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.

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.

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.

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.

Celiac-like Enteropathy Associated With Mycophenolate Sodium in Renal Transplant Recipients.

BACKGROUND: Although colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium. METHODS: The patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis. RESULTS: Both patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine. CONCLUSIONS: Celiac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.

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.

IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms.

Different Insulin-like growth factor-I (IGF-I) mRNA transcripts are produced by alternative splicing and particularly the IGF-IEc isoform has been implicated in the development and/or progression of various types of cancer. In the present study, we examined the potential role of IGF-IEc expression as a new immunohistochemical marker of aggressiveness in neuroendocrine neoplasms (NENs). We utilized immunohistochemical analysis in tissue specimens of 47 patients with NENs, to evaluate the expression of IGF-IEc (%) and Ki-67 proliferation index (%). Specimens from patients with tumors of different tissue origin, of either primary or metastatic lesions and of different grade were examined. Cytoplasmic IGF-IEc staining was found in 23 specimens of NENs or NECs: 10 pancreatic, 4 small bowel, 3 gastric, 1 lung, 1 uterine and 4 poorly differentiated of unknown primary origin. Ki-67 and IGF-IEc expression was positively correlated in all the samples studied (r=0.31, p=0.03). IGF-1Ec expression was more prevalent in specimens originating from metastatic foci with high Ki-67 compared to primary sites with low Ki-67 expression (p=0.036). These findings suggest a possible role of IGF-IEc in NEN tumorigenesis and progression to metastases that could be used as an additional new marker of a more aggressive behavior and a potential drugable target.

Hepatitis B in renal transplant patients.

Hepatitis B virus (HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBsAg(-) recipients. Moreover, in the cases of immunized HBsAg(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBsAg(+) and HBsAg(-)/anti-HBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term.

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.

From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world.

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.

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.

Non-Whipple Operations in the Management of Benign, Premalignant and Early Cancerous Duodenal Lesions.

AIM: We reviewed our 20-year experience with non-Whipple operations (pancreas-preserving duodenectomy and transduodenal ampullectomy) for the treatment of benign, premalignant or early-stage malignant duodenal lesions. PATIENTS AND METHODS: Twenty-four patients who underwent non-Whipple operations between January 1996 and December 2015 were identified from an institutional database and retrospectively analyzed. RESULTS: Between 1996 and 2015, 10 patients underwent pancreas-preserving duodenectomy and 14 patients underwent transduodenal ampullectomy. The mean follow-up was 25.8 months (range=6-54 months) and no patient was lost to follow-up. Eighteen patients had preoperative diagnosis of duodenal adenomatosis, three patients had preoperative diagnosis of duodenal adenocarcinoma, one had a bleeding polyp and two had localized inflammation. Average operative time was 145 min (range=127-168 min) for transduodenal ampullectomy and 183 min (range=173-200 min) for pancreas-preserving duodenectomy (p<0.05). The estimated blood loss for transduodenal ampullectomy was 85 vs. 125 ml for pancreas-preserving duodenectomy (p<0.05). Early postoperative complications were noted in 13 cases (54.17%). There were no postoperative (90-day) deaths observed in this series and there were no recurrences during follow-up for the patients operated on with neoplastic lesions. CONCLUSION: For carefully selected patients, transduodenal ampullectomy and pancreas-preserving duodenectomy may be used in place of the Whipple operation for benign and occasionally early-stage malignant (Tis and T1) duodenal and ampullary disease.

Duodenal plexiform fibromyxoma as a cause of obscure upper gastrointestinal bleeding: A case report.

RATIONALE: We are reporting the first-to our knowledge-case of duodenal Plexiform Fibromyxoma causing obscure upper gastrointestinal bleeding. PATIENT CONCERNS: Plexiform fibromyxoma triggered recurrent upper gastrointestinal bleeding episodes in a 63-year-old man who remained undiagnosed, despite multiple hospitalizations, extensive diagnostic workups and surgical interventions (including gastrectomies), for almost 17 years. DIAGNOSES-INTERVENTIONS: During hospitalization for the last bleeding episode, an upper gastrointestinal endoscopy revealed an intestinal hemorrhagic nodule. The lesion was deemed unresectable by endoscopic means. An abdominal computerized tomography disclosed no further lesions and surgery was decided. The lesion at operation was found near the edge of the duodenal stump and treated with pancreas-preserving duodenectomy (1st and 2nd portion). OUTCOMES: Postoperative recovery was mainly uneventful and a 20-month follow-up finds the patient in good health with no need for blood transfusions.Plexiform fibromyxomas stand for a rare and widely unknown mesenchymal entity. Despite the fact that they closely resemble other gastrointestinal tumors, they distinctly vary in clinical management as well as the histopathology. Clinical awareness and further research are compulsory to elucidate its clinical course and prognosis.

Mucins in neoplasms of pancreas, ampulla of Vater and biliary system.

Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.

Elevated Serum Levels of the Antiapoptotic Protein Decoy-Receptor 3 Are Associated with Advanced Liver Disease.

Background. Decoy-receptor 3 (DcR3) exerts antiapoptotic and immunomodulatory function and is overexpressed in neoplastic and inflammatory conditions. Serum DcR3 (sDcR3) levels during the chronic hepatitis/cirrhosis/hepatocellular carcinoma (HCC) sequence have not been explored. Objective. To assess the levels and significance of sDcR3 protein in various stages of chronic liver disease. Methods. We compared sDcR3 levels between healthy controls and patients with chronic viral hepatitis (CVH), decompensated cirrhosis (DC), and HCC. Correlations between sDcR3 levels and various patient- and disease-related factors were analyzed. Results. sDcR3 levels were significantly higher in patients with CVH than in controls (P < 0.01). sDcR3 levels were elevated in DC and HCC, being significantly higher compared not only to controls (P < 0.001 for both) but to CVH patients as well (P < 0.001 for both). In addition, DcR3 protein was detected in large quantities in the ascitic fluid of cirrhotics. In patients with CVH, sDcR3 significantly correlated to fibrosis severity, as estimated by Ishak score (P = 0.019) or by liver stiffness measured with elastography (Spearman r = 0.698, P < 0.001). In cirrhotic patients, significant positive correlations were observed between sDcR3 levels and markers of severity of hepatic impairment, including MELD score (r = 0.653, P < 0.001). Conclusions. Circulating levels of DcR3 are elevated during chronic liver disease and correlate with severity of liver damage. sDcR3 may serve as marker for liver fibrosis severity and progression to end-stage liver disease.

Atrophic hepatocytes express keratin 7 in ischemia-associated liver lesions.

AIM: To investigate atrophic parenchymal changes in ischemic liver conditions. DESIGN: We studied 18 cases of hepatic lesions with atrophic changes due to altered blood flow (hepatic venous congestion n=15 including 4 cases with additional nodular regenerative hyperplasia-NRH, NRH n=1, and antiphospholipid syndrome with patchy parenchymal atrophy n=2). Metaplastic hepatocellular changes, hepatocyte proliferation, hepatic stellate cell (HSC) activation, and sinusoidal capillarization were examined immunohistochemically with antibodies to keratins (K) 7 and 19, Ki67, αSMA and CD34, respectively. RESULTS: K7 was positive and K19 was negative in zone 3 atrophic hepatocytes in venous congestion and in areas of plate atrophy, as well as in congested or compressed sites in NRH. Sinusoidal CD34-positivity indicating capillarization accompanied K7 immunoexpression. Masson trichrome revealed sinusoidal fibrosis to be restricted in atrophic areas, usually mild and in 7 cases focally dense. αSMA expression expanded beyond K7-positive areas. Ki67 was negative in K7-positive hepatocytes. CONCLUSION: Ischemic parenchymal changes are characterized by hepatocyte K7 immunoexpression, sinusoidal capillarization, HSC activation and lack of cellular proliferation, indicating an early reaction of the major liver parenchyma cellular components creating a more resistant microenvironment. These phenotypic alterations may prove valuable in the discrimination of ischemic liver lesions.

Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions.

Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, angiogenesis and metastasis. The present study aimed to evaluate the clinical significance of EphB4 and EphB6 protein expression in human malignant and benign thyroid lesions. EphB4 and EphB6 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 127 patients with benign (n = 71) and malignant (n = 56) thyroid lesions. Enhanced EphB4 and EphB6 expression was more frequently observed in malignant compared to benign thyroid lesions (p = 0.0508 and p = 0.0006, respectively). EphB4 and EphB6 expression also provided a distinct discrimination between papillary carcinoma and hyperplastic nodules (p = 0.0302 and p = 0.0013, respectively). In malignant thyroid lesions, enhanced EphB4 expression was significantly associated with larger tumor size (p = 0.0366). Enhanced EphB6 expression was significantly associated with larger tumor size (p = 0.0366), the presence of lymph node metastases (p = 0.0023), the presence of capsular (p = 0.0038), lymphatic (p = 0.0053) and vascular invasion (p = 0.0018) and increased risk of recurrence rate (p = 0.0038). The present study supported evidence that EphB4 and mainly EphB6 may participate in the malignant thyroid transformation, reinforcing their utility as useful biomarkers and possible therapeutic targets in this type of neoplasia.