Late port-site metastasis of unexpected gallbladder carcinoma after laparoscopic cholecystectomy: A case report.

INTRODUCTION: Incidental gallbladder carcinoma refers to a discovery of gallbladder cancer during or after cholecystectomy. Late port-site metastasis (PSM) following Laparoscopic cholecystectomy (LC) is rare with an incidence rate of 10.3%. PATIENT CONCERNS: We report a case of a 58-year-old man who presented with a painful abdominal wall mass for 6 weeks. He had a history of LC for symptomatic cholelithiasis, 8 years prior. DIAGNOSIS: Histopathological examination revealed a positive result for metastatic adenocarcinoma from the abdominal wall mass. Moreover, Positron emission tomography (PET) showed a small focus of intense fluorodeoxyglucose (FDG) uptake in the gallbladder bed, which was highly suspicious for malignancy. INTERVENTION: Decision was to proceed with surgery owing to uptake in the gallbladder bed with single-site metastasis to the previous port site. In addition, in the board meeting, an agreement was reached for performing distal pancreatectomy with splenectomy owing to uncertainty of malignancy based on what was discovered during the full metastatic workup. Diagnostic laparoscopy followed by midline laparotomy performed. Radical completion cholecystectomy with lymphadenectomy was done. Followed by complete resection of the anterior abdominal wall. Distal pancreatectomy and splenectomy were then performed. OUTCOME: Pathological diagnosis showed metastatic/invasive, moderately differentiated adenocarcinoma with positive margins on the posterior surface of excised port-site mass. The positive margins necessitated further chemoradiotherapy, followed by adjuvant chemotherapy until lung metastasis was identified. After this, the patient was scheduled for palliative chemotherapy. CONCLUSION: Presence of PSM is often associated with peritoneal metastasis. For this reason, it is advised to evaluate the patient for possible metastasis.

Nanocarrier - Mediated Salinomycin Delivery Induces Apoptosis and Alters EMT Phenomenon in Prostate Adenocarcinoma.

Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo. At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma.

Randomized clinical trial on D2 lymphadenectomy versus D2 lymphadenectomy plus complete mesogastric excision in patients undergoing gastrectomy for cancer (DCGC01 study).

BACKGROUND: It is unknown whether D2 lymphadenectomy + complete mesogastric excision for gastric cancer improves survival compared with just D2 lymphadenectomy. METHODS: Between September 2014 and June 2018, patients with advanced gastric cancer were randomly assigned (1 : 1) to laparoscopic D2 lymphadenectomy or D2 lymphadenectomy + complete mesogastric excision gastrectomy. The modified intention-to-treat population was defined as patients who had pathologically confirmed gastric adenocarcinoma (pT1 N1-3 M0 and pT2-4 N0-3 M0). The primary endpoint was 3-year disease-free survival. Secondary endpoints were the recurrence pattern and overall survival. RESULTS: The median follow-up of patients in the D2 lymphadenectomy group (169 patients) and patients in the D2 lymphadenectomy +complete mesogastric excision group (169 patients) was 55 (interquartile range 37-60) months and 51 (interquartile range 40-60) months respectively. Recurrence occurred in 50 patients in the D2 lymphadenectomy group (29.6%) versus 33 patients in the D2 lymphadenectomy + complete mesogastric excision group (19.5%) (P = 0.032). The 3-year disease-free survival was 75.5% (95% c.i. 68.3% to 81.3%) in the D2 lymphadenectomy group versus 85.0% (95% c.i. 78.7% to 89.6%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.042). The HR for recurrence in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 0.99) by Cox regression (P = 0.045). The 3-year overall survival rate was 77.5% (95% c.i. 70.4% to 83.1%) in the D2 lymphadenectomy group versus 85.8% (95% c.i. 79.6% to 90.2%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.058). The HR for death in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 1.02) (P = 0.058). CONCLUSION: Compared with conventional D2 dissection, D2 lymphadenectomy + complete mesogastric excision is associated with better disease-free survival, but there is no statistically significant difference in overall survival. REGISTRATION NUMBER: NCT01978444 (http://www.clinicaltrials.gov).

Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets.

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.

Treatment Related Acute Toxicities Between Treatment with 3D-CRT and IMRT in Localised Prostate Cancer.

OBJECTIVE:  To compare the acute toxicities of two radiation treatment techniques, intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (3D-CRT) in localised prostate adenocarcinoma. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Oncology, Dr. Ziauddin Hospital, Karachi, Pakistan, from July 2016 to June 2022. METHODOLOGY: Patients with localised prostate adenocarcinoma who underwent treatment using two different advanced radiotherapy techniques i.e., IMRT and 3D-CRT were recruited during the study period. They were followed up for six months for acute gastrointestinal (GI) and genitourinary (GU) adverse events (acute toxicities) related to both treatment modalities according to Modified radiation therapy oncology group (RTOG) criteria. The acute toxicities were assessed at the 2nd, 4th, and 6th week during treatment and at the 3rd and 6th month after treatment. RESULTS:  There were 78 patients, with 39 patients in each group. The mean age was 68 ± 10 years in the 3D-CRT and 68 ± 07 years in the IMRT group. Patients in the IMRT group exhibited markedly lower treatment-related acute GI and GU effects at the end of 4th and 6th weeks for anorectal pain (p = 0.04) and (p = 0.01) and burning micturition (p = 0.003) and (p = 0.01), respectively. Furthermore, at 3 months anorectal pain (p = 0.02), loose stools (p = 0.005), and burning micturition (p = 0.01) were present and at 6 months anorectal pain was (p = 0.01) still present. CONCLUSION: Radiation therapy modalities 3D-CRT and IMRT both showed acceptable toxicity profile in the management of localised prostate cancer, while IMRT group exhibited significantly lower treatment-related acute GI and GU effects. KEY WORDS: 3D-CRT (3-Dimensional Conformal Radiation Therapy), IMRT (Intensity-Modulated Radiation Therapy), Radiation toxicity.

Clinico-pathological study of esophageal mucoepidermoid carcinoma: a 10-year survival from a single center.

BACKGROUND: Mucoepidermoid Carcinoma of the Esophagus (MECE) is a relatively rare tumor type, with most of the current data derived from case reports or small sample studies. This retrospective study reports on the 10-year survival data and detailed clinicopathological characteristics of 48 patients with esophageal MEC. METHODS: Data were collected from 48 patients who underwent curative surgery for esophageal MEC at the Fourth Hospital of Hebei Medical University between January 1, 2004, and December 31, 2020. These were compared with contemporaneous cases of Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). Using the Kaplan-Meier method and multivariate Cox regression analysis, we investigated the clinicopathological factors affecting the survival of patients with MEC. RESULTS: The incidence of MECE was predominantly higher in males, with a male-to-female ratio of approximately 7:1. The mid-thoracic segment emerged as the most common site of occurrence. A mere 6.3% of cases were correctly diagnosed preoperatively. The lymph node metastasis rate stood at 35.4%. The overall 1-year, 3-year, 5-year, and 10-year survival rates for all patients were 85.4%, 52.1%, 37.0%, and 31.0%, respectively. Post 1:1 propensity score matching, no significant statistical difference was observed in the Overall Survival (OS) between MEC patients and those with Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC) (P = 0.119, P = 0.669). Univariate analysis indicated that T staging and N staging were the primary factors influencing the prognosis of esophageal MEC. CONCLUSIONS: MECE occurs more frequently in males than females, with the mid-thoracic segment being the most common site of occurrence. The rate of accurate preoperative endoscopic diagnosis is low. The characteristic of having a short lesion length yet exhibiting significant extramural invasion may be a crucial clinicopathological feature of MECE. The OS of patients with MEC does not appear to significantly differ from those with esophageal squamous carcinoma and adenocarcinoma.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Precise and automated lung cancer cell classification using deep neural network with multiscale features and model distillation.

Lung diseases globally impose a significant pathological burden and mortality rate, particularly the differential diagnosis between adenocarcinoma, squamous cell carcinoma, and small cell lung carcinoma, which is paramount in determining optimal treatment strategies and improving clinical prognoses. Faced with the challenge of improving diagnostic precision and stability, this study has developed an innovative deep learning-based model. This model employs a Feature Pyramid Network (FPN) and Squeeze-and-Excitation (SE) modules combined with a Residual Network (ResNet18), to enhance the processing capabilities for complex images and conduct multi-scale analysis of each channel's importance in classifying lung cancer. Moreover, the performance of the model is further enhanced by employing knowledge distillation from larger teacher models to more compact student models. Subjected to rigorous five-fold cross-validation, our model outperforms existing models on all performance metrics, exhibiting exceptional diagnostic accuracy. Ablation studies on various model components have verified that each addition effectively improves model performance, achieving an average accuracy of 98.84% and a Matthews Correlation Coefficient (MCC) of 98.83%. Collectively, the results indicate that our model significantly improves the accuracy of disease diagnosis, providing physicians with more precise clinical decision-making support.

Comprehensive analysis of T-cell regulatory factors and tumor immune microenvironment in stomach adenocarcinoma.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide and is associated with high morbidity and mortality rates. However, the specific biomarkers used to predict the postoperative prognosis of patients with gastric cancer remain unknown. Recent research has shown that the tumor microenvironment (TME) has an increasingly positive effect on anti-tumor activity. This study aims to build signatures to study the effect of certain genes on gastric cancer. METHODS: Expression profiles of 37 T cell-related genes and their TME characteristics were comprehensively analyzed. A risk signature was constructed and validated based on the screened T cell-related genes, and the roles of hub genes in GC were experimentally validated. RESULTS: A novel T cell-related gene signature was constructed based on CD5, ABCA8, SERPINE2, ESM1, SERPINA5, and NMU. The high-risk group indicated lower overall survival (OS), poorer immune efficacy, and higher drug resistance, with SERPINE2 promoting GC cell proliferation, according to experiments. SERPINE2 and CXCL12 were significantly correlated, indicating poor OS via the Youjiang cohort. CONCLUSIONS: This study identified T cell-related genes in patients with stomach adenocarcinoma (STAD) for prognosis estimation and proposed potential immunotherapeutic targets for STAD.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. DESIGN: Randomised, double blind, placebo controlled, phase 3 study. SETTING: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. PARTICIPANTS: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. INTERVENTIONS: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. MAIN OUTCOME MEASURES: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. RESULTS: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. CONCLUSIONS: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03777657.

Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models.

The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.

NSUN6 mediates 5-methylcytosine modification of METTL3 and promotes colon adenocarcinoma progression.

Colon adenocarcinoma (COAD) is a common and fatal malignant tumor of digestive system with complex etiology. 5-Methylcytosine (m5C) modification of RNA by the NSUN gene family (NSUN1-NSUN7) and DNMT2 reshape cell biology and regulate tumor development. However, the expression profile, prognostic significance and function of these m5C modifiers in COAD remain largely unclear. By mining multiple integrated tumor databases, we found that NSUN1, NSUN2, NSUN5, and NSUN6 were overexpressed in COAD tumor samples relative to normal samples. Clinically, high expression of NSUN6 was significantly associated with shorter survival (including both disease-free survival and overall survival) in COAD patients. NSUN6 was further confirmed to be upregulated at both tissue and cellular levels of COAD, suggesting that NSUN6 plays a critical role in disease progression. Through comprehensive gene enrichment analysis and cell-based functional validation, it was revealed that NSUN6 promoted the cell cycle progression and cell proliferation of COAD. Mechanistically, NSUN6 upregulates the expression of oncogenic METTL3 and catalyzes its m5C modification in COAD cells. Overexpression of METTL3 significantly relieved the cell cycle inhibition of COAD caused by NSUN6 deficiency. Furthermore, NSUN6 was negatively associated with the abundance of infiltrating immune cells in COAD tumors, such as activated B cells, natural killer cells, effector memory CD8 T cells, and regulatory T cells. Importantly, pan-cancer analysis further uncovered that NSUN6 was dysregulated and heterogeneous in various tumors. Thus our findings extend the role of m5C transferase in COAD and suggest that NSUN6 is a potential biomarker and target for this malignancy.

MRI-based radiomics feature combined with tumor markers to predict TN staging of rectal cancer.

The aim of this study is to evaluate the predictive ability of MRI-based radiomics combined with tumor markers for TN staging in patients with rectal cancer and to develop a prediction model for TN staging. A total of 190 patients with rectal adenocarcinoma who underwent total mesorectal excision at the First Affiliated Hospital of the Air Force Medical University between January 2016 and December 2020 were included in the study. An additional 54 patients from a prospective validation cohort were included between August 2022 and August 2023. Preoperative tumor markers and MRI imaging data were collected from all enrolled patients. The 190 patients were divided into a training cohort (n = 133) and a validation cohort (n = 57). Radiomics features were extracted by outlining the region of interest (ROI) on T2WI sequence images. Feature selection and radiomics score (Rad-score) construction were performed using least absolute shrinkage and selection operator regression analysis (LASSO). The postoperative pathology TNM stage was used to differentiate locally advanced rectal cancer (T3/4 or N1/2) from locally early rectal cancer (T1/2, N0). Logistic regression was used to construct separate prediction models for T stage and N stage. The models' predictive performance was evaluated using DCA curves and calibration curves. The T staging model showed that Rad-score, based on 8 radiomics features, was an independent predictor of T staging. When combined with CEA, tumor diameter, mesoretal fascia (MRF), and extramural venous invasion (EMVI), it effectively differentiated between T1/2 and T3/4 stage rectal cancers in the training cohort (AUC 0.87 [95% CI: 0.81-0.93]). The N-staging model found that Rad-score, based on 10 radiomics features, was an independent predictor of N-staging. When combined with CA19.9, degree of differentiation, and EMVI, it effectively differentiated between N0 and N1/2 stage rectal cancers. The training cohort had an AUC of 0.84 (95% CI: 0.77-0.91). The calibration curves demonstrated good precision between the predicted and actual results. The DCA curves indicated that both sets of predictive models could provide net clinical benefits for diagnosis. MRI-based radiomics features are independent predictors of T staging and N staging. When combined with tumor markers, they have good predictive efficacy for TN staging of rectal cancer.

Assessing Mismatch Repair Expression by Immunohistochemistry in Colorectal Adenocarcinoma -Insight from a Tertiary Care Centre.

BACKGROUND: Microsatellite instability (MSI) is a pattern of hyper mutation that occurs at microsatellite level in the genome and result due to error in the mismatch repair system. MSI is caused by defective mismatch repair (MMR) genes associated with either hyper methylation of MMR genes or BRAF mutations. Anti-MLH-1, anti-MSH-2, anti-MSH-6 and anti-PMS2 monoclonal antibodies are used for Immunohistochemical analysis. METHODS: The immunohistochemical expression of MSI proteins were assessed in 72 cases of colorectal carcinoma. These were classified based on the expression of MLH1, MSH2, MSH6 and PMS2 proteins. RESULTS: There were 57 percent of cases showing loss of at least one antibodies, and 43 percent cases showing intact expression of all antibodies (MLH1, MSH2, MSH6 and PMS2). CONCLUSION: In conclusion, our study provides valuable insights into the expression of mismatch repair in colorectal adenocarcinoma through immunohistochemistry analysis conducted at our tertiary care centre. These findings hold significant clinical implications, suggesting further testing for BRAF and MLH1 Promoter Hypermethylation to confirm possibility of Lynch syndrome. KEY WORDS: IHC, MMR, CRC.

AGA Clinical Practice Guideline on Endoscopic Eradication Therapy of Barrett's Esophagus and Related Neoplasia.

BACKGROUND & AIMS: Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). Endoscopic eradication therapy (EET) can be effective in eradicating BE and related neoplasia and has greater risk of harms and resource use than surveillance endoscopy. This clinical practice guideline aims to inform clinicians and patients by providing evidence-based practice recommendations for the use of EET in BE and related neoplasia. METHODS: The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients, conducted an evidence review, and used the Evidence-to-Decision Framework to develop recommendations regarding the use of EET in patients with BE under the following scenarios: presence of (1) high-grade dysplasia, (2) low-grade dysplasia, (3) no dysplasia, and (4) choice of stepwise endoscopic mucosal resection (EMR) or focal EMR plus ablation, and (5) endoscopic submucosal dissection vs EMR. Clinical recommendations were based on the balance between desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 5 recommendations for the use of EET in BE and related neoplasia. Based on the available evidence, the panel made a strong recommendation in favor of EET in patients with BE high-grade dysplasia and conditional recommendation against EET in BE without dysplasia. The panel made a conditional recommendation in favor of EET in BE low-grade dysplasia; patients with BE low-grade dysplasia who place a higher value on the potential harms and lower value on the benefits (which are uncertain) regarding reduction of esophageal cancer mortality could reasonably select surveillance endoscopy. In patients with visible lesions, a conditional recommendation was made in favor of focal EMR plus ablation over stepwise EMR. In patients with visible neoplastic lesions undergoing resection, the use of either endoscopic mucosal resection or endoscopic submucosal dissection was suggested based on lesion characteristics. CONCLUSIONS: This document provides a comprehensive outline of the indications for EET in the management of BE and related neoplasia. Guidance is also provided regarding the considerations surrounding implementation of EET. Providers should engage in shared decision making based on patient preferences. Limitations and gaps in the evidence are highlighted to guide future research opportunities.

Impact of the number of therapy lines on survival in advanced gastric and esophagogastric adenocarcinoma - a real-world retrospective analysis from Croatia.

The aim of the study was to conduct a retrospective database analysis to understand the current treatment patterns and outcomes to plan potential improvements in therapy delivery and patient selection. The electronic patient medical records of 225 patients with advanced gastric and esophagogastric adenocarcinoma treated at two Croatian high-volume tertiary centers from January 2018 to December 2021 were analyzed. Patients ineligible for chemotherapy (66 of 291, 22.7%) due to poor general condition or co-morbidities were not included in the study. The median overall survival (OS) for the whole cohort was 11.0 months (95% confidence interval (CI) 9.7-12.0). Of the 225 patients who received first-line therapy, 47.6%, 16.9%, and 3.1% received second-, third-, and fourth-line therapy, respectively. Survival correlated significantly with the number of treatment lines received (p<0.001), with a median OS from diagnosis of 7.8 (95% CI 6.6-9.4), 12.0 (95% CI 10.0-14.0), and 20.0 months (95% CI 18.0-23.0) for patients receiving 1, 2, and ≥3 lines of treatment, respectively. This study confirmed the positive impact of the number of chemotherapy lines on OS. This highlights the importance of the ratio of patients receiving multiple lines of therapy as well as the availability of new and effective drugs in real-life clinical practice. The selection of optimal therapy for each patient in the first-line therapy is important because a significant number of patients do not receive second-line therapy.

Fabrication and Characterization of Colorectal Cancer Organoids from SW1222 Cell Line in Ultrashort Self-Assembling Peptide Matrix.

Ultrashort self-assembling peptides (SAPs) can spontaneously form nanofibers that resemble the extracellular matrix. These fibers allow the formation of hydrogels that are biocompatible, biodegradable, and non-immunogenic. We have previously proven that SAPs, when biofunctionalized with protein-derived motifs, can mimic the extracellular matrix characteristics that support colorectal organoid formation. These biofunctional peptide hydrogels retain the original parent peptide's mechanical properties, tunability, and printability while incorporating cues that allow cell-matrix interactions to increase cell adhesion. This paper presents the protocols needed to evaluate and characterize the effects of various biofunctional peptide hydrogels on cell adhesion and lumen formation using an adenocarcinoma cancer cell line able to form colorectal cancer organoids cost-effectively. These protocols will help evaluate biofunctional peptide hydrogel effects on cell adhesion and luminal formation using immunostaining and fluorescence image analysis. The cell line used in this study has been previously utilized for generating organoids in animal-derived matrices.

[Clinicopathological features and prognosis of early-onset gastric cancer: a large-scale retrospective real-world study].

Objective: To clarify the clinicopathological features, prognosis, and recurrence pattern of early-onset gastric cancer (EOGC). Methods: Using data from the gastric cancer database of Zhongshan Hospital, Fudan University, we performed a retrospective, large-scale, real-world study of 5046 patients with gastric cancer who had undergone redical or palliative gastrectomy from January 2013 to December 2018, including 425 patients with EOGC (age ≤45 years) and 4621 controls. All those patients were pathologically confirmed adenocarcinoma with complete follow-up of five years. Residue gastric cancer and patients without complete clinical or follow-up data were excluded. We used a combination of outpatient and telephone follow-up, ending in October 2022 (median duration of follow-up 60 months), and compared the clinicopathological features and prognosis of the two groups. Results: The clinicopathological features of EOGC included female predominance (61.1% [262/425 vs. 26.3% [1217/4621], χ2=234.215, P<0.001), fewer comorbidities (31.3% [133/425] vs. 58.5% [2703/4621], χ2=34.378, P<0.001), poorer differentiation (90.6% [385/425] vs. 78.2% [3614/4621], χ2=30.642, P<0.001), higher proportion of diffuse type (53.9% [229/425] vs. 18.3% [846/4621], χ2=274.474, P<0.001), higher proportion of T4 stage (44.7% [190/425] vs. 37.5% [1733/4621], χ2=17.535, P=0.001), more lymph node metastases (60.5% [257/425] vs. 53.9% [2491/4621], χ2=6.764, P=0.009), and higher proportion of pathological stage III/IV (47.5% [202/425] vs. 42.4% [1959/4621], χ2=4.093, P=0.043). The 5-year overall survival rates of the EOGC and control groups were 55.1% and 49.1%, respectively. Overall survival was significantly better in the EOGC than in the control group (P<0.001). According to subgroup analysis, the prognosis of pathological stage I/II/III EOGC was better than that of the control group. Recurrence rates were similar in the two groups, whereas patients with EOGC had a higher proportion of peritoneal recurrence (7.8% [33/425] vs. 3.2% [146/4621], χ2=23.741, P<0.001) and a lower proportion of distant metastasis (4.9% [21/425] vs. 8.3% [385/4621], χ2=6.247, P=0.012). Conclusion: EOGC has unique clinicopathological features and recurrence patterns and resectable EOGC has a better prognosis, suggesting that patients with EOGC should be actively treated with the focus on preventing peritoneal recurrence.

Retrospective Study of Claudin 18 Isoform 2 Prevalence and Prognostic Association in Gastric and Gastroesophageal Junction Adenocarcinoma.

PURPOSE: Claudin 18 isoform 2 (CLDN18.2) is an emerging biomarker and therapeutic target in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. This study aimed to obtain deeper understanding of CLDN18.2 positivity patterns, prognostic implications, and associations with various demographic, clinical, and molecular characteristics in G/GEJ adenocarcinoma. METHODS: Archived tumor tissue samples from 304 patients with G/GEJ adenocarcinoma in the United States were assessed for CLDN18.2 positivity by immunohistochemistry. CLDN18.2 positivity was defined as ≥50% or ≥75% of tumor cells with CLDN18 staining intensity ≥2+. CLDN18.2 positivity patterns were analyzed for association with prognosis and clinicopathologic/demographic characteristics. Where possible, CLDN18.2 positivity was analyzed for matched tissue samples to assess concordance between primary and metastatic tumors and concordance before and after chemotherapy. RESULTS: The overall prevalence of CLDN18.2-positive tumors (with ≥75% cutoff) was 44.4% (n = 135 of 304). CLDN18.2-positive tumors had a prevalence of 51.4% (n = 91 of 177) in gastric and 34.6% (n = 44 of 127) in GEJ adenocarcinoma. With a ≥50% cutoff, the prevalence of CLDN18.2-positive tumors was 64.4% (n = 114 of 177) in gastric adenocarcinoma and 44.9% (n = 57 of 127) in GEJ adenocarcinoma. There was no association between overall survival and CLDN18.2 positivity using either threshold. Statistically significant associations were noted between CLDN18.2 positivity and sex, histologic type of G/GEJ adenocarcinoma, and adenocarcinoma subtype (≥75% cutoff), and metastasis site and tumor grade (≥50% cutoff). The overall concordance of CLDN18.2 positivity (≥75% cutoff) was 73% (27 of 37) for matched primary versus metastatic tumor samples and 74% (29 of 39) for matched samples before and after chemotherapy. CONCLUSION: This study demonstrated that CLDN18.2 positivity did not correlate with survival in G/GEJ adenocarcinoma, consistent with published data. On the basis of matched sample analysis, CLDN18.2 appears to demonstrate >70% concordance as a biomarker. Observed correlations with certain patient/tumor characteristics warrant further study.