bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes and barriers to cancer care delivery for patients with rectal cancer in Nairobi, Kenya.
Authors: Wanda Dulcie , Merrell Kenneth , Ojuka Daniel , Okumu Joel Omundi , Ochieng Primus 
Published: January 2023

17 Background: Rectal cancer is among the top ten cancers in Kenya with most patients presenting with locally advanced rectal cancer (LARC). Management requires multimodality treatment including neo-adjuvant therapy and surgery. There is limited data on the outcome for patients with LARC from Kenya and the broader region. The aim of our study was to evaluate outcomes of LARC from a tertiary hospital in Nairobi, Kenya, to identify barriers to care and methods to improve cancer outcomes. Methods: We conducted a retrospective study of patients with LARC treated at the Kenyatta National Hospital between January 2016 and January 2020. Patients with histologic confirmation of rectal cancer, received neo-adjuvant treatment, and had available survival data in the electronic medical record were included in the analysis. A data abstraction tool was used to collect patient demographics and cancer outcomes including age, gender, tumor stage, cancer and vital status. Overall and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 182 patients were identified that met inclusion on the study. The median age of 53 years (range, 21 - 82) years, 52.5% were female and 94.5% had cT3 (57.5%) or cT4 (37%) disease and 75% of patients had N+ disease. The time from symptoms onset to diagnosis and diagnosis date to treatment was 14 and 3.6 months, respectively. months76% of patients were from rural regions of Kenya. Most patients (95%) received long-course chemoradiation (50.4 Gy/28 fractions) with concurrent Capecitabine 825 mg/m2 chemotherapy. Only 5% (n=9) of patients had resection after neoadjuvant therapy. The median progression free and overall survival after neo-adjuvant treatment respectively was 24 months (IQR: 23 – 25 months) and 36 months (IQR: 24 – 36 months), respectively. Presence of comorbidities (OR =7.87, 95% CI: 3.46 – 17.89, p<0.001), tumor staging cT3 (OR = 2.34, 95% CI: 1.13 – 7.49, p =0.013), tumor staging cT4 (OR =4.02, 95% CI: 2.12 – 10.34, p =0.004) and increase in duration of symptoms by one month (OR =1.04, 95% CI: 1.01 – 2.14, p =0.003) were significantly associated with lower overall survival. Conclusions: Our results represent one of the largest series of outcomes for rectal cancer from Sub-Saharan Africa and serves as a baseline for clinical improvement. The long interval from symptom onset to diagnosis represents an area for patient intervention and development of screening protocols. Further exploration into the barriers that limit access to surgery is warranted and development of a non-operative protocol may serve the patient population due to the limited capacity of surgery.
Plasma central carbon metabolite changes associated with KRAS mutation and circulating tumor DNA (ctDNA) status in colorectal cancer (CRC).
Authors: Kim Daniel Myung , Aguirre Francesca Paola , Gangi Alexandra , Alvarez Rocio , Zhou Lisa , ten Hoeve Johanna , Liao Yi Jou , Graeber Thomas , Hendifar Andrew Eugene , Osipov Arsen , Sankar Kamya , Cho May Thet , Abbas Anser , Davelaar John , Hitchins Megan Philippa , Gong Jun 
Published: January 2023

181 Background: KRAS mutations have been widely characterized as markers of poor prognosis in CRC. In stage IV CRC, KRAS mutations are predictive of benefit to anti-EGFR therapy. ctDNA has increasingly been recognized as a prognostic biomarker in CRC as well. We evaluated the association between plasma metabolites and KRAS mutation or ctDNA status in a longitudinal, observational cohort of patients with stage I-IV CRC. Methods: This was a retrospective analysis of prospectively collected blood samples from a single-institute cohort of patients with stage I-IV CRC. All blood samples were collected at pre-chemotherapy baseline. A modified Epi proColon 2.0 CE (Epigenomics AG) assay was used for plasma ctDNA testing on the methylated SEPTIN9 gene (mSEPT9). ctDNA positivity was defined as a mSEPT9 percentage of methylation reference (PMR) value greater than zero. Up to 150 metabolites of central carbon metabolism were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by ANOVA. The mean AUC was used in patients with metabolites measured from > 1 timepoint of collection. Patients were stratified by ctDNA status (positive or negative) and KRAS mutant (MT) or wildtype (WT) status. Results: A total of 32 patients were included with median age 65 years (range 20-90). The majority were female (53%) and had stage IV disease (78%). Of 25 patients with stage IV CRC, 88% had pre-chemotherapy blood samples collected in the first-line setting. Most patients were KRAS MT (44%) compared to KRAS WT (37%) or unknown KRAS status (19%). The most common KRAS MT subtypes were G12D (29%), G12V (29%), G13D (21%), and G12C (14%). The mean overall survival in this cohort was 27.4 months while the mean mSEPT9 PMR value was 2553.6. When stratified by ctDNA status, ctDNA positivity was associated with decreased levels of essential amino acids (lysine, methionine, threonine) and the non-essential amino acid arginine (all p < 0.05). Compared to KRAS WT tumors, KRAS MT tumors were associated with increased levels of proline, phenylalanine, and intermediates of glycolysis (lactate), MTA cycle (SAM, 5-Methioadenosine), and O-GlcNAcylation (GlcNac, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of associating central carbon metabolites with ctDNA and KRAS mutation status. As ctDNA positivity and KRAS MT status have evolving prognostic potential in CRC, associated metabolic signatures may identify metabolic pathways for novel biomarker development. Our findings also show that KRAS MT CRC appears to be enriched in intermediates of glycolytic, methyl donor, and O-GlcNAcylation pathways.
Comparative analysis of tumor immune microenvironment in primary tumors vs metastatic tissue in microsatellite stable metastatic colorectal cancer.
Authors: Fakih Marwan , Ye Jian , Wang Chongkai , Ashok Arya , Mauer Elizabeth , Chao Calvin Y. 
Published: January 2023

187 Background: We previously demonstrated differences in responses to checkpoint inhibitors between liver and non-liver metastases (mets) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Here, we investigate differences in tumor microenvironment (TME) and mutational landscape of primary and mCRC sites. Methods: We used the Tempus clinicogenomic database to select de-identified cases of MSS mCRC which underwent Tempus xT testing. Tempus xT is a 648-gene NGS panel that detects somatic alterations and includes RNA sequencing. Gene expression patterns of different immune cells were used to predict their relative abundance within the tumor. Analyzed tumors were divided into 4 categories based: primary tumor (colon), liver, lung, and peritoneal mets. Demographics, genomic alterations, tumor mutational burden (TMB), PD-L1 expression, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared between all 4 categories. Chi-squared/Fisher’s exact tests or Kruskal-Wallis tests were used to assess statistical significance. Results: Genomic profiles from 4,345 unique mCRC patients were analyzed (Primary CRC = 1734; Liver = 1825; Lung = 443; Peritoneal = 343). Median TMB and PD-L1 expressions had small differences across sites that were statistically significant. KRAS mutations were more frequent and SMAD4 mutations were less prevalent in lung mets. RNA-Seq revealed significant differences in immune cell composition. Lung mets exhibited a higher percentage of B cells and lower percentage of macrophages than liver and peritoneum (p< 0.001), similar to primary tumors. CD4+ T cells were highest in primary tumors, whereas CD8+ T cells were highest in lung mets (p < 0.001). Conclusions: The TME of lung mets has a more favorable immune composition (increased CD8+ T cells and B cells, decreased macrophages) than that of liver and peritoneal mets, suggesting that MSS mCRC to the lung may potentially be more responsive to immunotherapy.[Table: see text]
Biomarker analysis from a phase I/I1b study of regorafenib and nivolumab (rego/nivo) in microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Yu James , Kim Youngchul , Mehta Rutika , Miao Ruoyu , Strosberg Jonathan R. , Imanirad Iman , Kim Dae Won , Kim Richard D. 
Published: January 2023

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P<0.001), SFTPA1 ( P<0.001), ERICH6B ( P<0.001) , XIST ( P<0.001), IGHV2-26 ( P<0.001), RETNLB ( P=0.005), VWA5B1 ( P=0.033), IGHV3-53 ( P<0.001), POTEH ( P=0.015), IGHV1-3 ( P=0.001) and downregulation of 70 genes including AFAP1-AS1 ( P=0.022), PRSS21( P<0.001), NTSR1 ( P<0.001), CALB1 ( P=0.033), FAM83A ( P=0.013), TBL1Y ( P=0.045), WNT7A ( P=0.022), PADI1 ( P<0.001), KRT6A ( P=0.030), KRT17 ( P=0.002) on RNA sequencing in the DC compared to PD. GO pathway enrichment analyses revealed 44 significantly upregulated pathways including positive regulation of B cell activation ( P<0.001), B cell receptor signaling pathway ( P<0.001), Phagocytosis engulfment ( P<0.001), Fc-gamma receptor signaling pathway involved in phagocytosis ( P<0.001), endocytosis ( P<0.001), immunoglobulin receptor binding ( P<0.001), serine-type endopeptidase activity ( P<0.001) in the DC compared with PD group. Nine downregulated pathways including cell-substrate junction assembly ( P<0.001), extracellular matrix (ECM) organization ( P=0.030), and ephrin receptor activity ( P=0.046) were observed in the DC compared with PD. KEGG pathway enrichment analysis revealed 8 significantly downregulated pathways including PI3K-Akt signaling ( P=0.009), ECM-receptor interaction ( P=0.006), Focal adhesion ( P=0.028), and Glycine, serine and threonine metabolism ( P=0.007) pathways in the DC compared with PD. Conclusions: RNAseq and following gene set enrichment analysis between pts with DC and PD revealed several dysregulated pathways involving immune regulation including macrophage and B cell activation, and also PI3-Akt signaling, ECM organization/receptor interaction, and adhesion, which are consistent with previous translational studies in other solid tumors. These dysregulated genes and pathways related to differentially expressed genes may need to be further evaluated as potential predictive biomarkers for rego/nivo or other tyrosine kinase inhibitor plus PD-1 blockade in MSS-CRC.
Comparison of treatment utilization and clinical outcomes among elderly patients with colon cancer from a limited-resource and high-resource setting.
Authors: El Hajj Joanna , Sanjeevaiah Aravind , Kainthla Radhika , Al Mutar Salwan , Kazmi Syed Mohammad Ali 
Published: January 2023

20 Background: Elderly colon cancer patients face unique age-specific challenges during their treatments. The resource availability at the healthcare facility can affect their cancer-related outcomes. We evaluated the utilization of therapies and compared outcomes among elderly colon cancer patients treated in a limited-resource versus a high-resource healthcare setting. Methods: Patients >70 years of age with stage II-IV colon adenocarcinoma diagnosed between 2011 and 2017 were identified from the tumor registry of a large safety-net hospital (limited-resource setting), and an NCI-designated Comprehensive Cancer Center (high-resource setting). We compared the frequencies of categorical variables using Chi-square and Fisher’s exact tests and used a t-test to compare continuous variables between the limited-resource and high-resource setting patients. A multivariate survival analysis was performed using the Cox proportional hazard models adjusting for age, race/ethnicity [Hispanic, non-Hispanic White (NHW), and non-Hispanic Black (NHB)], BMI (<18.5 and > 18.5), gender, hospital setting (limited-resource vs. high-resource setting), staging (II, III, and IV), laterality of the tumor (right or left) and performance of surgery. Results: One-hundred-twenty-one elderly colon cancer patients were identified; the median age at diagnosis was 75 years (IQR 72-80.5), predominantly females (53%). Fifty-four patients (44.6%) received treatment in the limited-resource setting while sixty-seven (55.4%) were treated in the high-resource setting. Most patients were NHW (46%), followed by NHB (25%) and Hispanics (23%). Hispanic patients were more frequent in the limited-resource setting (44% vs 6%) while NHW were more frequent in the high-resource setting (73.8% vs. 14.8%). Utilization of surgery (83% vs. 85%, p-value = 0.8), the use of adjuvant chemotherapy for stage III colon cancer (34.8% vs. 65.2%; p-value = 0.295) and palliative chemotherapy among stage IV (39% vs. 61%; p-value = 0.5) was not significantly different among the elderly patients treated in the limited-resource setting as compared to high-resource setting. On the multivariate survival analysis, stage IV disease (p-value = 0.002) and limited-resource setting (HR = 0.37, 95% CI = 0.19-0.71, p-value = 0.003) were independently associated with survival in this cohort. Conclusions: Elderly patients treated in the limited-resource setting had lower survival as compared to those treated in the high-resource setting. There was a trend toward lower utilization of chemotherapy for stage III and IV elderly colon cancer patients in the limited-resource setting compared to the high-resource setting. The patient or system-related factors that may contribute to this disparity should be further explored.
What genes predict response to neoadjuvant chemoradiation in locally advanced rectal cancer? A systematic review based on gene expression profiling.
Authors: Or Michelle , Lin Jessica , Lam Johnson , Hau Eric , Sundaresan Puma 
Published: January 2023

200 Background: Curative management of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiation therapy (nCRT) followed by radical surgery. Pathological complete response (pCR) is seen in 15-27% of patients. The response to nCRT may be influenced by genetic variations. Gene signatures therefore may serve as biomarkers for predicting response or resistance to nCRT. We conducted a systematic review on genetic biomarkers for response prediction to nCRT in LARC and identify common genes or ontology pathways. Methods: A systematic search of electronic databases (MEDLINE, PubMed and EMBASE) was performed for relevant recent studies. Studies were screened as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with search terms “rectal neoplasm”, “rectal cancer”, “gene”, “gene expression”, “gene expression profile”. The relevant studies were selected for full-text review. Studies that reported gene expression profile to predict response to nCRT were included. Results: Twelve of 367 studies screened were included. Most studies used microarray or real-time reverse transcription PCR. Six of these assessed for gene predictors of pCR with 2 studies reporting correlation between certain genes and pCR: thymidylate synthetase; gene set (including LMNB2, MLF2, DDX1, EIF4A1, FOXO3A, ILF3 and SEMA3C); 19 genes including (NPSR1, HYAL1, FGFBP1, PLLP and MALL). Common gene ontology pathways identified included DNA break repair via homologous recombination and apoptotic pathways. Conclusions: Multiple genes were identified as prospective biomarkers for nCRT in LARC patients. Further studies are required to validate these identified genes to personalize treatment for LARC patients.
A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.
Authors: Yoshinami Yuri , Osumi Hiroki , Takashima Atsuo , Sawada Ryoichi , Ouchi Kota , Wakatsuki Takeru , Ooki Akira , Nakayama Izuma , Fukuoka Shota , Ogura Mariko , Takahari Daisuke , Chin Keisho , Hirano Hidekazu , Shoji Hirokazu , Okita Natsuko Okita , Boku Narikazu , Kato Ken , Ishizuka Naoki , Yamaguchi Kensei , Shinozaki Eiji 
Published: January 2023

206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001), and between two groups divided at the median: tumor diameter (> 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), carcinoembryonic antigen level (> 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (> 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.
Association of punctate TAK1 expression with mortality in patients with microsatellite-stable colorectal cancer.
Authors: Galbraith Norman James , Al-Badran Sara SF , Hatthakarnkul Phimmada , Pennel Kathryn AF , Quinn Jean A. , Loi Lynette , Maka Noori , Steele Colin William , Roxburgh Campbell SD , McMillan Donald C. , Horgan Paul G. , Edwards Joanne 
Published: January 2023

220 Background: Microsatellite stable (MSS) colorectal cancer continues to have limited options for personalised therapeutic targets. The NFKB pathway is known to play an important role in inflammation-related carcinogenesis but has yet to be translated into therapies for the clinical patient. The aim of this study was to investigate the expression of cytoplasmic and punctate TAK1 (transforming growth factor β-activated protein kinase 1) in colorectal cancer and its relationship to immune checkpoint expression and prognosis. Methods: Patients undergoing primary colorectal cancer resection between 1997 and 2007 at Glasgow Royal Infirmary (UK) were studied for clinicopathological data and immunohistochemistry (IHC) performed on archival FFPE tissue from resected specimens. Antibodies for TAK1, PD-1, PD-L1, IKK alpha and other proteins were used for IHC, with digital analysis (QuPath) for quantification of cytoplasmic staining and punctate score for juxta-nuclear TAK1 assessment. Kaplan-Meier curves were created with log-rank test to determine survival. Cox-proportional hazards regression were used to determine multivariate hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 898 patients who underwent colorectal resection were identified. Higher TAK1 punctate expression was observed in left colon and rectal cancer, compared with right sided disease (p = 0.045). MMR proficient tumours had higher frequencies of high TAK1 punctate expression (p < 0.001). Both cytoplasmic and punctate TAK1 expression correlated with IKK expression (p < 0.050). High cytoplasmic TAK1 expression was associated with increased PD-1 and PD-L1 expression (p < 0.001). Punctate TAK1 expression was associated with worse survival (p = 0.037). These differences were accentuated in patients with MSS status (p = 0.016). On multivariate analysis, high punctate TAK1 expression remained a predictor of worse cancer-specific survival (HR 1.843, CI 1.129-2.956, p = 0.011). Conclusions: TAK1 expression was associated with MSI status, and higher TAK1 expression correlates with upregulated PD-1 and PD-L1 expression. High punctate TAK1 expression predicted cancer-specific survival. In subgroup analysis of MSS patients, high punctate TAK1 expression was associated with poor survival. Further interrogation into this pathway may identify inflammation-related therapeutic targets in MSS patients with colorectal cancer.
Serum trefoil factor family 3 as a biomarker for the detection of colorectal cancer.
Authors: Lee Hyun Seok 
Published: January 2023

229 Background: Colorectal cancer is one of the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for timely diagnosis and effective treatment. Our aim in the present study was to detect the serum level of trefoil factor family 3 (TFF3) and evaluate the diagnostic accuracy of TFF3 in patients with colorectal cancer. Methods: We prospectively collected serum samples from 72 subjects (36 patients with colorectal cancer and 36 healthy controls) in the derivation cohort. The validation cohort prospectively included 70 subjects (35 patients with colorectal cancer and 35 healthy controls). The levels of serum TFF3 and carcinoembryonic antigen (CEA) were examined using enzyme-linked immunosorbent assay. Results: The serum levels of TFF3 in patients with colorectal cancer was significantly higher compared with that in the healthy controls (9.34±12.2 ng/mL vs. 3.60±1.58 ng/mL, P = 0.008) in the derivation cohort. Using a cutoff of 3.85 ng/mL in the derivation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of advanced colorectal cancer were 0.972, 0.611, and 0.875, respectively. The sensitivity of serum TFF3 for the detection of colorectal cancer was superior (97.2%) to that of CEA (36.1%) in the derivation cohort. In the validation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of colorectal cancer were 0.771, 0.486, and 0.751, respectively. Similarly, the sensitivity of serum TFF3 for the detection of colorectal cancer was also superior (77.1%) to that of CEA (22.9%) in the validation cohort. Conclusions: Serum TFF3 is a potential biomarker for the detection of colorectal cancer and is more effective compared with CEA.