bluuebunny/crossref_metadata_2025 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.
Genomic characterization in gastrointestinal cancer patients based on cfDNA sequencing.
Authors: Wang Minghua , Zheng Zhi , Wang Zhouyang , Cheng Shaochen , Chen Yaru , Liu Yuanyuan , Ren Xiaojing
Published: June 2023

e15507

Background: Gastrointestinal cancer (GIC) is one of the most prevalent cancers worldwide. Late stages diagnosis is one of the main reasons for poor prognosis of GIC. The invasive nature of endoscopy assay has greatly decrease the willingness for early screening, nearly 50% of patients diagnosed with GIC were in advanced stages. With the advanced of next-generation sequencing (NGS) technology, liquid biopsy has quickly gaining interest in early cancer screening. In order to address the poor prognosis of GIC, mutation features and potential biomarkers were investigated using NGS data from 169 Chinese GIC patients with blood derived cell-free DNA (cfDNA). Methods: Blood-derived cfDNA sampels were collected from Chinese patients with colorectal cancer (CRC) (n = 121) and gastric cancer (GC) (n = 48) and then performed pan-cancer sequencing panel targeting 680 cancer-related genes. Genomic alterations of single nucleotide variations, short indels and tumor mutation burden were analyzed. Two-sided Fisher’s exact test was used for all statistical analyses. COSMIC data was retrieved from COSMIC database version 97. Results: Among GC patients, the proportion of patients possessing mutations in TP53 (43.75% vs 37%, p = 0.49) and KRAS (10.42% vs 5.6%, p = 0.19) showed consistent distribution with COSMIC database. While KIT (14.58% vs 3.42%, p = 0.0014) and SYNE1 (10.42% vs 30.8%, p = 0.0021) showed varied distribution outcomes. CRC patient cohort also showed coherent distribution compared with COSMIC database. No significant difference was detected between the two cohorts in TP53 (51.5% vs 44.57%, p = 0.085), KRAS (36.53% vs 32.33%, p = 0.24), APC (44.91% vs 47.74%, p = 0.48) and PIK3CA (14.37% vs 14.10%, p = 0.91). However, the proportion of SYNE1 mutation is still significantly lower than in the COSMIC database (17.37% vs 29.31%, p = 0.0006). As all patients from the study cohort are Chinese, whether a lowered occurrence of SYNE1 mutation is specific to Chinese or certain region can be further studied. Conclusions: This study revealed that the mutational landscape of liquid biopsy cfDNA sequencing is highly consistent with existing database, which has consolidated the feasibility of liquid biopsy in early cancer detection. Besides, this study also revealed a lowered occurrence of SYNE1 and increased KIT mutation in the cohort. While increased KIT mutation can be explained by the proportion of recruited gastrointestinal stromal tumor patients, the lowered SYNE1 can provide new insights into region-specific diagnosis and treatment selection.
Prevalence of hypertension, hyperlipidemia and diabetes in colon cancer patients and its impact on physical health and quality of life reported in the All of Us research program.
Authors: Osei Noah , Eun Yong , Mohamed Salih Rajaa , Olusoji Rahman Adesoji , Ahluwalia Meena
Published: June 2023

e15515

Background: The NIH All of Us research program is a prospective, nationwide cohort study currently enrolling more than 594,000 people in the United States. Chronic diseases such as hypertension (HTN), type 2 diabetes mellitus (T2DM), and hyperlipidemia (HLD) are associated with increased morbidity and mortality in cancer patients. Few studies have assessed the impact of each illness on colon cancer patients using extensive population data in the United States. In this study, we investigate the prevalence of these disorders in colon cancer patients and how they affect physical health and quality of life using the All of Us research database. Methods: In this cross-sectional study, we included participants from All of Us dataset version 6, which includes data collected between May 6, 2018, and January 1, 2022, who had available electronic health records (EHR) data. We identified individuals with colon cancer using the ICD-9/ICD-10 diagnosis code and then examined the presence of three disease conditions from the EHR data. Each disease's prevalence and odds ratio were calculated among colon cancer patients (N = 2,366) compared to all participants with available EHR data (N = 258,188). Responses to two questions (perception of overall physical health and quality of life) were studied with options scored from 1 (Poor) to 5 (Excellent). We compared the mean scores between colon cancer patients and colon cancer patients with HLD (N = 1,254), T2DM (N = 356), and HTN (N = 1,234). The odds ratio was calculated using unconditional maximum likelihood estimation. The study compared scores using the Wilcoxon rank sum test, with a significance level of P < 0.05. Analysis was performed in the web-based platform Jupyter Notebook using the programming language R. Results: The prevalence of HTN, HLD, and T2DM in participants with colon cancer was 52.3%, 53.0%, and 15.1%, respectively, compared to 21.6%, 22%, and 7.9% in all participants. The calculated odds ratio of HTN, HLD, and T2DM in participants with colon cancer was 4.05 (95% confidence interval: 3.74-4.40), 4.06 (3.74-4.41), and 2.08 (1.86-2.33), respectively. Mean scores of physical health and quality of life were significantly lower in colon cancer with T2DM patients compared to colon cancer patients. However, the scores of participants with colon cancer and HLD or colon cancer and HTN were not significantly different from participants with colon cancer. Conclusions: Our analysis shows that individuals with colon cancer have a higher prevalence of HTN, T2DM, and HLD than all participants in the All of Us database. T2DM in colon cancer patients is associated with poor self-reported physical health and quality of life. This highlights the importance of regular screening and optimal control and management of chronic disorders in patients with colon cancer.
The risk of cerebrovascular accidents in colon cancer in the United States: A population-based national study.
Authors: Alkrekshi Akram , Al Armashi Abdul Rahman , Elantably Dina , Wang Jiasheng , Hammad Faris , Al Zubaidi Anas , Brell Joanna M.
Published: June 2023

e15516

Background: Colon cancer is the 3rd most common cause of cancer death in the United States. However, death rates have been decreasing due to increased uptake of screening and advances in treatment; as a result, there are more than 1.5 million survivors. In addition, cancer as a risk for venous thromboembolism (VTE) is established, and the underlying mechanisms of VTE are shared with arterial thromboembolism. Yet, there is a lack of population-based data to define the risk of cerebrovascular accidents (CVA) in colon cancer. Methods: Retrospectively we analyzed data from a nationwide commercial database (Explorys, IBM) from 1999 to October 2022. It aggregates records from 26 healthcare systems across 50 states with almost 80 million patients. We identified adults over 18 years old with colon cancer and obtained data on risk factors, including sex, age over 65 years, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), atrial fibrillation, obesity, and tobacco use. Multivariable logistic regression was used to adjust for the variables collected. All tests were two-sided, and a p-value ≤ 0.05 was considered statistically significant. Results: A population of 69,339,860 was included. Colon cancer was diagnosed in 304,650 (0.4%) and CVA in 237,290 (0.3%). Males made 45%. The colon cancer group, compared to the background population, had a higher prevalence of patients aged over 65 years (66.8% vs. 30.7%), HTN (61% vs. 21.1%), HLD (50.7% vs. 16.9%), DM (31.4% vs. 8.8%), obesity (20.7% vs. 8.0%), tobacco use (12.5% vs. 6.6%) and CVA (5% vs. 0.3%). Multivariable logistic regression of variable studies (Table). Colon cancer was significantly associated with CVA. Conclusions: Our study included over 69 million adults, making it the most extensive population-based study of the risk of CVA in colon cancer in the United States. After adjustment for most established risk factors that may confound the result, colon cancer was associated with a significantly increased risk of CVA, and it was preceded only by HTN. Colon cancer portrayed more risk than atrial fibrillation. Limitations of population-based studies are several, including inaccuracies and miscoding. Our findings suggest that colon cancer survivors and patients with stable disease on treatment may have their prognosis and quality of life jeopardized by CVA. Prospective studies are needed, and management of modifiable risk factors in collaboration with primary care is paramount. [Table: see text]
The risk of myocardial infarction and heart failure in colon cancer in the United States: A population-based national study.
Authors: Brell Joanna M. , Elantably Dina , Al Armashi Abdul Rahman , Wang Jiasheng , Hammad Faris , Al Zubaidi Anas , Alkrekshi Akram
Published: June 2023

e15517

Background: Colon cancer ranks third in cancer mortality and estimated new cases in the United States. Along with the improved treatment and increased participation in screening, there are more than 1.5 million survivors. Venous thromboembolism (VTE) is associated with cancers due to various mechanisms that are common with arterial thromboembolism. Still, there are limited population-based studies on the risk of myocardial infarction (MI) and heart failure (HF) in colon cancer. Methods: Retrospectively we analyzed data from a nationwide commercial database (Explorys, IBM) from 1999 to October 2022. It gathers records from 26 healthcare systems in 50 states with nearly 80 million patients. We identified adults over 18 years old with colon cancer, MI, and HF. In addition, we obtained data on risk factors, including sex, age over 65 years, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), atrial fibrillation, obesity, and tobacco use. Multivariable logistic regression (MLR) was used to adjust for the variables collected. All tests were two-sided, and a p-value ≤ 0.05 was considered statistically significant—data presented as odds ratio (OR) with a 95% confidence interval (CI). Results: A population of 69,339,860 was included. Colon cancer was diagnosed in 304,650 (0.4%), MI in 1,691,900 (2.4%), and HF in 2,415,450 (3.5%). Males made 45%. The colon cancer group, compared to the background population, had a higher prevalence of patients aged over 65 years (66.8% vs. 30.7%), HTN (61% vs. 21.1%), HLD (50.7% vs. 16.9%), DM (31.4% vs. 8.8%), obesity (20.7% vs. 8.0%), and tobacco use (12.5% vs. 6.6%). MLR of variable studies (Table). Colon cancer was significantly associated with MI and HF. Conclusions: This is the largest population-based study of the risk of MI and HF in colon cancer in the United States. After adjustment for established risk factors that may confound the result, colon cancer was independently associated with a significant increase in the risk of MI and HF. Raising awareness among oncologists and cardio-oncologists' involvement at the time of diagnosis is essential to optimally and aggressively manage modifiable risk factors. Prospective studies are needed. [Table: see text]
Identification and evaluation of a reliable, non-invasive diagnostic method using serum microRNA expression to diagnose high-risk colorectal cancer candidates.
Authors: Foo Dominic Chi-Chung , Ng Lui , Law Wai-Lun
Published: June 2023

e15519

Background: Screening is of paramount importance in early colorectal cancer detection which can significantly reduce its mortality. This study aims to identify a non-invasive diagnostic method using serum microRNA expression to diagnose colorectal cancer patients. Methods: Serum samples were prospectively collected from CRC patients or normal subjects during 2017 to 2021 in Queen Mary Hospital of Hong Kong and divided into 3 study cohorts: Training cohort (n = 129 per group), Validation cohort (n = 200 per group) and Prediction cohort (n = 260). Quantitative PCR was applied to detect the serum level of 20 candidate microRNAs. Multiple linear regression was used to formulate a serum microRNA panel for diagnosing CRC patients. The performance was evaluated by ROC analysis. The cost-effectiveness was investigating by comparing the cost of two CRC diagnostic strategies comprising of (i) colonoscopy alone and (ii) microRNA panel and followed by colonoscopy strategies to microRNA panel tested positive patients. Results: The values of 3 pairs of serum microRNAs, including miR-106b/miR-1246, miR-106b/miR-16 and miR-106b/miR-21 showed statistical significant difference between CRC patients and normal subjects. A serum microRNA panel formulated from these 3 pairs of microRNAs was able to diagnose CRC patients from normal subjects with high accuracy for both training cohort [AUC: 0.9078 (95% CI, 0.9122 To 0.9734; p < 0.0001)] and Validation cohort (AUC: 0.8904), suggesting that this microRNA panel had a consistent performance across different patient cohorts. Our prediction cohort showed that this microRNA panel was able to screen CRC patients with 85.8% sensitivity, 80.95% specificity, 86.9% positive predictive value and 79.4% negative predictive value. Cost-effectiveness analysis revealed that the strategy of combining serum miRNA test and colonoscopy was a more cost-effective approach compared to colonoscopy alone. The average cost saved per patient was around HK$4010. Conclusions: The serum miRNA test was a feasible, promising and cost-effective non-invasive biomarker for diagnosing CRC patients from normal subjects.
Genomic characterization of MSI-H and TMB in gastrointestinal cancer.
Authors: Zheng Zhi , Wang Zhouyang , Cheng Shaochen , Zhou Yujun , Liao Wenting , Zhen Baoling , Chen Yaru
Published: June 2023

e15524

Background: Microsatellite instability (MSI) is a molecular marker of a deficient in mismatch repair (MMR) system. It is one of the main hallmarks in colorectal cancer (CRC) and gastric cancer (GC), occurring in 15% and 18% of CRC and GC respectively. Mutations occur in MMR system genes will impair DNA mismatch recognition and cause accumulation of mutations in DNA microsatellite regions. As a result, microsatellite instability-high (MSI-H) patients often possess an abnormally high number of somatic mutations and would lead to high tumour mutation burden (TMB), which is a prevalent biomarker in cancer immunotherapy. Here we analysed the genomic landscape of 974 gastrointestinal cancer patients to provide new insights on the relationship between MSI, TMB and other genetic mutation characteristics. Methods: Panel sequencing targeting 680 cancer-related genes were performed on patients with colonrectal cancer (n = 569), gastric cancer (n = 375), intestinal cancer (n = 25) and oesophagal cancer (n = 5) on either fresh tumour tissue or formalin-fixed paraffin embedded tumor DNA. Genomic alterations including single nucleotide variations, short insertions and deletions, copy number variations, tumour mutation burden and micro-satellite instability were analysed. Results: Among the 974 patients, 86 patients (8.83%) were classified as MSI-H based on evaluation of 117 MMR-related loci, while rest of the patients (n = 888, 91.2%) were classified as microsatelite stable (MSS). In MSI-H cohort, 68.6% of the patients were classified as TMB-H with a TMB level higher than 10 Muts/Mb, while in MSS cohort, only 3.71% of the patients were classified as TMB-H. The TMB value of MSI-H cohort is also significantly higher than the MSS cohort (p < 0.0001, two-tailed T-test). Meanwhile, we discovered that proportion of patients with mutated lysine methyltransferase family gene KMT2D (54.65% vs 7.17%, p < 0.0001), KMT2B (48.84% vs 3.25%, p < 0.0001) and KMT2C (44.19% vs 7.17%, p < 0.0001) showed significant difference between MSI-H and MSS cohorts (Two-sided Fisher’s exact test). Conclusions: This study demonstrated that MSI-H is highly correlated with TMB-H, providing a new insight of evaluating gastrointestinal cancer treatment on MSI-H patients. The study also revealed novel MSI-H genetic mutation landscape for KMT gene family. Concurrent with recent researches, this study further boosts the potential of KMT genes to be used as a biomarker in both diagnosis and immunotherapy treatment.
Oncologic outcomes in patients with radiation associated rectal adenocarcinoma.
Authors: Omer Dana Mohamed Rashid , Verheij Floris S , Luthra Anisha , Rosen Roni , Thompson Hannah M , Romesser Paul Bernard , Paty Philip , Garcia-Aguilar Julio , Sanchez-Vega Francisco
Published: June 2023

e15529

Background: The rectal wall is often irradiated during pelvic radiotherapy for prostate cancer, potentially increasing the risk of rectal adenocarcinoma. The oncologic outcomes of rectal adenocarcinoma in previously irradiated patients remain largely unknown. Methods: We performed a retrospective analysis of patients with stage I-IV rectal adenocarcinoma after radiotherapy for prostate cancer (RCRPC). Clinical characteristics and treatment were compared to a background set of patients with rectal cancer not associated with prostate cancer (RCNAPC). We investigated the differences in survival using propensity score matching (1:1 ratio). Patients were matched based on stage, tumor size, distance from anal verge and circumferential tumor location, but were unable to be matched on age. Five-year disease-free survival (DFS), overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were visualized using Kaplan-Meier curves and statistical significance was assessed using log-rank tests. Results: The study included 66 RCRPC patients treated with prostate brachytherapy (n = 19), external beam radiation therapy (n = 31) or both (n = 16). The median latency period between the completion of prostate radiotherapy and the diagnosis of rectal cancer was 11.7 years. The median follow-up from rectal cancer diagnosis was 2.4 years. The median prostate radiation dose was 74 Gy. Compared to the 609 RCNAPC patients, the RCRPC group was older (median 78 vs 55 years, P < 0.001) and more likely to be stage I (24% vs 5%, P < 0.001). Tumors were more frequently found within the distal rectum (47% vs 22%, P < 0.001) and along the anterior rectal wall (33% vs 11%, P < 0.001). Patients in the RCRPC group were less likely to receive neoadjuvant chemotherapy (50% vs. 93%, P < 0.001), neoadjuvant radiation (21% vs 85%, P < 0.001), or undergo surgery (54% vs 61%, P < 0.001) compared to the RCNAPC group. The oncologic outcomes for the RCRPC group and matched cohort of patients with RCNAPC are presented in table 1. Conclusions: Patients with radiation associated rectal cancer have earlier stage tumors but show higher rates of distant metastasis and lower survival compared to nonirradiated patients. They are older and less likely to receive chemotherapy or radiation and are often poor candidates for radical surgery. Whether the worse outcomes are attributable to differences in patient characteristics, available treatment options or a more aggressive biology remains unknown. [Table: see text]
Colorectal cancer mortality in young adults in the United States.
Authors: Didier Alexander , Hamouda Danae M. , Sutton Jeffrey M.
Published: June 2023

e15530

Background: Colorectal cancer (CRC) is typically considered a disease that affects older adults. However, recently a concerning increase in the incidence rates of CRC among young adults (age < 50) has been noted. Given the limited analysis of colorectal cancer mortality assessing for age-based differences, we aimed to characterize trends in mortality rates of CRC between 1999 and 2020 in the United States, with the hypothesis that younger patients would also experience an increasing morality rate from CRC in concert with the increasing incidence. Methods: We queried the Centers for Disease Control database for mortality statistics with an underlying cause of death of colon and rectal cancer between the years 1999 - 2020. Crude mortality rates (CMR) were calculated per 100,000 deaths. Patients were stratified based on early-onset (30-49 years), average-onset (50-69 years), and late-onset (70+ years) CRC. For each cohort, we examined race and U.S. Census Region variables to assess drivers in mortality. Temporal trends were assessed using Joinpoint regression software. Average annual percent change (AAPC) were considered statistically significant if p < 0.05. Results: Between 1999 and 2020, 1,166,158 deaths due to CRC occurred and the CMR decreased from 20.3 to 15.7. For patients aged > 70, colorectal cancer mortality rate decreased from 148.6 to 75.9 at an average of 3.2% annually during this time frame. For the group aged 50-69, there was a decrease in CMR from 32.7 to 24.2, reflecting an average annual decrease of1.4%. In patients aged 30-49, CMR increased from 3.6 to 4.2, reflecting an average annual percent increase in mortality of 0.7%. This increase in CRC mortality in the youngest cohort occurred independent of geographical location. Mortality in young adults increased the fastest in the West at a rate of 1.1% annually and slowest in the South at 0.4% annually. Similar increases in mortality rates were identified when cohorts were stratified by race, with Non-Hispanic American Indian/Native American populations experiencing the most rapid increases in mortality at 3.4% annually. Conclusions: These results demonstrate age-related disparities in recent CRC mortality trends. While the overall mortality of CRC has decreased over the last two decades, this decrease was largely due to declining mortality in older adults. In contrast, younger adults experienced a sharp rise in CRC mortality rates, increasing at an average annual percentage increase of almost 1% each year independent of racial or geographic factors. These results highlight a concerning emerging trend with significant public health implications and provide rationale for increased surveillance in young adults.
Tumor immune environment in colitis-associated colorectal cancers: Comparison with sporadic colorectal cancers.
Authors: Li Wenliang , Xu Ning , Huang Fengchang , Yu Kun , Yang Quan
Published: June 2023

e15531

Background: Persistent inflammatory diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) contribute to the tumor initiation and progression in colitis-associated cancers (CAC). Intestinal damage caused by persistent inflammation promotes clonal expansion of somatic and epithelial cells and alters the immune microenvironment. A comprehensive investigation in comparing the tumor immune environment in CAC with sporadic colorectal cancers (CRC) will provide more clinical usefulness of immunoprofiling in CRC. Methods: Thirteen patients with CAC (6 with UC and 7 with CD) and 10 patients with sporadic colorectal cancer from our hospital were enrolled in the study. FFPE samples from patients were analyzed for the tumor infiltrating lymphocytes [PD-L1+, CD3+, CD4+, CD8+, CD20+, CD68+, CD163+] by multiplex immunofluorescence technique. The core and peritumor areas annotated by pathologists on images. Then artificial intelligence (AI) algorithms delineated the tumor-enriched segments and stroma, and calculated the density and percentage of each marker in two regions. A nonparametric approach (Kruskal–Wallis) was used to compare the density and percentage of immune cells between CAC and sporadic colorectal cancer groups. Results: In the stroma area, the density (counts per mm2) of PD-L1+CD68+ cells in patients with CAC were significantly higher than those in sporadic cancer patients (p < 0.05). However, the density of PD-L1+CD68+ did not show significant differences related to disease types (CAC or sporadic CRC) in the tumor-enriched segments. Significantly, the density of CD3+CD4+ cells and the percentage of CD68+CD163- cells in patients with CAC showed a trend of higher density than those in sporadic cancer patients in the stroma area (all, 0.05 < p < 0.1). The density and the percentage of CD20+ cells in CAC patients had a higher density tendency than those in sporadic cancer patients both in the tumor-enriched segments and stroma (all, 0.05 < p < 0.1). Other indicators in tumor-enriched segments and stroma, such as CD3+, CD4+, CD8+, CD68+CD163+ and PD-L1+, had no significant difference between CAC and sporadic CRC patients, regardless of the percentage or the density. Conclusions: We identified that the tumor immune environment of CAC was different from that of sporadic CRC. Some tumor infiltrating lymphocytes such as PD-L1+CD68+ cells infiltrated more in CAC than those in sporadic cancer, suggesting that CAC may respond better to immunotherapy than sporadic CRC. However, this hypothesis requires a further validation with a larger sample size.