Gastrointestinal Tumors Research Articles

A clinical case of gastrointestinal stromal tumor of the duodenum

Background. Gastrointestinal stromal tumors localized in the duodenum are very rare and account for only 4–5%. They can be asymptomatic, while reaching large sizes and causing dangerous complications. Gastrointestinal stromal tumors of the duodenum are a special problem for diagnosis and treatment. Therefore, it is relevant to highlight the issue of their detection and treatment on the example of the presented clinical case. Purpose – present a description of the literature and present a rare clinical case of gastrointestinal stromal tumor of the duodenum. Material and methods. The patient, a 49-year-old woman, was diagnosed with a tumor of the abdominal cavity during a routine preventive ultrasound examination. The patient underwent a laboratory and instrumental examination, which included determination of blood and urine parameters, video esophagogastroduodenoscopy, contrast x-ray examination of the gastrointestinal tract, contrast-enhanced computer tomography and contrast-enhanced magnetic resonance imaging of the abdominal cavity. Results. The patient underwent surgical resection of the tumor of the duodenum. During the immunohistochemical study, the tumor cells were positive for markers DOG-1, CD117. As a result, «Gastrointestinal stromal tumor of the wall of the duodenum of a low degree of malignancy pT2N0M0R0» was diagnosed. During the six-month follow-up of the patient, no data on tumor recurrence were found. The relatively rare frequency of gastrointestinal tumors of the duodenum leads to difficulties at the diagnostic stage. In this clinical case, the tumor was asymptomatic, was not visualized during video esophagogastroduodenoscopy and was suspected during ultrasound examination. This indicates the importance of preventive examinations. Oncological awareness of doctors is extremely important for early diagnosis of oncology. Conclusion. Based on the analysis of the literature, the data on the epidemiology, clinical picture, methods of diagnosis and treatment of this rare pathology are displayed.

Long-term retention rate, adverse event temporal patterns and rescue treatment strategies of mycophenolate mofetil in systemic sclerosis: insights from real-life.

Mycophenolate mofetil (MMF) is a mainstay for the treatment of systemic sclerosis (SSc). The occurrence and implications of MMF-related adverse events on drug retention rates in real life remain poorly defined. We aimed to determine the MMF retention rate and to investigate the causes and patterns of discontinuation, adverse events (AEs) and treatment options used after discontinuation. SSc patients who started MMF treatment underwent a retrospective longitudinal assessment for up to 5 years. We documented the incidence, predictors, and impacts of MMF treatment on gastrointestinal intolerance, infections, laboratory abnormalities, and cancer. Rescue strategies implemented after MMF discontinuation were recorded. The 5-year MMF retention rate of 554 patients stood at 70.7% and 19.6% of them stopped MMF due to AEs. One out of every four patients experienced a dose reduction or discontinuation of MMF due to AEs, with gastrointestinal intolerance being the predominant cause. The 5-year cumulative incidence rates for gastrointestinal intolerance, cancer, severe infections, and laboratory toxicity leading to MMF discontinuation were 6.4%, 4.1%, 3.1%, and 2.1%, respectively. Lower respiratory tract was the most affected, with bacteria being the predominant causative agent. Intestinal and pulmonary circulation involvement were tied to elevated AE rates and MMF discontinuation. The most common approaches post-MMF cessation were "watch and wait" and switch to rituximab. MMF use in SSc appears to be limited by the occurrence of AEs, both in terms of persistence and dosing of the drug. Rescue options after MMF discontinuation are limited and many patients remain without immunosuppressant.

Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis

BackgroundFluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency.MethodsThe meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics.ResultsThere were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96–87.05; p < 0.05).ConclusionsThis study improves our comprehension of how the DPYD gene impacts cancer patients receiving fluoropyrimidine chemotherapy. Identifying mutations associated with dihydropyrimidine dehydrogenase deficiency may help predict the likelihood of serious side effects and fatalities. This knowledge can be applied to adjust medication doses before starting treatment, thus reducing the occurrence of these critical outcomes.Graphical abstract

SUMOylation-induced membrane localization of TRPV1 suppresses proliferation and migration in gastric cancer cells

Gastric cancer (GC) remains a significant health challenge due to its high mortality rate and the limited efficacy of current targeted therapies. A critical barrier in developing more effective treatments is the lack of understanding of specific mechanisms driving GC progression. This study investigates the role of Transient Receptor Potential Vanilloid 1 (TRPV1), a non-selective cation channel known for its high Ca2+ permeability and tumor-suppressive properties in gastrointestinal cancers. Specifically, we explore the impact of SUMOylation—a dynamic and reversible post-translational modification—on TRPV1’s function in GC. We demonstrate that SUMOylation of TRPV1 inhibits cell proliferation and migration in MGC-803 and AGS GC cells. By mutating amino acids near TRPV1’s existing SUMO motif (slKpE), we created a bidirectional SUMO motif (EψKψE) that enhances TRPV1 SUMOylation, resulting in further suppression of GC cell proliferation and migration. In vivo studies support these findings, showing that TRPV1 SUMOylation prevents spontaneous tumorigenesis in a mouse GC model. Further investigation reveals that TRPV1 SUMOylation increases the protein’s membrane expression by inhibiting its interaction with the adaptor-related protein complex 2 mu 1 subunit (AP2M1). This elevated membrane expression leads to increased intracellular Ca2+ influx, activating the AMP-activated protein kinase (AMPK) pathway, which in turn inhibits the proliferation and migration of GC cells.

Malignant pleural effusions: Are we better than the past?

Objective: Malignant pleural effusion (MPE) is indicative of advanced-stage disease and a poor prognosis in almost all cancer types. Lung and breast cancers are the predominant malignancies causing MPE, collectively representing over 60% of the total. In recent years, cancer has become a type of chronic disease, with advancements in diagnostic tools and treatment strategies. Our objective was to assess the evolution of primary diagnoses, survival rates, and associated variables among individuals with MPE in recent years. Materials and Methods: A retrospective search was conducted on the demographics, comorbidities, primary cancer sites, diagnostic interventions, and laboratory results of patients diagnosed with MPE between January 1, 2005, and July 30, 2018. Results: Of the 663 patients who have MPE, the female/male ratio was 373/290. The mean age was 59.2 ± 14.0 at the time of diagnosis. The most common cancers were lung cancer (30.9%), breast cancer (23.3%), and gastrointestinal system cancers (16.62%). It was observed that the rate of MPE due to lung cancer increased gradually over the years. Initially, breast cancer constituted the most prevalent diagnosis in 28.2% of cases, whereas lung cancer rose to the top as the most prevalent in the second and third five-year periods (28.9% and 37.4%, respectively). Overall, the median survival time was 2.07 months. Kaplan-Meier analysis also revealed that survival times did not change significantly over fourteen years. Conclusion: Advances in diagnostic methods and treatment modalities have altered the most common primary cancer causing MPE in recent years but have not contributed to survival time.

Diverse applications of probiotics in health and disease

Probiotics play diverse roles in promoting health and well-being, encompassing gut microbiota balance, digestive health, immune function, gut barrier integrity, metabolic health, and mental well-being. With the beneficial effects of probiotics, individuals may improve their gastrointestinal health, boost immune function, and reduce the risk of various diseases. These probiotics compete with pathogens and support gut and immune homeostasis to help in the prevention and cure of gastrointestinal disease, immune disorders, diabetes, obesity, cancer and allergic disorders, etc. Probiotic-rich foods and supplements into the diet offer a proactive approach to maintaining overall health and optimizing the functioning of the gut. Probiotics help to maintain immune homeostasis and decrease the risk of inflammatory disorders and allergic conditions. Several probiotic strains are available on the market and are being consumed in the form of foods, supplements, or drugs for health benefits. Lactobacilli, Bifidobacteria, and Bacillus species are common probiotic strains.

Immunotherapy of gastrointestinal malignancies (gastroesophageal and colorectal carcinoma)

esophageal cancer, gastric cancer, colorectal cancer, gastrointestinal tract tumors, immunotherapy, immune checkpoint inhibitors, anti-PD-1/L1 antibodies, anti-CTLA4 antibodies, microsatellite instability.

Unveiling the Effects of Cruciferous Vegetable Intake on Different Cancers: A Systematic Review and Dose-Response Meta-analysis.

Epidemiological studies indicated that cruciferous vegetable intake is associated with positive health outcomes. However, the role of cruciferous vegetables may have differential impacts on various cancers. This meta-analysis aims to review recent epidemiological studies on the link between cruciferous vegetables and various cancers. It seeks to identify the optimal intake dose and timing of cruciferous vegetables influencing their association with cancer risk. Studies on cruciferous vegetables and cancer were searched in PubMed, NCBI, Web of Science, and Elsevier databases from 1978 to June 2023. Extracted data from 226 relevant case-control and cohort studies were expressed by standardized mean difference and 95% CI, followed by the subgroup analysis to eliminate heterogeneity. Intake of cruciferous vegetables can prevent cancers, with an odds ratio of 0.77 and risk ratio (RR) of 0.96. The intake levels of cruciferous vegetables associated with the risk of colorectal cancer, lung cancer, upper gastrointestinal cancer, gynecological cancer (ovarian cancer and endometrial cancer), bladder cancer, renal cancer, and prostate cancer were found to be 5.41 servings/week, 5.41 servings/week, 5.5 servings/week, 7.4 servings/week, 5.5 servings/week, 4.85 servings/week, and 3 servings/week, respectively. In a cohort followed for 2 to 15 years, limited consumption of cruciferous vegetables was correlated with a higher cancer RR. In the Asian population, cruciferous vegetables had a significant relationship with lung cancer, head and neck squamous cell carcinoma, and esophageal cancer. Conversely, cruciferous vegetables are predominantly associated with colorectal, renal, gynecological, and prostate cancer in the American population. This study highlights the complex link between cruciferous vegetables and cancer, influenced by factors such as cancer type, region, intake level, and follow-up duration.

Restrictive Diets in Digestive Cancers: Prevalence, Contributing Factors, Foods Concerned and Patients' Beliefs (Prospective Study of 100 Cases)

Cancer is a major cause of disease-related malnutrition; the prevalence of malnutrition and muscle loss is high in digestive cancers and is thought to be associated with a poor prognosis. The aim of this prospective study is to investigate changes in dietary habits following a diagnosis of gastrointestinal cancer that are likely to cause or aggravate malnutrition, to assess the existence of restrictive diets involving the permanent elimination of certain essential aliments (meat, dairy products, etc.), to identify the factors that influence patients to adopt them, and to assess the degree to which patients believe in the effectiveness of these diets in curing cancer.  Materials and Methods: 100 patients aged 18 and over, diagnosed with one of the following digestive cancers: colorectal, gastric, pancreatic, oesophageal, hepatocellular carcinoma or biliary tract cancer; were interviewed using an electronic questionnaire.  Results: Among the patients we interviewed, 69% had adopted a restrictive diet following the diagnosis of digestive cancer. The products permanently eliminated included white sugar and/or sweetened foods in 83% of cases, red meat in 80%, tinned food in 77%, dairy products in 61%, spices in 54%, fried food in 49%, white meat and eggs not produced organically in 44%, processed meat in 33%, and all white meat and eggs in 17% and 14% respectively; This diet was recommended mainly by the patient’s entourage (friends and family) in 81% of cases, by other patients and their relatives (58%) and by personal research on the internet in 36% of cases. In addition, 37% of patients believe that this type of diet contributes to curing cancer.  Conclusion: 69% of patients in the study were on a restrictive diet, and more than a third of them believed that this diet could help cure their digestive cancers. Raising awareness among patients and their families is essential to prevent malnutrition and muscle loss, and thus improve the outcome of the cancer.

Electrical Tumor Detection Probe Calibrated to Diagnose Gastrointestinal Cancer Mass in Real-Time.

Background: The primary objective of this research is to propose an intra-operative tumor detection probe calibrated on human models of gastrointestinal (G.I.) cancers, enabling real-time scanning of dissected masses. Methods: Electrical Gastrointestinal Cancer Detection (EGCD) measures impedimetric characteristics of G.I. masses using a handpiece probe and a needle-based head probe. Impedance Phase Slope (IPS) and impedance magnitude (Z1kHz) are extracted as the classification parameters. EGCD was tested on palpable G.I. masses and compared to histopathology results. Results: Calibration was carried out on 120 GI mass samples. Considering pathological results as the gold standard, most cancer masses showed Z1kHz between 100 Ω and 2500 Ω while their IPS was between -15 and -1. The EGCD total sensitivity and specificity of this categorization in G.I. cancer patients with palpable tumors were 86.4% and 74.4%, respectively (p-value < 0.01). Conclusion: EGCD scoring can be used for 3D scanning of palpable tumors in G.I. tumors during surgery, which can help clarify the tumors' pathological response to neoadjuvant chemotherapy or the nature of intra-operative newly found G.I. tumors for the surgeon to manage their surgical procedure better.

Plant-Derived Alkaloids as a Potential Source of Treatment for Colorectal Cancer over the Past Five Years: A Comprehensive Review.

The gastrointestinal cancer known as colorectal cancer (CRC) is caused by a variety of genetic and epigenetic alterations in the intestinal epithelium of the colon and rectum. It is becoming more common every year. In view of this significant progress, it is urgent and imperative for researchers to work more in this direction in order to improve this health situation that is a major concern for society. Certain phenomena, such as the development of resistance by certain cells as well as the failure of certain therapies, play a part in the significantly changed situation. However, plants have always been used for their therapeutic virtues due to the large number of compounds they contain. Among them, alkaloids (more than 20,000 alkaloids have been isolated from plants, of which about 600 are known to be bioactive), which are one of the most diverse and extensively investigated classes of compounds among natural products, can be consider as a promising approach with regard to their numerous biological activities in general and, in particular their activities against colorectal cancer. This work aims to undertake deeper research on the examination of alkaloids that can be used as lead compounds in the treatment of colorectal cancer. The databases used during the literature searches were Web of Science, PubMed/Medline, and Scopus. This methodology allowed us to obtain 11 studies and 24 alkaloids (axidimins A-D, tabersonine, 19R-hydroxytabersonine, 11-hydroxytabersonine, 11-methoxytabersonine, vandrikidine, fusiformine A, 3-oxotabersonine, 3-oxo-11-methoxytabersonine, melodinine W2, venalstonidine, scandine, (-)-larutienine A, solasonin, berbamine dihydrochloride, nitidine chloride, GB7 acetate, berberine, boldine, Worenine, and chaetocochin J). Axidimin C and axidimin D showed significant cytotoxic effects on CRC (HCT116 cells) with IC50 values of 5.3 and 3.9 μM, respectively, and they were more active than 5-fluorouracil and etoposide (IC50 = 6.4 and 10.6 μM, respectively) taken as references. These two compounds induced G2/M phase arrest in HCT116 cells by downregulating cyclin B1 and cdc2 expression. Subsequently, promoting apoptosis via modulation of Bax and Bcl-2 levels, they enhanced p38 MAPK expression, leading to G2/M cell cycle arrest and apoptosis in HCT116 cells. Chaetocochin J possess significant activity against three different CRC cell lines [RKO (0.5 μM < IC50 = 0.56 μM < 1.0 μM), HCT116 (0.5 μM < IC50 = 0.61 μM < 1.0 μM) and SW480 (0.5 μM < IC50 = 0.65 μM < 1.0 μM)]. The 21 remaining compounds have a moderate anti-colorectal cancer activity. Thus, we believe that axidimin C, axidimin D and chaetocochin J could be promising compounds to fight colorectal cancer cell carcinoma. Nevertheless, future analysis should be performed on the study of the toxicologies of axidimin C and axidimin D.

Exploring the heterogeneity of interstitial cells of Cajal and their properties in gastrointestinal mesenchymal tumors applying single-cell RNA sequencing analysis

BackgroundGastrointestinal mesenchymal stromal tumors (GISTs) are a group of intramural tumors that exhibit a wide range of morphologies. Dysfunction or loss of interstitial cells of Cajal (ICCs) is correlated with the disorders of gastrointestinal motility. At present, the characterization and molecular mechanisms underlying the role of ICCs in GIST are still not clear.MethodsThe GSE162115 dataset from Gene Expression Omnibus database was processed using Seurat package for quality control, data normalization, and cell clustering. Differential expression and functional enrichment analyses were performed using the FindAllMarkers function and clusterProfiler package. Cellular heterogeneity was assessed by CytoTRACE and potential regulatory mechanisms of ICCs in GISTs were investigated using SCENIC. Cellular communication was inferred and analyzed applying the CellChat package.ResultsEight clusters were identified based on 34,861 cells. Intra-tumor samples had a higher proportion of ICCs than peri-tumor. ICCs were related to cell cycle and glycolytic activity in intra-tumor samples, while those in peri-tumor samples were involved in immune response. Further analysis identified four ICC subgroups (subcluster 1–4), of which subcluster 3 showed the most typical stem cell properties and interacted with the rest of the cells through the MIF-CD74 (CD44) protein.ConclusionThis study analyzed the heterogeneity and stem cell properties of ICCs in GISTs, revealing the molecular mechanisms and potential therapeutic targets for GISTs.

Role of immunotherapy in the overall survival of gastrointestinal cancer patients with liver metastases

Role of immunotherapy in the overall survival of gastrointestinal cancer patients with liver metastases

Effect of smoking on the risk of gastrointestinal cancer after cholecystectomy: A national population-based cohort study.

The role of smoking in the incidence of colorectal cancer (CRC) or gastric cancer (GC) in populations undergoing cholecystectomy has not been investigated. To evaluate the effect of smoking on CRC or GC development in cholecystectomy patients. A total of 174874 patients who underwent cholecystectomy between January 1, 2010 and December 31, 2017 were identified using the Korean National Health Insurance Service claims database. These patients were matched 1:1 with members of a healthy population according to age and sex. CRC or GC risk after cholecystectomy and the association between smoking and CRC or GC risk in cholecystectomy patients were evaluated using adjusted hazard ratios (HRs) and 95%CIs. The risks of CRC (adjusted HR: 1.15; 95%CI: 1.06-1.25; P = 0.0013) and GC (adjusted HR: 1.11; 95%CI: 1.01-1.22; P = 0.0027) were significantly higher in cholecystectomy patients. In the population who underwent cholecystectomy, both CRC and GC risk were higher in those who had smoked compared to those who had never smoked. For both cancers, the risk tended to increase in the order of non-smokers, ex-smokers, and current smokers. In addition, a positive correlation was observed between the amount of smoking and the risks of both CRC and GC. Careful follow-up and screening should be performed, focusing on the increased risk of gastrointestinal cancer in the cholecystectomy group, particularly considering the individual smoking habits.

Spectrum aided vision enhancer enhances mucosal visualization by hyperspectral imaging in capsule endoscopy.

Narrow-band imaging (NBI) is more efficient in detecting early gastrointestinal cancer than white light imaging (WLI). NBI technology is available only in conventional endoscopy, but unavailable in magnetic-assisted capsule endoscopy (MACE) systems due to MACE's small size and obstacles in image processing issues. MACE is an easy, safe, and convenient tool for both patients and physicians to avoid the disadvantages of conventional endoscopy. Enabling NBI technology in MACE is mandatory. We developed a novel method to improve mucosal visualization using hyperspectral imaging (HSI) known as Spectrum Aided Visual Enhancer (SAVE, Transfer N,Hitspectra Intelligent Technology Co., Kaohsiung, Taiwan). The technique was developed by converting the WLI image captured by MACE to enhance SAVE images. The structural similarity index metric (SSIM) between the WLI MACE images and the enhanced SAVE images was 91%, while the entropy difference between the WLI MACE images and the enhanced SAVE images was only 0.47%. SAVE algorithm can identify the mucosal break on the esophagogastric junction in patients with gastroesophageal reflux disorder. We successfully developed a novel image-enhancing technique, SAVE, in the MACE system, showing close similarity to the NBI from the conventional endoscopy system. The future application of this novel technology in the MACE system can be promising.

Self-reported cancer-related cognitive impairment is associated with perturbed neurotransmission pathways.

Cancer-related cognitive impairment (CRCI) is reported by 45% of patients with cancer. Significant gaps in knowledge remain regarding the mechanisms that underlie CRCI. Using a data-driven approach, the study purpose was to evaluate for perturbed pathways associated with membership in the High versus the Low CRCI profiles. Patients completed the Attentional Function Index six times over two cycles of chemotherapy. Using findings from a previous latent profile analysis, subgroups of patients with high versus low levels of CRCI were evaluated (i.e., High versus Low CRCI profiles). Gene expression was quantified using either ribonucleic (RNA)-sequencing or microarray analyses and pathway impact analyses were performed. Signaling pathways were defined using the Kyoto Encyclopedia of Genes and Genomes database. A total of 508 patients had data available for analysis. Of the 261 patients in the RNA-sequencing sample, 48.7% were in the High class and 51.3% were in the Low class. Of the 247 patients the microarray sample, 46.6% were in the High class and 53.4% were in the Low class. Pathway impact analyses identified seven perturbed pathways related to neurotransmission (i.e., glutamatergic synapse, GABAergic synapse, dopaminergic synapse, serotonergic synapse, long-term depression, cholinergic synapse, retrograde endocannabinoid signaling). This study is the first to describe associations between self-reported CRCI in patients receiving chemotherapy for breast, gastrointestinal, gynecological, or lung cancer and seven neurotransmission pathways. These findings provide new insights into potential targets for mechanistically based interventions.

Therapeutic, Clinicopathological, and Molecular Correlates of PRKACA Expression in Gastrointestinal Cancers.

PRKACA alterations have clear diagnostic and biological roles in the fibrolamellar variant of hepatocellular carcinoma and a potential predictive role in that cancer type. However, the roles of PRKACA have not been comprehensively examined in gastric and colorectal cancers (GC and CRC). This study, therefore, sought to investigate the roles of PRKACA expression in GC and CRC. The clinico-genomic data of 441 GC and 629 CRC cases were analyzed for therapeutic, clinicopathological, and biological correlates using appropriate bioinformatics and statistical tools. Furthermore, the deregulation of PRKACA expression in GC and CRC was investigated using correlative and regression analyses. The results showed that PRKACA expression subsets were enriched for gene targets of chemotherapeutics, tyrosine kinase, and β-adrenergic inhibitors. Moreover, high PRKACA expression was associated with adverse clinicopathological and genomic features of GC and CRC. Gene Ontology Enrichment Analysis also showed that PRKACA-high subsets of the GI cancers were enriched for the biological and molecular functions that are associated with cell motility, invasion, and metastasis but not cell proliferation. Finally, multiple regression analyses identified multiple methylation loci, transcription factors, miRNA species, and PRKACA copy number changes that deregulated PRKACA expression in GC and CRC. This study has identified potential predictive and clinicopathological roles for PRKACA expression in GI cancers and has added to the growing body of knowledge on the deregulation of PRKACA in cancer.

Clinical characteristics, treatment strategy, and clinical outcomes in type 2 intestinal failure

Objective: To evaluate the characteristics, clinical management and clinical outcomes of type 2 intestinal failure (IF). Methods: A descriptive case-control study was carried out. The inclusion criteria were as follows: (1) the diagnosis of IF was performed according to the European Society for Parenteral and Enteral Nutrition (ESPEN) consensus statement. (2) using a requirement for parenteral nutrition (PN) of 28 days or more as surrogate marker. (3) a multidisciplinary team (MDT) included surgeons, nutritionist, pharmacist, stoma therapists, and critical care physicians. (4) complete laboratory data. Patients with type 1 and type 3 IF and those who do not cooperate with follow-up. All the data of 67 type II IF were collected from the database in Sir Run Run Shaw Hospital from Jan 2016 to Dec 2023. The pathophysiology, clinical management, and outcomes of type II IF were analyzed. Results: A total of 67 type II IF were included. The median age was 54 (15-83) with 43 males and 24 females. The body mass index was (17.5±3.8) kg/m2, the incidence of malnutrition was 67.2% (45/67), the incidence of sarcopenia was 74.6% (50/67), the median number of previous surgeries was 2.0 (1-13), and the median duration time of PN was 2.1 (1-12) months. The underlying disease of type 2 IF included 36 Crohn`s disease, 2 ulcerative colitis, 3 radiation enteritis, 2 intestinal Behcet's disease, 4 mesenteric infarction, 1 aggressive fibromatosis, 5 abdominal cocoon syndrome, 5 gastrointestinal perforation, 1 hernia, 4 intestinal dysmotility, and 4 other reasons (gastrointestinal tumor, trauma, and non-Hodgkin's lymphoma). According to the pathophysiology of IF, there were 33 intestinal fistula, 12 intestinal dysmotility, 6 mechanical obstruction, 13 short bowel syndrome, and 3 extensive small bowel mucosal disease. After treatment with MDT, 67 patients with type 2 IF received nutritional support therapy for intestinal rehabilitation treatment, of which 36 patients recovered with oral diet or enteral nutrition, 31 patients underwent reconstructive surgery after intestinal rehabilitation treatment failure. The median duration time of reconstructive surgery was 2.7 (1-9) months. 24 patients recovered intestinal autonomy after surgery, with 7 deaths, including 6 deaths due to abdominal infections and 1 case of intestinal dysmotility with abiotrophy and liver failure. Conclusion: Standardized multidisciplinary treatment plays an important role in type II intestinal failure, and it promotes patients with intestinal failure regain enteral autonomy.

Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancer.

CLDN18.2 is a surface membrane protein crucial for maintaining tight junctions in gastric mucosal cells and is highly expressed in gastric, esophageal, and pancreatic cancers. Thus, CLDN18.2 is suited for exploration as a clinical target for chimeric antigen receptor T-cell (CAR-T) therapy in these indications. Although CAR-T therapies show promise, a challenge faced in their development for solid tumors is the immunosuppressive tumor microenvironment, often characterized by the presence of immune and stromal cells secreting high levels of transforming growth factor beta (TGF-β). Addition of TGF-β armoring can potentially expand CAR-T activity in solid tumors. We report on the preclinical development of a CLDN18.2-targeting CAR-T showing effectiveness in CLDN18.2-positive gastric, esophageal, and pancreatic tumor models. The lead lentivirus product contains a unique single-chain variable fragment, CD28 and CD3z costimulatory and signaling domains, and dominant negative TGF-β receptor armoring, enhancing targeting and safety and counteracting suppression. We developed a shortened cell manufacturing process to enhance the potency of the final product, AZD6422. AZD6422 exhibited significant antitumor activity and tolerability in multiple patient-derived tumor xenograft models with various CLDN18.2 and TGF-β levels, as determined by immunohistochemistry. Efficacy of armored CAR-Ts in tumor models with elevated TGF-β was increased in vitro and in vivo. In vitro restimulation assays established greater persistence and cytolytic function of AZD6422 compared with a traditionally manufactured CAR-T. AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.

The Gut Microbiota Impacts Gastrointestinal Cancers through Obesity, Diabetes, and Chronic Inflammation

The gut microbiota’s pivotal role in human health is increasingly evident, particularly in chronic conditions like obesity, diabetes, and inflammatory diseases. This intricate symbiotic relationship influences metabolic balance and immune responses. Notably, gut microbial dysbiosis is linked to obesity’s metabolic disruption and chronic low-grade inflammation. Similarly, in diabetes, the microbiota’s impact on insulin resistance and glucose metabolism is becoming evident. Chronic inflammation, a common denominator in these conditions, is also a recognized precursor to carcinogenesis. This intersection prompts a compelling question: does the gut microbiota’s influence extend to gastrointestinal cancers like colorectal and pancreatic cancer? These malignancies are closely intertwined with inflammation and metabolic dysregulation. Exploring whether the microbial signatures associated with chronic conditions overlap with precancerous or cancerous states offers new perspectives. This article reviews emerging evidence on the interplay between the gut microbiota, chronic conditions, and gastrointestinal cancers. By elucidating these connections, we aim to uncover potential avenues for innovative diagnostic, preventative, and therapeutic strategies in colorectal and pancreatic cancer management.