Toru Igari

Enhanced expression of mRNAs of antisecretory factor-1, gp96, DAD1 and CDC34 in human hepatocellular carcinomas

To identify differentially expressed genes in hepatocarcinogenesis, we performed differential display analysis using surgically resected hepatocellular carcinoma (HCC) and adjacent non-tumorous liver tissues. We identified four cDNA fragments upregulated in HCC samples, encoding antisecretory factor-1 (AF), gp96, DAD1 and CDC34. Northern blot analysis demonstrated that these mRNAs were expressed preferentially in HCCs compared with adjacent non-tumorous liver tissues or normal liver tissues from non-HCC patients. The expression of these mRNAs was increased along with the histological grading of HCC tissues. These mRNA levels were also high in three human HCC cell lines (HuH-7, HepG2 and HLF), irrespective of the growth state. We also demonstrate that sodium butyrate, an inducer of differentiation, downregulated the expression of AF and gp96 mRNAs, supporting in part our pathological observation. Immunohistochemical analysis revealed that gp96 and CDC34 proteins were preferentially accumulated in cytoplasm and nuclei of HCC cells, respectively. Overexpression of these genes could be an important manifestation of HCC phenotypes and should provide clues to understand the molecular basis of hepatocellular carcinogenesis.

Expression of homeodomain protein CDX2 in gallbladder carcinomas

Purpose Caudal-related homeobox protein CDX2 plays an important role in the regulation of cell proliferation and differentiation of the intestinal epithelium. CDX2 is associated with intestinal metaplasia and carcinomas of the stomach, but the role of CDX2 in gallbladder carcinogenesis remains unknown.Methods We analyzed the expression of CDX2 and intestinal apomucin MUC2 in gallbladder cancer cell lines at the mRNA level by the RT-PCR method. We also investigated the expression of CDX2 and MUC2 in 68 primary gallbladder carcinomas by the immunohistochemical staining method and compared the expression of CDX2 with the clinicopathological factors in the gallbladder carcinoma cases.Results Expression of CDX2 and MUC2 was found in three of four gallbladder cancer cell lines at the mRNA level. In addition, we found that CDX2 was absent in the normal gallbladder epithelium, but the CDX2 protein was expressed in 25 of the 68 (36.8%) gallbladder carcinomas. Interestingly, in the tubular type gallbladder carcinomas, the frequency of CDX2 expression was much higher in the well-differentiated type than the moderately and poorly differentiated types, the difference being statistically significant (P<0.01). CDX2 expression showed a relationship with expression of MUC2 (P<0.04) in the gallbladder carcinomas. CDX2 was expressed in intestinal metaplasia and dysplasia, which are hypothesized to be premalignant conditions.Conclusion These results imply that CDX2 plays an important role in gallbladder carcinogenesis with intestinal differentiation.

Hepatocellular carcinoma with osteoclast-like giant cells: Possibility of osteoclastogenesis by hepatocyte-derived cells

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast‐like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast‐like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate‐resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease‐9, in osteoclast‐like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor‐kappa B (RANK) in the giant cells and receptor activator of nuclear factor‐kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte‐derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast‐like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.

Development of Pancreatic Cancer, Disease-specific Mortality, and All-Cause Mortality in Patients with Nonresected IPMNs: A Long-term Cohort Study

PURPOSE To determine the cumulative incidence, disease-specific mortality, and all-cause mortality of pancreatic cancer (PC) in patients with intraductal papillary mucinous neoplasms (IPMNs) and to identify imaging findings that are associated with these outcomes. MATERIALS AND METHODS This retrospective study had institutional review board approval, and the need to obtain patient consent was waived. Data from an electronic database were analyzed and supplemented by chart reviews for 285 patients with nonresected IPMNs who were periodically followed up with imaging (1273 multidetector computed tomography and 750 magnetic resonance cholangiopancreatography examinations). The Kaplan-Meier method was used to estimate the cumulative development of PC, PC mortality, and all-cause mortality (factors were compared by using the log-rank test). RESULTS Over a median imaging follow-up period of 39 months, 12 (4.2%) of 285 patients developed PC; the cumulative 5-year PC incidence was 3.9% for branch duct (BD)-IPMNs, 45.5% for main duct (MD)-IPMNs (P < .01), 7.7% for cysts 30 mm or larger, and 5.3% for cysts smaller than 30 mm (P = .82). Over a median survival follow-up period of 47.5 months, seven (2.5%) of 285 patients died of PC and 14 (4.9%) patients died of other causes. Cumulative 5-year PC mortality was 2.1% for BD-IPMNs, 18.5% for MD-IPMNs (P < .01), 2.6% for cysts 30 mm or larger, and 2.8% for cysts smaller than 30 mm (P = .90). Cumulative 5-year all-cause mortality was 5.5% for BD-IPMNs, 18.5% for MD-IPMNs (P < .01), 12.5% for cysts 30 mm or larger, and 5.9% for cysts smaller than 30 mm (P = .89). CONCLUSION Five-year PC development, disease-specific mortality, and all-cause mortality were approximately 4%, 2%, and 6% for BD-IPMNs and 46%, 19%, and 19% for MD-IPMNs, respectively. The presence of an MD-IPMN, but not cyst size, was significantly associated with PC development and subsequent mortality.

Acute Hepatitis C in HIV-1 Infected Japanese Cohort: Single Center Retrospective Cohort Study

Objectives HCV co-infection is a poor prognostic factor in HIV-1-infected patients. Although the number of newly reported patients who show seroconversion is increasing, the clinical features are still unclear, especially in Asian countries. Design A single-center retrospective cohort study of patients diagnosed between 2001–2012. Methods Acute hepatitis C (AHC) was diagnosed upon detection of high serum ALT (>100 IU) followed by anti-HCV seroconversion. Clinical characteristics, HIV-1-related immunological status and IL-28B genotypes (rs12979860, rs8099917) were collected. We compared these variables between patients with and without spontaneous clearance of HCV and between responders and non-responders to treatment with pegylated interferon (PEG-IFN) plus ribavirin. Results Thirty-five patients were diagnosed with AHC during the study period. The majority (96.9%) were MSM. Three were lost to follow-up. Seventy-five percent of patients with AHC (24/32) were asymptomatic and found incidentally to have high serum ALT. Compared to those who did not show spontaneous clearance, patients with spontaneous HCV viral clearance showed more symptoms and more severe abnormalities related to acute hepatitis. Spontaneous clearance was seen in 4 out of 28 patients with CC+TT genotype, but not in 6 patients with IL-28B CT+TG genotype. PEG-IFN plus ribavirin treatment was initiated in 12 out of 28 cases without spontaneous clearance. The sustained virological response rate was high (81.8%, 9/11), even in cases with CT+TG genotype infected with HCV genotype 1b (SVR 2/2). Conclusions Careful attention to AHC is needed in HIV-1-infected MSM. Early diagnosis and PEG-IFN plus ribavirin treatment should be considered for AHC cases.

A familial case of mitochondrial disease resembling Alport syndrome

A 38-year-old man with mild sensorineural hearing loss, diabetes mellitus, proteinuria, and slight renal dysfunction was admitted to our hospital for a renal biopsy to determine the cause of kidney disease. His elder sister and mother also had sensorineural hearing loss and renal failure, suggesting the existence of a common genetic disease in this family. Although the clinical features of the patient were similar to features of Alport syndrome, renal biopsy revealed no sign of Alport syndrome. We next considered a possibility of a mitochondrial kidney disease described by Jansen in 1997. Indeed, genetic analysis of mitochondrial DNA clarified the existence of A3243G mutation in the patient and his sister. This syndrome should be recognized by nephrologists as a differential diagnosis of Alport syndrome, diabetic nephropathy, and primary glomerular diseases.

Relationship between clinical factors and severity of esophageal candidiasis according to Kodsi's classification

Severe Candida esophagitis (CE) may lead to development of strictures, hemorrhage, esophagotracheal fistula, and a consequent decrease in quality of life. Although the severity of CE has been classified based on macroscopic findings on endoscopy, the clinical significance remains unknown. The aim of the study was to elucidate the predictive clinical factors for endoscopic severity of CE. Patients who underwent upper endoscopy and answered questionnaires were prospectively enrolled. Smoking, alcohol, human immunodeficiency virus (HIV) infection, diabetes mellitus, chronic renal failure, liver cirrhosis, systemic steroids use, proton pump inhibitor use, H2 blocker use, and gastrointestinal (GI) symptoms were assessed on the same day of endoscopy. GI symptoms including epigastric pain, heartburn, reflux, hunger cramps, nausea, dysphagia, and odynophagia were assessed on a 7-point Likert scale. Endoscopic severity was classified as mild (Kodsis grade I/II) or severe (grade III/IV). Of 1855 patients, 71 (3.8%) were diagnosed with CE (mild, n = 48; severe, n = 23). In the CE patients, 50.0% (24/48) in the mild group and 23.1% (6/23) in the severe group did not have any GI symptoms. In HIV-infected patients (n = 17), a significant correlation was found between endoscopic severity and declining CD4 cell count (Spearmans rho = -0.90; P < 0.01). Multivariate analysis revealed that GI symptoms (odds ratio [OR], 3.32) and HIV infection (OR, 3.81) were independently associated with severe CE. Patients in the severe group experienced more epigastric pain (P = 0.02), reflux symptoms (P = 0.04), dysphagia (P = 0.05), and odynophagia (P < 0.01) than those in the mild group. Of the GI symptoms, odynophagia was independently associated with severe CE (OR 9.62, P = 0.02). In conclusion, the prevalence of CE in adults who underwent endoscopy was 3.8%. Silent CE was found in both mild and severe cases. Endoscopic severity was associated with characteristic GI symptoms and comorbidity of HIV infection. A decline in immune function correlated with CE disease progression.

Predictive Clinical Factors in the Diagnosis of Gastrointestinal Kaposi's Sarcoma and Its Endoscopic Severity

Background The diagnosis of gastrointestinal (GI) involvement in Kaposis sarcoma (KS) is important to make because the need for treatment depends on the extent of the disease. Moreover, severe GI lesions can cause serious complications. Endoscopy with biopsy is an extremely useful method to diagnose GI-KS. However, determining the indications for endoscopy is difficult because KS can occur without GI symptoms or cutaneous KS. This study sought to clarify predictive clinical factors for GI-KS and its severity on endoscopy. Methodology/Principal Findings A total of 1,027 HIV-infected patients who underwent endoscopy were analyzed. Sexual behavior, CD4 count, HIV RNA, history of highly active antiretroviral therapy (HAART), GI symptoms, and cutaneous KS were assessed. Endoscopic severity including bulky tumor, ulceration, and number of lesions were evaluated. Thirty-three patients had GI-KS and 46 patients cutaneous KS. Among the GI-KS patients, 78.8% (26/33) had no GI symptoms and 24.2% (8/33) had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4 <100 cells/µL, HIV RNA ≥10,000 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among these factors, cutaneous KS was closely related to GI-KS on multivariable analysis. Among patients without cutaneous KS, MSM and CD4 count <100 cells/µL were the only independent clinical factors related to GI-KS. Bulky tumor was significantly associated with CD4 <100 cells/µL and large number of lesions was significantly associated with HIV-RNA ≥10,000 copies/mL. Conclusions To diagnose GI-KS, clinical factors need to be considered before endoscopy. The presence of GI symptoms is not useful in predicting GI-KS. MSM and CD4 count <100 cells/µL are predictive factors among patients without cutaneous KS. Caution should be exercised especially in patients with low CD4 counts or high HIV viral loads as they are more likely to develop severe GI-KS lesions.

NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: A case report and a literature review

Nuclear protein in testis (NUT) midline carcinoma (NMC) is an extremely aggressive carcinoma that is genetically defined by rearrangement of the NUT gene. Herein, we describe a case of NMC in a young Japanese man, and review 31 cases of NMC in the literature. The present case was of a massive tumor of the anterior and middle mediastinum in a 26-year-old man. The tumor included 2 types of poorly differentiated tumor cells and was immunohistochemically positive for the NUT-specific antigen, epithelial membrane antigen (EMA), cluster of differentiation 99 (CD99) antigen, CD45RO antigen, keratins, p63, and p40. The patient died 2 months after the initial diagnosis. At least two-thirds of the 31 NMC cases in the literature were immunohistochemically positive for EMA, p63, and AE1/AE3. However, some exceptional NMC cases are keratins-negative/CD99-positive like Ewing sarcoma or CD45RO-positive like the present case.

Impact of HIV infection on colorectal tumors: a prospective colonoscopic study of Asian patients.

Background:Non-AIDS defining cancer has recently become a major problem in HIV-infected patients. Little has been reported on whether HIV infection is a risk factor for colorectal adenoma, especially in Asians. Methods:The study was conducted under a prospective cross-sectional design and included all adults who underwent colonoscopy. Subjects were matched by age and sex to compare the prevalence of colorectal adenoma, adenocarcinoma, polyps, and other tumors. Detailed risk factors were assessed, including lifestyle habits, medications, comorbidities, gastrointestinal symptom rating scale, HIV-associated factors, and human papillomavirus infection. To evaluate the effects of HIV infection on adenoma, the odds ratio (OR) was estimated by multivariate logistic regression. Results:A total of 177 HIV-infected patients and 177 controls were selected for analysis. No significant difference was noted in the prevalence of adenoma (n = 29 vs. 40, P = 0.14). Multivariate analysis adjusted by baseline demographics and risk factors showed that HIV is not associated with increased risk of adenoma (adjusted OR = 0.66, P = 0.16). Kaposi’s sarcoma was more common in HIV-infected patients (n = 6 vs. 0, P = 0.03). Among HIV-infected patients, advanced age was an independent and significant risk factor for adenoma (adjusted OR = 2.28, P < 0.01). CD4 count, HIV-RNA, history of antiretroviral treatment, and oncogenic human papillomavirus infection were not risk factors for adenoma. Conclusions:HIV infection was not identified as risk for adenoma in Asian patients. However, advanced age was independently associated with increased risk of adenoma. HIV-infected patients should not miss screening opportunity for colorectal adenoma and other gastrointestinal malignancies.