Colorectal neoplasia in patients with primary sclerosing cholangitis undergoing liver transplantation: a Nordic multicenter study

Abstract Objective. Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant. Material and methods. In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis. Results. Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia. Conclusion. The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.     

Association of in utero sensitization to Schistosoma haematobium with enhanced cord blood IgE and increased frequencies of CD5- B cells in African newborns

This study investigated in utero priming as a consequence of maternal parasitic infections. Cord blood plasma samples of 63 African newborns were assessed by enzyme-linked immunosorbent assay for their content of total and schistosome-specific or filaria-specific IgE and IgG4. The frequencies of lymphocyte phenotypes in cord blood were also determined by using flow cytometry, and were compared with those of European newborns. We found significantly increased schistosome soluble egg antigen (SEA)-specific IgE in cord plasma of those born to mothers with schistosome infections and correlations between fetal and maternal SEA-specific and filaria antigen-specific IgE. These data are evidence for in utero priming of the fetal immune system to maternal helminth infections. Furthermore, we show significantly enhanced percentages of CD5- B cells in African newborns cord blood compared with Europeans, which is consistent with earlier maturation of the African fetal immune system.     

Cryptorchidism and endocrine disrupting chemicals

Prospective clinical studies have suggested that the rate of congenital cryptorchidism has increased since the 1950s. It has been hypothesized that this may be related to environmental factors. Testicular descent occurs in two phases controlled by Leydig cell-derived hormones insulin-like peptide 3 (INSL3) and testosterone. Disorders in fetal androgen production/action or suppression of Insl3 are mechanisms causing cryptorchidism in rodents. In humans, prenatal exposure to potent estrogen diethylstilbestrol (DES) has been associated with increased risk of cryptorchidism. In addition, epidemiological studies have suggested that exposure to pesticides may also be associated with cryptorchidism. Some case-control studies analyzing environmental chemical levels in maternal breast milk samples have reported associations between cryptorchidism and chemical levels. Furthermore, it has been suggested that exposure levels of some chemicals may be associated with infant reproductive hormone levels.     

Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs

Background

The value of performing post-therapy routine surveillance imaging in patients with Hodgkin lymphoma is controversial. This study evaluates the utility of positron emission tomography/computed tomography using 2-[18F]fluoro-2-deoxyglucose for this purpose and in situations with suspected lymphoma relapse.

Design and Methods

We conducted a multicenter retrospective study. Patients with newly diagnosed Hodgkin lymphoma achieving at least a partial remission on first-line therapy were eligible if they received positron emission tomography/computed tomography surveillance during follow-up. Two types of imaging surveillance were analyzed: “routine” when patients showed no signs of relapse at referral to positron emission tomography/computed tomography, and “clinically indicated” when recurrence was suspected.

Results

A total of 211 routine and 88 clinically indicated positron emission tomography/computed tomography studies were performed in 161 patients. In ten of 22 patients with recurrence of Hodgkin lymphoma, routine imaging surveillance was the primary tool for the diagnosis of the relapse. Extranodal disease, interim positron emission tomography-positive lesions and positron emission tomography activity at response evaluation were all associated with a positron emission tomography/computed tomography-diagnosed preclinical relapse. The true positive rates of routine and clinically indicated imaging were 5% and 13%, respectively (P=0.02). The overall positive predictive value and negative predictive value of positron emission tomography/computed tomography were 28% and 100%, respectively. The estimated cost per routine imaging diagnosed relapse was US$ 50,778.

Conclusions

Negative positron emission tomography/computed tomography reliably rules out a relapse. The high false positive rate is, however, an important limitation and a confirmatory biopsy is mandatory for the diagnosis of a relapse. With no proven survival benefit for patients with a pre-clinically diagnosed relapse, the high costs and low positive predictive value make positron emission tomography/computed tomography unsuitable for routine surveillance of patients with Hodgkin lymphoma.     

Effect of heterotopic noxious conditioning stimulation on electrical and pressure pain thresholds in two different anatomical regions

Objectives. The aims of the study were to investigate the influence of heterotopic noxious conditioning stimulation (HNCS) on pain thresholds in the orofacial and spinal regions and to find out whether there are gender differences in this respect. Material and Methods. Thirty healthy subjects (15 of each sex) with a mean (SD) age of 25.1 (4.4) years participated. Pain thresholds to electrical (EPT) and pressure stimuli (PPT) were recorded in the masseter muscle and 1st upper incisor (tooth), as well as in the fingertip, before, during, and 5 and 15 min after a cold pressor task to the contralateral hand immersed in ice-cold water for a maximum of 5 min. Results. With the exception of the EPT in the orofacial region, all pain thresholds increased during the HNCS and then returned to baseline during the 15 min follow-up. The significant changes in EPT were greater in the finger than in the tooth, while the changes in PPT were greater in the masseter muscle than in the finger. Electrical stimuli in the finger induced greater significant changes of pain thresholds than pressure. In the orofacial region, pressure induced greater significant changes in pain thresholds during HNCS than electrical stimuli did. The HNCS induced pain of high intensity and unpleasantness, i.e. varying between 5 and 10 on the numeric rating scale (NRS). There were no gender differences in the response to the HNCS. Conclusion. We conclude that, in general, HNCS induced by cold pressor stimulation increases pain thresholds, but the magnitude of the effect differs between the orofacial region and the finger and is influenced by the tissue and type of test stimuli.     

Lack of CD44 variant 6 expression in rectal cancer invasive front associates with early recurrence

AIM: To investigate the prognostic value of CD44 variant 6 (CD44v6), a membranous adhesion molecule, in rectal cancer.METHODS: Altogether, 210 rectal cancer samples from 214 patients treated with short-course radiotherapy (RT, n = 90), long-course (chemo) RT (n = 53) or surgery alone (n = 71) were studied with immunohistochemistry for CD44v6. The extent and intensity of membranous and cytoplasmic CD44v6 staining, and the intratumoral membranous staining pattern, were analyzed.RESULTS: Membranous CD44v6 expression was seen in 84% and cytoplasmic expression in 81% of the cases. In 59% of the tumors with membranous CD44v6 expression, the staining pattern in the invasive front was determined as “front-positive” and in 41% as “front-negative”. The latter pattern was associated with narrower circumferential margin (P = 0.01), infiltrative growth pattern (P < 0.001), and shorter disease-free survival in univariate survival analysis (P = 0.022) when compared to the “front-positive” tumors.CONCLUSION: The lack of membranous CD44v6 in the rectal cancer invasive front could be used as a method to identify patients at increased risk for recurrent disease.     

Novel INF2 mutation p. L77P in a family with glomerulopathy and Charcot-Marie-Tooth neuropathy

Background

Mutations in inverted formin, FH2, and WH2 domain containing (INF2) are common causes of dominant focal segmental glomerulosclerosis. INF2 encodes a member of the diaphanous-related formin family, which regulates actin and microtubule cytoskeletons. Charcot-Marie-Tooth neuropathy (CMT) is a group of inherited disorders affecting peripheral neurons. Many reports have shown that glomerulopathy can associate with CMT. However, it has been unclear whether these two processes in the same individual represent one disorder or if they are two separate diseases.

Case diagnosis/treatment

Recently, INF2 mutations were identified in 12 of 16 patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. In this study, we report two cases of CMT-associated glomerulopathy that both showed INF2 mutations. A novel INF2 mutation, p. L77P, was identified in a family in which the dual phenotype was inherited in a dominant fashion. The pathogenic effect of p. L77P was proposed using a structural homology model. In addition, we identified a patient with a sporadic CMT-associated glomerulopathy carrying a known INF2 mutation: p. L128P.

Conclusions

Our study confirms the link between INF2 mutations and CMT-associated glomerulopathy and widens the spectrum of pathogenic mutations.     

Cost-effectiveness of vedolizumab compared with infliximab,adalimumab, and golimumab in patients with ulcerative colitis in the United Kingdom

Objective

To examine the clinical and economic impact of vedolizumab compared with infliximab, adalimumab, and golimumab in the treatment of moderately to severely active ulcerative colitis (UC) in the United Kingdom (UK).

Methods

A decision analytic model in Microsoft Excel was used to compare vedolizumab with other biologic treatments (infliximab, adalimumab, and golimumab) for the treatment of biologic-naïve patients with UC in the UK. Efficacy data were obtained from a network meta-analysis using placebo as the common comparator. Other inputs (e.g., unit costs, adverse-event disutilities, probability of surgery, mortality) were obtained from published literature. Costs were presented in 2012/2013 British pounds. Outcomes included quality-adjusted life-years (QALYs). Costs and outcomes were discounted by 3.5% per year. Incremental cost-effectiveness ratios were presented for vedolizumab compared with other biologics. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty.

Results

The model predicted that anti-tumour necrosis factor-naïve patients on vedolizumab would accrue more QALY than patients on other biologics. The incremental results suggest that vedolizumab is a cost-effective treatment compared with adalimumab (incremental cost-effectiveness ratio of £22,735/QALY) and dominant compared with infliximab and golimumab. Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. However, vedolizumab is cost-effective irrespective of variation in any of the input parameters.

Conclusions

Our model predicted that treatment with vedolizumab improves QALY, increases time in remission and response, and is a cost-effective treatment option compared with all other biologics for biologic-naïve patients with moderately to severely active UC.