tbuckley/cabot-search huggingface dataset:
Postoperative Joint Replacement Complications in Swedish Patients With a Family History of Venous Thromboembolism
Authors: Bengt Zöller, Peter J. Svensson, Jan Sundquist, Kristina Sundquist, MirNabi Pirouzifard
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The associations of a family history of venous thromboembolism (FH-VTE) with postoperative venous thromboembolism (VTE) and major bleeding after joint replacement surgical procedures are unknown. <h3>Objective</h3> To determine the risk of VTE and major bleeding in patients after primary hip or knee replacement surgical procedures. <h3>Design, Setting, and Participants</h3> Cohort study using nationwide population-based databases of Swedish patients without a history of VTE who underwent joint replacement surgical procedures. Patients who had primary hip or knee replacement surgical procedures between July 1, 2005, and August 31, 2012, were identified. Patients born after 1931 without previous VTE were identified in the Swedish Multi-Generation Register. Only individuals with at least 1 parent and 1 full sibling alive between 1964 and the date for the surgical procedure were included. The data analysis was performed from September 1, 2017, to June 15, 2018. <h3>Exposures</h3> Family history of VTE in a parent and/or a full sibling before the date of the surgical procedure. <h3>Main Outcomes and Measures</h3> Venous thromboembolism and major bleeding within 90 days of the surgical procedure. <h3>Results</h3> Of 69 505 study participants, 37 989 (54.7%) were women, and the median (interquartile range) age at the date of discharge was 65 (59-70) years. A total of 803 of 69 505 (1.2%) patients experienced postoperative VTE and 1285 (1.8%) experienced major bleeding. The cumulative VTE risk for those with FH-VTE was 231 of 15 858 (1.5%) and for those without an FH-VTE was 572 of 53 647 (1.1%) (<i>P</i> &lt; .001). The cumulative bleeding risk for those with FH-VTE was 261 of 15 858 (1.6%) and for those without an FH-VTE was 1024 of 53 647 (1.9%) (<i>P</i> = .03). There was an association of patients with an FH-VTE who had increased VTE risk (adjusted hazard ratio [HR], 1.36; 95% CI, 1.17-1.59) and reduced bleeding risk (adjusted HR, 0.84; 95% CI, 0.74-0.97). There was an interaction between time after discharge and FH-VTE regarding VTE and major bleeding. An FH-VTE was not associated with VTE after discharge during the first week (HR, 1.13; 95% CI, 0.86-1.49). After 7 days from discharge, FH-VTE was associated with VTE (HR, 1.49; 95% CI, 1.24-1.79). An FH-VTE reduced major bleeding risk during the first 7 days after discharge (HR, 0.78; 95% CI, 0.66-0.91) but not thereafter (HR, 1.10; 95% CI, 0.84-1.44). Postoperative VTE heritability (SE) was 20% (6%). <h3>Conclusions and Relevance</h3> Familial and most likely genetic factors appear to affect VTE and major bleeding risk following hip and knee replacement surgical procedures. Prolonged VTE prophylaxis might be beneficial in predisposed individuals. There may be a possible evolutionary advantage of prothrombotic genes protecting against traumatic bleeding.
Prevalence and Impact of De Novo Donor‐Specific Antibodies During a Multicenter Immunosuppression Withdrawal Trial in Adult Liver Transplant Recipients
Authors: Vadim Jucaud, Abraham Shaked, Michele DesMarais, Peter Sayre, Sandy Feng, Josh Levitsky, Matthew J. Everly
Journal: Hepatology (2018)

The development of human leukocyte antigen (HLA) donor‐specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy‐proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development ( P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS‐free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection ( P = 0.015). The majority of dnDSA were against HLA‐DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.
Using deep-learning radiomics to predict lung cancer histology.
Authors: Tafadzwa Lawrence Chaunzwa, David C. Christiani, Michael Lanuti, Andrea Shafer, Nancy Diao, Raymond H. Mak, Hugo Aerts
Journal: Journal of Clinical Oncology (2018)

8545 Background: Histologic phenotype is an important predictor of clinical outcomes in lung cancer. Tissue diagnosis is the most definitive approach to categorization, however, this is often technically challenging for thoracic lesions. In this study, we explore Deep-Learning Radiomics methods for non-invasive histology classification in early-stage Non-Small Cell Lung Cancer (NSCLC). Methods: A cohort of 157 patients with Stage I NSCLC identified as either adenocarcinoma or squamous cell carcinoma on pathology was used. All patients were surgical candidates at Massachusetts General Hospital between 2004-2010. Deep feature extraction from pretreatment CT images was conducted using a pre-trained VGG-16 convolutional neural network (CNN). In addition to appending fully-connected classifying layers to the network, a transfer learning approach was also employed using different classifiers. Three machine-learning classification models were independently evaluated on the extracted features: K-Nearest Neighbors (kNN), Random Forest Classifier (RF), and Least Absolute Shrinkage and Selection Operator (LASSO). Principal component analysis was employed in selecting features corresponding to 90% cumulative explained variance. A LASSO method was then used to select the best features. Models were trained on 100 patients and cross-validated on an independent test-set of 57 patients. Results: All models were able to perform binary classification of tumor histology (adenocarcinoma vs squamous cell carcinoma). The fully-connected CNN had the highest performance (AUC = 0.751). Other classifiers also showed significant predictive power after dimension reduction of the feature space (from 512 to 46), with AUC = 0.712 for LASSO (α = 0.1), and AUC = 0.689 for kNN (k = 5). RF had the lowest predictive performance (AUC = 0.533). 73% of the study group had adenocarcinoma vs 27% with squamous cell carcinoma, and ratios were balanced between training and validation sets. Conclusions: Deep-Learning Radiomics is a promising approach to non-invasive lung cancer histology classification. These methods can potentially augment other emerging techniques, such as liquid biopsy; offering complementary information to help in clinical decision making.
P01.026 Local control and radiologic effects in a glioblastoma patient treated with Tumor Treating Fields (TTFields) and chemotherapy
Authors: E Mergen
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are low intensity (1–3 V/cm), intermediate frequency (100 - 300 kHz) alternating electric fields for treating solid tumors. In the EF-14 trial, the combination of TTFields at a frequency of 200 kHz with adjuvant chemotherapy in patients with newly diagnosed glioblastoma (GBM) showed significantly increased progression-free survival (PFS), overall survival (OS) and long-term survival rates. Post-hoc analysis of the EF-14 trial revealed significantly prolonged OS upon recurrence in patients that received TTFields in combination with 2nd line therapy compared to patients treated with 2nd line therapy alone. Here, we report on a GBM patient who received TTFields as 1st-line and 2nd-line therapy in combination with chemotherapy. A 50-year-old male patient was diagnosed with an IDH1/IDH2 wildtype MGMT-promoter methylated GBM in June 2016. The tumor was completely resected and the patient was treated with concomitant radio-chemotherapy followed by chemotherapy with TMZ and TTFields therapy for eight months. TTFields therapy was subsequently stopped in accordance with the patient. The tumor recurred three month afterwards at the genu of the corpus callosum distant from the primary tumor. Surgery of the recurrent tumor was not possible due to infiltration of the corpus callosum. The patient then received radio-chemotherapy with TMZ followed by chemotherapy with procarbazine/CCNU in combination with TTFields therapy. Under this regimen, a change was observed in radiologic imaging: the recurred tumor appeared to be very homogenous with a smooth structure in contrast to the typical appearance of GBM. In the case presented, the combination of TTFields with procarbazine/CCNU was feasible and safe. Local control and a unique radiologic response to TTFields therapy in combination with chemotherapy upon recurrence of the tumor were detected. Follow-up radiologic assessments of patients treated with TTFields therapy may provide additional insights on tumor response to this therapy.
P04.84 Lysine-specific histone demethylase 1 (LSD1) contributes to the maintenance of Glioblastoma stem cell population
Authors: S Faletti, D Osti, C Richichi, I Marangoni, E Ceccacci, S Minucci, G Pelicci
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common, lethal and recurrent primary brain tumor in adults (median survival: 12–15 months, recurrence rate: 90%). Its dismal prognosis is, at least in part, due to the inefficacy of current therapies against GBM tumor initiating cells (TICs), a sub-population of GBM cells able to sustain GBM growth and relapse owing to their stem cell-like phenotype. Lysine specific histone demethylase 1 (LSD1) is an epigenetic regulator that sustains stem cell-like traits, cell proliferation and tumorigenesis, and whose overexpression has been reported in many tumors, including GBM. Notably, drugs that modify LSD1 activity are already available even if their applications are still at their infancy. Altogether, these observations prompted us to study the role of LSD1 in the GBM TIC maintenance. We targeted LSD1 using a chemical inhibitor and confirming the results by shRNA-mediated silencing and CRISPRCas9-mediated knock-out. We studied the biological significance of LSD1 in GBM TICs isolated from fresh GBM samples in vitro(cell proliferation, clonogenic capacity, stem cell frequency byExtreme Limiting Dilution Assay [ELDA algorithm]) and in vivo (orthotopic injection in immunocompromised mice). RNA-sequencing and Chromatin Immuno-Precipitation(ChIP)-sequencing were used to identify possible molecular targets. Differences in LSD1 expression were analyzed by analysis of variance (ANOVA). Kaplan-Meier analyses and log-rank test were used to assess mice survival. All other statistical tests were two-sided t-tests. We found that LSD1 is up-regulated in human GBM tissues and patient-derived TICs compared to normal counterparts. LSD1 targeting does not affect GBM TIC viability and proliferation, but reduces the stem cell frequency -both in vitroand in vivo-and prolongs the survival of GBM-patient-derived xenograftmodels. Preliminary data from RNA-sequencing and ChIP-sequencing provided a list of putative mediators of LSD1 biological activity, including genes known to be important for GBM biology and stemness maintenance. Our results highlight the importance of LSD1 for GBM TIC maintenance and GBM formation through mechanisms that are now under investigation. The importance of GBM TICs for GBM initiation and progression, together with LSD1 targetable nature, shed light on the therapeutic potential of LSD1 inhibitors for GBM management. Italian Association for Cancer Research (AIRC)
TCT-631 DILEMMA score predicts 1 year mortality in patients with coronary artery disease undergoing transcatheter aortic valve replacement
Authors: Ren Yik Lim, Michael Michail, Abdul Rahman Ihdayhid, Vivek Gupta, Liam McCormick, Robert Gooley, Om Narayan, Dennis Wong, Adam Brown
Journal: Journal of the American College of Cardiology (2018)
Genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with FOLFIRI/cetuximab (FIRE-3) or with first line cetuximab-based chemotherapy (JACCRO CC-05/06 AR).
Authors: Jordan David West, Wu Zhang, Sebastian Stintzing, Yu Sunakawa, Dongyun Yang, Shu Cao, Yan Ning, Martin D. Berger, Roel Gopez, Yuji Miyamoto, Satoshi Okazaki, Mitsukuni Suenaga, Marta Schirripa, Afsaneh Barzi, Diana L. Hanna, Akihito Tsuji, Wataru Ichikawa, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3595 Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system via ADCC (antibody-dependent cell-mediated cytotoxicity). Immune response through T-cell activation may also play a role in anti-tumor efficacy of chemotherapy. Our group previously showed immune response gene polymorphisms (IDO1, CD24, PDL1) were associated with clinical outcome in mCRC treated with cetuximab-based therapy (J Clin Oncol 31, 2013 (suppl; abstr 3567). Here we validated these findings in two independent cohort mCRC treated with cetuximab-based therapy (FIRE3 cetuximab arm and JACCRO CC-05/06 AR). Methods: Genomic DNA was isolated from tissue samples of 2 cohorts of mCRC patients. Cohort 1: 225 patients with all RAS wildtype treated in first-line with FOLFIRI/CET(arm A) from the FIRE-3 trial. Median age 64 yrs, male 71%, median OS 28.7 mos. Cohort 2: 74 Japanese KRASwt pts treated either with 1st-line modified FOLFOX6 (n = 27/57) or SOX (n = 47/67) in combination with CET. 57% males of pts, median age of 63 years and median OS were 33.9 mos, respectively. PCR-based direct Sanger sequencing was used to determine polymorphisms. Results: Our data showed that CD24 rs52812045 AA/GA genotype was significantly associated with shorter PFS compared to GG genotype in multivariate analysis {9.2(6.7,13.8) vs 11.8 (9.4, 18.9) mos, HR: 2.12; p = 0.018} in Japanese cohort, which is consistent with our previous findings. In FIRE3 cohort, IDO1rs3739319 GG genotype was significantly associated with longer PFS compared to AA/GA genotype in multivariate analysis {10.5(8.8, 12.6) vs 9.2(7.9, 10.6) mos, HR: 0.67; p = 0.011}. Also, IDO1rs3739319 showed a trend significance in OS {AA/GA: 33.1(27.6, 41.2) vs GG: 23.920.6, 36.6) mos; HR: 0.70; p = 0.063}. Recursive petitioning analysis of both cohorts showed IDO1 rs 3739319 is the most important snp to distinguish OS. Conclusions: Our data validated previously findings that polymorphisms in immune response gens IDO1 and CD24 may predict clinical outcomes in cetuximab-based therapy. Our findings indicate to combine anti-EGFR and immune checkpoint inhibitors in future clinical trials.
SP0044 What do we learn from rcts on the treatment effect on structural progression in axspa?
Authors: X. Baraliakos
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> The introduction of tumour necrosis factor inhibitors (TNFis) about 20 years ago has led to the hope of disease modification of ankylosing spondylitis, since biologics showed for the first time a decrease of inflammatory activity on MRI, with the latter being theoretically also directly linked to new bone formation. However, the first open-label extensions of randomized-controlled trials with a treatment duration of 2 years failed to show any positive effect on the radiographic progression in AS patients when compared to historical cohorts that had not been exposed to biologics. Nevertheless, later data indicated that this lack of influence on radiographic progression might have been due to many different reasons that were not taken into account in these first analyses, such as the radiographic status of patients at baseline, CRP levels or insufficient duration of follow-up. Furthermore, most recent data from MRI studies also indicated that the most important link to influence radiographic progression with biologics might not be the suppression of inflammation but the protection of bone to show tissue metaplasia to post-inflammatory findings, while early suppression of inflammation might be the key to even completely inhibit radiographic progression in AS patients. Indeed, most recent cohort data have been able to demonstrate an association between TNF-blocker treatment and reduced risk of spinal structural progression (e.g. formation of syndesmophytes). Furthermore, early escalation of treatment from NSAIDs to biologics and long-term treatment with biologics have also independently been able to show positive effects on radiographic progression in patients with AS. Finally, also newer biologics such as IL-17A inhibitors have also provided promising results in terms of overall low radiographic progression rates as measured by validated scoring systems. Currently, first head-to-head trials of different biologics are underway to examine any possible differences between the available compounds with a primary outcome of their effect on spinal radiographic progression. It remains to be shown whether and how these results will also become clinically relevant in terms of decrease or even inhibition of spinal mobility restrictions, in order to be able to postulate a ‘real’ disease modifying effect of biologic treatment in axial spondyloarthritis. <h3>Disclosure of Interest</h3> None declared
Open-label, randomized, multicenter, phase II trial designed to compare the efficacy of CAPTEM combination versus FOLFIRI as second line treatment in patients (pts) who have progressed on or after first-line oxaliplatin-containing chemotherapy for advanced, MGMT methylated, RAS mutated colorectal cancer (CRC).
Authors: Rosa Berenato, Filippo Pietrantonio, Marta Caporale, Ilaria Bossi, Gianluca Tomasello, Stefania Mosconi, Emanuela Paterno, Silvia Bozzarelli, Raffaella Longarini, Stefania Gori, Alberto Zaniboni, Alessandro Stefano Bertolini, Francesca Bergamo, Sandro Barni, Alessio Amatu, Daniele Fagnani, M. Giulia Zampino, Federica Morano, Maria Di Bartolomeo, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2016)

TPS3635 Background: Epigenetic silencing of O6-methylguanine-DNA methyltransferase (MGMT) during colorectal tumorigenesis is responsible for diminished DNA-repair of O6-alkylguanine adducts, leading to an enhancing chemosensitivity to alkylating agents such as temozolomide (TMZ). In two phase II studies, we showed that TMZ is effective in heavily pre-treated pts with advanced CRC and MGMT promoter methylation. Other studies in carcinoids cell lines demonstrated synergistic cell kill if 5-fluoracile and TMZ were delivered in a schedule-dependent manner. The CAPTEM regimen consists of TMZ for 5 days at 75 mg/m2/day bid on days 10–14 and capecitabine 750 mg/m2/day bid on days 1–14 of a 28-day cycle. Given the potential synergy of capecitabine and TMZ in MGMT methylated CRC, we planned a randomized study to evaluate the efficacy of CAPTEM versus FOLFIRI after failure of prior first-line oxaliplatin-based treatment in patients with advanced, MGMT methylated, RAS mutated CRC. Methods: This is an open-label, multicenter, randomized phase II trial. Up to 82 pts will be enrolled and randomized in a 1:1 ratio to receive FOLFIRI or CAPTEM as second-line treatment for up to 6 months or up to disease progression or unacceptable toxicity. Efficacy assessments will be performed every 8 weeks. Primary objective is progression-free survival (PFS). According to the results of the GERCOR study, the median PFS during second-line treatment with crossover from FOLFOX to FOLFIRI was 2.3 months. A one-sided log rank test with an overall sample size of 82 subjects achieves 90% power at a 5% significance level to detect an increase in median PFS from 2 months of the control group to 4 months. Secondary objectives: safety, quality of life, response rate and overall survival. Exploratory objectives: identification of potential biomarkers associated with activity of TMZ in tumor tissue (MGMT immunohistochemistry, methylBEAMing and next-generation sequencing) and in plasma (methylBEAMing and miRNA). Clinical trial information: NCT02414009.
Bayesian baskets: A novel approach to biomarker-based clinical trial design.
Authors: Brian Michael Alexander, Lorenzo Trippa
Journal: Journal of Clinical Oncology (2016)

e14057 Background: Identifying predictive biomarkers is essential to precision medicine and can make therapeutic development more efficient. A critical decision in designing of biomarker-based clinical trials is whether to include all patients or only biomarker positive patients. Platform trials must also prioritize biomarker/therapeutic hypotheses and accommodate varying degrees of confidence in biomarker hypotheses. We sought to generate a more efficient, flexible design that could accommodate varying hypotheses while making pre-trial choices explicit. Methods: We generated a procedure that utilizes prior knowledge of biomarker information by quantifying the belief in the strength of the biomarker-effect linkage and combined the procedure with a Bayesian adaptive randomization algorithm. To compare the utility of our design over naive balanced (NB) randomization and traditional “basket” (TB) trial designs, we iteratively simulated hypothetical multi-arm clinical trials under various scenarios. Results: Our “Bayesian basket” (BB) design was more efficient than NB randomized while generating more biomarker information than TB. For example, with 3 experimental arms, each with a potential biomarker that constituted between 40% and 60% of the overall population, and assuming a treatment effect HR = 0.65, the BB design required 42% to 52% less patients than NB when the treatment effect was truly only in the biomarker positive patients and 14% to 19% less patients when the effect was in the entire population. Compared with TB, BB required 23%-36% more patients when the effect was limited to biomarker positive patients only but generated data on predictive capacity while TB generated none. This efficiency loss was reduced to 3%-5% when the entire population benefitted from the treatment, but the time to get a positive result was reduced by 56% to 40% in the BB design. Conclusions: The BB design offers an efficient way to generate information on both experimental therapeutics and the predictive capacity of putative biomarkers. The design is flexible enough to accommodate varying levels of pre-trial confidence in biomarker/effect linkages in the same platform structure and makes clinical trial design decisions more explicit.