Liver stiffness measurements by 2-dimensional shear wave elastography compared to histological and ultrasound parameters in primary biliary cholangitis.

BACKGROUND AND AIMS: Liver stiffness measurements (LSMs) by 2-dimensional-shear-wave elastography (LSM2D-SWE) are now widely used in hepatology. However, relevant information for primary biliary cholangitis (PBC) is scant. We compare LSM2D-SWE with liver biopsy (LB) in a cohort of PBC patients in Greece. METHODS: Data of 68 LBs from 53 PBC patients were retrospectively analyzed and fibrosis stage was compared to LSM2D-SWE. Forty-six patients (86.8%) were females and at the time of LBx median (IQR) age was 62.6 (53.2-72.1). Demographic, UDCA treatment, histological and B-mode ultrasound data were tested for their influence on LSM2D-SWE estimates. RESULTS: Liver fibrosis stages F0-F4 were found in 4, 19, 19, 16 and 10 cases, respectively. Across stages F0-F4, the LSM2D-SWE was 5.6 (5.1-6.1), 7.0 (5.8-7.7), 9.1 (7.3-11.5), 10.8 (9.9-12.2) and 14.5 (11.9-25.7) kPa, respectively, with highly significant difference (p<.001). The LSM2D-SWE differed also significantly between F0 vs. F1 (p=.027), F1 vs. F2 (p=.005) and F3 vs. F4 (p=.017). The discriminatory ability of LSM2D-SWE for mild, significant, severe fibrosis and cirrhosis was highly significant in all comparisons (p<.001), with AUC2D-SWE 95.3%, 87.4%, 85.3% and 95.3% and accuracy 89.7%, 85.3%, 80.9% and 86.8%, respectively. Among 21 parameters tested, significant predictors of LSM2D-SWE by multiple linear regression were fibrosis stage, portal inflammation and parenchymal heterogeneity. The portal inflammation grade accounted for 32.2% of LSM variation with adjusted R2 0.428. CONCLUSIONS: In patients with PBC, LSM measurements by 2D-SWE can reliably discriminate between mild, significant, severe fibrosis and cirrhosis. Measurements are significantly affected by portal inflammation grade.

Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: a case report and literature review.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) have changed the way advanced malignancies are currently confronted, improving cancer patients' outcomes but also generating distinct immune-related (ir) adverse events. ICPIs-induced colitis is a common complication showing different clinical and histological manifestations. In the literature review, 14 cases with ICPIs related colon granulomas have been reported in 5 studies with either limited or unavailable information regarding histology. Granulomatous reactions can be mistakenly perceived as disease recurrence or progression. Better understanding and identification of this infrequent histological display can help to avoid misdiagnosis and mismanagement. CASE PRESENTATION: A 63-year-old female patient with metastatic melanoma was admitted to the hospital with symptoms of nausea, persistent diarrhea and shivering fever under consecutive treatments with ICPIs, initially pembrolizumab and subsequently ipilimumab. Sigmoidoscopy was performed revealing mucosal edema, hyperemia and erosions of the rectum and sigmoid colon. Histological evaluation of sigmoid colon mucosa biopsies revealed an unusual colitis pattern characterized by multiple intracryptal granulomas attributed to ICPIs therapy. Steroids were administered and the patient recovered. ICPIs treatment was discontinued. The patient was subsequently treated with chemotherapy but follow up radiology showed disease progression. A re-challenge with another ICPI regimen was decided and the patient is currently under immunotherapy with stable disease regarding melanoma status and without any sign of colitis recurrence. CONCLUSIONS: The present report provides detailed histological description of a distinctive ICPIs-induced granulomatous colitis and highlights the need for awareness of the distinct adverse events and reaction patterns in the context of immunotherapy.

Hepatic progenitor cells in metastatic liver carcinomas.

AIMS: Hepatic progenitor cells (HPCs) are activated in various liver diseases, but their role in the carcinomatous environment remains unknown. We aimed to identify the possible presence and topography of HPCs in liver metastases. METHODS AND RESULTS: We examined 14 liver resection specimens for colorectal adenocarcinoma (n = 13) and anal squamous cell carcinoma (n = 1) metastases. Immunohistochemical markers of colonic origin (keratin 20 and CDX2) and squamous cell origin (p63), HPC [keratin 19 (K19) and CD56] and stem cell (CD44) markers, and the biliary marker keratin 7 (K7), which may also highlight HPCs, were applied on routinely processed tissue sections. Double immunohistochemistry/immunofluorescence (K7/CDX2) and confocal microscopy were used on selected sections. K7-positive, Κ19-positive and CD56-positive ductular structures were encountered within the metastatic tumour (tumour interior and periphery), and in the immediate peritumoral area. Hybrid structures composed of HPCs and metastatic adenocarcinoma cells were recognised and confirmed by double immunostaining (K7/CDX2). Carcinoma cells were also observed singly or in groups within the epithelium of interlobular bile ducts and/or ductules in portal tracts without evidence of carcinomatous infiltration and at a distance from the metastatic foci. CONCLUSIONS: HPCs are observed at the periphery and in the interior of liver metastatic carcinomas. Bile ductules and small interlobular bile ducts may attract carcinoma cells serving as a potential 'metastatic niche', in line with their recognised role as HPC niches in non-neoplastic liver.

Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody Therapy.

Anti-CTL4-A therapy is associated with development of colitis. We characterized ipilimumab-associated colitis in nine melanoma patients (6 male, mean age: 55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2, and interval since last administration 3-wks. Endoscopic characteristics resembled inflammatory bowel disease and histology revealed predominance of plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17 effector pathways (>10-fold increase for IFN-γmRNA, >5-fold for IL-17A, p < 0.01 vs. controls). Significant elevation of FoxP3 was also detected. In conclusion, ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.

Clinical significance of farnesoid X receptor expression in thyroid neoplasia.

AIM: To evaluate the clinical significance of farnesoid X receptor (FXR) in thyroid neoplasia. PATIENTS & METHODS: FXR expression was assessed immunohistochemically on 88 thyroid neoplastic tissues (benign = 44, malignant = 44). RESULTS: Enhanced FXR was more frequently observed in papillary carcinomas compared with hyperplastic nodules (p = 0.0489). In malignant lesions, elevated FXR was associated with capsular (p = 0.0004) and vascular invasion (p = 0.0056) and increased follicular cells' proliferative rate (p < 0.0001). Elevated FXR expression was also associated with larger tumor size (p = 0.0086), presence of lymph node metastases (p = 0.0239) and lymphatic invasion (p = 0.0086) and increased recurrence rate risk (p = 0.0239). CONCLUSION: FXR may be associated with tumor aggressiveness that affects patients' survival in thyroid neoplasia.

Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions.

Histone deacetylases (HDACs) have been associated with human malignant tumor development and progression, and HDAC inhibitors are currently being explored as anticancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression in human malignant and benign thyroid lesions. HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 74 patients with benign and malignant thyroid lesions. Enhanced HDAC-2 and HDAC-6 expression was significantly more frequently observed in malignant, compared to benign, thyroid lesions (p = 0.0042 and p = 0.0069, respectively). Enhanced HDAC-2, HDAC-4, and HDAC-6 expression was significantly more frequently observed in cases with papillary carcinoma compared to hyperplastic nodules (p = 0.0065, p = 0.0394, and p = 0.0061, respectively). In malignant thyroid lesions, HDAC-1, HDAC-4, and HDAC-6 expression was significantly associated with tumor size (p = 0.0169, p = 0.0056, and p = 0.0234, respectively); HDAC-2 expression with lymphatic and vascular invasion (p = 0.0299 and p = 0.0391, respectively); and HDAC-4 expression with capsular invasion (p = 0.0464). The cellular pattern of HDAC-1 and HDAC-2 distribution (nuclear vs. nuclear and cytoplasmic) presented a distinct discrimination between malignant and benign thyroid lesions (p = 0.0030 and p = 0.0028, respectively) as well as between papillary carcinoma and hyperplastic nodules (p = 0.0036 and p = 0.0028, respectively). HDAC-1, HDAC-2, HDAC-4, and HDAC-6 may be associated with the malignant thyroid transformation and could be considered as useful biomarkers and possible therapeutic targets in this neoplasia.

Histological features of chronic hepatitis C in haemodialysis patients.

BACKGROUND & AIMS: HCV infection in haemodialysis (HD) patients is still a matter of investigation. The aim of this study was to determine the histology of chronic hepatitis C (CHC) in HCV-infected HD patients within the context of a comparative analysis including non-uraemic patients with CHC. The relative importance of virological, demographic and clinical parameters on disease manifestation was examined. METHODS: Sixty-one consecutive liver biopsies from HD patients and 326 from non-uraemic patients with chronic HCV infection were comparatively evaluated. RESULTS: Haemodialysis patients with CHC were older than control subjects (P = 0.031), showing a similar HCV genotype distribution (P = 0.328) and lower viral load (P = 0.001). CHC in HD patients was significantly milder according to stage (P = 0.033), grade and its parameters (periportal activity, portal inflammation and lobular activity) (P < 0.001). The frequency of lymphoid aggregates (10.2% vs. 50%, P < 0.001), bile duct lesions (1.7% vs. 22.1%, P < 0.001) and extent of steatosis (P = 0.022) in HD group was significantly reduced. Multivariate analysis showed that non-uraemic patients had 2.3 times higher risk of developing steatosis independently of genotype distribution and age. In HD group, genotype 3, longer HD duration and age at infection were significantly associated with steatosis, while older age at infection correlated with advanced fibrosis. CONCLUSIONS: Chronic hepatitis C in HD patients is usually very mild, losing its diagnostic histological features while patient's age and age at infection retain their prognostic significance. The weak inflammatory response, probably because of immunocompromised status and low viral load, may present a beneficial factor in the natural course of the disease.

The evolution of Helicobacter pylori antibiotics resistance over 10 years in Greece.

BACKGROUND: Increasingly, over time, antibiotic resistance is considered a problem for the efficacy of H. pylori eradication treatment. The aim of our study was to evaluate the changes in clarithromycin and levofloxacin resistance of H. pylori strains in Greek patients in two different time periods (in 2000 and in 2010). METHODS: Gastric biopsies of consecutive H. pylori-positive patients were investigated retrospectively. Mutations in H. pylori 23S rRNA and gyrA genes associated with resistance to clarithromycin and quinolones, respectively, were determined by allelic specific polymerase chain reaction. RESULTS: In the first time period (2000), H. pylori resistance patterns were evaluated in 50 and in the second period (2010) in 57 patients. During the first time period 30 and 0% of patients were infected with clarithromycin- or quinolone-resistant strains, respectively. In the second time period (2010), the percentage of patients infected with clarythromycin or quinolone resistance strains increased to 42 and 5.3%, respectively. CONCLUSIONS: Our study showed an increase in the prevalence of both clarithromycin and quinolones resistance of H. pylori. Although the resistance rate to quinolones increased over the years, it is relatively low justifying its use for the eradication of H. pylori infections.

Colonic mucosa barrier defects in collagenous and ischemic colitis.

AIMS: The subepithelial myofibroblasts (SEMFs) and the subepithelial band of macrophages (SEBM) are major components of the colonic mucosa barrier. Although their role in homeostasis is widely recognized, their contribution to disease states is largely unknown. Our aim was to explore histological characteristics of SEMFs and SEBM in collagenous and ischemic colitis in order to identify specific changes in distinct mucosa backgrounds lacking significant inflammation. METHODS: SEMFs, SEBM and lamina propria (LP) macrophages were identified immunohistochemically by alpha smooth muscle Actin and Cluster of Differentiation 68 respectively in 38 colonic biopsies [14 collagenous colitis (CC), 14 ischemic colitis (IC), 10 normal mucosa]. RESULTS: In CC, SEMFs were rarely detectable in the collagenous band while aSMA-negative pericryptal fibroblast-like cells appeared. In lower LP interconnecting SEMFs processes were formed. SEBM was preserved in areas with a collagenous layer up to 20 µm. In thicker layers, it was fragmented and gradually disappeared in parallel with engulfment of enlarged macrophages. LP macrophages were usually increased. In IC, slight SEMFs changes preceded discernible epithelial alterations. Rounding, disintegration and extinction of SEMFs constituted successive alterations coinciding with crypt shrinkage and denudation. SEBM displayed total or almost total abolishment in areas with crypt damage but also in sites with minimal changes and in adjacent normal mucosa. CONCLUSION: Our findings provide evidence of impairment of both mucosa barrier constituents in CC and IC. In CC, histological alterations are closely related to the collagenous layer which seems to affect SEMFs differentiation and migration as well as SEBM integrity. The early extinction of SEBM in IC is indicative of its high sensitivity to hypoxia and hypoperfusion.

Isolated nonspecific terminal ileitis: prevalence, clinical evolution and correlation with metachronous diagnosis of Crohn's disease: a retrospective study and review of the literature.

Background: The existing literature does not provide adequate guidance on the diagnosis and management of patients with nonspecific terminal ileitis, while data regarding the percentage of patients who ultimately develop Crohn's disease (CD) are scarce. We evaluated the prevalence and natural course of nonspecific terminal ileitis in patients who underwent colonoscopy during a 11-year period. Methods: All patients with endoscopic findings of terminal ileitis and nonspecific histological findings were included. Exclusion criteria were a clinical history of CD or any other disease that can cause terminal ileitis, or a recent history of using drugs implicated in lesions of the terminal ileum. Results: From 5353 colonoscopies, 92 patients with nonspecific terminal ileitis were identified (prevalence: 1.7%). Among these patients, 56 (61%) had available follow up for ≥6 months after the initial endoscopy. Main indications for endoscopy were chronic diarrhea (37.5%), screening endoscopy (23%), and abdominal pain (20%). Sixteen (29%) patients received medical treatment, while recession of symptoms was recorded in 19 of 43 symptomatic patients (44.1%). Twenty-three (41%) of the 56 patients underwent a second endoscopy and 15 (65.2%) cases had persistent endoscopic findings. Eleven (19.6%) of the 56 patients were eventually diagnosed with CD. The probability of CD diagnosis was significantly higher in patients with persistent symptoms (P=0.002) and endoscopic findings at follow up (P=0.038). Conclusions: Nonspecific terminal ileitis generally has a benign clinical course. However, patients with persistent symptoms and endoscopic lesions are at increased risk for subsequent development of CD.

Histological spectrum of mycophenolate mofetil-related colitis: association with apoptosis.

AIMS: The main purpose of this study was to define diagnostic histological characteristics of mycophenolate mofetil (MMF)-related colitis in association with crypt epithelial cell turnover. METHODS AND RESULTS: The examined material included 43 colonic biopsies from renal transplant recipients with MMF administration and persistent diarrhoea. Thirty-three cases showed MMF-related colitis, while 10 showed no significant changes. The histological findings were scored and correlated with the apoptotic index (AI) and with the proliferation rate (PR) of the crypt epithelium examined by TUNEL assay and Ki-67 immunoexpression. Ten cases of Crohn disease and 10 of ulcerative colitis were used as comparative groups. Crypt distortion and loss as well as increased apoptosis constituted the main features, their degree and combination leading either to an inflammatory bowel disease (IBD)-like (82%) or to a graft-versus-host disease-like pattern (18%). A high AI was associated more frequently with moderate and severe crypt distortion, while the values were significantly higher compared with the control groups (P < 0.01). High PR was noted in 18 of 29 (62.1%) of the cases. CONCLUSIONS: The diagnostic hallmark of MMF-related colitis is an IBD-like histological pattern in association with increased epithelial apoptosis, while apoptotic cell death seems to be a potential pathogenetic factor of mucosa injury.

Time of acquisition of HCV infection in renal transplant recipients: a major prognostic factor for disease progression.

BACKGROUND: This study aims to identify crucial factors affecting the evolution of liver disease in HCV-infected renal transplant recipients. METHODS: Forty-two HCV-infected recipients with known time of HCV acquisition were followed up for a mean (SD) of 7.6 ± 3.4 yr after transplantation with consecutive liver biopsies. Hepatitis progression was defined by: a) fibrosis progression ≥ 0.2 stages/yr and/or b) development of a cholestatic syndrome. RESULTS: Twenty-three patients (54.8%) displayed benign and 19 (45.2%) aggressive hepatitis progression. Hepatitis course was aggressive in 9.1% and 85% of the patients infected pre- and peri/post-transplantation, respectively (p < 0.001). In multivariate analysis, patients who acquired HCV infection peri- or after transplantation had an increased risk of an adverse outcome compared with those infected before transplantation (p = 0.001). HCV RNA levels at the time of first liver biopsy were lower in patients showing a benign course compared with those with aggressive evolution (p = 0.052). CONCLUSIONS: Time of acquisition of HCV infection is a major prognostic factor for hepatitis progression in the setting of renal transplantation. Immunosuppression was found to be determinant in the progression of HCV infection acquired peri- or post-transplantation. High viral load seems to be crucial in the pathogenetic process.

Significance of liver histology in HBsAg-positive, IgM anti-HBc-negative acute hepatitis B virus-related hepatitis.

AIMS: The natural course of HBsAg-positive, IgM anti-HBc-negative acute hepatitis B virus (HBV)-related hepatitis is unclear. The aim of this study was to evaluate the prognostic significance of histological features and hepatic expression of HBV antigens in such patients. METHODS AND RESULTS: Fifty patients with HBsAg-positive, IgM anti-HBc-negative acute hepatitis B who underwent liver biopsy during the acute hepatitis episode were studied [HBeAg seroconversion (n = 16), persistently positive for HBeAg (n = 9), and persistently negative for HBeAg (n = 25)]. Twenty-six cases had features of typical acute hepatitis only (group A), and 24 cases had changes suggesting pre-existing chronic hepatitis (group B). HBcAg and/or HBsAg immunoreactivity was detected less frequently in group A than in group B (31% versus 79%, P = 0.01). HBsAg clearance was observed in 24% of patients, almost exclusively in cases with HBeAg seroconversion. HBsAg loss was significantly more frequent in group A than in group B (52% versus 0%, P < 0.001), and in cases without rather than with immunohistochemical expression of HBV antigens (55% versus 0%, P < 0.001). In group A, HBsAg clearance was observed in 80%, 54% and 0% of patients with mild, moderate or severe acute hepatitis, respectively (P < 0.034). CONCLUSIONS: Histological information is very important for the prognosis of HBsAg-positive, IgM anti-HBc-negative acute hepatitis B. HBeAg seroconversion with underlying typical acute hepatitis changes of mild to moderate severity without hepatic expression of HBV antigens strongly predicts subsequent HBsAg loss.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) expression in human benign and malignant thyroid lesions.

BACKGROUND: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that contributes to tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of RCAS1 expression in human benign and malignant thyroid lesions. MATERIAL/METHODS: RCAS1 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 121 patients with benign and malignant lesions and was associated with type of thyroid histopathology and tumor stage parameters such as tumor size, lymph node metastases, capsular, lymphatic and vascular invasion. RESULTS: RCAS1 positivity, overexpression and staining intensity provided a distinct discrimination between benign and malignant thyroid cases (p=0.0006, p=0.0001 and p=0.0001, respectively), as well as between hyperplastic nodule and papillary carcinoma cases (p=0.0229, p=0.0001 and p=0.0001, respectively). RCAS1 positivity, overexpression and staining intensity also provided distinct discrimination between cases with Hashimoto thyroiditis and those with hyperplastic nodule (p=0.0221, p=0.0001 and p=0.0019, respectively). In the subgroup of malignant thyroid lesions, RCAS1 overexpression was significantly associated with large tumor size (p=0.0246), the presence of lymph node metastases (p=0.0351) and capsular invasion (p=0.0397). CONCLUSIONS: RCAS1 protein may participate in thyroid neoplastic transformation and could be considered as a useful biomarker to improve diagnostic scrutiny.

Histological diversity of anti-PD1-induced colitis.

AIM: Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. METHODS AND RESULTS: Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. CONCLUSIONS: Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions: an immunohistochemical study.

BACKGROUND: Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions. MATERIAL/METHODS: Eph-A2 and Eph-A4 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 131 patients with benign and malignant lesions. RESULTS: Eph-A2 was significantly overexpressed in malignant compared to benign thyroid lesions (p<0.001). Papillary carcinoma cases presented significantly increased Eph-A2 expression compared to those with hyperplasia nodules (p<0.001). Eph-A4 expression was not differentiated between cases with malignant or benign thyroid lesions. Papillary carcinoma cases presented significantly increased Eph-A4 expression compared to those with hyperplasia nodules (p=0.006). In the subgroup of malignant thyroid lesions, Eph-A2 and Eph-A4 expression was not associated with TNM stage, capsular, lymphatic or vascular invasion. CONCLUSIONS: The present data suggest that Eph-A2, but not Eph-A4, overexpression may be associated with the malignant transformation of thyroid neoplasia. Further studies conducted on cohorts including a higher proportion of patients with advanced nodal and metastatic disease are recommended to draw definite conclusions on the clinical significance of Eph proteins in thyroid neoplasia.

Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: an immunohistochemical study.

BACKGROUND: DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, and minimizes cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations in the expression levels of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins MSH2, MLH1 and MGMT in benign and malignant thyroid lesions. MATERIAL/METHODS: MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 90 patients with benign and malignant lesions. RESULTS: The expression levels of MLH1 was significantly upregulated in cases with malignant compared to those with benign thyroid lesions (p = 0.038). The expression levels of MGMT was significantly downregulated in malignant compared to benign thyroid lesions (p = 0.001). Similar associations for both MLH1 and MGMT between cases with papillary carcinoma and hyperplastic nodules were also noted (p = 0.014 and p = 0.026, respectively). In the subgroup of malignant thyroid lesions, MSH2 downregulation was significantly associated with larger tumor size (p = 0.031), while MLH1 upregulation was significantly associated with the presence of lymphatic and vascular invasion (p = 0.006 and p = 0.002, respectively). CONCLUSIONS: Alterations in the mismatch repair proteins MSH2 and MLH1 and the direct repair protein MGMT may result from tumor development and/or progression. Further studies are recommended to draw definite conclusions on the clinical significance of DNA repair proteins in thyroid neoplasia.

Apoptosis and hepatitis C virus infection in renal transplant recipients.

Hepatocellular injury in renal transplant recipients with hepatitis C virus (HCV) infection remains unclear. The suppressed immune response, in combination with increased viremia levels, provides a unique setting for the study of a potential HCV-induced apoptotic process. Liver biopsy specimens from 59 HCV-infected renal transplant recipients were examined histologically. DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling assay, and the CD8 T-cell count was assessed immunohistochemically.A low apoptotic index (0-2.5) was observed in 31 cases, a moderate index (2.6-5) in 16, and a high index (>5) in 12. Apoptotic cell death correlated significantly with viremia because it was demonstrated by higher HCV-RNA levels in cases with a high number of apoptotic cells (odds ratio, 2.96; 95% confidence interval, 1.0-8.5; P = .04). No correlation was found between the apoptotic index and hepatitis necroinflammatory activity, CD8 cell count, fibrosis stage, immunosuppressive therapy, or genotype. In HCV-infected renal transplant recipients, apoptotic cell death seems to be associated with high viral load, thus providing indications of viral interference in the pathogenetic process.