CI = [1.16; 5.04], p = .019) and male gender (weight = 2; OR = 2.25; 95% CI = [1.28; 3.97], p = .005). On the validation set (166 pts), a risk-index score ≥ 7 identified high risk pts, with a sensitivity of 70 %, specificity of 62 % and a positive predictive value of 78 %. Conclusions: This score could help “go/no go” decisions of chemotherapy in advanced cancer patients and reduces errors of life expectancy prediction from 80% to 22%. No significant financial relationships to disclose.
Association between delirium superimposed on dementia and mortality in hospitalized older adults: A prospective cohort study
Authors: Thiago J. Avelino-Silva, Flavia Campora, Jose A. E. Curiati, Wilson Jacob-Filho
Journal: PLoS Medicine (2017)

Hospitalized older adults with preexisting dementia have increased risk of having delirium, but little is known regarding the effect of delirium superimposed on dementia (DSD) on the outcomes of these patients. Our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in hospitalized older adults.This was a prospective cohort study completed in the geriatric ward of a university hospital in São Paulo, Brazil. We included 1,409 hospitalizations of acutely ill patients aged 60 y and over from January 2009 to June 2015. Main variables and measures included dementia and dementia severity (Informant Questionnaire on Cognitive Decline in the Elderly, Clinical Dementia Rating) and delirium (Confusion Assessment Method). Primary outcomes were time to death in the hospital and time to death in 12 mo (for the discharged sample). Comprehensive geriatric assessment was performed at admission, and additional clinical data were documented upon death or discharge. Cases were categorized into four groups (no delirium or dementia, dementia alone, delirium alone, and DSD). The no delirium/dementia group was defined as the referent category for comparisons, and multivariate analyses were performed using Cox proportional hazards models adjusted for possible confounders (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates). Overall, 61% were women and 39% had dementia, with a mean age of 80 y. Dementia alone was observed in 13% of the cases, with delirium alone in 21% and DSD in 26% of the cases. In-hospital mortality was 8% for patients without delirium or dementia, 12% for patients with dementia alone, 29% for patients with delirium alone, and 32% for DSD patients (Pearson Chi-square = 112, p < 0.001). DSD and delirium alone were independently associated with in-hospital mortality, with respective hazard ratios (HRs) of 2.14 (95% CI = 1.33-3.45, p = 0.002) and 2.72 (95% CI = 1.77-4.18, p < 0.001). Dementia alone did not have a significant statistical association with in-hospital mortality (HR = 1.69, 95% CI = 0.72-2.30, p = 0.385). Finally, while 24% of the patients died after discharge, 12-mo mortality was not associated with dementia or delirium in any of the diagnostic groups (DSD: HR = 1.15, 95% CI = 0.79-1.68, p = 0.463; delirium alone: HR = 1.05, 95% CI = 0.71-1.54, p = 0.810; dementia alone: HR = 1.19, 95% CI = 0.79-1.78, p = 0.399). Limitations to this study include not exploring the effects of the duration and severity of delirium on the outcomes.DSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia.
Addressing findings from the 2014 Surgeon General’s Report: Physician preference for supporting tobacco cessation in cancer patients.
Authors: Alix W. Pommerenke, Anthony Alberg, Ellen R. Gritz, Kenneth Michael Cummings, Thomas H. Brandon, Ivana T. Croghan, Carolyn Dresler, Roy S. Herbst, Scott Leischow, James Roger Marshall, Benjamin Toll, Graham Walter Warren
Journal: Journal of Clinical Oncology (2014)

e17508 Background: The 2014 Surgeon General’s Report concluded that smoking causes adverse outcomes and increased mortality in cancer patients. However, there are limited data on how to improve access to tobacco cessation services for cancer patients. Methods: In 2012, parallel surveys were sent to members of the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC) asking about tobacco assessment and cessation practices, perceptions of tobacco use, and barriers to providing cessation support for cancer patients. A follow up survey was delivered in 2013 to physicians at NCI Designated Cancer Centers (NDCC) providing potential solutions to deficits in tobacco cessation support for cancer patients. Results: A total of 1,507 responses were received for the IASLC survey (40% response), 1,197 responses for the ASCO survey (7% response), and 887 responses for the NDCC survey (13% response). Whereas 90% of respondents from all surveys reported regularly asking their patients about tobacco use and 87-92% reported believing tobacco use affects cancer outcomes, only 35-44% regularly discuss medications or assist with tobacco cessation. Lack of training in tobacco cessation interventions was reported as a dominant barrier to providing cessation support, but most physicians preferred that someone else in their clinic receive training. Nearly all respondents (99%) preferred that another clinical provider deliver cessation support, correlating with a high number of physicians reporting lack of time (45-70%) and resources (48-56%) as other dominant barriers. Only 11% reported concerns about cessation medications as a barrier to cessation support. Conclusions: The physicians who responded believe addressing tobacco use is an important part of cancer care and most ask about tobacco use, but few provide cessation support. To address the deleterious health effects that smoking causes in cancer patients, dedicated cessation support services are needed.