[A case of adult-onset type II citrullinemia in an elderly patient].

A 72-year-old man presented with consciousness disturbance. The results of brain magnetic resonance imaging and cerebrospinal fluid examination were normal, but triphasic waves were noted on electroencephalography. His plasma ammonia level was elevated due to which encephalopathy secondary to hyperammonemia was suspected. However, his liver function was normal, and no evidence of cirrhosis or portal-systemic shunt was noted. The patient's medical history revealed that he had a tendency to excessively consume pulse products since childhood, and an amino acid analysis showed elevation of citrulline and arginine levels. Thus, we diagnosed the patient with an extremely rare case of adult-onset type II citrullinemia, which was triggered by cessation of the intake of pulse foods (soybeans and peanuts) due to dental problems.

Leptomeningeal carcinomatosis associated with gastric cancer.

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is a rare but devastating complication of gastric cancer. METHODS: The subjects were 12 gastric cancer patients who were diagnosed as having LMC at the Shizuoka Cancer Center between October 2002 and March 2009. We conducted a retrospective survey of the medical records of the study subjects and collected data on the clinical features, treatment modalities employed/outcomes, and survival of the patients. RESULTS: Of the 12 patients, 9 (75%) were male, and the median age was 63 years. Histopathologically, the majority of the patients (83%) had diffuse-type adenocarcinoma. At the time of diagnosis of the LMC, the other major sites of metastasis were the peritoneum (75%) and lymph nodes (50%). The median duration from the diagnosis of gastric cancer to the diagnosis of LMC was 15.6 months. While the treatment strategy changed with time, intrathecal chemotherapy (n = 10), followed by whole brain irradiation (n = 7) and subsequent ventriculo-peritoneal shunt (n = 3) was performed in 10 of the patients. Improvement of neurological functions was observed in 6 of the 10 patients. The median overall survival time from the diagnosis of LMC in all the 12 patients was 60 days. One patient survived for a considerably long period of 532 days. CONCLUSIONS: Multidisciplinary treatment, including ventriculo-peritoneal shunt for LMC secondary to gastric cancer, may benefit selected patients, but further accumulation of clinical cases is necessary.

Risk factors and clinical courses of chemoradiation-related arterio-esophageal fistula in esophageal cancer patients with clinical invasion of the aorta.

BACKGROUND: Although concurrent chemoradiotherapy (CRT) is a standard treatment for esophageal cancer invading adjacent structures (T4-EC), arterio-esophageal fistula (AEF) occurs occasionally as a critical adverse event of T4-EC with CRT. The frequency, clinical course, and risk factors of AEF related to CRT are not well known. METHODS: We retrospectively analyzed 48 patients with T4-EC invasion of the aorta who were treated with 5-fluorouracil, cisplatin, and concurrent radiotherapy at our institution between September 2002 and April 2009. Treatment-related AEF was defined as AEF without obvious tumor progression. We evaluated the frequency, clinical courses, and risk factors of AEF. RESULTS: The median survival time was 10.6 months with a median follow-up time of 33.3 months. The 2-year survival rate was 25%. Treatment-related AEF was observed in 7 patients (14.6%) and 4 of them died of massive bleeding due to aortic AEF. In the other 3 patients with non-aortic AEF, hemorrhage could be arrested by transcatheter arterial embolization (TAE). In the univariate analysis of risk factors for AEF, lower serum cholesterol level was a risk factor for AEF (OR 14.7; 95% CI 1.58-137; P = 0.008). CONCLUSIONS: Although CRT has a curative potential even for patients with T4-EC invading the aorta, we should be aware of the relatively high incidence of treatment-related AEF. TAE may be successful in rescuing a non-aortic AEF patient. Low serum cholesterol level may be a risk factor for AEF, but further investigation is needed.

S-1 monotherapy as second-line treatment for advanced pancreatic cancer after gemcitabine failure.

OBJECTIVE: No standard salvage chemotherapy regimen has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a Phase II study of S-1 monotherapy was conducted in patients with gemcitabine-refractory advanced pancreatic cancer, the number of patients enrolled was small. METHODS: We retrospectively reviewed 84 consecutive patients who received S-1 monotherapy as a second-line treatment after gemcitabine failure at the Shizuoka Cancer Center between May 2004 and April 2008. The selection criteria in this study were age 20-75 years, ECOG performance status

Comparison of combination chemotherapy with irinotecan and cisplatin regimen administered every 2 or 4 weeks in pretreated patients with unresectable or recurrent gastric cancer: retrospective analysis.

BACKGROUND: Efficacy and safety of irinotecan and cisplatin administration every 2 weeks (biweekly regimen) or 4 weeks (4-weekly regimen) in patients with pretreated unresectable or recurrent gastric cancer was retrospectively evaluated. METHODS: Study patients comprised two cohorts: cohort 1, consisting of 31 patients received chemotherapy on a 4-weekly regimen; and cohort 2, consisting of 32 patients received chemotherapy on a biweekly regimen. In cohort 1, patients received irinotecan (70 mg/m(2)) on days 1 and 15 and cisplatin (80 mg/m(2)) on day 1 every 4 weeks; in cohort 2, patients received irinotecan (60 mg/m(2)) on day 1 and cisplatin (30 mg/m(2)) on day 1 every 2 weeks. RESULTS: Response rates were for cohorts 1 and 2 were 26% (7/27) and 28% (7/25) in patients with measurable lesions, median progression-free survivals were 3.5 and 4.3 months, and median survival times after irinotecan and cisplatin initiation were 9.5 and 10.1 months, respectively. The incidence of grades 3 and 4 hematological toxicities in cohorts 1 and 2 were 74% and 44% for leukopenia, 81% and 53% for neutropenia, and 45% and 28% for anemia, respectively. Incidences of grades 3 and 4 nonhematological toxicities were 23% and 12% for nausea, 23% and 9% for vomiting, 19% and 12% for anorexia, and 6% and 6% for febrile neutropenia, respectively. CONCLUSION: Irinotecan plus cisplatin chemotherapy administered on a biweekly regimen was comparable in efficacy to a 4-weekly regimen and might be more feasible than the 4-weekly regimen.

[A case of autoimmune pancreatitis accompanied with Mikulicz's disease].

A 73-year-old woman was referred to our hospital complainting of swelling of both eyelids and submandibular glands, nausea, and weight loss. She was given a diagnosis of autoimmune pancreatitis because of a marked elevation of serum IgG and IgG4 levels and diffuse swelling of the pancreas with stenosis of the main pancreatic duct. Biopsy obtained from the lachrymal gland revealed aggregated IgG4-positive plasma cells, leading to the diagnosis of Mikulicz's disease. PET-CT revealed an accumulation of FDG in the pancreas, lachrymal glands and submandibular glands, and lymph nodes in the mediastinum, hepatic hilium, bile duct and retroperitoneum. Three months after the initiation of steroid therapy, the serum levels of IgG and IgG4 decreased and FDG accumulations of the systemic lesions were no longer visible on PET.

Inhibition of glycogen synthase kinase 3beta during heart failure is protective.

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3beta in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3beta (Tg-GSK-3beta-DN) and tetracycline-regulatable wild-type GSK-3beta. GSK-3beta-DN significantly reduced the kinase activity of endogenous GSK-3beta, inhibited phosphorylation of eukaryotic translation initiation factor 2B epsilon, and induced accumulation of beta-catenin and myeloid cell leukemia-1, confirming that GSK-3beta-DN acts as a dominant negative in vivo. Tg-GSK-3beta-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the alpha-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater Emax after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3beta induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3beta-DN and nontransgenic mice, Tg-GSK-3beta-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3beta transgene in tetracycline-regulatable wild-type GSK-3beta mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3beta-DN in cardiac myocytes inhibited tumor necrosis factor-alpha-induced apoptosis, and the antiapoptotic effect of GSK-3beta-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3beta induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3beta inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3beta during heart failure could be compensatory.

Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin.

BACKGROUND: Although triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice. METHODS: In 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m(2)) was administered weekly, three times, for 3 weeks out of 4. RESULTS: The median number of courses was 3 (range, 1-38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia. CONCLUSION: Weekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting.

Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy.

Glycogen synthase kinase 3beta (GSK-3beta) negatively regulates cardiac hypertrophy. A potential target mediating the antihypertrophic effect of GSK-3beta is eukaryotic translation initiation factor 2Bepsilon (eIF2Bepsilon). Overexpression of GSK-3beta increased the cellular kinase activity toward GST-eIF2Bepsilon in neonatal rat cardiac myocytes, whereas LiCl (10 mmol/L) or isoproterenol (ISO) (10 micromol/L), a treatment known to inhibit GSK-3beta, decreased it. Immunoblot analyses using anti-S535 phosphospecific eIF2Bepsilon antibody showed that S535 phosphorylation of endogenous eIF2Bepsilon was decreased by LiCl or ISO, suggesting that GSK-3beta is the predominant kinase regulating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes. Decreases in eIF2Bepsilon-S535 phosphorylation were also observed in a rat model of cardiac hypertrophy in vivo. Overexpression of wild-type eIF2Bepsilon alone moderately increased cell size (+31+/-11%; P<0.05 versus control), whereas treatment of eIF2Bepsilon-transduced myocytes with LiCl (+73+/-22% versus eIF2Bepsilon only; P<0.05) or ISO (+84+/-33% versus eIF2Bepsilon only; P<0.05) enhanced the effect of eIF2Bepsilon. Overexpression of eIF2Bepsilon-S535A, which is not phosphorylated by GSK-3beta, increased cell size (+107+/-35%) as strongly as ISO (+95+/-25%), and abolished antihypertrophic effects of GSK-3beta, indicating that S535 phosphorylation of eIF2Bepsilon critically mediates antihypertrophic effects of GSK-3beta. Furthermore, expression of eIF2Bepsilon-F259L, a dominant-negative mutant, inhibited ISO-induced hypertrophy, indicating that eIF2Bepsilon is required for beta-adrenergic hypertrophy. Interestingly, expression of eIF2Bepsilon-S535A partially increased cytoskeletal reorganization, whereas it did not increase expression of atrial natriuretic factor gene. These results suggest that GSK-3beta is the predominant kinase mediating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes, which in turn plays an important role in regulating cardiac hypertrophy primarily through protein synthesis.

Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation.

Although stimulation of the beta-adrenergic receptor increases levels of cAMP and activation of the cAMP response element (CRE) in cardiac myocytes, the role of the signaling mechanism regulated by cAMP in hypertrophy and apoptosis is not well understood. In this study we show that protein expression of inducible cAMP early repressor (ICER), an endogenous inhibitor of CRE-mediated transcription, is induced by stimulation of isoproterenol (ISO), a beta-adrenergic agonist with a peak at approximately 12 hours and persisting for more than 24 hours in neonatal rat cardiac myocytes. ICER is also upregulated by phenylephrine but not by endothelin-1. Continuous infusion of ISO also increased ICER in the rat heart in vivo. Overexpression of ICER significantly attenuated ISO- and phenylephrine-induced cardiac hypertrophy but did not inhibit endothelin-1-induced cardiac hypertrophy. Overexpression of ICER also stimulated cardiac myocyte apoptosis. Antisense inhibition of ICER significantly enhanced beta-adrenergic hypertrophy, whereas it significantly inhibited beta-adrenergic cardiac myocyte apoptosis, suggesting that endogenous ICER works as an important regulator of cardiac hypertrophy and apoptosis. Inhibition of CRE-mediated transcription by dominant-negative CRE binding protein inhibited cardiac hypertrophy, whereas it stimulated cardiac myocyte apoptosis, thereby mimicking the effect of ICER. Both ISO and ICER reduced expression of Bcl-2, an antiapoptotic molecule, whereas antisense ICER prevented ISO-induced downregulation of Bcl-2. These results suggest that ICER is upregulated by cardiac hypertrophic stimuli increasing CRE-mediated transcription in cardiac myocytes and acts as a negative regulator of hypertrophy and a positive mediator of apoptosis, in part through both inhibition of CRE-mediated transcription and downregulation of Bcl-2.

Factors influencing trough and 90-minute plasma dabigatran etexilate concentrations among patients with non-valvular atrial fibrillation.

INTRODUCTION: Dabigatran etexilate, a direct oral anti-coagulation agent, is used in the prevention of thromboembolism in patients with non-valvular atrial fibrillation (NVAF). However, for reasons that are not fully understood, plasma dabigatran etexilate concentrations (PDC) vary significantly among patients. METHODS: We measured trough and 90min PDC in 98 patients with NVAF. To elucidate the cause of variations in PDC, we determined correlations between PDC and various factors including renal function, co-administration of a P-glycoprotein inhibitor, and the effects of three single nucleotide polymorphisms (SNPs) of the P-glycoprotein intestinal efflux transporter. To further determine the cause of PDC variations, we examined the relationship between PDC, activated partial prothrombin time (APTT), and D-dimer (DD) levels, which are surrogate markers for thrombotic risk. RESULTS: Multivariate analysis showed significant relations among creatinine, creatinine clearance, and CHA2D2-VaSc scores (p=0.04, p=0.01, and p=0.04, respectively). In addition, creatinine and creatinine clearance were significantly correlated with trough and 90min PDC (p<0.01), respectively. There was a clear linear relation between PDC and APTT, but not DD levels. However, higher DD levels (>0.5µg/mL) were associated with lower trough and 90min PDCs. CONCLUSIONS: Renal function and CHA2D2-VaSc scores affect PDC, suggesting these may be primary factors influencing the wide variation observed in PDCs under these conditions. Variations in APTT can primarily be explained by variations in PDC; patients with lower PDCs may have a higher risk of thromboembolism events.

Increased proliferation of endothelial cells with overexpression of soluble TNF-alpha receptor I gene.

Vascular endothelial growth factor (VEGF) can overcome a potential anti-angiogenic effect of TNF-alpha by inhibiting endothelial apoptosis induced by this cytokine. Soluble TNF-alpha receptor I (sTNFRI) is an extracellular domain of TNFRI and antagonizes the activity of TNF-alpha. Here we report that sTNFRI is able to stimulate the growth of endothelial cells not by antagonizing TNF-alpha. Exogenously added recombinant human sTNFRI stimulated significantly more cell growth of human umbilical venous endothelial cells (HUVEC) with a low dose (50-200 pg/ml) compared with smooth muscle cells. In contrast, monoclonal antibody against TNF-alpha did not stimulate growth of human HUVEC. The sTNFRI expression plasmid (pcDNA3.1 plasmid) was introduced into the cell culture using OPTI-MEM, lipofectin and transferrin. Growth of HUVEC transfected with sTNFRI vector also increased significantly compared with those transfected with control vector. HUVEC transfected with sTNFRI vector increased the extracellular domain of TNFRI mRNA levels, but did not affect the intracellular domain of TNFRI mRNA levels. Accumulation of sTNFRI significantly increased in conditioned medium from HUVEC transfected with sTNFRI vector compared with those transfected with control vector. HUVEC transfected with sTNFRI vector not only increased sTNFRI but also prevented shedding of sTNFRI from TNFRI. The TNF-alpha -induced internucleosomic fragmentation was also significantly prevented in HUVEC transfected with sTNFRI vector compared with those transfected with control vector. These results suggest that instead of growth factors such as VEGF, local transfection of the sTNFRI gene may have potential therapeutic value in vascular diseases in which TNF-alpha is also usually highly expressed.

Patient factors against stable control of warfarin therapy for Japanese non-valvular atrial fibrillation patients.

INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (<70 and ≥ 70 years; 49.6 ± 24.8% and 77.8 ± 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those ≥ 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 ± 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS: When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control.

Autoimmune pancreatitis without a response to steroid therapy: a case which met criteria after withdrawal of steroid.

Autoimmune pancreatitis (AIP) sometimes forms a pancreatic mass lesion, which is often difficult to distinguish from pancreatobiliary malignancy, however it generally responds to steroid therapy. A 70-year-old man was referred to our institute with the suspected diagnosis of pancreatic cancer due to a mass lesion detected at the pancreatic head. Various images demonstrated an ill-defined mass at the enlarged pancreatic head with focal narrowing of the main pancreatic duct. Serum antinuclear antibody (ANA) was negative (x40 dilution) on the onset. Forceps biopsy from the narrowed pancreaticobiliary duct and fine-needle aspiration biopsy under endoscopic ultrasonography (EUS-FNAB) ruled out pancreatobiliary malignancy. Steroid therapy was started at 40 mg per day but was not effective according to subsequent image analyses. Repeated EUS-FNA from the pancreatic mass was performed but was again negative for carcinoma. Seven months later, under steroid-off condition, still no response was recognized in the clinical image but the titer of serum ANA was increased to be positive (x80), satisfying the criteria of AIP in Japan (2006). Although very rare, this is a case meeting Japanese criteria of AIP after withdrawal of steroid without response to steroid in the clinical images, suggesting the necessity of careful follow-up.