Laboratory variation in the grading of dysplasia of duodenal adenomas in familial adenomatous polyposis patients.

To prevent duodenal and ampullary cancer in familial adenomatous polyposis (FAP) patients, a diagnosis of high grade dysplasia (HGD) plays an important role in the clinical management. Previous research showed that FAP patients are both over- and undertreated after a misdiagnosis of HGD, indicating unwarranted variation. We aimed to investigate the laboratory variation in dysplasia grading of duodenal adenomas and explore possible explanations for this variation. We included data from all Dutch pathology laboratories between 1991 and 2020 by retrieving histology reports from upper endoscopy specimens of FAP patients from the Dutch nationwide pathology databank (PALGA). Laboratory variation was investigated by comparing standardized proportions of HGD. To describe the degree of variation between the laboratories a factor score was calculated. A funnel plot was used to identify outliers. A total of 3050 specimens from 25 laboratories were included in the final analyses. The mean observed HGD proportion was 9.4%. The top three HGD-diagnosing laboratories diagnosed HGD 3.9 times more often than the lowest three laboratories, even after correcting for case-mix. No outliers were identified. Moderate laboratory variation was found in HGD diagnoses of duodenal tissue of FAP patients after adjusting for case-mix. Despite the fact that no outliers were observed, there may well be room for quality improvement. Concentration of these patients in expertise centers may decrease variation. To further reduce unwarranted variation, we recommend (inter)national guidelines to become more uniform in their recommendations regarding duodenal tissue sampling and consequences of HGD diagnoses.

Endoscopic management of duodenal adenomatosis in familial adenomatous polyposis-A case-based review.

Adenomatous polyposis (AP) diseases, including familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and MUTYH-associated polyposis (MAP), are the second most common hereditary causes of colorectal cancer. A frequent extra-colonic manifestation of AP disease is duodenal polyposis, which may lead to duodenal cancer in up to 18% of AP patients. Endoscopic surveillance is recommended at 0.5- to 5-year intervals depending on the extent of polyp growth and histological progression. Although the Spigelman classification is traditionally used to determine surveillance intervals, it lacks information on the (peri-)ampullary site, where 50% of duodenal carcinomas are located. Hence, information on the papilla has recently been added as a prognostic marker. Patients with duodenal adenoma(s) ≥10 mm and ampullary adenomas of any size are suggested to be referred to an expert center for endoscopic therapy, particularly endoscopic mucosal resection and endoscopic ampullectomy. Nonetheless, despite the logic of this approach, the long-term efficacy of endoscopic therapy is still to be demonstrated.

Low Incidence of Advanced Neoplasia in Serrated Polyposis Syndrome After (Sub)total Colectomy: Results of a 5-Year International Prospective Cohort Study.

INTRODUCTION: Serrated polyposis syndrome (SPS) is accompanied by a substantially increased colorectal cancer (CRC) risk. To prevent or treat CRC in patients with a very high polyp burden, (sub)total colectomy with ileorectal or ileosigmoidal anastomosis is regularly performed. The CRC risk after (sub)total colectomy might be decreased, but evidence is lacking. We aimed to assess the yield of endoscopic surveillance in patients with SPS who underwent (sub)total colectomy. METHODS: For this post hoc analysis, we used prospectively collected data from a large international prospective cohort study. We included patients diagnosed with SPS (World Health Organization type I and/or III) who underwent (sub)total colectomy. Primary endpoint was the cumulative 5-year incidence of CRC and advanced neoplasia (AN). RESULTS: Forty-eight patients (mean age 61 [±7.8]; 52% men) were included and followed up for a median of 4.7 years (interquartile range 4.7-5.1). None of the patients developed CRC during follow-up. Five patients developed AN, corresponding to a cumulative 5-year AN incidence of 13% (95% confidence interval 1.2-23). In 4 patients, AN was diagnosed at the first surveillance endoscopy after study inclusion, and in 1 patient, AN was detected during subsequent rounds of surveillance. The risk of AN was similar for patients with ileorectal and ileosigmoidal anastomosis (logrank P = 0.83). DISCUSSION: (Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS. Advanced neoplasms are mainly detected at the first endoscopy after (sub)total colectomy. Based on these results, after the first surveillance, intervals might be extended beyond the currently recommended 1-2 years.

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis.

OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias.

Inulin significantly improves serum magnesium levels in proton pump inhibitor-induced hypomagnesaemia.

BACKGROUND: Proton pump inhibitors (PPI) are among the most widely prescribed drugs to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a defect in intestinal absorption of Mg(2+) , can be a severe side effect of chronic PPI use. AIM: To restore serum Mg(2+) concentrations in PPI-induced hypomagnesaemia patients by dietary supplementation with inulin fibres. METHODS: Eleven patients with PPI-induced hypomagnesaemia and 10 controls were treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg(2+) levels served as the primary endpoint. RESULTS: Inulin significantly enhanced serum Mg(2+) levels from 0.60 to 0.68 mmol/L in PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in controls. As a consequence 24 h urinary Mg(2+) excretion was significantly increased in patients with PPI-induced hypomagnesaemia (0.3-2.2 mmol/day). Symptoms related to hypomagnesaemia, including muscle cramps and paraesthesia, were reduced during intervention with inulin. CONCLUSION: Inulin increases serum Mg(2+) concentrations under PPI maintenance in patients with PPI-induced hypomagnesaemia.

Esophageal and Gastric Cancer Pearl: a nationwide clinical biobanking project in the Netherlands.

Esophageal and gastric cancer is associated with a poor prognosis since many patients develop recurrent disease. Treatment requires specific expertise and a structured multidisciplinary approach. In the Netherlands, this type of expertise is mainly found at the University Medical Centers (UMCs) and a few specialized nonacademic centers. Aim of this study is to implement a national infrastructure for research to gain more insight in the etiology and prognosis of esophageal and gastric cancer and to evaluate and improve the response on (neoadjuvant) treatment. Clinical data are collected in a prospective database, which is linked to the patients' biomaterial. The collection and storage of biomaterial is performed according to standard operating procedures in all participating UMCs as established within the Parelsnoer Institute. The collected biomaterial consists of tumor biopsies, blood samples, samples of malignant and healthy tissue of the resected specimen and biopsies of recurrence. The collected material is stored in the local biobanks and is encoded to respect the privacy of the donors. After approval of the study was obtained from the Institutional Review Board, the first patient was included in October 2014. The target aim is to include 300 patients annually. In conclusion, the eight UMCs of the Netherlands collaborated to establish a nationwide database of clinical information and biomaterial of patients with esophageal and gastric cancer. Due to the national coverage, a high number of patients are expected to be included. This will provide opportunity for future studies to gain more insight in the etiology, treatment and prognosis of esophageal and gastric cancer.

Dysfunction of the cyclo-oxygenase pathway in the foetoplacental circulation in Type 1 diabetes mellitus.

AIM: In diabetes, perinatal morbidity is significantly increased. This may partly be related to functional changes in the foetoplacental vascular bed. In diabetes models, a defect in the cyclo-oxygenase pathway is a common observation. Therefore, we hypothesized that the human foetoplacental circulation of diabetic patients is characterized by dysfunction of the cyclo-oxygenase pathway, as well. METHODS: We performed ex-vivo perfusions of isolated placental cotyledons from healthy women (n = 14) and from patients with Type 1 diabetes (n = 9). The contribution of cyclo-oxygenase products to foetoplacental vascular tone was quantified by measuring the response to the cyclo-oxygenase inhibitor indomethacin. RESULTS: Baseline foetoplacental arterial pressure was comparable between controls and diabetic women (mean +/- sem, 21.7 +/- 1.2 vs. 24.4 +/- 2.0 mmHg). Maximum foetoplacental arterial pressure at highest dose of indomethacin was 32.8 +/- 3.0 mmHg in controls vs. 27.3 +/- 2.3 mmHg in diabetic women. The indomethacin-induced increase in pressure was reduced in diabetes (2.9 +/- 0.7 vs. 11.2 +/- 2.4 mmHg in controls, P = 0.01). CONCLUSIONS: Under baseline conditions, the net effect of all cyclo-oxygenase products in the foetoplacental vascular bed is vasodilation. In diabetes, this vasodilator effect seems significantly impaired.

Placental folate transport and binding are not impaired in pregnancies complicated by fetal growth restriction.

Maternal folate deficiency is associated with fetal growth restriction, however, transfer of folate across placentae of pregnancies complicated by fetal growth restriction has never been investigated. We studied whether maternal to fetal 5-methyltetrahydrofolate (5MTF) transport in the ex vivo dually perfused isolated cotyledon, binding of [(3)H] folate (PteGlu) to the syncytial microvillous membrane, and protein expression of folate receptor alpha (FR-alpha) and reduced folate carrier (RFC) in these placentae are disturbed. Placental clearance of 5MTF from the maternal perfusate appeared to be non-saturable over a range of 50 to 500 nm, independent of albumin and flow-independent. No statistically significant differences between placentae complicated with fetal growth restriction and uncomplicated pregnancies were observed. Binding characteristics of [(3)H-]PteGlu to microvillous membranes of fetal growth restriction versus control placentae were similar: B(max)of 3.9+/-2.0 (mean+/-s.d.) versus 4.0+/-1.6 pmol/mg protein and a K(d)of 0.037+/-0.010 versus 0.040+/-0.018 nm. Expression of FR-alpha and RFC were not different in placentae of both groups studied. In conclusion, fetal growth restriction appears not to be associated with impaired maternal to fetal placental folate transport, placental receptor binding, or expression of FR-alpha and RFC.

Nitric oxide-mediated vascular tone in the fetal placental circulation of patients with type 1 diabetes mellitus.

Endothelium-derived nitric oxide (NO) plays a key role in the regulation of vascular tone in health and disease. The present study addresses the contribution of NO to the baseline vascular tone in the fetal placental circulation of type 1 diabetic women. To this end, we performed ex-vivo dual perfusions of isolated cotyledons from seven women with type 1 diabetes mellitus and 24 healthy women. The fetal arterial pressure was considered to be a measure of fetal vascular resistance. The contribution of NO to the baseline vascular tone of the fetal placental circulation was quantified by addition of the NO-synthase inhibitor N(G)-nitro-arginine-methylester (L-NAME). Apart from the diabetic state, we studied the influence of exogenous insulin on the response to L-NAME. Mean (+/-SEM) baseline fetal arterial pressure was higher in diabetes (25.7+/-3.4 mm Hg vs 18.0+/-1.7 mm Hg, P<0.05). Maximum perfusion pressure after L-NAME was 87.9+/-7.1 mm Hg in diabetes vs 58.9+/-4.5 mm Hg in controls (P<0.01). The net L-NAME-induced increase in fetal arterial pressure was higher in diabetes (62.2+/-9.1 mm Hg vs 40.9+/-3.5 mm Hg, P<0.05). Although insulin induced a shift to the left of the L-NAME-curve, the net L-NAME-induced increase in fetal arterial pressure was not affected. We conclude that diabetes is associated with an increased baseline vascular tone of the fetal placental vascular bed. This can not be explained by attenuated NO-mediated effects. In contrast, the activity of the NO-pathway seems to be increased in diabetes. The latter observation seems not to be caused by high insulin levels.

Collagen synthesis in rat skin and ileum fibroblasts is affected differently by diabetes-related factors.

Untreated diabetes reduces wound strength: a concomitant reduction in collagen deposition has been found in cutaneous wounds but not in intestinal anastomoses. This raises the question if collagen synthesis in fibroblasts from skin and intestine reacts differently to the diabetic state. Fibroblast lines were established from healthy rat skin and ileum. Diabetic rat serum was collected from hyperglycaemic rats 3 days after intravenous injection of streptozotocin (200 mg/kg). Fibroblast cultures were grown to confluency in foetal calf serum and maintained in various concentrations of glucose, insulin, normal or diabetic rat serum. Collagen synthesis was measured by incorporation of [3H]-proline into Collagenase-Digestible-Protein. Collagen synthesis in fibroblasts from both skin and ileum was not affected by increasing glucose concentrations. Insulin strongly and specifically stimulated collagen synthesis in skin fibroblasts whereas in ileum fibroblasts only a nonspecific increase of total protein synthesis was observed. In skin fibroblasts, diabetic rat serum stimulated collagen synthesis to a significantly lesser extent than normal rat serum, whereas in ileum fibroblasts stimulation by serum was far less explicit and no difference was observed between normal and diabetic serum. The fact that ileum fibroblasts respond less strongly to culture in diabetic serum than skin fibroblasts may explain our prior finding that would collagen accumulation in intestinal anastomoses is virtually unaffected during diabetes and supports the existence of tissue-specific healing responses.