bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of clinically actionable biomarkers in an Indian cancer cohort using comprehensive genomic profiling (CGP): An institutional experience.
Authors: Ghosh Mithua , Balaram Gautam , ML Sheela , CR Krishna , Patil Shekar , PS Sridhar , Thungappa Satheesh Chiradoni , Bhattacharjee Somarat , Kodandapani Ramya , K Vijay , E Vijay , Ghorpade Suhas N. , Dasgupta Roshini , Naseer Mohammed , Katragadda Shanmukh , Ravichandran Aarthi , Ramaswamy Veena , Bj Srinivasa , Rao Vishal Uchila Shishir , Ajaikumar Basavalinga Sadasivaiah 
Published: June 2023

e15166 Background: CGP through Next-Generation Sequencing (NGS) has substituted single-gene testing to identify more druggable gene aberrations. The simultaneous detection of broad spectrum predictive biomarkers and molecular signatures including tumor mutational burden (TMB), microsatellite instability (MSI) burden, somatic BRCA, homologous recombination repair genes (HRR) and RNA variants by CGP provides a more cost efficient and tissue-preserving approach than serial single-biomarker analyses. Methods: 750 biopsy proven patients of various cancer spectrum at HCG cancer center were consented and profiled using Illumina TruSight Oncology 500 (TSO500) assay that interrogates 523 cancer-related genes on NextSeq in an IRB-approved prospective study. The findings were discussed in molecular tumor board (MTB) and recommendations from treating physicians were documented in patient records for change in clinical management and follow up. Results: A total of 1291 genomic alterations were detected in 750 cases (mean 1.7 mutations/sample). CGP identified genetic alterations with therapeutic and prognostic implications in 77% patients (Tier I- 34%, Tier II-64%, Tier III-14%). CGP revealed higher number of druggable genes (47%) than small panels (14%).Tumor agnostic markers for immunotherapy (IO) were observed in 20% of the current cohort, based on which IO was initiated and are on follow up. In 20% of the cohort, HRR pathway alterations including s BRCA (7%) were detected providing an option to treat with platinum or PARP inhibitors. Other significant alterations like EGFR, RAS/RAF, ERBB2, PIK3CA, cKIT, PDGFRA, ARID1A, ARID2, POLE, and FGFR were found. RNA sequencing yielded 54 RNA alterations (38 translocations and 16 splice variants). Androgen receptor splice variants were observed in 50% prostate carcinoma patients for whom taxane therapy was initiated. Other frequent fusions detected were: TMPRSS-ERG, RPS6KB1-VMP1, EML4-ALK, NTRK, PDGFRA and EWSR. Conclusions: CGP reports actionable and prognostic genetic alterations in 77% of patients who could potentially benefit by tumor-matched targeted and immunotherapy. Post MDT patients were assigned to approved therapies (5-80%) or change in clinical management (5-25%) based on the cancer type (Table). 25% patients were enrolled for investigator initiated clinical trials and are on follow up for clinical outcome and analysis of independent prognostic and therapeutic value of novel biomarkers in a larger cohort of Indian patient. [Table: see text]
The prognostic effect of ADH1B and ALDH2in lung adenocarcinoma.
Authors: Zhang Ying , Ma Jinan , Du Hongchun , Shi Ying , Willis-Owen Saffron A.G. , Moffatt Miriam F. , Zhang Youming 
Published: June 2023

e15167 Background: Alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) are major enzymes involved in the metabolism of carcinogenic acetaldehyde, converting alcohol to acetaldehyde and detoxifying acetaldehyde to harmless acetic acid, respectively. To investigate the role of ADH isoenzymes and ALDH isoenzymes in the development of lung adenocarcinoma (LUAD), we performed a retrospective analysis of gene expression. Methods: RNA sequencing data derived from 497 tumour samples and 54 adjacent normal samples were obtained from the Cancer Genome Atlas (TCGA) database. The transcript levels of ADH and ALDH family genes were compared between tumour tissue and adjacent normal tissue through a Wilcoxon test. The results were validated in transcriptomic data from 111 lung cancer patients available as part of a prior study. The diagnostic and prognostic value of ADH and ALDH family genes was further investigated by survival analysis and nomogram through the TCGA database. Insights into the mechanism of action were gained through gene set enrichment analysis (GSEA). Results: Numerous ADH and ALDH family genes showed nominally significant differential expression between tumour and adjacent normal tissues. The expression levels of ADH1B and ALDH2 showed significant and replicable depression in tumour tissue. Low expression of ADH1B and ALDH2 was associated with worse overall survival, with the combination of these genes providing greater prognostic value than the additive effects of these genes individually in the TCGA database. ADH1B and ALDH2 transcript levels were linked with the regulation of metabolism, cell cycle, DNA repair and cancer-associated pathways. A risk score model for predicting LUAD prognosis was developed and showed good performance in predicting 1, 3 and 5-year overall survival (OS). Consistent with TCGA results, our 111-patient replication dataset showed that the tumour-specific depression was most pronounced for ADH1B, and the lower expression was associated with vascular, pleural and lymphatic invasions. Moreover, smoking status and/or cumulative smoking history do not provide a direct, clinically accessible proxy for tumour ADH1B or ALDH2 expression. Conclusions: The combination of ADH1B and ALDH2 are potential prognostic markers in LUAD and may have utility as an independent clinical factor for evaluating the prognosis of LUAD.
Circulating tumor DNA methylation marker-based minimal residual diseases detection and recurrence monitoring of cancer.
Authors: Wang Huiyong , Pan Xiaobao , Wang Lin , Li Chao , Ma Chao , Yu Shuai , Meng Fanyang , Liu Jing , Liu Liang , Cao Zhanbo 
Published: June 2023

e15172 Background: Circulating tumor DNA (ctDNA) has been heralded as a promising tool to detect residual disease, relapse, and monitor treatment response by detecting molecular residual disease (MRD) in solid tumors. Numerous previous studies have demonstrated the molecular characteristics of ctDNA, such as the mutational landscape, single-nucleotide variations, copy number variations, and methylation landscape. Based on the methylation characteristics of ctDNA, we developed a novel MRD evaluation system (PcMM-qMSP) with ctDNA methylation markers, and evaluated the association of changes in ctDNA level with clinical outcome. Methods: We used sequencing data from public databases for data mining by clinical Natural Language Processing (NLP) to screen the pan-cancer ctDNA methylation markers (PcMM). A PcMM-based MRD detection method was established by quantitative methylation-specific PCR (qMSP). Moreover, 99 clinical blood samples [lung cancer (41), colorectal cancer (18), gastric cancer (5), pancreatic adenocarcinoma (16), liver cancer (6), cervical cancer (3), ovarian cancer (4), breast cancer (3), and unknown (3)] were collected to evaluate the consistency of ctDNA level between PcMM-qMSP and next-generation sequencing (NGS). Results: We evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility. PcMM-qMSP showed coefficients of variation (CVs) of the intra- and inter-batch assay of 0.42-0.65% and 0.05-0.27%, the accuracies were 100%. Best-in-class assays demonstrated a limit of detection (LoD) of approximately 30 copies of methylated DNA, with lower LoD at 10 copies. The evaluation results of 99 pan-solid tumor blood samples showed that the consistency of PcMM-qMSP and NGS in ctDNA level assessment was 0.82. The specific data are shown in the Table. Conclusions: PcMM is a pan-tumor specific methylation biomarker. The results demonstrated that PcMM-qMSP and NGS were highly functionally consistent for estimating ctDNA level. PcMM-qMSP detection time is less than 24 hours and costs USD 300 as compared to NGS, which takes seven days and costs USD 900. Hence, PcMM-qMSP is economical, rapid, accurate and highly sensitive for detecting pan-solid tumors. [Table: see text]
Pan-cancer analysis and KNSTRN as a potential prognosis biomarker.
Authors: Xiao Shanshan , Zou Yuqing , Wang Li , Wang Qian , Wang Tao 
Published: June 2023

e15180 Background: KNSTRN (Kinetochore-Localized Astrin-Binding) protein participates in the biological processes of chromosome alignment and segregation and is required for accurate mitosis. However, only a few researches have focused on the functional roles of KNSTRN in various cancers. Pan-cancer analysis facilitates better understanding the KNSTRN functions in tumor development and progression. Methods: In this study, RNA-Seq data of the tumor and the adjacent tissue, along with the patient information, were collected from 30 solid tumor types in TCGA database. For each tumor type, the tumor samples were stratified into High_KNSTRN (HK) or Low_KNSTRN (LK) based on the threshold of median KNSTRN expression. As an important prognostic biomarker in pan cancers, tumor mutation burdens (TMB) were evaluated between HK and LK groups. Highly and unqiuely expressed genes in each group were included for functional enrichment analysis. To further investigate the prognostic value of KNSTRN, Kaplan-Meier survival analyses were carried out based on the overall survival (OS) data. Moreover, the mutation types such as SNV, indel, CNV, and rearrangement ooccured in those tumor types were obtained from cBioPortal of Cancer Genomics platform. We also used TIMER2 database to evaluate the associations between KNSTRN expression and CAFs and CD8+ T cells infiltrating levels. Results: We found KNSTRN was significantly up-regulated in 20 cancer types and significantly down-regulated in THCA. Consistent with the previous studies, higher KNSTRN expression levels were significantly associated with shorter OS in most cancers. The most frequently detected mutations were found in MESO, SKCM and UCS. The “deep deletion” CNV was the most frequently occurred type in MESO and UCS, and the SNV mutations highly occurred in SKCM, which meant the KNSTRN mutations were quite diverse across various cancer types. In addition, KNSTRN expression and TMB were positively correlated, and the higher TMB indicated worse prognoses in 13 cancers. Highly expressed genes in the LK group mainly participated in immune response and a large family of environmental information processing pathways. Compared to highly expressed genes related pathways in HK group, KNSTRN may likely be involved in pro-tumor regulator pathways. Moreover, KNSTRN was positively correlated with immunosuppressive genes and CAFs cell infiltration levels but negatively correlated to CD8+ T cells in most cancers. Conclusions: Most of the cancers had up-regulated KNSTRN expressions compared with adjacent tissues. Higher KNSTRN expression was significantly associated with worse clinical outcomes in those cancers. Comprehensive downstream analysis revealed the underlying mechanism of KNSTRN in tumor development and its potential clinical value as a prognostic biomarker.
Effects of oncolytic bacteria, SGN1, against a broad spectrum of malignancies in pre-clinical and clinical studies.
Authors: Zhao Allan Zijian , Li Fanghong , Mai Jialuo , Zhou Sujin , Lai Yunhao , Lu Mengmeng , Liang Jincai 
Published: June 2023

e15184 Background: It has been widely reported over the past 40 years that almost all human cancer cells examined are strongly dependent on methionine for growth and metastasis, largely owing to the deficiency of cancer cells in methionine salvage pathway. To specifically deprive cancer tissues of methionine without affecting systemic methionine content, we have developed the first oncolytic bacteria drug, SGN1, that is based on the attenuated Salmonella typhimurium and its tumor targeting ability, and overexpresses an L-methioninase gene. Currently, SGN1 has been approved for, and entered, clinical trials in the US and Taiwan, China (NCT05103345 & NCT05038150). Methods: Cellular and animal models were used for examining the tumor-targeting effects and safety profiles of SGN1. We calculated the role of engineered Salmonella in cancer cells by RNA-seq analysis. Results: In preclinical cellular and xenograft models, SGN1 specifically targeted solid tumors， induced a sharp regression of several very divergent models of human carcinomas, caused a significant decrease of tumor cell invasion, and essentially eliminated the growth and metastasis of the xenograft tumors. RNA-Seq analysis revealed that the engineered Salmonella reduced the expression of a series of genes promoting cell growth, cell migration and invasion. Like the original attenuated Salmonella typhimurium (VNP20009), SGN1 has displayed excellent safety profiles based on the GLP-evaluation in multiple animal models. In preclinical human tumor-derived models, SGN1 exhibited strong inhibitory effects on tumor growth and metastasis in a broad spectrum of tumors, including, but not limited to, small cell lung carcinoma, osteosarcoma, hepatocellular cancer, breast cancer (including triple negative breast cancer), pancreatic cancer, prostate cancer, and cervical cancer. In investigator-initiated trial (IIT) studies, SGN1 significantly shrank, or completely lysed, patients’ tumor and ameliorated cachexia, while patients showed no severe adverse reaction except some transient fever and nausea. Conclusions: The first-in-class oncolytic bacteria, SGN1, featured with the ability of tumor-targeting and methionine hydrolysis, exhibits broad-spectrum antitumor activity and great potential for cancer therapy. Clinical trial information: NCT05038150 . Clinical trial information: NCT05103345 .
IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.
Authors: Helland Aslaug , Smeland Sigbjørn , Russnes Hege , Brabrand Sigmund , Puco Katarina , Niehusmann Pitt , Cameron Marte Grønlie , Blix Egil , Haug Ase , Oppdal Irja Alida , Heinrich Daniel , Meltzer Sebastian , Flobak Åsmund , Steinskog Eli Sihn , Torkildsen Cecilie Fredvik , Fagereng Gro Live , Dalhaug Astrid , Hjortland Geir Olav , Bjørge Line , Tasken Kjetil 
Published: June 2023

e15188 Background: Precision cancer medicine is evolving rapidly, with new drugs and biomarkers being developed. Advanced molecular diagnostics is a prerequisite for using some of the drugs, which might be approved on small or large subsets of patients. Drugs targeting a specific pathway or gene aberration, might be efficient in other tumour types harbouring the same molecular alteration, but not yet tried in randomized trials due to limited number of patients. This indicates that patients might benefit drugs that are on the market, not available for patients outside the existing indication. Methods: In this national-wide, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled into multiple parallel treatment cohorts. Patients with progressive disease on standard therapy, are eligible. Each cohort is defined by the patient’s tumour type, molecular profile, and study drug. Treatment outcome in each cohort is assessed by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Currently, 21 drugs are provided by six different pharmaceutical companies, and we are in process to acquire additional drugs for patients in this study. Molecular diagnostics with the TSO-500 gene panel are funded by the public health care system. In addition, patients included are offered analyses of circulating tumour DNA (ctDNA). The primary objective is to evaluate clinical benefit of treatment at 16 weeks of treatment, defined as complete response, partial response, or stable disease. Results: IMPRESS-Norway opened for accrual at April 1st 2021. As of January 24, 2023, tumour cells from 791 patients with advanced cancer, have been analysed with TSO-500, and 662 patients had been discussed at the national molecular tumour board. 150 patients (23%) were allocated to therapy in different treatment-cohorts in IMPRESS-Norway, and 11% were referred to other ongoing clinical studies or early access programs. Extended and updated data and frequency of targetable molecular alteration will be presented. Conclusions: Patients with advanced cancer progressing on standard treatment are referred to treatment in IMPRESS-Norway after advanced molecular diagnostics. Genetic alterations indicating benefit of the drugs currently available in the study, are detected in 23% of 662 evaluated patients. Clinical trial information: NCT04817956 .
Carboplatin and paclitaxel chemoradiation for localized anal cancer in patients not eligible for mitomycin and 5-fluorouracil.
Authors: DeZeeuw Alyssa , Grogan Patrick Thomas , Lemmon Kayla , Wilke Jenna , Bausch Anica , Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , Patel Monica Arun , Bassetti Michael F. , Deming Dustin A. 
Published: June 2023

e15500 Background: Anal cancer (AC) is a relatively uncommon malignancy in the United States, however, this disease continues to increase in incidence, especially in individuals over 50 years old. Current standard of care for locoregional disease includes mitomycin and 5-fluorouracil (M/5FU) with radiation. This combination is associated with significant toxicity limiting its use in those patients who are elderly or have multiple comorbidities. Carboplatin and paclitaxel (C/P) is now the preferred standard of care treatment regimen for metastatic AC. Weekly C/P has become a standard of care option in combination with radiation for locally advanced esophageal cancer. Here we evaluate the efficacy of weekly C/P chemoradiation in treating a cohort of patients unable to receive standard M/5FU chemoradiation. Methods: Subjects were consented to an IRB approved AC registry at the University of Wisconsin Carbone Cancer Center. Patients (pts) were identified to have received weekly infusional C/P concurrent with standard-dose radiation for localized AC between January 1, 2016 and December 1, 2022. Clinical response was determined based on evidence of disease on imaging or anoscopy and toxicities were graded according to CTCAE v5. Results: 8 pts (7F/1M; median age 76 (54-87)) were found to meet eligibility criteria. 6 had perianal cancers and 2 had cancers within the anal canal. 6 had T2 disease and 2 had T3 tumors. 2 had node positive disease. Dosing ranged from C (AUC 1.5-2), P (30-50mg/m2) and radiation (50.4-58 Gy). Patients completed a median of 82.5% (40%-100%) of intended treatments. Most common toxicities included leukopenia, anemia, perianal pain, and fatigue. Grade 3 or higher toxicities included neutropenia (3) of which 2 resulted in febrile neutropenia, and anemia (3). All patients had a complete clinical response. With a median follow-up of 17 mos (3-40 mos), no patients have had recurrence and all patients are still alive. Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive M/5FU. This regimen merits further investigation in prospective clinical trials.
Study on the mechanism of CXCR3 expression in paracancer and tumor tissues of colon cancer patients.
Authors: Wang Xiaoming , Wang Sen , Zhang Yangyang , Ni Hongyan , Xu Benling , Zhao Peng , Chen Guangyu , Yuan Long 
Published: June 2023

e15506 Background: Colorectal cancer (CRC) is one of the most common types of malignant tumors, and its incidence is increasing year by year.Chemokines are small cytokines or signaling proteins secreted by cells. They have the ability to induce directional chemotactic migration of nearby responding cells and can mediate intracellular signal transduction by binding to 18 G protein-coupled receptor families.C-X-C motif chemokine receptor 3 (CXCR3) is activated by three Interferon-γ inducible ligands CXCL9, CXCL10 and CXCL11 and encodes 368 amino acids. Its molecular weight was about 41KDa and the cDNA was 1104bp in length.In recent years, a large number of studies have confirmed that the expression of CXCR3 and its ligands in the body is closely related to tumor immunity, tumorigenesis and metastasis.Therefore, the aim of this study is to investigate the expression of CXCR3 in tumor and adjacent intestinal tissues of patients with colorectal cancer and the effects of related gene detection on tumor proliferation, migration, invasion and recurrence in patients with colorectal cancer. Methods: Flow cytometry was used to detect 40 colon cancer patients who had not received neoadjuvant therapy in the Department of General Surgery of the Affiliated Cancer Hospital of Zhengzhou University. The expression of CXCR3, PD-1, CD4+, CD45+ and CD8+T cells in tumor and para-tumor specimens (taken > 2cm from the edge of the cancer) was detected, and the expression characteristics of CXCR3 in colon cancer patients and its correlation with general clinical data were analyzed. The correlation between KRAS, MSS, MSI-H gene mutations and colon cancer was analyzed under the condition of different lymphocyte expression. Results: 1.CXCR3+CD8+T cells were significantly different, and CXCR3+CD4+T cells were significantly different. These results suggest that CXCR3 expression with different lymphocytes may play an important role in tumor cell growth.2.The difference of CD45+T cells was statistically significant. This suggests that the expression of CD45+T cells may also affect tumor growth.3.CXCR3+CD4+T cells may play a role in promoting tumor metastasis. Conclusions: The expression of CXCR3+CD8+T cells, CXCR3+CD4+T cells and CD45+T lymphocytes in tumor tissues of colon cancer patients is correlated with the expression of adjacent tissues. The expression of PD-1+CD8+ lymphocytes in tumor tissues is less than that in adjacent tissues, indicating that they are related to tumor metastasis and proliferation. CXCR3 may play an important role in lymph node metastasis, and PD-1 expression may also be related to patient gender. Therefore, the expression of CXCR3 and T lymphocytes in tumor tissues and adjacent tissues of patients is helpful for the diagnosis and treatment of colon cancer, and has important value in clinical application.