bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer.
Authors: Beeram Muralidhar , Chalasani Pavani , Wang Judy S. , Mina Lida A. , Shatsky Rebecca Arielle , Trivedi Meghna S. , Wesolowski Robert , Hurvitz Sara A. , Han Hyo S. , Patnaik Amita , Pambid Mary Rose , Jayanthan Aarthi , Huynh My-my , Los Gerrit , Dunn Sandra Elaine , Dorr Andrew 
Published: June 2021

e13043 Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.
A precision dosing application for prostate cancer patients treated with docetaxel and G-CSF.
Authors: Villette Claire , Hurry Christian , Mistry Hitesh , Millen Jim , Chassagnole Christophe 
Published: June 2021

e13585 Background: The aim of this study is to produce a precision dosing application for clinicians to control neutropenia in prostate cancer patients treated with both docetaxel and G-CSF. Chemotherapy-induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual’s dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk adverse environment to infections, raising the prospects that a clinician will administer G-CSF. Methods: We adapted and combined representations of endogenous and exogenous G-CSF action on CIN from the literature [2,3,4] to capture the inherent feedback effect of circulating neutrophils on progenitor proliferation as well as the stimulatory action of G-CSF injection on proliferation and maturation of progenitor cells. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669), we identified 134 patients treated with docetaxel with recorded weekly blood tests in the first and second cycle, including 27 also receiving G-CSF. We calibrated individualised patient models against neutrophil counts measured in the first cycle by minimising a Bayesian objective function and evaluated their ability to predict the levels observed in the second cycle. Results: The model was able to capture the main features of endogenous and exogenous G-CSF action on neutrophil count described in the literature, including endogenous-G-CSF-mediated rebound above baseline after chemotherapy-induced depletion [4], rapid rise in neutrophil count following exogenous G-CSF administration [5], as well as reduced chemotherapy-induced depletion and earlier recovery under G-CSF treatment compared to chemotherapy alone [5]. Conclusions: This tool has the potential to help determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel. References: Villettte C., et al., AACR; Cancer Res, 2019;79(13 Suppl): Abstract nr 677. Pastor, M.L., et al. 2013. Pharm. Res, 30(11), pp.2795-2807. Krzyzanski, W., et al. 2010. J. Clin. Pharmacol, 50(S9), pp.101S-112S. Quartino, A.L et al., 2014. Pharm. Res, 31(12), pp.3390-3403. Crawford, J., et al. 1991. N. Engl. J. Med, 325(3), pp.164-170.
Attributes and disease characteristics of patients seeking online second opinion for cancer.
Authors: Goud Rakesh Shankar , Jotwani Amit Kumar , Poovaiah Thirtha , Rajan Rejil , Waghmare Rama , Gururao Shashidhar 
Published: June 2021

e13620 Background: As we see rising cancer incidence in India, there is a parallelly increasing trend in patient-driven second medical opinions (SMO) in oncology. We analysed different attributes of patients seeking online second opinions through onco.com to help us understand the driving factors for patients. Here we present the patient and disease attributes to understand the reasons and perceived value of SMOs in oncology through an online platform. Methods: We did a retrospective analysis of 1,142 patients who availed online tumor board opinion through Onco.com between August 2018 & December 2020. Patient characteristics like age, gender, city of residence (metro or non-metro) & disease characteristics like cancer type and stage were recorded. Tumors included both solid and hematological malignancies. Results: Of the 1,142 patients, 87% (991) cases were solid tumors and the rest 13% (151) were hematological malignancies. Top 6 cancer types for which patients sought SMOs- Breast- 13%, Head & neck- 8.7%, Lung- 7.5%, Leukaemia- 5.8%, Lymphoma- 5.4%, & Ovarian- 5% cancers. Of the 991 solid tumour cases, 13% had early (stage I & II) disease, 24% had locally advanced (stage III) disease, 52% had metastatic disease & and 11% had recurrent disease. The mean age of patients was 50 years with equivalent gender distribution. 23% of patients seeking SMOs were young adults (17-44 years), 59% were older adults (45-70 years), and 9% patients were from elderly (>70 years) age group. City of residence- 39% patients were residents of metro (tier 1) cities and 61% were residents of non-metro (tier 2/3) cities. Conclusions: Advanced stage of disease (metastatic + recurrent) and non-metro city of residence were found to be the commonest attributes for majority of patients. Desperate nature of the situation in advanced stage of disease and lack of access to specialised oncology care in non-metro cities respectively appear to be the reasons for higher SMOs in these groups. Higher number of SMOs for younger age patients was disproportionate to the incidence of cancer in this age-group. A larger analysis of the contrarian opinions, compliance and clinical impact of second opinions in terms of better survival outcomes is warranted to see if patients get true value out of this exercise.
The brain metastasis journey: Experience from patient, caregiver, and physician surveys on diagnosis and treatment of brain metastases.
Authors: Kim Albert Eusik , WANG GI-Ming , Waite Kristin A , Elder Scott , Fine Avery , Ahluwalia Manmeet Singh , Brat Daniel J , Mehta Minesh P. , Page Robin , Dunbar Erin M. , Calderone Heather , Robins Debbie , DeVitto Ralph , Willmarth Nicole , Barnholtz-Sloan Jill , Brastianos Priscilla Kaliopi 
Published: June 2021

e14004 Background: Brain metastases (BM) is one of the most feared complications of cancer due to substantial neurologic sequalae, neuro-cognitive morbidity and grim prognosis. In the past decade, targeted therapies and checkpoint inhibitors have resulted in meaningfully improved overall survival for a minority of these patients. Accordingly, there is a growing need to identify issues surrounding patient survivorship and to standardize physician practice patterns for these patients. To date, there has not been a well-conducted formal study to specifically explore these questions of survivorship and practice standardization for BM patients. Methods: Here, we present results from a cross-sectional survey in which we analyzed responses from 237 BM patients, 209 caregivers, and 239 physicians. Surveys contained questions about BM symptoms, discussion of BM diagnosis by the clinician, psychosocial concerns, available treatment options for BM, BM patient advocacy resources, and BM-specific clinical trials. Results: Our survey revealed compelling findings about current care of BM patients. There were discrepancies in the perceived discussion of the implications of the diagnosis of BM, from the patient/caregiver and physician perspective. Important topics, such as prognosis and worrisome symptoms, were felt to have been discussed more frequently by physicians than by patients or caregivers. In our physician survey, private practice physicians, compared to academic physicians, were significantly more likely to recommend whole brain radiotherapy (61.1 vs 39.7%; p = 0.009). Participation in a clinical trial was one of the least recommended treatment options. Many physicians (59.1% private; 71.9% academic) stated that BM patients in their care are denied participation in a clinical trial, specifically due to the presence of BM. The consensus among physicians, patients and caregivers was that the highest yield area for federal assistance is increased treatment and research funding for BM. Conclusions: Our hope is that these findings will serve as a basis for future quality improvement measures to enhance patient-physician communication and patient well-being, continuing medical education activities detailing latest advances in BM for oncologists, and lobbying efforts to the federal government in prioritizing BM research, clinical trials, and patient survivorship.
Alternative ways to improving the quality of life in combination treatment for high-grade glioma.
Authors: Popov Ivan A. , Shikhlyarova Alla I. , Frantsiyants Elena M. , Rostorguev Eduard E. , Engibaryan Marina A. , Atmachidi Dmitriy P. , Kuznetsova Natalya S. , Kaplieva Irina V. , Bandovkina Valeria A. , Cheryarina Natalia D. , Pandova Olga V. 
Published: June 2021

e14031 Background: The steady increase in the rates of high-grade gliomas (HGG) and poor results of antitumor therapy actualizes the problems of improving surgical and chemoradiation treatment, as well as accompanying therapy technologies for managing secondary disorders of neurological, cognitive, and adaptive status of neurooncological patients. Transcranial magnetotherapy (TMT) helps managing disorders of brain activity at the level of systemic and local regulation, including the mechanisms of formation of general anti-stress reactions of the body, as the basis for improving the quality of life. The purpose of the study was to improve the quality of life of patients with HGG receiving surgical and radiation treatment with TMT. Methods: Neurological and cognitive functions were analyzed in 50 patients with HGG after TMT (1 - ultra-low-frequency magnetic field on the projection of the hypothalamus, 0.3-3.0-9.0 Hz, induction 3 mT; 2 - pulsed magnetic field on the tumor bed, 0.3-3.0-9.0 Hz, induction 15 mT) in the early postoperative period and with radiation therapy, total boost dose 60 Gy, 30 fractions. The results were evaluated with the Bartel, Karnofsky, MoCA and NIHSS scales. Types of general adaptive reactions were identified according to the criteria of the cellular composition of blood by Garkavi. Results: 84% patients after TMT had no neurological symptoms (NIHSS scale), vs. 48% in controls. The number of patients without cognitive dysfunctions (MoCA scale) before radiation therapy was 3.4 times higher than the control values and exceeded them by 4.0 times after radiotherapy. Similar positive dynamics was observed when testing with the Bartel scale, with mild (88.0±4.7% vs. 45.5±10.6% in controls; p < 0.05) and moderate (12±6.5% vs. 45.5±10.6% in controls; p < 0.05) dependence on others in everyday life, and testing with the Karnofsky performance status in patients with the index 90 (60±7.1% in the main group vs. 27.3±9.5% in controls; p < 0.05), in which the symptoms of the disease were insignificant. A 3.4-fold decrease in the frequency of acute stress (S) development was registered, with increased coefficient (C) of antistress (AS) reactions (C = AS/S) by 3.0 times relative to the control values. Conclusions: Antistress mechanisms of the integral response to TMT involved neurological and cognitive recovery, contributing to early rehabilitation and improving the quality of life. The reported study was funded by RFBR, project number 19-315-90082\19.
Pre-clinical evaluation of PV-10 for in vitro anti-tumor activity in refractory and high-risk adult solid tumors.
Authors: Tran Son , Thakur Satbir , Jain Mohit , Zhang Chunfen , Narendran Aru 
Published: June 2021

e14544 Background: PV-10 (10% rose bengal disodium; 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein) is a novel therapeutic agent previously shown to have potent anti-tumor activity following intratumoral injection in melanoma and refractory neuroblastoma, and currently is undergoing clinical testing as a single-agent for refractory metastatic neuroendocrine cancer (NCT02693067) and in combination with checkpoint inhibitors for metastatic melanoma (NCT02557321) and metastatic uveal melanoma (NCT00986661). Given the established clinical efficacy of PV-10 in adult melanoma and hepatic cancers via intratumoral injection, there is a need to evaluate the therapeutic potential of PV-10 in high-risk and refractory adult solid tumors via systemic administration. Our study aims to identify the clinical potential of systemically-delivered PV-10 by first generating prerequisite in vitro data for adult malignancies. Methods: Cytotoxicity assays were performed using the Alamar Blue assay to study the effects of PV-10 in vitro 96-hours post-treatment against a panel of adult solid tumor cell lines derived from breast (MCF-7, T-47D, MDA-MB-231), colorectal (HCT-116, LoVo, T-84), head and neck (CAL-27, Detroit-562, FaDu, UM-SCC-1), and testicular (NCC-IT, NTERA-2, TCAM-2) tissues. Light microscopy and Western blotting were used to investigate apoptosis induction and target modulation in tumor cells after PV-10 treatment. Results: In vitro results from our study demonstrate that PV-10 is cytotoxic at pharmacologically relevant concentrations across the indicated cell lines. Specifically, tumor cell lines originating from testicular tissues were highly sensitive to PV-10 treatment (Mean ± SD IC50: 37.5 ± 16.4 µM; n = 3) compared to breast (117.5 ± 71.0 µM; n = 3), colorectal (64.79 µM; n = 3), and head and neck (106.6 ± 29.2 µM; n = 4) cell lines. Western blot analyses showed dose- and time-dependent activation of pro-apoptotic protein markers in caspase-3 and PARP cleavage, indicating drug-induced apoptosis. Conclusions: This study provides the first pre-clinical results of PV-10 as a novel systemically-delivered therapeutic agent for a range of high-risk and refractory adult solid tumors. Data obtained from our in vitro experiments using a broad repertoire of cell lines that represent diverse molecular and phenotypic subtypes of solid tumors in adults can serve as prerequisite pre-clinical data to establish clinical testing in these populations.
A peptide-based neoantigen vaccine for patients with advanced pancreatic cancer refractory to standard treatment.
Authors: Yang Liu , Chen Shuqing , Mo Fan , Chen Zheling , Jiang Jiahong , Zhang Shanshan , Han Ning , Xu Yunyun , Ma Dongying , Wang Huimin , Guo Xiaojie , Luo Kai , Qiu Min , Huang Qinxue , Liu Liang 
Published: June 2021

e14563 Background: Tumor-specific neoantigens are considered as personalized and potential ultimate targets for cancer immunotherapy. Recently, neoantigen cancer vaccines have been designed to train the patient's immune system to specifically target and kill tumor cells. However, the safety and efficacy of neoantigen vaccines in pancreatic cancer treatment remain poorly understood. Methods: Personalized peptide neoantigen cancer vaccines were successfully designed and manufactured for pancreatic cancers with low tumor mutation burden. Seven patients with advanced pancreatic cancer refractory to standard treatments were enrolled and treated with personalized peptide neoantigen vaccine, iNeo-Vac-P01. Besides the evaluation of the safety and clinical efficacy of iNeo-Vac- P01, pre- and post-vaccination peripheral blood samples were collected to analyze the vaccine’s immunogenicity. Results: For all 7 patients, none sever vaccine-related adverse effects was witnessed. The mean progression free survival, overall survival (OS) and OS associated with vaccine treatment were 3.1, 24.1 and 8.3 months, respectively. For Patient P01, who had a 21-month OS associated with vaccine treatment, the abundance of the TCR clone remarkably increased after vaccination, indicating the potential of iNeo-Vac-P01 to specifically induce a subset of T cells to kill tumor cells. This study also demonstrated that the quantity of IFN-γ in peripheral blood might be a potential biomarker for OS. Conclusions: We believed that it was the first tentative study focused in the application of peptide-based neoantigen cancer vaccine in advanced pancreatic cancer. Promisingly, personalized peptide neoantigen vaccine might provide a new strategy to improve the limited clinical efficacy for pancreatic cancer. Clinical trial information: NCT03645148.
Exploration of the MSI landscape in Chinese pan-cancer patient by Next-Generation Sequencing.
Authors: Liu Xinlu , Xu Jiasheng , Sun Jian , Wei Deng , Zhang Xinsheng , Wang Danhua , Ma Tonghui 
Published: June 2021

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.
Preclinical monotherapeutic and anti-PD-1 synergistic anti-tumor efficacy of MNC-168, a novel human-derived live biotherapeutic product.
Authors: Lin Chuan-Sheng , Jiang Xianzhi , Li Baoxia , Xian Yibo , Su Xue , Liu Zhenzhen , Liang Jiening , Zhao Yingying , Deng Qianying , Huang Baojia , Zhang Tengxun , Zhu Ruijuan , Liang Yajun , Liang Zhengjiao , Xiao Chen , Kuang Zupeng , Zhao Guozhen 
Published: June 2021

e14581 Background: Human gut microbiome has been extensively demonstrated as a critical causative factor in determining the efficacy of cancer immunotherapy. Cumulative clinical evidences indicate the prevalent presence of Enterococcus species in the responder of anti-PD-1 treated patients. We here demonstrated the preclinical anti-tumor efficacy of a novel human derived Enterococcus strain MNC-168. Methods: Using multiple murine syngeneic cold tumor models and in vivo pharmacokinetics mouse model, we characterized the anti-tumor activity and pharmacokinetics of MNC-168 via oral-delivered route in monotherapy and immune checkpoint inhibitor (ICI) anti-mPD-1 combination. Systematic multi-omics analyses and in vitro mechanistic study were conducted to reveal the biomarkers and mode of action of MNC-168. Results: We found MNC-168 significantly and mono-therapeutically counteract tumor development in diverse tumor models, including colorectal cancer (with tumor inhibition ratio of 65.5%), hepatocellular carcinoma (27.4%), fibrosarcoma (33.5%) and renal carcinoma (56.4%). Notably, MNC-168 in combination with anti-mPD-1 synergistically exerted the tumor inhibition ratio up to 68.3-89.2% and significantly reverse anti-mPD-1 non-responsiveness. Integrated multi-omics analyses and in vitro validation study revealed the mechanism by which MNC-168 reinvigorates the immune system through targeting multiple routes, including activating systemic and tumor-resident innate and adaptive immunity, removal of tumor physical barrier, reinforced recruitment of tumor-infiltrating lymphocytes, and maintenance of immuno-stimulant activity via production of immune-simulating metabolites. Activation and boosting of interferon-γ production of CD8 T cells and CD4 T cells are the vital mediators for the anti-tumor ability of MNC-168. In vivo pharmacokinetics study shows that the anti-tumor efficacy of MNC-168 is positively correlated with gut-restricted abundance of MNC-168. Conclusions: MNC-168 is highly potently used as a first-in-class live biotherapeutic product for cancer monotherapy and promoting efficacy of ICI-mediated cancer immunotherapy.