Fatal gastrointestinal complications in Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mutations of the transcription factor 4 (Tcf4) gene. Individuals with PTHS often suffer from severe abdominal bloating and constipation. In this short communication, we discuss two individuals with PTHS who died unexpectedly due to gastrointestinal complications. We aim to increase awareness among healthcare professionals who care for individuals with PTHS, to ensure adequate screening and management of gastrointestinal symptoms in this population. Moreover, we discuss how fatal gastrointestinal complications may be related to PTHS and provide an overview of the literature.

Disc-like lesions in the intestinal tract after renal transplantation.

We report a case of intestinal lesions in a patient with a history of lupus nephritis and renal transplantation. Biopsy revealed an EBV-driven post-transplant lymphoproliferative disease (PTLD). An EBV-driven PTLD is a major complication after renal transplantation and is an important differential diagnostic consideration in the follow-up of renal transplant recipients.

Inhibition of the BMP pathway prevents development of Barrett's-associated adenocarcinoma in a surgical rat model.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

Smokeless Tobacco and Cigar and/or Pipe Are Risk Factors for Barrett Esophagus in Male Patients With Gastroesophageal Reflux Disease.

OBJECTIVE: To investigate the effect of smokeless tobacco (ST), cigar and/or pipe smoking (CP) on the development of Barrett esophagus (BE) in white male patients with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: A total of 1015 records of white male adults with BE (cases; n=508) or GERD (controls, n=507) were reviewed for lifestyle factors. Logistic regression analyses were performed after adjusting for lifestyle factors to assess the effects of ST and CP on the risk of developing BE. Differences between patients with BE and those with GERD were compared using chi-square and t tests. RESULTS: Patients with BE were significantly older than patients with GERD (mean age, 66±12 years for patients with BE and 55±15 years for patients with GERD; P<.001). The odds of developing BE in patients who used CS were 1.7 times higher than that in patients who never smoked cigarettes (odds ratio [OR], 1.7; 95% CI, 1.3-2.2). It was observed that when CS use was combined with either ST or CP use, the odds of having BE significantly increased (OR, 2.5; 95% CI, 1.2-5.2; P=.01 and OR, 1.9; 95% CI, 1.03-3.58; P=.04) in comparison to CS alone. There were no significant differences in body mass index and alcohol consumption between BE and GERD groups. CONCLUSION: This study suggests that there is indeed an association between CS and BE. We believe that this is the first time that ST and CP were associated with an even higher odds of developing BE. Further studies are needed to investigate whether the use of ST and CP is also associated with an increased risk of developing BE-associated adenocarcinoma.

Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.

OBJECTIVE: The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. METHODS: In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. RESULTS: A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). CONCLUSIONS: A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

Molecular mechanisms of Barrett's esophagus and adenocarcinoma.

The following on molecular mechanisms of Barrett's esophagus and adenocarcinoma contains commentaries on the mechanism of bile and gastric acid induced damage; the roles of BMP-4 and CDX-2 in the development of intestinal metaplasia; the transcription factors driving intestinalization in Barrett's esophagus; the contribution of bone marrow to metaplasia and adenocarcinoma; activation and inactivation of transcription factors; and a novel study design targeting molecular pathways in Barrett's esophagus.

Utility of biomarkers in prediction of response to ablative therapy in Barrett's esophagus.

BACKGROUND & AIMS: Photodynamic therapy (PDT) has been shown to be effective in the treatment of high-grade dysplasia (HGD)/mucosal carcinoma in Barrett's esophagus (BE). Substantial proportions of patients do not respond to PDT or progress to carcinoma despite PDT. The role of biomarkers in predicting response to PDT is unknown. We aimed to determine if biomarkers known to be associated with neoplasia in BE can predict loss of dysplasia in patients treated with ablative therapy for HGD/intramucosal cancer. METHODS: Patients with BE and HGD/intramucosal cancer were studied prospectively from 2002 to 2006. Biomarkers were assessed using fluorescence in situ hybridization performed on cytology specimens, for region-specific and centromeric probes. Patients were treated with PDT using cylindric diffusing fibers (wavelength, 630 nm; energy, 200 J/cm fiber). Univariate and multiple variable logistic regression was performed to determine predictors of response to PDT. RESULTS: A total of 126 consecutive patients (71 who underwent PDT and 55 patients who did not undergo PDT and were under surveillance, to adjust for the natural history of HGD), were included in this study. Fifty (40%) patients were responders (no dysplasia or carcinoma) at 3 months after PDT. On multiple variable analysis, P16 allelic loss (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.10-0.96) predicted decreased response to PDT. BE segment length (OR, 0.71; 95% CI, 0.59-0.85), and performance of PDT (OR, 7.17; 95% CI, 2.50-20.53) were other independent predictors of loss of dysplasia. CONCLUSIONS: p16 loss detected by fluorescence in situ hybridization can help predict loss of dysplasia in patients with BE and HGD/mucosal cancer. Biomarkers may help in the selection of appropriate therapy for patients and improve treatment outcomes.

Correlation of histology with biomarker status after photodynamic therapy in Barrett esophagus.

BACKGROUND: Currently, histology is used as the endpoint to define success with photodynamic therapy (PDT) in patients with high-grade dysplasia (HGD). Recurrences despite 'successful' ablation are common. The role of biomarkers in assessing response to PDT remains undefined. The objectives of the current study were 1) to assess biomarkers in a prospective cohort of patients with HGD/mucosal cancer before and after PDT and 2) to correlate biomarker status after PDT with histology. METHODS: Patients who underwent PDT for HGD/mucosal cancer were studied prospectively. All patients underwent esophagogastroduodenoscopy, 4-quadrant biopsies every centimeter, endoscopic mucosal resection of visible nodules, and endoscopic ultrasound. Cytology samples were obtained by using standard cytology brushes. Biomarkers were assessed by using fluorescence in situ hybridization (FISH). The biomarkers that were assessed included loss of 9p21 (site of the p16 gene) and 17p13.1 (site of the p53 gene) loci; gains of the 8q24(c-myc), 17q (HER2-neu), and 20q13 loci; and multiple gains. Patients received PDT 48 hours after the administration of sodium porfimer. Demographic and clinical variables were collected prospectively. Patients were followed with endoscopy and repeat cytology for biomarkers. The McNemar test was used to compare biomarker proportions before and after PDT. RESULTS: Thirty-one patients were studied. The median patient age was 66 years (interquartile range [IQR], 56-73 years), and 28 patients (88%) were men. The mean Barrett segment length was 5 cm (standard error of the mean, 0.5 cm). Post-PDT biomarkers were obtained after a median duration of 9 months (IQR, 3-12 months). There was a statistically significant decrease in the proportion of several biomarkers assessed after PDT. Six patients without HGD after PDT still had positive FISH results for 1 or more biomarkers: of these, 2 patients (33%) developed recurrent HGD. CONCLUSIONS: In this initial study, histologic downgrading of dysplasia after PDT was associated with the loss of biomarkers that have been associated with progression of neoplasia in Barrett esophagus. Patients with persistently positive biomarkers appeared to be at a higher risk of recurrent HGD. These findings should be confirmed in a larger study.

Dietary protein requirements and dialysate protein losses in chronic peritoneal dialysis patients.

BACKGROUND: Recommended dietary protein allowances for chronic peritoneal dialysis (PD) patients are approximately 60% higher than the dietary protein allowances for healthy adults. The relative contribution of dialysate protein and amino acid losses to these high protein requirements or total nitrogen losses is uncertain. METHODS: Following a peritoneal equilibration test, two 24-hour dialysate collections (24-1 and 24-2) were performed in 9 stable patients undergoing automated PD [4 males, 3 diabetics, age 43 +/- 5 years (mean +/- SEM), dialysis vintage 42 +/- 6 months, dialysate-to-plasma ratio of creatinine 0.61 +/- 0.04]. Dialysate effluent from nighttime cycling was collected separately from the daytime dwells. RESULTS: The measured 24-hour protein losses were 9.4 +/- 0.6 (24-1) and 10.8 +/- 0.8 (24-2) g/day. Even though day dwells accounted for 27% of daily dialysate volume, they accounted for 40% of daily protein and amino acid losses. The frequency of nighttime cycling and duration of dwell were significant predictors of peritoneal protein losses. Dialysate protein and amino acid losses constituted 24% +/- 2% and 3.1% +/- 0.3% of dialysate nitrogen and 14% +/- 1% and 1.7% +/- 0.1% of dietary nitrogen intake respectively. CONCLUSIONS: Treatment with automated PD is associated with somewhat higher 24-hour dialysate protein losses compared to previous reports among continuous ambulatory PD patients. Dialysate protein and amino acid losses constitute a small, albeit significant, proportion of total nitrogen appearance and thus may contribute to the increased dietary protein requirements of chronic PD patients.

Alpha-2-macroglobulin and albumin are useful serum proteins to detect subclinical peritonitis in the rat.

BACKGROUND: In experimental peritoneal dialysis (PD) studies, the occurrence of peritonitis is a confounder in the interpretation of effects of chronic peritoneal exposure to dialysis solutions. Since fluid cannot be drained in most experimental PD models in the rat, it is impossible to diagnose peritonitis based on dialysate white blood cell counts. To study the value of serum markers for the presence of peritonitis, alpha-2-macroglobulin (alpha2M) and albumin were measured in rats with and without peritonitis after chronic exposure to dialysis solutions. To further investigate the time course of these markers in relation to the severity of peritonitis, nondialyzed rats were challenged with increasing numbers of bacteria and followed for 28 days. METHODS: In the first study, alpha2M and albumin were measured in rats exposed to glucose/lactate-based dialysis fluid before sacrifice. A comparison was made between animals with peritonitis, as judged from the presence of extensive infiltrates after sacrifice (gold standard) and/or clinical signs of peritonitis, or absence of peritonitis and infiltrates. In the second study, rats were intraperitoneally (IP) injected with 3 different concentrations of Staphylococcus aureus, and serum alpha2M and albumin were measured at various time points. RESULTS: In the first study, serum alpha2M was higher and serum albumin was lower in animals with peritonitis compared to animals without peritonitis (both p < 0.05). In the second study, induction of alpha2M was clearly dependent on the inoculum concentration. Peak values of alpha2M were found at days 1 and 3. At all time points after inoculation, alpha2M was higher in all injected groups compared to the control group. Serum albumin values decreased in the highest inoculum group and remained decreased until 28 days after IP injection. Despite a low sensitivity, serum alpha2M > 40 mg/L and albumin < 32 g/L had a specificity of 100% for peritonitis. CONCLUSIONS: Measurement of alpha2M and albumin once per month is an additional tool in the diagnosis of silent peritonitis in the chronic peritoneal exposure model in the rat. Levels of alpha2M > 40 mg/L and albumin < 32 g/L are strong indicators for peritonitis. However, normal values do not exclude infectious peritonitis.

Diffusion correction of sodium sieving applicable in a peritoneal equilibration test.

Sodium sieving is a measure of free water transport. However its assessment is disturbed when a large difference exists between sodium concentrations in plasma and in dialysate--that is, when the diffusion rate is high. Based on previous findings concerning similarity in the mass transfer area coefficients (MTACs) of sodium and urate, we developed a model that corrects for high diffusion. The model enabled us to predict the dialysate sodium concentration resulting from diffusion alone at any time point during a dwell. The correction was based on knowledge of the intraperitoneal volume at any time point during the dwell, which can be calculated by using a volume marker (reference method). However, in a peritoneal equilibration test (PET), only the drained volume after 4 hours is available, and urate concentration is not routinely measured. Therefore, our objective in the present study was to investigate whether a diffusion correction using the MTAC of creatinine and the drained volume at the end of the dwell would be as accurate in estimating maximum sodium sieving as the reference method is. We analyzed standardized 4-hour dwells in 28 patients, 19 with stable PD and 9 with ultrafiltration failure. The dialysate consisted of a 3.86% glucose-containing solution to which dextran 70 was added as a volume marker. The correlation coefficient between the PET correction method and the reference method was 0.92 in all patients [0.90 in stable patients and 0.95 in the patients with ultrafiltration failure (p < 0.01 for all)]. We conclude that a diffusion correction for sodium can be made using PET data. A diffusion correction yields a better estimate of sodium sieving than does the sole use of the lowest dialysate-to-plasma (D/P) sodium irrespective of diffusion rate.