Impact of SGLT2 inhibitors on old age patients with heart failure and chronic kidney disease.

BACKGROUND: The heart failure (HF) "pandemic" is an ongoing critical issue related to the aging population. Among the new heart failure medications, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to provide clinical benefit in HF patients with chronic kidney disease (CKD). However, the efficacy and safety of SGLT2i in old age patients remains uncertain. METHODS: The OSHO-heart (Optimal Solution after Hospitalization in Onomichi for heart failure) is a prospective study of 213 patients aged ≥ 75 years-old hospitalized for acute decompensated HF with stage 3 to 4 CKD. The composite outcomes of HF rehospitalizations or cardiovascular death and the rate of decline in the estimated glomerular filtration rate (eGFR) were compared between the Loop (n = 76), tolvaptan (TLV) (n = 80) and SGLT2i (n = 57) groups, respectively. RESULTS: During follow-up (17.2 months, median), composite of HF rehospitalization or cardiovascular death events occurred in 30 (39.5%) in Loop, 19 (23.8%) in TLV and 8 (14%) in SGLT2i groups, respectively (Log-rank: P = 0.015). A multivariate analysis demonstrated that the continuation of SGLT2i (hazard ratio, 0.41; 95% CI, 0.19 to 0.78; P = 0.022) and an EF < 30% (hazard ratio, 2.19; 95% CI, 1.22 to 3.92; P = 0.009) were independently associated with the composite outcome. The rate of decline in the eGFR was significantly less in TLV and SGLT2i groups than Loop group (-1.64 vs. -1.28 vs. -5.41 ml/min/1.73 m2 per year, P = 0.007, respectively). CONCLUSIONS: SGLT2i therapy might reduce the combined risk of HF hospitalizations or cardiac death and preserve a worsening renal function in old age patients with HF and CKD.

Efficacy and Safety of Lenvatinib for Patients With Advanced Hepatocellular Carcinoma: A Retrospective, Real-world Study Conducted in Japan.

AIM: We evaluated real-world efficacy and toxicity of lenvatinib in 142 patients with advanced hepatocellular carcinoma (HCC) at six tertiary referral centres. PATIENTS AND METHODS: The patients with advanced HCC treated with lenvatinib were grouped into two categories based on REFLECT criteria for analysis of efficacy and safety. The primary endpoint was progression-free survival (PFS). RESULTS: The objective response rate (ORR) at week 12 of therapy was 41.5%, with a median PFS of 176 days. Child-Pugh score of 5 points, the presence of extrahepatic metastasis and adverse effects grade 2 or higher were considered independent factors associated with both better PFS and ORR. The ORR for patients who fulfilled the REFLECT inclusion criteria was significantly higher than that for those who did not. However, no significant differences in PFS were observed between the two groups. The incidence rate of adverse effects grade 3 or higher was 40.1%, which was similar for the two groups. CONCLUSION: Lenvatinib is safe and effective for patients, whether or not they satisfy REFLECT criteria. The result warrants replication in a larger study.

A surgically treated case of severe upper gastrointestinal hemorrhage with gastritis cystica polyposa.

BACKGROUND: Gastritis cystica polyposa (GCP) is a recently recognized entity histologically characterized by hyperplasia and cystic dilatation of the gastric glands spreading through the submucosal layer. Its symptoms include those affecting the upper gastrointestinal tract, such as upper abdominal pain, nausea, and anorexia, although some patients might be asymptomatic. GCP rarely causes severe hemorrhage. Recently, we encountered a GCP case that exhibited severe hemorrhage. CASE PRESENTATION: A 53 year-old man visited the emergency department complaining of hematemesis. He underwent distal gastrectomy and Billroth II reconstruction for duodenal ulcers 32 years ago. Upper gastrointestinal endoscopy detected bleeding from the reddened mucosa at the anastomosis; thus, tentative endoscopic hemostasis was conducted. Despite medical treatment with transfusion, melena with significant hemodynamic impairment persisted. He was treated again with endoscopic hemostasis and interventional radiology (IVR) but remained unresponsive to these procedures. He eventually underwent partial resection of the anastomosis site with Roux-en-Y reconstruction and finally achieved excellent postoperative recovery. Histopathological examination of the resected specimen suggested a GCP bleeding. CONCLUSIONS: GCP can indeed cause severe hemorrhage. Hemorrhage caused by GCP may not respond to endoscopic hemostasis or IVR; therefore, surgical treatment should be decided without delay.

Diverse Basis of ß-Catenin Activation in Human Hepatocellular Carcinoma: Implications in Biology and Prognosis.

AIM: ß-catenin signaling is a major oncogenic pathway in hepatocellular carcinoma (HCC). Since ß-catenin phosphorylation by glycogen synthase kinase 3ß (GSK3ß) and casein kinase 1ε (CK1ε) results in its degradation, mutations affecting these phosphorylation sites cause ß-catenin stabilization. However, the relevance of missense mutations in non-phosphorylation sites in exon 3 remains unclear. The current study explores significance of such mutations in addition to addressing the clinical and biological implications of ß-catenin activation in human HCC. METHODS: Gene alteration in exon3 of CTNNB1, gene expression of ß-catenin targets such as glutamate synthetase (GS), axin2, lect2 and regucalcin (RGN), and protein expression of ß-catenin were examined in 125 human HCC tissues. RESULTS: Sixteen patients (12.8%) showed conventional missense mutations affecting codons 33, 37, 41, and 45. Fifteen additional patients (12.0%) had other missense mutations in codon 32, 34, and 35. Induction of exon3 mutation caused described ß-catenin target gene upregulation in HCC cell line. Interestingly, conventional and non-phosphorylation site mutations were equally associated with upregulation of ß-catenin target genes. Nuclear localization of ß-catenin was associated with poor overall survival (p = 0.0461). Of these patients with nuclear ß-catenin localization, loss of described ß-catenin target gene upregulation showed significant poorer overall survival than others (p = 0.0001). CONCLUSION: This study suggests that both conventional and other missense mutations in exon 3 of CTNNB1 lead to ß-catenin activation in human HCC. Additionally, the mechanism of nuclear ß-catenin localization without upregulation of described ß-catenin target genes might be of clinical importance depending on distinct mechanism.

The Potential Role of Inflammation Associated with Interaction between Osteopontin and CD44 in a Case of Pulmonary Tumor Thrombotic Microangiopathy Caused by Breast Cancer.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare and fatal cancer-related complication. We herein present a case of PTTM that diagnosed antemortem by lung scintigraphy and pulmonary microvascular cytology. The patient was treated with steroid pulse therapy. Although her symptoms temporarily improved, she died of respiratory failure. An autopsy showed PTTM, and an immunohistochemical analysis revealed the expression of osteopontin and CD44 in macrophages that had migrated into the PTTM lesions. These findings suggest that inflammation associated with the interaction between osteopontin and CD44 may play an important role in PTTM.

Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma.

We sought to identify a secreted biomarker for ß-catenin activation commonly seen in hepatocellular carcinoma (HCC). By examination of our previously published genearray of hepatocyte-specific ß-catenin knockout (KO) livers, we identified secreted factors whose expression may be ß-catenin-dependent. We verified expression and secretion of the leading factor in HCC cells transfected with mutated (Hep3BS33Y)-ß-catenin. Serum levels of biomarker were next investigated in a mouse model of HCC with ß-catenin gene (Ctnnb1) mutations and eventually in HCC patients. Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers. Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT. Mice developing HCC with Ctnnb1 mutations showed significantly higher serum LECT2 levels. However patients with CTNNB1 mutations showed LECT2 levels of 54.28 ± 22.32 ng/mL (Mean ± SD; n = 8) that were insignificantly different from patients with non-neoplastic chronic liver disease (32.8 ± 21.1 ng/mL; n = 15) or healthy volunteers (33.2 ± 7.2 ng/mL; n = 11). Intriguingly, patients without ß-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46). While ß-catenin activation was evident in a subset of non-mutant ß-catenin HCC group with high LECT2 expression, serum LECT2 was unequivocally similar between ß-catenin-active and -normal group. Further analysis showed that LECT2 levels greater than 50 ng/ml diagnosed HCC in patients irrespective of ß-catenin mutations with specificity of 96.1% and positive predictive value of 97.0%. Thus, LECT2 is regulated by ß-catenin in HCC in both mice and men, but serum LECT2 reflects ß-catenin activity only in mice. Serum LECT2 could be a potential biomarker of HCC in patients.

Clinical outcomes and causes of death in Japanese patients with long-term inferior vena cava filter implants and deep vein thrombosis.

BACKGROUND AND PURPOSE: We assessed the causes of death and efficacy of permanent inferior vena cava (IVC) filters for preventing new pulmonary embolisms (PE) in Japanese deep vein thrombosis (DVT) patients with or without PE. METHODS AND SUBJECTS: We studied the clinical outcomes during the follow-up period of 1 day to 9 years (median: 18 months; mean: 28 months) in 66 of 72 consecutive patients (44 with acute PE, 27 with intrapelvic DVT, and 1 with floating femoral vein thrombosis). Fifty of 66 patients received anticoagulant therapy after the filter placement. RESULTS: Five patients died within 1 month (median 9 days) after the filter placement: three from recurrence of PE, one from cancer, and one from sepsis. Two of the three patients with recurrence of PE had preexisting intracardiac thrombi in the right atrium or main pulmonary artery before filter implantation. Ten patients died from the underlying disease (cancer: 7; brain hemorrhage: 1; amyotrophic lateral sclerosis: 1; pneumonia: 1) over 1 month after the filter placement (median follow-up period: 21 months). No new symptomatic PE recurrence was observed over 1 month after the filter placement. The 61 patients with long-term follow-up had no deterioration of DVT, and all the 31 patients who underwent multi-slice computed tomography showed no PE recurrence or filter thrombus occlusion, fracture, or migration. CONCLUSIONS: Underlying diseases and preexisting intracardiac thrombi may be the determining factors for the prognosis of DVT patients. Permanent IVC filters with anticoagulant therapy may be effective for preventing death from new PE in Japanese DVT patients.

An extremely large coronary aneurysm associated with a quadricuspid aortic valve in an adult patient.

A 68-year-old woman exhibited an increasingly protruding mass on the left heart border on chest X-ray. Transthoracic echocardiography revealed an echo-free mass in the anterior pericardial space. Transesophageal echocardiography revealed blood flow from the proximal left anterior descending coronary into a large coronary artery aneurysm measuring 61 mm × 51 mm in diameter and a quadricuspid aortic valve with a small cusp between the left and right coronary cusps. Coronary angiography demonstrated the presence of a coronary aneurysm connected to the proximal left coronary anterior descending artery. A giant coronary artery aneurysm and pulmonary artery fistulas extending from the left and right coronary arteries were confirmed by surgeons and successfully treated with surgery.

Cystine/glutamic acid transporter is a novel marker for predicting poor survival in patients with hepatocellular carcinoma.

Cystine/glutamic acid transporter (xCT) plays a role in tumor progression by regulating the redox status in several types of cancers. To demonstrate the importance of xCT expression for predicting the prognosis of hepatocellular carcinoma (HCC), we analyzed xCT gene expression in 130 paired HCC and non-cancerous tissues. xCT protein expression was confirmed using 7 HCC cell lines and samples from human subjects. xCT mRNA expression was detected in 34 (26%) tumor tissues. Expression of xCT was higher in HCC tissues compared to the corresponding normal tissues according to quantitative reverse transcriptase-polymerase chain reaction findings (P<0.0001). Patients in the group presenting with xCT mRNA expression showed poorer overall and disease-free survival than did those with an absence of xCT mRNA (P=0.0130 and 0.0416, respectively). xCT mRNA expression proved to be an independent factor for poor prognosis in a multivariate analysis of overall survival (hazard ratio, 1.68; 95% CI, 1.03-2.92). We observed xCT protein expression in both the HCC cell lines and in human tissue samples. In conclusion, the findings of the present study suggest that xCT is useful as a predictive marker for patient prognosis and that it may be a novel therapeutic target for HCC.

CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma.

The cylindromatosis (CYLD) gene is involved in tumor progression by acting as a negative regulator of nuclear factor-κB (NF-κB). However, the clinical significance of CYLD in patients with hepatocellular carcinoma (HCC) remains unclear. To demonstrate the clinical significance of CYLD expression, we analyzed CYLD gene expression in 124 paired HCC and non-tumor tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). CYLD gene expression was detected in the patients and the cut-off value was determined by the median value of tumor-to-non-tumor (T/N) ratio. qRT-PCR analysis showed that a low CYLD expression was associated with a high serum α-fetoprotein (AFP) value. Patients in the low CYLD expression group exhibited poorer overall survival compared to those in the high expression group (P=0.0406). Protein expression of CYLD was also investigated in 70 patients with HCC using immunohistochemistry. The findings showed that CYLD protein expression in tumor tissue was associated with CYLD gene expression (P=0.031). The findings of the present study suggest that CYLD is clinically associated with tumor development in HCC patients.

Characteristics of contractile activity in the renal artery of ovariectomized rats.

The incidence of cardiovascular disease is markedly lower in cycling, pre-menopausal women and post-menopausal women receiving estrogen than in men or untreated post-menopausal women. Clinical studies demonstrate a protective role of estrogen in hormone replacement therapy in terms of reducing cardiovascular risk. However, the benefits of hormone replacement therapy in cardiovascular disease remain unclear. We investigated the effects of estrogen on the contractile responses of the renal artery of ovariectomized Wistar rats (OVX) compared to both ovariectomized 17 beta-estradiol-treated rats (OVXE) and sham-operated (control) rats. Isometric contraction of renal artery was recorded with a strain gauge transducer. The maximum contractile response of the renal artery smooth muscle to KCl (80 mM) in the OVXE group was significantly higher than that in both the control and OVX groups. The phenylephrine (PE) concentration-response curves in all three groups indicated a greater sensitivity at lower concentrations of PE following treatment with 100 microM L-arginine methyl ester (L-NAME). The EC50 values for PE in the three groups were 2 times lower in the presence of L-NAME than those lacking exposure to L-NAME. The EC50 value for PE in the OVX group was approximately 3 times lower in the presence of L-NAME than in those lacking exposure to L-NAME and 100 nM BMY 7378, an alpha 1D-adrenoceptor antagonist. The rate of relaxation of the PE-induced contraction (T1/2) was significantly reduced in the OVX group relative to both the control and OVXE groups. T1/2 values after treatment with 100 microM L-NAME were slower than those lacking exposure to L-NAME in all groups. Further, the T1/2 value of the OVX group was 2 times greater than that of the control; this change was reversed in the OVXE group. In conclusion, our results suggest that estrogen regulates contraction and relaxation in the renal artery via NO synthase activity and alteration of the Ca2+ transport systems.

Duplicative medications in patients who visit multiple medical institutions among the insured of a corporate health insurance society in Japan.

OBJECTIVE: The objective of this paper is to describe the frequency of duplicative medication use and to estimate the drug cost associated with duplicative medications in patients who visit multiple medical institutions in Japan. METHODS: The subjects of this study were insurants of a corporate health insurance society. We examined claims of insurants who received prescriptions from multiple medical institutions in April 2002. We examined characteristics of insurants who received duplicative medications and calculated the cost of duplicated drugs. RESULTS: 8.8% received drugs with the same mechanism of action for overlapping administration periods. In terms of comparison among three age groups, 0-19 years old, 20-69 years old, and 70 years old or older, the percentage was higher in 0-19-year-old patients than in the other age groups. The cost of duplicated drugs was found to be 0.7% or 0.5% of the total drug cost, when calculated with higher-priced drugs and lower-priced drugs, respectively. CONCLUSIONS: This study suggests that pediatric and teenage patients as well as elderly patients require prudent management of medication to avoid duplicative medications and that at least an estimated 5.2-7.2 billion yen may be saved if duplicative medications can be completely eliminated nationwide.

Fabrication of hollow melamine-formaldehyde microcapsules from microbubble templates.

A fabrication method for hollow melamine-formaldehyde microcapsules from microbubble templates is presented. This method is based on the direct encapsulation of microbubbles, and thus does not require a liquid- or solid-core decomposition process. This study determined the conditions for controlling the surface morphology, shell thickness, and diameter distribution of hollow microcapsules. Results showed that the surface morphology of these hollow microcapsules depended on the reaction time, glycine concentration (pH of aqueous continuous phase) and pre-polymer concentration. The capsule shell thickness could be controlled by adjusting the concentration of aniline that had adsorbed on the microbubble surface and reacted with pre-polymer. The capsule diameter depended on the dissolution rate of gases, and the diameter of the hollow microcapsules fabricated from air microbubble templates ranged from 5 to 200 microm.