Celiac Disease Diagnosed after Gastrectomy for Gastric Cancer.

Celiac disease is a systemic autoimmune disorder leading to manifestations of malabsorption syndrome. A 47-year-old Japanese man developed severe diarrhea after surgery for gastric cancer. The diarrhea persisted for seven months, leading to a state of malabsorption. Celiac disease was suspected based on small bowel capsule endoscopy findings. The duodenal findings observed during gastric cancer surgery were reassessed, and Marsh-Oberhuber classification type 3c celiac disease was diagnosed. The anti-tissue glutaminase antibody test results were positive. The patient was started on a gluten-free diet, following which the diarrhea resolved, and the nutritional status improved. Adjuvant therapy after gastric cancer surgery was initiated.

Mixed ductal-lobular carcinoma: an analysis of CDH1 DNA copy number variation and mutation.

BACKGROUND: Mixed ductal-lobular carcinoma (MDL) of the breast is poorly understood. Dysfunction of E-cadherin, a cell adhesion protein encoded by the CDH1 gene located on 16q22.1, causes loss of cell adhesion and cellular polarity in lobular carcinoma (LC). This study focuses the aberrations of CDH1 in LC, ductal carcinoma (DC), and MDL to investigate the pathogenesis of MDL. METHODS: The CDH1 DNA value (ratio of CDH1 copy number to the reference gene, RNase P) was calculated by digital polymerase chain reaction analysis of a total of 113 breast carcinoma cases (51 LCs, 54 DCs, and 8 MDLs). CDH1 gene mutation assay was performed for 20/51 LCs, 8/54 DCs, and 8 MDLs cases. RESULTS: The CDH1 DNA values were lower in LCs (average: 0.664) than in DCs (average: 1.296) (p < 0.000). In MDL, The CDH1 DNA values were significantly lower in LC areas (average: 0.58), compared to that of DC areas (average: 1.08) (p = 0.004), and there is no significant difference between the intermingled areas (average: 1.05) and DC areas (p = 0.775). Moreover, CDH1 mutations occurred more frequently in MDLs than in pure LCs and DCs. In one MDL case, the identical CDH1 mutation was found in LC and DC areas. CONCLUSION: Our study presented that MDL had more frequent CDH1 mutations. There were two possible processes for cancer cells in LC areas: one process was via DC areas with a common ancestor, and another was an independent process from DC areas.

Altered Immunohistochemical Expression Patterns of HLA Class I during the Clinical Course of Cervical Intraepithelial Neoplasia.

It is unclear how immunohistochemical expression patterns of HLA class I in the pre-malignant phase of cervical intraepithelial neoplasia (CIN) alter during the clinical follow-up period. The present study aimed to demonstrate the correlation between the immunohistochemical expression pattern of HLA class I and the CIN grade through repeated examinations during the clinical course. Expression patterns of HLA class I, p16INK4a, and PD-L1 were immunohistochemically examined using formalin-fixed paraffin-embedded (FFPE) sections of biopsy or conization samples that were obtained from 20 patients diagnosed with CIN. The mRNA expression levels of HLA class I were analyzed by real-time reverse transcription polymerase chain reaction using FFPE sections of 14 patients, who were examined metachronously during the follow-up period. HLA class I expression was limited to the lower part of the epithelial thickness (M1 pattern) in more than half of CIN1 cases, and was present throughout the epithelial thickness (M2 pattern) in one fourth of CIN1 and CIN2 cases approximately. Heterogeneous expression (H pattern) was detected in half of CIN2 and CIN3 cases and in the all of squamous cell carcinoma cases. Metachronous examinations revealed that these immunohistochemical patterns altered more frequently than the CIN grade. The rate of change of HLA class I mRNA expression level was higher in cases with a progressed immunohistochemical pattern compared to those with regressed immunohistochemical pattern. In conclusion, the immunohistochemical pattern of HLA class I expression is associated with the CIN grade, and it is alterable during the clinical course, especially in CIN2.

A Case of Early Stage Bladder Carcinosarcoma in Late Recurrence of Urothelial Carcinoma after Transurethral Resection.

Carcinosarcomas of the urinary bladder are rare biphasic neoplasms, consisting of both malignant epithelial and malignant mesenchymal components, and the prognosis of this tumor is unfavorable in most patients with even possibility of resection of disease. A 77-year-old male with a history of transurethral resection (TUR) of urothelial carcinoma (UC) of the bladder and adjuvant intravesical chemotherapy with pirarubicin 10 years ago revisited our department with a gross hematuria. Cystoscopy demonstrated an approximately 2.5 cm nonpapillary tumor on the right wall of the bladder. Pelvic MRI showed the tumor without extending the base of the bladder wall. The tumor could be completely removed with TUR. The malignant epithelial elements consisted of high-grade UC and the majority of mesenchymal components were fibrosarcomatous differentiation based on immunohistochemical studies. The tumor could be pathologically also suspected to be an early stage on TUR specimens. Although he has received no additional intervention due to the occurrence of myocardial infarction at three weeks after the TUR, he has been alive with no evidence of recurrence of the disease 27 months after the TUR. Some early stages of bladder carcinosarcoma might have a favorable prognosis without aggressive treatments.

Particular gene upregulation and p53 heterogeneous expression in TP53-mutated maxillary carcinoma.

It has been demonstrated that tumor protein p53 (TP53) mutation in maxillary squamous cell carcinoma, is more treatment-resistant compared with the carcinoma without TP53 mutation. However, the association between TP53 mutation and treatment resistance remains unclear. As a first step in understanding the biological differences between tumors with and without TP53 mutation, a comprehensive gene expression analysis of maxillary squamous cell carcinoma with or without TP53 mutation was performed. A total of 42 genes were identified to be differentially expressed by >4-fold. Quantification of their mRNA using quantitative polymerase chain reaction indicated 18 genes with high expression and three genes with low expression in TP53 mutated tumors vs. TP53 wild-type tumors. The 18 genes included eight cell adhesion (DSC3, GRHL1, EPPK1, PROM2, ANXA8, DSP, JUP, and KRT6B) and four cell growth inhibition (SFN, CLCA2, SAMD9 and TP63) genes. Among these genes, DSC3, SFN, and CSTA, whose expression was markedly increased, also demonstrated high protein expression in immunohistochemical staining of TP53 mutated tumors. The TP53 mutated tumors demonstrated high nuclear staining of the TP53 protein only in tumor cells at the tumor margins adjacent to the stroma, whereas the tumor interior was negative for TP53. However, all tumor cells of TP53 wild-type tumors exhibited positive nuclear staining for the TP53 protein. The combined findings suggest that TP53 mutated tumors possess a phenotype opposite to that associated with cancer progression and malignant transformation, and exhibit tumor cell heterogeneity between the tumor interior and margins.

Expression of von Hippel-Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium.

BACKGROUND: Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel-Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance. METHODS: Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17. RESULTS: In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL. CONCLUSIONS: Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.

A case of symptomatic granular cell tumor of the sellar region with large calcification.

We report here a rare case of symptomatic granular cell tumor (GCT) of the sellar region with a large calcification. A 70-year-old woman presented with a sellar mass, accompanied by bitemporal hemianopia. The patient was diagnosed preoperatively as having a craniopharyngioma or a pituitary adenoma, because of the large calcification. The patient underwent surgical tumor resection via endoscopic trans-sphenoidal surgery and was diagnosed pathologically as having GCT. The patient's postoperative course was uneventful and her visual field disturbance improved soon after the operation. We briefly discuss the pathological discrimination of GCT and other sellar tumors, since there are many unclear points concerning this rare tumor.

A rare case of a pineoblastoma with a rhabdomyoblastic component.

Pineal anlage tumor (PAT) is a rare subtype of pineoblastoma (PB), which shows a poor prognosis. We report a case of a 5-year-old boy with PB with a rhabdomyoblastic component. He presented at a local clinic with vomiting and was transferred to our hospital following discovery of a pineal mass. An endoscopic biopsy was performed and was diagnosed as a PB with a rhabdomyoblastic component. Histopathology of PAT is characterized by both neuroectodermal and ectomesenchymal differentiation, and only a few confirmed cases have been reported. Although the histopathological features of the reported case resembled that of PAT, the ectomesenchymal component in the presented case was only a rhabdomyoblastic one. Therefore, we have diagnosed this case as PB with a rhabdomyoblastic component. As PAT is a rare pineal tumor, clinical, histopathological and genetic evaluation of additional cases is needed to define the characteristics of PAT as one of the pineal gland tumors.

Spontaneous Remission in a Case of Giant Cell Myocarditis with Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Giant cell myocarditis (GCM) is rapidly progressive fulminant myocarditis causing death or requiring cardiac transplantation despite various immunosuppression therapies. CASE REPORT: A 28-year-old woman with progressive shortness of breath and palpitation following an upper respiratory infection was referred to our institution. On admission, transthoracic echocardiography (TTE) revealed a preserved left ventricular ejection fraction (LVEF) with mildly impaired LV diastolic function despite extensive ECG abnormalities, a mildly elevated troponin I concentration, and moderately elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) concentration. The diagnosis of GCM was made by endomyocardial biopsy (EMB), which revealed extensive fibrosis and inflammatory infiltration with multinucleated giant cells, as well as scattered eosinophils and lymphocytes in the absence of granuloma formation. However, the patient's symptoms began to improve without any specific therapy within 2 weeks, followed by the normalization of the ECG abnormalities, TTE-determined diastolic function, and troponin I and NT-pro-BNP concentrations. In sub-acute phase, 18F-fluorodeoxyglucose positron emission tomography showed no evidence of inflammation, and repeat EMB showed a significant decrease in the inflammatory infiltration and fibrosis, including absence of giant cells. Given the favorable clinical course, the patient was discharged without medications. At the 6-month follow-up, the patient had no LV functional impairment, cardiovascular events, or arrhythmia. CONCLUSIONS: We encountered a rare case of atypical GCM in which clinical and histologic remission was achieved without immunosuppression therapy. There seems to be a population of GCM patients who improve without immunosuppression therapy. In monitoring GCM patients, clinicians should be aware of the possibility of spontaneous remission.

Solitary pulmonary metastasis from prostate cancer with neuroendocrine differentiation: a case report and review of relevant cases from the literature.

BACKGROUND: Solitary lung metastasis from prostate cancer is rare. There are few reports of such cases with neuroendocrine differentiation. CASE PRESENTATION: A 50-year-old man presented to our hospital with a chief complaint of dysuria. Histological examination revealed prostate cancer, which was classified as cT4 N0 M0, stage IV adenocarcinoma. Since the patient was at high risk, endocrine and radiation therapies were started. One year after starting radiation therapy, the patient developed bloody sputum. Chest radiography revealed a nodular shadow in his left lung (S5). Although 18-fluoro-2-deoxyglucose positron emission tomography revealed abnormal accumulation in the lesion, the cytological diagnosis was class IIIa, which did not yield a definitive diagnosis. Given that prostate specific antigen (PSA) was not elevated, a primary lung tumor was suspected, and thoracoscopic segmental resection of the lung was performed with lymph node dissection. The final pathological diagnosis was solitary lung metastasis from prostate cancer with neuroendocrine differentiation and mediastinal lymph node metastasis. The specimen showed a mixed pattern of conventional prostatic and neuroendocrine carcinomas. CONCLUSION: We herein report a case with neuroendocrine differentiation (NED), along with a review of the relevant literature, including histopathological findings. According to previous case reports, some patients with solitary lung metastasis from prostate cancer achieved relatively good long-term survival. We consider establishing the correct diagnosis and implementing an appropriate treatment plan to be essential in prostate cancer patients with oligometastases that have the potential to be neuroendocrine (NE) tumors.

Metastatic Tumor of the Spermatic Cord in Adults: A Case Report and Review.

Metastatic spermatic cord (SC) tumor is extremely rare. Recently, we experienced a case of late-onset metastatic SC tumor from cecal cancer. This case is a 68-year-old man presenting with a painless right SC mass. He had undergone a right hemicolectomy for cecal cancer 6 years ago. Radical orchiectomy and adjuvant chemotherapy with S-1 were performed. No recurrence was found after one year of follow-up. We identified a total of 25 cases, including our case, on a literature search via PubMed from January 2000 to April 2015. The most frequent primary sites of the tumors metastasizing to the SC were the stomach (8 cases, 32%) and the colon (8 cases, 32%), next the liver (2 cases, 8%), and kidney (2 cases, 8%). The majority of the cases underwent radical orchiectomy for the metastatic tumors of the SC. Over half of the cases received adjuvant interventions based on the regimens for the primary tumors. Prognosis in the patients with metastatic tumor of the SC was unfavorable except for late-onset metastasis. In patients with a mass in the SC and a history of neoplasm, especially in gastrointestinal tract, the possibility of metastasis from the primary cancer should be considered.

Gastrointestinal stromal tumor with nephrotic syndrome as a paraneoplastic syndrome: a case report.

INTRODUCTION: Paraneoplastic syndromes are disorders associated with clinical signs and symptoms caused by substances produced by malignant disease and are not directly related to the physical effects of a primary or metastatic tumor. We describe a patient with gastrointestinal stromal tumor of the stomach accompanied by nephrotic syndrome as paraneoplastic syndrome in whom symptomatic treatment was ineffective. Nephrotic syndrome caused by gastrointestinal stromal tumors is quite rare, and to the best of our knowledge this is the first time that such a case has been documented. CASE PRESENTATION: We describe a 69-year-old Asian woman with a gastrointestinal stromal tumor of the stomach accompanied by paraneoplastic syndrome. The patient had severe hypoalbuminemia and proteinuria, which were apparently attributed to a gastrointestinal stromal tumor. After preoperative treatment for hypoalbuminemia, the tumor was resected and nephrotic syndrome improved. Two years after her operation, she is still alive with neither tumor recurrence nor nephrotic syndrome. CONCLUSION: Patients with refractory nephrotic syndrome caused by a malignant tumor should be treated aggressively, even if they are in poor general condition. Otherwise, the opportunity for potentially curative surgery may be missed.

Semi-nested real-time reverse transcription polymerase chain reaction methods for the successful quantitation of cytokeratin mRNA expression levels for the subtyping of non-small-cell lung carcinoma using paraffin-embedded and microdissected lung biopsy specimens.

In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P<0.05) in adenocarcinoma (AD) than in squamous cell carcinoma (SQ), while CK6 and CK14 mRNA expression was significantly higher (P<0.05) in SQ than in AD. Each histology-specific CK, particularly CK18 in AD and CK6 in SQ, were shown to be correlated with a poor prognosis (P=0.02, 0.02, respectively). Our results demonstrated that a quantitative CK subtype mRNA analysis from lung biopsy samples can be useful for predicting the histology subtype and prognosis of advanced NSCLC.

Effect of endothelial cell proliferation on atherogenesis: a role of p21(Sdi/Cip/Waf1) in monocyte adhesion to endothelial cells.

OBJECTIVE: Uniform laminar shear stress (LS) and disturbed turbulent shear stress (DS) are thought to play opposite roles in preventing or inducing atherosclerosis. Endothelial cell (EC) growth and monocyte adhesion to ECs, an early event in atherosclerosis, are also oppositely regulated by LS and DS. However, how atherogenesis is affected by the regulation of growth by blood flow is unknown. Here we examined the role of p21(Sdi/Cip/Waf1) (p21), a growth inhibitor induced by LS, in monocyte adhesion to ECs. METHODS: p21 was overexpressed by transfecting a p21-expressing adenoviral vector into ECs. Factors linking EC growth, monocyte adhesion, and p21 were examined by microarray analysis, PCR and Western blotting. RESULTS: Compared with DS, in the presence or absence of TNFalpha, LS significantly inhibited EC growth and monocyte adhesion to ECs. Both EC proliferation and monocyte adhesion induced by DS were inhibited by p21-overexpression. LS suppressed the expression of thioredoxin-interacting protein (TXNIP). Thioredoxin (TRX) activity, which is suppressed by TXNIP, was therefore higher under LS than DS, as reported previously. p21-overexpression significantly suppressed the DS-induced TXNIP expression, and inhibited the expression of vascular cell adhesion molecule 1 and chemokine (C-C motif) ligand 5 (CCL5/RANTES), which stimulates leukocyte recruitment and is downregulated by ROS scavenging. CONCLUSION: p21 may function to prevent atherogenesis by regulating the redox balance, which leads to the inhibition of adhesion molecule and chemokine expression in ECs under LS.

Increased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma in human atherosclerosis.

To clarify the mechanism of atherosclerosis development in humans, we studied the mRNA and protein expression of PPAR subtypes in various types of atherosclerotic lesions and their correlation with cell proliferation and macrophage invasion. Human aortas were obtained from 35 autopsied cases, and each sample was divided into halves. One half was used for the analysis of mRNA or protein expression with RT-PCR or Western blotting, respectively. The other was microscopically classified into atheromatous plaque (AP), fatty streak (FS), and diffuse intimal thickening (DIT), and was analyzed immunohistochemically. The mRNA levels of both PPARs increased significantly in atherosclerosis and tended to increase in proportion to the severity of the lesion, and the expression of PPAR-alpha correlated with that of PPAR-gamma in FS and AP. The PPAR-gamma protein increased in AP. Monocytes/macrophages, as well as endothelial and smooth muscle cells, expressed the PPAR-gamma protein in plaques. This expression in the DIT was noted mainly in macrophages but was not correlated with the density of macrophages, suggesting that only certain macrophages express the PPARs in DIT. Cell proliferation did not correlate with PPARs expression in any lesion type. These findings suggest that PPARs may be associated with atheromatous plaque formation, and that PPAR-gamma may be involved in the early stages of human atherosclerosis.

Appropriate doses of granulocyte-colony stimulating factor reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.

AIM: To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. METHODS: Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 microg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 microg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. RESULTS: Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p<0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. CONCLUSIONS: Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.

Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene.

BACKGROUND: Although transplantation of mononuclear cells (MNCs) induces angiogenesis in myocardial infarction, transplantation requires a large amount of bone marrow or peripheral blood cells. We examined the effects of transplantation of peripheral MNCs expressing an exogenous vascular endothelial growth factor (VEGF) gene in a pig model of acute myocardial infarction (AMI). METHODS: MNCs were isolated from 20 ml peripheral blood from pigs and transfected with 10 microg of human VEGF165 plasmid (phVEGF). Myocardial infarction was induced by occlusion of the mid portion of the left anterior descending coronary artery (LAD) in anesthetized pigs. At 4 h after total occlusion, 5 x 10(6) VEGF-transfected MNCs were retrogradely transplanted into the pig via the coronary vein. Cardiac function, neovascularization and histology of the ischemic tissue were evaluated 4 weeks after transplantation. RESULTS: MNCs expressing hVEGF and infused via the coronary vein were efficiently delivered the heart in pigs with myocardial infarction. Transplantation of MNCs expressing hVEGF significantly increased left ventricular (LV) function, collateral vessels, and capillary density in heart from AMI model pigs. Transplantation of MNCs expressing hVEGF increased the wall thickness of the scar in the heart after AMI. CONCLUSIONS: Retrograde transplantation of peripheral blood MNCs expressing hVEGF efficiently induced angiogenesis and improved the impaired LV function in hearts of pigs with AMI. These findings indicate that angiogenic cells and gene therapy may be useful to treat ischemic heart disease.

Association of serum oxidized lipoprotein(a) concentration with coronary artery disease: potential role of oxidized lipoprotein(a) in the vasucular wall.

AIM: A new antibody reacted with an epitope in Lp(a) that has undergone oxidation treatment, but is not present in native Lp(a), was developed. Thus, we determined serum oxidized Lp(a) concentration in healthy volunteers, and coronary artery disease (CAD), diabetes mellitus (DM), and hypertensive patients. METHODS: We measured serum levels of oxidized Lp(a), Lp(a), LDL-cholesterol and HDL-cholesterol in 122 consecutive patients who underwent routine coronary angiography and had significant coronary artery stenosis (>75%), and 164 age-matched healthy volunteers. Moreover, serum native Lp(a), oxidized Lp(a) concentration, and pulse wave velocity (PWV) were determined in 181 hypertensive patients. RESULTS: Oxidized Lp(a) level in CAD patients with DM was significantly higher than in healthy volunteers (p<0.01). Moreover, serum oxidized Lp(a) concentration showed a significant positive correlation with pulse wave velocity, an index of arteriosclerosis (r=0.431, p<0.01). Of importance, the deposition of oxidized Lp(a) was readily detected in calcified areas of coronary arteries in patients with myocardial infarction. CONCLUSION: The present study demonstrated that oxidized Lp(a) may be a new risk factor for coronary artery disease. As the deposition of oxidized Lp(a) was detected in calcified areas of coronary arteries, oxidized Lp(a) might be implicated in endothelial dysfunction.