tbuckley/cabot-search huggingface dataset:
Preclinical evaluation of an engineered oncolytic herpes simplex virus for pediatric osteosarcoma.
Authors: Sara Hutchins, Raoud Marayati, Laura V. Bownes, Colin H. Quinn, Jerry E. Stewart, Gregory K. Friedman, Jennifer M. Coleman, G. Yancey Gillespie, James M. Markert, Elizabeth A. Beierle
Journal: Journal of Clinical Oncology (2021)

10040 Background: Osteosarcoma is the most common primary bone tumor in children. For those with relapsed or metastatic disease, the five-year survival rate is approximately 20%, and survivors often suffer from long-term disability from current therapies. The high morbidity and mortality for these patients highlight a great need for improved therapies. One such novel therapeutic approach is oncolytic herpes simplex virus (oHSV) immunovirotherapy. We previously demonstrated that M002, an engineered oHSV that contains deletions of the neurovirulence gene preventing infection of normal cells, effectively infects and kills neuroblastoma and rhabdomyosarcoma. Currently, similar oHSVs are being evaluated in early phase clinical trials for children and adults with relapsed or refractory brain tumors. To date, there has been limited investigation of oncolytic virotherapy in osteosarcoma. Thus, we sought to examine the ability of oHSV, M002, to infect and kill osteosarcoma cells in vitro. Methods: We evaluated two long-term passaged human osteosarcoma cell lines, U2-OS and MG-63. Flow cytometry was used to assess baseline expression of oHSV viral entry-mediated receptors (CD111, CD112, syndecan, HVEM). Single and multi-step viral recovery experiments measured virus infectivity and replication. Cells were infected with increasing multiplicity of infection (MOI) of M002, and cell viability was measured 72 hours post-infection via alamarBlue assay. Results: Both MG-63 and U2-OS cells expressed HSV entry molecules (Table) including high levels of the primary HSV entry molecule CD111. Single step virus recovery experiments in MG-63 cells infected at a MOI of 10 plaque-forming units (PFU)/cell demonstrated a 3 log-fold increase in virus titer from 12 to 24 hours post-infection. For multi-step experiments, MG-63 cells were infected with a MOI of 0.1 PFU/cell; viral replication significantly increased from 1.1x10 3 PFU at 6 hours post-infection to 3.8x10 10 PFU at 72 hours post-infection. M002 successfully decreased osteosarcoma viability with a lethal dose in 50% of cells (LD 50 ) of 2.82 and 0.67 PFU/cell for MG-63 and U2-OS cells, respectively. Notably, at a virus MOI of 5 PFU/cell, viability was decreased by 64% ± 0.1% (p&lt;0.001 vs control) in MG-63 cells and 96% ± 0.1% (p&lt;0.001 vs control) in U2-OS cells. Conclusions: MG-63 and U2-OS osteosarcoma cells express high levels of HSV entry receptors. Virus recovery experiments demonstrated the ability of M002 to infect cells and replicate over time. The viability of osteosarcoma cells significantly decreased following infection with M002. These data suggest M002 may be a promising novel therapeutic option for patients with osteosarcoma and warrant further investigation for translation to the clinical setting.[Table: see text]
Prediction of clinical efficacy by plasma concentration of apatinib in patients with solid tumor.
Authors: Hongtao He, Lixing Wang, Guanglei Huang, Rongfeng Liu, Meng Yuan, Penghui Xing, Baoen Shan, Jian Shi
Journal: Journal of Clinical Oncology (2021)

e15000 Background: To explore the correlation between plasma concentration of apatinib and clinical efficacy. Methods: 42 patients were enrolled. Plasma specimens of all patients were collected. At 7:40 am, fasting blood was drawn as plasma trough concentration (C trough ). At 8 am, apatinib mesylate (APA-M, 250mg qd) was orally administrated. At 11 am, venous blood was drawn as plasma peak concentration (C peak ). Each patient has C trough and C peak samples. A total of 84 plasma samples were obtained. The concentration of APA-M in plasma was determined by UPLC-MS/MS. Results: 1) 42 patients were evaluable. Treatment response was assessed by RECIST1.1. 2 patients achieved complete response (CR), 16 partial response (PR), 12 stable disease (SD) (tumor shrinks), 5 SD (tumor enlargement), 7 progressive disease (PD). Objective response rate (ORR) was 42.9% (18/42) and disease control rate (DCR) was 83.3% (35/42). 2) On day 1 and 456 after oral APA-M from different patients, median trough concentration (C trough median ) was 264.38 ng/ml (1.18 ng/ml-918 ng/ml), and median peak concentration (C peak median ) was 543.61 ng/ml (71.11 ng/ml-1609.4 ng/ml), respectively. 3) The C trough median in patients with CR, PR and SD (tumor shrinks) was significantly higher than that SD (tumor enlargement) and PD ( P＜0.05). There was significantly difference between CR and PR with SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR ( P＞0.05). (Table) 4) The C peak median in patients with CR, PR, SD (tumor enlargement) and PD was significantly higher than that SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR with SD (tumor enlargement) ( P＞0.05). (Table). Conclusions: The plasma C trough of Apatinib can predict the clinical efficacy of patients with solid tumor. Perspective clinical studies with adequate sample size are required to validate our results. [Table: see text]
A clinically acceptable strategy for sensitizing anti-PD-1 treatment by hypoxia relief
Authors: Mengshi Jiang, Bing Qin, Lihua Luo, Xiang Li, Yingying Shi, Junlei Zhang, Zhenyu Luo, Chunqi Zhu, Guannan Guan, Yongzhong Du, Jian You
Journal: Journal of Controlled Release (2021)
Feasibility and patient perception of a web-based exercise program during COVID pandemic in breast and ovarian cancer patients.
Authors: Marcos Iglesias Campos, Bella Pajares, Cristina Roldán Jiménez, Begona Jimenez, Emilio Alba, Antonio Cuesta Vargas
Journal: Journal of Clinical Oncology (2021)

e13623 Background: Current literature shows us that therapeutic exercise has multiple benefits in oncology patients, such as improvement in quality of life or a reduction in cancer-related fatigue. Furthermore, given the risk of obesity, both exercise and diet play a key role in recovery from cancer. As a consequence of the COVID-19 pandemic, oncology patients present more difficulties to attend programs as they are considered a risk population, so new online exercise programs should be developed to ensure that patients take advantage of them in the post-COVID era. The main objective was to study patient´s perspectives and the feasibility of a web-based tailored and supervised therapeutic exercise program during COVID pandemic. Methods: A prospective study was performance on patients recruited from the Medical Oncology Unit of the Hospital Virgen de la Victoria, Malaga. Participants were between 18 and 65 years old and diagnosed of early resected breast cancer after finishing chemotherapy (CT) or metastatic ovarian (MOC) or breast cancer (MBC) with or without active treatment. Patients had had a good performance status (PS) with no prior cardiovascular history, and they were excluded if they were not used to online technologies. The duration of the program was 3 months, twice a week, delivered by a physiotherapist and a nutritionist. At the end of the program, women were asked 9 questions about their perspectives on the program. All of them signed informed consent. Results: 17 breast cancer survivor (BCS), 10 MBC and 3 MOC patients were initially recruited. From 30 patients recruited, 5 BCS did not started the program because of clinical contraindication and 5 patients left due to personal issues. 15 out of the remaining 20 completed the survey. All of patients reported that the program had contributed to improve their mood during the pandemic due to issues such functional ability, feeling better or less asthenia, and serving as improvement and encouragement in their lives. 86,7% reported having met their objectives and 100% reported going to continue doing some type of exercise or physical activity on a regular basis after the program is finished. Regarding advantages of online format compared to the face-to-face one, they reported avoiding displacement and lower risk of contagion. Lately, if they could participate again, 50% reported they would prefer online, while the remining 50% would prefer traditional modality. Conclusions: At the light of these results, the tele-exercise program contributed to improve the mood and fatigue of patients during the pandemic. The web-based program seems to be feasible and allow patients to meet their objectives after program completion and encourage them to keep doing some type of physical activity.
Abstract A28: Concomitant use of antibiotics and immune checkpoint inhibitors in patients with solid neoplasms: Retrospective data from real-world settings
Authors: Akhil Kapoor, Vanita Noronha, Vijay M. Patil, Amit Joshi, Nandini Menon, Amit Janu, Kumar Prabhash
Journal: Cancer Research (2020)

Abstract Background: The use of antibiotics is known to alter the gut microbiome and it is hypothesized that use of antibiotics may also alter the response to checkpoint inhibitors (CPI). As data are limited from real-world settings, we performed a retrospective audit of patients who received CPI along with concomitant antibiotics. Patients and Methods: This study is a retrospective audit of prospectively collected database of patients who received CPI for advanced solid tumors in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. Antibiotic use was recorded from two weeks before the start of CPI and concomitantly with CPI. All statistical calculations were performed using SPSS statistical software for Windows version 20.0. Results: A total of 155 patients were identified to have received CPI during the study period, of which 70 (44%) patients received antibiotics. Median PFS in patients who received antibiotics was 1.7 months (95% CI: 1.1-2.3) against 3.6 months (95% CI: 2.3-4.8) for patients who did not receive antibiotics (p=0.912). Median OS in the patients who received antibiotics was 3.9 months (95% CI: 1.8-11.4) as compared to 9.2 months (95% CI: 4.2-12.3) for patients who did not receive antibiotics with a trend to significance with p=0.053 (HR-1.023; 95%CI: 1.00-1.04). Among the patients who received antibiotics, median OS for patients who received ≤10 days of antibiotics was 8.8 months (95% CI: 4.2-11.2) while for patients receiving &amp;gt;10 days of antibiotics, it was 2.8 months (95% CI: 1.2-4.4), p=0.025 (HR 2.0, 95% CI: 1.1-3.7). Conclusions: This study shows that judicious use of antibiotics is required in patients on CPI or scheduled to be started on CPI. Note: This abstract was not presented at the conference. Citation Format: Akhil Kapoor, Vanita Noronha, Vijay M. Patil, Amit Joshi, Nandini Menon, Amit Janu, Kumar Prabhash. Concomitant use of antibiotics and immune checkpoint inhibitors in patients with solid neoplasms: Retrospective data from real-world settings [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A28.
The Importance of Considering Frailty in Research on Older Adults
Authors: Michael A. Liu, Alexa Papaila, Alexander P. Diaz de Villalvilla
Journal: JAMA Internal Medicine (2021)

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Chemo-immunotherapy outcomes of KRAS-G12C mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung cancer.
Authors: Kathryn Cecilia Arbour, Biagio Ricciuti, Hira Rizvi, Matthew D. Hellmann, Helena Alexandra Yu, Marc Ladanyi, Mark G. Kris, Maria E. Arcila, Charles M. Rudin, Piro Lito, Mark M. Awad, Gregory J. Riely
Journal: Journal of Clinical Oncology (2021)

9088 Background: KRAS mutations are identified in approximately 30% of NSCLC, with G12C mutations being the most common subtype and representing 12% of all non-small cell lung cancer cases. Novel direct inhibitors are in clinical development and have shown promising activity, although the efficacy of these agents compared to other standard therapies for lung cancer is not yet known. We hypothesized that patients with KRAS-G12C mutations may have distinct responses to chemo-immunotherapy regimens both with respect to STK11 and KEAP1 co-mutation status and compared to patients with non-G12C subtypes. Methods: Patients with KRAS-mutant lung cancers at Memorial Sloan Kettering Cancer Center and Dana Farber Cancer Institute treated with chemo-immunotherapy regimens as first line therapy for advanced/metastatic disease were identified. Subset with KRAS G12C mutations non-G12C subtypes were compared and response to therapy was assessed by investigator. Baseline characteristics were compared with the Chi-square and Fisher’s exact test for categorical data and Wilcoxon rank-rum test for continuous data. Response evaluations where performed by investigators and compared between groups with the Fisher’s exact test. Progression free survival and overall survival was calculated from start of therapy to date of progression or death/last follow up, respectively and compared between groups using the Cox proportional-hazards model. Results: We identified 137 patients with KRAS -mutant NSCLC treated with chemo-immunotherapy: 45% (62/137) had mutations in KRAS-G12C and 55% harbored non-G12C mutations (17% G12V, 15% G12D, 4% G12A, 4% G12S, 3% G13D). The median OS was 21 and 14 months for G12C and non-G12C patients, respectively (p = 0.24). ORR to chemo-immunotherapy for patients harboring a KRAS-G12C mutation was 40% (25/62) compared to 31% (23/75) in non-G12C subtypes (p = 0.3). Median PFS was similar for both G12C and non-G12C subtypes (7.3 vs 6.1 months, respectively, p = 0.12). Concurrent STK11 mutation was identified in 40% of patients with KRAS-G12C and KEAP1 alterations were observed in 32% of patients. In patients with KRAS-G12C, co-mutation in STK11 and/or KEAP1 was associated with shorter PFS (15.8 vs 5.1 months, p = 0.01). Conclusions: KRAS-G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development. Treatment outcomes to chemo-immunotherapy are similar in patients with G12C and non-G12C subtypes. Outcomes are poor for patients with concurrent STK11 and/or KEAP1 mutations representing a significant unmet need.
Preliminary results of the phase II ALTER-H004: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of post surgery recurrence.
Authors: Zheng Wu, Zheng Wang, Lei Zhang, Xiaojing Song, Xilin Du, Kai Tan
Journal: Journal of Clinical Oncology (2021)

e16125 Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality worldwide. Presumably, adjuvant therapy is an efficient treatment for reducing recurrence in patients (pts) with hepatectomy, especially in those with high recurrence factors. Transarterial chemoembolization (TACE) can block the blood supply of the tumor, besides, high concentration of chemotherapeutic drugs can be accumulated within the tumor. It is recommended in several guidelines prophylactic TACE for pts with high recurrence risk factors after hepatectomy, which mainly include grade 1-2 microvascular invasion (M1-2) and portal vein tumor thrombus resection. Moreover, angiogenic inhibitors based therapy has constituted the crucial treatment strategy in HCC. As a novel multitarget tyrosine kinase inhibitor, anlotinib was demonstrated to be an effective first and second-line monotherapy for pts with advanced or recurrent HCC in China. The aim of this phase II trial was to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Methods: A total of 48 histologically confirmed HCC pts who undertook hepatectomy within 1-2 months will be enrolled. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5cm and &lt;10cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng’s classification Ⅰ/Ⅱ). Enrolled pts were received conventional TACE treatment with pirarubicin or epirubicin and platinum within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week off) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 26, 2021, 10 pts were enrolled and received at least once tumor assessment. According to RECIST version 1.1, 9 of them did not progress and 1 relapsed, in whom the DFS was 2.4 months. Most of treatment-related adverse events (TRAEs) were rash (20.0% Grade≤2), pain (20.0% Grade=1) and hypertension (10.0% Grade=1). Only one patient had grade 3 TRAE which was leukocytopenia (10.0%). No more grade 3 or above TRAEs occurred. Conclusions: The current results indicated that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited preliminary and implicational anti-tumor efficacy and manageable toxicity. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04213118.
Asymmetric multi-task attention network for prostate bed segmentation in computed tomography images
Authors: Xuanang Xu, Chunfeng Lian, Shuai Wang, Tong Zhu, Ronald C. Chen, Andrew Z. Wang, Trevor J. Royce, Pew-Thian Yap, Dinggang Shen, Jun Lian
Journal: Medical Image Analysis (2021)
Improving tumor mutational burden calibration in non-European patients.
Authors: Elio Adib, Amin Nassar, Elie Akl, Sarah Abou Alaiwi, Talal El Zarif, Habib El-Khoury, Guruprasad Ananda, Toni K. Choueiri, Alexander Gusev
Journal: Journal of Clinical Oncology (2021)

1559 Background: Tumor mutational burden (TMB), has been recently granted FDA approval as a biomarker for ICI treatment in tumors with a high mutation load (≥ 10/MB). To leverage this biomarker in the clinical setting, it is necessary to evaluate its application in diverse patient populations. In particular, tumor-only sequencing may overestimate TMB in non-EUR populations for which reference panels are small or unavailable, and thus have poorer predictive performance. Herein, we investigate the effect of TMB overestimation in non-EURs on patient diagnosis and clinical outcomes in a real world patient cohort. Methods: TMB was computed using a tumor-only NGS platform (Oncopanel) for 8349 cancer patients (pts) of 7 cancer types (Table). Genetic ancestry was inferred directly from tumor sequencing data and confirmed for a subset of pts using germline SNP arrays. TMB was compared using Wilcoxon rank-sum test between European (EUR) and non-EUR pts. TMB percentile rank by ancestral group (East Asian, African, European) and tumor histology was computed. In non-EUR pts, TMB was calibrated by reassigning its value to the corresponding percentile rank in EUR pts having the same cancer (AH-TMB). Tumors with raw TMB ≥ 10/MB were assigned as TMB-high (TMBH; with the rest referred to as TMBL for TMB-low) and those with calibrated AH-TMB ≥ 10/MB as AH-TMBH. A subset of pts treated with ICIs at DFCI and of EUR ancestry were analyzed. TMB was intentionally mis-calibrated in EURs (MC-TMB), to mimic the TMB overestimation observed in non-EURs. Associations between TMBH status and overall survival (OS) was assessed using Cox regression. Results: Uncalibrated TMB was significantly higher in tumors from non-EUR pts overall (p &lt;0.0001, Table) as anticipated, whereas this difference was not observed in tumors with matched germline filtering. We reassigned non-EUR pts into low/high groups using calibrated AH-TMB, which changed the assignment of 67/670 non-EURs, most of which (65/67) were downgraded from TMBH to AH-TMBL. In the ICI-treated cohort, there was a strong association between TMBH status and OS (p = 2e-11, HR = 0.6) whereas MC-TMBH (mimicking the miscalibration in non-EUR samples) had a weaker association with OS (p = 0.0013, HR = 0.8). Importantly, pts assigned to TMB-H due to miscalibration (90 TMB-L/MC-TMBH pts) had shorter OS compared to the true TMBH group (p = 3e-6, HR = 1.9). Conclusions: In this analysis, we showed that tumor-only sequencing platforms can overestimate TMB in non-EUR pts, impacting treatment decisions and outcomes. Replacing raw TMB counts with an ancestry-adjusted measure could optimize TMB application in the clinical setting when germline sequencing is not available. Accurate ancestry inference can be performed using tumor-only sequencing.[Table: see text]
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML
Authors: Xinan Qiao, Jun Ma, Tristan Knight, Yongwei Su, Holly Edwards, Lisa Polin, Jing Li, Juiwanna Kushner, Sijana H. Dzinic, Kathryn White, Jian Wang, Hai Lin, Yue Wang, Liping Wang, Guan Wang, Jeffrey W. Taub, Yubin Ge
Journal: Blood Cancer Journal (2021)

Abstract About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.