Clinical efficacy of combination therapy with ME3738 and pegylated interferon-alpha-2a in patients with hepatitis C virus genotype 1.

AIM: ME3738, a derivative of soyasapogenol B, enhances the anti-hepatitis C virus (HCV) effect of interferon in an in vitro replication system and an in vivo mouse model of HCV infection. ME3738 plus pegylated interferon (PEG IFN)-α-2a treatment for 12 weeks decreased HCV RNA levels in enrolled late virus responder (LVR) patients with relapsed HCV. Half of the patients reached undetectable HCV RNA level. The present clinical study of ME3738 was conducted in naïve chronic hepatitis C patients to investigate the sustained virological response (SVR) and safety of 48-week treatment with ME3738 plus PEG IFN-α-2a. METHODS: Subjects (n = 135) with genotype 1b chronic hepatitis C with high viral loads were divided into three groups (ME3738 50 mg b.i.d., 200 mg b.i.d. or 800 mg b.i.d.). ME3738 was administrated p.o. and PEG IFN-α-2a (180 µg/week) s.c. for 48 weeks, and SVR was assessed at 24 weeks of treatment-free follow up. RESULTS: The viral disappearance rates at 12 and 48 weeks were 23.0% and 48.9%, respectively. SVR was seen in 5.9% of subjects. ME3738 did not worsen the adverse reactions generally seen with PEG IFN-α-2a treatment, and any adverse reactions specific to ME3738 were not observed. CONCLUSION: ME3738 plus PEG IFN-α-2a treatment to naïve chronic hepatitis C patients showed an antiviral effect and a good safety profile up to 48 weeks. However, HCV RNA was again detected in many subjects after treatment termination. Even though ME3738 is not enough to suppress HCV reproduction in this treatment. ME3738 was concurrently used with PEG IFN-α-2a treatment; however, a clear additional effect on SVR was not confirmed.

Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: Summary of the annual nationwide survey between 2004 and 2009.

AIM: To summarize the annual nationwide survey on fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) between 2004 and 2009 in Japan. METHODS: The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals. RESULTS: Four hundred and sixty (n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus (HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation (LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF. CONCLUSION: The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved.

A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.

BACKGROUND: The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. AIMS: To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. METHODS: C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. RESULTS: Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-ß1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. CONCLUSIONS: Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.

Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease.

BACKGROUND: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is incompletely understood. Kupffer cells (KCs), phagocytic liver-resident macrophages, provide a protective barrier against egress of endotoxin from the portal to the systemic circulation. It is not known if KC phagocytic function is impaired in NAFLD. Super-paramagnetic iron oxide (SPIO) magnetic resonance imaging is a comparative technology dependent on KC phagocytic function. OBJECTIVE: To evaluate KC uptake function, in patients and experimental animals with NAFLD, using SPIO. METHODS: Abdominal CT and histological examination of liver biopsy specimens were used to estimate the degree of steatosis in patients with NAFLD and controls with chronic hepatitis C. SPIO-MRI was then performed in all patients. Normal rats fed a methionine-choline-deficient diet to induce non-alcoholic steatohepatitis (NASH), the more severe stage of NAFLD, and obese, insulin resistant, Zucker fa/fa rats with steatohepatitis, were also studied with SPIO-MRI and analysed for hepatic uptake of fluorescent microbeads. Immunohistochemical analysis evaluated the numbers of KCs in patients and rat livers. RESULTS: Relative signal enhancement (RSE), inversely proportional to KC function, was higher in patients with NAFLD than in controls and with the degree of steatosis on CT. RSE also positively correlated with the degree of steatosis on histology and was similarly higher in rats with induced severe NAFLD (NASH). On immunohistochemistry, defective phagocytic function was the result of reduced phagocytic uptake and not due to reduced KC numbers in rats or patients with NAFLD. CONCLUSIONS: KC uptake function is significantly impaired in patients with NAFLD and experimental animals with NASH, worsens with the degree of steatosis and is not due to a reduction of KC numbers.

A comparison of magnifying chromoendoscopy versus histopathology of forceps biopsy specimen in the diagnosis of minute flat adenoma of the colon.

Having noted a discrepancy between endoscopic and histopathological diagnoses in cases of minute adenomas of the colon, a prospective study was designed to clarify which is appropriate, magnifying chromoendoscopy or histopathology of a specimen obtained by biopsy forceps. A total of 208 patients comprised the study population. The endoscopic diagnoses were performed with magnifying colonoscopies. We separated the detected lesions with type III(L) pit pattern following Kudo's classification into two groups at random: in group A (n = 104) resected specimens were fixed with 20% buffered formalin without being flattened, whereas in group B (n = 104) the resected specimens were flattened using forceps before fixation and the specimens were cut under observation of their surface structure with stereomicroscopy. Comparison of the initial diagnoses between groups A and B showed that a total of 84.6% (88/104) of the lesions were diagnosed to be tubular adenomas histopathologically in group A, compared with 100% (104/104) in group B (P < 0.0001). Results for comparison of the secondary diagnoses between group A and group B showed that 14 of the 16 lesions were diagnosed as tubular adenomas histopathologically. Thereafter, 98.1% (102/104) of the lesions were diagnosed to be tubular adenomas histopathologically in group A (P = 0.4976). In conclusion, high-resolution magnifying chromoendoscopy is an appropriate procedure for the diagnosis of minute adenomas in comparison with histopathology of specimens obtained by biopsy forceps in this prospective study.

Carbonic anhydrase inhibitors. Cloning, characterization and inhibition studies of the cytosolic isozyme III with anions.

The cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozyme III (hCA III) has been cloned and purified by the GST-fusion protein method. Recombinant pure hCA III had the following kinetic parameters for the CO(2) hydration reaction at 20 degrees C and pH 7.5: k(cat) of 1.3 x 10(4) s(- 1) and k(cat)/K(M) of 2.5.10(5) M(- 1) s(- 1). The first detailed inhibition study of this enzyme with anions is reported. Inhibition data of the cytosolic isozymes hCA I - hCA III with a large number of anions (halides, pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrosulfide, sulfate, sulfamic acid, sulfamide, etc.), were determined and these values are comparatively discussed for these three cytosolic isoforms. Fluoride, nitrate, nitrite, phenylboronic acid and phenylarsonic acid (as anions) were weak hCA III inhibitors (K(I)s of 21-78.5 mM), whereas bicarbonate, chloride, bromide, sulfate and several other simple anions showed K(I)s around 1 mM. The best hCA III inhibitors were carbonate, cyanide, thiocyanate, azide and hydrogensulfide, which showed K(I)s in the range of 10-90 microM. It is difficult to explain the inhibitory activity of carbonate (K(I) of 10 microM) against hCA III, also considering the fact that this ion has an affinity of 15-73 mM for hCA I and II and is in equilibrium with one of the substrates of this enzyme, i.e., bicarbonate, which is a much weaker inhibitor (K(I) of 0.74 mM against hCA III, of 12 mM against hCA I and of 85 mM against hCA II).

Evaluation of the depth score of type V pit patterns in crypt orifices of colorectal neoplastic lesions.

BACKGROUND: We developed and evaluated the clinical usefulness of a scoring system that subclassified type VI: pit patterns. METHODS: We studied 119 colon cancer lesions (pTis, n = 26; pT1, n = 93) and 22 tubular adenoma lesions with severe atypia in which a type VI: pit pattern was visible under a stereomicroscope. Four type VI: pit pattern formation appearances (existing pits, marginal irregularities of the gland duct, narrowing of the gland duct lumen, and unclear outline of the gland duct) were defined, and the relationship between each appearance and the invasive depth of the cancer was evaluated. RESULTS: When the four type VI: pit pattern appearances were considered in a logistic regression analysis, the odds of a more invasive submucosal cancer were significantly increased by the appearance of marginal irregularities, a narrowed lumen, and an unclear outline. In the logistic regression analysis results, when 0.63 was used as the cutoff score for prediction of a more invasive submucosal cancer, 80 cases in the less invasive group were classified correctly (specificity, 1.0), whereas 53 (86.9%) of the 61 cases in the more invasive group were classified correctly (sensitivity, 0.869). CONCLUSIONS: It is important first to understand the usability and limitations of objective scoring of type V pit pattern findings and then to apply this score to the determination of cancer depth in order to accurately identify lesions suitable for endoscopic treatment.

Morphogenesis of a colorectal neoplasm with a type IIIS pit pattern inferred from isolated crypts.

BACKGROUND: The goal of this study was to clarify morphogenetic development in colorectal neoplasms with depressions by examining isolated crypts and their pit patterns. METHODS: Twelve colorectal neoplasms with depressions were examined endoscopically, stereomicroscopically, and histopathologically. The pit pattern was defined according to Kudo's classification. The HCl digestion method was used to isolate the crypts. For scanning electron microscopy observations of the surface structure, specimens were mounted on brass stubs, coated with gold, and then observed. RESULTS: In isolated crypts with bifurcation extending to the middle or all the way to the lesion surface, the crypt orifice was round with a type IIIS pit pattern. In those with bifurcations extending up to the upper portion, the crypt orifice was oval with a type IIIS pit pattern. Some crypts were almost completely separated into two. The orifice diameter of a nonbifurcated crypt was 95.1 +/- 28.1 microm, whereas the diameters of crypts with bifurcations extending to the middle or the upper part were 114.7 +/- 40.8 and 208.1 +/- 71.4 microm, respectively. Thus, the orifice diameter of a crypt with the bifurcation reaching the upper part was about twice that of orifices of nonbifurcated crypts or those with bifurcations extending to the middle. CONCLUSIONS: Our results indicate that colorectal neoplasms with depressions may enlarge by a process of crypt bifurcation in which a single crypt divides into two crypts.

Cloning, polymorphism, and inhibition of beta-carbonic anhydrase of Helicobacter pylori.

BACKGROUND: Carbonic anhydrase (CA) catalyzes the reversible hydration of CO(2) to bicarbonate and a proton, and alpha-class CA has been reported to facilitate the acid acclimation of Helicobacter pylori (hpalphaCA). The purpose of this study was to characterize the beta-class CA of H. pylori (hpbetaCA) and elucidate the role of this enzyme as a possible drug target for eradication therapy. METHODS: We isolated DNA clones of independent H. pylori strains obtained from patients with gastritis (n = 15), gastric ulcer (n = 6), or gastric cancer (n = 16), and then studied genetic polymorphisms. In addition, the susceptibility of H. pylori to sulpiride, an antiulcer drug and efficient inhibitor of both hpalphaCA and hpbetaCA, was studied with an in vitro killing assay. RESULTS: DNA sequences of all 37 hpbetaCA clones encoded a 221 amino acid polypeptide with a variety of polymorphisms (57 types of amino acid substitution at 48 residue positions). There was no polymorphism functionally relevant to the gastric lesion type. One strain included unique residues that were not seen in the other 36 clones from Japanese patients but which were found in a strain obtained from the United Kingdom. Sulpiride had killing effects at concentrations greater than 200 microg/ml for H. pylori, including strains resistant to clarithromycin, metronidazole, or ampicillin. CONCLUSIONS: Helicobacter pylori might have evolved independently in the Caucasian and Japanese populations. Dual inhibition of alpha-and beta-class CAs could be applied as alternative therapy for eradication of H. pylori.

Long-term effects of multimodal treatment for patients with resectable carcinoma of the pancreas.

The treatment of pancreatic carcinoma remains one of the most formidable challenges in oncology. Curative resection, currently the only available treatment option, provides no significant impact on long-term survival. The recent development of multimodal treatment options for pancreatic cancer has provided clinical benefits and improved patient survival. In this study, we retrospectively evaluated our experiences with multimodal therapy, including radiotherapy and chemotherapy with gemcitabine, for the treatment of resectable pancreatic cancer. Fifty-eight patients with ordinary pancreatic carcinoma who underwent surgical resection at Kochi Medical School were studied. The clinical and pathological factors and multimodal treatment for pancreatic carcinoma that influenced patient survival were analyzed. Cumulative 1-, 3- and 5-year survival rates after surgery for ordinary pancreatic carcinoma were 62.2, 20.3 and 20.3%, respectively. The overall 4-year survival rate of patients subjected to adjuvant chemotherapy with gemcitabine after curative resection for ordinary pancreatic carcinoma is 39.1%. Adjuvant chemotherapy with gemcitabine provided a significantly better prognosis for patients following curative surgical resection than curative surgical resection alone (P=0.035). Although the rate of survival was greater for patients who underwent radiotherapy than those who did not, the difference was not statistically significant (P=0.054). Postoperative local recurrence around the nerve plexus of celiac and superior mesenteric arteries was better controlled in patients who underwent radiotherapy than those who did not. Adjuvant chemotherapy with gemcitabine after curative resection provides a significant survival benefit for patients with pancreatic carcinoma. Our results suggest that the postoperative recurrence of ordinary pancreatic carcinoma will be reduced by multimodal treatment using radiotherapy and adjuvant chemotherapy with gemcitabine.

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study.

AIM: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. METHODS: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). RESULTS: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. CONCLUSION: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.

Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma.

BACKGROUND AND AIMS: Most patients with hepatocellular carcinoma (HCC) have underlying liver cirrhosis that is frequently associated with a state of protein energy malnutrition. The aim of this study was to evaluate the clinical benefit of perioperative supplementation of a branched-chain amino acid-enriched nutrient-mixture for patients undergoing liver resection for HCC. METHODS: A total of 112 patients with HCC who underwent hepatic resection were enrolled in this study. These patients were divided into two groups: 40 patients received perioperative supplementation of branched-chain amino acid-enriched nutrient-mixture (AEN group) and 72 patients did not (control group). Laboratory data, postoperative complications, duration of hospitalization, and survival were assessed for each group and compared. RESULTS: The overall incidence of postoperative complications was lower in the AEN group (17.5%) than in the control group (44.4%) (P = 0.01). Among the postoperative complications, surgical site infection and bile leakage was observed in 5% of patients in the AEN group and in 15.3% and 12.5% of patients in the control group, respectively. Ascites appeared after the surgery in 7.5% of patients in the AEN group and in 16.7% of patients in the control group. The duration of hospitalization was significantly shorter in the AEN group was than in the control group (P < 0.05). CONCLUSIONS: This study strongly suggests that perioperative supplementation of a branched-chain amino acid-enriched nutrient-mixture is clinically beneficial in reducing the morbidity associated with postoperative complications and in shortening the duration of hospitalization of patients with chronic liver disease who undergo liver resection for HCC.

Pancreatic transection using a sharp hook-shaped ultrasonically activated scalpel.

BACKGROUND AND AIMS: The operative mortality and morbidity associated with pancreatic surgery has been decreasing; however, pancreatic fistula remains a major cause of a potentially fatal complication. Although different devices and techniques have been proposed to reduce of the postoperative pancreatic fistula, none has gained unanimous acceptance. We herein describe a new technique for pancreatic transection using a sharp hook-shaped ultrasonically activated scalpel (UAS). MATERIALS AND METHODS: Between December 2004 and June 2006, 32 patients who had undergone pancreatectomies performed using the sharp hook-shaped UAS (Ethicon Endo-Surgery, Cincinnati, OH, USA) were studied. RESULTS: The incidence of pancreatic fistula in these patients was 6.3% (2/32). Both cases underwent a distal pancreatectomy. No patient had systemic organ failure induced by postoperative pancreatic fistula, and conservative drainage management improved the pancreatic fistula. No pancreatic fistulas developed in patients who underwent pancreaticoduodenectomy with a duct-to-mucosa anastomosis pancreaticojejunostomy after pancreatic transection using the sharp hook-shaped UAS. CONCLUSION: Pancreatic transection using the sharp hook-shaped UAS is an easy and useful method that facilitates detection of the main pancreatic duct with minimal blood loss. It may contribute to lower morbidity and mortality after pancreatic resection.

A long-survived case with solitary splenic metastasis from ovarian carcinoma.

A61-year-old postmenopausal woman with ovarian carcinoma was treated with two surgical operations and a series of platinum-based chemotherapy. A solitary metastasis into the splenic parenchyma was identified 33 months after the second surgery by abdominal computed tomography with an increased serum level of CA-125. She underwent a pancreaticosplenectomy and received platinum-based adjuvant chemotherapy continuously for 2 years. Her serum CA-125 level decreased to a normal range and she has lived without any recurrence for more than 10 years after the splenectomy. Solitary metastases from ovarian cancer into the splenic parenchyma are extremely rare. Among 18 cases previously reported, this present case shows the longest disease-free survival. Because these cases show favorable prognosis after splenectomy, surgical treatment should be considered along with adjuvant chemotherapy.

Carbonic anhydrase inhibitors. DNA cloning, characterization, and inhibition studies of the human secretory isoform VI, a new target for sulfonamide and sulfamate inhibitors.

The secretory isozyme of human carbonic anhydrase (hCA, EC 4.2.1.1), hCA VI, has been cloned, expressed, and purified in a bacterial expression system. The kinetic parameters for the CO2 hydration reaction proved hCA VI to possess a kcat of 3.4 x 10(5) s-1 and kcat/KM of 4.9 x 10(7) M-1 s-1 (at pH 7.5 and 20 degrees C). hCA VI has a significant catalytic activity for the physiological reaction on the same order of magnitude as the ubiquitous isoform CA I or the transmembrane, tumor-associated isozyme CA IX. A series of sulfonamides and one sulfamate have been tested for their interaction with this isozyme. Simple benzenesulfonamides were rather ineffective hCA VI inhibitors, with inhibition constants in the range of 1090-6680 nM. Better inhibitors were detected among such derivatives bearing 2- or 4-amino-, 4-aminomethyl-, or 4-hydroxymethyl moieties or among halogenated sulfanilamides (KI values of 608-955 nM). Some clinically used compounds, such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, sulpiride, and indisulam, or the orphan drug benzolamide, showed effective hCA VI inhibitory activity, with inhibition constants of 0.8-79 nM. The best inhibitors were brinzolamide and sulpiride (KI values of 0.8-0.9 nM), the latter compound being also a CA VI-selective inhibitor. The metallic taste reported as a side effect after the treatment with systemic sulfonamides may be due to the inhibition of the salivary CA VI. Some of the compounds investigated in this study might be used as additives in toothpastes for reducing the acidification produced by the relevant CO2 hydrase activity of enamel CA VI, which leads to the formation of protons and bicarbonate and may have a role in cariogenesis.

Fibrate for treatment of primary biliary cirrhosis.

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and gamma-guanosine 5'-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.

Duodenum-preserving pancreatic head resection for pancreatic metastasis from renal cell carcinoma: a case report.

INTRODUCTION: We report a case of duodenum-preserving pancreatic head resection (DPPHR) for the treatment of pancreatic head metastasis from renal cell carcinoma (RCC). CASE REPORT: The patient was a 59-year-old male with a medical history of RCC 18 years ago. Abdominal imaging studies revealed a hypervascular mass localized in the pancreatic head without distant metastasis or tumor invasion into the adjacent organs including the common bile duct and duodenum. Under the preoperative diagnosis of pancreatic metastasis from RCC, the tumor was completely resected by DPPHR. The pathological examination of the resected specimen confirmed the preoperative diagnosis. CONCLUSION: As lymph node metastasis has been rarely reported in previous cases of pancreatic metastasis from RCC, DPPHR should be considered as a less invasive surgical option to provide a favorable postoperative quality of life (QOL).

Pancreatic metastasis from renal cell carcinoma: report of three resected cases and review of Japanese cases.

Metastatic pancreatic tumors from renal cell carcinoma are clinically rare. We report three cases with pancreatic metastasis from renal cell carcinoma that occurred following nephrectomy for this disease. In all cases, dual-phase computed tomography following bolus injection of contrast material showed an identifiable enhancement pattern suggestive of the metastatic lesions from renal cell carcinoma. Pancreatectomy for these patients was performed and the postoperative course was favorable. These patients died 55 months, 79 months, and 134 months after surgery. Surgical resection is the recommended treatment and providing that all lesions can be removed, the patient outcome should be relatively good.

Xanthogranulomatous pancreatic abscess secondary to acute pancreatitis: two case reports.

Xanthogranuloma is a rare type of inflammation and very few cases have been reported in the pancreas. We report two cases with xanthogranulomatous pancreatic abscess that followed acute pancreatitis. In both cases, multiple pseudocysts in the pancreatic tail were infected with several species of bacteria and Candida albicans. In one case, abdominal angiography revealed a hypoperfused pancreatic tail due to prior atherosclerotic obliteration of the celiac and superior mesenteric arteries. In the other case, the splenic artery was completely occluded by a transarterial embolization performed to treat an aneurysm that appeared in the course of pancreatitis. In both cases, distal pancreatectomy was performed as inflammation of the pancreatic tail was resistant to conventional antibiotic therapy, and pathologic examination revealed xanthogranulomatous inflammation around the pancreatic tail and spleen. Although the underlying pathogenesis is unclear, the prolonged infection and/or relative hypoxia induced by hypoperfusion are likely causative factors for the xanthogranulomatous changes in these pancreatic abscesses.

Carbonic anhydrase inhibitors: DNA cloning and inhibition studies of the alpha-carbonic anhydrase from Helicobacter pylori, a new target for developing sulfonamide and sulfamate gastric drugs.

We have cloned and sequenced Helicobacter pylori alpha-class carbonic anhydrase (hpCA) from patients with different gastric mucosal lesions, including gastritis (n=15), ulcer (n=6), and cancer (n=16). Although several polymorphisms were newly identified such as 12Ala, 13Thr, 16Ile, and 168Phe, there was no significant relevance of any polymorphism with gastric mucosal lesion types. A library of sulfonamides/sulfamates has been investigated for the inhibition of hpCA, whereas new derivatives have been obtained by attaching 4-tert-butyl-phenylcarboxamido/sulfonamido tails to benzenesulfonamide/1,3,4-thiadiazole-2-sulfonamide scaffolds. All types of activity for inhibition of hpCA have been detected. Dorzolamide and simple 4-substituted benzenesulfonamides were weak inhibitors (KI 873-4360 nM). Sulfanilamide, orthanilamide, some of their derivatives, and indisulam showed better activity (KI 413-640 nM), whereas most of the clinically used inhibitors, such as methazolamide, ethoxzolamide, dichlorophenamide, brinzolamide, topiramate, zonisamide, etc., acted as medium-potency inhibitors (KI 105-378 nM). Some potent hpCA inhibitors were detected too (KI 12-84 nM) among acetazolamide, 4-amino-6-chloro-1,3-benzenedisulfonamide and some newly designed compounds incorporating lipophilic tails. Some of the newly prepared derivatives had selectivity ratios for inhibiting hpCA over hCA II in the range of 1.25-3.48, showing thus some selectivity for inhibiting the bacterial enzyme. Since hpCA is essential for the survival of the pathogen in acid, it might be used as a new pharmacologic tool in the management of drug-resistant H. pylori.