Phenotypic and metabolomic characteristics of mouse models of metabolic associated steatohepatitis.

BACKGROUND: Metabolic associated steatohepatitis (MASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced MASH, which is characterized by the high levels of fats, sugars, and cholesterol in diets, are commonly used in research. However, mouse models accurately reflecting the progression of MASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of MASH severity in relation to human MASH. METHODS: We performed a comparative analysis of three mouse models of diet-induced MASH in terms of phenotypic and metabolomic characteristics; MASH was induced using different diets: a high-fat diet; a Western diet; and a high-fat, high-cholesterol diet. Liver cirrhosis was diagnosed using standard clinical approaches (e.g., METAVIR score, hyaluronan level, and collagen deposition level). Mouse serum samples were subjected to nuclear magnetic resonance spectroscopy-based metabolomic profiling followed by bioinformatic analyses. Metabolomic analysis of a retrospective cohort of patients with hepatocellular carcinoma was performed; the corresponding cirrhosis scores were also evaluated. RESULTS: Using clinically relevant quantitative diagnostic methods, the severity of MASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and MASH progression. Notably, the levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) significantly increased with fibrosis progression. During the development of diet-induced MASH in mice, the strongest upregulation of expression was noted for VLDL receptor. Metabolomic analysis of a retrospective cohort of patients with cirrhosis indicated lipoproteins (e.g., VLDL and LDL) as predominant biomarkers of cirrhosis. CONCLUSIONS: Our findings provide insight into the pathophysiology and metabolomics of experimental MASH and its relevance to human MASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for MASH development that may be targeted for the development of noninvasive diagnosis.

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether.

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/ß-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/ß-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Epigenetic regulation of human WIF1 and DNA methylation situation of WIF1 and GSTM5 in urothelial carcinoma.

WNT inhibitory factor 1 (WIF1) is known to function as a tumor suppressor gene; it inhibits oncogene activation by preventing WNT signaling. This study investigated the epigenetic regulation of WIF1 gene in bladder cancer. We observed a positive relationship between WIF1 mRNA expression and survival probability of bladder cancer patients. The WIF1 gene expression could be enhanced by DNA demethylation drug 5-aza-2'-deoxycytidine (5-aza-dC) and histone deacetylase inhibitor trichostatin A (TSA), suggesting that epigenetic modifications could regulate WIF1 gene expression. Overexpression of WIF1 inhibited cell proliferation and migration in 5637 cells, confirming the tumor suppressor role of WIF1. 5-Aza-dC dose dependently increased WIF1 gene expression while reducing DNA methylation level, suggesting that reversing WIF1 DNA methylation could activate its gene expression. We collected the cancer tissues and urine pellets of bladder cancer patients and only urine pellets from non-bladder cancer volunteers for DNA methylation analysis, but the methylation level of WIF1 gene -184 to +29 did not differ between patients and controls. We also analyzed glutathione S-transferase Mu 5 (GSTM5) gene methylation level because GSTM5 DNA hypermethylation was suggested to be a tumor biomarker in our previous study. It confirmed a higher GSTM5 DNA methylation in bladder cancer patients than in controls. In summary, this study suggests that the 5-aza-dC activated WIF1 gene which showed an anti-cancer effect, while WIF1 promoter -184 to +29 did not provide a suitable methylation assay region in clinical samples. In contrast, GSTM5 promoter -258 to -89 is a useful region for DNA methylation assay because it shows a higher methylation level in bladder cancer patients.

The correlation of epithelial-mesenchymal transition-related gene expression and the clinicopathologic features of colorectal cancer patients in Taiwan.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the world. It has been the most prevalent malignancy in Taiwan for consecutive thirteen years. Despite the diversity of its etiologic and pathophysiologic factors, a biological process named as epithelial-mesenchymal transition (EMT) is indispensable in the progression of epithelial cancer. Our aim is to investigate the correlation between the expression of 8 EMT-related proteins (E-cadherin, ß-catenin, claudin-1, CD44, N-cadherin, fibronectin, vimentin, S100A4) and the clinicopathologic features of CRC in Taiwan, along with the DNA CpG epigenetic status of CD44 gene. In immunohistochemical assessment, decreased expression of E-cadherin is statistically associated with the progression of cancer stage, while decreased expression of claudin-1 as well as increased ß-catenin nuclear translocation and N-cadherin expression is statistically associated with the progression of histopathologic grade. E-cadherin, nuclear ß-catenin and claudin-1 are also associated with other important prognostic factors, including nodal metastasis, tumor deposits, and elevated serum CA 19-9 levels. In addition, the left-sided colon and rectal cancers show increased nuclear translocation of ß-catenin compared to the right-sided colon cancers, while the rectal cancers show increased fibronectin expression compared to the right-sided and left-sided colon cancers. Moreover, vimentin is aberrantly expressed in one case of signet-ring cell carcinoma. The DNA methylation levels of CD44 gene promoter between the tumoral and non-tumorous tissues by NGS comparison showed statistical difference on six CpG sites. However, such difference may not be sufficient because these DNA methylation proportions are too low to inactivate CD44 gene. Our results demonstrate the expression of E-cadherin, claudin-1, and nuclear ß-catenin is closely related to the clinicopathologic prognostic determinants of CRC in Taiwan. The DNA methylation level of CD44 gene and its protein expression, however, show no correlation with the clinicopathologic features in CRC.

Gene expression and DNA methylation regulation of arsenic in mouse bladder tissues and in human urothelial cells.

According to a report of the International Agency for Research on Cancer, arsenic and inorganic arsenic compounds are classified into Group 1 carcinogens with regard to human health. Epidemiological studies indicate that arsenic is one of the main risk factors for the development of bladder cancer. In the present study, arsenic­altered gene expression in mouse bladder tissues and in human urothelial cells was compared. In the mouse model, sodium arsenite­induced mouse urothelial hyperplasia and intracellular inclusions were present. Following DNA array analysis, four genes with differential expression were selected for quantitative real­time PCR assay. The genes were the following: Cystathionine ß­synthase (CBS), adenosine A1 receptor (ADORA1), metastasis­associated lung adenocarcinoma transcript 1 (MALAT1) and Wnt inhibitory factor 1 (Wif1). The results indicated a significant increase in the levels of Cbs and Adora1. The analysis of the DNA CpG methylation levels of the mouse Cbs and Adora1 genes revealed no significant change. In contrast to these observations, the four genes were further analyzed in the human normal urothelial cell line SV­HUC1. The data indicated that WIF1 gene expression was decreased by sodium arsenite, whereas this was not noted for CBS, MALAT1 and ADORA1. Sodium arsenite decreased mRNA and protein expression levels of the WIF1 gene. In addition, the methylation levels of the WIF1 gene were increased. Sodium arsenite inhibited cell proliferation and promoted cell migration as demonstrated in cell functional assays. The gene status was compared in 8 human urothelial cell lines, and WIF1 mRNA expression levels were determined to be higher, whereas DNA CpG methylation levels were lower in SV­HUC1 cells compared with those noted in the other 7 bladder cancer cell lines. In summary, the data indicated that sodium arsenite decreased WIF1 gene expression and promoted cell migration. The increased methylation levels of WIF1 DNA CpG could be a potential biomarker for bladder cancer.

Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis.

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. METHODS: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. RESULTS: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. CONCLUSION: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

Ketamine­induced bladder dysfunction is associated with extracellular matrix accumulation and impairment of calcium signaling in a mouse model.

Due to the rising abuse of ketamine usage in recent years, ketamine­induced urinary tract syndrome has received increasing attention. The present study aimed to investigate the molecular mechanism underlying ketamine­associated cystitis in a mouse model. Female C57BL/6 mice were randomly divided into two groups: One group was treated with ketamine (100 mg/kg/day of ketamine for 20 weeks), whereas, the control group was treated with saline solution. In each group, micturition frequency and urine volume were examined to assess urinary voiding functions. Mouse bladders were extracted and samples were examined for pathological and morphological alterations using hematoxylin and eosin staining, Masson's trichrome staining and scanning electron microscopy. A cDNA microarray was conducted to investigate the differentially expressed genes following treatment with ketamine. The results suggested that bladder hyperactivity increased in the mice treated with ketamine. Furthermore, treatment with ketamine resulted in a smooth apical epithelial surface, subepithelial vascular congestion and lymphoplasmacytic aggregation. Microarray analysis identified a number of genes involved in extracellular matrix accumulation, which is associated with connective tissue fibrosis progression, and in calcium signaling regulation, that was associated with urinary bladder smooth muscle contraction. Collectively, the present results suggested that these differentially expressed genes may serve critical roles in ketamine­induced alterations of micturition patterns and urothelial pathogenesis. Furthermore, the present findings may provide a theoretical basis for the development of effective therapies to treat ketamine­induced urinary tract syndrome.

Brain metastasis from renal urothelial carcinoma successfully treated by metastasectomy.

Upper tract urothelial cancer (UTUC) arises from the urothelial lining of the urinary tract. UTUC spreads in several different ways including direct invasion, lymphatic spread, and hematogeneous metastases. Regional lymph nodes are commonly the initial site of metastasis, followed by the liver, lung, and bone. Brain metastasis is uncommon in patients with urothelial carcinoma. Here, we report an uncommon case of kidney urothelial carcinoma with brain metastasis in a 55-year-old woman presenting with dysarthria with right side limb weakness. The patient recovered well after resection of the brain lesion without any sequelae after 1 year of follow-up.

The interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine on urothelial carcinogenesis in mice.

The bladder is an important organ for the storage of excreted water and metabolites. If metabolites with carcinogenic characteristics are present in urine, the urothelial lining of the bladder could be damaged and genetically altered. In this study, we analyzed the interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) on mouse bladder carcinogenesis. Our previous study found that arsenic affects BBN-altered urothelial enzymatic activity, protein expression, DNA oxidation and global DNA CpG methylation levels. In this study, two mouse models were used. First, after administering a co-treatment of BBN and arsenic for 20 weeks, BBN alone led to a urothelial carcinoma formation of 20%, and arsenic promoted a BBN-induced urothelial carcinoma formation of 10%. The protein expression of GSTM1, GSTO1, NQO1, and p21 did not change by arsenic along with the BBN co-treatment, but the Sp1 expression increased. In the second mouse model, BBN was a pretreatment promoter; arsenic dose-dependently deteriorated BBN-promoted dysplasia by 10% and 40% at 10 ppm and 100 ppm, respectively. Conversely, BBN pretreatment also accelerated arsenic-induced dysplasia by 30%. The urothelial carcinogenic effect reversed after ceasing BBN for a period of 20 weeks. In summary, three conclusions were drawn from this study. The first is the mutual promotion of arsenic and BBN in bladder carcinogenesis. Second, arsenic dosages without bladder carcinogenicity (10 ppm) or with slight carcinogenicity (100 ppm) promote BBN-induced mice bladder cancer progression. Finally, the dysplastic urothelium had reverted to near-normal morphology after ceasing BBN intake for 20 weeks, providing a good suggestion for people who want to quit smoking.

Downregulation of glutathione S-transferase M1 protein in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced mouse bladder carcinogenesis.

Bladder cancer is highly recurrent following specific transurethral resection and intravesical chemotherapy, which has prompted continuing efforts to develop novel therapeutic agents and early-stage diagnostic tools. Specific changes in protein expression can provide a diagnostic marker. In our present study, we investigated changes in protein expression during urothelial carcinogenesis. The carcinogen BBN was used to induce mouse bladder tumor formation. Mouse bladder mucosa proteins were collected and analyzed by 2D electrophoresis from 6 to 20 weeks after commencing continuous BBN treatment. By histological examination, the connective layer of the submucosa showed gradual thickening and the number of submucosal capillaries gradually increased after BBN treatment. At 12-weeks after the start of BBN treatment, the urothelia became moderately dysplastic and tumors arose after 20-weeks of treatment. These induced bladder lesions included carcinoma in situ and connective tissue invasive cancer. In protein 2D analysis, the sequentially downregulated proteins from 6 to 20 weeks included GSTM1, L-lactate dehydrogenase B chain, keratin 8, keratin 18 and major urinary proteins 2 and 11/8. In contrast, the sequentially upregulated proteins identified were GSTO1, keratin 15 and myosin light polypeptide 6. Western blotting confirmed that GSTM1 and NQO-1 were decreased, while GSTO1 and Sp1 were increased, after BBN treatment. In human bladder cancer cells, 5-aza-2'-deoxycytidine increased the GSTM1 mRNA and protein expression. These data suggest that the downregulation of GSTM1 in the urothelia is a biomarker of bladder carcinogenesis and that this may be mediated by DNA CpG methylation.

Brain biopsy-proven intravascular lymphomatosis presenting as rapidly recurrent strokes-two case reports.

PURPOSE: Intravascular lymphomatosis (IVL) is rare and usually goes undiagnosed until the time of autopsy because of its protean neurological manifestations. CASE REPORT: In this report, we describe two women who developed rapidly recurrent strokes within one to two months. In both cases, brain magnetic resonance imaging showed progression of bilateral cerebral infarcts, and histopathology from brain biopsy confirmed the diagnosis of IVL. The first case did not receive chemotherapy and died of septic shock one month after diagnosis. The second case received whole brain radiotherapy followed by rituximab-containing chemotherapy, and experienced partial improvement of neurological deficits. However, she began to deteriorate in consciousness at 8 months and became stuporous at 10 months after the onset of symptoms. CONCLUSION: IVL should be considered as a possible etiology if multiple strokes occur in a short period of time.

Young-aged woman with invasive ductal carcinoma arising in atypical microglandular adenosis: a case report.

Microglandular adenosis (MGA) and atypical microglandular adenosis (AMGA) are extremely rare and unique forms of adenosis of the breast. Both forms of adenosis are strongly associated with carcinoma arising in microglandular adenosis (MGACA) and are recognised as precursor lesions of invasive breast carcinoma. Here we provide a clinical report of a young Taiwanese woman who was diagnosed with MGACA and AMGA by means of echo-guided core biopsy. The subsequent lumpectomy revealed a spectrum of lesions ranging from MGA and AMGA to ductal carcinoma in situ (DCIS) and invasive carcinoma. All of the above lesions have similar immunohistochemical results (expression of S-100 protein, the absence of oestrogen receptors, progesterone receptors and Her2/neu, and the lack of p63 and the smooth muscle myosin-heavy chain) with a rather different Ki-67 labelling proliferation index. This report is of practical interest because the diagnosis of AMGA and MGACA had already been made via needle biopsy.

Quantitative correlation between sonographic textural feature and histopathological components for breast cancer: preliminary results.

In this study, the sonographic texture and the histopathological features of breast cancer were objectively characterized. Textural dissimilarity is demonstrated to correlate well with the corresponding histopathological components. The normalized percentage of both fibrosis area and cellular area has highly linear correlation with the textural feature of dissimilarity. The correlation coefficients are -.880 and .857, respectively. The cancerous region with increased fibrous tissues shows low textural dissimilarity and has a strong tendency of negative correlation, whereas the cancerous region with increased cellularity exhibits high textural dissimilarity and a good positive correlation. These results have not been reported so far, and they can be used to predict cellular and fibrotic portions of breast cancer for biopsy or surgery planning, disease progression monitoring, and therapeutic effect evaluation. The proposed image analysis method may also be extended to similar characterization of cancerous tissue in other applications.

Neurophysiologic changes after preganglionic and postganglionic nerve-root constriction: an experimental study in the rat.

STUDY DESIGN: We investigated changes in spinal somatosensory-evoked potential (SSEP) and nerve action potential (NAP), correlated behavior, and associated pathologic observation in experimental radiculopathy. OBJECTIVES: To create a rat model of sacrococcygeal radiculopathy for determining the validity of SSEP and NAP. SUMMARY OF BACKGROUND DATA: We examined the diagnostic sensitivity and value of electrophysiologic tests for evaluating lumbosacral root disease conflict. An appropriate animal model can help verify the value of these tests. METHODS: Preganglionic lesion group rats were given 2 loose ligatures around the cauda equina at the sacrum, and postganglionic lesion group rats were given 2 loose ligatures on the conjunction of the sacrococcygeal nerve roots and the caudalis nerve after they had received a laminectomy. Control group rats received a sham operation. SSEPs and NAPs were recorded preligature and postligature, and 3 times after surgery. These electrophysiologic observations were compared and correlated with tail-flick reflex and histology. RESULTS: All experimental group rats developed thermal hyperalgesia on day 14, as indicated by a significant reduction in TFL (tail-flick latency), which continued for 3 months. Amplitude decreased significantly and latency increased significantly in all SSEP recordings immediately after the operation; these changes persisted for 3 months. There were no significant differences between the experimental groups, but there were significant differences between the control and experimental groups. NAP amplitude and latency from the caudalis nerves did not change in any group in the first 2 postoperative weeks. From the second postoperative week until the 3-month follow-up, amplitude was significantly decreased and latency prolonged in the postganglionic group but unchanged in the others. CONCLUSIONS: Both SSEP and NAP are useful for evaluating electrophysiologic changes after various radiculopathies. The data also suggest that the conductivity of the peripheral nerve (NAP) was affected by the postganglionic compression of the corresponding nerve root, but not by the preganglionic lesion.

Eosinophilic pleural effusion as the first presentation of angioimmunoblastic T cell lymphoma.

Eosinophilic pleural effusion (EPE), defined as pleural effusion that contains at least 10% eosinophils among the leukocytes, can be a manifestation of a great variety of diseases. However, eosinophilia is a relatively rare finding in malignant pleural effusions, and it has been used as an indicator of good prognosis. In clinical experience, very few cases of malignant lymphomas accompanied by EPE have been reported. In this report, we present an 82-year-old otherwise healthy man with the initial presentation of left EPE. Pleural biopsy could not yield a definite diagnosis initially. Hookworm ova were also found in the stool and parasite associated with EPE was suspected. However, after anti-parasitic agent treatment with mebendazole, the pleural effusion did not improve. Six months later, bilateral neck, axillary and inguinal lymphadenopathy developed, and lymph node biopsy confirmed the diagnosis of angioimmunoblastic T cell lymphoma, with positive CD10 expression. Therefore, we retrospectively carried out CD10 staining of the sample obtained from pleural biopsy and the positive result confirmed that the etiology of EPE was due to malignant T cell lymphoma. The patient refused chemotherapy and he died 1 month later.

Inflammatory pseudotumor of the nasal cavity.

Inflammatory pseudotumor is usually found in the orbits and lungs, but rarely in the sinonasal area. We present a 59-year-old woman with a right nasal mass. This lesion caused nasal bleeding and blockage. Image study showed that the solid mass eroded the bony structure and pushed the nasal septum toward the left side. Wide excision was done via lateral rhinotomy. Although its clinical picture mimicked a malignant tumor, histological examination showed an inflammatory process composed of a mixture of lymphoplasmacytic infiltrate, histiocytic cells, and spindled fibroblastic/myofibroblastic cells. Both culture and pathology identified no microorganism. No evidence of recurrence was found after follow-up for more than 2.5 years. The clinical behavior of inflammatory pseudotumor was confusing and tended to be mistaken as malignancy. Its diagnosis and management could be a great challenge for clinicians.

Quantitatively characterizing the textural features of sonographic images for breast cancer with histopathologic correlation.

OBJECTIVE: In this study, quantitative characterization of sonographic image texture and its correlation with histopathologic findings was developed for facilitating clinical diagnosis. A statistical feature matrix was applied to quantify the texture difference (ie, the dissimilarity) of the sonographic images for malignant and benign breast tumors. METHODS: Thirty-three patients were recruited for this study. Imaging was performed on a commercially available sonographic imaging system in clinical use. The parameters used for image acquisition were kept the same during clinical examination. RESULTS: On the basis of dissimilarity values, 3 phenomena were noted in the relatively large malignancies studied. First, stellate carcinoma showed the least dissimilarity on sonographic images; second, circumscribed carcinoma showed the most dissimilarity; and third, malignant tissue mixed with fibrous and cellular parts (dense lymphocyte infiltration and prominent intraductal tumors) had dissimilarity values in between. Image textures with smaller dissimilarity values (especially for those values <4.4 in our study) are likely to be stellate carcinoma. CONCLUSIONS: From the experimental results, it is shown that the cellular and fibrous content with spatial distribution of breast masses determine the dissimilarity values on sonographic images. The dissimilarity may be used to quantitatively represent the image texture and is well correlated with the histopathologic description.

Application of technetium-99m-labeled human serum albumin scan to assist surgical treatment of protein-losing enteropathy in Cronkhite-Canada syndrome: report of a case.

Cronkhite-Canada syndrome is a rare form of nonhereditary gastrointestinal polyposis associated with ectodermal change and protein-losing enteropathy. Here we report a 63-year-old male presenting with diffuse gastrointestinal polyposis, onychodystrophy, cutaneous pigmentation, alopecia, diarrhea, hypoalbuminemia and lower leg edema. Technetium-99m-labeled human serum albumin scan confirmed the patient to have protein-losing enteropathy, which originated from the transverse and descending colon. Subtotal colectomy was performed. Albumin level and ectodermal change were gradually improved during three years of outpatient clinic follow-up. Based on our finding, Technetium-99m-labeled human serum albumin scintigraphy is helpful to localize the protein-losing origins and surgery is an effective treatment for Cronkhite-Canada syndrome with protein-losing enteropathy.

Allelic loss of 14q32 in the pathogenesis of gastrointestinal and ampullary malignancies: mapping of the target region to a 17 cM interval.

PURPOSE: The genetic basis for gastrointestinal and ampullary carcinomas remains uncertain. This study was performed to pinpoint novel chromosomal region involved in the tumorigenesis of gastrointestinal tract. METHODS: We screened the allelic status on 16 chromosomal arms in a patient with synchronous ampullary carcinoma and gastric cancer, but who had no family history of familial cancer syndrome. The significance of the shared 14q deletion was examined on clinical cohorts of sporadic gastric (n=12) and ampullary (n=10) carcinoma, respectively. Then, high-density allelotype mapping was performed on 14q32 by using 23 microsatellite markers for the synchronous tumors. RESULTS: The synchronous gastric and ampullary carcinomas had no frameshift mutations in the APC, MSH2, MSH3, and MSH6 genes. Among the microsatellite markers screened, only D14S267 showed identical loss in the synchronous tumors. The same allelic loss was also detected in one of ampullary carcinomas (10%) and two of gastric cancers (16.7%). Fine mapping of 14q determined a minimally deleted region between D14S65 and D14S1010 (17 centiMorgans) for the synchronous tumors. CONCLUSIONS: This study illustrates a paradigm using molecular genetic approach in identifying chromosome 14q32 that may harbor a tumor suppressor gene involved in the pathogenesis of a subset of gastrointestinal and ampullary malignancies.

Fibrolamellar hepatocellular carcinoma with a recurrence of classic hepatocellular carcinoma: a case report and review of Oriental cases.

A 72-year-old Chinese male, hepatitis B carrier, received a right hepatic trisegmentectomy in 1997 for fibrolamellar hepatocellular carcinoma. Serum alpha-fetoprotein was in the normal range until two years after the operation, a rapid increase to 241 ng/mL occurred and computed tomography showed a 2-cm-sized recurrent nodule in the caudate lobe. Because computed tomography arterioportography showed additional multifocal nodules in the residual liver, transarterial embolization was performed. Four months after the first transarterial embolization, the caudate tumor grew to 6 cm and serum alpha-fetoprotein increased to 6090 ng/mL. Prior to the second transarterial embolization, this new hepatic lesion received a biopsy and showed a characteristic feature of classic hepatocellular carcinoma, which was different from the previous one. Four months after the second transarterial embolization, computed tomography showed no recurrent tumor and serum alpha-fetoprotein subsequently normalized. Twenty-two months after the first transarterial embolization, a 2.5-cm-sized tumor recurred again at the lateral segment. At this time, serum alpha-fetoprotein (3.6 ng/mL) was not elevated. He received the third transarterial embolization and is still alive. Recurrence of fibrolamellar hepatocellular carcinoma after hepatic resection has been reported to be high, but a case report with a character of muticentric, multifocal, and metachronous recurrences of fibrolamellar and classic type hepatocellular carcinoma is very rare. This is the second case report in the literature.