tbuckley/cabot-search huggingface dataset:
Abstract 18431: Proprotein Convertase Subtilisin Kexin Type 9 Mutations: A Significant Contributor to Familial Hypercholesterolemia in the Western Cape Region of South Africa
Authors: Roeland Huijgen, Dirk J Blom, Bharati D Ratanjee, Brigitte C Brice, Karen H Wolmarans, Gabriele A Solomon, David Marais
Journal: Circulation (2017)

Introduction: Familial hypercholesterolemia (FH) is a common genetic disorder characterized by hypercholesterolemia and markedly increased risk of cardiovascular disease. A causal mutation is mostly identified in the low-density-lipoprotein cholesterol receptor (LDLR) gene or in the apolipoprotein B (APOB) gene, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function (gof) mutations account for a small minority (<1 %). Genetic work-up in a cohort of FH patients in Cape Town yielded several novel PCSK9 mutations. Hypothesis: The majority of these PCSK9 mutations are gof, to be confirmed by genetic cascade screening. Methods: Individuals referred to the lipid clinic of Groote Schuur Hospital between 1980 and 2016 with clinically diagnosed FH underwent genetic analysis of the LDLR, and if applicable the APOB and PCSK9 genes. Families, in whom a PCSK9 mutation of unknown significance was found, underwent genetic cascade screening as well as laboratory and clinical assessments. Results: A ...
Clinical characteristics of desmoplastic pleural malignant mesothelioma: A case series of 19 patients.
Authors: Yoko Tomita, Amanda Segal, Yi-Jin Kuok, Anna K. Nowak, Arman Hasani
Journal: Journal of Clinical Oncology (2014)

e18545 Background: Desmoplastic malignant mesothelioma (dMM) is a rare histological subtype of malignant mesothelioma (MM). Clinical behaviour of this entity including its sensitivity to modern systemic therapy (ST) such as platinum/pemetrexed has not been well characterised previously. Methods: Pleural dMM cases were identified through the pathology department and lung cancer patient management databases of a major referral centre for MM in Western Australia. The available histopathology was re-examined for confirmation. Clinical data were collected from the hospital notes as well as review of available imaging with CT and PET scans. Results: 19 dMM cases were found for the period of January 2005 to May 2013. 18 patients were males and the average age of diagnosis was 70.9 years with 1 patient being diagnosed post-mortem. The average number of separate attempts at biopsy required for the diagnosis was 2.6 (median 2, range 1-6). No diagnoses were made on cytological specimens only. Sarcomatoid and biphasic cell types were predominant, although 4 patients had epithelioid dMM. Of 12 patients treated with ST, 11 received platinum/pemetrexed. The best recorded CT response was PR in 1 patient, PD in 1 patient, and SD in 8 patients. Treatment details were not available on 1 patient. The average number of platinum/pemetrexed (or ralitrexed) cycles administered was 4.2 (range 2-6). The mOS was 14.8 months (1.5-31.7); 14.8 months for those receiving ST (n=12) and 14.7 months for patients not receiving ST (n=7). Conclusions: Diagnosis of dMM requires a histological specimen containing adequate amount of the representative malignant tissue and patients frequently need several samples collected. dMM was predominantly seen in males and was associated with all the cell subtypes of MM. The rate of SD during ST is higher than expected, and the rate of PR and PD lower than expected. mOS is higher than expected for the general MM population. This suggests that dMM may have a more indolent course than non-dMM, and the effect of chemotherapy may be less in dMM than non-dMM cases.
The prognostic significance of ErbB-1 (EGFR), ErbB-2 (HER2), and c-MET overexpression in resectable gastric carcinoma (GC).
Authors: Aleksandra Paliga, Horia Marginean, Bibianna Maria Purgina, Basile Tessier, Derek J. Jonker, E. Celia Marginean
Journal: Journal of Clinical Oncology (2014)

3109 Background: This study investigates the prognostic value of overexpression of EGFR, HER2 and c-Met by immunohistochemistry (IHC) in Canadian patients with GC and correlates expression with clinicopathologic characteristics. Methods: Tissue microarrays (TMA) containing 4 cores/tumor were constructed from 120 consecutive GC resected between 2002-2008, stained for EGFR, HER2 and c-Met by IHC, and scored by 3 pathologists, from 0-3+, based on membranous and cytoplasmic staining intensity respectively. EGFR and c-Met score greater than 2 and HER2 3+ was considered overexpressed. Receptors’ expression was compared with clinicopathological characteristics and survival. Results: Of 113 evaluable cases – median age 64 (range 29-94), 72% were male, histologic type: intestinal 76%, diffuse 14%, mixed 10%. We observed no correlation between T, N stage and EGFR, HER2 or c-Met overexpression. Differences were observed according to histologic type: intestinal type expressed more frequently HER 2 (10/12; p=0.26) and c-Met (51/65; p=0.02). EGFR and c-Met positive and HER2 negative trended to inferior overall survival (OS). As previously reported, the prognostic effect of c-Met overexpression was time-dependent, with OS curves separating after 26 months, trending to inferior OS in the c-Met + group. Conclusions: In our study, HER2 overexpression in GC trended to superior OS, while EGFR and/or c-Met overexpression trended to poor OS. However, only the group of EGFR+/ c-Met+/HER2-, although quite small, reached statistical significance. Larger studies to confirm our findings are warranted, since targeted therapy may provide a major therapeutic advance. IHC expression n/% Median OS in months HR [95% CI], p-value Present Absent EGFR overexpression 17/15 15 30 1.60 [0.89-2.87], p=0.11 HER2 overexpression 12/11 85 29 0.51 [0.22-1.18], p=0.11 c-Met overexpression 65/58 28 48 1.17 [ 0.74-1.87], p=0.49 EGFR+/c-Met+/HER2- 11/10 13 months 0.18 [0.02-1.43], p=0.04 EGFR-/c-Met-/HER2+ 3/3 not reached
Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data
Authors: Wei Yang, Nicole M. Warrington, Sara J. Taylor, Paula Whitmire, Eduardo Carrasco, Kyle W. Singleton, Ningying Wu, Justin D. Lathia, Michael E. Berens, Albert H. Kim, Jill S. Barnholtz-Sloan, Kristin R. Swanson, Jingqin Luo, Joshua B. Rubin
Journal: Science Translational Medicine (2019)

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment.
Incidence and Outcome of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in a Population-Based Cohort of 3165 Patients in Sweden
Authors: Sara Harrysson, Sandra Eloranta, Sara Ekberg, Gunilla Enblad, Mats Jerkeman, Sverker Hasselblom, Björn E Wahlin, Per-Ola Andersson, Karin E Smedby
Journal: Blood (2018)
K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways
Authors: Matthias Scheffler, Michaela A. Ihle, Rebecca Hein, Sabine Merkelbach-Bruse, Andreas H. Scheel, Janna Siemanowski, Johannes Brägelmann, Anna Kron, Nima Abedpour, Frank Ueckeroth, Merle Schüller, Sophia Koleczko, Sebastian Michels, Jana Fassunke, Helen Pasternack, Carina Heydt, Monika Serke, Rieke Fischer, Wolfgang Schulte, Ulrich Gerigk, Lucia Nogova, Yon-Dschun Ko, Diana S.Y. Abdulla, Richard Riedel, Karl-Otto Kambartel, Joachim Lorenz, Imke Sauerland, Winfried Randerath, Britta Kaminsky, Lars Hagmeyer, Christian Grohé, Anna Eisert, Rieke Frank, Leonie Gogl, Carsten Schaepers, Alessandra Holzem, Martin Hellmich, Roman K. Thomas, Martin Peifer, Martin L. Sos, Reinhard Büttner, Jürgen Wolf
Journal: Journal of Thoracic Oncology (2018)

IntroductionAlthough KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes.MethodsDiagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients.ResultsWe identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds.ConclusionKRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
RPPA-Profiling Identifies Patients with Low Phosphorylation Levels of HSF1 at Serine 326 As Potential Candidate for Bortezomib Treatment in Addition to Standard Therapy in Pediatric Acute Myeloid Leukemia
Authors: Fieke W Hoff, Wendy Hu, Yihua Qiu, Alan S Gamis, Richard Aplenc, E. Anders Kolb, Todd A Alonzo, Amina A Qutub, Eveline S. de Bont, Sophia W.M. Bruggeman, Steven M. Kornblau, Terzah M. Horton
Journal: Blood (2018)
Abstract 12622: Gut-microbiota-derived Trimethylamine-N-oxide levels and Risk of Major Adverse Cardiovascular Events: A Systematic Review and Meta-analysis of Prospective Cohort Studies
Authors: Yoriko Heianza, Wenjie Ma, Lu Qi
Journal: Circulation (2016)

Introduction: Gut microbial metabolite trimethylamine-N-oxide (TMAO) has been implicated as a novel risk factor for cardiovascular events. The strength and consistency of the association between blood levels of the gut microbiota-related risk factor and cardiovascular events or deaths remain unclear. Hypothesis: We performed a systematic review and meta-analysis of prospective cohort studies to quantify the association of blood levels of TMAO and the risk of major adverse cardiovascular events (MACE). Methods: PubMed and Embase databases were searched up to 3 May 2016 and prospective studies with either quantitative estimates of the association of blood TMAO levels with incident MACE were included. MACE was indicated by myocardial infarction, stroke, heart transplant, heart failure, other ischemic cardiovascular events or death (either cardiovascular or all-cause). Two reviewers independently extracted data and assessed study quality. Generalized least-squares trend estimation was used to assess dose-response relationships. Summary relative risk (RR) for higher TMAO levels as compared to lower levels was calculated using only prospective cohort studies. Results: A total of 12 cohorts were included in the meta-analysis. High circulating TMAO levels were associated with an increased risk of MACE with a pooled RR of 1.76 (95% confidence interval: 1.50, 2.07; heterogeneity p = 0.22; I-squared = 22.8%) compared with low TMAO levels. Elevated TMAO levels were consistently associated with an increased risk of MACE regardless of older ages, high prevalence of diabetes, histories of cardiovascular diseases or renal failure at the baseline across studies. Pooled adjusted RR (95% confidence interval) of MACE was 1.02 (1.01, 1.04) per 1 μM (n=6 cohorts) or 1.22 (1.12, 1.32) per log-transformed 1 SD (n=4) increment in TMAO levels. Conclusions: Higher blood TMAO levels were consistently and dose-dependently associated with the development of MACE across diverse populations, independently of traditional risk factors.
A phase I study of metformin and chemotherapy in solid tumors.
Authors: Athena Kritharis, Jennifer Caplain, Shrikar Rajagopal, Elizabeth Grimm, Philip N. Tsichlis, Robert Martell, Wasif M. Saif
Journal: Journal of Clinical Oncology (2014)

2560 Background: Metformin has recently received increased attention because of its potential antitumorigenic effects on a number of cancers. It activates AMP-related pathways leading to inactivation of mTOR and suppression of its downstream effectors, crucial for cancer growth. Data also suggests reduced incidence of cancer and better response to chemotherapy with metformin. We conducted a prospective phase I study to assess safety of metformin + chemotherapy in pts with solid tumors. Methods: We conducted delayed start randomized trial of non-diabetic pts in 2 stages. In stage 1, we randomized pts to 2 arms: concurrent arm (metformin + chemo) vs. delayed arm (chemo alone). In stage 2, pts in delayed arm were crossed over to receive metformin. Pts received metformin 500mg twice daily + chemotherapy to define DLTs in both stages. Secondary endpoints assessed AEs (CTCAE v.3.0) and response rates (RECIST). Translational correlates included effects of metformin on expression and phosphorylation of AMPK by western blot in PBMCs. Results: A total of 100 pts were enrolled (51 in delayed arm vs. 49 concurrent arm). There were 17 tumor types (CRC = 14, breast = 11). 26 chemoregimens were combined with metformin. Rate of DLTs in pts receiving metformin + chemotherapy was 6.1% vs. 7.8% in pts receiving chemotherapy alone (Table). DLTs seen with addition of metformin included those associated with established chemo AEs. No lactic acidosis or hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of metformin. 28% of pts with measurable tumor markers showed improvement. AMPK phosphorylation showed a 4 to 6 fold increase in AMPK phosphorylation after metformin. Conclusions: This large phase I study suggests that metformin can be given safely with chemotherapy and offers a platform for future studies. Post-metformin increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our pts. Clinical trial information: NCT01442870.DLTs. Run-in stage Chemo w/out DLT Stage 1 Chemo + metformin vs. chemo Stage 2 Chemo + metformin Concurrent N= 49 1=G3 fatigue (2%) N= 49 3=G3 anemia, ↓albumin, ↑ALT (6.1%) N= 49 N/A Delayed N=51 2=G3 Thrombo- cytopenia, HFS (3.8%) N=51 4=G3 syncope, dehydration, ↑bilirubin (7.8%) N=51 2=G3 dehydration, vomiting, proteinuria (3.8%)
Serum GGTP as an HCC prognostic marker in patients with both low and high AFP levels.
Authors: Brian I. Carr, Vito Guerra
Journal: Journal of Clinical Oncology (2014)

e15116 Background: Alpha-fetoprotein (AFP) has been a poor surveillance tool, in part because many small HCCs are AFP negative, but a useful treatment response tool. We aimed to compare AFP positive and negative HCC patients for clinical and tumor characteristics and survival. Methods: A 2,440 HCC patient cohort was dichotomized according to the median blood AFP value (33 ng/ml). Clinical and tumor characteristics and survival were compared, using Chi-square test for categorical variables, Kruskal-Wallis rank test and Wilcoxon rank-sum test (Mann-Whitney test) for continuous variables to test associations between groups and Z test for proportions was used for comparison between two categorical variables and a Cox model for survival. Results: 1,416 patients or 58% of the total cohort were AFP –ve patients and 56% of them had tumors <3cm. The remaining 44% of AFP –ve patients had tumors with 6cm mean diameter. 42% of AFP +ve patients had tumors <3cm with mean serum AFP of 1,180 ng/ml. 58% of AFP +ve patients had larger tumors, with mean diameter of 6.2cm and mean AFP of 7984 ng/ml. Small <3cm HCC patients with –ve or +ve AFP were compared. There were significant differences only for PVT incidence and worse survival for AFP +ve patients. Larger tumor size patients with –ve or +ve AFP were then compared. AFP +ve patients also had significantly worse PVT incidence and survival, but additionally had significantly higher serum alkaline phosphatase (ALKP), gamma glutamyl transpeptidase (GGTP) and bilirubin levels, and tumor size and multifocality. Separate analysis of AFP –ve and +ve patients, showed that those with higher GGTP values had significantly worse survival, regardless of tumor size and independently of bilirubin level. Multiple Cox proportional hazard model analysis revealed an increased HR for both GGTP and ALKP, singularly and together. Highest HRs were for AFP+GGTP and AFP+ALKP. Conclusions: Low AFP patients constituted the majority. Their survival was better than for high AFP patients in each size group. GGTP may be a useful prognostic marker for both low and high AFP patients.
Capture Sequencing Is a Useful Method for Comprehensive Clonality Analysis Based on Ig/TCR Gene Rearrangements in Acute Lymphoblastic Leukemia
Authors: Dai Nishijima, Mitsuko Akaihata, Yuka Iijima-Yamashita, Tomomi Yamada, Yuichi Shiraishi, Hiroko Tanaka, Toshinori Hori, Satoru Miyano, Keizo Horibe, Masashi Sanada
Journal: Blood (2018)
Unsuccessful Cytogenetics and Outcomes in Acute Leukemia
Authors: Lauren Lee, Helene Bruyere, Michael J Barnett, Raewyn Broady, Donna L. Forrest, Alina S. Gerrie, Donna E. Hogge, Stephen H. Nantel, Sujaatha Narayanan, Maryse Power, David Sanford, Kevin Song, Heather J. Sutherland, Cynthia L Toze, Jennifer White, Yasser Abou Mourad
Journal: Blood (2018)
Impact of patient navigation on women with cervical abnormalities.
Authors: Electra D. Paskett, Donald Dudley, Gregory S. Young, Brittany Brewer, Kristen J. Wells, Beth Calhoun, Tracy Ann Battaglia, Kevin Fiscella, Steven R. Patierno, Victoria Warren-Mears
Journal: Journal of Clinical Oncology (2014)

6569 Background: Almost 40% of women with cervical abnormalities fail to return for timely and proper follow-up care with higher rates among minority/underserved populations. As part of the Patient Navigation Research Program (PNRP), we examined the effect of patient navigation (PN), vs usual care on timely follow-up for women with cervical abnormalities. Methods: Cervical patients from 4 PNRP sites were divided into low- and high-risk sets and analyzed separately. Low-risk patients (n=2,088) were those who enrolled with an initial pap finding of ASCUS with a positive high-risk HPV serotype, atypical glandular cells or LGSIL. High-risk patients were those who enrolled with an initial finding of HGSIL (n=229). A dichotomous outcome of resolution within 180 days was used for the low-risk set, and resolution by 60 days for the high-risk, consistent with guidelines. A logistic mixed-effects regression model was used to evaluate the intervention effect using a random effect for arm within institution. A backwards selection process was used for multivariable model building considering the impact of each predictor on the intervention effect. Results: The final multivariable model for resolution within 180 days for the low-risk cases included arm, age, race and an interaction between race and arm. Patients aged 30+ years showed an increased odds of resolution as compared to those under 30, regardless of arm (Table). The PN arm showed an improvement in the odds of resolution across all racial groups, but significant positive effects were observed in non-English speaking Hispanics (p=0.0002). Conclusions: Patients with low-risk lesions showed a benefit from PN with a significantly increased odds of resolution within 180 days for non-English speaking Hispanics. At-risk populations can particularly benefit from PN programs. Clinical trial information: NCT01569672 NCT00613275.Multivariable model estimated ORs (95% CI) for resolved within 180 days for low-risk patients. Predictor Comparison OR for resolved within 180 days (95% CI) p-value Age 30-39 vs. <30 1.74 ( 1.32, 2.30) <.0001 40+ vs. <30 1.65 ( 1.20, 2.25) 0.002 Race by arm Black: PN vs. control 1.41 ( 0.69, 2.88) NS White: PN vs. control 1.58 ( 0.78, 3.17) NS Hisp-Eng: PN vs. control 2.02 ( 0.95, 4.32) 0.07 Hisp-NonEng: PN vs. control 5.88 ( 2.81, 12.29) 0.0002
Fentanyl exposure after subcutaneous and transdermal administration: Results from a population pharmacokinetic study in cancer patients.
Authors: Astrid W. Oosten, João A. Abrantes, Siv Jönsson, Peter de Bruijn, Wendimagegn Ghidey Alemayehu, Evelien J.M. Kuip, Erik A.C. Wiemer, Carin C. D. Van Der Rijt, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2014)

9540 Background: Transdermal (td) fentanyl is widely used for the treatment of cancer-related pain but is unsuitable for fast titration for severe pain. Titration with subcutaneous (sc) fentanyl is safe and effective. Nonetheless, little is known about the pharmacokinetics (PK) of sc fentanyl compared to the td route and the optimal scheme for rotation from sc to td fentanyl is unknown. Therefore, we performed a population pharmacokinetic study to unravel sc and td fentanyl PK and rotations in cancer patients (pts). Methods: Plasma samples for PK analysis were collected from hospitalized pts treated with td or sc fentanyl for moderate-severe cancer-related pain. Pts who were titrated with sc fentanyl were rotated to td fentanyl 1:1 in case of adequate pain control with stable doses. After patch application, sc administration was continued in unchanged dose for 6 hours and in a 50% dose for another 6 hours (Kornick et al, 2001). Baseline and outcome parameters of treatment were registered. PK data were analyzed employing NONMEM, utilizing the model as described for td use (Kokubun et al, 2012) as a starting point. Expected fentanyl levels during and after rotation were calculated using the final model. Results: A median of 13 (range 1-86) samples were available for 47 pts, during td administration for 5, sc for 10 and both for 32 pts. The CL/F was estimated to 33.5 L/h following td fentanyl and 54.5 L/h following sc fentanyl. In 7 out of 10 pts with plasma samples available during rotation from sc to td fentanyl, a rise in fentanyl plasma concentrations occurred with clinical signs of fentanyl-related toxicity in 4 pts. Also, calculated fentanyl levels showed a rise during rotation when using the two-step taper in 12 hours. Conclusions: This is the first study describing the pharmacokinetics of sc and td fentanyl in a single pt cohort. CL/F was lower for td fentanyl, suggesting that the dose of fentanyl assumed to be delivered using the td route is underestimated. When converting from sc to td fentanyl, the 12 hour method using a 2 step taper can lead to a rise in plasma fentanyl levels and carries a high risk of toxicity. Our new insights champion a shorter time period to rotate fentanyl from sc to td. Clinical trial information: EudraCT Number: 2009-013022-16.
Abstract 15431: Absence of LDL Measurement After an Atherosclerotic Cardiovascular Disease (ASCVD) Event Increases the Incidence of a Subsequent Major Adverse Clinical Event (MACE)-Real World Experience in a Large Integrated Healthcare System: The IMPRES Study
Authors: Kirk U Knowlton, Heidi T May, Tami L Bair, Jeffrey L Anderson, Donald L Lappé, Joseph B Muhlestein
Journal: Circulation (2017)

Introduction: There has been considerable discussion regarding the value of follow up LDL-C measurements after initiation of statin therapy for secondary prevention. We therefore set out to determi...