A single institution's 21-year experience with surgically resected pancreatic neuroendocrine tumors: an analysis of survival and prognostic factors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) comprise a heterogeneous group of tumors with a varied biological behavior. In the present study, we analyzed the experience of 79 pNETs resected between 1999 and 2014. The pathologic prognostic factors (European Neuroendocrine Tumor Society, ENETS; and AJCC) classification, vascular invasion (VI), proliferation index (ki-67) and the presence of necrosis were retrospectively reviewed. METHODS: The clinical data of 79 patients with pNETs who underwent surgery were retrospectively analyzed. Mortality rates and Kaplan-Meier estimates were used to evaluate survival over time for pathologic stages, tumor functionality, and vascular invasion. Cox proportional hazards models were used to calculate the hazard ratio regarding ENETS, AJCC staging, sex, tumor functionality and vascular invasion. RESULTS: The male:female ratio was 40:39. Twenty-one patients (26%) had functional tumors and 58 (73.4%) had non-functional tumors, of which 35 (44.3%) were diagnosed incidentally. Seventeen Whipple procedures, 46 distal pancreatectomies (including 26 laparoscopic and 20 open procedures), 8 laparoscopic central pancreatectomies, 1 laparoscopic resection of the uncinated process and 7 enucleations (one laparoscopic) were performed. Vascular invasion and necrosis were observed in 29 of 75 cases (38.6%) and in 16 cases (29%), respectively. The comparison between survivor functions of ENETS staging categories showed statistically significant differences (p = 0.042). Mortality rate was higher in patients with non-functioning tumors compared with hormonally functioning tumors (p = 0.052) and in those with vascular invasion (p = 0.186). CONCLUSIONS: In spite of the heterogeneity of pNETs, the ENETS TNM classification efficiently predicts long-term prognosis. The non-functioning tumors and the presence of vascular invasion are associated with poor prognosis.

Immune monitoring of immunosuppression withdrawal of liver transplant recipients.

UNLABELLED: Several studies have shown that some liver transplant recipients may tolerate immunosuppression withdrawal. Mechanisms and biomarkers of tolerance are not well known. METHODS: Twenty-four LT patients with immunosuppression side-effects underwent progressive immunosuppression withdrawal. Peripheral lymphocyte populations and secretion of cytokines were analyzed at baseline and during withdrawal until tolerance (n = 15) or rejection (n = 9), as well as 3 months after tolerance achievement or rejection resolution (as follow-up). Immunological markers were compared among groups. RESULTS: The percentages of CD3+CD4+ cells progressively decreased in both groups. CD3+CD8+ cells gradually increased in tolerant patients. B lymphocytes gradually decreased in tolerant and initially in non-tolerant patients, reverting at rejection. Regulatory T cells progressively increased until rejection in non-tolerants, decreasing to basal levels after renewing immunosuppression; no significant changes were found in tolerant patients. The percentages and absolute counts of natural killer cells significantly increased in both groups, being more evident in tolerant patients. The secretion of several cytokines was higher in non-tolerant patients when rejection was diagnosed. CONCLUSIONS: The greater increase of natural killer cells in tolerant patients suggests their potential role in the tolerance phenomenon.

Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation.

CONTEXT: Wingless-type mouse mammary tumor virus integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the noncanonical Wnt signaling pathway. Secreted frizzled-related protein (SFRP)-5 acts as a decoy receptor that binds and sequesters WNT5A, preventing activation of frizzled receptors and attenuating the noncanonical Wnt signaling. OBJECTIVE: The aim of the study was to evaluate the involvement of WNT5A and SFRP5 in obesity and obesity-related comorbidities as well as to explore their effect in visceral adipose tissue inflammation. PATIENTS AND METHODS: Samples obtained from 90 subjects were used. Circulating and gene expression levels of WNT5A and SFRP5 were analyzed in different metabolic tissues. The effect of TNF-α and lipopolysaccharide on the transcript levels of WNT5A and SFRP5 in adipocytes was explored. We also investigated whether WNT5A itself can activate an inflammatory response. RESULTS: Increased circulating levels of WNT5A in obese patients (P < .05) were decreased (P < .001) after gastric bypass. In this line, WNT5A mRNA in visceral adipose tissue was increased (P < .05) in obese patients with gene expression levels of SFRP5 being down-regulated (P < .05). WNT5A mRNA expression was significantly enhanced (P < .01) by lipopolysaccharide and TNF-α treatment, whereas no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P < .05) IL-6, IL1B, MMP2, MMP9, and SSP1 mRNA expression in human adipocyte cultures. CONCLUSIONS: Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.

Characterization of the CD40L/Oncostatin M/Oncostatin M receptor axis as an antiviral and immunostimulatory system disrupted in chronic HCV infection.

BACKGROUND & AIMS: Oncostatin M (OSM) is an inflammatory cytokine which interacts with a heterodimeric receptor formed by gp130 and either OSMRß or LIFR. Here we have analysed OSM and its receptors in livers with chronic hepatitis C (CHC) and studied the factors that regulate this system. METHODS: OSM, OSM receptors and OSM-target molecules were studied by immunohistochemistry and/or qPCR analysis in livers from CHC patients and controls. We determined the production of OSM by CD40L-stimulated antigen presenting cells (APC) and its biological effects on HuH7 cells containing HCV replicon (HuH7 Core-3'). RESULTS: OSM was upregulated in livers with CHC and its production was mapped to CD11c+ cells. OSM levels correlated directly with inflammatory activity and CD40L expression. In vitro studies showed that OSM is released by APC upon interaction with activated CD4+ T cells in a CD40L-dependent manner. Culture of HuH7 Core-3' cells with supernatant from CD40L-stimulated APC repressed HCV replication and induced IL-7 and IL-15Rα. These effects were dampened by antibodies blocking OSM or gp130 and by silencing OSMRß. In CHC livers OSMRß and LIFR were significantly downregulated and their values correlated with those of OSM-induced molecules. Experiments in HuH7 cells showed that impaired STAT3 signaling and exposure to TGFß1, two findings in CHC, are factors involved in repressing OSMRß and LIFR, respectively. CONCLUSIONS: OSM is a cytokine possessing vigorous antiviral and immunostimulatory properties which is released by APC upon interaction with CD40L present on activated CD4+ T cells. In livers with CHC, OSM is overexpressed but its biological activity appears to be hampered because of downregulation of its receptor subunits.

Prognostic value of clinical, morphologic, and immunohistochemical factors in patients with bronchiolitis obliterans-organizing pneumonia.

Bronchiolitis obliterans-organizing pneumonia (BOOP) is an inflammatory and fibrosing disease involving the distal bronchioles, bronchiolar ducts, and alveoli. We studied 91 patients with BOOP. Univariate analysis was used to relate age, sex, smoking, morphology, and expression of immunohistochemical markers CD68, D2-40, CD31, CD34, collagen IV, collagen III, platelet-derived growth factor receptor, and vascular endothelial growth factor (VEGF) with the response to corticosteroid therapy. Seventy-two patients had idiopathic BOOP and 19 secondary BOOP. The median age of the patients was 59.54 years. Most patients were current or former smokers. All cases had a patchy lesion consisting of small buds of fibromyxoid tissue in small bronchioles, bronchiolar ducts, and alveoli. The buds contained collagen and reticulin fibers, fibroblasts, macrophages, mononuclear inflammatory cells, and vessels in different proportions. We found no morphologic differences between primary and secondary BOOP. Patients younger than 38 years and nonsmokers had a significant good response to corticosteroid therapy. Favorable morphologic predictors were the presence of large bronchial plugs and mild inflammatory reaction (P = .093). By immunohistochemistry, the presence of collagen IV with the absence of collagen III, CD68-positive cells and positive VEGF were associated with a good response to corticosteroid therapy. We conclude that age, smoking, localization, and extension of proliferative intrabronchiolar plugs and positive immunostains for CD68, VEGF, and collagen IV with negative collagen III were useful to predict response to corticosteroid therapy and relapse.

Liver disease induced by radioembolization of liver tumors: description and possible risk factors.

BACKGROUND: To the authors' knowledge, liver damage after liver radioembolization with yttrium90-labeled microspheres has never been studied specifically. METHODS: Using a complete set of data recorded prospectively among all patients without previous chronic liver disease treated by radioembolization at the authors' institution from September 2003 to July 2006, patterns of liver damage were identified and possible risk factors were analyzed. RESULTS: In all, 20% of patients developed a distinct clinical picture that appeared 4 to 8 weeks after treatment and was characterized by jaundice and ascites. Veno-occlusive disease was the histologic hallmark observed in the most severe cases. This form of sinusoidal obstruction syndrome was not observed among patients who never received chemotherapy or in those in whom a single hepatic lobe was treated. Relevant to treatment planning, a possible risk factor was a higher treatment dose in relation to the targeted liver volume. A transjugular intrahepatic stent shunt improved liver function in 2 patients with impending liver failure, although 1 of them eventually died from it. CONCLUSIONS: Radioembolization of liver tumors, particularly after antineoplastic chemotherapy, may result in an uncommon but potentially life-threatening form of hepatic sinusoidal obstruction syndrome that presents clinically with jaundice and ascites.

Dysregulation of apoptosis is a major mechanism in the lymph node involvement in colorectal carcinoma.

The purpose of this study was to define gene expression profile changes in colorectal tumors in order to identify target genes involved in neoplastic progression. cDNA microarray analysis was used to detect differences in gene expression profiles between colon tumor samples obtained from 20 patients in different tumor stages. Genes included in the cDNA microarray were selected according to their role in the cell cycle, apoptosis process, drug resistance and transcription factor regulation. Cluster analysis showed 2 well differentiated gene expression profiles between colorectal tumors with or without lymph node involvement. Some of these genes are important regulators of apoptotic pathways (DAD1, APO3, DRAK1 or BIK), suggesting that this process could be associated with node involvement. Subsequent analysis of certain genes identified in the microarray analysis were confirmed by quantitative real-time PCR. Our data suggest that microarray technology could discriminate between the involvement of regional lymph node in colon cancer where apoptosis-related genes would be implied. This preliminary analysis also suggests that the gene expression profile may be useful in improving risk-group stratification.

Angiomyolipoma and PEComa are immunoreactive for MyoD1 in cell cytoplasmic staining pattern.

The family of tumors derived from mesenchymal perivascular epithelioid cells (so-called PEComas) includes angiomyolipoma, lymphangioleiomyomatosis, clear cell sugar tumor of the lung, clear cell myomelanocytic tumor of ligamentum teres/falciform ligament, and abdominopelvic sarcoma of perivascular epithelioid cells. These tumors were characterized by coexpression of melanocytic (HMB-45) and muscle markers. MyoD1 transcription factor has crucial role in commitment and differentiation of mesenchymal progenitor cells to myogenic lineage. Antibodies to MyoD1 protein (nuclear immunoreactivity) have been shown highly valuable adjuncts in the diagnosis of rhabdomyosarcomas. To evaluate expression of the transcription factor MyoD1 in PEComas, we performed immunohistochemistry. Monoclonal antibody 5.8A for MyoD1 was used on a series of cases of formalin-fixed, paraffin-embedded angiomyolipoma (n = 19), lymphangioleiomyomatosis (n = 3), clear cell sugar tumor of the lung (n = 1), and abdominopelvic sarcoma of perivascular epithelioid cells (n = 2). All cases showed strong granular immunostaining in the tumor cell cytoplasm with the anti-MyoD1 antibody. Cytoplasmic reactivity was noted in the spindle cells, fat cells, and epithelioid cells. Nuclei were negative in all tumors studied, and a clean background was obtained. Several normal and neoplastic human tissues have also been immunostained for MyoD1 without any positive cytoplasmic staining, with the exception of 2 alveolar soft part sarcomas. Cytoplasmic immunostaining with monoclonal antibody 5.8A for MyoD1 in PEComas may correspond to cross-reactivity with an undetermined cytoplasmic protein. Great caution should be exercised in interpreting the immunostaining results with anti-MyoD1 antibody 5.8A.

Predicting Metastatic Risk of Gastrointestinal Stromal Tumors: Role of Cell Proliferation and Cell Cycle Regulatory Proteins.

Gastrointestinal stromal tumors (GIST) are a heterogeneous group of neoplasms whose biologic behavior is difficult to predict. The aim of this study is to evaluate the prognostic value in GIST of some oncoproteins involved in regulation of cell proliferation. Tumor size, mitosis, necrosis, and p53, c-myc, and bcl-2 protein expression of 32 GIST were studied. Proliferative index was assessed with Ki67. The 32 cases were grouped into the following clinical categories: (1) clinically benign (BN) were defined as disease-free survival greater than 3 years (n=10); (2) clinically malignant (MN) in which local recurrence or metastasis occurred regardless of the follow-up time (n=15); and (3) clinically indeterminate (ID) owing to follow-up <3 years without metastasis or local recurrence (n=seven). Discriminant analysis was used to allocate any tumor to one of the two prognostic groups (BN or MN). In univariate analysis all six factors studied above proved to be of significant prognostic value. Using a multivariate stepwise discriminant analysis to take into account the interrelationship between factors, we found that c-myc expression was the most important prognostic factor, followed, in order of statistical weight, by size and Ki67. These were combined to define a discriminant score ([10.75 x c-myc]+[0.39 x size]+[0.078 x Ki67]-15.54=score), which was capable of correctly identifying tumors in our series whose known clinical behavior was BN or MN in 92% of the cases. The classification score was applied subsequently to the seven clinically ID cases: Three (42.9%) were predicted as BN, and four (57.1%) were predicted as MN. Both expression of oncoprotein c-myc and the proliferative index provide prognostic information in GIST, in addition to morphologically established prognostic factors such as size. These factors in a discriminant analysis proved to be useful for the clinical classification of GIST into BN or MN and to predict the clinical outcome of clinically ID tumors. Int J Surg Pathol 8(2):133-144, 2000