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Background & Aims Lynch syndrome is the most common inherited cause of colorectal cancer (CRC). Contemporary and mutation-specific estimates of CRC-risk in patients undergoing colonoscopy would optimize surveillance strategies. We performed a prospective national cohort study, using data from New Zealand, to assess overall and mutation-specific risk of CRC in patients with Lynch syndrome undergoing surveillance. Methods We performed a prospective study of 381 persons with Lynch syndrome in New Zealand (98 with Lynch-syndrome associated variants in MLH1, 159 in MSH2, 103 in MSH6, and 21 in PMS2). Participants were offered annual colonoscopy starting at age 25 y, and those who underwent 2 or more colonoscopies before December 31, 2017 were included in the final analysis. Patients with previous colonic resection, history of CRC or diagnosis of CRC at index colonoscopy were excluded. Results Study participants underwent 2061 colonoscopies during 2296 person-y; the median observation-period was 4.43 y and mean-age at enrollment was 43 y. Eighteen patients developed CRC (8 with variants in MLH1, 8 in MSH2, and 2 in MSH6) after a median follow-up period of 6.5 y (range 1–16 y). Eighty-three percent of patients had a surveillance colonoscopy in preceding 24 months before diagnosis of CRC; 94% were diagnosed with stage 0–II CRC and there was no CRC-related mortality. The overall-risk of developing CRC in the 5 y after first surveillance colonoscopy was 2.49% (95% CI, 1.18–5.23); cumulative risks for CRC in patients with Lynch syndrome-associated variants in MLH1, MSH2, or MSH6 by age 70 y were 17.7%, 17.8%, and 8.5%, respectively. Age-adjusted CRC-risk in patients with variants in MSH6 was lower than in MLH1 (hazard ratio, 0.2; 95% CI, 0.04–0.94; P = .02). Of patients with CRC, 33% had an adenomatous polyp resected from same segment in which a colorectal tumor later developed. Conclusions The risk of CRC in patients with Lynch syndrome-associated mutations in MSH6 or PMS2 was significantly lower than in patients with mutations in MLH1. Incomplete adenomatous polyp resection might be responsible for one third of surveillance-detected CRCs.

Autoimmune pancreatitis (AIP) is a rare systemic fibroinflammatory disorder. The disease usually occurs in elderly men and offers an excellent response to steroid treatment. AIP in childhood is exceedingly rare. We report the first case of AIP in a boy with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD). He presented with a six-year history of intermittent bloody diarrhoea. Colonoscopy revealed severe pancolitis and ileitis in keeping with IBD. Abnormal liver function tests and magnetic resonance cholangiopancreatography (MRCP) findings confirmed PSC and subsequent occurrence of renal lesions and pancreatic abnormalities on computed tomography imaging were suspicious for AIP. Immunoglobulin G4 (IgG4) serum levels were elevated and treatment with steroids led to complete resolution of renal lesions, pancreatic changes and normalization of IgG4 and liver function tests. Follow-up MRCP 6 months later revealed unchanged biliary abnormalities in keeping with PSC. The differentiation between PSC and extrapancreatic AIP affecting the biliary tree and liver is critical given the dramatic response of AIP to steroids. Recent recommendations therefore include IgG4 measurement in every adult with possible PSC. Our case documents for the first time that AIP has to be considered as a differential diagnosis in childhood PSC. IgG4 measurement should be recommended universally in possible PSC.

Background and Aim: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. Methods: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN : TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. Results: The addition of 100–300 mg allopurinol daily and thiopurine dose reduction (17–50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11 643 (3 365–27 832) to 221 (55–844) pmol/8 × 108 red blood cells (RBC; P = 0.0005), increased 6-TGN from 162 (125–300) to 332 (135–923) pmol/8 × 108 RBC (P = 0.0005), and reduced the 6-MMPN : 6-TGN ratio from 63 (12–199) to 1 (0.1–4.5) (P = 0.0005). There was a significant reduction in steroid dose requirements at 12 months (P = 0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. Conclusions: In those with a high 6-MMPN : 6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (20), which is indicative of a poor thiopurine response.Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared.The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol.In those with a high 6-MMPN:6-TGN ratio (20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.