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PURPOSE Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Aim To report the long term results of the CROSS trial with a minimum follow-up of 10 years. Background Neoadjuvant chemoradiotherapy according to the Dutch randomised controlled ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) has become standard of care for patients with cancer of the oesophagus or oesophagogastric junction. Methods Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction were randomised between neoadjuvant chemoradiotherapy (five weekly cycles of intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m² of body-surface area]) with concurrent 41.4 Gy radiotherapy given in 23 fractions of 1.8 Gy, 5 days per week) plus surgery versus surgery alone. Primary endpoint was overall survival, defined from date of randomisation to date of all-cause death or to last day of follow-up. Analysis was by intention-to-treat. Results Between March 2004 and 2008, eight centres enrolled 368 patients. Some 178 were analysed in the chemoradiotherapy plus surgery group and 188 in the surgery alone group. After a median follow-up for surviving patients of 146.6 months (IQR 133.5-156.6), median overall survival was 49.0 months (95%CI 34.7-76.6) in the neoadjuvant chemoradiotherapy plus surgery group compared to 25.1 months (95%CI 19.1-39.4) in the surgery alone group, which was significantly different (HR 0.71 [95%CI 0.55-0.90]; log-rank p=0·005). Ten-year overall survival was 38% (95%CI 31%-45%) in the neoadjuvant chemoradiotherapy followed by surgery group compared to 26% (95%CI 20%-33%) in the surgery alone group (HR 0.69 [95%CI 0.54-0.89]). For patients with squamous cell carcinoma ten-year overall survival was 46% (95%CI 33%-64%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 23% (95%CI 13%-40%) in the surgery alone group. For patients with adenocarcinoma ten-year overall survival was 36% (95%CI 29%-45%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 26% (95%CI 20%-35%) in the surgery alone group. Conclusion Survival benefit of patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction receiving neoadjuvant chemoradiotherapy persists for at least 10 years compared to patients undergoing surgery alone.

Background In early (T1) oesophageal adenocarcinoma (OAC), the histological profile of an endoscopic resection specimen plays a pivotal role in the prediction of lymph node metastasis and the potential need for oesophagectomy with lymphadenectomy. Objective To evaluate the inter-observer agreement of the histological assessment of submucosal (pT1b) OAC. Methods Surgical and endoscopic resection specimens with pT1b OAC were independently reviewed by three gastrointestinal pathologists. Agreement was determined by intraclass correlation coefficient for continuous variables, and Fleiss' kappa (κ) for categorical variables. Bland–Altman plots of the submucosal invasion depth were made. Results Eighty-five resection specimens with pT1b OAC were evaluated. The agreement was good for differentiation grade (κ=0.77, 95% confidence interval (CI) 0.68–0.87), excellent for lymphovascular invasion (κ=0.88, 95% CI 0.76–1.00) and moderate for submucosal invasion depth using the Paris and Pragmatic classifications (κ=0.60, 95% CI 0.49–0.72 and κ=0.42, 95% CI 0.33–0.51, respectively). Systematic mean differences between pathologists were detected for the measurement of submucosal invasion depth, ranging from 297 µm to 602 µm. Conclusions A substantial discordance was found between pathologists for the measurement of submucosal invasion depth in pT1b OAC. Differences may lead to an over- or underestimation of the lymph node metastasis risk, with grave implications for the treatment strategy. Review by a second gastrointestinal pathologist is recommended to improve differentiating between a favourable and an unfavourable histological profile.

Item does not contain fulltext BACKGROUND: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. METHODS: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. FINDINGS: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84.1 months (range 61.1-116.8, IQR 70.7-96.6), median overall survival was 48.6 months (95% CI 32.1-65.1) in the neoadjuvant chemoradiotherapy plus surgery group and 24.0 months (14.2-33.7) in the surgery alone group (HR 0.68 [95% CI 0.53-0.88]; log-rank p=0.003). Median overall survival for patients with squamous cell carcinomas was 81.6 months (95% CI 47.2-116.0) in the neoadjuvant chemoradiotherapy plus surgery group and 21.1 months (15.4-26.7) in the surgery alone group (HR 0.48 [95% CI 0.28-0.83]; log-rank p=0.008); for patients with adenocarcinomas, it was 43.2 months (24.9-61.4) in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 months (13.0-41.2) in the surgery alone group (HR 0.73 [95% CI 0.55-0.98]; log-rank p=0.038). INTERPRETATION: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Background & Aims: We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism,liver histology and long-term outcome in chronic hepatitis B (CHB)patients. Methods: We enrolled 531 consecutive treatment na€ive CHBpatients diagnosed from 1985 to 2012 with an available liver biopsy for reas-sessment, and sample for genetic testing. Data on all-cause mortality andhepatocellular carcinoma (HCC) at long-term follow-up were obtained fromnational database registries. Results: The prevalence of steatohepatitisincreased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001).The association was altered by both gender (P = 0.010) and overweight(P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronouncedamong non-overweight females (adjusted OR 13.4, 95%CI: 3.7–51.6,P < 0.001), and non-overweight males (adjusted OR 2.4, 95%CI: 1.4–4.3,P = 0.002). Furthermore, PNPLA3 GG genotype was associated with irondepositions (OR 2.8, 95%CI: 1.2–6.4, P = 0.014) and lobular inflammation(OR 2.2, 95%CI: 1.1–4.5, P = 0.032), but not with advanced fibrosis (OR1.1, 95%CI: 0.7–1.8, P = 0.566). The median follow-up was 10.1 years (inter-quartile range 5.6 – 15.8), during which 13 patients developed HCC and 28died. Steatohepatitis was associated with all-cause mortality [Hazard ratio(HR) 3.1, 95%CI: 1.3 –7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9 9.2,P = 0.078), but no significant association was observed for PNPLA3. Conclu-sions: In this cohort of biopsied CHB patients, PNPLA3 was independentlyassociated with steatosis, steatohepatitis, lobular inflammation and irondepositions, but not with advanced fibrosis, HCC development or all-causemortality. The effect of PNPLA3 on steatohepatitis was particularly pro-nounced among female patients without severe overweight.Chronic hepatitis B (CHB) infection affects approxi-mately 350 million people worldwide (1). Whenpatients are infected with the hepatitis B virus (HBV) atbirth or in early childhood, and to a lesser extent inadulthood, an ineffective immune response directed atthe virus can result in chronic liver inflammation. Sub-sequently, this can lead to cirrhosis, hepatocellular carci-noma (HCC), liver failure and death (1, 2). Globally,30% of cirrhosis and 53% of HCC is attributable toCHB (2).Over the past decades obesity and its associatedmorbidities has reached epidemic proportions, particu-larly in developed countries. Nowadays, there areapproximately 500 million obese men and women, anumber which has almost doubled since 1980 (3). Non-alcoholic fatty liver disease (NAFLD) is one of the manyexpressions of corpulence and affects up to 30% ofadults (4). Steatosis could progress to steatohepatitis, acondition which subsequently leads to cirrhosis in 10–29% of individuals within 10 years. Moreover, 4–27%of patients with steatohepatitis associated cirrhosisdevelop HCC (4). Steatosis is a risk factor for diseaseprogression and HCC development in patients chroni-cally infected with the hepatitis C virus (HCV) as well(5, 6). However, its impact on the progression of CHBrelated liver disease is still unknown (7–9). Previous

Objectives: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT.Background: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Methods: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups.Results:One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgeryalone arm (hazard ratio per 10 additionally resected nodes, 0.76; P = 0.007), but not in the multimodality arm (hazard ratio 1.00; P = 0.98). Conclusions: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers. In the absence of risk factors, for example, cirrhosis or hepatitis B or C virus infection, HCC diagnosis might be difficult. We aimed to explore the value of immunohistochemical characteristics to diagnostics and prognosis, and whether these immunohistochemical characteristics differ from those of HCC in a cirrhotic liver, possibly indicating an aberrant pathogenetic pathway. Paraffin-embedded, formalin-fixed tissue slides from liver resection specimens of the patients with HCC in a non-cirrhotic liver were analysed. From January 2000 through April 2011, 799 patients with HCC were admitted to our hospital; in total, 47 patients with 50 HCCs in a non-cirrhotic liver were operated. These tumours were stained positive for α-fetoprotein (AFP) in 30%, CD34 in 88%, cytokeratine 7 (CK7) in 44%, CK19 in 12%, glypican-3 (GPC-3) in 40%, glutamine synthetase in 62% and β-catenin in 32%. There was similarity in immunohistochemical expression of several markers comparing HCC in a non-cirrhotic liver with HCC in a cirrhotic liver. Moderate or poorly differentiated HCC more often expressed β-catenin and GPC-3 and showed a higher percentage of MIB-1-positive hepatocytes. A positive AFP immunohistochemical staining was significantly related with a high preoperative AFP serum level (p=0.001). None of the immunohistochemical stainings were associated with a worse overall survival. Of the patients treated with a surgical resection, 17 had recurrence of HCC and these patients more often had a positive CK19 staining (p=0.048). In conclusion, immunohistochemical expression of several markers in HCC in a non-cirrhotic and cirrhotic liver was comparable. Immunohistochemical markers have limited additional value to characterise HCC in non-cirrhoitc livers.

Summary 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been investigated as a tool for monitoring response to neoadjuvant chemo- and chemoradiotherapy (CT and CRT, respectively) and as a predictor for survival in patients with esophageal cancer. In contrast to patients who undergo neoadjuvant CT, it is not known whether patients who are clinically identified as responders after neoadjuvant CRT show better disease-free survival (DFS) than patients identified as nonresponders. The aim of the study was to determine the predictive value of FDG-uptake measured prior to and early during neoadjuvant CRT. Patients treated with neoadjuvant CRT between 2004 and 2009 within a randomized trial were included. FDG-uptake was measured at baseline and after 14 days of CRT. According to the PERCIST-criteria, patients were allocated to have metabolic response, stable disease, or progression. Patients were followed until recurrence of disease or death. The predictive value of FDG-PET was determined with univariable and multivariable analysis in patients who underwent potentially curative surgery. One-hundred and six patients were included in the analysis. Minimal follow-up for surviving patients was 60 months. No significant differences in DFS were found between patients with metabolic response, stable disease, or progression, with 5-year DFS rates of 66%, 53%, and 67%, respectively (P = 0.39). Relative change in FDG uptake after 14 days of CRT is not associated with DFS in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy followed by surgery. These measurements should not be used for prognostication in this specific group of patients.

Dendritic cells (DCs) are key cells in innate and adaptive immune responses that determine the pathophysiology of Crohn's disease. Intestinal DCs migrate from the mucosa into mesenteric lymph nodes (MLNs). A number of different markers are described to define the DC populations. In this study we have identified the phenotype and localization of intestinal and MLN DCs in patients with Crohn's disease and non-IBD patients based on these markers. We used immunohistochemistry to demonstrate that all markers (S-100, CD83, DC-SIGN, BDCA1-4, and CD1a) showed a different staining pattern varying from localization in T-cell areas of lymph follicles around blood vessels or single cells in the lamina propria and in the MLN in the medullary cords and in the subcapsular sinuses around blood vessels and in the T-cell areas. In conclusion, all different DC markers give variable staining patterns so there is no marker for the DC. (J Histochem Cytochem 56:233–241, 2008)

Introduction: During the last decade, whole slide images (WSI) have been used in many areas of pathology such as teaching, research, digital archiving, teleconsultation and quality assurance testing. However, WSI have as yet not much been used for upfront diagnostics because of the lack of validation studies. Objectives: The aim of this study was to test the feasibility of WSI for primary diagnosis of urinary tract pathology. Materials and Methods: 100 consecutive urinary tract biopsies and resections which had been diagnosed conventionally between the years 2008-2009 were scanned at 20× magnification, and rediagnosed by two pathologists on WSI, having the original clinical information available, but blinded to the original diagnoses. Original and WSI diagnoses were compared and classified as concordant, slightly discordant (without clinical consequences) and discordant. Results: Original and WSI based rediagnosis were concordant in 87% of the cases. Original and WSI diagnosis were slightly discordant in 8% of cases. Major discrepancies with clinical or prognostic implications were founded in only 5 cases. However, for 6 out of the 13 discrepancies, WSI based diagnoses were considered to be better than the original diagnoses. Conclusion: Primary diagnostics of urinary tract specimens can be reliably done on WSI. Further improvements of image resolution may help to increase diagnostic accuracy and WSI acceptance in routine pathology.

BACKGROUND. As an alternative to surgical resection, endoscopic treatment modalities are being explored for the treatment of patients with early esophageal carcinoma. This study aimed to evaluate patterns of local growth and regional dissemination of early adenocarcinoma of the esophagus or esophagogastric junction, as these pathologic features may contribute to rational therapeutic decision making. METHODS. Among 173 patients who underwent esophageal resection for invasive adenocarcinoma (1993‐1998), 32 (19%) had early stage cancer (pT1). Clinical records, pathology reports, and original slides of the surgically resected esophagus were reviewed in each case. RESULTS. In 12 patients tumor invasion was limited to the mucosa, whereas in 20 patients the tumor showed infiltration of the submucosa. All cancers were associated with intestinal metaplasia. Areas of high grade dysplasia accompanied 27 of the 32 cancers (84%). Intramucosal cancer had no lymph node metastasis but presented as multifocal disease in 42% of cases and extended under preexisting squamous mucosa in 17% of cases. In submucosal cancer, lymph node metastases were present in 30% of cases. Disease specific 3-year survival for patients with intramucosal cancer was 100% and for those with submucosal cancer 82% (P 5 not significant). CONCLUSIONS. Based on the local growth pattern of intramucosal adenocarcinoma of the esophagus or esophagogastric junction, endoscopic treatment of patients with this disease should be applied with caution. For submucosal carcinoma, surgery is the mainstay of treatment, as lymph node metastasis is frequently present. Both subclassifications of early cancer show a favorable outcome after esophagectomy. Cancer 2000;88:2429 ‐37. © 2000 American Cancer Society.

Background/Aims: Serum bilirubin is a prognostic factor in untreated primary biliary cirrhosis (PBC), but this has been less extensively documented for patients treated with UDCA. The aims of this study were to define the effects of UDCA on serum liver tests and to assess prognostic factors in patients on prolonged UDCA treatment. Methods: Analysis of laboratory parameters obtained before and during treatment with UDCA of 203 PBC patients who were followed for a mean of 48 months. Univariate and multivariate analyses were performed to assess the prognostic value of pre-entry and follow-up variables with respect to treatment failure and survival. Results: Actuarial 5-year incidences of treatment failure and transplantion-free survival were 27 and 79%, respectively. According to the univariate analysis the following variables were significantly associated with prognosis: pre-entry presence of cirrhosis and pretreatment levels of serum bilirubin and albumin, bilirubin levels during follow-up, the occurrence of biochemical remission and normalisation of serum bilirubin. Multivariate analysis revealed that bilirubin during follow-up was the best predictor. Alkaline phophatase, aspartate aminotransferase and IgM decreased significantly during the first 6 months of treatment and subsequently remained at this lower level. Serum bilirubin showed the same initial pattern, but a significant increase was observed after 4 years of treatment. Conclusions: Serum bilirubin in both UDCA-treated and untreated patients is the most powerful predictor of prognosis for PBC. The partial therapeutic efficacy of UDCA is illustrated by the finding that serum bilirubin, in contrast to alkaline phosphatase and the transaminases, appears to increase after 4 years of treatment.

Background Recent reports have shown that hepatitis E virus (HEV) infection can become chronic in solid-organ transplant recipients, but few studies have systematically investigated the clinical consequences of this chronic HEV infection in solid-organ transplant (SOT) recipients. Methods We have undertaken an in-depth study of 6 chronic HEV-infected heart transplant recipients to gain further insight into the clinical, biochemical and virologic presentation of this disorder. Results In 6 patients (2.3%) chronic HEV infection, genotype 3, was identified. Immunosuppression in these patients was tacrolimus-based, combined with either everolimus or prednisolone and/or mycophenolate mofetil. Median follow-up after case detection was 26 months (range 21 to 40 months). All chronic HEV cases had elevated liver enzyme values. IgM antibodies at presentation were positive in 2 of 6 (33%) patients. Liver histology in 4 of 6 (67%) patients showed advanced fibrosis within 2 years after infection. One patient spontaneously cleared the HEV infection: 1 after dose reduction of immunosuppressive therapy and 3 during ribavirin therapy. One patient has yet to clear the virus and remains on ribavirin therapy. Conclusions Chronic HEV infection in heart transplant (HTx) recipients may lead to rapid fibrosis of the liver. We advise additional HEV RNA screening in solid-organ transplant recipients with elevated liver enzymes, because antibody production is often delayed, as demonstrated in these patients. Dose reduction of immunosuppressive therapy should be the first intervention strategy to achieve viral clearance in chronic HEV-infected immunocompromised patients. Ribavirin treatment should be considered in cases of chronic HEV.

To assess trends in patient characteristics and treatment outcomes in a large cohort of patients who underwent oesophagectomy for oesophageal carcinoma in a tertiary referral centre over a period of 16 years.Retrospective cohort study.We carried out a trend analysis on collected data on demographic and clinico-pathological characteristics, complications and survival of patients who underwent oesophagectomy between January 1993 and December 2008 at the Academic Medical Center in Amsterdam (AMC), the Netherlands. Patients were subsequently divided into three comparably-sized groups according to the year of operation: group 1 (1993-1998; n = 332), group 2 (1999-2004; n = 312), and group 3 (2005-2008; n = 296).A total of 940 patients underwent oesophagectomy during the total study period. Transhiatal oesophagectomy was performed more often during the first two time periods (65 and 64%, respectively), while the transthoracic approach was used more often in the third period (53%). The proportion of patients who underwent a microscopically radical resection increased significantly over the three periods of time. In-hospital mortality in all three periods was low, between 3.2%-3.4%. The three-year survival rate improved significantly over the three periods (p = 0.018), from 42% and 48% to 53% in the most recent period.Over the past 16 years in-hospital mortality in patients undergoing oesophagectomy for a potentially curable oesophageal carcinoma at the AMC, has been stably low. The total number of complications increased during these periods. Long-term survival improved during this time to a three-year overall survival of more than 50% in the most recent period.

Four patients who received an auxiliary partial liver graft for decompensated liver cirrhosis due to hepatitis B (HBV), associated in two cases with hepatitis D virus (HDV) superinfection, were studied. The sequential appearance of hepatitis B and D antigens in the grafts was investigated in serial liver biopsies by immuno-histochemical methods and compared with the viral antigenic profiles of the host livers. The histological changes in the liver grafts were studied in relation to the viral expression patterns. One week after transplantation, expression of HBsAg was already apparent in two grafts. HBcAg was found in the graft of the only patient with HBcAg in the host liver. HDAg was expressed in the grafts of both patients with HDV superinfection; in one of these cases HDAg was present without HBsAg. At 3 months, viral antigen expression was maximal. Expression of HBsAg and HBcAg in the grafts of the two HDV-positive patients was, however, less extensive than in the two HBV-positive patients. All patients developed a mild lobular hepatitis, histologically demonstrated between the 47th and 107th posttransplantation day. In the two HBV-positive, HDV-negative patients, cirrhotic tranformation of the graft occurred within 1 year. In the HDV-positive patients only a mild chronic active hepatitis with slight or moderate fibrosis was observed after 1 year. We conclude that recurrence of HBV and HDV infection in auxiliary liver grafts is demonstrable within 1–3 weeks. HBV infection in liver grafts may be a rapidly progressive disease. Coinfection with HDV does not aggravate the acute hepatitis and may even suppress the progression of chronic HBV.

Erythromelalgia is caused by platelet-mediated acral inflammation and arteriolar thrombosis in thrombocythemia in its primary form or associated with polycythemia vera. The prompt and lasting relief of burning pain by low-dose aspirin is a prerequisite for the diagnosis of thrombocythemic erythromelalgia. Here we extend observations on the occurrence of erythtromelalgia in thrombocythemia associated with primary myelofibrosis, Philadelphia-chromosome positive micromegakaryocytic myelofibrosis, and myelodysplastic syndrome type II. It is concluded that erythromelalgia may occur in thrombocythemia of all variants of chronic myeloproliferative disease as well as myelodysplastic syndrome if platelet counts are sufficiently high.

Objective: To determine the prevalence and type of histological abnormalities in duodenal mucosa associated with Giardia lamblia in children who undergo esophagogastroduodenoscopy. Materials and Methods: Duodenal biopsies containing G lamblia were retrieved from all paediatric patients who had undergone endoscopy in our centre in the last 20 years. These biopsies were scored for histological abnormalities by a single pathologist using a semiquantative scale and staged according to the Marsh criteria. In those with a Marsh stage above 0, the presence of coeliac disease was investigated. Results: After excluding all patients with concomitant coeliac disease, 4 out of 32 (13%) patients had a biopsy showing crypt hyperplasia and 1 out of 32 (3%) had partial villous atrophy. No intraepithelial lymphocytosis was found. In our cohort, 2 patients with giardiasis and mild histological abnormalities were diagnosed with coeliac disease only after a repeated endoscopy and serology were performed; in 1 of them after a delay of 5 years. Other histological abnormalities frequently observed were increased eosinophilic infiltration of the lamina propria (35%) and lymph follicle formation (35%). Infiltration of neutrophilic and eosinophilic granulocytes in the epithelial layer was observed less frequently (16% and 9%, respectively). Conclusions: Villous atrophy, intraepithelial lymphocytosis and/or crypt hyperplasia are rare in children with giardiasis who undergo esophagogastroduodenoscopy. Therefore, other causes, particularly coeliac disease, should always be suspected. This study, however, suggests that giardiasis can cause chronic mucosal inflammation, often of an eosinophilic nature, in these children. JPGN 49: 304-308, 2009

The photocoagulating properties of the water-jet-cooled Nd:YAG laser (1,064 nm) have been studied in a rat tumor model. A colon carcinoma CC531 was implanted in the liver; 20 days after inoculation, laser therapy was performed with 600 J, 850 J, 1,200 J, 1,700 J, or 2,400 J at a power setting of either 10 or 20 W. Liver damage was determined in tissue specimen on day 1 after treatment and by serum levels of alanine aminotransferase and aspartate aminotransferase on day 1 and 2. Tissue specimen of day 36 were used to evaluate tumor remission. Liver function was assessed by antipyrine clearance on day 2. Light microscopic examination on day 1 showed coagulative necrosis up to 10 mm in diameter at 1,700 J and 20 W. At 20 W, liver damage was 22% larger than at 10 W (P = 0.0001). A significant relationship was found between laser energy and liver damage with complete tumor destruction in all animals at 2,400 J. No deterioration in liver function was found. The results of this study show the ability of the water-jet-cooled Nd:YAG laser to produce tumor coagulation necrosis with minor liver damage.

Objective To compare the diagnostic accuracy of contrast enema (CE), anorectal manometry (ARM), and rectal suction biopsy (RSB) for the detection of Hirschsprung's disease (HD). Study design Following a prospective protocol, infants suspected of HD underwent all 3 index tests. Children with positive results on 2 or more index tests or who continued to have severe bowel problems underwent a full thickness biopsy as reference standard. Clinical follow-up was the reference standard in all other children. Results Between 2000 and 2003, 111 consecutive patients (67 boys; median age, 5.3 months) in whom HD was suspected were enrolled. HD was found in 28 patients. RSB had the highest sensitivity (93%) and specificity (100%) rates, but values were not significantly different from CE (sensitivity, 76%; specificity, 97%) or from ARM (sensitivity, 83%; specificity, 93%). Inconclusive test results occurred in 8 infants with CE, in 15 infants with ARM because of agitation, and in 2 infants with RSB. Conclusion RSB is the most accurate test for diagnosing HD, and it has the lowest rate of inconclusive test results.

Evaluating the efficacy of therapy in experimental inflammatory bowel disease (IBD) requires information about inflammatory activity in bowel segments or leukocyte recruitment and about kinetics in the follow-up of treatment. This study evaluated a noninvasive scintigraphic technique able to assess neutrophil trafficking in a mouse model of dextran sulfate sodium (DSS)-induced colitis.Groups of 4 BALB/c mice were assessed at baseline and after 1, 3, 5, and 8 d of treatment with DSS. Donor neutrophils were harvested by rinsing of the peritoneal cavity with phosphate-buffered saline 5 h after intraperitoneal injection of proteose peptone contained in phosphate-buffered saline and labeled with freshly prepared (99m)Tc-hexamethylpropylene amine oxime (HMPAO). Pinhole SPECT of the abdomen was performed 1 h after reinjection of 50 MBq of labeled neutrophils. In addition, the severity of inflammation was determined by histologic examination. The possibilities of the technique were illustrated by scintigraphic assessment of neutrophil trafficking with and without blocking of neutrophil migration by a CD97 monoclonal antibody in mice with DSS-induced colitis.Colonic uptake of (99m)Tc-HMPAO neutrophils was determined with dedicated animal pinhole SPECT in mice with DSS-induced colitis and correlated well with histologic findings (R = 0.81) and wet colon weight (R = 0.87) and moderately with clinical weight loss (R = 0.62). The neutrophil uptake ratio was reduced significantly (P0.01) by blocking of neutrophil migration capacity with the CD97 antibody.Animal pinhole SPECT can be used to study inflammatory activity and neutrophil recruitment in vivo in experimental colitis.

Blockade of lymphocyte recruitment to the intestinal mucosa is considered a useful therapy for inflammatory bowel disease (IBD) and anti-alpha4 antibodies have clinical benefit in patients with active Crohn's disease. The aim of this study was to evaluate a scintigraphic technique to assess lymphocyte homing to the colon in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis (TNBS colitis) in vivo.TNBS-sensitized and nonsensitized murine total lymphocytes or CD4+ lymphocytes were radiolabeled with 111In-oxinate. Cells were injected into control mice (n = 5) or mice with TNBS colitis (n = 5). Specific abdominal radioactive uptake was determined by SPECT using a dedicated pinhole system 48 h after cell transfer. Radioactive colon uptake was correlated with histology and colon weight as parameters of inflammation.The radioactive colon uptake was most evident in mice with TNBS colitis that received sensitized lymphocytes (uptake ratio [mean +/- SEM], 0.51 +/- 0.03 vs. 0.22 +/- 0.04; P = 0.004). The sensitized 111In-labeled lymphocytes exacerbated colitis compared with nonsensitized lymphocytes. The colon uptake correlated well with both colon weight and histologic score (R2 = 0.836 and 0.933, respectively). The use of purified 111In labeled CD4+ lymphocytes resulted in a similar scintigraphic pattern. Administration of an anti-alpha4 antibody decreased radioactivity colon uptake of the (111)In-labeled cells compared with the control antibody in mice with TNBS colitis (uptake ratio, 0.72 +/- 0.14 to 0.33 +/- 0.03; P = 0.012).Animal pinhole SPECT can be applied for temporal and spatial analysis of the lymphocyte homing process in experimental colitis. This technique makes possible the in vivo evaluation of therapeutic efficacy of new drugs that interfere with lymphocyte migration. Moreover, colon uptake of radioactivity can be used as a parameter of disease activity in experimental colitis.

In their paper published in Gut , Farges et al report that in 23 out of 218 patients, areas of hepatocellular carcinoma (HCC) within hepatocellular adenoma (HCA) were observed, and the risk of malignant transformation was 4% in women and 47% in men.1 Hypothesising that HCC may arise from HCA is based on the assumption that at a certain point in time residual HCA or a transition zone with dysplastic changes (as found in colorectal cancers) is present within the malignant liver lesion.2 The postulated theory presented by Farges et al may have great implications for the management of HCA. HCA, a rare benign liver tumour mostly occurring in young women, carries a small risk of malignant transformation …

Cholestatic liver injury is associated with an increased susceptibility toward endotoxin-induced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R(-/-)) mice, which are unresponsive to IL-1alpha and IL-1beta, and normal IL-1R(+/+) mice. Bdl elicited increases in hepatic IL-1alpha and IL-1beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R(-/-) and IL-1R(+/+) mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in sham-operated IL-1R(-/-) and IL-1R(+/+) mice were largely similar, but cholestatic IL-1R(-/-) mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1alpha and IL-1beta are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl.

BACKGROUND Hospital mortality after esophagectomy has decreased from 29% to 7.5% over the last decades because of improved surgical techniques and better perioperative care. Suggestions have been made that a further decrease in hospital mortality may be achieved by centralization of esophagectomies in high volume centers. METHODS The effect of hospital volume on hospital mortality after esophagectomy in the Netherlands was analyzed based on data from the Dutch National Medical Registry and the Dutch Network and National Database for Pathology over the period 1993–1998. RESULTS Annually, approximately 310 (range, 264–321) esophagectomies are performed in the Netherlands. Fifty-two percent are performed in 43–55 low volume centers (1–10 resections a year). Six percent are performed in 1–3 medium volume centers (11–20 resections a year). The remainder (42%) is performed in two high volume centers (> 50 resections a year). Hospital mortality is 12.1%, 7.5% and 4.9% respectively (P < 0.001). The high volume centers seem to see slightly more advanced tumors than the low and medium volume centers. CONCLUSIONS There is a significant (inverse) relation between hospital mortality and hospital volume for esophageal resection in the Netherlands. Although hospital mortality is not the only measure for quality of care, these data suggest a potential beneficial effect to centralization of esophagectomy in the Netherlands. Cancer 2001;91:1574–8. © 2001 American Cancer Society.

A case of nonseminomatous testicular cancer and enlarged mediastinal lymph nodes, which were interpreted as metastases, is reported. When there was no change after two courses of chemotherapy, a mediastinoscopy was performed and the results showed sarcoidosis.

A mesenchymal tumor with the macroscopic and microscopic features of a fetal rhabdomyoma arose in the liver of a 14-year-old boy. Thirteen years previously this boy had been treated for a fetal rhabdomyomatous nephroblastoma with nephrectomy and--for subsequent peritoneal disseminations--with surgical excision, radiotherapy, and chemotherapy. The unusual hepatic location of the rhabdomyomatous tumor in this patient supports the view that this mature tumor developed from a metastasis of the original nephroblastoma. As such, this case may represent an example of irreversible change of a malignant process into a benign tumor probably caused by the action of systemic chemotherapy.

To compare UW-solution (UW) and Euro-Collins (EC) for long-term liver preservation we investigated the morphology and metabolic capacity of rat liver after 18 and 42-hours cold-storage in either UW or EC.After harvesting the rat liver was transferred to a perfusion chamber where it was perfused for 10 min with UW or EC at 4°C. Thereafter livers were stored at 4°C in UW or EC for 18 hours (both groups n = 6) or for 42 hours (both groups n = 8). After 18-hr or 42-hr cold-storage a 2-hr warm perfusion (37°C) was started with Krebs-Ringer solution with carbogen to which 125Iodine-triiodothyronine (T3) was added. Control livers (n = 8) were immediately perfused with Krebs-Ringer without cold-storage. The following parameters were assessed: ASAT-levels in the perfusate, T3-metabolites in the bile and the perfusate, the perfusion pressure, the volume of bile secreted and light-microscopical morphology at the end of the warm perfusion period.After cold storage in UW-solution the ASAT-levels in the perfusate were lower than after storage in EC as well as the perfusion pressures. These livers demonstrated a better T3-metabolism and secreted more bile than EC-stored livers. Histological examination showed more tissue damage in the EC-stored livers than in the UW stored livers.We conclude that cold-storage of rat liver in UW-solution resulted in a better morphology and metabolic capacity as compared with EC-solution.

We report a case of renal failure in a newborn infant due to membranous glomerulonephritis. The patient was anuric in the first 3 weeks of life, after which renal function recovered. The serum of the mother contained IgG antibodies which reacted with tubular brush borders and glomeruli of adult and fetal human kidneys. Reactivity with renal epithelium from human kidneys was detected. We suggest that a transplacental, passive Heymann nephritis-like mechanism was the pathogenesis of the neonate's symptoms, although the antigen(s) involved was shown not to be gp 330 or any of the renal antigens known to be involved in experimental nephropathies.

For production of monoclonal antibodies (McAbs), hybrid cells were prepared by fusion of spleen cells of BALB/c mice immunized with the human prostatic cancer cell line PC-82 and the P3-X6(3)Ag8.653 murine myeloma cell line. Supernatants of approximately 500 hybrid clones were screened for prostate specific antibodies using an ELISA on PC-82 cells. A selection of antibodies was further tested for their specificity on a large series of different tissues. A broad cross reactivity pattern was obtained. Most cross reactivity was with pancreatic tissue, kidney, and bowel. One antibody turned out to react with prostate stromal cells. Two McAbs (ER-Pr 1 and ER-Pr 2) reacted solely with prostatic epithelium. Monoclonal antibody affinity chromatography combined with SDS-PAGE showed that both antibodies were directed against a 35-kD protein. Immunoblotting revealed that this protein is identical to prostatic antigen (PA). The epitope detected by ER-Pr 1 and ER-Pr 2 was largely preserved after formalin-fixation of prostatic tissues which renders these antibodies very suitable for routine examination of tissue sections.

The case of a 61-year-old woman with a surgically resected solitary cholangiocarcinoma of the liver is reported, where many discrete multiple bile duct hamartoma (MBDH) were also seen. The latter is a congenital lesion of the liver that potentially may be confused with widespread metastatic disease. The relationship between cholangiocarcinoma and MBDH was studied histologically by the use of an immunoperoxidase technique for cytokeratin. MBDH was strongly positive for cytokeratin, while the neoplasm showed this to a lesser extent, but a clear continuity between the MBDH epithelial cells and those of the neoplasm was demonstrated by the use of this technic. The potential use for the various cytokeratins in the differentiation of primary from secondary liver tumors, is discussed. This differentiation is a significant problem to the pathologist. Although cholangiocarcinoma may, on occasion, be associated with various congenital lesions of the bile ducts, the association with MBDH is extremely rare, this being only the third reported case.

In order to investigate the reproducibility of grading systems for prostatic carcinoma currently in use, a comparative histological grading study was done. These studies were carried out on tissue sections from radical prostatectomy specimens (N=50) stained with hematoxylin and eosin. Five pathologists with varying professional experience participated in the study, using five different grading systems: those of Broders, Brawn, Gleason (for statistical compilation the modified version), Mostofi, and a modified Mostofi grading method recently described by Schroeder and Mostofi. Weighted kappa coefficients ranged from 0.21 to 0.52. None of the systems investigated demonstrated a high degree of reproducibility (k>0.70). Reproducibility of the systems described by Broders and Brawn was reasonably good (k=0.52 and 0.41, respectively). With the modified Gleason method (rearrangement of Gleason scores into 3 grades), a considerable difference was noted between the numerical agreement score (among at least 3 observers) and the measured kappa value (100% and 0.30, respectively). The methods described by Mostofi and Schroeder-Mostofi revealed only limited reproducibility (k=0.21 and 0.34, respectively).