Molecular Characterization of Acute Cellular Rejection Occurring During Intentional Immunosuppression Withdrawal in Liver Transplantation.

Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period, its molecular phenotype is confounded by peri- and postoperative proinflammatory events. To unambiguously define the molecular profile associated with rejection, we collected sequential biological specimens from 55 patients at least 3 years after liver transplantation who developed rejection during trials of intentional immunosuppression withdrawal. We analyzed liver tissue and blood samples obtained before initiation of drug withdrawal and at rejection, alongside blood samples collected during the weaning process. Gene expression profiling was conducted using whole-genome microarrays and real-time polymerase chain reaction. Rejection resulted in distinct blood and liver tissue transcriptional changes in patients who were either positive or negative for hepatitis C virus (HCV). Gene expression changes were mostly independent from pharmacological immunosuppression, and their magnitude correlated with severity of histological damage. Differential expression of a subset of genes overlapped across all conditions. These were used to define a blood predictive model that accurately identified rejection in HCV-negative, but not HCV-positive, patients. Changes were detectable 1-2 mo before rejection was diagnosed. Our results provide insight into the molecular processes underlying acute cellular rejection in liver transplantation and help clarify the potential utility and limitations of transcriptional biomarkers in this setting.

Liver stiffness 1 year after transplantation predicts clinical outcomes in patients with recurrent hepatitis C.

The value of transient elastography (TE) to assess clinical outcomes in hepatitis C recurrence after liver transplantation (LT) has not been explored so far. We studied 144 hepatitis C-infected and 48 non-hepatitis C virus (HCV)-infected LT recipients and evaluated the prognostic value of TE 1 year after transplantation to predict clinical decompensations and graft and patient survival. In HCV patients, cumulative probabilities of liver decompensation 5 years after LT were 8% for patients with liver stiffness measurement (LSM) <8.7 kilopascals (kPa) versus 47% for patients with LSM ≥ 8.7 kPa (p<0.001). Five-year graft and patient cumulative survival were 90% and 92% in patients with LSM<8.7 kPa (p<0.001) and 63% and 64% in patients with LSM ≥ 8.7 kPa, respectively (p<0.001). Patients with low LSM 1 year after LT had excellent outcomes independently from receiving antiviral treatment or achieving sustained virological response (SVR). In contrast, graft survival significantly improved in patients with LSM ≥ 8.7 kPa who achieved SVR. No association between outcomes and LSM at 12 months was observed in non-HCV patients. In conclusion, LSM 1 year after LT is a valuable tool to predict hepatitis C-related outcomes in recurrent hepatitis C and can be used in clinical practice to identify the best candidates for antiviral therapy.

Severe Hepatitis C Recurrence as a Risk Factor for Opportunistic Infections in Liver Transplant Recipients.

OBJECTIVE: The aim of the study was to determine the clinical characteristics, frequency of opportunistic infections (OI), and the outcomes for liver transplant recipients with severe hepatitis C virus (HCV) recurrence. In addition, the objective was to evaluate HCV recurrence as a risk factor for developing an OI. METHODS: We conducted a retrospective observational study recording all liver transplant recipients from July 1, 2003, to December 31, 2012. Patients with liver disease due to HCV were selected. Active surveillance of infections was conducted periodically, and patients were classified according to presence of severe HCV recurrence. RESULTS: Three hundred seventy patients underwent liver transplantation because of chronic HCV. One hundred forty-seven patients presented severe recurrence (SR) (49%) and 50 (17%) of them had post-liver transplant cholestatic hepatitis C. Patients with SR presented OI, especially cytomegalovirus (CMV) infections and invasive fungal infections, more frequently than patients without SR (33% vs 13%; P < .001). From the diagnosis of SR to the presentation of OI, the median number of days was 169 (6-2083). Acute allograft rejection (OR 1.8 95% confidence interval [CI] 1.1-3.3) donor age ≥60 years (OR 2.9 95% CI 1.3-6.8), and SR (OR 2.8, 95% CI 1.6-5.1) were independently associated with the development of OI in liver transplant recipients. CONCLUSION: A high index of suspicion of opportunistic infections must be maintained when faced with severe HCV recurrence in liver transplant recipients. Moreover, active surveillance against CMV infection and other prophylactic strategies against opportunistic infections should be considered.

EUS FNA in intraductal papillary mucinous tumors of the pancreas.

BACKGROUND/AIMS: There is little information concerning the potential role of fine-needle aspiration guided by endoscopic ultrasonography in the pathologic diagnosis of intraductal papillary mucinous tumors of the pancreas. METHODOLOGY: Patients with an intraductal papillary mucinous tumor of the pancreas suggested by endoscopic ultrasonography underwent fine-needle aspiration guided by endoscopic ultrasonography in order to investigate the presence of mucin and/or cytologic changes consistent with this diagnosis. A group of 111 patients with other pancreatic lesions explored during the same period of time was used as a control group. RESULTS: Fine-needle aspiration guided by endoscopic ultrasonography was safely performed in 19 patients and supported the diagnosis in 17 of them. Nine out of the 17 patients with suspicion of intraductal papillary mucinous tumors of the pancreas went to surgery and this diagnosis was confirmed in the resected specimen in all of them. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EUS FNA in the diagnosis of IPMT were 82%, 100%, 100%, 92% and 94% respectively. CONCLUSIONS: Fine-needle aspiration guided by endoscopic ultrasonography is a good technique to support the diagnosis of intraductal papillary mucinous tumors of the pancreas and should be considered in this group of patients if pathologic confirmation is judged to be necessary.

Does Helicobacter pylori have a pathogenic role in bronchiectasis?

AIM: To investigate the presence of Helicobacter pylori (H. pylori) in bronchial biopsies of patients with bronchiectasis, by histochemical and immunochemical staining. SETTING: 800-bed tertiary university hospital. METHODS: Observational study. PATIENTS: forty-six patients with bronchiectasis in a stable clinical condition and 8 control patients. INTERVENTIONS: Serum samples determination of IgG levels for H. pylori by ELISA. Immunostaining with an anti-H. pylori antibody (NCL-HPp, Novocastra) of bronchial mucosa obtained by fiberoptic bronchoscopy from both patients with bronchiectasis and controls. RESULTS: Twenty-one out of 46 patients with bronchiectasis (46%) had positive serology for H. pylori. We obtained 40 bronchial biopsies in patients with bronchiectasis and 8 bronchial biopsies in control patients. No evidence of H. pylori was obtained in the bronchial samples of both patients and controls. CONCLUSIONS: The results of our study could not demonstrate the presence of H. pylori in bronchial specimens from patients with bronchiectasis.

Loss of heterozygosity of p53 gene and p53 protein expression in human colorectal carcinomas.

The p53 gene is a tumor suppressor gene located on chromosome 17p. Deletions of this chromosome and point mutations of p53 have been implicated in the development of colonic neoplasms. We have analyzed the loss of heterozygosity of the human p53 tumor suppressor gene in 40 cases of colorectal carcinoma using two restriction fragment length polymorphisms detected by BglII and AccII restriction enzymes. p53 gene product expression was studied immunohistochemically in 64 colorectal carcinomas, 18 adenomas, and 40 normal colonic mucosae using an anti-human p53 monoclonal antibody (Pab 1801) and the avidin-biotin-peroxidase complex technique. Twelve of the 40 patients (30%) were polymorphic for the p53 gene. In ten of these informative patients (83%), the tumor samples showed the loss of one allele when compared with normal colorectal samples of the same patient. One of the homozygous patients showed a loss of both p53 alleles. p53 immunostaining was observed in 43 of 64 carcinomas (67%) but only in two adenomas (11%). These two positive adenomas showed areas of carcinoma in situ. The normal mucosa was always negative. No relation could be found between p53 immunostaining and the degree of differentiation, the extension of the tumor, or the Ki-67 proliferative index. Mucinous carcinomas and right-side carcinomas were less p53 immunoreactive (25% and 52%, respectively) than the usual adenocarcinomas (73%) and distal tumors (72%). These findings suggest that p53 may be a target of chromosome 17 deletions and that this gene may play a role in the malignant transformation of adenomas. BglII and AccII restriction fragment length polymorphism analysis of the p53 gene may be a useful and direct technique to detect allelic loss of this gene in tumors.

[Intestinal occlusion due to pancreatitis mimicking stenosing neoplasm of the splenic angle of the colon]. / Oclusión intestinal secundaria a pancreatitis que mimetiza una neoplasia estenosante del ángulo esplénico del colon.

Colonic involvement in patients with severe acute pancreatitis or chronic pancreatitis is common and complications such as paralytic ileus, segmental necrosis and pancreatic-colonic fistulae have been described. However, mechanical occlusion of the colon due to pancreatitis is infrequent. We present the case of a 45-year-old man with occlusion of the colon secondary to asymptomatic pancreatitis mimicking a locally advanced stenosing neoplasm of the splenic angle. Ten years prior to the present episode the patient had presented acute alcoholic pancreatitis complicated by a pseudocyst requiring surgery. The current reason for admission was abdominal colic pain and constipation with onset 5 days previously. Contrast enema was administered showing colonic occlusion caused by stenosis at the splenic flexure, suggesting the presence of a neoplasm. Urgent laparotomy showed the presence of a tumor originating in the colon that infiltrated the splenic hilum. Subtotal colectomy and en-bloc splenectomy were performed. Histopathological analysis showed pericolonic inflammation and fibrosis secondary to pancreatitis; the colonic mucosa showed no tumoral infiltration. To date, fewer than 30 cases of this infrequent complication have been published.

Primary nodal marginal zone lymphomas of splenic and MALT type.

The existence of primary nodal marginal zone lymphomas (MZL) is controversial, as is their relationship to putative extranodal counterparts. Most nodal lymphomas with monocytoid B cell/marginal zone differentiation exhibit the morphologic and immunophenotypical characteristics of extranodal MALT-lymphomas. Splenic marginal zone lymphoma (SMZL) is also of putative marginal zone derivation, but it differs immunophenotypically from MALT lymphoma. To clarify the relationship between nodal and extranodal MZLs and to investigate the possible existence of a nodal variant of SMZL, 36 MZL initially considered to be primary nodal neoplasms were examined. Other low-grade lymphomas with marginal zone differentiation were excluded (small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL], follicular lymphoma, and mantle cell lymphoma). Six nodal MZLs showed morphologic and phenotypic characteristics similar to those of SMZL, whereas 30 tumors were more similar to MALT-type lymphomas. The six tumors with SMZL features showed a polymorphic infiltrate surrounding residual germinal centers with absent or very attenuated mantle cuffs. These lymphomas were IgD positive (6/6) but cyclin D1 (0/5), CD5 (0/6), and CD23 (0/6) negative. Five of these patients came for treatment in stage I or II. No patient manifested splenomegaly, peripheral blood, and/or bone marrow infiltration either at diagnosis or during follow-up. Lymph nodes from 30 patients with MALT-type features showed a perisinusoidal and perivascular infiltration of monocytoid/centrocytoid cells and residual germinal centers with a relatively well-preserved mantle cuff. The neoplastic cells were negative for IgD (0/17), cyclin D1 (0/8), and CD5 (0/12). Seven of 16 (44%) patients with a detailed history and clinical follow-up had evidence of extranodal lymphoma. These observations suggest that most nodal B cell lymphomas with marginal zone differentiation are of the MALT type and that they are frequently associated with an extranodal component. In addition, a primary nodal counterpart of splenic MZL also exists, and may occur in the absence of splenomegaly.

Metastatic carcinoma of the breast resembling early gastric carcinoma.

We describe a case of gastric metastasis from a lobular carcinoma of the breast in a 45-year-old woman who had undergone a left mastectomy with axillary dissection 7 years earlier. At the current presentation, she had been experiencing progressive epigastric discomfort for 3 months. The initial diagnosis was early gastric carcinoma, diffuse type, based on gastric biopsy findings and ultrasonographic endoscopy. A definitive diagnosis of metastatic breast cancer was confirmed after subtotal gastrectomy of a presumed primary early gastric carcinoma. Although gastrointestinal metastases from breast cancer are not rare, the early stage of the gastric lesion and the absence of further disease dissemination make this case unusual. The onset of gastrointestinal symptoms in a patient with a history of breast carcinoma should prompt the physician to rule out the possibility of gastric metastases.

Clinico-pathological correlations in meningiomas: a DNA and immunohistochemical study.

We have studied 41 meningiomas classified histologically as benign, atypical or anaplastic. There were 26 females and 15 males and the mean age was 53 years. 36 tumours were supratentorial, 4 infratentorial and one spinal. Flow cytometry was performed on paraffin-embedded tissue using a selective staining technique for DNA. The ploidy index of DNA and percentage of cells in the S and G2/M phases were calculated. Results were correlated with clinical, histological and immunohistological data. 16/41 tumours were found to be diploid, 17/41 aneuploid and 8/41 could not be analysed. Significant correlations were found between aneuploid tumours and some qualitative features such as recurrence, pleomorphism, high cellular density, mitotic activity and brain and soft tissue infiltration. A high proliferative index appeared to be associated with clinical aggressiveness. No particular correlation between the expression of cytokeratin and epithelial membrane antigen markers and flow cytometry was found. Our results suggest that DNA flow cytometry in meningiomas may be of value in predicting the behaviour of these neoplasms and confirm that epithelial pattern in meningiomas is not linked to increased anaplasia or poor prognosis.

[Non-gastric mucosa-associated lymphoid tissue (MALT) lymphomas: analysis of 14 patients]. / Linfomas del tejido linfoide asociado a mucosas (MALT) de localización extragástrica: análisis de 14 casos.

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphomas are a well defined group of B-cell non-Hodgkin's lymphomas, that arise in a wide variety of extranodal sites, most frequently in the stomach and related to Helicobacter pylori infection. The aim of the present study was to analyze the presenting features, natural history and outcome in 14 patients with non-gastric MALT lymphoma. PATIENTS AND METHODS: The main clinical data, treatment and outcome were recorded for the 14 patients with non-gastric MALT lymphoma diagnosed at a single institution in a 12 year period. The median age was 68 years and 13 patients were females. Diagnosis was made according to the REAL classification criteria. RESULTS: The initial location was thyroid (3 patients), parotid (three), submaxilar gland (three), skin (two), Waldeyer's ring (one), breast (one), lung (one), small bowel (one), liver (one) and ovary (one). At diagnosis 3 patients had > or = 2 extranodal involved sites. Autoimmune disorders were present in 5 patients: Hashimoto's thyroiditis (three), Sjögren's syndrome (one) and both (one). Two patients had a poor performance status (ECOG > 1) and B-symptoms. Five patients (36%) were in stage IV, two of them because of bone marrow infiltration. All patients had a normal serum LDH level, and 5 had high beta 2-microglobulin level. The treatment consisted in surgical resection (2 patients), surgery and radiotherapy (one), surgery and chemotherapy (two), chemotherapy and radiotherapy (two) and chemotherapy alone (7 patients, three of them with doxorubicin-containing regimens). Twelve patients were evaluable for response. Complete response, partial response and failure rates were 75, 17 and 8%, respectively. Two of the 11 responders progressed, one of them with advanced stage disease. The actuarial 4-year disease-free survival was 77% (CI 95%: 47-100%). After a median follow-up of 3.4 years, 100% of the patients were alive. CONCLUSION: Non-gastric MALT lymphomas may be associated with autoimmune disorders, may present as disseminated disease and have a very good outcome.

[Hepatocellular carcinoma in a patient with hereditary hemochromatosis without cirrhosis]. / Carcinoma hepatocelular en una paciente afectada de hemocromatosis hereditaria sin cirrosis.

Hepatocellular carcinoma in patients with hereditary hemochromatosis in the cirrhotic phase is one of the complications causing greatest mortality and may present in spite of removal of excess iron by bloodletting. Hepatocellular carcinoma is usually considered to occur in cirrhotic livers and consequently measures for the early diagnosis of this complication are only recommended in this type of patient. We present the case of a 69-year-old female patient with non-cirrhotic hemochromatosis who, 6 years after undergoing successful treatment, developed hepatocellular carcinoma. This observation should be added to the 12 cases published in the literature. Criteria should be established for the early diagnosis of hepatocellular carcinoma in patients with hereditary hemochromatosis, irrespective of whether they have cirrhosis.

[Evaluation of the efficacy and efficiency of a multidisciplinary unit for the treatment of patients with colorectal cancer]. / Evaluación de la eficacia y eficiencia de una unidad multidisciplinaria para la atención de pacientes con cáncer colorrectal.

INTRODUCTION: Because of the increased complexity of the diagnostic-therapeutic approach to colorectal cancer (CRC), these patients should be managed in specialized multidisciplinary units. The aim of this study was to evaluate the efficacy and efficiency of a CRC unit (CRCU) in the diagnostic-therapeutic management of these patients. PATIENTS AND METHODS: Two groups of 50 patients with colon cancer treated in our center before and after the implementation of the CRCU were selected. Fulfillment with the protocol in terms of tumoral staging, surgical and adjuvant treatment, follow-up, interval until treatment, hospital stay, morbidity and early mortality, and the overall duration of the diagnostic-therapeutic process was analyzed. In addition, clinical workload was evaluated and a cost-minimization analysis was performed. RESULTS: The CRCU reduced the interval until surgery (20.3 12.0 vs 28.0 20.4 days; p = 0.05), hospital stay (9.8 7.7 vs 14.5 9.3 days: p = 0.01), the time to the start of adjuvant treatment (29.4 10.2 vs 39.7 19.8 days; p = 0.03) and the overall duration of the process (60.4 23,8 vs 82.1 46.1 days; p = 0.05), representing a saving of 978.85 E per patient. This improvement took place despite an increase in clinical workload (24% in 5 years in relation to the number of admissions) and had no effect on morbidity (26 vs 24%; NS) or immediate mortality (6 vs 4%; NS). CONCLUSION: Specialized multidisciplinary units increase the efficacy and efficiency of the management of patients with CRC.

[Hospital registry of pancreatic tumors. Experience of the Hospital Clínic in Barcelona (Spain)]. / Registro hospitalario de tumoraciones pancreáticas. Experiencia del Hospital Clínic de Barcelona.

OBJECTIVE: To describe the characteristics of patients included in the pancreatic tumor registry of the Hospital Clínic of Barcelona. PATIENTS AND METHOD: All patients with pancreatic tumors attended between July 1990 and March 2003 were registered. Data collection included: age, gender, date of diagnosis, diagnosis, histology, size, location and tumor stage, and treatment. The correlation between tumor stage and age, date of diagnosis, and tumor location was also evaluated. RESULTS: Six hundred thirty patients with pancreatic tumors were included, representing an incidence of 60 patients/year. The mean age was 66 years and the male-to-female ratio was 1,18:1. The most frequent lesion was malignant tumor of the pancreas (92%), and the most frequent histological type was pancreatic ductal adenocarcinoma (73%). The most frequent location was the head of the pancreas (64%). In 28% of the patients, pancreatic cancer was diagnosed in stage I and II. Resection was performed in 31% of patients, whereas 48% of the patients received no treatment. The ratio between local (stage I)/disseminated (stage IV) disease was 0,34. The ratio between stage I/IV increased with age, diagnosis prior to 1994, and tumor location in the head of the pancreas. CONCLUSION: Hospital tumor registries can be used to define the profile of the attended population, which can help to delineate the best diagnostic-therapeutic strategy and can be useful in clinical research.

Recommendations of a group of experts for the pathological assessment of tumour regression of liver metastases of colorectal cancer and damage of non-tumour liver tissue after neoadjuvant therapy.

Colorectal cancer (CRC) incidence has increased during the past decades in Spain, being the first malignant tumour in incidence. Observed mortality for CRC is mainly due to liver and lung metastases. The only curative treatment is surgery; new surgical techniques and neoadjuvant treatments have increased the number of surgery candidate patients. Patients should be managed with a multidisciplinary approach that includes imaging techniques, chemotherapy, surgery and pathological assessment. As an answer to this approach, a group of pathology experts interested on CRC liver metastases aimed to review the diagnosis and prognosis of liver mestastases and developed practical recommendations for its assessment. The expert group revised the current literature and prepared questions to be discussed based on available evidence and on their clinical practise. As a result, recommendations for the assessment of tumour regression of liver metastases are proposed, which could be implemented in oncology centres allowing assessment standardisation for these patients. Prospective multi-center studies to evaluate these recommendations validity will further contribute to improve the standard care of CRC liver metastases patients.