bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Differential expression of long noncoding RNAs in patients with metastatic and nonmetastatic colorectal cancer.
Authors: Kutilin Denis S. , Gusareva Marina A. , Kosheleva Natalia G , Zinkovich Mikhail S. , Gvaramiya Astanda K. , Gappoeva M. A. , Fatkina Natalya B. , Krokhmal Julia N. , Vasilieva Ekaterina O. , Karnauhova Elena A. , Donskaya Aliya K. , Rozenko Lyudmila Ya. , Legostaev Vladislav M. , Shlyakhova Olga V. , Lyman Natalia A. , Balitsky Gennady V. , Kravchenko A. B. , Nosov V. A. , Babenkov Oleg Y.
Published: June 2021

e15023

Background: Long non-coding RNAs (lncRNA) play an important role in many biological processes, and their dysregulation can lead to various diseases, including colorectal cancer (CRC). In recent years, interactions between lncRNA, miRNA and mRNAs in development of CRC have attracted more and more attention. However, the currently obtained data on the complex regulatory interactions between lncRNA and microRNA during metastasis in patients with CRC are fragmentary, often contradictory and obtained on samples that are not significant in size. Therefore, the aim of the study was to analyze the features of lncRNA expression in CRC patients without metastases, with lymph nodes metastases and with liver metastases. Methods: The study included 200 patients with colon adenocarcinoma. The patients were divided into 3 groups: without metastases (T2N0MO, group 1, n = 100), with lymph node metastases (T2-3N1-2M0, group 2, n = 60) and with liver metastases (T3N2M1-2, group 3, n = 40). RNA isolation was performed by guanidine-thiocyanate-phenol-chloroform extraction. The lncRNA list was generated based on bioinformatic analysis. The relative expression of 20 lncRNAs (NEAT1, HELLPAR, AP000766.1, LINC00265, MIRLET7BHG, OLMALINC, AC245884.8, MEOX2-AS1, MEG3, NORAD, HCG11, WASIR2, AC005332.7, PURLN, OIP5-AS1, SNHG14, TUG1, XIST, MALAT1, FAM66E) was evaluated by RT-qPCR method. Differences were assessed using the Mann-Whitney test, and the Bonferroni correction was used to correct multiple comparisons. Results: Differential expression of 5 lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR) was found between CRC patients without metastases and patients with metastases to lymph nodes and liver. Thus, in group 1, expressions of MALAT1, TUG1 and HELLPAR were lower by 2.5, 4.0 and 5.5 times (p < 0.005) than in combined group of patients with metastases to lymph nodes and liver, and XIST and LINC00265 expressions were higher by 2.2 and 3.4 times (p < 0.05), respectively. Differential expression of 2 lncRNA (NORAD, WASIR2) was also found between group 2 and group 3. The NORAD expression in patients in group 3 was 5.5 times (p < 0.05) lower than in patients in group 2, and WASIR2 expression, on the contrary, was 2.5 times (p < 0.05) higher in patients in group 3. Conclusions: Thus, differential expression of lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR, NORAD and WASIR2), associated with regulation of proliferation and invasive ability of tumor cells, was found in 3 groups of CRC patients.
The SGLT-2 inhibitor dapagliflozin reduces cell death and apoptosis in cardiomyocytes exposed to trastuzumab and doxorubicin through NLRP3-mediated pathways.
Authors: Maurea Nicola , Quagliariello Vincenzo , De Laurentiis Michelino , Cavalcanti Ernesta , Paccone Andrea , Buccolo Simona , Iovine Martina , Botti Gerardo
Published: June 2021

e15041

Background: The clinical trial “DECLARE-TIMI 58” (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. We aimed to study if dapagliflozin could exerts cardioprotective and anti-inflammatory effects in doxorubicin and trastuzumab-induced cardiotoxicity through the analysis of multiple biochemical mechanisms. Methods: HL-1 adult cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity (MTS assay), study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), and of intracellular Ca2+ homeostasis. Moreover, anti-inflammatory studies were also performed (protein expression of NLRP3 inflammasome; p65/NF-κB and cytokines involved in cardiotoxicity (interleukins 1β, 8 and 6). Results: Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab. Its cardioprotective properties are explainable by the reduction of intracellular Ca2+ overload (-47,6% vs cells treated only to anticancer drugs; p<0,001), of the lipid peroxidation phenomena (mean reduction of 35-43 % compared to cells exposed only to anticancer drugs; p<0,001). Moreover, cardiomyocytes exposed to dapagliflozin during anticancer drugs have a reduced expression of pro-inflammatory cytokines involved in cardiotoxicity (- 37,3 % for interleukin-1β; -39,5 for Interleukin 8 ; -41,3 % for Interleukin 6 ; p<0,001 for all). Notably, dapagliflozin reduces p65-NF-κB activation (- 36,5% vs cells treated only to anticancer drugs) and inhibits of 27,8 % the expression of NLRP3 inflammasome that consequently improves the mitochondrial homeostasis of cardiomyocytes. Conclusions: Dapagliflozin demonstrated cardioprotective properties during doxorubicin and trastuzumab exposure. Dapagliflozin improves the Ca2+ homeostasis and inhibits the pro-inflammatory “NLRP3- NF-κB –cytokines” pathways. The overall picture obtained provides the proof of concept for translational studies designed to investigate the cardioprotective use of dapagliflozin in HER2+ breast cancer patients.
TrxR1 to promote adriamycin resistance in MCF-7 breast cancer cells by upregulating both gene expression level and enzyme activity: Reversed by shikonin.
Authors: Yang JinQing , Tang Jinhai
Published: June 2021

e15070

Background: Adriamycin is one of the effective drugs commonly used in the treatment of advanced breast cancer, but its high incidence of drug resistance and cardiotoxicity limit the application of doxorubicin. Recent evidence shows that increased antioxidant capacity of cancer cells is associated with resistance to chemotherapy. Shikonin, a derivative of Lithospermum erythrorhizon Sieb.et Zucc, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that shikonin was enabled to directly binding and inhibiting TrxR1, which significantly downregulates intracellular ROS in cancer cells, suggesting that shikonin might be a promising drug candidate. In this study, we identified the relationship between TrxR1 and chemotherapeutic drug resistance in cancer cells and effects of shikonin with and without adriamycin on adriamycin-resistance cells. Methods: The direct DTNB reduction assay was employed to test the enzyme activity of TrxR1. Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an CCK8 assay and Annexin V-FITC/PI-labeled flow cytometry. Drug resistance was evaluated by inhibitory concentration (IC50) values and immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). TrxR1 knockdown was silenced by siRNA, leading to reducing the IC50 value of ADR-resistant MCF-7 cells. Dysfunctional endoplasmic reticulum was measured by western blot analysis of endoplasmic reticulum (ER) stress signaling pathways and observation of morphology using a transmission electron microscope. Results: We found that the TrxR1 was significantly enhanced in adriamycin-resistant (ADR/MCF7) cells.Furthermore, the decreased TrxR1 function by TrxR1-knockdown or TrxR1 inhibitor piperlongumine increased MCF-7 cells sensitivity to adriamycin. Treatment of ADR/MCF7 cells with shikonin (2.5,5,10,20,40 μM) dose-dependently inhibited TrxR1 enzyme activity and the clearance of dysfunctional endoplasmic reticulum, and induced cell apoptosis. Conclusions: Our results suggest that TrxR1 is critical for adriamycin resistance in breast cancer cells(ADR/MCF7),and shikonin or other inhibitors of TrxR1 would be potential in the treatment of cancer cells with adriamycin resistance.
A pan-cancer study on characteristic of CDK4/6 amplification between Chinese and Western patients.
Authors: Zhang Yamin , Cui Zilin , Shi Rui , Liu Xiaolong , Li Yang , Guo Taiyan , You Xia , Zhang Qin , Duan Qianqian , Qi Chuang
Published: June 2021

e15074

Background: CDK4/6 kinases associate with cyclin D proteins during transition from G1 to S phase of the cell cycle. Amplification of CDK4/6 may elicit the activity of cyclin D, which hyperphosphorylates RB, ultimately leading to uncontrolled cell proliferation. Currently, three CDK4/6 inhibitors are used in breast cancer, ovarian cancer and sarcoma. Herein, we investigate the prevalence of CDK4/6 amplification in Chinese and Western cancer patients, hope to find more cancer subtypes with CDK4/6 amplification. Methods: Next-generation sequencing data and clinical data were collected from 10828 TCGA pan-cancer patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 4181 Chinese pan-cancer patients (Chinese cohort). CDK4 and CDK6 amplification were calculated on the two cohorts following the same criteria. Results: In total, 182 (4.4%) of the 4181 Chinese patients and 529 (4.9%) of the 10828 Western patients had CDK4 amplification, 133 (3.2%) of the 4181 Chinese patients and 475 (4.4%) of the 10828 Western patients had CDK6 amplification. In Western cohort, the top 5 CDK4 amplification-associated cancer types were sarcoma, glioblastoma multiforme, lung adenocarcinoma, ovarian carcinoma, and adrenocortical carcinoma, and the top 5 CDK6 amplification-associated cancer types were esophageal carcinoma, ovarian carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, sarcoma. In Chinese cohort, the top 5 CDK4 amplification-associated cancer types were lung adenocarcinoma, melanoma, sarcoma, stomach carcinoma, liver cancer, and the top 5 CDK6 amplification-associated cancer types were lung adenocarcinoma, stomach carcinoma, liver cancer, melanoma, glioma. In addition, CDK4 amplification in Chinese cohort, 22 (11%) of the 203 Chinese bone and soft tissue sarcoma patients had CDK4 amplification, and 4 (2%) of the 203 had CDK6 amplification. Bone and soft tissue sarcoma types with CDK4 / 6 amplification including soft tissue sarcoma, bone cancer, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, synovial sarcoma. Conclusions: Our study provided a characteristic of CDK4/6 amplification in Chinese and Western pan-cancer patients. Analysis revealed frequent CDK4 / 6 amplification in lung cancer, sarcoma, stomach carcinoma, ovarian carcinoma and liver cancer. It is suggested patient with these cancer types may potentially benefit from CDK4/6 inhibitor.
Synergizing microdissection with ddPCR to advance precision oncology.
Authors: Johann Donald Joseph , Shin Ik Jae , Peterson Erich , Steliga Matthew V , Muesse Jason , Marino Katy , Laun Sarah , Greisman Valerie , Emmert-Buck Michael , Tangrea Michael
Published: June 2021

e15083

Background: Improving patient treatment outcomes based on the application of advanced molecular profiling methodologies applied to pathological specimens is the purview of precision oncology. Optimal utilization of tumor tissue from diagnostic biopsies remains an unmet medical need. This is especially relevant today since precision oncology is a rapidly evolving field where timely tumor genotyping is essential for the indication of many advanced and targeted therapies. National Comprehensive Cancer Network (NCCN) guidelines now mandate molecular testing for clinically actionable targets in certain malignancies. Patients diagnosed with advanced non-small cell lung cancer (NSCLC) are commonly of an older age and have significant co-morbidities. Clinical dilemmas regarding the ability to obtain adequate amounts of tissue for tumor genotyping frequently occur. In these cases, the tumor tissue may have been obtained by an image-guided biopsy, and the diagnosis of NSCLC proper determined via cytology. Adequate tissue for tumor genotyping and/or a more advanced mutational analysis to identify oncogenic drivers may not be available, and the opportunity to explore more optimal therapy options (eg, TKI in lieu of chemotherapy) is lost. Methods: Following a formal pathology review formalin fixed paraffin embedded (FFPE) specimens were examined using advanced immuno-based laser capture microdissection (LCM). In preparation for droplet digital PCR (ddPCR), nucleic acids were extracted from samples and run with a series of positive and negative controls. Results: Utilizing lung cancer as an example, an improved genotyping approach for NSCLC solid tumors was developed and tested. The strategy involves optimization of the microdissection process and analysis of a large number of identical target cells from FFPE specimens sharing similar characteristics, in other words, single-cell subtype analysis. Immunostaining status, cell phenotype, and spatial location within a histological section are examples of shared characteristics that can guide cell procurement. Conclusions: With this approach, tumor molecular analysis is enhanced through the synergy between microdissection and ddPCR. Here we demonstrate a methodology that illustrates genotyping of a solid tumor from a small tissue biopsy sample in a time and cost-efficient manner, using immunohistochemistry-directed LCM along with the detection and absolute quantitation of mutations by ddPCR.
Levels of the IGF system components in malignant lesions of the lungs with preventive effect of 1,3-diethylbenzimidazolium triiodide in the experiment.
Authors: Trepitaki Lidia K. , Kaplieva Irina V. , Frantsiyants Elena M. , Volkova Viktoriya L. , Kharagezov Dmitry A. , Leyman Igor A. , Stateshny Oleg N. , Milakin Anton G.
Published: June 2021

e15095

Background: The system of insulin-like growth factors (IGF) is involved in carcinogenesis, since it promotes proliferation and survival of tumor cells. The purpose of the study was an analysis of the dynamics of the IGF system components in the lungs of rats with antitumor effect of 1,3-diethylbenzimidazolium triiodide. Methods: The main group included male (n=27) and female (n=27) white outbred rats with sarcoma 45 inoculated into the subclavian vein (2×106 cells in 0.5 mL saline) but not developed in the lungs due to administration of 1,3-diethylbenzimidazolium triiodide (intragastrically, 0.4 mg/kg once a day according to the regimen: administration for 5 days with a 2-day interval). Control group included males (n=14) and females (n=14) with sarcoma 45 growing in the lungs without treatment. Intact groups included 5 males and 5 females. After 4, 5 and 8 weeks of the experiment animals were decapitated, and levels of IGFI, IGFII, IGFBP1, IGFBP2 and IGFBP3 were measured by ELISA in 10% lung homogenates (CUSABIO BIOTECH Co., Ltd., China). Results: The sarcoma development in the lung was accompanied by the IGFI increase by 2.4-3.0 times in males and by 4.3 times in females, and the opposite IGFII dynamics: an increase in males (by 4.6 times) and decrease in females (by 4.3 times), together with the IGFBP decline. 1,3-diethylbenzimidazolium triiodide upregulated IGFI levels in the lungs of all rats on average by 1.3 times (p<0.05) and normalized IGFII in males, while increasing it in females by 1.6 times (p<0.05), together with higher (compared to controls) IGFBP levels. Conclusions: Preventive antitumor effect of 1.3-diethylbenzimidazolium triiodide is based on the stabilization of the IGF system grossly altered during the malignant process development in the lung.
Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial.
Authors: Lai Eleonora , Loupakis Fotios , Ziranu Pina , Aprile Giuseppe , Zaniboni Alberto , Madeddu Clelia , Lonardi Sara , Mosconi Stefania , Smiroldo Valeria , Beretta Giordano D. , Murgioni Sabina , Rosati Gerardo , Zampino M. Giulia , Gelsomino Fabio , Conca Veronica , Mascia Luigi , Cavanna Luigi , Morelli Cristina , Della Torre Silvia , Scartozzi Mario ,   On behalf of GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente, Italian Group for the Study of Gastrointestinal Tumors)
Published: June 2021

e15503

Background: Data on anti-angiogenic second line treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR drug are lacking and no validated biomarkers are available. We present the pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456), a biologically enriched, prospectively stratified phase 2 study assessing the aflibercept use in this setting. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy and candidates for second-line FOLFIRI/aflibercept are eligible for the DISTINCTIVE trial. Pts are prospectively allocated to a favorable (F) or unfavorable (U) prognostic group, according to Elisa-assessed baseline (BL) VEGFR2 plasma levels (PL). Other circulating angiogenic factors are evaluated at BL, first tumor assessment (TA1) and disease progression (PD). Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression). Sample size: 151 pts (one-sided test, α: 0.1, β: 0.2). Results: From 04/2018 to 06/2020, 73 pts were enrolled. Complete data from 44 pts were available for interim analysis. 33 pts (75%) achieved DCR (26 pts/59% SD, 7 pts/16% PR). Globally, median OS was 11.9 months (m) (95%CI 10 – 14.2). 24 (54.5%) pts were prospectively assigned to F group (VEGFR2 PL > 4 ng/ml) and 20 (45.5%) to U group (VEGFR2 PL ≤4 ng/ml). OS in F group was 13.1 m (95%CI 9.6 – 14.2) vs 11.9 m (95%CI 6.8 – 11.9) in U group (HR 0.76 p = 0.6218). PFS was 9.8 m [95%CI 5.7 – 24.2] in F group vs 4.2 m [95%CI 2.5 – 14.2] in U group (HR 0.41 p = 0.0105). We also found preliminary correlation with PD as shown in table. Conclusions: Interim analysis showed high activity of FOLFIRI/aflibercept in RAS WT anti-EGFR pretreated mCRC pts. VEGFR2 showed promising ability to predict aflibercept efficacy. Our data on circulating angiogenic biomarkers are likely to further compose the landscape of anti-angiogenic activity in mCRC pts. Clinical trial information: NCT04252456. [Table: see text]
Novel molecular classification of colorectal cancer and correlation with long-term survival.
Authors: Mangi Fayaz Hussain , Shaikh Tanweer Ahmed , Soria Daniel , Qureshi Jawaid Naeem , Ujjan Ikram Uddin , Syed Binafsha Manzoor
Published: June 2021

e15514

Background: Colorectal cancer (CRC) is a heterogeneous disease, however there is limited information available regarding molecular classification and correlation with long term clinical outcome. Methods: Over the period of 11 years (2008 to 2018) totals 435 patients of colorectal cancer were reported and their tumour blocks and complete set of clinical information was available for 201 patients. Immunohistochemistry was done for ER, PR, HER 2-neu, Ki-67, Bcl-2, E-Cadherin, P53, CEA, EGFR, and VEGF. PDL1, CDX-2 and CK 20. The biological pattern characterized by partitioned clustering method as described using R software. Survival analysis was done by using Kaplan Meier method. Results: There were 201 patients including 54.7% male and females were 45.3 %. Median survival was 28 months. Cluster analysis showed four novel clusters (Table), with major difference based on Ki67, CDX2 and p53. These classes showed difference in median survival, where common class 1 showed higher survival while common cluster 4 showed poor survival. Conclusions: There are at least four distinct molecular classes of colorectal cancer which can be potentially utilized in clinical practice. Pattern of Novel molecular classification of colorectal cancer and correlation with long term survival.[Table: see text]
Pooled analysis of POLE-mutant colorectal cancer characteristics.
Authors: Li Sharon , Panda Anshuman , Ciner Aaron , Ganesan Shridar , Hochster Howard S.
Published: June 2021

e15515

Background: Colorectal cancers (CRC) with pathogenic mutations in POLE (mPOLE) represent a unique subgroup with distinct clinical and molecular features and may exhibit a robust response to immune checkpoint blockade. Due to low prevalence, clinical features of this subgroup remain incompletely characterized. Methods: We utilized data from the Oncology Research Information Exchange Network (ORIEN) , using the Total Cancer Care (TCC) protocol in 18 centers across the US, to identify mPOLE CRC cases through October 2020. Prevalence, genomic and clinical features of mPOLE CRC within ORIEN were compared with other public databases, including AACR GENIE (version 8.0) , TCGA pan-cancer atlas, and a cohort from DFCI via cbioportal . Given the small sample size of mPOLE patients in each cohort, we pooled available data to compare characteristics of mPOLE CRC with CRC cases without pathogenic mutations in POLE (wtPOLE). Results: Detailed results are illustrated in the table. Out of 1564 CRC patients in ORIEN, 140 patients (9%) had POLE mutations, but only 11 patients (<1%) had pathogenic POLE mutations, compared to <2% in TCGA, <1% in DFCI, and <0.5% in the AACR GENIE cohorts. mPOLE CRC was associated with significantly higher tumor mutational burden and lower copy number alterations in all cohorts with data. In ORIEN, median age at diagnosis was significantly lower in mPOLE patients and at least 5 years younger than mPOLE patients from other cohorts. No other variable was statistically significant within ORIEN. When available clinical data from all cohorts were pooled, mPOLE was significantly associated with male sex, younger age at diagnosis, and early stage (I/II) disease. Conclusions: The ORIEN data set showed <1% patients with pathogenic POLE mutations. When pooled with the available public data sets, we see emergence of a unique clinical phenotype. Additional outcome data from ORIEN TCC database will be reported. We acknowledge the participation and assistance of the ORIEN investigators, with thanks. wtPOLE vs mPOLE in pooled and individual large cohort studies.[Table: see text]
Analysis of the relationship between different prognosis factors in patients with advanced colon cancer and progression-free survival.
Authors: Richardet Eduardo , Magi Ignacio , Acosta Luciana Paola , Ferreira Maria gimena , Molina Matias , Richardet Martin Eduardo
Published: June 2021

e15518

Background: Colon tumors are a heterogeneous group of disease. As a result of the accumulation of different genetic and epigenetic alterations, the mutation of the RAS, BRAF oncogene and microsatellite instability stands out. A new line of research are immunological and inflammatory factors, the infiltrating lymphocytes of the tumor stroma (TILs) and the neutrophil to lymphocyte radio (NLR) have been studied by our work team. We understood could that these factors were associated with the survival rate in our patients. The main objective of this reseach is to determine the relationship between NLR and progression-free survival (PFS) in patients with advanced colon cancer. Secondary objective is to determine the relationship between the location of the primary tumor, RAS status, TILs, and PFS. in the same group of patients. Methods: A total of 93 medical records of patients with advanced colon cancer was analyzed. Those pts who had recieved first-line chemotherapy treatment with a FOLFOX scheme plus a monoclonal antibody were included. All patients had to have a minimum follow-up of 12 months. Regarding NLR, the patients were classified into two groups: high ( = > 4) and low ( < 4). Four TILs cut-off points were determined: > 40% intense; between 11-40% moderate, 1-10% mild, and 0% absent, which were group into two categories: intense and moderate; slight and absent. Localization was divided into left and right, and KRAS status was divided into mutated and wild-type (WT). PFS was calculated using the Kaplan-Meier test. Results: The median PFS of the general population was 8.74 (7.39-11.07) months. The median PFS was 9.86 (7.82-13.41) vs 5.09 (4.43-10.84) months for low and high NLR respectively, with statistical significance (p: 0.01). When the percentage of patients without progression after one year of treatment was analyzed, the difference was 45% vs 14% in favor of NLR < 4 on ≥4, this difference was also statistically significant (p: 0.02). PFS in relation to TILs after one year of follow up was 33% (8.61 months) for moderate-intense infiltrate vs 30% of mild-absent (7.10 months). PFS was 9.79 months for KRAS WT pts vs 7.82 months for mutated KRAS. In terms of location, PFS was 9.79 months for the left colon vs 8.28 months for the right colon. These factors did not have a statistically significant difference. Conclusions: The results of the study show how NLR < 4 is a prognostic factor with a positive impact on PFS. It should be noted that the median survival rates were numerically higher in moderate-intense vs mild-absent TILs, also in KRAS WT vs mutated and in left vs right location. It should also be noted that the possibly there was not a statistically significant difference between them due to the limited number of patients per what we will continue working on in the recruitment and analysis of these patients.
VEGFR2 expressions in Th1 and CD8+ cytotoxic T lymphocytes (CTL) in colon cancer patients.
Authors: Artac Mehmet , Ceylan Ayca , Karakurt Eryılmaz Melek , Araz Murat , Karaagac Mustafa , Artac Hasibe , Emiroglu Melike
Published: June 2021

e15535

Background: VEGF receptors have an important role for inhibiting adaptive immun response in colon cancer. Therefore, we analyzed VEGF receptors in circulating T cell subsets according to stage in colon cancer patients. Methods: The prospective study group consisted of 50 patients with histologically confirmed colon cancer and 30 person without any cancer history as a control group. Peripheral blood specimens were collected from the patients after the diagnosis before inducing chemotherapy and radiotherapy. Patients with active infections or autoimmune disorders, who were treated with steroids and antibiotics in the last four weeks before the study enrollment were excluded from the study group. VEGFR2 expressions in circulating T cell subsets (Th1, Th2, Th17, CTL) were analyzed by flow cyctometry. Results: Age and gender were not different between the all study groups. Mean circulating CD4+ folicullar cells were less in colon cancer patients (9.54%±3.99) than the control group (12.03%±4.34), (p < 0.01). Mean circulating CD8+ follicular cells were higher in metastatic colon cancer (n = 26) 2.48% ± 1.68, than the non-metastatic colon cancer patients (n = 24) 1.63% ± 1.37, (p = 0.02). Mean VEGFR2 expressions in Th1 cells were higher in colon cancer patients 248.8 (Mean Flourescein intensity-MFI) than the control group 224.6, (P = 0.006). Mean VEGFR2 expressions in CTL were higher in colon cancer patients (381.8) than the control group (284.7), (p < 0.001). PD-1 expressions were not different between the colon cancer patients and the control group in all circulating T cell subsets. Mean VEGFR2 expressions in Th17 cells were higher non-metastatic colon cancer patients than the metastatic colon cancer patients (326.5 and 268.4 MFI, respectively, p = 0.02). Conclusions: VEGFR2 expressions are increased in circulating Th1 and CTL subsets in colon cancer patients. Whereas PD-1 expressions were not different in circulating T cell subsets than the control. VEGFRs may play an important role for the inhibition of circulating T cell subsets in colon cancer.
Efficacy, treatment modalities, and safety of regorafenib in Chinese metastatic colorectal cancer patients: A multiple centers real-world study.
Authors: Jiang Zhichao , Sun Yongkun , Zhang Wen , Liu Ning , Qiu Wensheng , Jiang Tao , Li Sheng , Sun Ning , Li Xiaoyou , Zhu Liangjun , Liu Zimin , Zhou Ai-Ping
Published: June 2021

e15569

Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with regorafenib improved the overall survival (OS) in two phase 3 trials. Regorafenib has been recognized as a standard third line treatment in mCRC. However, the efficacy and safety of regorafenib in real world for Chinese patients is lacking. Methods: Patients of mCRC treated with at least one cycle of regorafenib (40, 80, 120 or 160mg OD for 21 days, as a 28-day cycle) from August 2017 to June 2020 in three Chinese medical centers were enrolled. Data of demographic, treatment, dosimetry, safety and survival was collected retrospectively. The primary endpoint was OS. Secondary endpoints were progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of adverse events (AEs). Results: 372 patients were enrolled, of whom 266 (71.5%) accepted regorafenib alone and 106 (28.5%) received combination therapy with regorafenib. In these patients, 75 (20.16%) and 275 (73.9%) patients received regorafenib as third or higher line treatment. Starting dose was 160mg in 93 (25.0%) patients, 120mg in 74 (19.9%) patients, 80mg in 142 (38.2%) patients and 40mg in 7 (1.9%) patients. The maintenance dose was confirmed in 236 patients. Among them, 111 (46.6%) and 75 (31.8%) accepted 80 and 120mg as the last daily dose. Only 50 (21.2%) patients could receive 160mg as a long-term therapy. Median follow-up time was 15.2 months. ORR and DCR were 3.8% and 55.3%. The mPFS was 3.1 months (95%CI: 2.50-3.53) and mOS was 10.2 months (95% CI: 9.27-11.93) . The mOS of 80, 120 and 160mg last daily dose were 10.5, 14.1 and 14.3 months, respectively. Patients received regorafenib in combination with other drugs including chemotherapy or PD-1 inhibitor had longer survival compared with regorafenib alone with mOS of 15.5 (95% CI: 10.1-19.0) and 9.7 months (95% CI: 7.8-11.0) (p = 0.004). The mOS of patients developed lung metastasis and the counterpart with liver metastasis was13.3 versus 9.7 months. The common AEs were anemia (26.1%), hyperbilirubinemia (25.3%), liver injury (24.7%), thrombocytopenia (18.0%) and recorded hand-foot skin reaction (HFSR) (19.6%). The most common grade 3-4 AEs included hyperbilirubinemia (3.5%), recorded HFSR (3.5%), anemia (2.2%) and thrombocytopenia (1.1%). Due to most patients was reviewed in clinic, some data of AEs was missing or incomplete. Conclusions: In the real world, regorafenib showed promising efficacy and manageable toxicities in Chinese patients with refractory mCRC. The dose of 120mg of regorafenib seemed to have a similar survival benefit compared with 160mg. In addition to a better tolerance, 120mg may be a more suitable dose for Chinese mCRC patients. Clinical trial information: NCT04735991. [Key words] Colorectal cancer; Regorafenib; Real world