Sporadic Adenomas Research Articles

Novel Protein-Based Vaccine against Self-Antigen Reduces the Formation of Sporadic Colon Adenomas in Mice.

Simple SummaryColorectal cancer remains a leading cause of cancer-related mortality worldwide. However, high-risk populations with a genetic predisposition for colorectal cancer could benefit greatly from novel and efficacious immunopreventive strategies that afford long-lasting protection. The achaete-scute family bHLH transcription factor 2 (Ascl2) has been identified as a promising target for immunoprevention of colorectal cancer, based on its induction during the formation and progression of colorectal tumors and its minimal expression observed in healthy tissue. The goal of the present study was to determine the efficacy of a protein-based vaccine targeting Ascl2 in combination with an anti-PD-1 treatment in a spontaneous colorectal cancer mouse model. This novel vaccine strategy promotes potent tumor-specific immunity, and prevents the formation of colon adenomas in mice. The results demonstrate that Ascl2 is a promising target for immunoprevention for individuals at elevated risk of developing colorectal cancer.Novel immunopreventive strategies are emerging that show great promise for conferring long-term protection to individuals at high risk of developing colorectal cancer. The KISIMA vaccine platform utilizes a chimeric protein comprising: (1) a selected tumor antigen; (2) a cell-penetrating peptide to improve antigen delivery and epitope presentation, and (3) a TLR2/4 agonist to serve as a self-adjuvant. This study examines the ability of a KISIMA vaccine against achaete-scute family bHLH transcription factor 2 (Ascl2), an early colon cancer antigen, to reduce colon tumor formation by stimulating an anti-tumor immune response. Vaccine administrations were well-tolerated and led to circulating antibodies and antigen-specific T cells in a mouse model of colorectal cancer. To assess preventive efficacy, the vaccine was administered to mice either alone or in combination with the immune checkpoint inhibitor anti-PD-1. When delivered to animals prior to colon tumor formation, the combination strategy significantly reduced the development of colon microadenomas and adenomas, as compared to vehicle-treated controls. This response was accompanied by an increase in the intraepithelial density of CD3+ T lymphocytes. Together, these data indicate that the KISIMA-Ascl2 vaccine shows great potential to be a safe and potent immunopreventive intervention for individuals at high risk of developing colorectal cancer.

Comparison of Risk of Metachronous Advanced Colorectal Neoplasia in Patients with Sporadic Adenomas Aged < 50 Versus ≥ 50 years: A Systematic Review and Meta-Analysis.

No specific recommendations are available for the surveillance of young patients aged <50 years undergoing polypectomy. We aimed to compare the risk of metachronous advanced colorectal neoplasia (ACRN) between patients aged ≥50 years and those aged <50 years who underwent polypectomy. Studies published between January 1980 and June 2020 that examined the risk of metachronous ACRN were searched. We performed a meta-analysis for the metachronous ACRN risk in patients with sporadic colorectal adenomas according to the age groups (≥50 vs. <50 years). Eight individual studies were included in the meta-analysis. The risk of metachronous ACRN was higher in patients aged ≥50 years than in those aged <50 years without significant heterogeneity (odds ratio (OR) (95% CI): 1.62 (1.34–1.96), I2 = 14%). The impact of the age group on the risk of metachronous ACRN was identified in both the low-risk (LRA) and high-risk (HRA) adenoma groups (≥50 vs. <50 years: LRA, OR 1.88 (95% CI 1.30–2.70); HRA, OR 1.50 [95% CI 1.13–2.00]). In conclusion, patients aged <50 years had a lower risk of metachronous ACRN than older patients. Young patients with sporadic adenomas do not require more intensive surveillance; rather, the surveillance interval may be extended in these patients.

Parathyroid Carcinoma: An Experience from the Indian Primary Hyperparathyroidism Registry

ObjectiveTo describe the details of widely invasive parathyroid carcinoma (WIPC) patients admitted in the Endocrinology department of our institute during the last 22 years and to compare their clinical, biochemical, and hormonal profile with minimally invasive parathyroid carcinoma (MIPC) and sporadic parathyroid adenoma patients. MethodsThis is a retrospective analysis of data from the Indian primary hyperparathyroidism registry. ResultsOf the 547 primary hyperparathyroidism patients in the registry, 5 (2 men and 3 women) had WIPC (0.9%) and 7 (1 man and 6 women) had MIPC (1.3%), with median ages of 45 (interquartile range, 41-51) years and 47 (interquartile range, 28-48) years, respectively. Among the patients with WIPC, renal manifestations were present in 5 patients, skeletal manifestations in 4 patients, and palpable neck masses in 4 patients. Three patients had distant metastases and 2 had cervical lymph node involvement. All 5 patients had surgical resection of their cancers, with persistent disease in 4 patients, but all patients died within 2 years after surgery. One patient with MIPC had a palpable parathyroid nodule; none had lymph nodal or distant metastases. None of the patients with MIPC died during the median follow-up of 18 (interquartile range, 12-18) months. Patients with WIPC had significantly higher serum calcium level compared with sporadic parathyroid adenoma patients with skeletal and renal manifestations. ConclusionAccurate histopathologic classification of parathyroid carcinoma is important as WIPC is associated with a more aggressive clinical course and a higher risk of mortality than MIPC.

Genetic and Epigenetic Causes of Pituitary Adenomas.

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

Endoscopic mucosal resection of sporadic duodenal nonampullary adenoma: outcomes of 130 patients with a long-term follow up in two tertiary French centers

BackgroundThe long-term outcomes and safety of endoscopic mucosal resection (EMR) of sporadic duodenal adenoma (SDA), and the management of adverse events need to be confirmed.MethodsA bicentric retrospective study was performed including all patients who underwent EMR for SDAs from 2003-2016. The primary aim was to evaluate the efficiency of EMR for SDA. The secondary objectives were to assess safety, recurrence management, predictive factors for treatment success, and adverse events.ResultsOne hundred thirty patients (134 procedures) were included (median age 65 years, 49.3% male). The mean SDA size was 20.7 (range 5-50) mm. Of the SDAs, 58.2% were category 3 of the Vienna classification, 35.8% were category 4, and 5.9% were category 5. The median follow up was 25.0 (range 2-120) months. Complete mucosal resection was achieved for 129/134 lesions (96.2%), with en bloc resection in 59/134 (44%). Recurrence occurred in 28.6% of cases (30/105 procedures). Recurrence was successfully treated by new endoscopic procedures in 72.2% (13/18) and by surgery in 27.8% (5/18). Delayed bleeding occurred in 13.4% of cases (18/134) and was successfully managed endoscopically. The perforation rate was 3.7% (5/134); perforations were managed without surgery in 60% (3/5 patients) of cases.ConclusionsEndoscopic treatment of SDA appears to be effective and relatively safe in tertiary centers. All bleeding complications were endoscopically controlled, and perforation was rare. Recurrence was frequent but could be managed endoscopically. EMR is confirmed as a first-line treatment in cases of SDA, and surgery is useful only if repeated EMRs fail.

Exceptional Localization of a Prolactinoma as Part of Familial Isolated Pituitary Adenomas

The syndrome of familial isolated pituitary adenomas (FIPA) or predisposition to pituitary adenomas (PAP) is characterized by the presence within the same family of at least two isolated pituitary adenomas without any other type of associated endocrine tumor. These pituitary tumors may present as homogenous with the same tumor phenotype or heterogeneous with different patterns of pituitary tumor phenotypes (GH, Prolactine, ACTH secretion or non-functioning pituitary adenomas) within the same kindred. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. We report the case of a prolactinoma attached to the pituitary stalk as part of FIPA, revealed by erectile dysfunction.

Pituitary Adenomas Evade Apoptosis via Noxa Deregulation in Cushing's Disease

Introduction: Sporadic pituitary adenomas are common (>10%) in the general population. Microadenomas (< 1 cm across) can become symptomatic with adrenocorticotropin oversecretion causing Cushing’s disease (CD), leading to high morbidity and mortility. Pathogenic mechanisms in a majority of adenomas including wildtype CD adenomas remain unknown. Mechanistic studies are hindered by a lack of in-vitro models and normal human pituitary gland controls. We hypothesized that comparative analysis of human adenomas with syngeneic normal pituitary glands could reveal pathogenic mechanisms driving CD. Methods: We surgically annotated adenomas and en-route adjacent normal glands in 34 patients. We performed single cell RNAseq and captured 28,724 cells in 6 patients (3 CD and 3 non-CD; 5 pairwise), bulk RNAseq in 7 patients (5 CD and 2 non-CD; 5 pairwise) and DNA methylation analysis in 6 patients (3 CD and 3 non-CD). We confirmed the mechanisms of sporadic CD adenoma pathogenesis in 2 additional syngeneic pairs of human cell lines and using a novel murine normal corticotroph-enriched cell line. Results: Using marker-based classification, we confirmed canonical resident cell classes including corticotrophs in the human pituitary gland. We found SOX2+/S100B+ folliculostellate cells which play a role in pituitary cell replenishment and homeostasis in the normal gland but not in the adenoma compartment. Within the terminally differentiated corticotrophs in the adenoma compartment, we discovered a subset of proliferating cells with upregulation of canonical oncogenes, histone modifiers and DNA repair genes. We also found that consensus dominant genes including PMAIP1 (encoding the pro-apoptotic BH3 only Bcl-2 protein noxa) sharply demarcated adenoma cells from normal gland. The PMAIP1 locus was hypomethylated in CD adenomas compared to non-CD samples. However, despite epigenetic and transcriptional upregulation, we found proteasomal degradation of noxa protein in CD adenomas. Using the selective proteasomal inhibitor bortezomib, we were able to rescue noxa ex-vivo and in-vitro, induce apoptosis, and reduce cell survival of adenoma cell lines. Conclusions: We defined the transcriptionl and DNA methylation landscape of human pituitary adenomas compared to adjacent normal gland tissue. We identified proteasomal-mediated noxa degradation despite PMAIP1 overexpression as an escape mechanism from apoptosis in adenomatous corticotrophs. The proteasomal inhibitor bortezomib rescued noxa and induced apoptosis in adenoma cells, highlighting its potential as a novel therapeutic strategy in CD.

Non-conventional dysplasia in inflammatory bowel disease is more frequently associated with advanced neoplasia and aneuploidy than conventional dysplasia.

Several different non-conventional morphological patterns of epithelial dysplasia have been recently described in inflammatory bowel disease (IBD), but there is limited information regarding their clinicopathological and molecular features, as well as potential risk for high-grade dysplasia (HGD) or colorectal cancer (CRC) compared with conventional dysplasia developing in IBD. A total of 317 dysplastic lesions from 168 IBD patients were analysed. All lesions were re-reviewed and subtyped as either conventional [including tubular adenoma-like (n=183) and tubulovillous/villous adenoma-like (n=56)] or non-conventional dysplasia [including dysplasia with increased Paneth cell differentiation (DPD, n=40), crypt cell dysplasia (CCD, n=14), goblet cell deficient (GCD, n=10), hypermucinous (n=7), sessile serrated lesion (SSL)-like (n=4) and traditional serrated adenoma (TSA)-like (n=3)]. DNA flow cytometry was performed on 70 low-grade conventional (n=24) and non-conventional (n=46) dysplastic biopsies to determine their malignant potential and molecular pathways to HGD or CRC. Eleven sporadic tubular adenomas with low-grade dysplasia (LGD) were utilised as controls. Seventy-eight non-conventional dysplastic lesions were identified in 56 (33%) of the 168 patients, whereas 239 conventional dysplastic lesions were identified in 149 (89%) patients. Although both non-conventional and conventional dysplasias were most often graded as LGD at diagnosis (83% and 84%, respectively), non-conventional dysplasia (38%) was more likely to develop HGD or CRC in the same colonic segment than conventional dysplasia (19%) on follow-up (P<0.001). Almost half (46%) of non-conventional dysplastic samples showed aneuploidy, whereas only 8% of conventional dysplasia (P=0.002) and 9% of sporadic tubular adenomas (P=0.037) did. Also, non-conventional dysplasia more frequently presented as a flat/invisible lesion (41%) compared with conventional dysplasia (18%) (P<0.001). Among the non-conventional subtypes (n=78), DPD was the most common (n=40; 51%), followed by CCD (n=14; 18%), GCD (n=10; 13%), hypermucinous (n=7; 9%), SSL-like (n=4; 5%) and TSA-like (n=3; 4%) variants. Hypermucinous dysplasia (mean=2.1cm) was significantly larger than DPD, SSL-like, TSA-like and GCD variants (mean=1.0, 1.2, 1.2 and 1.9cm, respectively) (P=0.037). HGD or CRC was more likely to be associated with CCD (n=13; 93%), hypermucinous (n=4; 57%), GCD (n=4; 40%) and SSL-like (n=3; 75%) variants than DPD (n=6; 15%) and TSA-like dysplasia (n=0; 0%) on follow-up (P<0.001). Furthermore, the rate of aneuploidy was significantly higher in CCD (100%), hypermucinous (80%) and GCD (25%) variants than in DPD (12%), SSL-like dysplasia (0%) and TSA-like dysplasia (0%) (P<0.001). Non-conventional morphological patterns of dysplasia are not uncommon in IBD, detected in 33% of the patients. The higher frequencies of advanced neoplasia (HGD or CRC) and aneuploidy in non-conventional dysplasia, in particular CCD, hypermucinous and GCD variants, suggest that they may have a higher malignant potential than conventional dysplasia or sporadic tubular adenomas, and thus need complete removal and/or careful follow-up. Greater than 40% of non-conventional dysplasia presented as a flat/invisible lesion, suggesting that IBD patients may benefit from random biopsy sampling in addition to targeted biopsies. The majority of non-conventional subtypes appear to develop via the chromosomal instability pathway, whereas an alternative serrated pathway may be responsible for the development of at least a subset of SSL-like and TSA-like dysplasias.

Circulating and Tissue Expression Profile of MicroRNAs in Primary Hyperparathyroidism Caused by Sporadic Parathyroid Adenomas.

ABSTRACTWe investigated the expression profile of selected microRNAs (miRs) in serum and tissue samples from patients with sporadic parathyroid adenomas (sPAs). This was a prospective, controlled cohort study. Forty patients with sPAs who had undergone parathyroidectomy (PTX) were included. MiR extraction was performed from (i) 40 formalin‐fixed paraffin‐embedded samples (FFPEs) of sPAs, (ii) 10 FFPEs of normal parathyroid tissue (NPT), (iii) serum samples of the 40 patients with sPAs (t1 = baseline; t2 = 2 months post‐PTX), and (vi) serum samples of 10 healthy individuals (controls; t1 = baseline and t2 = 2 months later). Ten miRs were selected based on their interaction with genes related to parathyroid tumorigenesis (miR‐17‐5p, miR‐24‐3p, miR‐29b‐3p, miR‐31‐5p, miR‐135b‐5p, miR‐186‐5p, miR‐195‐5p, miR‐330‐3p, miR‐483‐3p, and miR‐877‐5p). At tissue level, the relative expression of miR‐17‐5p, miR‐31‐5p, miR‐135b‐5p, miR‐186‐5p, and miR‐330‐3p was significantly decreased (fold change [FC]: 0.17, FC: 0.03, FC: 0.01, FC: 0.10, FC: 0.10, respectively; all p values <0.001), and the expression of miR‐24‐3p and miR‐29b‐3p was significantly increased (FC: 12.4, p < 0.001; FC: 18.5, p = 0.011, respectively) in sPA compared with NPT samples. The relative expression of miR‐135b‐5p was also significantly decreased in the serum samples of patients compared with controls (FC: 0.7, p = 0.035). No significant differences were found in the serum samples of patients before and after PTX. MiRs that regulate genes linked to parathyroid tumors such as menin 1 (miR‐24‐3p, miR‐29b‐3p), cyclin D1 (miR‐17‐5p), calcium sensing receptor (miR‐31‐5p, miR‐135b‐5p), cyclin‐dependent kinase inhibitors (miR‐186‐5p), and β‐catenin (miR‐330‐3p) were significantly deregulated in sPAs compared with NPT samples, suggesting a role for epigenetic changes in parathyroid tumorigenesis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Endoscopic papillectomy; a retrospective international multicenter cohort study with long-term follow-up

BackgroundEndoscopic papillectomy (EP) is considered a relatively safe and minimally invasive treatment for papillary adenomas. In the literature a significant risk for local recurrence is described. The aim of this study was to evaluate long-term recurrence rates and time-to-recurrence. Additionally, risk factors for recurrence, malignancy and adverse events were studied.MethodsThis is a retrospective study in consecutive patients with papillary adenomas who underwent EP in two tertiary referral hospitals between 2001 and 2018. Primary outcome was recurrence in patients with at least 1-year endoscopic follow-up. Secondary outcomes were surgery free survival, adverse events, and mortality within 30 days after the index procedure.ResultsA total of 259 patients were found eligible [median age 66 years, 130 male (50.2%)]. Forty-three patients were known with familial adenomatous polyposis (FAP) (16.6%). At least 1-year endoscopic follow-up was available in 154 patients with a total follow-up of 586 person-years and median of 40 months [interquartile range (IQR) 25–75]. Recurrence occurred in 24 cases (15.6%) of which 8 were known with FAP, leading to a recurrence incidence rate of 4.1 per 100 person-years with a median time-to-recurrence of 29 months (IQR 14.75–59.5). Fifty-three patients underwent at least 5-year follow-up, in 6 (11.3%) of them recurrence was encountered after 5 years of which four were known with FAP. No risk factors for recurrence could be identified. Adverse events occurred in 50/259 patients (19.3%). One patient died within 30 days after the procedure. Papillary stenosis occurred in 19/259 (7.3%) of the patients. There were no cases of malignant degeneration during follow-up.ConclusionsRecurrence after EP occurs in a significant proportion of patients and occurs even 5 years after EP. This emphasizes the need for long-term follow-up. We advise to consider at least 5-year follow-up in case of a sporadic adenoma, unless comorbidity makes follow-up clinically irrelevant.

Associations of Novel Dietary and Lifestyle Inflammation Scores with Incident, Sporadic Colorectal Adenoma.

Colorectal carcinogenesis is mechanistically linked to inflammation and is highly associated with diet and lifestyle factors that may affect chronic inflammation. We previously developed dietary (DIS) and lifestyle (LIS) inflammation scores, comprising inflammation biomarker-weighted components, to characterize the collective contributions of 19 food groups and four lifestyle exposures to systemic inflammation. Both scores were more strongly directly associated with circulating inflammation biomarkers in three validation populations, including a subset of the study population described below, than were the previously reported dietary inflammatory index and empirical dietary inflammatory pattern. We calculated the DIS and LIS in three pooled case-control studies of incident, sporadic colorectal adenoma (N = 765 cases and 1,986 controls) with extensive dietary and lifestyle data, and investigated their associations with adenoma using multivariable unconditional logistic regression. For those in the highest (more proinflammatory) relative to the lowest (more anti-inflammatory) quintiles of the DIS and LIS, the multivariable-adjusted ORs were 1.31 [95% confidence interval (CI), 0.98-1.75; P trend = 0.09] and 1.98 (95% CI, 1.48-2.66; P trend < 0.001), respectively. These associations were strongest for adenomas with high-risk characteristics and among men. Those in the highest relative to the lowest joint DIS/LIS quintile had a 2.65-fold higher odds (95% CI, 1.77-3.95) of colorectal adenoma. These results support that diets and lifestyles with higher balances of pro- to anti-inflammatory exposures may be associated with higher risk for incident, sporadic colorectal adenoma. Our findings support further investigation of the DIS and LIS in relation to colorectal neoplasms.

The efficacy of aspirin and metformin combination therapy in patients with rectal aberrant crypt foci: a double-blinded randomized controlled trial

BackgroundThe incidence and mortality rates of colorectal cancer (CRC) continue to increase worldwide. Therefore, new preventive strategies are needed to lower the burden of this disease. Previous studies reported that aspirin could suppress the development of sporadic colorectal adenoma. In addition, metformin is a biguanide derivative that is long widely used for the treatment of diabetes mellitus and has recently been suggested to have a suppressive effect on carcinogenesis and cancer cell growth. Both drugs exhibit a chemopreventive effect, but their efficacy is limited.Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are more prevalent in patients with cancer and adenomas, and considered a reliable surrogate biomarker of CRC. Thus, we designed a prospective trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of aspirin combined with metformin on colorectal ACF formation in patients scheduled for polypectomy.MethodsThis study is a double-blind randomized controlled trial that will be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients will be recruited for the study and the number of ACF in the rectum will be counted at the baseline colonoscopy. Then, the participants will be allocated to one of the following two groups; the aspirin plus placebo group or the aspirin plus metformin group. Patients in the aspirin plus placebo group will receive oral aspirin (100 mg) and placebo for 8 weeks, and those in the aspirin plus metformin group will receive oral aspirin (100 mg) and metformin (250 mg) for 8 weeks. After 8 weeks of administration, polypectomy will be performed to evaluate changes in the number of ACF, and the cell-proliferative activity in the normal colorectal mucosa and colorectal polyps.DiscussionThis is the first study proposed that will explore the effect of aspirin combined with metformin on the formation of colorectal ACF in humans.Trial registrationThis trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000028259. Registered 17 July 2017.

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Solute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis.

Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed "loss of gradient" reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 - 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.

Dysregulation of IL6/IL6R-STAT3-SOCS3 signaling pathway in IBD-associated colorectal dysplastic lesions as compared to sporadic colorectal adenomas in non-IBD patients

BackgroundIL6-IL6R-STAT3-SOCS3 signaling pathway is known to play important roles in regulating intestinal epithelial homeostasis, in pathogenesis of inflammatory bowel disease (IBD), and in tumorigenesis of colorectal neoplasia. We studied the expressions of these factors in IBD-associated dysplasia and compared to sporadic colorectal adenomas in non-IBD individuals. Materials and methodsThe expression of IL6, IL6R, STAT3, and SOCS3 within dysplastic as well as background non-dysplastic epithelial cells was evaluated by immunohistochemistry in 26 sporadic colorectal adenomas in non-IBD patients, 32 adenoma-like and 30 non-adenoma-like dysplastic lesions in IBD (41 ulcerative colitis, 21 Crohn’s disease) patients. The level of expression of each factor was arbitrarily scored as 0, 1, 2, and 3. ResultsIn both IBD and non-IBD lesions, neoplastic epithelium showed a higher expression of all factors, except the IL6R, as compared to non-neoplastic epithelium. For non-neoplastic epithelium between IBD and non-IBD settings, the colitic epithelium showed a similar IL6, lower IL6R, higher STAT3, and higher SOCS3 expression. As compared to non-IBD adenomas, IBD-associated dysplasia showed a significantly lower IL6, lower IL6R, higher STAT3, and lower SOCS3 expression. Most notably, a parallel-elevation pattern of STAT3/SOCS3 expressions was seen in non-IBD adenomas but an inverse-expression pattern of STAT3/SOCS3 seen in IBD dysplastic lesions. No significant differences existed between adenoma-like and non-adenoma-like lesions. ConclusionsIL6/IL6R-STAT3-SOCS3 signaling pathway does not seem to be preferentially associated with IBD-associated dysplasia. However, the STAT3-SOCS3 interaction appears dysregulated in IBD, characterized by a loss of STAT3/SOCS3 balance,i.e., loss of the normal negative regulation of SOCS3.

Effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS-Lynch): study protocol for a multicenter, double-blind, placebo-controlled randomized controlled trial

Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20–25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial—a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial—was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo.Trial registrationClinicalTrials.gov NCT02813824. Registered on 27 June 2016. The trial was prospectively registered.

Serum and tissue expression profile of microRNAs that regulate genes related to the pathogenesis of sporadic parathyroid adenomas

Serum and tissue expression profile of microRNAs that regulate genes related to the pathogenesis of sporadic parathyroid adenomas

Sporadic adenoma or ulcerative colitis associated neoplasia? The endoscopist’s information has an impact on diagnosis and patient management

BackgroundDiagnosing low grade intraepithelial neoplasia (LGIN) in patients with ulcerative colitis (UC) is difficult. Distinguishing between sporadic adenoma (SA) and UC associated LGIN is even more challenging but has clinical impact. We aimed to examine, if the morphological distinction between both entities is reliably possible, how it influences patient’s outcome and the role of the endoscopist in this decision with respect to current endoscopy classification schemes. MethodsSeven pathologists retrospectively reevaluated 425 cases of LGIN in UC patients, diagnosed between 2009 and 2017 with preceding expert consensus and follow up in two separate readings, based on published morphological differentiation criteria. In the first evaluation, the observers were blinded to any clinical data. In the second evaluation, they knew patients’ age as well as endoscopic features. They also rated their subjective diagnostic certainty. ResultsDiagnostic correctness improved significantly in the second assessment as did the pathologists’ confidence in their diagnoses (p < 0.001 - p = 0.019). Knowledge of clinical and endoscopical data led to a higher percentage of SA (71.8% vs. 85.6%). UC associated LGIN showed significant earlier LGIN relapse as well as more high grade intraepithelial neoplasia and carcinoma during follow up (p < 0.001, p < 0.001, p = 0.005). ConclusionsDistinction between SA and UC associated LGIN is important as it has an impact on patients’ follow up and treatment. Morphological distinction remains difficult with moderate interobserver variability. Adequate clinical information significantly improves pathologists’ diagnoses as well as their confidence in their diagnoses.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA).

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.

Reduced Calcium Sensing Receptor (CaSR) Expression Is Epigenetically Deregulated in Parathyroid Adenomas.

Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorigenesis, but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices. Forty sporadic parathyroid adenomas and 10 control parathyroid tissues were studied. Real-time quantitative PCR (qPCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed. Real-time qPCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P < 0.0001) in parathyroid adenomas. Immunohistochemistry revealed reduced protein expression of CaSR in 90% (36/40) of adenomas. The promoter 2 region of CaSR displayed significant hypermethylation in 45% (18/40) of the adenomas compared with the controls (6.7%; 1 of 10) (P < 0.002). Bisulphite sequencing analysis revealed maximum methylated CpG at glial cell missing 2 binding site on the CaSR promoter 2 compared to other CpG sites. The methylation status of CaSR correlated directly with plasma intact parathyroid hormone levels in patients with parathyroid adenoma. With chromatin immunoprecipitation-qPCR analysis, H3K9me3 levels showed increased enrichment by 10-fold in adenomas and correlated with CaSR-mRNA expression (r = 0.61; P < 0.003). Treatment with 5-aza-2'deoxycytidine restored the expression of CaSR in a parathyroid cell line. Our data suggest that hypermethylation and increased H3K9me3 of the CaSR promoter 2 are involved in silencing CaSR expression in sporadic parathyroid adenoma.