A Randomized Controlled Trial of Betamethasone on Fatigue in Patients With Advanced Cancer.

CONTEXT: Fatigue is one of the most uncomfortable physical symptoms seen in patients with advanced cancer. Previous studies have reported on the efficacy of corticosteroids from Western countries. OBJECTIVES: To assess the effectiveness of 4mg betamethasone improving fatigue among Japanese patients with advanced cancer. METHODS: A randomized, double-blind, placebo-controlled trial enrolled eligible patients with advanced cancer expected to survive 1-2 months, with an Eastern Cooperative Oncology Group Performance Status of 2-3, and experiencing fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-15-palliative criteria. Participants received twice-daily oral administration of 2 mg betamethasone (4 mg/d) or placebo for seven days, with fatigue assessed using EORTC QLQ-C15-PAL subscale and numerical rating scale (NRS) score (at baseline and day seven). The trial was registered under the University Hospital Medical Information Network (UMIN)000011913. RESULTS: Among the 267 screened patients, 81 were eligible, of which 70 were evaluable (betamethasone, 33; placebo, 37). The mean difference in the EORTC-QLQ-C15-PAL fatigue subscale was -8.2 (95% CIs: -22.3, 0.0; P = 0.178) and in a NRS for fatigue was -1.2 (95% CIs: -2.5, -0.01; P = 0.048), respectively. Emotional function, appetite loss, and global-health were slightly better in the betamethasone group than in the placebo group. CONCLUSION: The impact of betamethasone 4 mg/d on alleviating fatigue in patients with advanced cancer in the last weeks of life did not reach statistical significance in the EORTC-QLQ-C15-PAL as the primary endpoint, however, it was significant in the NRS, the secondary endpoint.

Effects and risk factors of TAS-102 in real-world patients with metastatic colorectal cancer, EROTAS-R study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an anticancer drug for metastatic colorectal cancer (CRC). This study aimed to analyze the effects and risk factors about effects of TAS-102 in real-world patients with metastatic CRC (the EROTAS-R study). METHODS: This study retrospectively analyzed 271 patients aged ≥ 20 years who underwent TAS-102 for metastatic CRC at nine related institutions from 2014 to 2021. Therapeutic results of TAS-102 + bevacizumab (Bev) and TAS-102, effect predictors, adverse events (AE), and AE predictors were examined. RESULTS: The backgrounds of all cases were as follows: average age, 66.7 ± 10.9 years; male ratio, 59.5%; performance status (PS) 0/1/2, 43.5%/50.6%/5.9%; and tumor site right/left, 25.5%/74.5%. The therapeutic results of 109 cases receiving TAS-102 + Bev and 162 cases receiving TAS-102 were as follows: disease control rate, 53.2% vs. 28.0% (p < 0.01); progressive free survival (PFS), 6.2 vs. 4.2 months (p < 0.01); and overall survival (S), 11.8 vs. 9.3 months (p = 0.03). Multivariate analysis for effect-related factors (odds ratio (OR), 95%confidence interval (CI)) showed the following: PS1 + 2 (0.257, 0.134-0.494, p < 0.01) and a combination of Bev (3.052, 1.598-5.827, p < 0.01). The rates of grade 3 AE for TAS-102 + Bev and TAS-102 were 53.2% and 48.8%, respectively (p = 0.47). Various AE predictors were as follows: male sex (p = 0.69), age ≥ 75 years (p = 0.59), PS1 + 2 (p = 0.20), body surface area < 1.53 m2 (p = 0.26), eGFR < 50 ml/min (p = 0.02), and AST ≥ 50 IU/L (p = 0.64). CONCLUSION: A better OS and PFS comparing TAS-102 + Bev to TAS-102 for CRC was achieved in a large number of real-world patients.

An Unusual Case of Acute Cholecystitis with Amyloidosis: A Case Report and Literature Review.

We present an extremely rare case of amyloid A (AA) deposition in the gallbladder and review the literature on similar cases. The patient was a 76-year-old man who had been diagnosed with mild bronchiectasis three years previously, who was admitted to the hospital with right upper quadrant pain and fever. Computed tomography revealed swelling and wall thickening of the gallbladder with a small gallstone. The patient was diagnosed with acute cholecystitis and cholelithiasis and underwent open cholecystectomy. A postoperative histological examination revealed extensive AA deposition in the gallbladder wall. Thus, the definitive diagnosis was acute cholecystitis with AA amyloidosis.

[Bacillus cereus septicemia and necrotizing fasciitis in a patient with liver cirrhosis: a case report].

A 54-year-old woman with hematemesis was referred to our hospital. She had a history of liver cirrhosis and diabetes mellitus. After inserting a Sengstaken-Blakemore tube, we performed endoscopic variceal ligation for ruptured esophageal varices. On the third day of admission, she developed septicemia and necrotizing fasciitis caused by Bacillus cereus. She was successfully treated with early debridement of both lower extremities and intravenous treatment with vancomycin, ciprofloxacin, and clindamycin. Although B. cereus is an attenuate bacterium, it can occasionally cause fatal infection in immuno-compromised individuals, such as those with liver cirrhosis.

The incidence of contrast-induced nephropathy (CIN) following transarterial chemoembolisation (TACE) in patients with hepatocellular carcinoma (HCC).

PURPOSE: The purpose of this retrospective study was to investigate the incidence of contrast-induced nephropathy (CIN) caused by transarterial chemoembolisation (TACE) in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: One hundred forty-one patients treated between 2005 and 2008 undergoing 305 consecutive sessions of TACE were enrolled. CIN was defined as an increase in the serum creatinine level of more than 0.5 mg/dl or more than 25 % from baseline within 3 days after TACE without any other identifiable cause of acute kidney injury. RESULTS: CIN by the present definition was observed after 2.6 % of the TACE sessions. No patient showed clinical signs or symptoms of acute renal failure, or required haemodialysis. None of the patients with an estimated glomerular filtration rate of <60 ml/min/1.73 m(2) developed CIN. CONCLUSION: The present study suggests that TACE is a relatively safe procedure in terms of the risk of CIN under vigorous periprocedural hydration and that the incidence of CIN is comparable to that of AKI associated with intravenous CM administration. KEY POINTS: • CIN would be lower for non-coronary arterial intervention than for coronary intervention. • The present study suggests that the CIN rates following TACE are low. • The incidence of CIN is comparable to that after intravenous CM administration.

Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma.

AIM: Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC. METHODS: In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups. RESULTS: Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort. CONCLUSION: Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years.

Direct cholangioscopy combined with double-balloon enteroscope-assisted endoscopic retrograde cholangiopancreatography.

Double-balloon enteroscope (DBE)-assisted endoscopic retrograde cholangiopancreatography (ERCP) is an effective endoscopic approach for pancreatobiliary disorders in patients with altered gastrointestinal anatomy. Endoscopic interventions via DBE in these postoperative settings remain difficult because of the lack of an elevator and the use of extra-long ERCP accessories. Here, we report the usefulness of direct cholangioscopy with an ultra-slim gastroscope during DBE-assisted ERCP. Three patients with choledocholithiasis in postoperative settings (two patients after Billroth II gastrojejunostomy and one patient after Roux-en-Y gastrojejunostomy) were treated. DBE was used to gain access to the papilla under carbon dioxide insufflation, and endoscopic sphincterotomy was performed with a conventional sphincterotome. For direct cholangioscopy, the enteroscope was exchanged for an ultra-slim gastroscope through an incision in the overtube, which was inserted directly into the bile duct. Direct cholangioscopy was used to extract retained bile duct stones in two cases and to confirm the complete clearance of stones in one case. Bile duct stones were eliminated with a 5-Fr basket catheter under direct visual control. No adverse events were noted in any of the three cases. Direct cholangioscopy with an ultra-slim gastroscope facilitates subsequent treatment within the bile duct. This procedure represents another potential option during DBE-assisted ERCP.

A case of hepatitis C-associated osteosclerosis with xanthogranulomatous cholecystitis.

A 62-year-old woman presented with a markedly increased serum ALP level of skeletal origin during a regular follow-up of chronic hepatitis C. Serum calcium, phosphorus, and intact-PTH levels were normal and bone turnover markers were increased. Her generalized bone density was diffusely increased. These findings were consistent with hepatitis C-associated osteosclerosis (HCAO). She underwent cholecystectomy, as gallbladder cancer was suspected; however, histopathological findings demonstrated xanthogranulomatous cholecystitis. After cholecystectomy, serum ALP level and bone turnover markers were gradually decreased. This may indicate the existence of a novel osteogenic factor in the gallbladder in HCAO.

[A case of serous cystadenoma of the pancreas associated with obstructive jaundice during long-term follow up].

A 68-year-old man had been followed up since March, 1997 because of a cystic tumor of the pancreas head. The patient developed obstructive jaundice and was admitted to our hospital in June, 2007. The tumor size on CT scan had increased from 3.6 cm to 5.9 cm during the 10-year period. After endoscopic biliary drainage, pancreatoduodenectomy was performed. Pathological diagnosis of the resected specimen was serous cystadenoma. Serous cystadenoma of the pancreas is known as a benign tumor with indolent progression and is likely to be symptomatic if the tumor size exceeds 4 cm. However, biliary obstruction is a rare complication of serous cystadenoma. We report this rare case here with references to the literature.

[Histological complete response in a case of advanced gastric endocrine carcinoma treated by irinotecan plus cisplatin].

A 65-year-old man was admitted because of epigastralgia and body weight loss. A 50-mm tumor found at the lesser curvature of the gastric antrum was histologically diagnosed as endocrine carcinoma. A computed tomography (CT) scan showed liver metastasis and multiple lymph node metastasis. We started chemotherapy with irinotecan and cisplatin every 4 week. After three courses of treatment, the primary lesion was estimated PR, the metastasis CR, and the synthesis PR. Then we performed distal gastrectomy with lymph node dissection. Histological findings revealed no cancer cells.

Prediction of breakthrough hepatitis due to lamivudine-resistant hepatitis B virus by a sensitive semiquantitative assay using peptide nucleic acids.

OBJECTIVE: The aim of this study was to predict breakthrough hepatitis and analyze the dynamics of lamivudine-resistant hepatitis B virus in patients treated with lamivudine. METHODS: Fifty-five chronic hepatitis B patients treated with lamivudine were included. The emergence of YMDD motif mutants was detected by peptide nucleic acid (PNA) mediated PCR clamping with a detection limit of 10(1) YMDD mutants. We then performed a semiquantitative PCR assay of subjects in whom YMDD mutants were detected. This assay detects 10(2.7)-10(7.7) copies of mutant virus per 1 ml of serum. RESULTS: YMDD mutants were detected in 28 (51%) of the 55 patients. Eight patients stopped medication before viral breakthrough. YMDD mutants appeared transiently despite the continuance of lamivudine therapy in 12 patients. In all 8 patients with breakthrough hepatitis, the quantities of YMDD mutants ranged from 10(2.7)-10(4.7) copies/ml in the two to three months before clinical breakthrough. In contrast, in 12 patients without viral breakthrough, there were always less than 10(2.7) copies/ml YMDD mutants. CONCLUSIONS: Lamivudine-resistant viruses sometimes disappear even during lamivudine administration. Our sensitive quantitative assay proved useful for early detection of YMDD mutants and a threshold of 10(2.7) copies/ml is suggested for predicting viral breakthrough.

PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats.

Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor which is known to affect oxidative stress and PPARalpha ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARalpha ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA+WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARalpha ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver.

Lamivudine therapy for Japanese patients with cirrhosis B.

OBJECTIVE: The aim of this study was to investigate the emergence of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy and to compare the emergence patterns of YMDD mutants in cirrhotic and noncirrhotic patients. METHODS: Eighteen cirrhotic and 37 noncirrhotic patients with chronic hepatitis B were studied. The emergence of YMDD mutants was determined before, as well as at 1, 3, 6, 9 and 12 months after treatment using a highly sensitive method based on polymerase chain reaction. RESULTS: Although YMDD mutants were elicited early, the emergence of YMDD mutants was not always associated with breakthrough hepatitis. YMDD mutants appeared in cirrhotic and noncirrhotic patients: in 22 and 8% at 1 month, 13 and 21% at 3 months, 46 and 19% at 6 months, 30 and 19% at 9 months, and 83 and 27% at 12 months, respectively. CONCLUSION: YMDD mutants emerge more frequently in cirrhotic than noncirrhotic patients during the early period on lamivudine treatment. The highly sensitive method may be useful for monitoring the development of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy.

Activated Kupffer cells play an important role in intra-hepatic Th1-associated necro-inflammation in Concanavalin A-induced hepatic injury in mice.

BACKGROUND/AIMS: To examine whether or not activated Kupffer cells play an important role in intra-hepatic Th1-associated necro-inflammation in Concanavalin A (Con A)-induced hepatic injury in mice. METHODS: Con A was administered to Balb/c mice pretreated with or without gadolinium chloride (GdCl(3)). Kupffer cell activation was evaluated by their ability to produce superoxide anions in situ under liver perfusion with nitro blue tetrazolium (NBT). Hepatic concentration of cytokines was measured by ELISA and the mRNA expression of CXC chemokine receptor 3 (CXCR3) was evaluated by RT-PCR. Immunohistochemical detection of CD4 positive lymphocytes in the liver was also performed. RESULTS: GdCl(3)-pretreatment significantly (P<0.01) reduced the serum levels of alanine aminotransferase (ALT) in Con A-treated mice. Formazan deposition in Kupffer cells, the hepatic concentration of tumor necrosis factor-alpha and interferon-gamma, the mRNA expression of CXCR3 and the CD4 positive lymphocytes in the liver were decreased in GdCl(3)-pretreated mice as compared with those without GdCl(3)-pretreatment (P<0.05, respectively). CONCLUSIONS: Activated Kupffer cells, which produce superoxide anions, are involved in Con A-induced hepatic necro-inflammation in mice possibly through the activation of Th1-associated immune response mediated by CD4 and/or CXCR3 positive cells recruited into the liver.

Novel single nucleotide polymorphisms of the cytokeratin 19 pseudogene are associated with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterized by chronic inflammation and destruction of intra-hepatic bile ducts. However, the pathogenesis of PBC has not been fully delineated. We examined whether patients with PBC harbor genomic mutations of the cytokeratin 19 (CK19) gene since that gene is specifically expressed in biliary epithelial cells. Thirty-six patients with PBC, 26 patients with other liver diseases, and 36 healthy volunteers were enrolled in this study, but there were no significant differences in the genomic sequence of the CK19 gene between those groups. On the other hand, novel single nucleotide polymorphisms (SNPs) of the CK19 pseudogene, C341T, T524G and A754G, were frequently detected in PBC patients. These results suggest that those novel SNPs of the CK19 pseudogene may be associated with PBC and may prove useful for predicting susceptibility to PBC.

Detection of YMDD mutant using a novel sensitive method in chronic liver disease type B patients before and during lamivudine treatment.

BACKGROUND/AIMS: The emergence of lamivudine-resistant hepatitis B virus (HBV) was reported in patients with prolonged lamivudine administration. There was no report of the existence of tyrosine-methionine-aspartate-aspartate (YMDD) mutant in non-lamivudine treated chronic hepatitis B patients. In the present study, we developed a sensitive assay and applied it to the detection of YMDD mutant. METHODS: We developed peptide nucleic acid (PNA) mediated polymerase chain reaction clamping for detecting mutations in a YMDD motif of the hepatitis B virus DNA polymerase gene. We studied YMDD mutants in a patient with HBV DNA breakthrough longitudinally and in non-lamivudine treated patients (36 patients). RESULTS: We could detect as little as 0.01-0.001% of mutant viruses coexisting in 10(5)-10(9) copies of wild-type viruses using this assay. YMDD mutant was detected 7 months before clinical breakthrough, which was 6 months earlier than using the conventional restriction fragment length polymorphism assay. YMDD mutants were also detected in four of 18 anti-HBe antibody positive untreated chronic hepatitis type B: YMDD+tyrosine-valine-aspartate-aspartate (YVDD) in two patients and YMDD+tyrosine-isoleucine-aspartate-aspartate (YIDD) in two patients, however, none in HBe antigen positive patients. CONCLUSIONS: We developed a highly sensitive assay for detecting YMDD mutants. This is an effective procedure for monitoring patients during or before lamivudine treatment and can provide more insights into the therapeutic strategies for chronic hepatitis B patients.

Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma for five years and improves the long-term survival of chronic hepatitis C patients.

The development of hepatocellular carcinoma (HCC) was significantly reduced in both sustained responders (SR) and transient biochemical responders (TR) in chronic hepatitis C (CH-C) patients who received interferon (IFN) therapy. However, the long-term clinical outcome of TR remains unclear. One thousand three hundred and seventy CH-C Japanese patients who received IFN therapy and 54 control cirrhotic patients were enrolled. TR were defined as those patients who showed a normal serum alanine aminotransferase level (<==30 IU/l) at the end of therapy and then relapsed. Mean follow-up period was 5.6 years (6.1 years in 48 cirrhotic patients) in the IFN group and 8.3 years in the 54 control cirrhotic patients. HCC was detected in 114 patients in the IFN group among whom 4 were in the 425 SR, 21 were in the 359 TR and 89 were in the 586 non-responders (NR). The cumulative incidence of HCC was significantly (P=0.0001) inhibited in both SR and TR compared with NR. Its inhibitory effect in TR was within 5 years. Platelet count did not significantly decrease for 2-4 years after IFN therapy in TR, but it significantly decreased in NR 2 years after IFN therapy. The cumulative survival in both SR and TR was significantly higher than NR (SR vs NR; P=0.0001, TR vs NR; P=0.0305). These results indicate that IFN therapy lowers the rate of the progression of HCC and improves the long-term survival even in CH-C patients who transiently respond to IFN therapy.