tbuckley/cabot-search huggingface dataset:
Hyperprogressive disease in patients with metastatic genitourinary tumors treated with immune checkpoint inhibitors.
Authors: Cristina Suárez, Rafael Morales-Barrera, Alonso Garcia-Ruiz, Macarena Gonzalez, Marta Ligero, Claudia Valverde, Cesar Serrano, Joaquin Mateo, Raquel Perez-Lopez, Joan Carles
Journal: Journal of Clinical Oncology (2019)

448 Background: Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients (pts) treated with immune checkpoint inhibitors (ICI). The rate and outcome of HDP in pts with metastatic renal carcinoma (RCC) and urothelial carcinoma (UC) are unknown. Here, we report the percentage of HPD in a cohort of pts with GU malignancies treated at our center and explore associations with clinical variables. Methods: Medical records from pts treated in phase I-III clinical trials with ICI alone or in combination between July 2013 and June 2018 were retrospectively reviewed. We defined HPD according to the radiologic VHIO´s criteria (ASCO 2018). Associations between HPD and categorical or continuous variables were evaluated using Fisher exact test and Wilcoxon test respectively. OS were estimated with the Kaplan-Meir method. Statistical analyses were performed using the R statistical software (R version 3.5.0). Results: Overall, 104 pts received therapy with ICI. Of these patients, 16 were not included for the analysis (6 pts with absence of measurable disease, 6 pts did not have CT scan available after the clinical progression and 4 pts treated with ICI plus chemotherapy). Thus, 88 pts were included for the analysis, 29 (33%) with RCC and 59 (67%) with UC. Median follow-up was 7.4 months. Median age was 66.5 years (range 29-91 y).Twenty-three pts (26%) were treated with ICI monotherapy and 65 pts (74%) in combination (anti-CTL4, antiangiogenics, PARP inhibitors, FGFR inhibitors). Forty-seven pts (53%) received ICI as second-line therapy or later. By RECIST v1.1, 26 (30%), 19 (21%) and 43(49%) pts had a best response of progressive disease, stable disease or partial+complete response, respectively. We identified 9 pts (10%) who meet the HPD criteria, 2 pts with RCC and 7 with UC. HPD was associated with anemia at baseline (p = 0.058). Pts with HPD had a trend toward lower overall survival (OS) compared with pts with non-HPD (8.87 vs 4.77 months; p = 0.065). Conclusions: These findings demonstrate that HPD is a phenomenon seen in a significant proportion of pts with RCC and UC and should be taken in account. We found that HPD is associated with poor OS and the anemia at baseline was correlated with HPD.
Analyzing ring moiety additions to the A-ring of camptothecin.
Authors: David A. Westover, Chunyang Jin, Mansukh Wani, Fengzhi Li
Journal: Journal of Clinical Oncology (2015)

e13529 Background: Two camptothecin (CPT) analogues, irinotecan and topotecan, are currently approved by the FDA for the treatment of several advanced cancers. Over the last decade, interest in CPTs with ring moiety additions has led to numerous publications and clinical trials. Our group recently reported on a novel CPT analogue (FL118) with a methylenedioxy ring addition. We observed that, compared to clinically-used CPTs, FL118 showed improved potency and lower affinity for a drug efflux transporter, ABCG2, a common cause of resistance to CPTs in the clinic. Our next step is to determine whether CPT analogues with other ring moiety additions share these characteristics. In this study, we systematically assessed a number of CPT analogues with ring moiety additions to the A-ring for their potency and affinity to ABCG2. Methods: Cancer cells that expressed high levels of ABCG2 protein were treated with CPT analogues for 72 hours in the presence or absence of Ko143, a highly selective ABCG2 inhibitor. EC50 values and relative ABCG2-induced resistance (EC50 in absence of ABCG2 inhibitor / EC50 in presence of ABCG2 inhibitor) were calculated. Results: Each CPT analogue with a ring moiety added to the A-ring was observed to be more potent than the corresponding CPT analogue with no added ring group. Of the ring groups tested, methylenedioxy additions conveyed the greatest increase in potency. Addition of ring moieties alone did not increase affinity for ABCG2, though subsequent modifications to other parts of the CPT backbone could increase ABCG2 affinity. Conclusions: Individual ring moiety addition, even very electronegative additions (e.g., di-fluoro-methylenedioxy), resulted in no affinity increase for ABCG2. This is surprising, since our group and others have demonstrated that electronegative functional groups increase ABCG2-dependent efflux. Further experiments are underway to assess whether CPTs with electronegative ring additions share favorable properties of clinically-used CPT analogues.
Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study
Authors: Yu Tian, Elham Kharazmi, Kristina Sundquist, Jan Sundquist, Hermann Brenner, Mahdi Fallah
Journal: BMJ (2019)

Abstract Objective To explore the risk of colorectal cancer in family members of patients with colorectal cancer, with an emphasis on subtypes of second degree relatives, especially half siblings, which were lacking in the literature. Design Ambidirectional cohort study. Setting Nationwide Swedish Family Cancer Data (record linkage). Participants All people residing in Sweden and born after 1931, with their biological parents, totalling &gt;16 million individuals (follow-up: 1958-2015); of those with clear genealogy, 173 796 developed colorectal cancer. Main outcome measures Lifetime (0-79 years) cumulative risk and standardised incidence ratio of colorectal cancer among first degree relatives and second degree relatives. Results The overall lifetime cumulative risk of colorectal cancer in siblings of patients was 7%, which represents a 1.7-fold (95% confidence interval 1.6 to 1.7; n=2089) increase over the risk in those without any family history of colorectal cancer. A similarly increased lifetime cumulative risk (6%) was found among half siblings (standardised incidence ratio 1.5, 95% confidence interval 1.3 to 1.8; n=140). The risk in people with colorectal cancer in both a parent and a half sibling (standardised incidence ratio 3.6, 2.4 to 5.0; n=32) was close to the risk in those with both an affected parent and an affected sibling (2.7, 2.4 to 3.0; n=396). Family history of colorectal cancer in only one second degree relative other than a half sibling (without any affected first degree relatives), such as a grandparent, uncle, or aunt, showed minor association with the risk of colorectal cancer. Conclusion Family history of colorectal cancer in half siblings is similarly associated with colorectal cancer risk to that in siblings. The increase in risk of colorectal cancer among people with one affected second degree relative was negligible, except for half siblings, but the risk was substantially increased for a combination of family history in one affected second degree relative and an affected first degree relative (or even another second degree relative). These evidence based findings provide novel information to help to identify people at high risk with a family history of colorectal cancer that can potentially be used for risk adapted screening.
Differential molecular expression profile according to glioblastoma (GB) location.
Authors: Emilie Denicolai, Emeline Tabouret, Carole Colin, Philippe Metellus, Isabelle Nanni, Celine Boucard, Aurelie Tchoghandjian, Nathalie Baeza-Kallee, Frederic Fina, Olivier L. Chinot, Dominique Figarella-Branger
Journal: Journal of Clinical Oncology (2015)

2030 Background: Initial GB topography occurred throughout the brain without established specific molecular profile. Our previous study suggested that cortical and subventricular GB exhibit distinct transcriptome profile. Based on these preliminary results, our objective was to evaluated the expression of ten selected genes (VEGFC, FLT4, MET; HGF, CHI3L1, PROM1, NOTCH1, DLL3, PDGFRA, and BCAN) according to GB locations. Methods: Fifty nine patients with newly GB were retrospectively included according to the availability of pre-surgery MRI and frozen tumors. Tumor locations were classified into cortical and periventricular (PV) locations, which were next segregated according to cerebral lobes: cortical fronto-parietal (N = 19), cortical temporal (N = 5), PV fronto-parietal (N = 12), PV temporal (N = 12), and PV occipital (N = 12). Expression levels of the selected genes were determined using real-time quantitative PCR, and were correlated with tumor locations. Results: Cortical GB were characterized by a lower expression of two mesenchymal genes, VEGFC (p = 0.001) and HGF (p = 0.001), than periventricular GB. Among cortical GB sub-groups, genes expressions were homogenous. In contrast, PV locations exhibit distinct expression profiles. PV temporal tumors were associated with higher expression of two proneural and cancer stem cell genes, NOTCH1 (p= 0.028) and PROM1 (p = 0.033) while PV fronto-parietal tumors were characterized by a higher expression of FLT4 (p= 0.037) and CHI3L1 (p= 0.006). PV occipital GB were associated with a lower expression of VEGFC (p = 0.032) than other PV GB and an over-expression of MET, correlated to MET amplification. Finally, VEGFC and HGF expressions were correlated (p < 0.001) as well as NOTCH1 and PROM1 expressions (p < 0.001). Conclusions: Our results suggest a differential expression profile of the selected genes according to initial GB location. These results should be validated in a prospective study.
National trends and pathologic outcomes of neoadjuvant chemotherapy among patients with micropapillary variant urothelial carcinoma of the bladder.
Authors: Juan Javier-Desloges, Alejandro Abello, Jamil Syed, Michael Leapman
Journal: Journal of Clinical Oncology (2019)

477 Background: Micropapillary variants of urothelial cell carcinoma (UCC) are associated with aggressive clinical behavior including an increased risk of regional and distant metastasis. Although neoadjuvant chemotherapy (NAC) improves survival for patients with UCC who achieve a complete pathologic response (pT0), less is known regarding the uptake of this practice in patients with micropapillary variant (MV) or its effect on pathologic response. Methods: We queried the National Cancer Database to identify all patients with a diagnosis of UCC including MV from 2004-2014. We restricted our analysis to patients who underwent radical cystectomy with or without NAC. We compared clinical, demographic, and pathologic characteristics and evaluated time trends associated with use of NAC. Following propensity score matching to balance covariates associated with the receipt of NAC, we used logistic regression models to study the association of NAC use and pT0 rate. Dual analyses were performed among patients with clinical stage II (cT2) disease, as well as the entire cohort (all stages). Results: We identified 102,266 patients, including 101,272 (99.03%) pure UCC and 994 (0.97%) MV. Patients with MV were younger (Median 70 years vs 73 years, p &lt; 0.001), more commonly male (79.0 vs 73.6% p &lt; 0.001), were more commonly treated in academic centers (66.43% vs 44.77%), there was no difference between urban/rural areas. Use of NAC among patients with cT2 increased in the entire cohort from 27% on 2004 to 49.7% in 2014 for UCC, and from 50% to 58% for MV. Among patients with cT2 disease, 38.4% of UCC received NAC and 49% MV received NAC (P &lt; 0.001). Following propensity score matching, receipt of NAC was associated with pT0 for both histological diagnoses (OR 2.13 95% CI: 1.65-2.78 p &lt; 0.001). This effect persisted on restriction to patients with cT2 (OR 3.32, 95% CI: 2.32-4.75, p &lt; 0.001). Conclusions: There has been increased use of NAC among patients with micropapillary variant. Patients with cT2 micropapillary variant were equally like to be achieve a pathologic complete response to NAC as were patients without histologic variants of urothelial cell carcinoma.
Body mass index (BMI) and toxicities and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Dylan J Martini, Julie M. Shabto, Yuan Liu, Bradley Curtis Carthon, Alexandra Speak, Elise Hitron, Greta Russler, Sarah Caulfield, Kenneth Ogan, Wayne Harris, Viraj A. Master, Omer Kucuk, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2019)

613 Background: BMI has been explored as a prognostic factor in cancer pts and treatment-related toxicities have been associated with responses to VEGF-targeted therapy in mRCC pts. We investigated the association of BMI and adverse events (AEs) and CO in mRCC pts treated with cabo. Methods: A retrospective analysis of 65 pts with mRCC treated with cabo at Winship Cancer Institute from 2016 to 2018 was performed. Overall survival (OS), progression-free survival (PFS), and objective response (OR) were used to measure CO. OS and PFS were calculated from first cabo dose to death and radiographic or clinical progression, respectively. An OR was defined as a partial response (PR) or a complete response (CR) using RECISTv1.1. BMI was collected at baseline (BL) and 6 (±2) weeks after cabo initiation. AEs were obtained from clinic notes. Univariate analysis (UVA) of association between BMI and CO was carried out using logistic regression model for OR and proportional hazard model for OS and PFS. Results: The median age was 63 years and 26% were African American. The majority were either IMDC intermediate or poor-risk (59% and 34%, respectively). Most pts (67%) had a BMI ≥ 25 and the median BMI at BL was 26.6. There was no difference in incidence of AEs between pts with BMI &lt; 25 and pts with BMI ≥ 25. Gastrointestinal (GI) AEs incidence was also comparable among pts with a BMI ≥ 25 (62%) and pts with BMI &lt; 25 (57%, p = 0.666). Increased BMI at 6W was significantly associated with prolonged OS and increased baseline BMI at BL showed a trend towards longer OS (Table). Conclusions: Increased BMI may be associated with improved CO in mRCC pts treated with cabo, but there may not be a difference in AEs based on BMI. Larger analyses are needed to validate these findings. [Table: see text]
Assessment of the clinical presentation of patients with at least two deleterious mutations on multi-gene panel testing.
Authors: Jeffrey N. Weitzel, Kathleen Reilly Blazer, Bita Nehoray, John Kidd, Thomas Paul Slavin, Ilana Solomon, Mariana Niell-Swiller, Christina Rybak, Jennifer Saam
Journal: Journal of Clinical Oncology (2015)

1514 Background: Technical advances have upended the established paradigm of testing high penetrance cancer predisposition genes based on syndromic features. National guidelines now include discussion of multi-gene panels. However, significant gaps in our knowledge of gene-specific phenotypes have been identified, and the effects of various gene combinations are unknown. Methods: We examined results from patients tested with a 25-hereditary cancer gene panel in a CLIA approved laboratory. Clinical history was obtained from test requisition forms. Results: Of 55,803 patients tested, 3,953 (7.1%) had a single deleterious mutation, and 106 (0.19%) had mutations in at least two genes. Breast or colon cancer was the most common diagnosis among the probands (42.8-46.8% and 10.4-12.9%, respectively for single and dual mutation carriers). There were 19 different genes among the dual mutation carriers; both were high penetrance in 47 cases, 42 were combinations of high with moderate and 17 were a combination of 2 moderate penetrance genes. The most common second mutations were in MUTYH, ATM and CHEK2. Of 20 patients with 2 MUTYH mutations, 4 did not report either CRC or a polyp history. Common combinations included 6 BRCA2/PMS2, and 5 each for BRCA1/ATM, BRCA2/ATM and CHEK2/PALB2. Of 27 patients with mutations in two high penetrance genes (APC, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, p16, PMS2, TP53), 11/27 showed a mixed phenotype, consistent with both; 16/27 only reflected the phenotype of one of the two. There was no significant difference in age at cancer onset ( < or > age 50 years) or probability of being unaffected; 23/89 (25.8%) dual mutation carriers vs.1205/3953 (30.5%) single mutation carriers (Chi-Square = 1.1941, p = .2745). Conclusions: Discovery of more than one deleterious mutation by multi-gene panel testing confounds accurate prediction of the phenotype or magnitude of risk. Despite a trend for more dual mutation carriers to be affected with cancer, the sample size was inadequate to reach statistical significance. Some cases with two high penetrance gene mutations only manifested one's phenotype. There is no obvious effect of low penetrance genes (e.g., ATM) on high penetrance gene phenotypes.
RATES OF CLINICAL REPORTING AND ACTIONS TAKEN BASED ON CORONARY CALCIUM ON CANCER COMPUTED TOMOGRAPHY SCANS IN PATIENTS AT RISK FOR CARDIOVASCULAR DISEASE AFTER POTENTIALLY CARDIOTOXIC CANCER TREATMENT
Authors: Matthew C. Hooks, Prabhjot Nijjar, Ko-Hsuan Chen, Michelle Wang, Milkeesso Foge, Ryan Cullen, Tejaswini Maganti, Anne Blaes, Chetan Shenoy
Journal: Journal of the American College of Cardiology (2019)
Impact of body mass index (BMI) in a breast cancer Argentinian population.
Authors: Marvin Albert Mizrahi, Maria Ines Bianconi, Paula Micone, Mario Edmundo Barugel, Claudio Storino, Gustavo Jankilevich
Journal: Journal of Clinical Oncology (2015)

e12622 Introduction:Obesity has been highlighted as one of the main causes associated with cancer 1 2. The impact of BMI 3 to Overall Survival (OS) and disease-free survival (DFS) is controversial 4 5 6 7 8 9 10. The proposal of the authors is to analyze the impact in a population of Argentine patients (pts) assisted in a public hospital. Background: Assess the impact of BMI on DFS and OS in pts diagnosed with Breast Cancer (BC) stages I to III. Methods: A retrospective, longitudinal study of medical records of pts diagnosed with BC stages I to III, treated in the division of Gynecology and Oncology Section was performed in the period between January 2005 and December 2013. Based on WHO BMI 20151standard weight 18-25, overweight > 25-30, obesity grade 1 > 30-35, obesity grade 2 > 35-40, obesity grade 3 > 40, mild malnutrition < 18-17, moderate malnutrition < 17-16 with severe malnutrition < 16. The pts were stratified by stages, age, menopausal status and immunophenotype. (Hormone sensitive Her 2 -, Hormone sensitive Her 2 +, Her 2 +, Triple Negative). It should be pointed out that pts are treated according to their body surface area, regardless of their BMI, with standard chemotherapy treatment. 11 12 Results: We reviewed 385 medical records between 2005 and 2013, 346 were pts were stages I to III. Median age was 61 years. BMI was evaluated in 245 pts: 32% normal, 32% overweight, 20 % obesity grade 1, 9%, obesity grade 2, 6% obesity grade 3, 0.4% mild malnutrition, 0, 4% moderate malnutrition, severely malnourished 0%. At the time of evaluation 250 (72%) were alive, 41 (12%) had died and 55 (16%) as were lost to follow-up Comparison with of normal weight vs obesity in the whole population was: OS 34 vs 43 months (m) (P = 0.24) and DFS was 37 vs 28 m (P = 0.16). In the subset of pts with stages II and III, hormone-sensitive, under 50 years, comparing normal weight vs. overweight and obesity, we obtained DFS 52 vs 42 m (P = 0.04), and OS of 55 vs 44 m (P = 0.05). Conclusions: The BMI had no impact in DFS or OS. We consider essential to implement treatments according to body surface regardless of BMI. Obesity in subset of pts, appeared to have an adverse impact in DFS and OS in pts with BC stages II and III, hormone-sensitive, under 50 years. This finding deserves to analyze this variable in prospective studies
Functionalized DNA Hydrogels Produced by Polymerase‐Catalyzed Incorporation of Non‐Natural Nucleotides as a Surface Coating for Cell Culture Applications
Authors: Alexander Finke, Ann‐Kathrin Schneider, Anna‐Sophie Spreng, Marcel Leist, Christof M. Niemeyer, Andreas Marx
Journal: Advanced Healthcare Materials (2019)

Abstract Cells from most mammalian tissues require an extracellular matrix (ECM) for attachment and proper functioning. In vitro cell cultures therefore must be supplied with an ECM that satisfies both the biological needs of cells used and the technical demands of the experimental setup. The latter include matrix functionalization for cell attachment, favorable microscopic properties, and affordable production costs. Here, modified DNA materials are therefore developed as an ECM mimic. The material is prepared by chemical cross‐linking of commonly available salmon sperm DNA. To render the material cell‐compatible, it is enzymatically modified by DNA polymerase I to provide versatile attachment points for peptides, proteins, or antibodies via a modular strategy. Different cells specifically attach to the material, even from mixed populations. They can be mildly released for further cell studies by DNase I‐mediated digestion of the DNA material. Additionally, neural stem cells not only attach and survive on the material but also differentiate to a neural lineage when prompted. Furthermore, the DNA material can be employed to capture and retain cells under flow conditions. The simple preparation of the DNA material and its wide scope of applications open new perspectives for various cell study challenges and medical applications.
Abstract MP18: Trajectories of Oral Anticoagulation Adherence After First Atrial Fibrillation Diagnosis
Authors: Inmaculada Hernandez, Meiqi He, Nemin Chen, Samir Saba, Walid Gellad
Journal: Circulation (2019)

Introduction: Regardless of the benefits of stroke prevention, only 50% of atrial fibrillation (AF) patients recommended for oral anticoagulation (OAC) actually use these medications. We identified groups of patients with similar OAC adherence patterns, and evaluated what patient characteristics affect group membership. Hypothesis: We hypothesized that patients continuously adherent to OAC would be more likely to reside in the Midwest and Northeast and have higher socioeconomic score (SES) than patients who never used OAC. Methods: Using Medicare claims data, we identified continuously enrolled beneficiaries with a first diagnosis of AF in 2014-2015 (n=36,185). We calculated the proportion of days covered with OAC in the first 12 months after first diagnosis. Using group-based trajectory models, we identified trajectories of OAC adherence. We constructed multinomial logistic regression to evaluated how a comprehensive list of demographics, system-level factors and clinical characteristics (list in figure) affected group membership. Results: We identified 4 trajectories of OAC adherence: patients who never used OAC (group 1, 43.6%), late OAC initiators (group 2, 7.6%), early OAC initiators who discontinued OAC (group 3, 8.9%), and continuously adherent patients (group 4, 39.9%). Black race, eligibility for low income subsidy, residence in segregated metropolitan areas (measured by index of dissimilarity), residence in the Southeast, Southwest or West, higher HAS-BLED score, and chronic kidney disease decreased the odds of belongings to the continuously adherent group. Conclusions: Trajectories of OAC adherence were highly variable, and were determined not only by demographics and clinical characteristics, but also system-level factors including income level, segregation measures, and region of residence. These trajectories may be useful in the implementation of targeted strategies to mitigate OAC underuse in stroke prevention.