A case of cerebrotendinous xanthomatosis with massive xanthomas but without a considerable increase in serum cholestanol levels.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the sterol 27-hydroxylase gene (CYP27A1). Due to the deficiency of 27-hydroxylase, the synthesis of bile acids from cholesterol is impaired and excessive cholestanol accumulates in various tissues, such as the central nervous system, tendons, and lenses. Patients with CTX typically manifest intellectual decline, pyramidal tract symptoms, cerebellar symptoms, tendon xanthomas, juvenile cataracts, neonatal jaundice, chronic diarrhea, osteoporosis, and premature cardiovascular disease. Here, we report the atypical case of a 35-year-old female with CTX having massive xanthomas but without a considerable increase in serum cholestanol levels (3.9 µg/mL). In the differential diagnosis of xanthoma, CTX should not be ruled out even if the serum levels of cholestanol are not high, and genetic testing is necessary to make the appropriate diagnosis.

A Novel Missense MEN1 Mutation in a Sporadic Case of Multiple Endocrine Neoplasia Type 1 Complicated with Papillary Thyroid Carcinoma.

Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder, resulting from MEN1 gene abnormalities, which causes tumors mainly in the endocrine glands. We experienced a sporadic case of MEN1 complicated with papillary thyroid carcinoma (PTC) and found a novel missense mutation in the patient's MEN1 gene. Her older sister, who showed no typical symptom of MEN1, had a history of PTC, suggesting the presence of another genetic factor involved in PTC development. This case suggests the importance of an individual's genetic background in the development of MEN1 complications.

Serum 25-hydroxycholesterol levels are increased in patients with coronavirus disease 2019.

BACKGROUND: 25-hydroxycholesterol (25HC), produced by cholesterol 25-hydroxylase (CH25H) in macrophages, has been reported to inhibit the replication of viral pathogens such as severe acute respiratory syndrome coronavirus-2. Also, CH25H expression in macrophages is robustly induced by interferons (IFNs). OBJECTIVE: To better understand the serum level increase of 25HC in coronavirus disease 2019 (COVID-19) and how it relates to the clinical picture. METHODS: We measured the serum levels of 25HC and five other oxysterols in 17 hospitalized COVID-19 patients. RESULTS: On admission, 25HC and 27-hydroxycholesterol (27HC) serum levels were elevated; however, 7-ketocholesterol (7KC) levels were lower in patients with COVID-19 than in the healthy controls. There was no significant correlation between 25HC serum levels and disease severity markers, such as interferon-gamma (IFN-γ) and interleukin 6. Dexamethasone effectively suppressed cholesterol 25-hydroxylase (CH25H) mRNA expression in RAW 264.7 cells, a murine leukemia macrophage cell line, with or without lipopolysaccharide or IFNs; therefore, it might mitigate the increasing effects of COVID-19 on the serum levels of 25HC. CONCLUSIONS: Our results highlighted that 25HC could be used as a unique biomarker in severe COVID-19 and a potential therapeutic candidate for detecting the severity of COVID-19 and other infectious diseases.

Sex-specific Association of Primary Aldosteronism With Visceral Adiposity.

Context: The association between primary aldosteronism and obesity, especially its sex difference, remains unknown. Objective: To assess the association for each subtype of primary aldosteronism with obesity parameters including visceral adipose tissue and differences between sexes. Methods: In this case-control study, 4 normotensive controls were selected for each case with primary aldosteronism. Multivariable conditional logistic regression models were used to estimate the association between each type of primary aldosteronism and obesity indicators. We used a random forest to identify which visceral or subcutaneous tissue areas had a closer association with disease status. Results: The study subjects included 42 aldosterone-producing adenoma cases (22 women) and 68 idiopathic hyperaldosteronism cases (42 women). In multivariable conditional logistic regressions, aldosterone-producing adenoma was significantly associated with body mass index only in men (odds ratio [OR] [95% CI)], 4.62 [1.98-10.80] per 2.89 kg/m2) but not in women (OR [95% CI], 1.09 [0.69-1.72] per 3.93 kg/m2) compared with the matched controls, whereas idiopathic hyperaldosteronism was associated with body mass index in both men (OR [95% CI], 3.96 [2.03-7.73] per 3.75 kg/m2) and women (OR [95% CI], 2.65 [1.77-3.96] per 3.85 kg/m2) compared with the matched controls. In random forests, visceral adipose tissue areas were the better predictor of both aldosterone-producing adenoma and idiopathic hyperaldosteronism than subcutaneous adipose tissue. Conclusions: Aldosterone-producing adenoma cases were obese among men, but not among women. Idiopathic hyperaldosteronism cases were obese among both men and women. Visceral adipose tissue may contribute to the pathophysiology of primary aldosteronism.

AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4.

Valosin-containing protein (VCP) is a member of AAA-ATPase superfamily involved in various cellular functions. To investigate the pathophysiological role of VCP in metabolic disorders, we generated knock-in mice bearing an A232E mutation in VCP, a known human VCP pathogenic variant. When heterozygous mutant mice (A232E/+) were fed a high-fat diet, we observed that fatty liver was ameliorated and the proteolytic processing of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was impaired. Further co-immunoprecipitation analysis in wildtype mice revealed interactions of VCP with SREBP1 and a rhomboid protease, RHBDL4, in the liver, and these interactions were attenuated in A232E/+ mice. Consistent with these results, we show that knockdown or chemical inhibition of VCP or RHBDL4 in human hepatocytes impaired the proteolytic processing of SREBP1. Finally, we found that knockdown of E3 ligases such as glycoprotein 78 and HMG-CoA reductase degradation protein 1 disrupted the interaction of VCP with SREBP1 and impaired the proteolytic processing of SREBP1. These results suggest that VCP recognizes ubiquitinylated SREBP1 and recruits it to RHBDL4 to promote its proteolytic processing. The present study reveals a novel proteolytic processing pathway of SREBP1 and may lead to development of new therapeutic strategies to treat fatty liver diseases.

Leptin sensitizing effect of 1,3-butanediol and its potential mechanism.

Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma ß-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.

Myeloid HMG-CoA Reductase Determines Adipose Tissue Inflammation, Insulin Resistance, and Hepatic Steatosis in Diet-Induced Obese Mice.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell-specific reduction of HMG-CoA reductase (Hmgcr m-/m- ), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr m-/m- mice than in control Hmgcr fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr m-/m- and Hmgcr fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell-specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell-specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Loss of ACAT1 Attenuates Atherosclerosis Aggravated by Loss of NCEH1 in Bone Marrow-Derived Cells.

AIM: Acyl-CoA cholesterol acyltransferase 1 (ACAT1) esterifies free cholesterol to cholesteryl esters (CE), which are subsequently hydrolyzed by neutral cholesterol ester hydrolase 1 (NCEH1). The elimination of ACAT1 in vitro reduces the amounts of CE accumulated in Nceh1-deficient macrophages. The present study aimed at examining whether the loss of ACAT1 attenuates atherosclerosis which is aggravated by the loss of NCEH1 in vivo. METHODS: Low density lipoprotein receptor (Ldlr)-deficient mice were transplanted with bone marrow from wild-type mice and mice lacking ACAT1, NCEH1, or both. The four types of mice were fed a high-cholesterol diet and, then, were examined for atherosclerosis. RESULTS: The cross-sectional lesion size of the recipients of Nceh1-deficient bone marrow was 1.6-fold larger than that of the wild-type bone marrow. The lesions of the recipients of Nceh1-deficient bone marrow were enriched with MOMA2-positive macrophages compared with the lesions of the recipients of the wild-type bone marrow. The size and the macrophage content of the lesions of the recipients of bone marrow lacking both ACAT1 and NCEH1 were significantly smaller than the recipients of the Nceh1-deficient bone marrow, indicating that the loss of ACAT1 decreases the excess CE in the Nceh1-deficient lesions. The collagen-rich and/or mucin-rich areas and en face lesion size were enlarged in the recipients of the Acat1－/－ bone marrow compared with those of the recipients of the WT bone marrow. CONCLUSION: The loss of ACAT1 in bone marrow-derived cells attenuates atherosclerosis, which is aggravated by the loss of NCEH1, corroborating the in vitro functions of ACAT1 (formation of CE) and NCEH1 (hydrolysis of CE).

Inflammasome Activation Aggravates Cutaneous Xanthomatosis and Atherosclerosis in ACAT1 (Acyl-CoA Cholesterol Acyltransferase 1) Deficiency in Bone Marrow.

Objective- ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency. Approach and Results- Ldlr-null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1-null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1-null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF-α (tumor necrosis factor-α) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein). Conclusions- Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.

Biomechanical study of optimum anchorage in dome-shaped high tibial osteotomy.

PURPOSE: There has been no report to date on any biomechanical study regarding the strength of fixation at the osteotomy site in dome-shaped high tibial osteotomy (HTO). In this study, we evaluated the biomechanical strength of a spacer that we improved and determined the medial site of HTO. METHODS: HTO correction angles of 15° and 20° were used in all experiments, which were performed on lower leg specimens from pigs ( n = 12). The osteotomy site was fixed by a locking plate and screws with a spacer. Compression (600 N/min until 1100 N) and extended cyclic loading (200 cycles at 1000-2000 N) were performed to compare initial displacements in HTO specimens with and without spacers. RESULTS: The reduction ratios of displacement with and without spacers at HTO correction angles of 15° and 20° were 37% and 27%, respectively. No effect of the spacer at the correction angle of 15° was observed in the cyclic loading; however, the maximum displacement and amplitude were reduced with the spacer at the correction angle of 20°. CONCLUSIONS AND CLINICAL RELEVANCE: When the HTO correction angle is small, the effect of the spacer is uncertain. However, the spacer is effective at an HTO correction angle of 20°.

Malignant triton tumor of the duodenum: report of a case.

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

Peliosis Hepatis Mimicking Malignant Hypervascular Tumors.

BACKGROUND: Peliosis hepatis is an uncommon vascular condition characterized by multiple, randomly distributed, blood-filled, and cyst-like cavities throughout the liver. The unique clinical nature consisting of an asymptomatic, benign, and incidental finding sometimes conceals itself even until autopsy. However, the exact pathomechanism remains as yet unproven. METHOD: We encountered the patient with multiple hypervascular masses in the whole liver and investigated the clinicopathological features underlying this condition. RESULTS: Detailed herein is a case of peliosis hepatis on the basis of our findings. Our patient illustrated a lethal instance which mimicked a malignancy although it is usually an indolent finding. CONCLUSION: Peliosis hepatis should always be borne in mind as a differential diagnosis of atypical hypervascular hepatic lesion, especially in patients with clinical conditions described in the text.

Adipose-specific lipoprotein lipase deficiency more profoundly affects brown than white fat biology.

Adipose fat storage is thought to require uptake of circulating triglyceride (TG)-derived fatty acids via lipoprotein lipase (LpL). To determine how LpL affects the biology of adipose tissue, we created adipose-specific LpL knock-out (ATLO) mice, and we compared them with whole body LpL knock-out mice rescued with muscle LpL expression (MCK/L0) and wild type (WT) mice. ATLO LpL mRNA and activity were reduced, respectively, 75 and 70% in gonadal adipose tissue (GAT), 90 and 80% in subcutaneous tissue, and 84 and 85% in brown adipose tissue (BAT). ATLO mice had increased plasma TG levels associated with reduced chylomicron TG uptake into BAT and lung. ATLO BAT, but not GAT, had altered TG composition. GAT from MCK/L0 was smaller and contained less polyunsaturated fatty acids in TG, although GAT from ATLO was normal unless LpL was overexpressed in muscle. High fat diet feeding led to less adipose in MCK/L0 mice but TG acyl composition in subcutaneous tissue and BAT reverted to that of WT. Therefore, adipocyte LpL in BAT modulates plasma lipoprotein clearance, and the greater metabolic activity of this depot makes its lipid composition more dependent on LpL-mediated uptake. Loss of adipose LpL reduces fat accumulation only if accompanied by greater LpL activity in muscle. These data support the role of LpL as the "gatekeeper" for tissue lipid distribution.

Macrophage lipoprotein lipase modulates the development of atherosclerosis but not adiposity.

The role of macrophage lipoprotein lipase (LpL) in the development of atherosclerosis and adiposity was examined in macrophage LpL knockout (MLpLKO) mice. MLpLKO mice were generated using cre-loxP gene targeting. Loss of LpL in macrophages did not alter plasma LpL activity or lipoprotein levels. Incubation of apolipoprotein E (ApoE)-deficient ß-VLDL with peritoneal macrophages from ApoE knockout mice lacking macrophage LpL (MLpLKO/ApoEKO) led to less cholesteryl ester formation than that found with ApoEKO macrophages. MLpLKO/ApoEKO macrophages had reduced intracellular triglyceride levels, with decreased CD36 and carnitine palmitoyltransferase-1 mRNA levels compared with ApoEKO macrophages, when incubated with VLDL. Although both MLpLKO/ApoEKO and ApoEKO mice developed comparable hypercholesterolemia in response to feeding with a Western-type diet for 12 weeks, atherosclerosis was less in MLpLKO/ApoEKO mice. Epididymal fat mass and gene expression levels associated with inflammation did not differ between the two groups. In conclusion, macrophage LpL plays an important role in the development of atherosclerosis but not adiposity.

[Distal gastrectomy for initially unresectable gastric cancer with pyloric stenosis following gastrojejunostomy and S-1 plus CDDP chemotherapy].

We report a case of advanced gastric cancer with pyloric stenosis, in which a curative resection was performed following gastrojejunostomy and S-1 based chemotherapy. A 46-year-old female presenting with vomiting was diagnosed with unresectable gastric cancer with pyloric stenosis after a detailed examination. She underwent laparotomy, which revealed a T4 tumor invading the pancreas head and involving the gallbladder. A gastrojejunostomy was performed. After the operation, chemotherapy of S-1(100mg/body, days 1-21)plus cisplatin(85mg/body, day 8)was administered. After 4 courses, the tumor size was markedly reduced upon imaging examinations. Six months after gastrojejunostomy, distal gastrectomy was curatively performed. The pathological findings were type 3, por1, pT4a(SE), pN1, M0, pStage III A. After 5 courses of S-1(100mg/day, days 1-28)as adjuvant chemotherapy, she had a recurrence at a lymph node behind the pancreas head. Despite irinotecan+cisplatin following docetaxel therapy, she had no effective benefits and died from the cancer 17 months after the first operation. The prognosis of unresectable gastric cancer with pyloric stenosis is not promising; however, gastrojejunostomy following S-1-based chemotherapy could lead such patients to curative resection and a longer survival time.

Depot-specific expression of lipolytic genes in human adipose tissues--association among CES1 expression, triglyceride lipase activity and adiposity.

AIM: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity. METHOD: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. RESULTS: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. CONCLUSIONS: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.

The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages.

RATIONALE: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. OBJECTIVE: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. METHODS AND RESULTS: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions. CONCLUSIONS: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.

Expression of the tumor suppressor gene maspin and its significance in intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Maspin is a member of the serpin family of protease inhibitors and is thought to inhibit carcinoma invasion, metastasis, and angiogenesis and induce apoptosis. We examined maspin expression immunohistochemically and assessed its significance in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS: We examined 39 surgically resected specimens of IPMN that included 17 adenomas (IPMAs), 5 borderline tumors (IPMBs), 4 non-invasive carcinomas (non-invasive IPMCs), and 13 invasive carcinomas (invasive IPMCs). Immunostaining was performed according to the EnVision ChemMate method. The degree of maspin expression was scored and assessed according to the percentage and staining intensity of positive cells. RESULTS: Maspin expression was minimal in normal pancreatic duct epithelium, whereas in IPMNs, maspin was expressed in neoplasms of all stages. Maspin expression increased with increasing grade from IPMAs, IPMBs, to non-invasive IPMCs but decreased significantly in invasive IPMCs. No specific association between maspin expression and mucin type was found. Analysis of maspin expression with respect to clinicopathologic factors in cases of invasive IPMC revealed a greater extent of invasion in cases of low maspin expression and significantly fewer apoptotic cells in the tumor. CONCLUSIONS: Maspin was expressed at high levels in IPMNs at various stages from adenoma to invasive carcinoma, and our results suggest that maspin may be involved in the occurrence and progression of IPMN. In addition, our data suggest that the apoptosis-inducing action of maspin suppresses invasion and progression of IPMN.

Immunohistochemical analysis of nestin and c-kit and their significance in pancreatic tumors.

The purpose of the present study was to clarify the difference of expression of two stem cell markers, nestin and c-kit, among various pancreatic epithelial tumors and evaluate their utility. Immunohistochemistry was done for 99 surgically resected pancreatic tumor specimens, including 20 ductal adenocarcinoma (DAC), two undifferentiated carcinomas (UC), 31 intraductal papillary-mucinous neoplasms (IPMN), six mucinous cystic neoplasms (MCN), five serous cystadenomas (SCA), six acinar cell carcinomas, two pancreatoblastoma (PB), eight solid-pseudopapillary neoplasms (SPN), and 19 endocrine neoplasms (EN). Nestin was widely expressed in four SPN, one PB, one SCA, sarcoma areas in two UC, one MCN, and one DAC, and an area of oncocytic component in one IPMN. Some of these SPN, SCA and sarcomatous or oncocytic components in which nestin was expressed, also coexpressed c-kit. Additionally, partial (scattered) expression of c-kit was observed in ductal elements of 16 DAC, eight IPMN, five MCN, and one UC, one SCA, and three EN. The eight c-kit-positive IPMN included four of 23 adenoma-to-border lesions and four of eight non-invasive-to-invasive carcinomas. The three EN were all carcinomas. These indicate that expression of two stem cell markers is different by tumor type, but the utility of judging direction or degree of differentiation and malignant grade on the basis of their expression status is suggested.

[Case of submucosal esophageal carcinoma with multiple liver metastasis showing high serum levels of CEA and CA19-9].

A 57-year-old man was admitted because of abdominal fullness. An abdominal ultrasonographic study disclosed multiple space-occupying lesions (SOL) in the liver. On blood examinationC the serum levels of CEA and CA19-9 were significantly high while those of AFP and SCC were within normal ranges. Endoscopically biopsied specimens of the lower esophagus histologically revealed poorly differentiated squamous cell carcinoma. Pathohistologically similar findings were obtained from the needle biopsied specimen of the SOL in the liver. Thus the patient was diagnosed as having squamous cell carcinoma of the esophagus with liver metastasis. On the 41st hospital day the patient died and an autopsy was performed. Although multiple metastases were recognized, cancer cells were limited within the submucosa of the esophagus. Immunostaining of CEA and CA19-9 was positive on the carcinoma cells both in the esophagus and the liver. Thus a relation between the biological malignancy of esophageal cancer and serum levels of CEA and CA19-9 was suggested.