Alterations of UHRF family Expression and was regulated by High Risk Type HPV16 in Uterine Cervical Cancer.

The altered protein expression of inverted CCAAT box-binding protein of 90 kDa/ubiquitin-like with PHD and RING finger domains 1 (ICBP90/UHRF1), and Np95-like ring finger protein (NIRF)/UHRF2, which belong to the ubiquitin-like with PHD and RING finger domains (UHRF) family, is linked to tumor malignancy and the progression of various cancers. In this study, we analyzed the UHRF family expression in cervical cancers, and it's regulation by human papillomavirus (HPV). Western blotting was performed to analyze protein expression in cervical cancer cell lines. Immunohistochemical analysis were used to investigate the expression of UHRF family and MIB-1 in cervical cancer tissues. Transfection were done for analyze the relationship between UHRF family and HPVs. We showed that NIRF expression was decreased and ICBP90 expression was increased in cervical cancers compared to normal counterparts. Western blotting also showed that NIRF expression was quite low levels, but ICBP90 was high in human cervical cancer cell lines. Interestingly, ICBP90 was up regulated by high risk type HPV16 E6 and E7, but not low-risk type HPV11. On the other hand, NIRF was down regulated by high risk type HPV16 E6 but not by E7. Low risk type HPV11 E6 did not affect the NIRF expression at all. We propose that ICBP90 overexpression, and reduced NIRF expression, found in cervical cancers, is an important event of a cervical carcinogenesis, and especially ICBP90 may offer a proliferating marker and therapeutic target for treating uterine cervical cancers.

Acute Liver Injury and Bilateral Pulmonary Artery Thrombosis due to Hypereosinophilic Syndrome: A Case Report.

A 46-year-old Japanese man was referred to our hospital because of a marked increase in his eosinophil count (22,870/µL) and elevated liver enzyme levels. Computed tomography (CT) showed thrombi measuring approximately 8 cm in both femoral veins. A liver biopsy revealed eosinophilic infiltration, hepatocyte necrosis, fibrosis, and multiple thrombi. We suspected acute liver injury and deep vein thrombosis associated with hypereosinophilic syndrome and initiated steroids and heparin treatment. Four days after starting treatment, the patient experienced sudden chest pain and cardiopulmonary arrest. CT revealed bilateral pulmonary artery thrombosis, and despite administration of a tissue plasminogen activator, the patient died.

Alterations of UHRF Family Expression and UHRF1/ICBP90 Inhibits Phosphatase and Tensin Homolog Expression in Endometrial Cancer.

INTRODUCTION: The altered protein expression of inverted CCAAT box-binding protein of 90 kDa/ubiquitin-like with PHD and RING finger domains 1 (ICBP90/UHRF1) and Np95-like ring finger protein (NIRF)/UHRF2, which belong to the ubiquitin-like with PHD and RING finger domains (UHRF) family, is linked to tumor malignancy and the progression of various cancers. To determine the role of NIRF and ICBP90 in endometrial tumorigenesis, we evaluated ICBP90 and NIRF expression levels in endometrial cancers. Also molecular alterations of phosphatase and tensin homolog (PTEN) expression are the important event for endometrial carcinogenesis; therefore, we investigated the involvement between ICBP90 and PTEN expression. METHODS: We used Western blot for NIRF, ICBP90, and PTEN expression, mutation analysis of NIRF gene, and immunohistochemical staining for the expression of NIRF and ICBP90. For immunohistochemical staining, we examined atypical endometrial hyperplasia, endometrial cancers, and noncancerous samples. RESULTS: Our data showed that the reduced expression of NIRF and overexpression of ICBP90 occurred in atypical endometrial hyperplasia and endometrial cancer compared to the normal endometrium. The decrease in NIRF expression was significantly correlated with histological grade. Expression of ICBP90 was high, especially in the peripheral margin of a cancer nest. Western blot analysis of endometrial cancer cell lines referred an opposite correlation between ICBP90 and PTEN expression. CONCLUSION: Our findings suggested that continually overexpressed ICBP90 may contribute to the inhibition of PTEN expression, which is a frequent and important event in endometrial carcinogenesis. We propose that the reduced NIRF expression and ICBP90 overexpression is an early event in endometrial carcinogenesis; thus ICBP90 may be useful as a therapeutic target in this disease.

Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis.

BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis; therefore, useful biomarkers and treatments are needed. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a member of the TGF-ß superfamily, are elevated in patients with pancreaticobiliary cancers. However, the effect of MIC-1 on BTC is unknown. Therefore, we investigated the effect of MIC-1 on BTC and assessed whether MIC-1 is a biomarker of or therapeutic target for BTC. METHODS: MIC-1 expression in BTC cells was determined by performing histological immunostaining, tissue microarray (TMA), western blotting, and reverse transcription PCR (RT-PCR). Cell culture experiments were performed to investigate the effect of MIC-1 on BTC cell lines (HuCCT-1 and TFK-1). The relationships between serum MIC-1 levels and either the disease state or the serum level of the apoptosis marker M30 were retrospectively verified in 118 patients with pancreaticobiliary disease (individuals with benign disease served as a control group, n = 62; BTC, n = 56). The most efficient diagnostic marker for BTC was also investigated. RESULTS: MIC-1 expression was confirmed in BTC tissue specimens and was higher in BTC cells than in normal bile duct epithelial cells, as determined using TMA, western blotting and RT-PCR. In cell culture experiments, MIC-1 increased BTC cell proliferation and invasion by preventing apoptosis and inhibited the effect of gemcitabine. In serum analyses, serum MIC-1 levels showed a positive correlation with BTC progression and serum M30 levels. The ability to diagnose BTC at an early stage or at all stages was improved using the combination of MIC-1 and M30. The overall survival was significantly longer in BTC patients with serum MIC-1 < the median than in BTC patients with serum MIC-1 ≥ the median. CONCLUSIONS: MIC-1 is a useful diagnostic and prognostic biomarker and might be a potential therapeutic target for BTC.

Septic shock in a woman with a hydatidiform mole: A case report.

Hydatidiform moles can be fatal because of the risk of massive bleeding or thyroid storm; however, they rarely occur concomitantly with sepsis. We present herein the case of a woman with a hydatidiform mole with septic shock. A 30-year-old multiparous woman with Basedow's disease presented with fever, amenorrhea, and vaginal bleeding. Transvaginal ultrasonography revealed an enlarged uterus with an intrauterine vesicular mass (74.3 × 93.0 mm). Human chorionic gonadotropin level was 994,000 mIU/mL. C-reactive protein was elevated, and blood cultures were positive (gram-negative rods), indicating infection. After administering antibiotics (tazobactam and piperacillin), blood pressure suddenly decreased (69/45 mmHg), requiring stabilization with noradrenaline and albumin. The uterine contents were naturally expelled, followed by dilatation and curettage after her vital signs and general condition gradually improved. The pathological diagnosis was a complete hydatidiform mole. Culture of the intrauterine contents revealed Escherichia coli, leading to the potentially fatal diagnosis of septic shock associated with a hydatidiform mole.

Systemic treatment for coexisting mucinous urethral adenocarcinoma and prostate adenocarcinoma.

INTRODUCTION: Mucinous urethral adenocarcinoma is a rare and progressive cancer of the prostatic urethra. Reports on palliative systemic treatment for mucinous urethral adenocarcinoma are few. We present a case of coexisting mucinous urethral and prostate adenocarcinomas managed with systemic treatment. CASE PRESENTATION: A 66-year-old man presented with gross hematuria and urinary retention. Prostate-specific antigen level was elevated, at 99 ng/mL, and prostate biopsy revealed moderately to poorly differentiated adenocarcinoma. Hormone therapy and standard chemotherapy for prostate adenocarcinoma were ineffective. Prostate re-biopsy revealed coexisting mucinous urethral and prostate adenocarcinomas. Gemcitabine + cisplatin chemotherapy and folinic acid + 5-fluorouracil + irinotecan chemotherapy temporarily suppressed the cancer, but 14 months after presentation, he developed liver metastasis and died. Autopsy revealed metastasis of both mucinous urethral adenocarcinoma and carcinosarcoma. CONCLUSION: Mucinous urethral adenocarcinoma is difficult to diagnose in coexistence with prostate adenocarcinoma. This was an extremely rare case showing chemoresistance due to epithelial-mesenchymal transition.

Interleukin-33/ST2-Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis.

Interleukin (IL)-33 was recently described as a new member of the IL-1 family; members of this family have proinflammatory activity. IL-33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL-33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male-to-female ratio was 6:59. Serum IL-33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL-33 expression in liver sections from patients with AIH. In particular, serum IL-33 and sST2 levels were significantly higher in acute-onset AIH than in chronic-onset AIH. Serum IL-33 levels were positively correlated with serum total bilirubin (TB), alanine aminotransferase (ALT), and necroinflammatory activity in AIH. We performed multivariate logistic regression analysis and found serum IL-33 levels to be independent factors for severe activity. Serum sST2 levels were positively correlated with serum TB and ALT and negatively correlated with serum albumin and prothrombin time in AIH. In particular, serum sST2 levels were significantly higher in severe symptoms of AIH. Serum IL-33 and sST2 levels in patients with AIH responsive to treatment with prednisolone were significantly decreased after treatment. Interestingly, serum IL-33 level was associated with a significantly increased risk of relapse. Conclusion: IL-33/ST2 may play an important role in the pathogenesis and severity of AIH and may be a promising target for AIH therapy.

Case of atypical femoral fractures that mimicked the typical imaging findings of prostate cancer-induced bone metastasis.

INTRODUCTION: Atypical femoral fractures are atraumatic or minimally traumatic fractures and rare side effects of bone resorption inhibitors. Bone resorption inhibitors are frequently used in the treatment of prostate cancer. CASE PRESENTATION: A 62-year-old man complained of difficulty in walking and left lower limb pain. Androgen deprivation and denosumab therapy for prostate cancer-induced bone metastasis was initiated 27 months ago. Even though the prostate-specific antigen level did not increase, imaging studies indicated the possibility of bone metastasis. The patient underwent bone biopsy; however, no malignancy was detected. Afterward, he had a fall, causing a complete fracture in his left femur. CONCLUSION: Atypical femoral fractures occasionally mimic typical imaging findings and outcomes of bone metastasis. This case is important for recognizing such cases.

The efficacy of serum cell death biomarkers for diagnosing biliary tract cancer.

In this study, we determined the efficacy of the cell death biomarker cytokeratin 18 for diagnosing biliary tract cancer (BTC). We recruited 36 patients with BTC (Malignant group) and 45 patients with benign biliary tract disease (Benign group) for this study. We used M30 and M65 as cell death biomarkers. M30 levels indicate apoptosis, and M65 levels indicate both apoptosis and necrosis. M30 and M65 levels were significantly higher in the Malignant group than in the Benign group (142.4 ± 117.0 vs 48.9 ± 71.2 U/l, P < 0.001; 1513.3 ± 837.4 vs 882.2 ± 831.2 U/l, P = 0.001). The diagnosability of M30 was the highest of the four markers (CEA, CA19-9, M30, M65) (cut-off value: 74.429 U/l, sensitivity: 72.2%, specificity: 77.1%, AUC: 0.771). The sensitivity of M30 (cut-off value: 74.429 U/l) was significantly higher than that of biliary cytology (76% (19/25) vs 12% (3/25), P < 0.001), and the accuracy of M30 was significantly higher than that of biliary cytology (78.3% (36/46) vs 52.2% (24/46), P = 0.015). The sensitivity of M30 (cut-off value: 74.429 U/l) was significantly higher than that of biliary cytology and brush cytology (72.4% (21/29) vs 24.1% (7/29), P < 0.001). In conclusion, cell death biomarkers were increased in patients with BTC, and M30 could efficiently diagnose BTC.

Immunotherapy for pulmonary squamous cell carcinoma and colon carcinoma with pembrolizumab: A case report.

RATIONALE: Novel treatment strategies such as immunotherapy are being evaluated to further improve the outcomes of colorectal cancer patients. To our knowledge, this is the first report to show both the successful treatment of pulmonary squamous cell carcinoma (SCC) with pembrolizumab alongside histological and immunohistochemical findings of resected colon cancer under immunotherapy for lung cancer. PATIENT CONCERNS: This patient was a 70-year-old man who presented with a right lung tumor and simultaneous adenocarcinoma of the sigmoid colon. DIAGNOSES: Biopsy examination revealed squamous cell carcinoma in the right lung and adenocarcinoma of the sigmoid colon. INTERVENTIONS: The patient underwent successful pembrolizumab treatment as first-line immunotherapy for lung cancer, as demonstrated by computed tomography, and the sigmoid colon tumor was excised during an immunotherapy-free window. OUTCOMES: No unusual tumor growth in the right lung or abnormal abdominal signs was observed during the 9-month follow-up. LESSONS: Microscopically, the resected colon cancer specimen was characterized by numerous lymphoid cells in the partial stroma, with a large number of infiltrating lymphocytes consisting of CD3+, CD8+ T cells. In summary, this case demonstrates how immunotherapy affects PD-L1-negative colon cancer and indicates future treatment prospects.

Serum levels of a cell death biomarker predict the development of cirrhosis-related conditions in primary biliary cholangitis.

Non-invasive predictors for the development of cirrhosis-related conditions are needed for patients with primary biliary cholangitis (PBC). We investigated the association between cytokeratin-18 fragments (M30 and M65) and liver histology, treatment response and the development of cirrhosis-related conditions in patients with PBC. We retrospectively reviewed the clinical data of 111 individuals with biopsy-proven PBC. Serum M30 and M65 levels were measured using stored sera. M30 were significantly decreased after treatment, but there was no significant change in the M65 levels. M65 was significantly higher in non-responders according to the Paris-I and Paris-II definitions. In the multivariate analysis, high levels of M65 were significantly associated with advanced Scheuer stage (odds ratio 5.86; 95% confidence interval 0.55-22.2; P = 0.009) and with the development of cirrhosis-related conditions (hazard ratio 3.94; 95% confidence interval: 1.06-14.5, P = 0.039). Among PBC patients without cirrhosis, those with high serum M65 levels at baseline were at higher risk of developing cirrhosis-related conditions (log-rank test; P = 0.001). High levels of serum M65 may be a non-invasive and early predictor of the development of cirrhosis-related conditions in PBC patients. Our findings may help initiate therapies earlier for those at risk for cirrhosis.

A combined human case of Dirofilaria ursi infection in dorsal subcutaneous tissue and Anisakis simplex sensu stricto (s.s.) infection in ventral subcutaneous tissue.

BACKGROUND: Dirofilaria ursi is a filarial nematode that parasitizes the subcutaneous tissues of the American black bear (Ursus americanus) and Japanese black bear (Ursus thiabetanus japonicus). D. ursi that has parasitized black bears has the potential to subsequently infect humans. In addition, extra-gastrointestinal anisakiasis is less common in Japan. CASE PRESENTATION: We report a case of ventral subcutaneous anisakiasis and dorsal subcutaneous dirofilariasis that was acquired in Fukushima, in the northern part of Japan. The patient was an 83-year-old Japanese female, and subcutaneous parasitic granulomas were present on her left abdomen (near the navel) and left scapula. A pathological examination of the surgically dissected tissue sections from each region demonstrated eosinophilic granulomas containing different species of parasites. To enable the morphological and molecular identification of these parasites, DNA was extracted from paraffin-embedded sections using DEXPAT reagent, and the cytochrome oxidase 2 (COX2), internal transcribed spacer 1 (ITS1), 5.8S and ITS2 regions of the Anisakis larvae, and the 5S rRNA region of the male Dirofilaria were sequenced. The PCR products were examined and compared with DNA databases. Molecular analysis of the COX2 and 5S rRNA sequences of each worm revealed that the nematode found in the ventral region belonged to Anisakis simplex sensu stricto (s.s.) and the male Dirofilaria found in the dorsal region was classified as D. ursi. CONCLUSION: The present case showed a combined human case of D. ursi and A. simplex s.s. infections in subcutaneous tissues. The results of this study will contribute to the identification of unknown parasites in histological sections.

Serum Free Light Chain Only Myeloma with Cytoplasmic IgM.

In the past decade, the serum free light chain (FLC) immunoassays have become widely available enabling greater sensitivity in the diagnosis and management of monoclonal light chain diseases. Here, we describe a rare case of serum free light chain only myeloma with cytoplasmic IgM. A 75-year-old woman presented with a progressively worsening lumbosacral pain. FDG PET/CT images showed increased FDG uptake in the sacral mass, vertebral bodies, and ribs. Laboratory data found hypogammaglobulinemia and the bone marrow aspirate revealed only 2.2% of plasma cells. The serum and urine protein electrophoresis did not detect a monoclonal band. However, the serum FLC immunoassays reported an abnormal kappa/lambda ratio (0.001) indicating the presence of monoclonal lambda FLC. The sacral tumor biopsy revealed proliferation of plasma cells and immunohistochemical staining showed that the plasma cells were positive for CD138, IgM, and lambda light chain but negative for CD20. This case may have previously been described as a nonsecretory IgM myeloma but recently would be identified as free light chain only myeloma. The immunohistochemical and genetic features of the clonal plasma cells in free light chain only myeloma need to be further investigated to better understand the relevance and incidence of this myeloma type.

The utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases.

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) present with distinct clinical features. The term "PBC-AIH overlap syndrome (OS)" has been adopted to describe the condition characterized by occurrence of both PBC and AIH, although this clinical entity is difficult to define. This study aimed to assess the utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of AIH, PBC, and OS. Immunohistochemistry was performed with anti-human IgG, IgM, and CD138 to detect specific plasma cells in the liver. Predominant IgG staining was observed in AIH (85.7 %), while equivocal (46.1 %) or predominant (38.5 %) IgM staining was observed in PBC. In OS, equivocal (20 %) or predominant (80 %) IgG staining was observed. The IgM/IgG ratio was significantly higher in PBC than in AIH or OS (P < 0.005). Histological findings revealed significantly higher IgM expression in PBC at cholangitis activity grades 2-3 compared to those at cholangitis activity grades 0-1. In contrast, a significantly higher IgG expression was observed in PBC at hepatitis activity and fibrosis grades 2-3 compared to those at hepatitis activity and fibrosis grades 0-1. Taken together, periportal plasmacytic infiltrates with variable immunohistochemistry patterns of IgG and IgM expression characterized different autoimmune liver diseases.

Early detection of colon cancer by amino acid profiling using AminoIndex Technology: a case report.

Most tumor markers have low detection rates for curable stages of cancer and are therefore not satisfactory for use in a healthy population. A new cancer risk calculation method, AminoIndex Cancer Screening (AICS), uses multiple plasma amino acid concentrations to calculate the risks for several cancers simultaneously and is suggested to have a high detection rate for early-stage cancers and a low false-positive rate for adenomas. Here, we describe a male patient with a family history of colorectal cancer who underwent AICS. He was judged as Rank C for colorectal cancer, which reportedly has a specificity of 95%, a sensitivity of 41%, and an estimated positive predictive value of 0.67%. He underwent colonoscopy for a secondary screening, which revealed a 10-mm adenoma-like lesion in the ascending colon, with a biopsy report of partial carcinoma. The tumor was endoscopically removed and diagnosed as carcinoma in situ (carcinoma in adenoma). This early detection method allowed complete resection of the carcinoma, and the patient is in remission. This is the first case in which a curable cancer was detected using AICS. With its high detection rate for early-stage cancers and its ease of use, this tool, which recently became available in Japan, may be beneficial for simultaneous screening of the general population for multiple cancers. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2145080259887842.

[A case of curatively resected locally advanced pancreatic cancer with combined resection of the portal vein and common hepatic artery after neoadjuvant chemotherapy].

A man in his 40s had a locally advanced pancreatic head cancer invading the portal vein( PV) and common hepatic artery (CHA). He underwent 5 courses of neoadjuvant chemotherapy( gemcitabine+S-1), which reduced the tumor volume and cancer antigen 19-9 (CA19-9) level. R0 resection was performed via sub-stomach preserving pancreatoduodenectomy with combined resection of the PV and CHA. Adjuvant chemotherapy with gemcitabine was administered at 4 weeks after the operation. Relevant neoadjuvant chemotherapy is considered to contribute to R0 resection of locally advanced pancreatic cancer. Here, we report a case of a successful R0 resection after neoadjuvant chemotherapy for locally advanced pancreatic cancer.

A case of gastrointestinal stromal tumor with pneumomediastinum.

A 52-year-old man noticed physical weariness and anorexia in November 2008. Severe anemia was found. Pneumomediastinum was detected using x-ray and CT scanning. Esophagogastroduodenoscopy revealed a submucosal tumor with a deep ulcer in the anterior wall of the upper stomach, causing anemia. Partial gastrectomy was performed because microperforation was suspected. The resected specimen showed spindle-shaped tumor cells that were c-kit positive and CD34 positive on immunohistological staining, suggesting a diagnosis of gastrointestinal stromal tumor (GIST). Although emphysema in the abdominal cavity was not observed, air leakage from gastric GIST with necrosis in the upper stomach was inferred as the cause of pneumomediastinum.

Loss of L-PHA-, PNA-, or ConA-reactive oligosaccharides is associated with a poor prognosis in human Burkitt's lymphoma.

The expression of cell surface oligosaccharides is associated with various biological phenomena. To clarify the relationship between lectin binding and the survival of patients with Burkitt's lymphoma, tumor samples from nine patients with Burkitt's lymphoma were analyzed by lectin histochemistry. Kaplan-Meier analysis showed that survival is significantly shorter for patients with negative reactivity for lectins from Phaseolus vulgaris (L-PHA), Arachis hypogaea (PNA), or Canavalia ensiformis (ConA) than for those with positive reactivity for these lectins. Immunohistochemistry for N-acetylglucosaminyltransferase V, which synthesizes beta1,6-branched oligosaccharides such as L-PHA-reactive oligosaccharides, was positive in 8 of 9 patients, but there was no correlation between its expression and that of L-PHA-reactive oligosaccharides. Collectively, a loss of L-PHA-, PNA-, or ConA-reactive oligosaccharides is closely associated with a poor prognosis in patients with Burkitt's lymphoma.

Regulatory roles of cell surface sialylation in sphingolipid-induced cell death in human B cell lymphoma.

Sphingolipid metabolites are important regulators of cell growth and death. In the present study, we examined the function of cell surface sialic acid in exogenous sphingosine-1-phosphate (S-1-P) or sphingosine-induced cell death. HBL-2 human diffuse large B cell lymphoma cells were incubated with or without Vibrio Cholerae neuraminidase followed by S-1-P or sphingosine. Flow cytometric analysis using Limax flavus agglutinin, a sialic acid-specific lectin, showed that sialylated glycoconjugates are present on the surface of HBL-2 cells and that they were removed by neuraminidase. In addition, the pretreatment with neuraminidase enhanced S-1-P- and sphingosine-induced cell death, an effect that was not dependent on caspase activation. Furthermore, the cell death induced by S-1-P and sphingosine was morphologically distinct from apoptosis. We further examined S-1-P-induced cell death in two clones of HBL-8 Burkitt lymphoma cells with different amounts of cell surface sialic acid. Clone 3G3, which is hypersialylated, was less sensitive to S-1-P than the 3D2 clone, which is hyposialylated, suggesting that the extent of surface sialylation influences the sensitivity to S-1-P. In conclusion, S-1-P and sphingosine induce cell death, and the sensitivity of human B lymphoma cells to these agents appears to depend on the amount of sialic acid on their cell surfaces.