tbuckley/cabot-search huggingface dataset:
Contemporary outcomes for adults with AML requiring ICU admission.
Authors: Danielle Hammond, Koji Sasaki, Alexis Geppner, Fadi Haddad, Shehab Mohamed, Daniel Rivera, Maria Siddiqui, Yasmin Alwash, Jorge Ramos Perez, Kiyomi Morita, Kunhwa Kim, Sherry Pierce, Cristina Gutierrez, Naveen Pemmaraju, Gautam Borthakur, Courtney Denton Dinardo, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M. Kantarjian, Tapan M. Kadia
Journal: Journal of Clinical Oncology (2021)

7025 Background: Patients (pts) with AML frequently encounter life-threatening complications requiring transfer to an intensive care unit (ICU). Methods: Retrospective analysis of 145 adults with AML requiring ICU admission at our tertiary cancer center 2018-19. Use of life-sustaining therapies (LSTs) and overall survival (OS) were reported using descriptive statistics. Logistic regression was used to identify risk factors for in-hospital death. Results: Median age was 64 yrs (range 18-86). 47% of pts had an ECOG status of ≥ 2 with a median of at least 1 comorbidity (Table). 117 pts (81%) had active leukemia at admission. 68 pts (47%) had poor-risk cytogenetics (CG) and 32 (22%) had TP53-mutated disease. 61 (42%), 27 (19%) and 57 pts (39%) were receiving 1 st , 2 nd and ≥ 3 rd line therapy. 33 (23%) and 70 pts (48%) were receiving intensive and lower-intensity chemotherapy, respectively, and 77 pts (53%) were concurrently on venetoclax. Most common indications for admission were sepsis (32%), respiratory failure (24%) and leukocytosis (12%); Table outlines additional ICU admission details. Median OS from the date of ICU admission was 2.0 months (mo) for the entire cohort and 6.9, 1.6 and 1.2 mo in pts with favorable-, intermediate- and poor-risk CG. Median OS of pts receiving frontline vs. ≥ 2 nd line therapy was 4.2 vs. 1.4 mo (P&lt;0.001). Median OS in pts requiring 0-1 vs. 2-3 LSTs was 4.1 vs. 0.4 mo (P&lt;0.001). OS was not different by age, co-morbidity burden nor therapy intensity. In a multivariate analysis that included SOFA scores, only adverse CG (OR 0.35, P = 0.028), and need for intubation with mechanical ventilation (IMV; OR 0.19, P = 0.009) were associated with increased odds of in-hospital mortality. Conclusions: A substantial portion of pts with AML survive their ICU admission with sufficient functionality to return home and receive subsequent therapy. In contrast to general medical populations, age, co-morbidities, and SOFA scores were not independently predictive of in-hospital mortality. Disease CG risk and the need for IMV were the strongest predictors of ICU survival. This suggests that many pts with AML can benefit from ICU care.[Table: see text]
Verification of statistical oncological endpoints on encrypted data: Confirming the feasibility of real-world data sharing without the need to reveal protected patient information.
Authors: Ravit Geva, Barliz Waissengrin, Dan Mirelman, Felix Bokstein, Deborah T. Blumenthal, Ido Wolf, Sharon Pelles, Zohar Duchin, Lior Liram, Yuriy Polyakov, Marcelo Blatt
Journal: Journal of Clinical Oncology (2021)

e18725 Background: Healthcare data sharing is important for the creation of diverse and large data sets, supporting clinical decision making, and accelerating efficient research to improve patient outcomes. This is especially vital in the case of real world data analysis. However, stakeholders are reluctant to share their data without ensuring patients’ privacy, proper protection of their data sets and the ways they are being used. Homomorphic encryption is a cryptographic capability that can address these issues by enabling computation on encrypted data without ever decrypting it, so the analytics results are obtained without revealing the raw data. The aim of this study is to prove the accuracy of analytics results and the practical efficiency of the technology. Methods: A real-world data set of colorectal cancer patients’ survival data, following two different treatment interventions, including 623 patients and 24 variables, amounting to 14,952 items of data, was encrypted using leveled homomorphic encryption implemented in the PALISADE software library. Statistical analysis of key oncological endpoints was blindly performed on both the raw data and the homomorphically-encrypted data using descriptive statistics and survival analysis with Kaplan-Meier curves. Results were then compared with an accuracy goal of two decimals. Results: The difference between the raw data and the homomorphically encrypted data results, regarding all variables analyzed was within the pre-determined accuracy range goal, as well as the practical efficiency of the encrypted computation measured by run time, are presented in table. Conclusions: This study demonstrates that data encrypted with Homomorphic Encryption can be statistical analyzed with a precision of at least two decimal places, allowing safe clinical conclusions drawing while preserving patients’ privacy and protecting data owners’ data assets. Homomorphic encryption allows performing efficient computation on encrypted data non-interactively and without requiring decryption during computation time. Utilizing the technology will empower large-scale cross-institution and cross- stakeholder collaboration, allowing safe international collaborations. Clinical trial information: 0048-19-TLV. [Table: see text]
Abstract 12191: Local Brain Atrophy of Parahippocampal Gyrus is Prominent in Malnourished Heart Failure Patients Without Dementia
Authors: Tomomi Meguro, Yuko Meguro, Toshio Nagai
Journal: Circulation (2019)

Introduction: Malnourished heart failure (HF) patients without dementia may have potential risk of cognitive impairment (CI) that weakens the effect of treatment. Local brain atrophy of parahippoca...
Neoadjuvant prehabilitation therapy for locally advanced non-small-cell lung cancer: Optimizing outcomes throughout the trajectory of care.
Authors: Severin Schmid, Enrico Maria Minnella, Sara Najmeh, Jonathan Cools-Lartigue, Lorenzo Ferri, David Mulder, Christian Sirois, Scott Peter Owen, Francesco Carli, Jonathan Spicer
Journal: Journal of Clinical Oncology (2021)

e20545 Background: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. Methods: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery at the McGill University Health Center between 2015-2020. Patients who were screened for the prehabilitation program were identified. Screening included assessment of physical performance, nutritional status and signs for anxiety and depression. 6-minute-walk test was used as a functional outcome parameter of prehabilitation. Results: We identified a total of 93 patients who underwent neoadjuvant therapy. Of these, 12 patients were screened to undergo a prehabilitation program. For 1 patient surgical intervention was too soon to complete the program, 1 patient dropped out after the first and another patient was deemed fit to undergo surgery without intervention. Thus, 9 patients completed full neoadjuvant prehabilitation therapy. Postoperative median length of stay was 2 days (IQR 1-5) and there were no mortalities. We found major complications in 1 patient and minor complications (prolonged air leak) in 2 cases. Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 35 meters (SD 39). Conclusions: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.
Abstract 11446: Impact of PRECISE-DAPT Score on Long-term Prognosis in Patients With Acute Myocardial Infarction
Authors: Takuya Ando, Kazuhiko Nakazato, Takatoyo Kiko, Takeshi Shimizu, Akiomi Yoshihisa, Takayoshi Yamaki, Hiroyuki Kunii, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2019)

Background: The prediction of bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score predicts the bleeding risk in patients t...
Articular cartilage and osteochondral tissue engineering techniques: Recent advances and challenges
Authors: Wenying Wei, Honglian Dai
Journal: Bioactive Materials (2021)

In spite of the considerable achievements in the field of regenerative medicine in the past several decades, osteochondral defect regeneration remains a challenging issue among diseases in the musculoskeletal system because of the spatial complexity of osteochondral units in composition, structure and functions. In order to repair the hierarchical tissue involving different layers of articular cartilage, cartilage-bone interface and subchondral bone, traditional clinical treatments including palliative and reparative methods have showed certain improvement in pain relief and defect filling. It is the development of tissue engineering that has provided more promising results in regenerating neo-tissues with comparable compositional, structural and functional characteristics to the native osteochondral tissues. Here in this review, some basic knowledge of the osteochondral units including the anatomical structure and composition, the defect classification and clinical treatments will be first introduced. Then we will highlight the recent progress in osteochondral tissue engineering from perspectives of scaffold design, cell encapsulation and signaling factor incorporation including bioreactor application. Clinical products for osteochondral defect repair will be analyzed and summarized later. Moreover, we will discuss the current obstacles and future directions to regenerate the damaged osteochondral tissues.
Heterozygous <i>OAS1</i> gain-of-function variants cause an autoinflammatory immunodeficiency
Authors: Thomas Magg, Tsubasa Okano, Lars M. Koenig, Daniel F.R. Boehmer, Samantha L. Schwartz, Kento Inoue, Jennifer Heimall, Francesco Licciardi, Julia Ley-Zaporozhan, Ronald M. Ferdman, Andrés Caballero-Oteyza, Esther N. Park, Brenda M. Calderon, Debayan Dey, Hirokazu Kanegane, Kazutoshi Cho, Davide Montin, Karl Reiter, Matthias Griese, Michael H. Albert, Meino Rohlfs, Paul Gray, Christoph Walz, Graeme L. Conn, Kathleen E. Sullivan, Christoph Klein, Tomohiro Morio, Fabian Hauck
Journal: Science Immunology (2021)

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
Impact of recurrence on health-related quality of life in patients at high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma (MIUC): Results from the phase 3 CheckMate 274 trial.
Authors: Matt D. Galsky, Johannes Alfred Witjes, Jürgen Gschwend, Julia Braverman, Edward Broughton, Federico Nasroulah, Hasan Alhasani, Mario Maira-Arce, Xiaomei Ye, Ling Shi, Melissa Hamilton, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2021)

4540 Background: Patients (pts) undergoing radical surgery for MIUC face a high risk of disease recurrence. Recurrence is associated with worse survival, but its effect on health-related quality of life (HRQoL) is unclear. This post hoc analysis assessed the impact of recurrence on HRQoL using data from the phase 3 CheckMate 274 trial. Methods: Pts who had undergone radical surgery for high-risk MIUC (≤ 120 days previously) were randomized 1:1 to nivolumab 240 mg Q2W or placebo for ≤ 1 year. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D-3L every 4–6 weeks during treatment; 35 and 115 days after the last dose; and every 3 months after that until the end of the study (EQ-5D-3L only). The analysis included pts with a valid HRQoL assessment at baseline and at ≥1 post-baseline visits. Confirmed deterioration in HRQoL was defined as worsening exceeding an a priori points threshold (± 10 for the EORTC QLQ-C30 domains, –7 for the EQ-5D visual analogue scale [VAS]) at ≥ 2 consecutive visits. Recurrence was classified as local only or distant (with or without local recurrence). The effect of recurrence on HRQoL deterioration was assessed by Cox proportional hazards regression with recurrence as a time-dependent covariate. The models controlled for treatment arm and baseline HRQoL score, and were stratified by PD-L1 expression, pathologic nodal status, and use of neoadjuvant cisplatin-based chemotherapy. Results: The analysis included 645 pts for EORTC QLQ-C30, of whom 71 (11%) had local recurrence only and 136 (21%) had distant recurrence during the HRQoL assessment period; and 648 pts for EQ-5D-3L. with recurrence had a significantly higher risk of confirmed deterioration in all HRQoL domains than those without recurrence (see table). However, hazard ratios were consistently greater for distant recurrence than for local recurrence across all HRQoL domains. For local recurrence only, a higher risk of confirmed deterioration in HRQoL compared to no recurrence was observed only for global health status/QoL. Conclusions: Recurrence, particularly distant recurrence, had a significant, negative impact on HRQoL. This suggests that treatment delaying recurrence after radical surgery for high-risk MIUC may prevent or delay HRQoL deterioration in these pts. Clinical trial information: NCT02632409. [Table: see text]
Collaborating with low- and middle-income countries: Experience from two of the United Kingdom’s comprehensive cancer centers.
Authors: Emma Foreman, Isla Leslie, Hannah Lyons, Katherine Piddock, Anguraj Sadanandam, Alison Sanneh, Susannah Jane Stanway, Julie Webb, Richard Cowan
Journal: Journal of Clinical Oncology (2021)

e23014 Background: The number of annual global cancer deaths is rising and the majority of this burden, for a multitude of reasons, falls in low- and middle- income countries (LMICs). With the United Nations’ 3rd and 17th Sustainable Development Goals in mind (which include by 2030 “reduce by one third premature mortality from non-communicable diseases” and “partnership for the goals”) a survey was undertaken at the UK’s two largest comprehensive cancer centres to scope individual and team endeavours to work with colleagues in less well-resourced countries. Methods: Employees at the Royal Marsden Foundation Trust (RM) and Institute of Cancer Research (ICR) in London and Surrey, UK and The Christie NHS Foundation Trust (Christie), Manchester were invited to complete a survey to capture collaborative clinical care, research, education and training. Results: Responses were received from 520 multidisciplinary individuals across the 2 centres to two similar questionnaires. A large number had experience of working in some capacity in, or in collaboration with an LMIC. At the RM 14.62% of respondees were currently working with colleagues in LMICs. At The Christie 13.22% of staff had experience of working in LMICs in a supportive capacity. Those currently collaborating with colleagues in LMICs were working in a wide range of countries across Asia, Africa and South America in a range of initiatives spanning clinical care, research, education and training. Of those who answered the survey 64% at The Christie said they’d like to hear more about opportunities to be involved in supporting global health care, and 89% at RM/ICR said they’d be interested in joining a collaborative group working on global oncology initiatives at the institutions. Conclusions: This survey highlights the body of willing, interested individuals keen to work with colleagues in LMICs to improve cancer outcomes. The launch of the UK Global Cancer Network in 2020 will build upon these two surveys with a planned national survey of global health and cancer work undertaken by individuals in 2021.
Association of low RKIP expression with poor prognosis in non-small cell lung cancer.
Authors: Lingbin Meng, Rui Ji, Damian A. Laber, Xuebo Yan, Xiaochun Xu
Journal: Journal of Clinical Oncology (2021)

3068 Background: Raf1 kinase inhibitor protein (RKIP) is able to bind Raf1 to inhibit Ras-Raf-MEK-ERK signaling, a major oncogenic pathway. It has been reported that reduced RKIP expression associates with poor prognosis in many cancers, including gastric adenocarcinoma, gliomas and bladder cancer. However, there are only several studies on its role in non-small cell lung cancer (NSCLC) and the conclusion is still controversial. Hence, we performed this study to assess the prognostic significance of RKIP in our NSCLC population. Methods: Between June 2017 and June 2020, 156 NSCLC patients treated at our hospital were included for the present study. None of the patients had received chemotherapy, radiotherapy or surgery before. Their tumor tissues and surrounding normal lung tissues were collected for immunostain and western blot analysis of RKIP expression and ERK signaling. We collected information about gender, age, histological differentiation, tumor size, TNM stage, and lymph node status. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of various variables in a univariate and multivariate setting. Results: Immunostain and western blot results showed a lower RKIP expression and a higher p-ERK level in cancer tissues compared with the surrounding normal tissues. A reduced RKIP expression with high level of p-ERK was also observed in TNM stages III and IV as compared with I and II. Pearson's chi-squared test confirmed low RKIP expression associated with poorer TNM stage ( p&lt; 0.001) and N-stage ( p&lt; 0.05). No significant correlation was observed between RKIP expression level and gender, age, histological type or tumor size. Kaplan-Meier survival analysis revealed that patients with low RKIP expression had significantly worse overall survival than patients with high RKIP expression ( p= 0.019, log-rank). This conclusion was consistent in the stage I&amp;II patients ( p= 0.011, log-rank) but not in the stage III&amp;IV patients ( p= 0.711, log-rank). Univariate Cox proportional hazards regression analysis indicated Tumor size, TNM stage and RKIP expression significantly affected overall survival of the NSCLC patients. Multivariate Cox proportional hazards regression analysis confirmed RKIP expression remained a significant predictor of survival after correcting for the effects of Tumor size and TNM stage (hazard ratio = 1.730, 95% confidence interval = 1.017 – 2.942, p = 0.043). Conclusions: In this study, low RKIP expression was a poor prognostic indicator in NSCLC as it significantly correlated with poorer TNM stage, N-status, and overall survival. Our findings suggest that by inhibiting Ras-Raf-MEK-ERK pathway RKIP may play an anti-tumor role in NSCLC.
Identification of potential germline (GL) variants by routine clinical comprehensive genomic profiling (CGP) and confirmatory GL testing in 24 tumor types.
Authors: Kristen Hanson, Michael Mullane, Erica Schnettler, Dean C. Pavlick, Garrett M. Frampton, Maureen Cooper, Deborah Wham, Michael A. Thompson, Jennifer Godden, Mary Walters, Jeffrey Michael Venstrom, Kimberly McGregor
Journal: Journal of Clinical Oncology (2021)

10596 Background: Tumor CGP may identify both somatic and GL variants, though confirmatory testing is required to verify which variants originate from the GL. Studies have shown CGP can identify patients who both do and do not meet criteria for genetic counseling (GC). Ideally, improved annotation from tumor CGP could more appropriately direct GC referrals. We explore how a computational algorithm might be used to influence GC and confirmatory GL testing for variants in inherited cancer predisposition genes. Methods: 849 patients from the Aurora Oncology Precision Medicine Program who had routine hybrid-capture based CGP by Foundation Medicine from 8/2018-8/2020 were eligible. A previously published algorithm, SGZ (Sun et al PMID 29415044) which incorporates allele frequency, aneuploidy, and admixed copy number modeling was used to predict whether each single nucleotide variant (SNV) was GL or somatic. SGZ predictions for SNVs in 24 actionable inherited cancer predisposition genes were available to Aurora for review as part of standard screening to identify appropriate GC referrals. For patients who had GL testing, variants in genes on both assays were compared. Results: 76 pathogenic (P) or likely pathogenic (LP) variants predicted to be GL by SGZ were detected in 73/849 (9%) patients: ATM (7), BAP1 (2), BRCA1 (13), BRCA2 (8), BRIP1 (1), CHEK2 (18), FH (0), FLCN (2), MLH1 (1), MSH2 (0), MSH6 (3), MUTYH (12), PALB2 (3), PMS2 (1), POLE (0), RAD51C (1), RAD51D (0), RET (1), SDHA/B/C/D (0,0,0,0), TSC2 (0), and VHL (3). 27/73 (37%) patients had GL testing. 25/26 (96%) variants were confirmed to be GL in origin and 1 additional variant was detected by CGP in a region not interrogated by the GL assay: ATM (2/2), BRCA1 (6/6), BRCA2 (2/2), BRIP1 (1/1), CHEK2 (9/9), FLCN (0*/1), MSH6 (1/1), MUTYH (2/2), PALB2 (1/1), RAD51C (1/1), and VHL (0/1). Variants were confirmed in bladder, breast, CRC, glioma, NSCLC, ovary, pancreas, prostate, sarcoma, and gastric cancer. The VHL variant was discordant in a leiomyosarcoma. Conclusions: We identified the potential real-world clinical impact of computationally screening solid tumor patients undergoing routine CGP for potential P/LP GL variants. Predicting GL results with SGZ for 24 inherited cancer predisposition genes was highly concordant with confirmatory GL testing independent of tumor type. CGP annotations can facilitate GC referral and GL testing for at-risk patients, particularly in tumor types which may not typically meet guidelines for GL testing.[Table: see text]