Intestinal Tumors Research Articles

Chlorella alleviates the intestinal damage of tilapia caused by microplastics

Polyethylene microplastics (MPs) of the different sizes may result in different response in fish. Studies showed microorganisms adhered to the surface of MPs have toxicological effect. Juveniles tilapia (Oreochromis niloticus, n = 600, 26.5 ± 0.6 g) were dispersed into six groups: the control group (A), 75 nm MP exposed group (B), 7.5 μm group (C) and 750 (D) μm group, 75 nm + 7.5 μm+750 μm group (E) and 75 nm + Chlorella vulgaris group (F), and exposed for 10 and 14 days. The intestinal histopathological change, enzymic activities, and the integrated “omics” workflows containing transcriptomics, proteomics, microbiota and metabolomes, have been performed in tilapia. Results showed that MPs were distributed on the surface of goblet cells, Chlorella group had severe villi fusion without something like intestinal damage, as in other MPs groups. The intestinal Total Cholesterol (TC, together with group E) and Tumor Necrosis Factor α (TNFα, except for group B) contents in group F were significantly increased, cytochrome p450 1a1 (EROD, group B and E) significantly increased, adenosine triphosphate (ATP), lipoprotein lipase (LPL) and caspase 3 (except group B) also significantly increased at 14 d. At 14 days, group E saw considerably higher regulation of the actin cytoskeleton, focal adhesion, insulin signaling pathway, and AGE-RAGE signaling pathway in diabetes complications. Whereas, chlorella enhanced the focal adhesion, cytokine-cytokine receptor interaction, and MAPK signaling pathways. PPAR signaling pathway has been extremely significantly enriched via the proteomics method. Candidatus latescibacteria, C. uhrbacteria, C. abyssubacteria, C. cryosericota significantly decreased caused by MPs of different particle sizes. Carboxylic acids and derivatives, indoles and derivatives, organooxygen compounds, fatty acyls and organooxygen compounds significantly increased with long-term duration, especially PPAR signaling pathway. MPs had a size-dependent long-term effect on histopathological change, gene and protein expression, and gut microbial metabolites, while chlorella alleviates the intestinal histopathological damage via the integrated “omics” workflows.

Intestinal organoid modeling: bridging the gap from experimental model to clinical translation.

The 3D culture of intestinal organoids entails embedding isolated intestinal crypts and bone marrow mesenchymal stem cells within a growth factor-enriched matrix gel. This process leads to the formation of hollow microspheres with structures resembling intestinal epithelial cells, which are referred to as intestinal organoids. These structures encompass various functional epithelial cell types found in the small intestine and closely mimic the organizational patterns of the small intestine, earning them the name "mini-intestines". Intestinal tumors are prevalent within the digestive system and represent a significant menace to human health. Through the application of 3D culture technology, miniature colorectal organs can be cultivated to retain the genetic characteristics of the primary tumor. This innovation offers novel prospects for individualized treatments among patients with intestinal tumors. Presently established libraries of patient-derived organoids serve as potent tools for conducting comprehensive investigations into tissue functionality, developmental processes, tumorigenesis, and the pathobiology of cancer. This review explores the origins of intestinal organoids, their culturing environments, and their advancements in the realm of precision medicine. It also addresses the current challenges and outlines future prospects for development.

Impact of prophylactic wound closure in colorectal ESD on postoperative wound complications: A meta-analysis.

Endoscopic submucosa dissection (ESD) has been applied extensively in the treatment of large intestine tumours due to its high total excision ratio. Nevertheless, there is a high incidence of adverse reactions in colon ESD, and the efficacy of prophylactic ESD following ESD in prevention of postoperative haemorrhage is still disputed. The purpose of this meta-analysis is to evaluate the effectiveness of prophylaxis of wound closure in large intestine ESD after operation. For eligibility, we looked through three databases: PubMed, Embase and Cochrane Library. Heterogenity was measured by means of a chi-square method of Q-statistic and an I2 test. Fixed or random effects models were used for data processing. Based on the retrieval policy, we found a total of 1286 papers, and then we collected nine papers to extract the data. Regarding postoperative haemorrhage, there was a significant reduction in the risk of wound haemorrhage in the wound closure group than in the control group (OR, 0.29; 95% CI, 0.19-0.44 p < 0.0001). No statistical significance was found in the incidence of perforation in the wound closure and the control group (OR, 0.45; 95% CI, 0.19-1.03 p = 0.06). There was a significant reduction in the incidence of postoperation fever among those in the wound closure group than in the control group (OR, 0.37; 95% CI, 0.15-0.93 p = 0.04). Preventive endoscopic closure decreased the rate of ESD in colon disease, but did not significantly decrease the rate of postoperation perforation and postoperative fever. Future research will be required to clarify the risk factors and classify high-risk individuals in order to formulate a cost-effective prevention strategy.

Systemic inflammation in pregnant women with HIV: relationship with HIV treatment regimen and preterm delivery.

HIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD. A nested 1 : 1 case-control study ( N = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (<37 weeks of gestational age). The following inflammatory biomarkers were measured in plasma samples using immunoassays: soluble CD14 (sCD14) and sCD163, intestinal fatty acid-binding protein, interleukin (IL)-6, interferon γ, and tumor necrosis factor α. We fit regression models to assess associations between second trimester biomarkers (measured before ART initiation at 13-23 weeks of gestational age and 4 weeks later), treatment regimen, and PTD. We also assessed whether inflammation was a mediator in the relationship between ART regimen and PTD. Persistently high interleukin-6 was associated with increased PTD. Compared with zidovudine alone, the difference in biomarker concentration between week 0 and week 4 was significantly higher ( P < 0.05) for both protease inhibitor-based regimens. However, the estimated proportion of the ART effect on increased PTD mediated by persistently high biomarker levels was 5% or less for all biomarkers. Persistently high IL-6 during pregnancy was associated with PTD. Although protease inhibitor-based ART was associated with increases in inflammation, factors other than inflammation likely explain the increased PTD in ART-based regimens compared with zidovudine alone.

Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

Connecting atrial fibrillation to digestive neoplasms: exploring mediation via ischemic stroke and heart failure in Mendelian randomization studies.

Notwithstanding the acknowledged interplay between atrial fibrillation (AF) and the emergence of digestive system neoplasms, the intricacies of this relationship remain ambiguous. By capitalizing univariable Mendelian Randomization (MR) complemented by a mediated MR tactic, our pursuit was to elucidate the causative roles of AF in precipitating digestive system malignancies and potential intermediary pathways. This research endeavor seeks to scrutinize the causal clinical implications of whether genetic predispositions to AF correlate with an increased risk of digestive system malignancies, employing MR analytical techniques. Utilizing a dataset amalgamated from six studies related to AF, encompassing over 1,000,000 subjects, we performed univariable MR assessments, employing the random-effects inverse-variance weighted (IVW) methodology as our principal analytical paradigm. Subsequently, a mediated MR framework was employed to probe the potential mediating influence of AF on the nexus between hypertension (HT), heart failure (HF), ischemic stroke (IS), coronary artery disease (CAD), and digestive system neoplasms. The univariable MR evaluation unveiled a notable causal nexus between the genetic inclination toward AF and the genetic susceptibility to colon, esophageal, and small intestine malignancies. The mediated MR scrutiny ascertained that the genetic inclination for AF amplifies the risk profile for colon cancer via IS pathways and partially explains the susceptibility to esophageal and small intestine tumors through the HF pathway. Our investigative endeavor has highlighted a definitive causative association between genetic inclination to AF and specific digestive system neoplasms, spotlighting IS and HF as instrumental mediators. Such revelations furnish pivotal perspectives on the complex genetic interconnections between cardiovascular anomalies and certain digestive tract tumors, emphasizing prospective therapeutic and diagnostic worthy of pursuit.

Diagnosis and staging of small intestinal neuroendocrine tumors with CT enterography and PET with Gallium-68: preoperative risk stratification protocol.

Pre-operative diagnosis and staging of small intestine neuroendocrine tumors (SI-NETs) remain sub-optimal, with open palpation during surgery still considered the gold standard. This limits a standardized implementation of minimally invasive surgery (MIS). The aim of this single-center retrospective study was to assess a tailored diagnostic work-up to identify candidates at low risk of undetected disease who may benefit from MIS. Patients diagnosed with SI-NETs between 2013 and 2022 who underwent contrast-enhanced computed tomography enterography (CTE) and Ga68-DOTATOC-positron emission tomography-CT (68Ga DOTATATE PET/CT) preoperatively and subsequently underwent open surgical resection were included. Imaging studies were reassessed by two radiologists. Combined use of CTE and 68Ga DOTATATE PET/CT in determining primary lesion disease burden (number of lesions) and LN disease stage (distal and proximal relative to superior mesenteric vessels) was assessed, using surgical reports and pathology as gold standard. Overall, 56 patients were included. Sensitivity of CTE and 68Ga DOTATATE PET/CT for at least one primary SI-NET was 100% and 94%, respectively. In the presence of concordance between studies, combined use of CTE and 68Ga DOTATATE PET/CT for detection of single primary tumors improved specificity to 89% (n = 25/28) with a positive predictive value of 87.5% (n = 21/24). Distal LN disease was identified in 89.2% of cases (n = 33/37). The association of single lesion and distal LN disease was found pre-operatively in 32% of patients (n = 18). Combined use of CTE and 68Ga DOTATATE PET/CT enables identifying low-risk surgical candidates (single SI-NET lesions with distal LN disease).

BAMLET administration via drinking water inhibits intestinal tumor development and promotes long-term health

Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET (bovine alpha-lactalbumin made lethal to tumor cells) can act as a peroral treatment for colorectal cancer. ApcMin/+ mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/β-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone ApcMin/+ mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.

Multicentric lymphoma in a donkey with intestinal and bone marrow involvement

BackgroundLymphoma is a common neoplasm in horses but is reported much less commonly in donkeys. In this case report, we describe the macroscopic, microscopic and immunohistochemical features of a multicentric lymphoma with intestinal and bone marrow involvement.Case presentationA geriatric female donkey with history of chronic lameness was found dead. Post-mortem examination revealed advanced emaciation, periodontal disease, left front foot laminitis and multiple, soft, white to yellow tan intestinal transmural masses, up to 12 cm in diameter. Cytology suggested a round cell intestinal neoplasm. The femur of the left hint limb was double the size of the normal contralateral, with suspected neoplastic infiltration and replacement of bone marrow and bone. Histologically we diagnosed a lymphoma in the intestine and left femur. Immunohistochemically, the neoplastic cells showed CD3 immunolabelling, supporting a diagnosis of a multicentric T-cell lymphoma.ConclusionsTo the authors’ knowledge, this is the first time multicentric lymphoma is diagnosed in donkeys. Further studies of the genetic background, clinical, laboratory, histopathologic, and immunohistochemical, as well as the pathogenesis of lymphoma, is needed to better understand the uniquely low frequency of this neoplasm in donkeys.

Gastric foreign body granuloma resembling gastric cancer: a case report

Fishbones are frequently swallowed by foreign objects that can penetrate the gastrointestinal tract. Nonetheless, it is quite uncommon for these fishbones to become lodged within the tract, resulting in the formation of foreign body granulomas that resemble submucosal tumors. When encountering this situation, it's important to consider differential diagnoses such as gastric intestinal stromal tumor, gastric leiomyoma, and gastric neurofibroma. We present a case of gastric foreign body granuloma that presents with dull aching epigastric pain. The patient gave a vague history of displaced intrauterine contraceptive devices (IUCD). Contrast CT and PET scan showed a gastric antral mass possibly a gastric cancer or a migrating IUCD. Endoscopic ultrasound (EUS) suggested a perigastric foreign body reaction due to the presence of a linear echogenic structure in between the markedly thickened gastric antral wall and the right lobe of the liver. EUS-guided fine needle biopsy (EUS-FNB) revealed non-specific inflammatory reaction. Afterward, surgical exploration unveiled the cause of the mass as a foreign body granuloma caused by a perforating fishbone.

Genomic comparison of urothelial mucinous adenocarcinoma and colorectal mucinous adenocarcinoma biomarkers and therapeutic implications.

650 Background: Urothelial mucinous adenocarcinoma (UC-MUC-AC), arising from the urothelium, is a rare condition (&lt;2%), typically presenting at an advanced stage with an unfavorable prognosis. The lack of a standard treatment protocol adds complexity, requiring the extension of treatments from UC or organ-specific MUC-AC such as colorectal. Notably, UC-AC bears a histopathological resemblance to intestinal tumors, constituting the predominant subtype. Alternatively, treatment decisions based on gene expression similarities in lieu of histological similarities are an evolving concept in rare cancers. This is an unexplored area in UC-MUC-AC treatment, prompting our hypothesis that an all-encompassing genomic profile could reveal analogous biomarkers shared with CRC-MUC-AC. Methods: Three techniques: DNA sequencing, RNA sequencing (WTS), and immunohistochemistry (IHC) sequencing (protein) with varying measures for gene expression were analyzed at Caris Life Sciences in Phoenix, AZ. Histopathology was used to categorize five cancer site groups: (1) UC arising in the bladder, ureter, urethra, or renal pelvis with any transitional cell carcinoma (TCC)-non-MUC-nonAC [N156 samples], (2) UC nonTCC-nonMUC-AC [N83], (3) UC-MUC-AC [N16], (4) CRC-MUC-AC [N3100] and (5) CRC nonMUC-AC [N38205]. Our primary aim was to determine which group was closest to Group 3, our control. Our secondary aim was to determine if Group 2 was genetically closer to Group 1 or 5. Only genes with positive expression were included in the cluster analysis. ANOVA analysis was conducted to further explore the relationships between the groups. A log transformation was performed to achieve normality. To further investigate pairwise comparisons, a post hoc Dunnett test was employed. Results: In our first analysis, Group 3 UC-MUC-AC gene expression ratio was predominately associated with UC Groups 1 &amp; 2 (24 of 33), and farther to CRC Groups 4 &amp; 5 (9/33) (all p-values &gt;0.05). In the second analysis, the ANOVA overall model comparing gene expression between the histological groups 1, 2 &amp; 5 was statistically significant (p=0.0018). The Dunnett test revealed a farther difference between Group 2, UC nonTCC-nonMUC adenocarcinoma, and 5, CRC non-MUC-AC (p-value =0.001), but closest between Group 2 and 1, UC-TCC-nonMUC-nonAC (p =0.100). Conclusions: Our findings indicate that next-generation sequencing technology has the potential to aid in treatment decisions based on the site of origin, such as UC-AC, rather than relying on traditional histopathological descriptive approaches for extrapolating evidence from treatment protocols used for other cancer origins like CRC. Future research on artificial intelligence could aid physicians with more informed treatment decisions by providing additional insight into how closely tumors match cancer types' genomic and transcriptomic signatures.

Abstract B011: Lower incidence of small intestinal adenocarcinomas may be due to constrained copy number karyotype and increased immune surveillance

Abstract Aim: To evaluate the genomic profiles of duodenal adenocarcinomas and explore the role of the immune system in the evolution of these cancers. Introduction: Tumours of the small intestine are rare and represent the smallest fraction of all gastrointestinal (GI) cancers despite being the largest organ in the GI tract. As a result, they have not been well characterised at the molecular level, and consequently are often clinically managed similarly to colorectal cancers. Methods: Here we performed shallow whole-genome sequencing (sWGS) on 125 cases of the most common adenocarcinomas in the small intestine, duodenal adenocarcinomas, and compared their somatic copy number aberrations to 880 upper and lower GI primary adenocarcinomas from the TCGA. Furthermore, we reanalysed published whole exome sequencing (WEX) from a further 91 small intestinal carcinomas to assess the immune landscape. Results: In our sWGS cohort, we found that duodenal adenocarcinomas have a significantly lower incidence of genome doubling (20%) than elsewhere in the GI tract (colon=43.6%, stomach=44%, rectum=55%, oesophagus=64.3%). Percentage of genome altered (PGA) is affected by the amount of genome doubling present, by median centering the proportion of the genome altered we could circumvent this. Duodenal cancers also had a significantly lower median centered percentage genome aberrated (mPGA) than colon (p=6.3 × 10-4, es=0.176), rectal (p=3 × 10-5, es=0.279), stomach (p=1.5 × 10-8, es=0.309) and oesophageal (p=1.2 × 10-11, es=0.546) adenocarcinomas. Inter-tumour heterogeneity of copy number alterations was lowest in duodenal cancers compared to other GI cancer types (p&amp;lt;2.22 × 10-16 for all and effect size &amp;gt; 0.7 for all). Within the previously published WEX cohort of small intestinal adenocarcinomas, we observed a higher proportion of clonal mutations that are neoantigens (vs not-neoantigens) in immune escaped tumours than non-escaped tumours (p=0.016) and found that small intestinal tumours are more likely to be immune escaped than colon cancers. Escaped small intestinal tumours were associated with a significantly decreased overall survival compared to non-escaped tumours (HR 2.197 (95% CI, 1.736– 46.63); p=0.009). Further, dNdS analysis indicated strong immune-mediated negative selection on clonal non-synonymous mutations in the immunopeptidome in most tumours. Conclusions: The decreased inter-tumour heterogeneity of karyotypes amongst small intestinal cancers compared to other GI cancers could indicate more restricted routes for karyotype evolution in the small intestine. Our data also suggest a more pertinent role for immune-predation than elsewhere in the GI tract. Together this may explain their lower incidence. Citation Format: Salpie Nowinski, Vickna Balarajah, Ann-Marie Baker, Riku Katainen, Christine Hughes, Qingli Guo, Luis Zapata, Eszter Lakatos, Hemant M. Kocher, Trevor A. Graham. Lower incidence of small intestinal adenocarcinomas may be due to constrained copy number karyotype and increased immune surveillance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B011.

A rare but interesting case of small intestinal tumor diagnosed by transrectal EUS-FNA (with video).

A rare but interesting case of small intestinal tumor diagnosed by transrectal EUS-FNA (with video).

Prognostic factors for liver metastasis in patients with small intestinal stromal tumor: A retrospective analysis of surveillance, epidemiology, and end results.

Liver metastasis (LIM) is the most common distant site of metastasis in small intestinal stromal tumors (SISTs). The aim of this study was to determine the risk and prognostic factors associated with LIM in patients with SISTs. Patients diagnosed with gastrointestinal stromal tumors between 2010 and 2019 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression models, as well as a Cox regression model were used to explore the risk factors associated with the development and prognosis of LIM. Additionally, the overall survival (OS) of patients with LIM was analyzed using the Kaplan-Meier method. Furthermore, a predictive nomogram was constructed, and the model's performance was evaluated using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). A total of 1582 eligible patients with SISTs were included, among whom 146 (9.2%) were diagnosed with LIM. Poor tumor grade, absence of surgery, later T-stage, and no chemotherapy were associated with an increased risk of developing LIM. The nomogram prediction model achieved an AUC of 0.810, 95% Confidence Interval (CI) 0.773-0.846, indicating good performance, and the calibration curve showed excellent accuracy in predicting LIM. The OS rate of patients with LIM was significantly lower than that of patients without LIM (p<0.001). Patients with SISTs who are at high risk of developing LIM deserve more attention during follow-up, as LIM can significantly affect patient prognosis. The nomogram demonstrated good calibration and discrimination for predicting LIM.

Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice.

Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8α, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNγ and upregulation of NFkB signaling pathways. Subset 2 does not express IFNγ, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.

Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells.

Neuroendocrine tumors of the small intestine (SI-NETs) often develop lymph node metastasis (LNM)-induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI-NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF-). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF- within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF- formalin-fixed, paraffin-embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549-gene expression panel were differentially expressed in MF+ patients compared to MF-. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2-fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF-, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF- patients. RT-qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF- patients. IHC staining confirmed the enrichment of α-smooth muscle actin-positive fibrosis in MF+ compared to MF- patients with corresponding increase of COMP-expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer-associated fibroblasts enriched environment, it seems to be a promising new target for MF research.

Risk of second cancers in long term survivors of neuroendocrine tumors of the large intestine.

600 Background: There is an increasing incidence of neuroendocrine tumors (NET) of the colon and rectum likely related to increased screening colonoscopy and availability of better diagnostics. Most of these tumors identified during screening are low grade early-stage tumors with high cure rates. Data on long term risk of recurrence of NET and other second cancers is lacking. We studied the incidence rates of all second malignancies in survivors of NET of the colon and rectum. Methods: We analyzed data from the Surveillance, Epidemiology and End Results (SEER), Research Data 17 Registries, Nov 2022 Sub (2000-2022) to determine the risk of second malignancies in patients with an initial cancer diagnosis of NET of the colon and rectum. With these criteria we had overall 17,907 patients and 157,720 patient years of follow up. The relative risk of subsequent malignancies is reported as a standardized incidence ratio (observed incidence [O]/expected incidence [E]). Incidence ratios are analyzed over time from initial diagnosis to assess long term risk. Results: Survivors of NET of the large intestine are at highest risk of malignancy of the rectum (O/E: 6.4, CI: 7.26 - 5.21, N= 239) and this increased risk of rectal cancer persists even 10 years after the initial diagnosis (0/E: 3.8, CI: 5.37- 2.6, N= 32). There is no increased risk of cancer of the colon excluding rectum (O/E: 0.98, CI: 1.18-0.81, N= 114). Even after 10 years from diagnosis there is increased risk of recurrence of the NET of the Colon (O/E: 1.28, CI: 1.55-1.06, N=110) and NET of the Rectum (O/E: 1.12, CI: 1.23- 1.02, N= 433). There is also increased incidence of small intestine cancer (O/E: 2.92, CI: 4.17- 1.97, N=30), Prostate cancer (O/E: 1.28, CI: 1.41- 1.15, N=400), Kidney and renal pelvis cancer (O/E: 1.53, CI: 1.86 -1.25, N= 104), Thyroid cancer (O/E: 1.63, CI: 2.12-1.23, N= 55) and Nodal Non-Hodgkins Lymphoma (O/E: 1.34, CI: 1.71-1.03, N=64). Conclusions: Survivors of NET of the large intestine are at risk of developing subsequent malignancies. The information presented may help physicians in effectively monitoring survivors for second cancers at various timeframes from their initial diagnosis.

Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Spectrum of intestinal lesion: A clinicopathological study in a tertiary care centre

Intestine has wide spectrum of diseases comprising neoplastic and non-neoplastic lesions. Inflammatory bowel diseases are showing increasing trend and intestinal neoplasms are the most frequently observed and leading cause of death in India. This study aims to find the occurrence of various intestinal lesions, classify them as neoplastic and non-neoplastic and to correlate the histopathological findings with clinical profile of patient in tertiary care hospital of north India. 1129 biopsies and resection specimens of intestinal lesions were examined over a period of two years. Sections were fixed, paraffin embedded and stained by H&amp;E. Immunohistochemistry was applied wherever required. Nearly two third patients were males in their second decade who presented with abdominal pain as the most common complaint and majority were diagnosed with non-neoplastic diseases. Among non-neoplastic lesions non-specific inflammation was predominant in small intestine (47.04% cases) and appendicitis (55.0%) in large intestine. Adenocarcinoma was predominant in both small and large intestine with 80.77% and79.45% of neoplastic cases respectively. This work gives a panoramic view of different intestinal pathologies and emphasises on the need of planning accurate diagnostic and screening strategies along with effective treatment plans both for neoplastic as well as non-neoplastic diseases.

Black rice diet alleviates colorectal cancer development through modulating tryptophan metabolism and activating AHR pathway.

Consumption of dietary fiber and anthocyanin has been linked to a lower incidence of colorectal cancer (CRC). This study scrutinizes the potential antitumorigenic attributes of a black rice diet (BRD), abundantly rich in dietary fiber and anthocyanin. Our results demonstrate notable antitumorigenic effects in mice on BRD, indicated by a reduction in both the size and number of intestinal tumors and a consequent extension in life span, compared to control diet-fed counterparts. Furthermore, fecal transplants from BRD-fed mice to germ-free mice led to a decrease in colonic cell proliferation, coupled with maintained integrity of the intestinal barrier. The BRD was associated with significant shifts in gut microbiota composition, specifically an augmentation in probiotic strains Bacteroides uniformis and Lactobacillus. Noteworthy changes in gut metabolites were also documented, including the upregulation of indole-3-lactic acid and indole. These metabolites have been identified to stimulate the intestinal aryl hydrocarbon receptor pathway, inhibiting CRC cell proliferation and colorectal tumorigenesis. In summary, these findings propose that a BRD may modulate the progression of intestinal tumors by fostering protective gut microbiota and metabolite profiles. The study accentuates the potential health advantages of whole-grain foods, emphasizing the potential utility of black rice in promoting health.