Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), ...confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.
Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic ...lineages. An association with hematological neoplasms has been reported. Testicular RDD is rarely described, with only 9 reported cases in the literature. Genetic data to assess clonal relationships between RDD and other hematological neoplasms remain scarce. We describe an instance of testicular RDD against a background of chronic myelomonocytic leukemia (CMML), with genetic studies in both neoplasms.
A 72-year-old patient with a history of CMML sought evaluation of growing bilateral testicular nodules. Solitary testicular lymphoma was suspected; orchidectomy was performed. The diagnosis of testicular RDD was established morphologically and confirmed immunohistochemically. Molecular analysis of testicular lesions and of archived patient bone marrow revealed the KRAS variant c 0.35 G>A / p.G12D in both, suggesting a clonal relationship.
These observations support classifying RDD as a neoplasm that can be clonally related to myeloid neoplasms.
Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from ...pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs.
Type I IFN signalling was studied in mice with conditional deletion of Ifnar1 in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM).
Ifnar1(-/-(IEC)) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnar1-sufficient littermates. While Ifnar1(-/-(IEC)) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1(+/+(IEC)) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice that where diminished upon co-housing.
IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the host-microbiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation.
Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal ...method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (
r
) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from
r
= 0.46 to
r
= 0.91 for H&E and from
r
= 0.73 to
r
= 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin 10HPF: ICC = 0.83 and 1HPF: ICC = 0.8. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement 10HPF: ICC = 0.58 and 1HPF: ICC = 0.49. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores.
Controversy exists about CYP2D6 genotype and tamoxifen efficacy.
A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that ...randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism.
The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04 and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30).
In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.
Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is ...thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6–treated cancer patients. It is shown that IL-6–induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6–induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.
Correct risk assessment of disease recurrence in patients with early breast cancer is critically important to detect patients who may be spared adjuvant chemotherapy. In clinical practice this is ...increasingly done based on the results of gene expression assays. In the present study we compared the concordance of the 70-gene signature MammaPrint (MP) with the 12 gene assay EndoPredict (EP).
Representative tissue of 48 primary tumours was analysed with the MP during routine diagnostic purposes. Corresponding formalin-fixed, paraffin-embedded tissue was thereafter analysed by the EP test. Risk categories of both tests were compared.
41 of 48 tumours could be directly compared by both tests. Of the 17 MP low risk cases, only 9 were considered low risk by EP (53% agreement) and of the 24 MP high risk cases, 18 were high risk by EP (75% agreement). Discrepancies occurred in 14 of 41 cases (34.1%). There was only a weak and non-significant correlation between the MP and EP test with an overall concordance of only 66%. The original therapeutic recommendation was based on the MP and would have been changed in 38% of the patients following EP test results. 4 patients developed distant metastases. The respective tumours of these patients were all classified as high risk by the EP, but only 3 were classified as high risk by the MP.
Both tests resulted in different treatment recommendations for a significant proportion of patients and cannot be used interchangeably. The results underscore the urgent need for further comparative analyses of multi-genomic tests to avoid misclassification of disease recurrence risk in breast cancer patients.
Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 ...SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).
Endometriosis is associated with a high number of chronic pelvic pain and reduced quality of life. Colorectal resections in case of bowel involvement of endometriosis are associated with an ...unneglectable morbidity in young and healthy patients. There is no linear correlation established between the degree of symptoms and stage of endometriosis. The aim of this study was to correlate the histological findings to preoperative pain scores in colorectal resected patients with endometriosis.
Twenty-five patients who underwent laparoscopic colorectal resection for endometriosis between 2014 and 2019 were included in this retrospective study. Pain level was assessed preoperatively and postoperatively via phone call in May 2020. Histopathology was correlated to preoperative symptoms and postoperative outcome.
Average follow-up time was 38.68 months (± 19.92). Preoperative VAS-score was 8.32 (± 1.70). We observed a significant reduction of pain level in all patients after surgery (p ≤ 0.005). Pain levels were equal regarding the presence of satellite spots and various degrees of infiltration depth. The resection margins were clear in all patients. Postoperative complications occurred in 6 cases (24%) and anastomotic leakage was observed in 3 patients (12%). Average VAS-score at time of follow-up was 1.70 (± 2.54).
Our data demonstrate that adequate colorectal resection leads to reduction of pain and an increase of quality of life irrespective of histopathological findings. An experienced team is necessary to improve intraoperative outcome and to reduce postoperative morbidity in case of complication.
Gastritis cystica profunda (GCP) is a rare disease that shows multiple cystic gastric glands dispersed within the submucosa of the stomach. GCP occurs most commonly in patients who have undergone ...previous gastric surgery and presents as subepithelial tumor or a polypoid lesion. Here, we report the case of GCP in a 79-year-old patient who had undergone Billroth II gastric resection. During upper gastrointestinal endoscopy multiple lesions like tiny holes in the mucosa were observed. Endoscopic ultrasound showed cystic structures in the gastric submucosa. Biopsies finally proved the dispersed mucosal glands in the submucosa, which are pathognomonic for GCP. So far, in all published cases, GCP presented as polypoid lesions with no mucosal damage in upper gastrointestinal endoscopy. It is for the first time that GCP has been diagnosed with cystic lesions connected to the gastric lumen with a porus in each of the cysts.
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