tbuckley/cabot-search huggingface dataset:
The devil is in the details…or not? A primer on individual patient data meta-analysis
Authors: Sachin Sud
Journal: Annals of Internal Medicine (2009)

A systematic review is the process by which primary studies are identified, critically appraised, and interpreted according to a predefined plan to answer clinically important questions with minimal bias and random error. When the results are quantitatively combined, the review is referred to as a “meta-analysis.” Meta-analysis provides more precise estimates of treatment benefits and harms, may reveal treatment effects that would otherwise go undetected in individual trials, and provides a succinct “bottom line” for a clinical question based on the best available evidence.1 A variation of this method is individual patient data (IPD) meta-analysis where analyses are done using original data and outcomes for each person enrolled in relevant studies; patient databases from each study are combined into a single large database, and analysed using methods that account for variation both within studies and between studies.

What is the difference between conventional and IPD meta-analysis? In conventional meta-analysis, aggregated data are extracted from published and unpublished reports according to a predetermined protocol. Analysis is performed by calculating a weighted average for effect (eg, relative risk) across randomised trials.2 Limitations of this approach include risk of publication bias,3 heterogeneity in trial results,4 inability to perform intention-to-treat analyses when relevant patient data are excluded or missing,5 and limited methodological quality of source studies.6 Because each randomised trial in a …
Chemotherapy treatment patterns for early-stage breast cancer (ESBC): Decreasing use of anthracycline-based regimens.
Authors: Katherine M. Serrurier, Jimmy Hwang, Joseph P. McGuire, Ann C. Griffin, Michelle E. Melisko, Hope S. Rugo
Journal: Journal of Clinical Oncology (2012)

141 Background: Anthracyclines (A), given in sequence or combination with other agents, have been the mainstay of adjuvant chemotherapy (CTX) for ESBC for more than two decades. Recent molecular studies have questioned the value of A for lower risk disease. A single prospective trial presented in 2005 and published in 2006 (Jones et al) compared docetaxel and cyclophosphamide (TC) to doxorubicin and cyclophosphamide and reported improved disease free survival (2006) and overall survival (2009) with TC. We sought to understand the impact of this study on the type of CTX regimens used to treat ESBC. Methods: Using the UCSF Cancer Registry database and including patients who received at least one cycle of CTX at UCSF, we recorded use of A or non-anthracycline (NA) based CTX regimens in women with ESBC and correlated type of CTX with tumor stage, receptor status, and age. Based on the publication date of TC we looked at the use of A versus NA based CTX during two time periods, 2000-2005 and 2006-2010. Results: 1,116 patients met criteria for inclusion; 17 were excluded due to inadequate information. Patient characteristics were: median age 49 (range 21-78), stage I (24%), stage II (56%), and stage III (20%), 50% hormone receptor (HR) +, 25% HER2 +, 17% HR-/HER2-. From 2000-2010, 80% received A CTX. Overall use of A decreased from 95% to 65%, while use of NA based CTX increased from 5% to 35%. The table compares use of NA CTX during the two time periods by clinical variables. Conclusions: Use of NA CTX increased significantly over the 2nd half of the last decade in all cases except those patients with stage III disease. The timing of this marked change correlates with publication of TC, and emphasizes the impact of positive phase III trials on treatment practice. This study was supported by the UCSF Cancer Registry. [Table: see text]
Abstract LB-212: Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models
Authors: Grazia Saturno, Filipa Lopes, Maria Romina Girotti, Ion Niculescu-Duvaz, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Louise Johnson, Natasha Preece, Amaya Viros, Malin Pedersen, Robert McLeary, Ruth Knight, Rebecca Lee, Denys Holovanchuk, Paul Lorigan, Nathalie Dhomen, Richard Marais, Caroline Springer
Journal: Cancer Research (2016)

Abstract KRAS is mutated in ∼80% of pancreatic ductal adenocarcinoma (PDAC), ∼35% of colorectal cancer (CRC) and ∼20% of non-small-cell lung cancer (NSCLC). KRAS remains an intractable drug target and targeting the downstream pathway component is ineffective because feedback mechanisms or parallel pathways provide alternative routes to cell proliferation and/or survival. Here we show that a new panRAF/SRC inhibitor, CCT3833, is active in KRAS-mutant PDAC, CRC and NSCLC. We demonstrate that CCT3833 inhibits tumor growth in several KRAS-driven cancers via inhibition of RAF and SRC, eliciting therapeutic efficacy at well-tolerated doses in mouse models of human cancer. CCT3833 has already entered clinical trials (NCT02437227) for BRAF mutant and BRAF inhibitor-resistant melanomas and these new data show that it is also effective in KRAS mutant cancers, potentially providing a new therapeutic option for these patients. Citation Format: Grazia Saturno, Filipa Lopes, Maria Romina Girotti, Ion Niculescu-Duvaz, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Louise Johnson, Natasha Preece, Amaya Viros, Malin Pedersen, Robert McLeary, Ruth Knight, Rebecca Lee, Denys Holovanchuk, Paul Lorigan, Nathalie Dhomen, Richard Marais, Caroline Springer. Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models. [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 LB-212.
Abstract 962: Deregulated transcription of mouse satellite sequences accelerates oncogenic processes via functional inhibition of YBX1 protein
Authors: Takahiro Kishikawa, Motoyuki Otsuka, Kazuhiko Koike
Journal: Cancer Research (2016)

Abstract Highly repetitive tandem arrays located at centromere and pericentromere regions of the chromosomes had been considered epigenetically silent by heterochromatin modification. However, the deregulated transcription of the non-coding satellite sequences exists in human and mouse pancreatic cancer tissues. This aberrant expression can be detected even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are pre-cancerous lesions to invasive pancreatic cancer. To examine the biological roles of these aberrantly expressed satellite RNAs during the carcinogenesis steps, we established genetically-modified mouse PanIN-derived cells, in which mouse major satellite (MajSAT) RNAs were ectopically expressed. MajSAT RNA expressing PanIN-derived cells showed the increased chromosomal instability and the rate of spontaneous point mutations in the genomic as well as in the mitochondrial DNAs. We identified YBX1 protein as a binding protein specifically with MajSAT RNA by RNA immunoprecipitation. MajSAT RNA inhibited nuclear translocation of YBX1 under oxidative damage, which reduced the DNA damage repair activity of YBX1. The mutation rate of genomic and mitochondrial DNAs, and transformation rate were rescued by YBX1 overexpression in these cells. These findings indicate that satellite transcripts at the early stage of cancer development may act as “mutagens” and accelerate oncogenic processes. Citation Format: Takahiro Kishikawa, Motoyuki Otsuka, Kazuhiko Koike. Deregulated transcription of mouse satellite sequences accelerates oncogenic processes via functional inhibition of YBX1 protein. [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 962.
Case 3-1971
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Edwin P. Maynard, Benjamin Castleman
Journal: New England Journal of Medicine (1971)

Presentation of Case First admission. A 67-year-old man entered the hospital because of fever.Four and a half years previously, after a trip to Mexico, he had a brief episode of fever. Six months later, after a visit to Hawaii, his temperature rose for one day to 104°F, accompanied by shaking chills. A physician performed blood tests and informed him that his liver was abnormal. X-ray films of the gallbladder and the bile ducts failed to show opacification. Three and a half years before admission fever recurred, and he was admitted to another hospital. X-ray films of the gallbladder region . . .
Founder effect and a high prevalence of BRCA1 mutations among young Mexican triple-negative breast cancer (TNBC) patients.
Authors: Cynthia Mayte Villarreal-Garza, Jeffrey N. Weitzel, Erika Sifuentes, Marcia Llacuachaqui, Josef Herzog, Danielle Castillo, Rob Royer, Maria Cristina Magallanes-Hoyos, Rosa Maria Alvarez-Gómez, Lenny Gallardo, Fernando Lara-Medina, Luis Alonso Herrera, Steven Narod
Journal: Journal of Clinical Oncology (2014)

1522 Background: Previous studies have shown that the prevalence of BRCA mutations among young TNBC patients is elevated. Current guidelines recommend that women ≤60 years with TNBC be referred for genetic counseling. Different studies in Mexico have shown an early age of onset of BC and a high prevalence of TNBC, which suggests that BRCA mutations may account for a higher proportion of breast cancers in this population. However, there is limited information regarding BRCA mutation prevalence mainly due to lack of access to clinical BRCA gene analyses in Mexico. Methods: The purpose of this study is to analyze BRCA mutation frequency in a cohort of young Mexican TNBC patients using a panel assay of 114 recurrent BRCA mutations found in women of Hispanic ancestry (HISPANEL) on the Sequenom platform. Mexican women diagnosed with TNBC at or before age 50 were prospectively recruited from the National Cancer Institute in Mexico City. Patients were screened by HISPANEL and by PCR for the Mexican founder BRCA1 ex9-12del large rearrangement. Results: Among 190 consecutive TNBC cases, the median age of diagnosis was 42 years old and 69% were younger than 45 years. The majority of patients presented with locally advanced disease (69%). A BRCA mutation was detected in 43/190 (23%) of patients (42-BRCA1, 1-BRCA2), and BRCA1 ex9-12del accounted for 42% of the mutations. Only 45% of the BRCA mutation carriers had a family history of breast and/or ovarian cancer. Samples were processed in a two-week period, with a total cost of $4,000 USD. Conclusions: There is a remarkable prevalence of BRCA1 mutations among young TNBC patients in our population. The first documented Mexican founder mutation, BRCA1 ex9-12del, was the most frequent BRCA mutation and is likely responsible for a significant burden of disease in women from Southern Mexico. The HISPANEL can be completed within 72 hours from sample collection, at a modest cost of $20 USD per sample, and implementation among women of Mexican ancestry could reduce overall genotyping cost and increase access to cancer prevention among underserved women in Mexico and the U.S.
Integrated Plaque and Plasma Proteo-Lipidomics Reveal Novel Signatures of Coronary Atherosclerotic Plaque Disruption
Authors: R Lee, D Adlam, R Fischer, K Di Gleria, A Valli, P Charles, J McGouran, N Ruparelia, S Dawkins, R K Kharbanda, R P Choudhury, C Antoniades, B M Kessler, K M Channon
Journal: Circulation (2013)
Prevalence of KRAS gene mutation in ampullary cancer in Thai patients.
Authors: Piyada Sitthideatphaiboon, Chinachote Teerapakpinyo, Naruemon Klaikaew, Suebpong Tanasanvimon, Chanida Vinayanuwattikun, Napa Parinyanitikul, Nattaya Poovorawan, Virote Sriuranpong
Journal: Journal of Clinical Oncology (2014)

e15175 Background: Ampullary cancer has been regards to have a better prognosis than the other periampullary tumors. Certain data suggests that the difference may stem from certain distinct biology such as K-ras mutation. Prior reports show a large variation of the prevalence of K-ras mutation from 0 to 75% in ampullary carcinomas. We sought to characterize the prevalence ofK-ras mutations in ampullary carcinoma in Thai patients. Methods: We reviewed hospital medical records of ampullary carcinoma patients who were treated at the King Chulalongkorn Memorial Hospital (KCMH) from 1 Jan 2006 to 31 Dec 2012. There were 63 patients with histologically confirmed ampullary adenocarcinoma. Formalin-fixed paraffin embedded tissues were analyzed for K-ras mutation at codon 12 and 13 using the PCR amplification and pyrosequencing method method (Pyromark Q96 ID; Qiagen). The clinical characteristics and treatment outcomes were analyzed in correlation with pathological data and K-ras mutation status (with Chi-square or Fisher exact test). Results: There were 29 (46%) of 63 tumor tissues harbored K-ras mutation. Most mutations occurred at codon 12 in 28 of 29 (96.6%) patients and codon 13 in 1 (3.4%) patient. K-ras gene mutations tended to have poorer performance status, more TNM stage III-IV, poorly or undifferentiated histologic grade, positive surgical margin and metastases to regional lymph nodes than K-ras wild types, but these differences were not statistically significant. The overall survival (OS) of the whole population was 38.34 months (95% confidence interval of 21.28 – 55.41 months) and the 5-year overall survival rate was 24.8%. There was a trend of a non-statistically significant improvement in overall survival in patients whose tumor tissues displayed wild type K-ras over mutant K-ras with median OS 44.32 and 29.93 months, respectively (p = 0.35). Conclusions: We found moderately high prevalence of K-ras mutation in Thai ampullary carcinoma patients at 46%. Further evaluation of K-ras mutation in a larger population of ampullary carcinoma is warranted.
S13 Early Persistent Childhood Wheeze is a Risk for more Troublesome Young Adult Asthma: Abstract S13 Table 1
Authors: C Hodgekiss, SH Arshad, RJ Kurukulaaratchy
Journal: Thorax (2015)

<h3>Background</h3> Until recently being a wheezy infant was not felt to confer significant respiratory health risks in later life. Using the Isle of Wight Birth Cohort (IOWBC) we assessed the association of persistent childhood wheeze with young adult lung function, wheezing status/morbidity, allergic comorbidity and smoking. <h3>Methods</h3> The Isle of Wight Birth Cohort (n = 1,456) was reviewed at 1, 2, 4, 10 and 18-years with recording of current wheeze at each visit. At 10-years, 4 separate childhood wheeze phenotypes were defined. Those who wheezed in the first 4-years of life and at 10-years were labelled Persistent-Wheezers (PW). The outcome of PW was then assessed at 18-years to determine the effects of early life persistent wheeze on adult lung health. <h3>Results</h3> Wheezing occurred in 57.7% PW at 18-years. Asthma prevalence in PW fell from 76.0% to 58.2% over adolescence and PW comprised 38% of currently diagnosed asthma at 18-years. PW had significantly impaired lung function at 18-years compared to Non-Wheezers (NW) who never wheezed in the 1<sup>st</sup> decade of life. This included impaired FEV1, FEV1/FVC ratio and FEF25–75 along with significantly elevated bronchodilator response (BDR), bronchial hyperresponsiveness (BHR), exhaled Nitric Oxide (FeNO) plus significantly reduced gain in FEF 25–75 over adolescence (Table 1). Compared to NW at 18-years, PW were significantly more likely to have atopy, eczema, and rhinitis (Table 1). Of concern, prevalence of current smoking (44.4%) at 18-years was significantly greater in PW than NW as was passive smoke exposure through the life course (Table 1). <h3>Discussion</h3> Our findings highlight young adult respiratory consequences of PW. While there was some outgrowth of disease over adolescence a considerable proportion of PW showed significant airways disease at 18-years. We previously showed that PW already have impaired lung function by 10-years and these further findings suggest that phenomenon tracks through adolescence with possible additional effects on small airways growth. The longer term consequences of that finding allied to the high smoking prevalence in this phenotype merit attention.
OP26 Predicting thrombotic complications after liver transplantation in patients with Budd Chiari syndrome
Authors: R Westbrook, D Orr, N Heaton, J O'Grady, R Patel, N Lea, A Quaglia, A Pagliuca, R Arya, G Mufti, M Heneghan
Journal: Gut (2010)

Introduction  Myeloproliferative disorders (MPD) are the commonest cause of Budd Chiari syndrome (BCS). A somatic mutation of the tyrosine kinase JAK2 gene (JAK2V617F) is present in a large proportion of patients with MPD and is used as a screening tool to detect occult MPD. Recently a germline 46/1 haplotype block and mutations in the TET2 gene have also been implicated in the pathogenesis of MPD. We evaluate whether these underlying genetic abnormalities are relevant to the occurrence of thrombotic complications post liver transplantation (LT).  Method  Samples of DNA were extracted from total blood or bone marrow. Real-time PCR was performed to screen for JAK2 mutations. TET2 mutations were analysed by next generation high throughput DNA sequencing (Roche 454). DNA was analysed by pyrosequencing for two SNP9s which tag the 46/1 haplotype. Histology of liver biopsies performed for graft dysfunction were reviewed for evidence of veno-occlusive disease (VOD). The INR post LT and patient outcomes were recorded.  Results  36 patients underwent LT for BCS between 1995 and 2008. Median duration of follow-up after LT was 40 months (1–195 months) and 1-year survival was 84%. Pro-coagulant conditions were identified in 22 patients (MPD n=17, Protein C Deficiency n=2, Behcet9s n=2 and lupus anti-coagulant n=1). The remaining 14 patients were classed as idiopathic. Overall, 22/36 (61%) were positive for the JAK2 mutation, 6/27 (22%) for the TET2 mutation and 19/26 (73%) for the 46/1 haplotype. In the idiopathic cohort, 8/13 (63%) tested positive for JAK2 suggesting latent MPD. All patients were treated with warfarin following LT. Thrombotic complications occurred in 12/36 (33%) and included hepatic artery thrombosis (n=3, 2/3 being late), VOD (n=7), splenic vein thrombosis (n=1) and portal vein thrombosis (n=1), at a median time of 40 months post LT (range 1–164 months). Re-transplantation was more common in those with thrombotic complications (7/12 (58%) vs 1/24 (4%), (p=0.0006)) and mortality was higher (4/12, (25%) vs 3/24, (13%)), but this did not reach statistical significance (p=0.2). The presence of a JAK2 mutation was associated with the development of a thrombotic complication post LT (11/12 vs 1/24, p=0.01). Neither the 46/1 haplotype nor the TET2 mutation was associated with an increase in post LT thrombotic complications or morbidity. Mean INR was not significantly different in those patients who developed a thrombotic complication (2.73 vs 2.70, p=NS).  Conclusion  A JAK2 mutation appears to be associated with an increased risk of recurrent BCS and other thrombotic complications post LT. Thrombotic complications following LT are associated with an increase in morbidity and mortality. In patients with a JAK2 mutation, the role of additional anticoagulation or JAK2 inhibitor therapy needs to be investigated to try and prevent thrombotic complications.
HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation
Authors: W Herr, Y Eichinger, J Beshay, A Bloetz, S Vatter, C Mirbeth, E Distler, U F Hartwig, S Thomas
Journal: Leukemia (2016)
Abstract 15580: Persistence of the Effects of Time-to-Reperfusion on Myocardial Damage at 6 Months of Follow-up: Cardiovascular Magnetic Resonance Insights
Authors: Emanuele Canali, Chiara Bucciarelli-Ducci, Marvo Francone, Laura De Luca, Daniele Berardi, Antonella Mattatelli, Michela Pagliaro, Massimo Mancone, Iacopo Carbone, Bettina Conti, Giuseppe Cannavale, Gennaro Sardella, Francesco Fedele, Luciano Agati
Journal: Circulation (2010)

Objectives: In patients with ST-segment elevation myocardial infarction (STEMI) few studies have analyzed if time-to-reperfusion maintains its influence on myocardial damage far from the acute even...
Analysis of prognostic factors for 60-day mortality: Evaluation of a randomized phase III trial investigating FUFIRI versus mIROX as first-line treatment of metastatic colorectal cancer (mCRC).
Authors: C. Giessen, A. Schalhorn, S. Stintzing, V. Heinemann
Journal: Journal of Clinical Oncology (2010)

3554 Background: Mortality rates in published irinotecan-based randomized trials range between 1.7% and 5.0%. Prognostic factors for death within the first 60 days of treatment in mCRC studies have not been published yet. The purpose of this analysis was to evaluate clinical, histopathological and lab-report data associated with PFS and OS as published by Koehne et al. (Annals of Oncology 13: 308, 2002) and to identify prognostic factors of 60-day mortality in pts receiving first-line therapy of mCRC. Methods: Data from a randomized phase III study comparing FUFIRI vs. mIROX in 479 pts were evaluated. According to Koehne et al. we analyzed: Platelets, alkaline phosphatase (AP), white blood cell count (WBC), haemoglobin, number of tumor sites, LDH, CEA, CA 19-9 and several other baseline parameters. Prognostic factors were estimated via uni- and multivariate logistic regression analysis. Apart from Karnofsky performance status (KPS), none of these factors were part of the in- or exclusion-criteria in the FIRE trial. Results: The total 60-day mortality rate was 5.0% (24/479). 60- day mortality was observed in 5.5% (13/238) of pts in the FUFIRI-arm and in 4.6% (11/241) in the mIROX-arm (p = 0.680). Mortality was qualified as disease-related in 71% (17 pts) and treatment-related in 29% (7 pts) (p = 0.695). Univariate analysis showed KPS, LDH, AP and WBC as prognostic factors for death within first 60 days of treatment. In multivariate analysis, only high LDH-levels (p = 0.010) and an elevated WBC (p = 0.006) remained as significant, independent prognostic factors. Low KPS showed a strong trend, but failed to reach statistical significance (p = 0.057) as did AP and the number of metastatic sites. Conclusions: In this study, 71% of early deaths were disease-related, while only 29% were possibly related to study medication. Independent prognostic factors for death within the first 60 days of treatment were LDH and WBC. KPS showed a strong trend in multivariate analysis. Future trials may consider LDH and WBC for definition of exclusion criteria. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis