Iosu Sola

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=1 5); 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.

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.

Nuclear factor‐κB in the liver of patients with chronic hepatitis C: Decreased RelA expression is associated with enhanced fibrosis progression

The mechanisms of liver damage in chronic hepatitis C virus (HCV) infection are poorly understood. The transcription factor, nuclear factor‐κB (NF‐κB), regulates the expression of genes involved in apoptosis, inflammation, and antiviral response. It plays a protective role in several forms of liver damage. In this study, we analyzed NF‐κB by gel mobility shift assay and immunohistochemistry in liver biopsies from HCV‐infected patients, and we have determined the hepatic levels of the components of the NF‐κB system by semiquantitative polymerase chain reaction (PCR). We found that NF‐κB was activated in the liver of patients with chronic hepatitis C. Neither NF‐κB activity nor the RNA levels of NF‐κB subunits showed correlation with liver inflammatory activity, viral load, or HCV genotype. By contrast, hepatic mRNA values of RelA, the main element of active NF‐κB, correlated inversely with apoptosis (r = −.68; P < .05) and with the rate of fibrosis progression (r = −.51; P < .04). In intermediate/rapid fibrosers, RelA mRNA levels were significantly decreased as compared with slow fibrosers (P < .003) and with normal livers (P < .03). In conclusion, we found that NF‐κB is activated in chronic HCV‐infected livers, and that the expression of RelA is inversely correlated with liver cell apoptosis and with the rate of fibrosis progression. Our data thus suggest that RelA expression may protect against liver fibrosis and hepatocellular damage.

Morbidity, mortality, and pathological response in patients with gastric cancer preoperatively treated with chemotherapy or chemoradiotherapy

Significant tumor downstaging has been achieved in patients with localized gastric adenocarcinoma by preoperative chemoradiotherapy (ChRT) or induction chemotherapy (Ch). However the influence of ChRT and Ch on postoperative outcomes has not yet been clarified, with very few studies examining this issue. We retrospectively analyzed the efficacy in terms of pathological response and early postoperative complications of two protocols of preoperative ChRT and Ch for locally advanced gastric cancer.

Mast cells in chronic rejection of human renal allografts.

Abstract An increased number of mast cells (MCs) is found in renal specimens of patients with diseases associated with persistent chronic inflammation. MCs proliferation is partly dependent on the presence of T lymphocytes. Both chronic inflammation and T-lymphocytes are essential in the development of chronic rejection (CR), and probably for the infiltration of MCs. MC-derived products such as heparin, histamine, and serine proteases may be responsible for endothelial proliferation and excess collagen production by fibroblasts. In this study, a quantitative evaluation of the MCs infiltration in kidney allografts with CR is performed. The extent of renal fibrosis was analysed in samples stained with Masson’s trichrome. To evaluate the potential relationship between MCs and fibrosis in CR we analysed 30 kidneys with CR (25 from nephrectomies and 5 from autopsies). Ten transplanted kidneys obtained from patients died by causes not related with rejection were used as controls. CR was graded according to the Banff schema, which assesses the degree of vasculopathy, tubular atrophy, interstitial fibrosis and transplantation glomerulopathy. Giemsa-stained sections and immunohistochemistry using anti-MC tryptase and c-kit monoclonal antibodies were used to detect MCs. The mean number of MCs per 20 high-power fields (HPF) in the transplanted kidney with CR was 101.8±15.3 in the renal cortex and 46.60±6.52 in the medulla. MCs were significantly more numerous in CR with respect to normal kidneys, both in the cortex (P<0.01; Mann-Whitney U test) and in the medulla (P<0.01; Mann-Whitney U test). There was a positive correlation between the number of MCs and extent of fibrosis (P<0.01; Kruskal-Wallis one-way anova test) and tubular atrophy (P<0.01). These results suggest that MCs may play a role in the process of development of interstitial fibrosis in CR.

Metastatic osteosarcoma presenting as a small-bowel polyp. A case report and review of the literature.

Gastrointestinal metastases of osteosarcoma are an extraordinarily rare event and, as far as we can determine, have been reported previously only 5 times; these cases represent an unusual pattern of progression. We describe a 21-year-old man with an osteosarcoma of the right tibia that was removed 4 years previously. Two years later, the patient showed lung metastases. At his most recent presentation, he complained of abdominal pain, nausea, vomiting, and anorexia. Radiologic examination revealed an abdominal mass close to the jejunum and 3 nodules in the liver. One metastasis was an ulcerated and pedunculated polypoid mass located in the mucosa of the bowel, and the other involved the entire thickness of the jejunum. This unusual phenomenon represents an alteration in the natural history of osteosarcoma as a result of increased long-term survival.

FNAC guided by computed tomography in the diagnosis of primary pancreatic adenosquamous carcinoma : A report of three cases

BACKGROUND Pancreatic adenosquamous carcinoma (ASqC) is an unusual histologic subtype of nonendocrine neoplasia of the pancreas. Although fine needle aspiration cytology (FNAC) is now accepted as a reliable procedure for the diagnosis of pancreatic malignancies, many of these unusual tumors are still diagnosed after surgery or at necropsy. CASES Between January 1995 and July 1996, 3 of 35 primary pancreatic malignant tumors were diagnosed as ASqC based on computed tomography-guided FNAC. After cytologic diagnosis, all three patients were treated with neoadjuvant chemotherapy and radiotherapy. Two patients completed the treatment and underwent a surgical pancreatic-duodenectomy with antrectomy. The remaining patient is currently under treatment. That patient had a highly infiltrative pancreatic mass that affected the muscular small bowel wall. An endoscopic biopsy was performed. The cytologic diagnosis was confirmed by histology in all cases. Immunohistochemically both components, squamous and glandular, showed reactivity for several keratins, while only the glandular pattern was reactive with carcinoembryonic antigen (CEA). CONCLUSION FNAC is an accurate, rapid and sensitive tool in the diagnosis of ASqC of the pancreas. We recommend a careful search for both malignant components. Immunoreactivity for CEA can be of help in the detection of the glandular component of this tumor.

Decrease of Apoptosis Rate in Patients with Renal Transplantation Treated with Mycophenolate Mofetil

Background/Aims: Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF prevents acute graft rejection in organ transplants. The aim of this investigation is to study whether MMF has any influence on apoptosis and proliferation rates of cells other than lymphocytes. Methods: We conducted a retrospective study of renal allograft biopsies taken during the 1st week after transplantation in 25 patients receiving triple therapy with prednisone, ciclosporin and azathioprine 75 mg/day and in 25 patients treated with MMF at a dose of 2 g/day instead of azathioprine, in order to investigate the differences in the proliferation and apoptosis rates of the glomerular, tubular, interstitial and endothelial cells of the kidney. Twelve normal kidneys were used as controls. Conventional histopathological techniques were applied as usual for pathological diagnosis. Proliferative activity was assessed by use of MIB-1 antibody. Sections of formalin-fixed, paraffin-embedded tissue blocks were stained for the presence of apoptotic cells by TUNEL assay. Evaluation of proliferative or apoptotic rates was made by counting the number of positive cells in 10 glomeruli and in 10 transversely cut tubuli in each biopsy. The positive cells in the interstitium were counted in ten high-power fields. Positive cells in the endothelium were scored semiquantitatively from 0 to 3: 0 = none, 1 = isolated cells, 2 = small groups of cells, 3 = most endothelial cells. Mann-Whitney U and chi-square tests were used for intergroup comparisons. Results: All biopsies were normal or had borderline (Banff classification) acute rejection. MIB–1 rates were similar in both groups, without statistical differences (p > 0.05) between them. Significantly lower apoptotic rates were found in the group treated with MMF in tubular epithelium (23.41 ± 8.86 vs. 57.4 ± 13.42; p = 0.021), in glomerular (1.25 ± 0.78 vs. 5.3 ± 1.66; p = 0.027), and interstitial cells (1.58 ± 0.6 vs. 5.8 ± 1.54; p = 0.043). Apoptosis in endothelial cells (p > 0.05) was similar in both groups. Conclusion: We conclude that treatment with MMF of kidney transplant patients does not affect the proliferative rate of cells of the allograft, but decreases the number of apoptotic cells in tubular epithelium.

CD44v6 expression is related to progression in renal epithelial tumours

Expression of CD44 variant isoform including exon 6 has been associated to tumour progression in several carcinomas. However, no studies have been performed to assess the prognostic value of the expression of this marker in renal cell tumours.

Case Report: Effectiveness of Lamivudine in Treatment of Acute Recurrent Hepatitis B After Liver Transplantation

In spite of long-te rm prophylaxis with hepatitis B immune globulin (HBIG), recurrence of hepatitis B virus (HBV) infection in the graft constitute s the leading cause of morbidity and mortality among patients unde rgoing liver transplantation (LT) due to HBV-induced live r cirrhosis (1). In many of these patients acce lerated HBV replication overcomes the protective effect of HBIG (2). Inte rferon therapy, which is partially effective against HBV in immunocompetent patients (3), is of limited value in post-LT HBV graft infection (4). Lamivudine , a nucleoside analog that inhibits the reverse transcriptase activity of HBV, has shown promising results in HBV infection in both immunocompetent (5) and HIV-immunosuppre ssed patients (6). Signi® cant improve ments in live r histology have been demonstrated after one year treatment with lamivudine in immunocompetent patients (7). Indeed, administration of lamivudine before and after LT has also been effective in preventing hepatitis B recurrence after LT (8), and this drug lacks the serious side effects found with other nucleoside analogues (9). We report on a LT patient in whom lamivudine was an effective therapy for acute recurrent HBV hepatitis. CASE REPORT