tbuckley/cabot-search huggingface dataset:
Postoperative concurrent chemoradiotherapy plus apatinib in patients with malignant glioma: From one single research institute.
Authors: Zhichao Fu
Journal: Journal of Clinical Oncology (2021)

e14049 Background: Antiangiogenic therapy is a choice for the treatment of malignant glioma patients. Vascular endothelial growth factor receptors (VEGFRs) inhibitors block the new formation around the tumor and cut down the supply of oxygen, nutrients and metabolic waste, so that the tumor is hard to proliferate and metastases.Objective To explore the effectiveness and safety of apatinib in patients with malignant glioma. Methods: This is a retrospective and prospective case-control study conducted in a single center. Patients with new postoperative pathological diagnosis of malignant glioma (WHO IIĨIV) were selected. Enrolled patients received concurrent chemoradiotherapy (radiotherapy60Gy/30f/6w; TMZ75mg/m 2 ,po,d1-d42) combined with or without apatinib (250mg, po, d1-d42,qd), then maintain 6 cycles(28 days a cycle)of TMZ chemotherapy(200mg/m 2 , d1-d5) .The primary endpoints were investigator-assessed progression free survival (PFS) and the grade of peritumoral brain edema (PTBE) evaluated by edema index(EI). The secondary endpoint was investigator-observed overall survival. Hazard ratios of PFS and OS were compared between trials in a Cox proportional hazards model. Results: Between October 2017 and March 2019, 47 patients (23 in apatinib group and 24 in control group) were enrolled in this study.The median age was 47 years in apatinib group (range from 19 to 73 years) versus 48 years in control group(range from 24 to 68 years). The results elucidated that the median PFS of the apatinib group was longer than that of the control group, but the difference was not statistically significant.(9.26 months vs. 6.69 months; hazard ratio, 0.65; 95% confidence interval [CI], 0.31 to 1.25; P=0.1906).As for median overall survival, the results of two groups were almost similar.(14.42 months vs. 14.36 months; hazard ratio, 0.74; 95%CI, 0.36 to 1.52; P=0.4036). Cox multivariate regression model revealed that apatinib was not a prognostic factor for PFS and OS (P&gt;0.05). As of the statistical date, there were 7 patients with stable disease (SD), 16 patients with progressive disease (PD) and 13 patients with death in the apatinib group; whereas in the control group, the condition of 3 patients remained stable, the other 21 patients had progressed, with 19 unfortunate deaths. The grade of PTBE was improved in 15 of 23 patients (65.2%, 5/23 patients used corticosteroids) in apatinib group versus 6 of 24 (25%, 14/24 patients used corticosteroids) in control group. There was no grade 3 or 4 adverse events and serious adverse events. Conclusions: Compared with control group, apatinib group still improved mPFS by 2.57 months in patients with malignant glioma, but there was no statistical significance (P&gt;0.05).The results also indicated that apatinib conferred a significant beneficial effect on PTBE improvement. All occurred adverse reactions were moderate and controllable. Clinical trial information: NCT03567135.
Relative dose intensity (RDI) of nab-P in gem+nab-P combination in pancreatic cancer treatment and the prognostic role of baseline NLR.
Authors: Hrishi Varayathu, Lincil Kurian, Anju Murugan, Hephzibah Sara Mathew, Sonia Rani, Beulah Elsa Thomas, Lalram Sangi, Shalaka Somayaji, Smruthy Ann Mathew, Sunny Kumar Gupta, Priyank Tripathi, Suhail Sayeed Mufti, Radheshyam Naik, Basavalinga Sadasivaiah Ajaikumar
Journal: Journal of Clinical Oncology (2021)

e16269 Background: Combination of Gem+Nab-P is considered as a dose intense regimen which exhibits synergistic cytotoxic activity and equally effective in increasing survival as FOLFIRINOX regimen in pancreatic cancer. However, number of patients who tolerates such dose intense regimen is found to be less in Indian population. The importance of maintaining optimum RDI is well-known however a low RDI may reflect a poor tolerability. Therefore, the present study aimed to identify desired relative dose intensity and explore the potential of baseline NLR as a prognostic biomarker. Methods: A retrospective chart review was performed of 26 patients with a median age of 65.5 years who received this drug combination either as first-line or second-line treatment for pancreatic adenocarcinoma at a single institution. Treatment outcome was measured using overall survival and toxicities were classified according to CTCAE guidelines. The thresholds for RDI of Gem and Nab-P, and baseline NLR cut-off for predicting survival was calculated by constructing ROC curves. Results: Median overall survival was 11.5 months. Median RDI of Gem and Nab-P was found to be 79% (30-94) and 71% (39 –114) respectively. We estimated a RDI cut-off of 67% in Nab-P and 68% in Gem and observed a statistically significant favorable outcome in patients who received Nab-P with RDI &gt; 67% ( p-0.021). No significant relationship of Gem RDI with outcome was observed. Median overall survival was found to be higher in patients with a baseline NLR &lt; 2.35, patients on D1, D8, D15 treatment regimen and those who received Nano particle bound paclitaxel. Complete assessment of study subjects are enlisted in the table. Grade 3 neuropathy, fatigue, and hyponatremia were reported in 2, 5 and 4 patients respectively. Grade 2 skin rashes and neuropathy were seen in 3 patients each. Conclusions: Our study concludes that tolerability of Gem+Nab P is a concern and it is expected to exhibit a durable response only if it achieves an optimum RDI of Nab-P. The study indicates varied efficacy in different pharmaceutical preparations of paclitaxel favoring the use of nano-particle formulations. The study also indicates that baseline NLR is an important prognostic biomarker in pancreatic cancer[Table: see text]
m=6A修飾は造血発生時の内因性二本鎖RNAの形成と有害な自然免疫応答を阻止する【JST・京大機械翻訳】
Authors: Gao Yimeng, Vasic Radovan, Song Yuanbin, Teng Rhea, Liu Chengyang, Gbyli Rana, Biancon Giulia, Nelakanti Raman, Lobben Kirsten, Kudo Eriko, Liu Wei, Ardasheva Anastasia, Fu Xiaoying, Wang Xiaman, Joshi Poorval, Lee Veronica, Dura Burak, Viero Gabriella, Iwasaki Akiko, Fan Rong, Xiao Andrew, A Flavell Richard, Li Hua-Bing, Tebaldi Toma, Halene Stephanie
Journal: Immunity (2020)
Interprofessional care team practices and perspectives on immuno-oncology (IO) therapies for metastatic non-small cell lung cancer (mNSCLC): Insights from a nationwide survey.
Authors: Breanne Y. Farris, Anne Jacobson, Jeffrey D. Carter, Cherilyn Heggen, Mark A. Socinski
Journal: Journal of Clinical Oncology (2021)

e21147 Background: Appropriate molecular testing, biomarker-directed treatment selection, and management of immune-related adverse events (irAEs) are essential best practices for managing patients with mNSCLC who are eligible for IO therapies. Identifying real-world challenges among mNSCLC care teams is necessary to inform educational interventions that support optimal care. Methods: From 10/2020 to 01/2021, 75 health care professionals (HCPs) who treat mNSCLC completed surveys assessing practice patterns, challenges, and confidence related to the use of IO therapies. To reflect current real-world practice across treatment settings, surveys were administered at 10 clinics nationwide and through a large oncology practice network. Results: Participants represented the interprofessional mNSCLC care team: oncologists (50%), primary care physicians (23%), advanced practice professionals (13%), and nurses (13%). Nearly one-third reported that PD-L1+ mNSCLC presented greater management challenges than other mNSCLC sub-types. Regarding patients who are eligible for IO therapies, the most commonly reported challenges were applying pathology results to treatment decisions (29%), differentiating IO therapies (19%), and managing irAEs (19%). Case-based questions revealed gaps in care relative to guidelines: 65% incorrectly identified which patients should be tested for PD-L1; 49% failed to identify the most appropriate IO regimen based on case details; and 65% failed to identify an inappropriate strategy for managing mild irAEs (Table). Further, HCPs reported inappropriate reasons to exclude patients from IO therapy and suboptimal use of supportive care measures. Confidence gaps echoed these challenges; most HCPs reported less-than-high confidence in their ability to apply molecular test results to treatment decisions (80%), differentiate IO therapies based on PD-L1 expression (65%), or coordinate irAE care (85%). Conclusions: In current real-world practice, mNSCLC care teams report challenges in biomarker testing and interpretation; differentiation of IO therapies based on patient, disease, and treatment factors; and irAE management. These identified gaps represent key opportunities for future interventions to improve mNSCLC care. [Table: see text]
CAUSE OF LIVER INJURY IN 5,642 JAPANESE TYPE 2 DIABETES MELLITUS PATIENTS - NATIONWIDE STUDY
Authors: Park H, Nakamura N, Nakatou T, Tanaka N, Okanoue T, Yasui K, Kawata S, Kohgo Y, Takamura T, Ueki K, Uto H, Shima T
Journal: Hepatology (2011)
EMBR-20. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA
Authors: Alberto Delaidelli, Gian Luca Negri, Que Xi Wang, Albert Huang, Simran Sidhu, Joyce Zhang, Yue Zhou Huang, Betty Yao, Sofya Langman, Andrii Vislovukh, Volker Hovestadt, Michael Taylor, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common pediatric intracranial tumor and leading cause of childhood related cancer deaths. Group 3 affiliation and genetic amplifications of the MYC oncogene are predictors of adverse outcome in MB, underscoring a dire need for novel and more effective therapeutic approaches. The let-7 family of small non-coding RNAs (miRNAs) is known to inhibit tumor progression and regulate metabolism by targeting and degrading several cellular mRNAs, including MYC. Indeed, let-7 miRNAs are frequently repressed in several cancer types, including in MYC-driven MB. We previously reported that the mRNA translation elongation regulator eukaryotic Elongation Factor-2 Kinase (eEF2K) is a pivotal mediator of cancer cell adaptation to nutrient deprivation. In the current work, we identified a potential binding site for let-7 miRNAs on the eEF2K 3’ untranslated region (UTR). In addition, eEF2K mRNA and let-7 miRNA expressions negatively correlate in MB, suggesting a potential regulation of the former by the latter. Let-7 miRNAs transfection decreases eEF2K mRNA and protein levels (by ~40–50%). Down-regulation of luciferase activity by let-7 miRNAs is impaired upon mutation of the let-7 binding site on the eEF2K 3’UTR. Inhibition of eEF2K significantly reduces survival of MYC-amplified MB cell lines under nutrient deprivation, altering their mRNA translation rates. Knockout of eEF2K increases survival of MYC-amplified MB xenografts when mice are kept under calorie restricted diets. We conclude that let-7 miRNAs degrade the eEF2K mRNA by binding to its 3’UTR, indicating that let-7 repression in MYC-driven MB is partially responsible for increased eEF2K levels. Moreover, the let-7-eEF2K axis constitutes a critical mechanism for MYC-driven MB adaptation to acute metabolic stress, representing a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs, as eEF2K activity appears critical under metabolic stress conditions.
Event free survival in adults with relapsed ALL who underwent front-line therapy with CALGB 10403.
Authors: Suravi Raychaudhuri, Ilana Yurkiewicz, Gabriel N. Mannis, Bruno C. Medeiros, Steve E. Coutre, Lori S. Muffly, Michaela Liedtke
Journal: Journal of Clinical Oncology (2021)

e19005 Background: CALGB 10403 is a pediatric-inspired ALL regimen that has recently been shown to have improved survival rates in adolescents and young adults with ALL when compared to historical outcomes with traditional adult ALL regimens (Stock et. al, 2019). Methods: This is a retrospective cohort study of ALL patients who received induction CALGB 10403 at Stanford University (both on and off trial), achieved CR1, and subsequently relapsed. Primary outcome of interest was event free survival from time of diagnosis. Events were defined as relapse or death. Secondary outcomes were overall survival and event free survival from first relapse. Patients were censored at time of last clinical follow up. Results: 25 patients met inclusion criteria and received front-line CALGB 10403 from April 2010 to September 2018. At the time of initial diagnosis median age was 30 years (range 18 – 39 years). 68% of patients were male. 48% of patients were overweight and 40% were obese. 76% of patients had precursor B cell ALL while 24% had T cell ALL. 12% had CNS disease at diagnosis. 36% of patients had WBC greater than 30k. 12% of patients had CRLF2 rearrangement. 12% of patients were MRD positive after first induction. 20% of patients received rituximab. Median event free survival time from diagnosis was 20 months (range 3 – 79 months) and median overall survival time was 53 months. Blinatumomab was the most common salvage therapy after 1 st relapse, followed by inotuzumab. 15 patients (60%) achieved CR2, of which 4 (27%) were MRD positive after 2 nd induction. 15 patients (60%) went to HSCT. Of the patients who achieved CR2, 8 relapsed for a second time. Median event free survival time after first relapse was 23 months. Survival 1 year after relapse was 60%. 11 of the 25 patients were alive at last follow up. Median follow up time of survivors was 6 years. Conclusions: This is a descriptive retrospective cohort study of adult patients in a real world setting who received CALGB 10403 induction and subsequently relapsed. Compared to other studies of relapsed ALL patients who were induced with traditional chemotherapy (Fielding et. al, 2007), survival 1 year after relapse was much higher (60% vs. 22%). As CALGB 10403 becomes an increasingly common induction regimen for AYA and adults with ALL, further outcomes study is required.[Table: see text]
Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.
Authors: Zhongxing Bing, Weiran Wang, Danhua Wang, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]
HGG-32. ONC201 AND ONC206 TARGET TUMOR CELL METABOLISM IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PRECLINICAL MODELS
Authors: Justyna M Przystal, Chiara Cianciolo Cosentino, Sridevi Yadavilli, Jie Zhang, Sandra Laternser, Erin R Bonner, Matt Biery, Nicholas A Vitanza, Carl Koschmann, Jason Cain, Sebastian M Waszak, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2021)

Abstract Diffuse midline gliomas (DMGs) remain incurable cancers and new treatments are urgently needed. One promising new therapeutic avenue for these cancers is targeting of metabolic vulnerabilities including a heightened dependence on mitochondrial metabolism. We and others have shown that the oral, brain-penetrant imipridone drugs ONC201 and ONC206 target mitochondrial metabolism in cancer cells. In particular, ONC201 and ONC206 hyper-activate the mitochondrial protease ClpP, impair mitochondrial oxidative phosphorylation (OXPHOS), activate the integrated stress response (ISR) signaling pathway, and induce apoptosis in DMG preclinical models. We validated ClpP as a key target of ONC206 by showing that CRISPR/Cas9-mediated CLPP knockout significantly decreased ONC206 sensitivity in DMG cells. We further showed that imipridone-mediated ClpP activation resulted in significant degradation of the chaperone protein ClpX. Moreover, ONC201 and ONC206 treatment inhibited mitochondrial respiration, decreased mitochondrial membrane potential and triggered extensive mitochondrial structural damage, including disintegration of mitochondrial cristae. Time-course RNA sequencing of five DMG cell lines treated with ONC201 and ONC206, alone or in combination, revealed robust ATF4 and CHOP upregulation, indicating potent activation of ISR signaling. Notably, ATF4/CHOP upregulation was strongest in ONC201/6 combination-treated cells, indicating synergy between the two drugs. We further explored drug combinations by testing ONC201 together with ONC206, Panobinostat, JQ1, and Osimertinib to identify synergistic combination treatments. The strongest synergistic effect was found over a broad IC50 range for ONC201 and ONC206. Finally, we showed that ONC201 and ONC206 significantly prolonged survival of mice bearing brainstem DIPG xenografts. Ongoing studies include assessment of the in vivo efficacy of ONC201 and ONC206 across different CNS tumor models, as well as investigation and validation of clinically relevant biomarkers of response to treatment. In summary, our preclinical data strongly support the utility of the mitochondrial targeting agents ONC201 and ONC206 for the treatment of DMG and other malignant brain tumors.
A pilot study of physical activity in newly diagnosed elderly patients with multiple myeloma.
Authors: Adam F Binder, Bryan Spinelli, Rebecca Melillo, Nicole Crane, Laura D'Adamo, Mary K Martinelli, Ubaldo Martinez-Outschoorn, Meghan Butryn
Journal: Journal of Clinical Oncology (2021)

e20027 Background: Compared to a baseline normative population, patients with multiple myeloma (MM) have decreased physical function[1]. Studies have revealed that sarcopenia[2, 3], decreased performance status[4], and poor performance on biometric testing[3, 5] predicts worse survival in patients with advanced, incurable malignancies. Physical activity (PA) has been shown to mitigate these effects and in some cases improve cancer specific survival [6-9]. However, there is a need for further research in this area for patients with hematologic malignancies. Here in we describe the results of a pilot study to assess a physical activity intervention in elderly patients with newly diagnosed multiple myeloma. Methods: We designed a single arm, feasibility study utilizing physical and behavioral therapy interventions to help participants adhere to a prescribed exercise program. Eligible patients (age ≥65 years old) were recruited from the multiple myeloma treatment clinic. Baseline, 3-month and 6-month assessments occurred. The intervention included both text messaging and video visits with behavioral coaches and physical therapists to monitor activity levels, review and modify exercise plans, , and enhance motivation and self-efficacy. Our primary aim was to establish the feasibility of recruitment, enrollment, and adherence of the exercise intervention. Our secondary objective was to evaluate changes in fitness (6 minute walk test, grip strength, and the Short Physical Performance Battery). Results: Between 11/18/2019-03/04/2020, 9 participants enrolled on the study (goal of 20). New enrollment was halted due to the COVID-19 pandemic. Median age of the participants was 70 (range 65-86). Six (67%) were female. Eight participants (89%) completed the 6-month intervention. Participants completed 97.8% of the scheduled visits. At 3 and 6 months there was a mean change of moderate/vigorous activity of 26.0% (SD 89.6%) and -0.5% (SD 56.4%) respectively. At 3 and 6 months there was a mean change in step count per day of -5.1% (SD 25.3%) and -1.3% (SD 32.2%) respectively. Overall fitness was preserved over the 6-month period. Conclusions: Prior to COVID-19 pandemic, the study was on track to meet feasibility endpoints of recruitment, enrollment, and retention. The primary endpoint of increasing physical activity was not met. However, adults in our region experienced a 20-30% reduction in physical activity during the pandemic [10]. In the target population, reductions in the absence of intervention may have been even greater, given their pronounced vulnerability to COVID-19 complications. Thus, the true benefits of the intervention may have been difficult to detect during this period. Lack of a control arm is a limiting factor in making further conclusions about the potential benefits of our intervention.
Team huddle, education and infection screening as effective tools in continuing cancer care delivery during the peak of COVID-19 pandemic in 2020 in the Bronx, NY: Experience from a public teaching hospital.
Authors: Surabhi Pathak, Roshni Narurkar, Mohammed Hasan Khan, Bei Jiang, May Nyein Chann Soe, Monica Muppidi, Caroline Hwang
Journal: Journal of Clinical Oncology (2021)

e13500 Background: COVID-19 pandemic has affected healthcare delivery, particularly in the hard-hit areas. During the peak of COVID-19 pandemic crisis in the New York city, our outpatient oncology infusion center, located within a public teaching hospital in the South Bronx remained active. We implemented twice daily team huddle, staff and patient education, and infection screening tools and modified treatment plans based on social, personal and disease related factors. We evaluate the effectiveness of the above strategies in timely delivery of critical oncological care. Methods: Patients treated from the March 1, 2020 to the May 8, 2020 were included. De-identified data from medical charts were analyzed using IBM SPSS Version 27.0. Bivariate logistic regression analysis was applied to identify factors associated with COVID-19. Results: In total, 170 patients were treated in 576 visits. Median age was 60.7 years, 44% Hispanic and 41% Black, median Charlson Comorbidity index (CCI) was 6.6. Fifty percent received cytotoxic chemotherapy, 44% targeted therapies and the remaining received immune-checkpoint inhibitors. Of the 170 patients, six developed severe COVID-19 requiring hospitalization. Their median age was 63 years with average of 10.5 days from infusion center visit to COVID-19 and median CCI score was 9, higher than the rest of the cohort. Two patients died, 3 made complete recovery, 1 enrolled in hospice. Two patients contracted mild COVID-19 managed in the outpatient setting. Diabetes mellitus was associated with severe COVID-19 [OR: 25.9 (95%CI: 1.3-519, p=0.03)]. Age, gender, type of cancer and oncological treatment, smoking, CCI, growth factor support, nursing home residence, statin use were not associated with risk of developing severe COVID-19 Conclusions: Cancer treatment in the outpatient setting using an approach focused on careful patient selection, infection prevention strategies and strong team communication is feasible and allows for continuity of critical oncological care. Receipt of cancer directed therapy was not associated with higher risk for infection compared to risks associated with community-based transmission.. In communities with high community-based transmission, careful selection of patients for oncological based treatment is paramount.