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.

Fatal case of TAFRO syndrome with unilateral adrenal hemorrhage in early-stage disease.

Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly comprise TAFRO syndrome, which was proposed as a distinct clinical entity from iMCD without TAFRO syndrome (iMCD-NOS) due to its aggressive clinical course, refractoriness to corticosteroids, presence of thrombocytopenia, increased level of alkaline phosphatase, and normal level of gammaglobulin. However, diagnosing TAFRO syndrome in its early stages is challenging because it is rare and its diagnostic criteria are complicated. We describe a patient with TAFRO syndrome and adrenal hemorrhage who demonstrated a rapid decline in her clinical condition and did not respond to steroid pulse therapy, resulting in a fatal outcome. In the early stage of her clinical course, she developed unilateral adrenal hemorrhage with mild thrombocytopenia and normal clotting times, suggesting adrenal hemorrhage as a unique manifestation of TAFRO syndrome. In general, patients with TAFRO syndrome exhibit a more aggressive clinical course and poorer outcome than those with iMCD-NOS. To ameliorate this poor prognosis, it is important to diagnose the disease early and immediately start powerful immunosuppressive agents such as tocilizumab. Based on this case, adrenal hemorrhage may suggest TAFRO syndrome, and facilitate the rapid diagnosis of this complicated and rare disease.

Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis. CASE PRESENTATION: A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years. CONCLUSION: Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.

Ancylostoma ceylanicum, novel etiological agent for traveler's diarrhea-report of four Japanese patients who returned from Southeast Asia and Papua New Guinea.

BACKGROUND: Countries in the Southeast Asia region have a high prevalence of soil-transmitted helminth, such as roundworm, whipworm, and hookworms [Ancylostoma duodenale, Necator americanus, Ancylostoma ceylanicum]. Recent molecular-based surveys have revealed that A. ceylanicum, a zoonotic hookworm, is likely the second most prevalent hookworm species infecting humans in that part of the world, while others have noted that this infection is an emerging public health risk not only for indigenous people but also for visitors from other countries. CASE PRESENTATION: We recently encountered four cases of A. ceylanicum infection in Japanese individuals who returned from Southeast Asia and Papua New Guinea. Case 1 was a 25-year-old male who stayed in a rainforest in Malaysia for 4 weeks, where he developed abdominal pain and diarrhea in the third week. Eleven adult worms (five males, six females) were expelled after treatment with pyrantel pamoate and identified as A. ceylanicum based on morphological characteristics and DNA sequences of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. Case 2 was a 26-year-old male who spent 2 years as an overseas cooperation volunteer for agriculture in Papua New Guinea. He did not note any symptoms at that time, though eggs were detected in feces samples at a medical check-up examination after returning. Although collection of adult worms was unsuccessful, DNA analysis of the eggs for cox1 and the ribosomal internal transcribed spacer (ITS)-1 and ITS-2 genes demonstrated that they were A. ceylanicum. Case 3 was a 47-year-old male who spent 1 month in a rural village in Lao People's Democratic Republic and began suffering from watery diarrhea from the third week. A total of nine adult worms (three males, six females) were collected by endoscopic procedures and following treatment with pyrantel pamoate. Morphological examination and molecular analyses of the cox1 gene showed that they were A. ceylanicum. Case 4 was a 27-year-old male who participated in group travel to India for 5 days. Three weeks after returning, he developed abdominal pain and diarrhea. Hookworm eggs were found in feces samples and developed into larvae in culture, which were identified as A. ceylanicum based on molecular analysis of the cox1 gene. Eosinophilia was observed in all of the cases prior to treatment. CONCLUSIONS: A. ceylanicum should be recognized as an important etiologic pathogen of hookworm diseases in travelers to countries in the Southeast Asia and West Pacific Ocean regions.

Ancylostoma ceylanicum hookworm infection in Japanese traveler who presented chronic diarrhea after return from Lao People's Democratic Republic.

Ancylostoma (A.) ceylanicum, one of the most common species of hookworms infecting dogs and cats, also causes patent infections in humans and is now considered to be the second most common hookworm species infecting populations in southeast Asia. A Japanese patient who returned from a visit to Thailand and Lao People's Democratic Republic (PDR) was presented with intermittent watery diarrhea with eosinophilia. Hookworm eggs were found in feces samples, and adult worms were confirmed to be present in the jejunum with capsule endoscopy and double balloon enteroscopy. A diagnosis of A. ceylanicum infection was made based on the morphology of the adult worms along with findings of a PCR-based molecular study using larvae obtained from a fecal sample culture. The infection was considered likely to have been obtained during a 1-month stay in a Laotian village, where the patient had eaten local food, worn sandals on bare feet, and lived as a local native villager, though he had stayed in modern hotels during the visit to Thailand.

Efficacy of alogliptin in preventing non-alcoholic fatty liver disease progression in patients with type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease worldwide and is characterized by chronic liver inflammation and fibrosis leading to cirrhosis and increased risk of liver cancer in a proportion of patients. Effective anti-fibrotic agents have yet to be approved for the treatment of NAFLD. The present study aimed to evaluate the efficacy of dipeptidyl peptidase 4 inhibitors (DPP4-I) in the prevention of NAFLD progression in NAFLD patients with type 2 diabetes. The study was a single arm, multi-centre, non-randomised study of NAFLD patients with type 2 diabetes. NAFLD was diagnosed according to ultrasonographic findings. All the patients received 25 mg/day of alogliptin for 12 months. The efficacy of alogliptin in preventing NAFLD progression was assessed using overall NAFIC scores [non-alcoholic steatohepatitis (NASH), ferritin, insulin and type IV collagen 7S] and individual component scores according to baseline haemoglobin A1c (HbA1c) levels. Of the 39 patients enrolled in the study, 16 patients (40.3%) had NAFIC scores >2 points, indicating the presence of NASH. NAFIC scores markedly decreased following 12 months of alogliptin administration, but remained >2 points in 10 patients, indicating that NASH may have persisted in these patients. The relative risks for persistent NASH were 4.92 (95% confidence interval, 0.61-40.0) in the highest HbA1c tertile group compared with those in the lowest group. However, no statistically significant linear trend was observed across all HbA1c categories (P=0.145). DPP4-I may have efficacy against NAFLD progression in patients with type 2 diabetes with relatively lower HbA1c levels. DPP4-I may represent a potential new therapeutic strategy for the prevention of disease progression in NAFLD patients with type 2 diabetes.

Comparison between percutaneous radiofrequency ablation and surgical hepatectomy focusing on local disease control rate for colorectal liver metastases.

BACKGROUND/AIMS: Therapeutic efficacy of radiofrequency ablation (RFA) for colorectal liver metastases (CRLM) was compared with hepatic resection (HR), focusing on local disease control rate as well as risk factors of recurrence and patients survival. METHODOLOGY: From April 2002 to March 2012, 32 patients underwent RFA and 60 patients underwent HR for CRLM. The rate of local recurrence along the ablated or resected margin was evaluated in these patients. RESULTS: The local recurrence was seen in 8 patients (13.3%) after HR, and 15 (46.9%) after RFA. Multivariate analysis of all patients revealed that RFA as an initial therapy (P < 0.001), venous invasion liver metastases (P = 0.049) were independent risk factors for local recurrence. Subgroup analysis showed that local recurrence rate after RFA was significantly higher than that after HR in patients with tumors 20 mm or larger (P < 0.001), while there was no significant difference in local recurrence rate between RFA and HR in patients with tumors less than 20 mm (P = 0.676). CONCLUSIONS: RFA showed a high risk of local recurrence in comparison to HR especially in patients with tumors larger than 20 mm. Indication of RFA should be restricted drastically considering the limitation of efficacy.

[A case of infectious mononucleosis with splenic infarction].

A 22-year-old man complaining of persisting high fever and right hypochondralgia was admitted to our hospital for infectious mononucleosis with splenic infarction detected by computed tomography. The splenic infarction deteriorated with a marked elevation of inflammatory parameters. This necessitated the commencement of methylprednisolone pulse therapy, resulting in prompt amelioration of inflammation and a reduction in cytokine levels. Including our case, only 9 cases of mononucleosis with splenic infarction have been reported to date; however, splenic infarction should be considered because it is a significant complication of infectious mononucleosis.

Repetitive and safe transgene expression in rat liver is achievable by adenoviral infusion into the common bile duct.

To examine the feasibility of adenovirus-mediated gene transfer into the liver, we examined whether adenoviral infusion into the common bile duct could induce repetitive and safe transgene expression in rat livers. Recombinant adenovirus carrying a reporter lacZ gene was repetitively infused retrogradely into the common bile duct of rats. LacZ expression in rat livers was estimated histochemically by X-gal staining and quantitatively by a chemiluminescent reporter gene assay after the first, second and third adenoviral infusion into the common bile duct. To assess the safety of repetitive adenoviral infusion into the common bile duct, various liver- and kidney-related serum parameters, and liver damage were examined biochemically and histologically, respectively. Retrograde adenoviral infusion into the common bile duct achieved sufficient and safe lacZ expression in rat livers. Although transgene expression in the liver was transient, the second and third adenoviral infusion into the common bile duct could induce the expression of the same transgene in the liver. Furthermore, repetitive adenoviral infusion into the common bile duct caused no significant reverse reactions. Because retrograde adenoviral infusion into the common bile duct is a clinically practical method by using a widely used endoscopic technique, namely endoscopic retrograde cholangiography, these results suggest that retrograde adenoviral infusion into the common bile duct is a practical gene therapy modality in clinical settings.

Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse.

It has been suggested that the tissue inhibitor of metalloproteinases-1 (TIMP-1) is involved in spontaneous resolution of liver fibrosis. The aim of this study was to investigate whether TIMP-1 altered spontaneous resolution of liver fibrosis in conjunction with matrix metalloproteinases (MMP) inhibition and hepatic stellate cell (HSC) activation. The livers of liver-targeted TIMP-1 transgenic (TIMP-Tg) and control hybrid (Cont) mice were harvested at 0, 3, 7, and 28 days following spontaneous recovery from CCl(4)-induced liver fibrosis. The extent of fibrosis resolution, MMP expression, alpha-smooth-muscle actin (alpha-SMA) positive cells, and procollagen-(I) messenger RNA (mRNA) in the liver were assessed at the respective periods in both groups. We also examined the effect of TIMP-1 on HSC apoptosis. The TIMP-Tg mice showed significantly attenuated resolution of spontaneous liver fibrosis compared with the Cont mice. The hydroxyproline content, number of alpha-SMA positive cells, and procollagen-(I) mRNA rapidly decreased with time in the Cont mice, whereas these markers were little changed in TIMP-Tg mice. The level of the active form of metalloproteinases-2 (MMP-2) in the TIMP-Tg mice was less than that in the Cont mice. TIMP-1 markedly decreased the nonparenchyma apoptotic cells in the liver fibrosis resolution model, and it also inhibited HSC apoptosis associated with suppression of caspase-3 activity in vitro. In conclusion, TIMP-1 significantly attenuated spontaneous resolution of liver fibrosis by the combination of a net reduction of the MMP activity and suppression of apoptosis in HSC.

Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats.

BACKGROUND/AIMS: It is suggested that the renin-angiotensin system (RAS) is involved in tumor development and fibrogenesis. The aim of the present study was to examine the effect of RAS inhibition on the liver enzyme-altered preneoplastic lesions and fibrosis development. METHODS: The effects of the clinically used angiotensin-I converting enzyme inhibitor (ACE-I), perindopril (PE), on two different rat model of liver carcinogenesis models induced separately by diethylnitrosamine (DEN) and a choline-deficient L-amino acid-defined (CDAA) diet were studied. This CDAA model was also used to elucidate the effect of PE on liver fibrosis development. RESULTS: The immunohistochemical evaluation revealed that the glutathione S-transferase placental form (GST-P), and gamma-glutamyltransferase (GGT)-positive preneoplastic foci significantly decreased in the livers of the PE-treated groups. In CDAA-induced liver fibrosis model, PE revealed a marked inhibitory effect of liver fibrosis development. The hepatic hydroxyproline, serum fibrosis markers, alpha-smooth muscle actin (alpha-SMA) immunopositive cells in number, and alpha-(III) pro-collagen mRNA expression were significantly suppressed by PE treatment. These inhibitory effects of PE were achieved even at a clinically comparable dose (2 mg/kg per day). CONCLUSIONS: These results suggested that the RAS is involved in liver carcinogenesis and fibrosis development.

Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma.

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are potent and representative factors involved in tumor development. It has been reported that bFGF and VEGF showed a synergistic effect in both in vitro and in vivo angiogenesis. However, the interaction of these factors on tumor development and angiogenesis, including hepatocellular carcinoma (HCC), has not yet been elucidated. In this study, we examined the combined effect of bFGF and VEGF overexpression by means of a combination of a retroviral tetracycline (tet)-regulated (Retro-Tet) gene expression system, which can manipulate the gene expression in vivo by providing tet in the drinking water, and a conventional plasmid gene expression system. In an allograft study, bFGF and VEGF overexpression synergistically increased tumor growth and angiogenesis in the murine HCC cells. This synergistic effect also was found in established tumors. VEGF messenger RNA (mRNA) expression in the tumor was increased 3.1-fold by bFGF-overexpression, and the bFGF-induced tumor development was significantly attenuated by treatment with KDR/Flk-1 neutralizing monoclonal antibody. In conclusion, these results suggest that bFGF synergistically augments VEGF-mediated HCC development and angiogenesis at least partly by induction of VEGF through KDR/Flk-1.