tbuckley/cabot-search huggingface dataset:
Novel mutations and expression of SMAD4 gene in chronic myeloid leukemia patients.
Authors: Yogender Shokeen, Vibha Taneja, Neeta Raj Sharma, Sachin - Minhas, Mayank Jauhri, Shyam Aggarwal
Journal: Journal of Clinical Oncology (2016)

7058 Background: SMAD4 gene is an important element of tumor suppressor Transforming growth factor (TGF)-β- Smad pathway. It is found differentially expressed and mutated in variety of solid cancers. In this study, we examined the role of SMAD4 gene in Chronic Myeloid Leukemia (CML) patients. Methods: CML patients (n = 20) were considered strictly according to inclusion criteria (Age: 18+, Confirmation of BCR-Abl by PCR and FISH test). Patient pool included IM responsive cohort (n = 10), IM resistant cohort (n = 8) and 2 treatment naïve patients. Healthy controls (n = 17) were also included (Age: 18+). Next Generation Sequencing (Illumina TS) was used for sequencing of exons with exon-intron margins. mRNA levels were studied by Real-Time PCR. Beta Actin was used as housekeeping gene. The study was approved by Institutional Ethics Committee. Results: SMAD4 mRNA levels were down-regulated in 59% CML patient and only 17% patients revealed increased expression. In responders, 50% patients exhibited down-regulation with 25% patients presented and over-expression, whereas in IM resistant group, more than 60% patients had low transcript levels and only12% patients showed higher expression. Expression data was correlated with sequencing findings. The gene had 7 mutations. Variation in Intron 7 was shared by all three patient groups. Two genetic variations in Exon 12 (g.48604844T > A & g.48604849G > C) were reported in IM responders. Both the mutations were present in 3’ UTR region 6560 bases upststream of transcription end site. Resistant group had 4 genetic changes, with 3 intronic and 1 mutation in Exon 5 (g.48581300G > T).This change occured in codon 202, replaces Alanine by Serine, which in turn changes amino acid property from Hydrophobic non-polar to hydrophilic polar. All 3 mutations reported above were never reported to best of our knowledge.. Treatment naïve patients had no specific mutation. Conclusions: Data suggest decreased SMAD4 RNA levels IM resistant patients compared to responders. Genetic changes in Exon 5 and Exon 12 could be related to mRNA level changes. Mutations reported in this study seem acquired after occurrence of disease as no exclusive genetic change was found in new patients. This study indicates the role of SMAD4 gene in CML.
Comorbid conditions in patients with castration-resistant prostate cancer (CRPC) receiving abiraterone.
Authors: Phoebe Cheng, Megan Veresh Caram
Journal: Journal of Clinical Oncology (2016)

e16578 Background: Abirateroneimproves survival in metastatic CRPC, but it can result in the development and/or worsening of hypertension, diabetes, cardiac disease, and obesity. We sought to assess the course of these chronic conditions in patients receiving abirateronein practice. Methods: We identified patients with CRPC who were treated with abirateroneat the University of Michigan. Patients were excluded if they were being treated concurrently with another therapy for CRPC other than androgen deprivation or osteoclast inhibitors. Medical record abstraction identified patient and disease factors, the development and/or worsening of key comorbid conditions, and hospitalizations in the 12-month period after the start of abiraterone. Results: Out of an estimated 237 eligible patients, complete abstraction was performed in 107 (45%); patient characteristics were compared to the patients enrolled in COU-AA-302 (Table). Within the first year of treatment, 33% of patients developed a new comorbid disease or experienced worsening of a pre-existing condition, and 34% required at least one hospitalization or emergency room (ER) visit. Reasons for hospitalization and ER visits included abiraterone toxicity (16%), symptoms of CRPC (49%), and other (35%). Among the 83 patients who discontinued abiraterone, 10% discontinued due to toxicity. Conclusions: Abirateronewas relatively well-tolerated with few discontinuing therapy due to toxicity. However, 33% of patients experienced the development or worsening of a comorbid condition, a factor that could be included in decision making for providers and patients. Further investigation into factors that predict the development or worsening of comorbidity is warranted. Study Sample COU-AA-302 p-value* Age (Median, range) 72 (52-91) 71 (44-95) 0.31 Gleason ≥ 8 (%) 62 54 0.12 Metastases (%) 98 100 < 0.01 Bone 81 51 < 0.01 Lymph nodes 47 49 0.69 Viscera 17 0 < 0.01 Prostate specific antigen at start of treatment (Median, range) 37 (2-3147) 42 (0-3927) 0.36 Eastern Cooperative Oncology 80 100 < 0.01 Group Performance Status 14 0 < 0.01 0-1 6 0 < 0.01 2 3 *One-sample binomial tests and one-sample median tests were used to compare the current study sample to patients in COU-AA-302.
TCT-740 Impact of calcific mitral stenosis on survival in patients with aortic stenosis treated with TAVR
Authors: Anna Sannino, Srinivasa Potluri, Benjamin Pollock, Giovanni Filardo, Ambarish Gopal, Robert Stoler, Molly Szerlip, Michael Mack, Paul Grayburn
Journal: Journal of the American College of Cardiology (2018)
Adding peri-transplant rituximab to nonmyeloablative (NMA) conditioning before allogeneic hematopoietic cell transplantation (allo-HCT) to improve disease-related outcomes in patients with chronic lymphocytic leukemia (CLL): Phase II clinical trial.
Authors: Mazyar Shadman, Mohamed L Sorror, Brenda M. Sandmaier, Barry Storer, Thomas R. Chauncey, Niels Smedegaard Andersen, Dietger Niederwieser, Judith Shizuru, Benedetto Bruno, Michael Pulsipher, Richard T. Maziarz, Edward D. Agura, Parameswaran Hari, Amelia A. Langston, Michael B. Maris, Peter A McSweeney, Rainer Storb, David G. Maloney
Journal: Journal of Clinical Oncology (2016)

7052 Background: We report the results of a phase II trial using peri-transplant rituximab coupled with NMA conditioning for treatment of high risk CLL. Results are compared to the historical data with a focus on high-risk cytogenetics (CG). Methods: 50 patients (Pts) were enrolled into the study between 2009- 2014. Conditioning regimen consisted of Fludarabine 90 mg/m2, TBI 2 Gy and rituximab (R) (days -3, +10, +24, +36). For comparison, we analyzed data from 165 CLL pts who had an allo-HCT between 1997- 2014. Both cohorts (n=215) contributed to the multivariate models. Results: Pts with vs. without rituximab had similar 3-year OS (54% vs 50%), PFS (45% vs 40%), and NRM (38% vs. 28%). However, relapse rate was significantly lower among rituximab patients (17% vs. 31%; p = 0.04). In multivariate analysis and among all patients (n=215), factors associated with PFS were unrelated donor (HR 0.59; p=0.01) and high risk CG (HR 1.87; p=0.005). Relapse rate was associated with rituximab (HR 0.36; P=0.009), unrelated donor (HR 0.25; P < 0.001) and high risk CG (HR 4.9; P < 0.001). NRM was associated with higher HCT-CI (HR 3.5; P=0.005). Among high risk CG group (n=78), PFS was longer in pts with unrelated donors (HR 0.2; P<0.001) and relapse rate was associated with rituximab (HR 0.4; P=0.04), unrelated donor (HR 0.2; P=0.0006) and HCT-CI (HR 0.28; p=0.01). No factor was independently associated with OS in either group. Conclusions: Addition of rituximab to a NMA conditioning regimen reduced relapse rates; regardless of high-risk cytogenetics. Current efforts are focused on strategies to further decrease the NRM rate. Clinical trial information: NCT00867529. Phase-2 trial (n=50) Historical group (n=165) Median follow-up, m (range) 25 (2.5 – 63) 25 (0.3 – 181) Age, median (range) 60 (35-74) 57.6 (38 – 72) Prior treatments: Median, n (range) 4 (1-10) 4 (0-12) PR/CR at transplant, n (%) 21 (46%) 79 (50%) del 17p, n (% of tested pts) 27 (55%) 28 (21%) complex, n (% of tested pts) 18 (37%) 28 (21%) Unrelated donor 34 (68%) 80 (49%) Bulky (≥ 5 cm) lymph node, n (%) 11 (22%) 19 (15%) Pts with HCT-CI ≥ 3 21 (42%) 57 (36.5%)
Visualization techniques for identifying patients cohorts for hypothesis-testing in cancer research.
Authors: Shivaprasad Narayanan, Hannah Beird, Jennifer Brooke Goldstein, Jianjun Zhang, Chris Belmont, Bryan Lari, Dhiraj Pathak, Jeff Jin, Gregory Barbosa, Trey Kell, Vamshi Punugoti, Edward Suh, Brett Smith, Andrew Futreal
Journal: Journal of Clinical Oncology (2016)

e23203 Background: The MD Anderson Cancer Center Translational Research Accelerator (TRA) platform is implemented to capture, store and integrate over 230,000 patient records, associated diagnoses, treatments, adverse events and response data. Leveraging the power of the platform, millions of these records are organized and optimized for multi-dimensional querying and quick response time. This platform enables researchers to identify patient cohorts across many dimensions. Traditional patient cohort identification is a workflow driven method of selecting and narrowing down patients based on different attributes in a certain sequence. New ways of visualizing data allows researchers to interactively identify patient cohorts and in the process, identify hidden patterns. Methods: Researcher’s evaluated data attributes in TRA and identified 21 most frequently used attributes for cohort identification. Patient Selection tool was developed where these attributes were displayed as filters that dynamically adjust based on selections. After identifying a cohort, Researchers can drag and drop from a vast collection of 1,000 attributes to a workspace for visualization. We can also perform interactive visual analytics. Results: We segmented more than 17 million records on various filters to arrive at different cohorts with fast response times. Once the cohort of interest was identified, we assembled focused datasets to perform analytics. Visualization software allowed us to analyze large quantities of data in order to consolidate into effortlessly visualized charts and graphs. Conclusions: Displaying data as automatically adjusting filters provides a novel way of visualizing text data. It allows multi-dimensional querying and patient selection based on clinical and molecular data. Selecting patients quickly into cohorts and allowing data assembly within cohorts using drag-drop method significantly reduces time in research, thus facilitating the generation of new insights, hypotheses and testing in a much more facile, rapid fashion.
Alleviating mechanical constraints to ventilation with heliox improves exercise endurance in adult survivors of very preterm birth
Authors: Joseph W Duke, Amy M Zidron, Igor M Gladstone, Andrew T Lovering
Journal: Thorax (2018)

Adult survivors of very preterm birth (PRET) have significantly lower aerobic exercise capacities than their counterparts born at term (CONT), but the underlying cause is unknown. To test whether expiratory flow limitation (EFL) during exercise negatively affects exercise endurance in PRET, we had PRET and CONT exercise to exhaustion breathing air and again breathing heliox. In PRET, EFL decreased and time-to-exhaustion increased significantly while breathing heliox. Heliox had a minimal effect on EFL and had no effect on time-to-exhaustion in CONT. We conclude that aerobic exercise endurance in PRET is limited, in part, by mechanical ventilatory constraints, specifically EFL.
Outcomes of solid tumor malignancies in patients of Jehovah’s Witness faith.
Authors: Rachael Chang, Shawgi Sukumaran, Richard John Woodman, Ganessan Kichenadasse, Christos Stelios Karapetis, Bogda Koczwara, Sina Vatandoust, Amitesh Chandra Roy
Journal: Journal of Clinical Oncology (2017)

e18176 Background: Jehovah's Witness (JW) patients with cancer present unique challenges due to their refusal of blood and blood products which limits supportive care options in the setting of cancer treatment. This study was aimed at determining their cancer specific outcomes. Methods: A retrospective analysis of case records of JW with solid tumors presented between 2005 and 2015 was conducted. Patient demographic data, diagnosis, treatment details and survival outcomes were collected and analysed. Results: A total of 63 JW were identified (39 females; 24 males); median age was 70 years (25-90). The most common cancer was breast (n=16) followed by colorectal (n=10). 27 JW had advanced disease (TNM stage 4), 48 patients had ECOG 0-1 and 22 JW had anaemia (Hb&lt;120g/L for women and &lt;130g/L for men) at the time of diagnosis. While surgery and radiation were uniformly accepted when recommended, 7 out of 42 refused chemotherapy. Median OS was 64 months in early stage (TNM stages 1-3) and 11 months in advanced stage. At presentation blood transfusion was considered unacceptable by all patients under any circumstances. 19 patients rejected transfusion even after symptomatic or life threatening anaemia. They had 1 year overall survival rate of 42% compared with 84% for those who did not require transfusion (HR 4.31, CI 1.96- 9.49, P=0.001). When adjusted for age and ECOG, these results were significant in early stage (P &lt;0.026) but not in late stage (P= 0.6). Treatment was suboptimal in 14 JW patients due to early treatment discontinuation or inferior chemotherapy regimen used to avoid pancytopenia. Median OS in this group was 15 months compared to 46 months who had optimal treatment (HR 2.5, CI 1.07- 6.27, P =0.034). 17 JW received bone marrow stimulating agents like erythropoietin or G-CSF. They helped with dyspnoea and maintaining chemotherapy dose intensity. Conclusions: Refusal of blood components may have negative impact on long term cancer outcome of JW due to compromised chemotherapy dose intensity. Strategies to deliver optimum therapy while being sensitive of religious perceptions will help in improving outcomes for this group.
Neutrophil-lymphocyte-ratio to complement the prediction ability of PD-L1 expression for outcomes in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors.
Authors: Diana Saravia, Naoyuki Okabe, Wungki Park, Deukwoo Kwon, Laura Mezquita, Young Kwang Chae, Raja Mudad, Mohammad Jahanzeb, Benjamin Besse, Hiroyuki Suzuki, Gilberto Lopes
Journal: Journal of Clinical Oncology (2018)

e15102 Background: PD-L1 expression is an imperfect predictor of outcomes for patients (pts) with advanced non-small cell lung cancer (aNSCLC) treated with PD-1/PD-L1 inhibitors (PD-1/L1i). Immunosuppressive tumor microenvironment is an important resistance mechanism and can compromise the outcome of PD-1/L1i. High Neutrophil-to-Lymphocyte Ratio (NLR) is a peripheral blood marker that is associated with poor outcomes and suggests higher myeloid-lymphoid balance. Here we show enhancement of outcome prediction by adding baseline NLR to PD-L1 expression. Methods: We used a retrospective cohort of 107 aNSCLC pts from the authors' institutions in the United States and Japan who received PD-L/L1i. We categorized patients into three groups: good: PD-L1 ≥ 50% AND NLR < 5, intermediate: PD-L1 ≥ 50% OR NLR < 5, poor: PD-L1 < 50% AND NLR ≥ 5. We correlated the outcome of each group with overall survival (OS) and progression free survival (PFS). We calculated receiver operating characteristic (ROC) to assess the predictive performance. Results: Median follow-up was 11.1 months (M) (95% Confidence Interval [CI]: 8.7-13.4). 50 pts had PD-L1 < 50% and 57 pts ≥50%. 66 pts had NLR < 5 and 41 pts ≥5. There were 29, 65, and 13 pts in good, intermediate, and poor groups, respectively. Median OS for good group was not reached and it was 15.1 M (CI: 9.5-21.0) and 3.2 M (CI: 2.5-4.0), respectively for intermediate and poor groups. Median Progression Free Survival (PFS) was 12.8 M (CI: 4.4-21.4), 5.5 M (CI: 1.3-9.7), and 1.5 M (CI: 0.6-1.3), respectively. By combining NLR and PD-L1, time-dependent area under ROC curves for OS at 6, 12, and 18 M was 0.68 (CI: 0.54-0.82), 0.71 (CI: 0.58-0.84), 0.66 (CI: 0.55-0.77), and 0.66 (CI: 0.55-0.78) as compared to 0.60 (CI: 0.47-0.72), 0.70 (CI: 0.58-0.82), and 0.65 (CI: 0.55-0.76), respectively when using PD-L1 only. Conclusions: Combining NLR and PD-L1 enhanced accuracy of outcome prediction. This result raises a hypothesis that this method can better identify resistant aNSCLC pts treated with PD-1/L1i. International validation and a prospective cohort is strongly supported and underway.
Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection
Authors: Huanle Luo, Evandro R. Winkelmann, Shuang Zhu, Wenjuan Ru, Elizabeth Mays, Jesus A. Silvas, Lauren L. Vollmer, Junling Gao, Bi-Hung Peng, Nathen E. Bopp, Courtney Cromer, Chao Shan, Guorui Xie, Guangyu Li, Robert Tesh, Vsevolod L. Popov, Pei-Yong Shi, Shao-Cong Sun, Ping Wu, Robyn S. Klein, Shao-Jun Tang, Wenbo Zhang, Patricia V. Aguilar, Tian Wang
Journal: Journal of Clinical Investigation (2018)

The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1-/-) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1-/- macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication.
Evaluation of BRCA1/2 and homologous recombination defects in ovarian cancer and impact on clinical outcomes.
Authors: Melinda S. Yates, Kirsten Timms, Molly S Daniels, Holly D. Oakley, Mark F. Munsell, Jerry S. Lanchbury, Karen H. Lu
Journal: Journal of Clinical Oncology (2017)

5511 Background: Recent studies show that germline or somatic BRCA1/2 mutations and homologous recombination (HR) defects can be used to predict response to PARP inhibitors in recurrent ovarian cancer. However, the impact of defects in BRCA1/2 and HR genes on overall clinical outcomes are not yet defined for patients undergoing neoadjuvant chemotherapy (NACT) versus upfront surgical debulking (USD). Methods: Previously untreated ovarian cancer patients were prospectively enrolled under approved IRB protocol. Germline and tumor BRCA1/2 mutation testing and methylation were analyzed when sufficient tumor and blood was available. Mutation in 21 additional hereditary cancer genes (including HR genes) was also evaluated. Tumor HR defects were scored on LOH, telomeric allelic imbalance, and large-scale state transitions (as previously described). Presence of germline or somatic BRCA1/2 mutations, BRCA1 methylation, HR score ≥42, or germline mutation in other HR genes were defined together as HRD positive. Results: Of 299 enrolled patients, 129 (43%) received USD and 170 (57%) received NACT. Patients receiving USD had better outcomes compared to NACT, including overall survival (OS, 65.8 vs 45.2 months, p = 0.0003) and event free survival (EFS, 24.8 vs 15.6 months, p &lt; 0.0001). In the overall cohort, EFS was significantly longer for HRD positive patients vs HRD negative (20.5 vs 16.3 months, p = 0.0268). Patients with somatic and germline BRCA1/2 mutations had longer OS vs BRCA1/2 negative (65.3 vs 46.1 months, p = 0.0403). Overall outcomes were worse in NACT compared to USD, but impact of BRCA1/2 mutations and HR defects was stronger in this group. NACT patients with any HR defect had longer EFS (19.7 vs 14.5 months, p = 0.0247). NACT patients with BRCA1/2 germline mutations had longer OS (65.3 vs 38.3 months, p = 0.0230). NACT patients with BRCA1/2 germline mutation had longer EFS (22.6 vs 14.6 months, p = 0.0047). OS and EFS in USD patients were significantly changed based on only debulking status; mutation or HR status did not have a statistically significant effect. Conclusions: While HR defects and BRCA1/2 mutations influence overall outcomes for ovarian cancer patients, the impact is stronger in NACT compared to USD.
Bax/Bcl-2 and caspase 3 pathway-mediated apoptosis induced by gentiopicroside in human colorectal cancer cells.
Authors: Yun Yang, Jiannan He, Shaoju Jin, Lin Chen
Journal: Journal of Clinical Oncology (2018)

e15665 Background: Colorectal cancer (CRC) is one common malignant disease with poor prognosis. Gentiopicroside, main compound in Gentiana and Cephalaria plants, has been reported that it can effect cell proliferation or apoptosis in some tumors. But its influence and mechanism on CRC are not clear yet. Based on our primary study, we tried to figure out the possible effects of gentiopicroside in human CRC cells. Methods: Cell apoptosis was investigated through cell proliferation assay, cell growth curve and clone formation assay in HCT116 cells. The morphological change and apoptosis rate were estimated by Hoechst 33258. Apoptosis via the Bax/Bcl2 and caspase 3 pathway induced by gentiopicroside were also detected by RT-PCR and Western-blot. Furthermore, the level of Bax/Bcl2 and caspase 3 pathway were detected by RT-PCR and Western-blot in through transplanting CRC cells into BALB/c nude mice. Results: MTT assay and Trypan blue staining showed that gentiopicroside reduced HCT116 cells proliferation and clone formation ability. Hoechst 33258 staining also showed that gentiopicroside induced cells apoptosis. Moreover, in nude mice groups, gentiopicroside induced lighter body weight, slower tumor growth speed, and smaller volume and lighter tumor weight. After treated with gentiopicroside, levels of Bax and caspase 3 were increased, and the level of Bcl2 was reduced by in vitro cell culture. Furthermore, gentiopicroside increased levels of Bax and caspase 3 and inhibited the level of Bcl2, which subsequently induced apoptosis via the Bax/Bcl2 and caspase 3 pathway in vivo. Conclusions: Gentiopicroside induced apoptosis through the Bax/Bcl2 and caspase 3 pathway in HCT116 cells. Our study suggests that gentiopicroside has cytotoxic effect on colorectal cancer cells via the induction of apoptosis and in vitro and in vivo.