tbuckley/cabot-search huggingface dataset:
Efficacy and safety of MUC1 targeted CIK cells for the treatment of advanced liver cancer.
Authors: Yin Ying Lu, Haoyang Yu, Yunxia Tang
Journal: Journal of Clinical Oncology (2021)

e16278 Background: To assess the efficacy and safety of CIK treatment with MUC1/CD3 bis-Ab for patients with advanced liver cancer. Methods: A total of 11 patients were enroll from when in which hospitals, including 5 male and 6 female patients with a median age of 59 years old. Trial Design and Treatment: All participants provided written informed consent before enrollment. The study protocol was approved by the institutional review board at each participating center. All methods and procedures associated with this study were conducted in accordance with the Good Clinical Practice guidelines and accorded ethically with the principles of the Declaration of Helsinki and local laws. This phase I clinical study was a single-armed open-labeled trial. All patients received targeted activated CIK cell treatment of 6x10 9 cells/month until the disease progressed, the patient could not tolerate the treatment, or the study endpoint had reached. PBMC were collected from each patient on D0. After PBMC collection, patients received 10 mg/day decitabine for 5 consecutive days (D0–D4). On D14 the first batch of CIK cells were harvested and the infusion of cells was performed in two consecutive days (total cells ≥ 6x10 9 ). The bispecific antibody was infused together with CIK cells. After cell infusion, the bispecific antibody was infused alone for another 3 days. Each treatment course lasted for 4 weeks, with a total of 4 courses. Results: Efficacy: 9 patients completed 4 or fewer courses of CIK bispecific antibody treatment, and 2 patients completed 9 courses of treatment. Till the data cut-off date of Dec. 31, 2020, 9 patients died, of whom 5 patients achieved SD and 4 patients had PD. Two patients (case 1 &amp; 2) are still alive, of whom one achieved PR and one achieved SD during CIK treatment, and both achieved CR after subsequent PD-1 inhibitor treatment when the disease progressed. The PFS ranged from 1-16.7 months with a median PFS of 4 months, and the OS ranged from 3.9-32.7 months with a median OS of 13.2 months. The DCR of CIK treatment reached 63.6%. Safety: All 11 patients developed fever after cell infusion, which subsided after a few hours by oral administration of Xinhuangpian. 2 patients developed anorexia. Other AEs included debilitation, drowsiness, nausea, hepatotoxicity and dizziness. Five patients discontinued treatment due to serious AEs. Conclusions: This study showed that adjuvant CIK cell immunotherapy prolongs the survival time of patients with advanced liver cancer, which is mainly due to the local tumor chemotaxis of CIK cells via the MUC1/CD3 bispecific antibody and the decitabine pretreatment. Clinical trial information: NCT03146637.
Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).
Authors: Takaya Ikeda, Hajime Oi, Kiyotaka Yoh, Shingo Matsumoto, Terufumi Kato, Kazumi Nishino, Atsushi Nakamura, Ichiro Nakachi, Jun Sakakibara-Konishi, Haruko Daga, Naoki Furuya, Kageaki Taima, Eiji Iwama, Noriyuki Ebi, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Yoshitaka Zenke, Koichi Goto
Journal: Journal of Clinical Oncology (2021)

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.
INTASYL self-delivering RNAi therapy specifically dual-targeting BRD4 and PD-1 to elicit complete tumor responses and evidence of synergy in a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice.
Authors: Benjamin Cuiffo, Melissa Maxwell, Dingxue Yan, Brianna Rivest, James Cardia, Simon P Fricker
Journal: Journal of Clinical Oncology (2021)

e14537 Background: The therapeutic potential of targeting bromodomain and extra-terminal motif (BET) protein BRD4 is supported by promising preclinical data in multiple cancer contexts. However, clinical trials of BET inhibitors (BETi) have overall shown limited clinical efficacy and only passable safety profiles as monotherapy. BET proteins are now also understood to control a wide range of immunoregulatory pathways. Preclinical data suggests a synergistic impact with immune checkpoint blockade (ICB) targeting PD-1. Trials assessing the potential of BETi in rational combination with ICB are underway. The INTASYL platform is a self-delivering RNAi technology enabling efficient delivery into target cells without need for specialized drug delivery systems. INTASYL provides specific, robust, and durable on-target gene silencing. Furthermore, INTASYL moieties targeting multiple specific targets can be formulated together, providing a highly versatile platform for providing multi-targeted combination therapy in a single drug substance. Methods: Here we assessed the efficacy of mouse/human BRD4-targeting INTASYL PH-894 as monotherapy or co-formulated with mouse PD-1 targeting INTASYL mPH-762, in treating a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice. On-target, specific silencing of BRD4 and PD-1 was demonstrated in vitro. In vivo, mice bearing tumors of ̃150 mm 3 (N = 12/arm) were treated intratumorally on Days 1, 3, 7, 10 &amp; 14 with of PH-894 or mPH-762 as single-agent, or PH-894/mPH-762 in combination at sub-optimal doses (0.1 mg/INTASYL/dose), or with PH-894/mPH-762 at half-suboptimal dose (0.05mg/INTASYL/dose) to assess potential synergistic impacts. Positive control groups received systemic (IP) (+)-JQ-1 (13.33mg/dose; qdx5), anti-mouse PD-1 antibody (75 µg; Days 1, 3, 7, 10, 14), or both treatments. Negative control animals received vehicle only. Tumor volumes and body weights were recorded longitudinally. Results: Compared to vehicle, suboptimal (+)-JQ-1, anti-PD-1, PH-894 or mPH-762 each elicited tumor control but not resolution as expected; while treatment with suboptimal PH-894/mPH-762 combo produced complete response (CR) in 75% (9/12) mice, outperforming combination treatment with (+)-JQ-1 and anti-PD-1 mAb [CR 58% (7/12) of mice]. Treatment with half-suboptimal doses of PH-894/mPH-762 resulted in CR for 42% (5/12) mice and tumor control exceeding that elicited by each monotherapy, suggesting potential synergy of the dual-targeting formulation. Tumors were isolated for mechanistic analyses of immune and tumor cells. Conclusions: These data demonstrate proof-of-concept of the therapeutic potential of rational dual-targeted INTASYL provided as single formulation in vivo, suggesting potential for meaningful clinical therapeutic impact.
A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults
Authors: Iain Templeman, Harry Alex Smith, Enhad Chowdhury, Yung-Chih Chen, Harriet Carroll, Drusus Johnson-Bonson, Aaron Hengist, Rowan Smith, Jade Creighton, David Clayton, Ian Varley, Leonidas Georgios Karagounis, Andrew Wilhelmsen, Kostas Tsintzas, Sue Reeves, Jean-Philippe Walhin, Javier Thomas Gonzalez, Dylan Thompson, James Alexander Betts
Journal: Science Translational Medicine (2021)

Daily energy restriction more effectively reduces body fat content than alternate-day fasting, with no evidence of fasting-specific health benefits.
Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory neuroblastoma.
Authors: Jia Zhu, Zijun Zhen, Juan Wang, Tingting Chen, Suying Lu, Feifei Sun, Junting Huang, Yi Que, Lian Zhang, Yizhuo Zhang, Xiaofei Sun
Journal: Journal of Clinical Oncology (2021)

e22009 Background: The combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed or refractory neuroblastoma (NB). Methods: Forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m 2 i.v. day 1), irinotecan (50 mg/m 2 /day i.v. days 1–5) and temozolomide (100 mg/m 2 /day p.o. days 1–5) (VIT) during the period 2011–2019. All toxicities were documented. Results: A total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade III or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. Overall objective response rates to VIT combination for patients with mediastinum, bone marrow/bone, lymph node, abdomen and brain involvement were 100.0%, 80.0%, 77.8%, 50.0%, 42.9%, respectively. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them. Conclusions: The shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.[Table: see text]
Abstract 10965: Anatomical Relationship Between the Right Coronary Artery and Cavo-tricuspid Isthmus: An Intracardiac Echocardiography Study
Authors: Carola Gianni, Gökoglan Yalçin, Sanghamitra Mohanty, Chintan Trivedi, Amin Al-Ahmad, J D Burkhardt, G J Gallinghouse, Rodney P Horton, Patrick M Hranitzky, Javier E Sanchez, Luigi Di Biase, Andrea Natale
Journal: Circulation (2019)

Introduction: Cavo-tricuspid isthmus (CTI) ablation is commonly performed for typical common atrial flutter. Although rare, complications might occur and it’s important to be aware of the anatomy t...
Type of tissue biopsy and outcomes in diffuse large B-cell lymphoma (DLBCL).
Authors: Sanjal Desai, Raphael Mwangi, Rebecca L. King, Matthew J. Maurer, James Robert Cerhan, Andew L. Feldman, Thomas Matthew Habermann, Eric Mou, Umar Farooq, Carrie A. Thompson, Yucai Wang, Thomas E. Witzig, Grzegorz S. Nowakowski
Journal: Journal of Clinical Oncology (2021)

e13569 Background: Progress in understanding the molecular biology of DLBCL has led to development of complex molecular classifications that rely on sequencing methods. These molecular clusters are defined by activation of distinct pathways and may aid in selecting targeted therapy. In the molecular era, tissue requirements in clinical trials have increased to ensure sufficient tissue for molecular testing, potentially resulting in bias for enrollment of patients with larger excisional biopsies (EB). We examined the impact of tissue biopsy method on outcomes of DLBCL in a prospective observational study. Methods: Consecutive adult patients with DLBCL within 9 months from their initial diagnosis were enrolled into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). Demographics, clinical variables, type of tissue biopsy (EB vs. core needle biopsy (CNB)) for initial diagnosis and initial treatment were recorded at baseline. Pts were contacted every 6 months from the date of diagnosis for first 3 years and then annually thereafter. Study objectives were event free survival (EFS) and overall survival (OS) by tissue biopsy method. Results: A total of 1061 patients with newly diagnosed DLBCL, from 2002 to 2015, were included. The table lists baseline characteristics of the cohort. 593 (56%) pts underwent EB and 468 (44%) underwent CNB for initial diagnosis. A significantly higher proportion of patients receiving CNB had performance status &gt;=2, advanced stage, high risk disease by international prognostic index (IPI), abnormal lactate dehydrogenase. Median time from diagnosis to treatment initiation (DTI) was significantly shorter in the CNB group (13 days) than EB group (19 days). 2-year EFS (60% vs 75%, HR 0.75 (0.6-0.9), p &lt;0.01) was significantly lower in CNB than EB group. There was a trend towards lower OS (75% vs 80%, HR: 0.8 (0.6-0.95), p =0.049) in CNB than EB group. Conclusions: Patients undergoing CNB are more likely to have higher risk disease, shorter DTI and survival compared to those undergoing EB. A need for large amount of diagnostic tissue in biomarker driven clinical trials may result in disproportional exclusion of high risk DLBCL pts who have inferior outcomes after standard treatment and could potentially benefit from novel agents, resulting in overperformance of the control arm. The need for tissue must be carefully balanced against resulting selection bias.[Table: see text]
Experience of low-intensity LED radiation (LILEDR) in combination treatment of radiation-induced rectal injuries.
Authors: Olga G. Rodionova, Vitaliy I. Voshedskiy, Pavel G. Sakun, Elena A. Sheiko, Marina A. Gusareva, Tatiana G. Chalabova, Alla V. Pustovalova, Anna A. Solntseva, Vladimir A. Dontsov, Ekaterina O. Vasilieva, Sergey N. Kabanov, Elena A. Karnaukhova, Yulia N. Krokhmal, Stanislav G. Vlasov
Journal: Journal of Clinical Oncology (2021)

e17514 Background: Malignant pelvic tumors account for more than 25% of cancer incidence in Russia. Radiation therapy is the most common treatment for such patients; however, 10-15% of patients develop radiation-induced complications of the pelvic organs, and more effective treatments are required to manage these complications. Methods: The study included 30 patients with cervical cancer T3NхM0 after combination treatment. 7-10 months after combined radiation treatment (total radiation dose to the primary focus 80 Gy), patients developed erosive ulcerative radiation rectitis (RTOG grade 1 and 2). Patients were divided into 2 groups: main group (n = 15) – conservative treatment combined with LILEDR. Each course included 10 LILEDR sessions, the red spectrum λ = 640 nm on the cubital vein projection (exposure time 5 minutes, dose 6.86 J/cm2) and locally on the ulcerated zones (exposure time 3 minutes, dose 3.96 J/cm2). Patients received 2 LILEDR courses with a 1-month interval. The control group received only conservative therapy. Results: Main clinical manifestations of rectitis (tenesmus, bloody mucous discharge) disappeared in the main group already on the 3-4th day of the first course, epithelialization of ulcerative defects occurred in a shorter period of 7-10 days. Soft superficial scars not causing rectal stenosis formed at the site of the ulcer by the end of LILEDR courses. The control group showed long periods of the ulcer epithelialization up to 30 days, late remission and a lingering recurrent character of the disease. Conclusions: LILEDR in combination with the main conservative therapy allows rapid managing with the clinical symptoms of radiation rectitis and regression of disorders developed after the complex treatment, which improves the quality of life of patients and shortens the rehabilitation period.
Stage migration in breast cancer: Better detection or semantics in staging?
Authors: Leah Elson, Nadeem Bilani, Hong Liang, Elizabeth Blessing Elimimian, Diana Saravia, Zeina A. Nahleh
Journal: Journal of Clinical Oncology (2021)

e18800 Background: As oncology treatment has evolved to become more individualized, prognostic rationale has also undergone important changes. In breast cancer, disease staging was historically based upon anatomic features of the primary tumor, in combination with involvement of adjacent/distant tissues. However, as the understanding of molecular/genomic involvement became more advanced, staging definitions were redefined to incorporate receptors, histologic grade, and genetic expression. In this analysis, we use autoregressive integrated moving average (ARIMA) forecasting to understand how AJCC updates to prognostic definitions have contributed to stage migration, and to comment on whether better detection, or definitional changes, may be responsible for the increasing incidence in early stage breast cancer. Methods: In this time series forecast, ARIMA models, per stage (early: stage I/II vs. late: stage III/IV) were constructed based on 2004-2016 historic breast cancer incidence rates, as reported by the NCDB. Multiple models were generated, using differing autoregressive parameters; the most predictive model was chosen using the lowest Bayesian Information Criteria (BIC), and mean absolute percentage error (MAPE) to ensure best fit. Similar methodology has already been published to predict prostate cancer incidence. The best fit models were applied to forecast annual incidence, in the NCDB, in 2017. These data were compared to the real-world data captured in 2017. Statistics were performed using modeling systems in SPSS, version 27. Results: n=1,661,971 cases were included for these models, and 12 years of pre-AJCC updated NCDB breast cancer data were used. Using ARIMA modeling, best fit, stationary averages were identified, with autoregressive and difference terms which contributed to the lowest BIC, and MAPE &lt; 5%, for both models. The best fit models forecasted 2017 incidence, by stage, without AJCC updates to staging criteria, and this data is compared to actual 2017 incidence with current updated AJCC 8 th staging criteria (Table). Conclusions: During 2017, the first year of AJCC staging updates, there was an observed decrease in late stage diagnoses, and increase in early stage diagnoses, when compared with incidence rates that were forecasted using the old, anatomic AJCC criteria. Therefore, part of the stage migration noted may be a product of staging semantics, using updated definitions. Confirming appropriate improvement in long-term outcomes, based on new staging would be helpful. It is also important for clinicians and public health officials to bear this in-mind when interpreting epidemiologic data, for allocating resources, as shifts in staging may be a product of guideline changes, and not necessarily screening efficacy or early detection only.[Table: see text]
Pulmonary fungal infections in acute leukemias and aggressive lymphomas: Analysis of the United States National Inpatient Database.
Authors: Oluwatobi Ozoya, Adaeze Ayuk, Odunayo Lawal, Josephine Emole
Journal: Journal of Clinical Oncology (2021)

e19042 Background: For patients undergoing intensive chemotherapy, pulmonary fungal infections (PFI) represent a major cause of morbidity and mortality. Our study examined predictors and outcomes of PFI in hospitalized patients (pts) with hematological malignancies in the current era of antifungal prophylaxis for high-risk patients. Methods: Using the 2018 National Inpatient Sample (NIS) database, we conducted a retrospective study of hospitalized pts aged ≥ 18 years, with acute leukemias or aggressive lymphomas. Hospitalizations were selected using International Classification of Disease, Tenth Revision (ICD-10) codes for leukemias, lymphomas and PFI (candidiasis, aspergillosis, cryptococcus, and mucormycosis). Demographics, comorbidities, and outcomes were compared between pts with and without PFI using Chi-squared test. Multivariable logistic regression was performed to explore predictors associated with PFI. Results: Of 205,525 hospitalizations that met the inclusion criteria, PFI was diagnosed in 1635 (0.8%). Frequent infections were aspergillosis (80%) and candidiasis (11%). Pts with acute myeloid leukemia (AML) accounted for 64% of all PFI. The PFI group, compared to non-PFI, were more likely to be non-Caucasian (39% vs 32%, p&lt;0.05), have higher Charlson comorbidity index (CI) [64% vs 55%, p&lt;0.01], longer mean length of stay (23 vs 9 days, p&lt;0.001), and more likely to have AML (64% vs 33%, p&lt;0.001). Pts with PFI had higher odds of acute respiratory failure, severe sepsis, and in-hospital mortality. Mortality rates for PFI and non-PFI group were 17% and 6% respectively (p&lt;0.001). Predictors associated with PFI were Hispanic or Native American race, Charlson CI ≥ 3, neutropenia, malnutrition, bone marrow transplant status and diagnosis of AML (Table). Conclusions: Our study identified clinical variables that predicted for PFI in patients with acute leukemias and aggressive lymphomas. Pts with these high-risk characteristics should get priority for close surveillance, mold-specific prophylaxis, and antifungal therapeutic drug monitoring. Selected predictors associated with pulmonary fungal infections. Adjusted Odds ratio (OR).[Table: see text]