Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

Influence of reduced-port laparoscopic surgery on perioperative indicators, postoperative recovery, and serum inflammation in patients with colorectal carcinoma.

BACKGROUND: Conventional five-port laparoscopic surgery, the current standard treatment for colorectal carcinoma (CRC), has many disadvantages. AIM: To assess the influence of reduced-port laparoscopic surgery (RPLS) on perioperative indicators, postoperative recovery, and serum inflammation indexes in patients with CRC. METHODS: The study included 115 patients with CRC admitted between December 2019 and May 2023, 52 of whom underwent conventional five-port laparoscopic surgery (control group) and 63 of whom underwent RPLS (research group). Comparative analyses were performed on the following dimensions: Perioperative indicators [operation time (OT), incision length, intraoperative blood loss (IBL), and rate of conversion to laparotomy], postoperative recovery (first postoperative exhaust, bowel movement and oral food intake, and bowel sound recovery time), serum inflammation indexes [high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)], postoperative complications (anastomotic leakage, incisional infection, bleeding, ileus), and therapeutic efficacy. RESULTS: The two groups had comparable OTs and IBL volumes. However, the research group had a smaller incision length; lower rates of conversion to laparotomy and postoperative total complication; and shorter time of first postoperative exhaust, bowel movement, oral food intake, and bowel sound recovery; all of which were significant. Furthermore, hs-CRP, IL-6, and TNF-α levels in the research group were significantly lower than the baseline and those of the control group, and the total effective rate was higher. CONCLUSION: RPLS exhibited significant therapeutic efficacy in CRC, resulting in a shorter incision length and a lower conversion rate to laparotomy, while also promoting postoperative recovery, effectively inhibiting the inflammatory response, and reducing the risk of postoperative complications.

Quantitative parameters of dual-layer spectral detector computed tomography for evaluating differentiation grade and lymphovascular and perineural invasion in colorectal adenocarcinoma.

PURPOSE: To explore the predictive value of dual-layer spectral detector CT (SDCT) quantitative parameters for determining differentiation grade, lymphovascular invasion (LVI) and perineural invasion (PNI) in colorectal adenocarcinoma (CRAC) patients. METHODS: A total of 106 eligible patients with CRAC were included in this study. Spectral parameters, including CT values at 40 and 100 keV, the effective atomic number (Zeff), the iodine concentration (IC), the slope of the spectral Hounsfield unit (HU) curve (λHU), and the normalized iodine concentration (NIC) in the arterial phase (AP) and venous phase (VP), were compared according to the differentiation grade and the status of LVI and PNI. The diagnostic accuracies of the quantitative parameters with statistical significance were determined via receiver operating characteristic (ROC) curves, and the area under the curve (AUC) was calculated. RESULTS: There were 57 males and 49 females aged 43-86 (69 ± 10) years. The measured values of the spectral quantitative parameters of the CRAC were consistent within the observer (ICC range: 0.800-0.926). The 40 keV-AP, IC-AP, NIC-AP, 40 keV-VP, and IC-VP were significantly different among the different differentiation grades in the CRAC (P = 0.040, AUC = 0.673; P = 0.035, AUC = 0.684; P = 0.031, AUC = 0.639; P = 0.044, AUC = 0.663 and P = 0.035, AUC = 0.666, respectively). A statistically significant difference was observed in 40 keV-VP, 100 keV-VP, Zeff-VP, IC-VP, and λHU-VP between LVI-positive and LVI-negative patients (P = 0.003, AUC = 0.688; P = 0.015, AUC = 0.644; P = 0.001, AUC = 0.688; P = 0.001, AUC = 0.703 and P = 0.003, AUC = 0.677, respectively). There were no statistically significant differences in the values of the spectral parameters of the PNI state of patients with CRAC (P > 0.05). CONCLUSION: The quantitative parameters of SDCT had good diagnostic efficacy in differentiating between different grades and statuses of LVI in patients with CRAC; however, SDCT did not have value for identifying the state of PNI.

Interactions between genistein and Wnt pathway in colon adenocarcinoma and early embryos.

The Wnt signaling pathway is one of the most ancient and pivotal signaling cascades, governing diverse processes in development and cancer regulation. Within the realm of cancer treatment, genistein emerges as a promising candidate due to its multifaceted modulation of various signaling pathways, including the Wnt pathway. Despite promising preclinical studies, the precise mechanisms underlying genistein's therapeutic effects via Wnt modulation remain elusive. In this study, we unveil novel insights into the therapeutic mechanisms of genistein by elucidating its inhibitory effects on Wnt signaling through macropinocytosis. Additionally, we demonstrate its capability to curtail cell growth, proliferation, and lysosomal activity in the SW480 colon adenocarcinoma cell model. Furthermore, our investigation extends to the embryonic context, where genistein influences gene regulatory networks governed by endogenous Wnt pathways. Our findings shed light on the intricate interplay between genistein, Wnt signaling, membrane trafficking, and gene regulation, paving the way for further exploration of genistein's therapeutic potential in cancer treatment strategies.

Effects of High-Mobility Group Box-1 on Mucosal Immunity and Epithelial Differentiation in Colitic Carcinoma.

Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.

Surgical and Oncologic Outcome following Sacrectomy for Primary Malignant Bone Tumors and Locally Recurrent Rectal Cancer.

INTRODUCTION: Bone sarcoma or direct pelvic carcinoma invasion of the sacrum represent indications for partial or total sacrectomy. The aim was to describe the oncosurgical management and complication profile and to analyze our own outcome results following sacrectomy. METHODS: In a retrospective analysis, 27 patients (n = 8/10/9 sarcoma/chordoma/locally recurrent rectal cancer (LRRC)) were included. There was total sacrectomy in 9 (incl. combined L5 en bloc spondylectomy in 2), partial in 10 and hemisacrectomy in 8 patients. In 12 patients, resection was navigation-assisted. For reconstruction, an omentoplasty, VRAM-flap or spinopelvic fixation was performed in 20, 10 and 13 patients, respectively. RESULTS: With a median follow-up (FU) of 15 months, the FU rate was 93%. R0-resection was seen in 81.5% (no significant difference using navigation), and 81.5% of patients suffered from one or more minor-to-moderate complications (especially wound-healing disorders/infection). The median overall survival was 70 months. Local recurrence occurred in 20%, while 44% developed metastases and five patients died of disease. CONCLUSIONS: Resection of sacral tumors is challenging and associated with a high complication profile. Interdisciplinary cooperation with visceral/vascular and plastic surgery is essential. In chordoma patients, systemic tumor control is favorable compared to LRRC and sarcomas. Navigation offers gain in intraoperative orientation, even if there currently seems to be no oncological benefit. Complete surgical resection offers long-term survival to patients undergoing sacrectomy for a variety of complex diseases.

Comparison of Complications in Patients with Ductal Cholangiocarcinoma (CCC) and Patients with Colorectal Liver Metastases (CRLMs) After Portal Vein Embolization (PVE): A Matched Cohort Study.

PURPOSE: To compare complications in patients with cholangiocarcinoma (CCC) and patients with colorectal liver metastases (CRLMs) after portal vein embolization (PVE) and to identify possible predictive factors. MATERIAL AND METHODS: Retrospective analysis of consecutive patients, who underwent PVE between July 2011 and March 2020. The study groups were matched for sex and age. Multivariable analysis was performed for the endpoints of complications categorized according for their respective effect on surgical treatment: "Minor" complications had no effect on subsequent surgical treatment, while "intermediate" and "severe" complications delayed or prevented surgery. RESULTS: A total of 160 patients with either CCC (n = 80) or CRLMs (n = 80) were included: 34/160 experienced complications: 27 (CCC: 21; CRLMs: 6) "minor", 4 (CCC: 3; CRLMs: 1) "intermediate", and 3 (CCC: 2; CRLMs: 1) "severe" complications respectively (p = .01). Patients with CCC received a biliary drainage 5 days on average before PVE. Baseline bilirubin levels were 1.1 mg/dl in CCC patients and 0.55 mg/dl in CRLMs patients (p < .01). Postinterventional infections were more common in CCC patients. The preintervention future liver remnant volume (odds ratio (OR) 0.93; 95% confidence interval (CI) 0.88-0.99; p = .02), body mass index (OR 1.19; 95% CI 1.04-1.36; p = .01), age (OR 0,91; 95% CI 0.84-0.99; p = .01), chemotherapy before PVE (OR 0.03; 95% CI 0.01-0.23; p < .01) and severe liver steatosis (OR 29.52; 95% CI 1.87-467,13; p = .02) were the only significant predictive factors for the occurrence of (minor) complications. CONCLUSION: PVE can be performed in CCC patients with prior biliary drainage, with similar procedural safety as in patients with CRLMs.

Association Between Membranoproliferative Glomerulonephritis and Colorectal Cancer - A Case Report.

Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular disease characterized by mesangial hypercellularity and thickening of the glomerular basement membrane (GBM). MPGN can be idiopathic or associated with malignancy, systemic immune complex disorders and chronic infections. It has rarely been associated with solid organ tumors, such as lung, gastric, breast or prostate cancer. We report a patient with MPGN and coexisting colorectal carcinoma. A 48-year-old man presented with anemia, loss of weight, hypertension, and nephrotic syndrome. The renal biopsy findings were compatible with type 1 MPGN. The antineutrophilic cytoplasmic antibodies, antinuclear antibodies, anti-GBM, serologic markers of hepatitis B and hepatitis C and tumor markers were negative. After ruling out the secondary causes of MPGN, the patient was treated with pulse doses of methylprednisolone and a single dose of cyclophosphamide. However, due to the worsening anemia and rectal bleeding, a colonoscopy was performed, which established a diagnosis of adenocarcinoma of the descending colon. The patient was treated with left hemicolectomy and oral corticosteroids. Within a year after the cancer treatment, the patient experienced a complete resolution of the proteinuria and improvement of the kidney function. Although rare, MPGN can be associated with hematologic malignancies and solid organ tumors. The most common causes of secondary MPGN should be ruled out before starting specific treatment. In our patient, cancer treatment has led to a subsequent remission of the nephrotic syndrome, which indicated that this association was not coincidental but rather causal. In patients with a tumor and concomitant glomerulopathy which is suspected to be paraneoplastic in etiology, the treatment of the underlying malignancy should be prioritized.

Targeted variant prevalence of FBXW7 gene mutation in colorectal carcinoma propagation. The first systematic review and meta-analysis.

FBXW7 is a tumour suppressor gene that functions as E3-ubiquitin-ligase, targeting numerous oncoproteins for degradation, i.e., Cyclin-E, c-Myc, and Notch. FBXW7 performs a pivotal role in regulating cell cycle progression. FBXW7 mutation is frequently implicated in various cancers. Methodology: A systematic review and meta-analysis done on several studies using "Preferred Reporting Items for Systemmatic Reviews and Meta-Analysis (PRISMA)" criteria and registered with PROSPERO (registration-number-CRD42023388845). The preliminary search comprises 1182 articles; however, 58 studies were subsequently chosen after eliminating non-eligible studies. To explore the prevalence of FBXW7 mutation among colorectal cancer patients, data were analysed using "OpenMeta Analyst and comprehensive meta-analysis-3.0 (CMA-3.0)" software. Results: This meta-analysis involves 13,974 respondents; most were males 7825/13,974, (56.0 %). Overall prevalence of FBXW7 mutations was 10.3 %, (95%CI: 8.6-12.4), I2 = 90.5 %, (P < 0.001). The occurrence of FBXW7 mutations was highest in Russia [19.0 %, (95%CI: 9.8-33.7)] and Taiwan [18.8 %, (95%CI: 8.7-35.9)], P-values< 0.05 while the least prevalence was reported in Netherland (4 %) and Italy (5 %), both P-values< 0.001. Overall prevalence of FBXW7 abberation was greatest amongst male gender: "53.9 %, (95%CI: 8.3-62.0 %)", Tumour location (colon): 59.8 %, (95%CI: 53.9-65), tumour site (left): 61.6 %, (95%CI: 53.8-68.9), Tumour-grade (Moderate): 65.9 %, (95%CI: 54.9-75.4 %), and Tumour late-stage: 67.9 %, (95%CI: 49.7-84.3 %), all P-values< 0.001. When stratified according to study-period, an increasing trend was noted from 2018 till present with the highest mutation rate recorded in 2022 (15.3 %). Conclusion: Overall prevalence of FBXW7 mutations was 10.3 % with male gender, left side, and late-stage being most mutated, and these outcomes conform with severally published articles on FBXW7 mutation.

Prognostic and therapeutic insights into colorectal carcinoma through immunogenic cell death gene profiling.

While the significance of immunogenic cell death (ICD) in oncology is acknowledged, its specific impact on colorectal carcinoma remains underexplored. In this study, we delved into the role of ICD in colorectal carcinoma, a topic not yet comprehensively explored. A novel ICD quantification system was developed to forecast patient outcomes and the effectiveness of immunotherapy. Utilizing single-cell sequencing, we constructed an ICD score within the tumor immune microenvironment (TIME) and examined immunogenic cell death related genes (ICDRGs). Using data from TCGA and GEO, we discovered two separate molecular subcategories within 1,184 patients diagnosed with colon adenocarcinoma/rectum adenocarcinoma (COADREAD). The ICD score was established by principal component analysis (PCA), which classified patients into groups with low and high ICD scores. Further validation in three independent cohorts confirmed the model's accuracy in predicting immunotherapy success. Patients with higher ICD scores exhibited a "hot" immune phenotype and showed increased responsiveness to immunotherapy. Key genes in the model, such as AKAP12, CALB2, CYR61, and MEIS2, were found to enhance COADREAD cell proliferation, invasion, and PD-L1 expression. These insights offered a new avenue for anti-tumor strategies by targeting ICD, marking advances in colorectal carcinoma treatment.

Comparison of genomic profiling of patient-matched primary colorectal and surgical resected distant metastatic (stage IV) colorectal carcinoma for drug actionability.

It is often difficult to obtain adequate tissue for genomic study from distant metastases for assessment of targeted therapy in colorectal carcinomas. The study aims to explore the genomic differences between matched distant metastatic colorectal carcinomas (mCRC) and primary carcinoma using surgical specimens of both with adequate tissue. Thirty-four paired primary and distant metastatic colorectal carcinoma samples (liver, ovary, and lung) were obtained from surgical excisions (not small biopsies) and are microsatellite stable. They were subjected to DNA sequencing using comprehensive next-generation sequencing. This included mutation concordance analysis and mutational signature analysis. The mutation concordance analysis showed 49.6% shared mutations between primary and metastatic tumours, with 23.0% mutations exclusive to primary tumours and 27.4% mutations exclusive to distant metastases. While many patients with KRAS/BRAF mutations had shared mutations, two cases had unique KRAS mutations in the primary tumours only. Additionally, TMB (tumour mutational burden) analysis revealed that half of the TMB-high (≥7.5 mutations/Mb) metastatic colorectal carcinomas had a low TMB (<7.5 mutations/Mb) in the primary tumours. The mutational signature analysis identified de novo signatures consistent with known single base substitution patterns such as SBS11 (alkylation agents) and SBS30 (base excision repair deficiency) post-chemotherapy. To conclude, this study demonstrates significant genomic variations in resected distant metastasis when compared to primary colorectal carcinomas when adequate tissue is available. This finding underscores the importance of considering these differences and selecting tissue for mutation analysis in planning targeted and effective treatment strategies for mCRC.

Unveiling the mille-feuille sign: a key to diagnosing ovarian carcinosarcoma in addition to ovarian metastasis from colorectal carcinoma on MRI.

PURPOSE: To clarify the diagnostic utility and formation of the Mille-feuille sign for ovarian carcinosarcoma (OCS) on MRI, and to evaluate the other MRI findings and serum markers compared to ovarian metastases from colorectal carcinoma (OMCRC). METHOD: Three blinded radiologists retrospectively reviewed MR images of 12 patients with OCS, 18 with OMCRC, and 40 with primary ovarian carcinoma (POC) identified by the electronic database of radiology reports. The interobserver agreement was analyzed using Fleiss' kappa test. Their MRI characteristics and tumor markers were compared using Fisher's exact test and Mann-Whitney's U test. Receiver operating characteristic curve analyses were used to determine the cutoff points for the ADC value. This study was approved by the institutional ethics committee. RESULTS: Interobserver agreement analysis was moderate or higher for all MRI characteristics. The frequency of Mille-feuille sign was comparable for both OCS and OMCRC groups, and predominantly higher than that of the POC group (p < 0.001, p < 0.001), respectively. Pathologically, the Mille-feuille sign in OCS reflected alternating layers of tumor cells with stroma and necrosis or intraluminal necrotic debris. Compared to OMCRC, intratumoral hemorrhage (p = 0.02), margin irregularity (p = 0.048), unilateral adnexal mass (p = 0.02), and low ADC values (p < 0.01) were more frequently observed and serum CEA levels was significantly lower (p = 0.007) in the OCS group. Under setting of the cutoff value of ADC at 0.871 × 10-3mm2/s, the discriminative ability for OCS showed 66.7% sensitivity, 94.4% specificity, and 81.0% accuracy, respectively. CONCLUSIONS: The Mille-feuille sign was seen in both OCS and OMCRC. MR findings of intratumoral hemorrhage, margin irregularity, unilateral adnexal mass, low ADC values, and low serum CEA levels can be useful in differentiating OCS from OMCRC.

Role of CTLA4 and pSTAT3 Immunostaining in Prognosis and Treatment of the Colorectal Carcinoma.

Background & Objective: Colorectal carcinoma (CRC) is the third leading cause of cancer-caused death worldwide and constitutes about 6.48% of all malignancies in Egypt. Studying the molecular profile of CRC is essential for developing targeted therapies. STAT3 and CTLA4 expression are considered as molecular abnormalities involved in the CRC progression and chemo-resistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate pSTAT3 and CTLA4 expression levels and their possible roles as prognostic and predictive biomarkers in CRC using immunohistochemistry (IHC). Methods: This retrospective study included 113 CRC patients. Tissue microarrays were constructed, followed by pSTAT3 and CTLA4 antibodies immunostaining. Their expression was assessed and compared with the clinicopathological parameters and survival data. Results: Both pSTAT3 and CTLA4 overexpression were significantly associated with poor prognostic parameters, such as the presence of distant metastasis (P=0.02 & 0.03), high grade (P<0.001 & 0.03), high mitotic count (P<0.001 & 0.03), high tumor budding group (P=0.008 & 0.04), infiltrating tumor border (P<0.001 & 0.007) respectively, and advanced pathological stage with pSTAT3 (P=0.02). A significant association was found between overexpression of both markers and short overall survival. Correlations between the H-score of pSTAT3 and CTLA4 in CRC showed a significant positive correlation (P<0.001). Conclusion: STAT3 and CTLA4 positivity may be linked to the development and progression of the CRC, and they may provide potential prognostic indicators and therapeutic targets for CRC patients.

Immunohistochemical Expression of Programmed Death Ligand- 1 (PD-L1) in Colorectal Carcinoma; A Cross-sectional Study.

Background & Objective: Colorectal carcinoma (CRC) is one of the most common cancers worldwide. The interaction of programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) plays an important role by inhibiting the immune mechanism by which cancer cells escape antitumor immunity. Immunotherapy using checkpoint inhibitors is a growing treatment modality in many cancers; one such is anti-PD1/PD-L1. The present study aimed to study the immunohistochemical (IHC) expression of PD-L1 in CRC and its association with various known clinicopathological parameters. Methods: This study was a 2-year prospective study and included 34 colectomy specimens diagnosed as colorectal adenocarcinoma. The expression of PD-L1 was evaluated on tumoral cells and tumor-infiltrating immune cells (TIICs) and was correlated with various clinicopathological parameters. Results: Immunohistochemical expression of PD-L1 on tumoral cells and tumor microenvironment in CRC revealed positivity in 17.65% of cases each. The PD-L1 expression on tumoral cells was associated with lymphovascular invasion (LVI) and perineural invasion (PNI) with P- values of 0.012 and 0.005, respectively, while PD-L1 expression on TIICs was associated with tumor budding with a P-value of 0.022. Conclusion: IHC expression of PD-L1 on tumoral cells and immune cells may be associated with some known poor prognostic factors. Since anti-PD1/PD-L1 is used for targeted therapy, it may be beneficial and economically feasible to evaluate PD-L1 in CRC and establish its role as a prognostic factor.

Helicobacter pylori infection is associated with the development of sporadic colorectal carcinoma and colorectal adenomatous polyps.

Helicobacter pylori (H. pylori) infection is a well-established carcinogen that has been extensively studied in the context of gastric diseases. Recent studies suggested a potential association between H. pylori and the risk of colorectal carcinoma (CRC). However, available data remains insufficient to definitively establish a causal relationship between H. pylori infection and the development of CRC and its precursor lesions. In our study, we reviewed all patients diagnosed with CRC in 2020 at our institution. H. pylori assessment was performed in all 92 CRC specimens by immunohistochemistry. Notably, two of the three patients detected with H. pylori infection are under the age of 50. Subsequently, we reviewed a total of 52 patients under the age of 50 diagnosed with CRC at our institution from 2015 to 2022. Among these patients, H. pylori infection was detected in 7 CRC specimens (13.46 %). All seven patients had adenocarcinoma on the left side of the colon. In exploring the link between H. pylori infection and the risk of developing CRC precursor lesions, we analyzed 242 patients who underwent colonoscopy guided polypectomy and also had stomach biopsies from 2015 to 2022. Of these patients, 21 were proved to be positive for H. pylori infection in the stomach, while the remaining 221 were negative. Among the H. pylori-positive group, 76.19 % (16 patients) exhibited adenomatous polyps, compared to 33.48 % (74 patients) in the H. pylori-negative patients (p=0.0001). However, no H. pylori was detected in any colonic adenomatous polyps. Our findings contribute additional evidence supporting the association between H. pylori infection and the development of sporadic CRC, probably a particular association with early-onset ones. Furthermore, gastric H. pylori infection appears to be linked to the higher prevalence of colonic adenomatous polyps, suggesting that individuals with gastric H. pylori infection may benefit from closer and earlier monitoring through colonoscopy.

Signaling pathways in colorectal cancer implications for the target therapies.

Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.

HER2-neu Expression and Survival in Colorectal Cancer in the South of Egypt; Immunohistochemistry and Genetic Study.

BACKGROUND: Colorectal cancer (CRC) is a major public health problem and one of leading cancer related death all over the world. One of the prognostic parameters that play a role in different types of cancer is HER2. However, the role of HER2 in CRC and its relation with clinicopathological features and survival is conflicting. We hypothesize that HER2 has different patterns of expression in CRC which may affect the prognosis of patients. MATERIAL & METHODS: We studied sixty specimens of colorectal carcinoma for HER2 immunohistochemistry and gene amplification and correlate it with clinicopathological features and patients` survival. RESULTS: Our data showed that negative HER2 expression was statistically associated with female gender (P = 0.010) and low & intermediate tumor budding (P = 0.030). There was a statistically significant relation between HER2 IHC and HER2 FISH amplification (P=0.000). Although neither HER2 immunoexpression and FISH amplification showed significant relation with overall survival nor disease free survival, HER2 amplified CRCs tended to have a worse survival compared with negative CRCs (40 months versus 50 months). The presence of male gender, lymphovascular invasion, nodal metastasis and distant metastasis (P = 0.013, 0.006, 0.006 and 0.000 respectively) were significantly statistically associated with poor overall survival. The presence of tumor grade III and high tumor budding (P = 0.035 and 0.007 respectively) were significantly statistically associated with shorter disease free survival. CONCLUSIONS: Our results showed that HER2 IHC 3+ staining is highly predictive of HER2 gene amplification in colorectal carcinomas. There is a tendency towards poorer prognosis in amplified HER2 CRC cases.

Demographic and clinical profile of patients undergoing colonoscopy at a tertiary care center in Nepal: a retrospective cross-sectional study.

Background: Colonoscopy is widely used as a tool for diagnosis, screening and treatment of various pathologies in the rectum, colon, and terminal ileum. The aim of this study is to evaluate the demographic, clinical, and histological parameters of the records of patients undergoing colonoscopy at a tertiary care hospital in Nepal. Materials and methods: This retrospective cross-sectional study included the hospital records of all patients who underwent colonoscopy from 2015 to 2019 in a tertiary care centre in Nepal. Results: A total of 1255 records were included in the study. The mean and standard deviation of age were 43.8 and 19 years, respectively. Among the total study population, 61.9% were males and 38.1% were females. Common indications for colonoscopy included lower gastrointestinal bleeding (27.7%), altered bowel habit (26.9%) and persistent or recurrent abdominal pain (17.3%). Only 3% of the patients who underwent colonoscopy had inadequate bowel preparation. The overall diagnostic yield of colonoscopy was 57.5%. Findings during colonoscopy included colorectal polyp (19.4%), internal haemorrhoids (8.2%) and colitis (6.5%). Having an age of 50 or more years was significantly associated with the presence of colorectal adenocarcinoma (P=0.017, χ2 test) with an odds ratio of 2.35 (95% CI: 1.14, 4.89). Furthermore, having a female sex was found to be significantly associated with the presence of colorectal adenocarcinoma (P=0.012, χ2 test) with an odds ratio of 2.43 (95% CI: 1.19, 4.97). Conclusion: In the authors' study, a smaller proportion of the colonoscopies was aimed at screening for colorectal carcinoma (CRC), when compared to studies in developed countries. The sex predisposition of CRC in the authors' study is in contrast to the global trend. The authors recommend conducting studies to determine the risk factors and need for CRC screening in the Nepalese population.

Expression levels and diagnostic value of serum GDNF, CEA and CA199 in patients with colorectal carcinoma.

Background: To investigate the expression levels and diagnostic value of glial cell line-derived neurotrophic factor (GDNF), carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) in patients with colorectal carcinoma (CRC). Methods: 50 CRC patients at our hospital from Feb. 2020 to Feb. 2021 were chosen as the malignant group, another 50 patients with benign colonic diseases were chosen as the benign group, and 50 healthy people who came to our hospital for physical examination during the same period were considered as the control group. Fasting peripheral venous blood was taken from all research subjects in the morning and tested by a fully-automated electrochemiluminometer to determine the GDNF, CEA and CA199 levels. The sensitivity and specificity of the combined detection of the three indexes for CRC were analyzed, and the receiver operating characteristic (ROC) curve was plotted to record the area under the curve (AUC). Results: The malignant group had remarkably higher CEA and CA199 levels (P<0.001) and a lower GDNF level (P<0.001) when compared with the benign and control groups. The sensitivity, specificity, positive predictive value and negative predictive value of the combined detection were 96.0%, 94.0%, 88.9% and 97.9%, respectively. Under combined detection, AUC (95% CI) = 0.950 (0.909-0.991), standard error = 0.021, and P<0.001. Conclusions: The combined diagnosis of serum GDNF, CEA and CA199 is a reliable method to improve the diagnostic accuracy of CRC, and this strategy can effectively reduce the missed diagnosis rate and has high application value in clinic.

The Relationship between Tumor Budding and Tumor Deposits in Patients with Stage III Colorectal Carcinoma.

Background/Objectives: Recently, some new morphological features of colorectal cancer have been discovered as important prognostic factors; in this paper, we study the relationship between tumor budding (TB) and tumor deposits (TDs). Methods: The retrospective cohort study included 90 patients with pathohistologically confirmed stage III CRC who were treated with radical surgical resection. All hematoxylin and eosin (H and E)-stained slides from each patient were reviewed, and histological parameters were recorded. The samples were divided into two groups with similar sizes: a group without TDs (N = 51) and a control group with TDs (N = 39). The presence and TB grade were further analyzed in these groups and compared with other clinical and histological features. Results: The prevalence of TB in the investigated cohort was unexpectedly high (94.4%). Overall, there were 23 (25.6%) Bd1, 20 (22.2%) Bd2, and 47 (52.2%) Bd3 cases. The presence of TDs was significantly associated with a higher number of TB (p < 0.001, OR 16.3) and, consequently, with a higher TB grade (p = 0.004, OR 11.04). A higher TB grade (p = 0.001, HR 2.28; 95% CI 1.93-4.76) and a growing number of TDs (p = 0.014, HR 1.52; 95% CI 1.09-2.1) were statistically significantly associated with shorter survival. Conclusions: TDs appear more often in patients with higher TB grades in stage III CRC. A higher TB grade and a growing number of TDs were statistically significantly associated with shorter overall survival. These results could give additional emphasis to the importance of TB as an adverse prognostic factor since a strong relationship with TDs has been demonstrated.