Early Predictors of Objective Response in Patients with Hepatocellular Carcinoma Undergoing Lenvatinib Treatment.

There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin-bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of ≥40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP ≥ 10 ng/mL; low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389; p = 0.001) and ALBI score (odds ratio, 6.866; p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.

Giant cavernous hepatic hemangioma shrunk by use of sorafenib.

Here we report a case of a 76-year-old man with a giant cavernous hepatic hemangioma of more than 20 cm in diameter. Since the hepatic hemangioma was actually growing and might possibly rupture and he complained of abdominal symptoms, we decided to perform interventional therapy. First we performed transcatheter arterial embolization (TAE) of the hepatic arteries. However, since this was not sufficiently effective, we added sorafenib (600 mg/day). As a result, the tumor shrank with symptomatic improvement. Subsequently, an adverse event occurred, and we suspended the sorafenib therapy. Then, the tumor began to grow, and we resumed administering sorafenib at 400 mg/day. The tumor shrank again, and we continued the sorafenib therapy thereafter. The tumor shrinkage, although possibly induced by the effect of TAE, is considered primarily due to the effect of treatment with sorafenib, because (1) TAE did not sufficiently reduce the blood supply to the inside of the tumor; (2) other tumors shrank in the area not targeted by TAE; and (3) the tumor grew during suspension of sorafenib therapy and shrank again after resuming the treatment.

[A case of primary hepatic malignant lymphoma accompanied by cholecystitis].

A 50-year-old man visited a physician due to continued right hypochondrium pain for a period of about two months. He was diagnosed with cholecystitis and was referred to our hospital. On arrival, he presented with mild tenderness in the right upper quadrant. Abdominal computed tomography (CT) showed small gallstones and a thickened gallbladder wall. At the same time, a low-density area expanding from the gallbladder bed was revealed. Magnetic resonance cholangiopancreatography (MRCP) showed a smooth stricture of the common hepatic duct. We suspected chronic cholecystitis and inflammatory change in the liver because of cholecystitis. However, malignant diseases could not be excluded, and conservative treatment with antibiotics was therefore performed. On post-hospitalization day 26, cholecystectomy was performed. Rapid diagnosis of a surgical wedged biopsy specimen of the liver showed infiltration of the hepatic sinusoids by atypical lymphocytes. Malignant lymphoma was highly suspected. After further examination, we obtained the diagnosis of primary hepatic CD5+diffuse large B-cell lymphoma. Cyclophosphamide+doxorubicin+vincristine+prednisolone(CHOP) with rituximab therapy was performed. Complete remission was achieved after 8 courses of therapy. However, tumor recurrence in the floor of the mouth occurred one year after the operation. Salvage chemotherapy is now being performed.

[A case of anorectal malignant melanoma appearing 1 year after endoscopic mucosal resection of a rectal adenocarcinoma].

We present a case of a 61-year-old woman who underwent endoscopic mucosal resection (EMR) for early-stage colorectal cancer. However, because the condition of the horizontal margin of the resected tumor was unknown, she further underwent local transanal excision. Lower gastrointestinal endoscopy performed 1 year later showed protruding lesions both on the scar tissue and in the vicinity. Biopsy revealed malignant melanoma. She then underwent laparoscopic abdominoperineal resection and colostomy. This was an extremely rare case of adenocarcinoma complicated by malignant melanoma after resection.

Eosinophilic gastroenteritis due to cow's milk allergy presenting with acute pancreatitis.

Eosinophilic gastroenteritis (EGE) is characterized by eosinophilic infiltration of the digestive organs, most commonly of the stomach and the duodenum. Symptoms of EGE are nonspecific and include nausea, vomiting, abdominal pain, dyspepsia, malabsorption, ascites and weight loss. The various symptoms of EGE depend on its location and the depth of gastrointestinal eosinophil infiltration. We report a case presenting with acute pancreatitis caused by a milk allergy. The patient's symptoms rapidly improved after treatment with corticosteroids, and he remained symptom-free for more than 20 months by the elimination of cow's milk from his diet. Serum titers of pancreatic enzymes and total bilirubin simultaneously recovered and blood eosinophil counts normalized. The causative allergens of EGE are too various to detect; however, allergologic exams revealed that a cow's milk allergy had provoked EGE in our case. Adult-onset cow's milk allergies are rare; when seen, however, they may present severe complications such as anaphylaxis, gastroenteritis and pancreatitis. When unaccountable gastrointestinal symptoms are observed, EGE caused by food allergies should be included in the differential diagnosis.

[A case of severe asthma and peach allergy that improved with omalizumab therapy: a case report].

A 30-year-old woman had refractory asthma. She had also experienced twice severe anaphylaxis episodes after ingesting peaches. The patient was extremely wary about reoccurrence of anaphylaxis and avoided ingesting any fruits, including peaches. She visited our hospital for testing and treatment for asthma and the peach allergy. Skin and serologic testing showed that she had a severe allergy to house dust, mites, and peaches. The food challenge test results showed that ingesting 6.5 g of the peach fruit induced dyspnea in the patient. Her asthma could not be controlled despite treatment involving a leukotriene receptor antagonist and combination inhalation of high-dose salmeterol xinafoate/fluticasone propionate. We advised the patient to keep strict avoidance ingesting peaches because of her food allergy. However, she hoped to overcome her food restrictions, especially those for fruits. We initiated treatment involving the recombinant humanized monoclonal anti-IgE antibody omalizumab (150 mg, once a month) to ensure that the asthma was controlled well and to improve the patient's diet. The asthmatic symptoms ameliorated, and the peak expiratory flow increased in a short time. We gradually reduced the restriction on peach consumption. This was achieved by rechallenging the patient with increasing doses of 290 mg of the peach fruit and was initiated at 28 weeks after starting omalizumab therapy. The restriction on peach consumption was lifted eventually, and the patient did not experience any allergic symptoms subsequently on ingesting peaches. Thus, for our patient, omalizumab therapy was highly effective in achieving remission from both asthma and peach allergy.

Cooperative activation of CCL5 expression by TLR3 and tumor necrosis factor-alpha or interferon-gamma through nuclear factor-kappaB or STAT-1 in airway epithelial cells.

BACKGROUND: CCL5/RANTES contributes to prolonged eosinophilic inflammation and asthma exacerbation after a viral infection. We studied the mechanism of CCL5 expression using viral product double-stranded RNA (dsRNA), a ligand of Toll-like receptor 3 (TLR3), and inflammatory cytokines in airway epithelial cells. METHODS: The airway epithelial cell line BEAS-2B was used in our in vitro study, and the levels of CCL5 mRNA and CCL5 protein expression were determined using real-time PCR and ELISA. The activity of the CCL5 promoter region and nuclear factor (NF)-kappaB was assessed by dual luciferase assay using specific luciferase reporter plasmids. We used actinomycin D to assess the stability of mRNA. Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was analyzed by Western blot. RESULTS: Synthetic dsRNA up-regulated the expression of CCL5 mRNA and CCL5 protein. Adding TNF-alpha or IFN-gamma to dsRNA further increased the expression of CCL5. The combination of TNF-alpha and dsRNA cooperatively activated the CCL5 promoter region and the NF-kappaB-specific reporter. IFN-gamma did not activate these reporters. However, it increased the stability of CCL5 mRNA induced by dsRNA. IFN-gamma phosphorylated STAT-1, but dsRNA did not. The effects of IFN-gamma were not evident in the cells transfected with short interfering RNA for STAT-1. CONCLUSIONS: Cross-talk between TLR3 signaling and inflammatory cytokines regulates the expression of CCL5 in airway epithelial cells. In this mechanism, TNF-alpha may activate NF-kappaB, in cooperation with TLR3 signaling. IFN-gamma may stabilize CCL5 mRNA up-regulated by TLR3. This mechanism may depend on STAT-1.

[A case report of internal hernia through an abnormal defect in the broad ligament of the uterus].

We report a rare case of internal hernia through an abnormal defect in the broad ligament of the uterus. A 49-year-old woman, without any previous surgery, was admitted because of vomiting and lower abdominal pain. Three days after admission a small amount of small intestinal gas was pointed out on her plain abdominal X-ray film. An enema examination by ileus tube revealed a pooling of gastrografin on the left side of the pelvic cavity, showing an obstruction of the ileum. Therefore, an emergency operation was performed, whereupon we found an abnormal defect in the left broad ligament of the uterus. This case describes an internal hernia through an abnormal defect in a female ileus patient without a history of surgery.

[Impact of inhaled corticosteroid prescription at discharge from the emergency room on exacerbations of asthma in Japanese hospital].

BACKGROUND: Inhaled corticosteroid (ICS) therapy has been reported to improve relapses of asthma following emergency room (ER) discharge, but the benefits of ICS prescription at discharge from the ER are unclear. OBJECTIVE: To assess background of the patients who visit ER, and determine whether the prescription of ICS at ER reduces relapses in the patients with asthma. METHODS: A prospective multi-center cohort study was conducted at 32 Japanese ERs. Patients aged two to 82 years who visited ER with moderate to severe exacerbation of asthma underwent questionnaire and follow-up three and six months later. The primary observations were of the asthma-related hospitalizations, ER visits, and unscheduled visits. RESULTS: Among 343 asthma patients (Children: 120, Adults: 223), 33% of children and 12% of adult patients were classified as intermittent asthma, retrospectively. The patients with intermittent had the same rates of hospitalization (29.6%) and ER visits (46.2%) as those with persistent (hospitalization rate: 24.7%, ER visits: 53.1%, ns) before enrolled. The odds ratio for hospitalization in the patients received ICS at the discharge from the ER, compared with the patients who did not received ICS, yielded 0.256 (95% confidence interval, 0.069 to 0.942; p=0.040) by multinomial logistic regression model. CONCLUSION: Prescribing ICS at discharge from the ER to asthma patients is associated with the reduction of risk for asthma-related hospitalization. For patients discharged from the ER, including mild intermittent asthma, ICS might be prescribed.

D-Penicillamine improved laparoscopic and histological findings of the liver in a patient with Wilson's disease: 3-year follow-up after diagnosis of Coombs-negative hemolytic anemia of Wilson's disease.

We report a 13-year-old girl who presented with hepatic failure and hemolytic anemia. Laboratory findings showed a normal serum copper level (104 microg/dl), high urinary copper level (2370 microg/dl), and low serum ceruloplasmin level (14.3 microg/dl). Slit-lamp examination revealed Kayser-Fleischer rings on her cornea, and she was diagnosed with Wilson's disease. Plasma exchange and continuous hemodiafiltration relieved the serious condition, after that laparoscopic examination was performed. Administration of D-penicillamine and restriction of dietary copper (<1 mg/day) were started, leading to a normalized serum alanine amino transferase (ALT) level. After 3 years, she again underwent laparoscopic examination, and the laparoscopic and histological findings of her liver were obviously improved. Management of the copper level can reverse severe liver fibrosis in Wilson's disease.

Percutaneous radiofrequency ablation with cooled electrodes combined with hepatic arterial balloon occlusion in hepatocellular carcinoma.

BACKGROUND: We have reported that percutaneous radiofrequency ablation (RFA) with balloon occlusion of the hepatic artery (balloon-occluded RFA), using an expandable electrode, increases the coagulation area. In this study, we investigated the efficacy of balloon-occluded RFA and balloon-microcatheter-occluded RFA, using a cool RF single electrode. METHODS: We studies 41 patients with 47 hepatocellular carcinoma (HCC) lesions. We treated 28 patients (32 nodules) with balloon-occluded RFA, 5 patients (6 nodules) with balloon-microcatheter-occluded RFA, and 8 patients (9 nodules) with standard RFA. Initial therapeutic efficacy was evaluated with dynamic computed tomography performed 1 week after one session of treatment. RESULTS: One session of treatment was done for 20 nodules (62.5%) in the balloon-occluded RFA group and for 4 nodules (66.7%) in the balloon-microcatheter-occluded RFA group. We compared the coagulation diameter for balloon-occluded RFA (7 nodules), balloon-microcatheter-occluded RFA (6 nodules), and standard RFA (9 nodules) after one application cycle (12 min). The greatest dimension of the area coagulated by balloon-occluded RFA was significantly larger (greatest long-axis dimension, 47.6 +/- 7.8 mm; greatest short-axis dimension, 33.4 +/- 7.5 mm) than that coagulated by standard RFA (greatest long-axis dimension, 35.3 +/- 4.7 mm; greatest short-axis dimension, 25.9 +/- 3.7 mm; P = 0.002 for greatest long-axis dimension; P = 0.041 for greatest short-axis dimension). However, there was significant difference only in the greatest short-axis dimension of the area coagulated comparing balloon-microcatheter-occluded RFA and standard RFA. CONCLUSIONS: We consider balloon-occluded RFA using a cool RF electrode to be superior to standard RFA for the treatment of HCC, especially when larger coagulation volumes are required.

Cytochrome c is a possible new marker for fulminant hepatitis in humans.

BACKGROUND: Cytochrome c is known as a substance related to apoptosis. We investigated serum cytochrome c levels in patients with fulminant hepatitis (FH) compared with these levels in patients with acute or chronic liver diseases. METHODS: Serum cytochrome c was measured by an electrochemiluminescence immunoassay (ECLIA) method. The numbers of patients were as follows: fulminant hepatitis (FH; n = 15), acute hepatitis (AH; n = 12), chronic hepatitis (CH; n = 30), chronic hepatitis with acute aggravation (CHA; n = 6), liver cirrhosis (LC; n = 30), hepatocellular carcinoma (HCC; n = 30), and healthy volunteers (controls; n = 9). RESULTS: The serum cytochrome c level in FH was 10 686 +/- 7787 pg/ml, with a significant difference (P < 0.01) compared to levels in the other groups. In the FH patients, the serum cytochrome c level was significantly correlated to serum mitochondria (m)-GOT, hepatocyte growth factor (HGF), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and alkaline phosphatase (ALP), and it was negatively correlated to serum alpha-fetoprotein (AFP), and total bilirubin (T.Bil.) The serum cytochrome c level seemed to parallel the severity of hepatic coma. Immunohistochemical study indicated TdT mediated dUTP nick end labeling (TUNEL)-positive cells in the livers of patients with FH. CONCLUSIONS: These results suggest that serum cytochrome c may be a possible new marker for acute liver failure.

Prognostic factors in patients with advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy.

BACKGROUND: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor. We aimed to clarify the prognostic factors in patients with advanced HCC receiving hepatic arterial infusion chemotherapy (HAIC). METHODS: Forty-four HCC patients were treated with HAIC, using low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) with/without leucovorin (or isovorin). Of these 44 patients, 15 received low-dose CDDP and 5-FU, and 29 received low-dose CDDP, 5-FU, and leucovorin or isovorin. Prognostic factors were evaluated by univariate and multivariate analyses of patient and disease characteristics. RESULTS: Of all patients, 5 and 12 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, 38%). The response rate (48.3%) in the low-dose CDDP and 5-FU with leucovorin/isovorin group was significantly better than that (20%) in the low-dose CDDP and 5-FU group (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative survival rates of the 44 patients were 39%, 18%, 12%, and 9%, respectively. The regimen using low-dose CDDP and 5-FU with leucovorin/isovorin tended to improve survival rates (P = 0.097). Univariate and multivariate analyses showed the same variables--the Child-Pugh score (P = 0.013, P = 0.018), alpha-fetoprotein (AFP) level (P = 0.010, P = 0.009), and therapeutic effect after HAIC (P = 0.003, P = 0.01), respectively, to be significant prognostic factors. CONCLUSIONS: Patients who had advanced HCC with favorable hepatic reserve capacity and a lower AFP level were suitable candidates for HAIC. Moreover, the regimen using low-dose CDDP and 5-FU with leucovorin/isovorin may be suitable for advanced HCC patients, because of the improvement in the response rate and survival compared with the low-dose CDDP and 5-FU regimen without leucovorin/isovorin.

Hepatocellular carcinoma with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) was originally believed to be a benign disease. However, it has been recently revealed that NASH could lead to irreversible liver disease in some patients. We report an unusual case of hepatocellular carcinoma (HCC) in a 76-year-old man with NASH. He had no history of alcohol consumption, drug use, or blood transfusion. He was negative for all serological viral markers and autoantibodies. In addition, he was obese (body mass index [BMI], 30.75 kg/m(2)) and had type 2 diabetes mellitus. A liver biopsy specimen showed moderate steatosis with necroinflammatory changes, ballooning degeneration, Mallory bodies, pericellular fibrosis, and evidence of nodular regeneration. He was diagnosed with NASH with cirrhosis. Simultaneously, a liver tumor, measuring 19 mm in diameter, was detected in segment 6. A tumor biopsy specimen revealed well-differentiated HCC, and imaging modalities confirmed the characteristics of HCC. To our knowledge, ten patients who had HCC with NASH were reported. In all patients with NASH and HCC, cirrhosis was present. Patients with NASH and cirrhosis may progress to HCC, and regular screening, based on tumor markers and imaging modalities, is needed to detect HCC in patients with NASH and cirrhosis.

Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell.

We have reported that Sho-saiko-to (TJ-9) prevents liver fibrosis in vivo. To gain further insights into the effect of TJ-9, the matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) balance was examined. Hepatic stellate cells (HSCs) were isolated from male Wistar rats and cultured with TJ-9 (0-1000 microg/ml) on uncoated plastic dishes for 4 days. To elucidate the effects on the MMPs/TIMPs balance by TJ-9, quantitative analysis of type IV collagen-degrading activity, gelatin zymography and reverse zymography were carried out. Northern blot analysis was performed to determine the expression of MMP-2, 13 and TIMP-1 mRNAs. TJ-9 treatment resulted in dose-dependent upregulation of MMP-2, 13 mRNA and downregulation of TIMP-1 mRNA up to 500 microg/ml. Gelatin zymography, reverse zymography and quantitative analysis of type IV collagen-degrading activity confirmed that TJ-9 increased MMP-2 activity and prevented TIMP-1, 2 activities in a dose-dependent manner. SB203580 diminished the reduction of mRNA as well as the activity of TIMP-1 by TJ-9 and induction of mRNA as well as the activity of MMP-2. These results show that TJ-9 increased MMP-2, 13 activity with reduced TIMP-1, 2 activities on HSCs possibly via P38 pathway.

Arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and isovorin for patients with advanced hepatocellular carcinoma, pilot study: Is a high dose of the biochemical modulator effective?

The authors report the efficacy of arterial infusion chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), and leucovorin (LV) for patients with advanced hepatocellular carcinoma (HCC). In this study, we evaluated the efficacy of our regimen with high-dose LV, using isovorin (IV) (high dose group), comparing the previous regimen (low-dose LV; low dose group). This is a retrospective, historical, and non-controlled trial. In the high dose group (n=15), one course of chemotherapy consisted of the daily administration of CDDP (10 mg/1 h, for 5 days) and IV (12.5 mg/10 min, for 5 days) followed by 5-FU (250 mg/5 h, for 5 days). In the low dose group (n=9), changing to the administration of LV (12 mg/day), the same regimen was employed. In principle, we did this 20 times. In the high dose group, complete response (CR) was found in two patients, and partial response (PR) in six patients. Thus, the response rate was 53%. In the low dose group, CR was found in two patients, and PR in three patients. Thus, the response rate was 56%. There were no significant differences in the response rate (P=0.71), the survival rate (P=0.29) and the toxicity between the two groups. We considered the recommended dose of LV to be 12 mg/day in our regimen, although this is a preliminary study.

Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.

BACKGROUND/AIMS: The herbal medicine Inchin-ko-to (TJ-135), extract power from three herbs, has recently been reported possessing anti-apoptotic activity. The aim of this study was to investigate whether TJ-135 has any influence on the development of preneoplastic lesions as well as liver fibrosis. METHODS: The effects of the TJ-135 were examined using the choline-deficient L-amino acid-defined diet-induced liver fibrosis model. In addition, the effect of TJ-135 on mitogen-activated protein (MAP) kinase, type III procollagen mRNA expression and the medium N-terminal procollagen III propeptide (PIIINP) concentration in a hepatic stellate cell line (LI90) were examined. RESULTS: TJ-135 prevented fibrosis in a dose-dependent manner up to 1.5% (w/w). TJ-135 also reduced the expression of type III procollagen mRNA in the liver, as well as the number of activated stellate cells. Furthermore, TJ-135 reduced the area of preneoplastic lesions in the liver. With LI90 cells, TJ-135 reduced MAP kinase (ERK and JNK but not P38) activities resulting in reduced type III procollagen mRNA and PIIINP concentrations in the medium in a dose-dependent manner. CONCLUSIONS: These results indicate that although TJ-135 has anti-apoptotic activity, TJ-135 does not increase preneoplastic lesions but significantly reduces liver fibrosis through the inhibition of stellate cell activation without a reduction of hepatocyte cell death.