Cumulative risk of developing a new symptom in patients with primary biliary cholangitis and its impact on prognosis.

Background and Aim: Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods: This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan-Meier analysis with propensity score matching and logistic progression analysis. Results: The cumulative risk of developing a new symptom after 10 and 20 years of follow-up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033-1.165; P = 0.002), the serum D-Bil level (HR, 6.262; 95% CI, 2.522-15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183-1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan-Meier analysis showed that the overall survival and liver-related death were not significant between patients with and without a new symptom. Conclusion: The cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D-Bil level, and Paris II criteria.

Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016.

AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

Effective prevention of sorafenib-related vascular damage induced adverse events and maintenance of hepatic function by dried bonito broth and histidine.

Background: Sorafenib (SOR) is an anti-angiogenic chemotherapeutic that prolongs the survival rates of patients with hepatocellular carcinoma. However, SOR also damages normal vasculature and causes associated adverse events, including hand-foot syndrome and hypertension (HT). We previously reported in an animal study that vascular damage resulted in the narrowing of the normal vascular dimension area in medaka fish (Oryzias), and histidine (HIS), a major amino acid contained in dried bonito broth (DBB), prevented these changes. Therefore, in the study, we analyzed the effects of DBB and HIS on SOR-related vascular damages and associated adverse events in patients. Materials and methods: Three-dimensional (3D) vascular images of abdominal regions reconstituted from computed tomography were assessed to compare vascular diameter prior to and following SOR administration in groups receiving SOR monotherapy, DBB+SOR, and HIS+SOR. The clinical courses of hand-foot syndrome and HT and the toxicities of SOR in biochemical assays were monitored and compared between the groups. Correlations between hepatic function and SOR-related changes in the portal venous area dimension were also assessed. Results: SOR-related vascular damage revealed narrowing of the normal abdominal vasculature in the human body, which was monitored using 3D images. The damage was ameliorated by DBB and HIS, however, HIS had a more marked effect, particularly on the renal arteries and portal vein (PV). Maintenance of blood flow contributed to the maintenance of total cholesterol, prothrombin time, albumin (ALB), and renal functions. Changes in the 3D vascular area dimension of the PV and level of serum ALB were significantly correlated. The occurrences of the clinical symptoms of hand-foot syndrome and HT were lower in the DBB- and HIS-treated groups. Conclusion: Our results clearly demonstrate that DBB and HIS prevented SOR-related abdominal vascular damage and effectively maintained hepatic function, and prevented clinical symptoms and toxicity. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000025937 and UMIN000026898).

A Case of Successful Treatment of Ruptured Pancreaticoduodenal Artery Aneurysm Caused by Celiac Artery Dissection.

A 52-year-old man was admitted due to severe epigastric lesion pain. Esophagus gastroduodenal endoscopy showed impaired duodenal dilatation, and contrast-enhanced computed tomography revealed a pancreaticoduodenal artery (PDA) aneurysm 13 mm in diameter below the head of the pancreas, retroperitoneal hematoma, idiopathic celiac artery (CA) dissection, and common hepatic artery disruption. Angiographic embolization with a mixture of N-butyl-1,2-cyanoacrylate and lipiodol was performed, and follow-up study showed improvement of the dilatation of the duodenum and disappearance of the aneurysm. Here we report a quite rare case of PDA aneurysm by idiopathic dissection of CA treated successfully with angiographic embolization.

Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model.

BACKGROUND: Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. METHODS: The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. RESULTS: Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. CONCLUSION: We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.

Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis.

UNLABELLED: There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. CONCLUSION: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity.

Rice cake ileus--a rare and ethnic but important disease status in east-southern Asia.

INTRODUCTION: Rice cake is a traditional but very popular food in Asia including Japan and has never been known as a cause of ileus. Rice cake is now becoming widespread in the United States and European countries along with other Japanese foods. We may encounter rice cake ileus all over the world. This study was aimed at characterizing the rice cake ileus. METHODS: We consecutively encountered 14 patients with rice cake ileus from April 2003 to October 2010 in our hospital. All of the characteristics of the cases were reviewed and analyzed. RESULTS: All patients had ingested rice cake by swallowing without chewing. It has most frequently occurred in January (57.1%). The main symptoms were abdominal colicky pain (100%) and nausea (85.7%) and physical findings included abdominal tenderness (100%) and muscular defense (28.6%). All patients improved by conservative therapy including fluid supply (100%), naso-gastric tube (28.6%) and long tube (28.6%) insertion. No patient needed emergency open surgery. CONCLUSION: Rice cake ileus which is caused by swallowing the rice cake without chewing, frequently occurs in January, has previous history of abdominal surgery and shows high density intestinal contents on CT and only needs conservative therapy. Globalism in food culture may provide a new disease entity. Therefore, we should be aware of this type of ileus and be prepared to manage it appropriately.

[Palliative anti-cancer chemotherapy is safely executable in a hemodialytic patient with unresectable advanced gastric cancer].

A 75-year-old man with chronic renal failure was on maintenance hemodialysis.He was admitted to our hospital for advanced gastric cancer with multiple liver metastases (cStage IV).Three courses of tegafur-uracil (300 mg/day daily) plus docetaxel (20 mg/m², every 3 weeks) as first-line treatment and nine courses of tegafur-uracil (same dose) plus CPT-11 (64 mg/m², day 1, 15, every 4 weeks) were given without any complications.Docetaxel and CPT-11 were given on days between hemodialyses. No severe adverse effects of more than grade 3 were encountered. The standard regimens in our country for unresectable advanced gastric cancer are the S-1 single or S-1/CDDP combined chemotherapies that have already been evidenced in the JCOG 9912 and SPIRITS trial. However, no standard chemotherapy for patients on hemodialysis has been reported as yet.Therefore, doctors in charge must arrange an individualized regimen for each patient, considering metabolic characteristics of each anti-cancer agent.In this context, our case was considered to be very suggestive, and that is why we report it here in detail.

TTF-1 is useful for primary site determination in duodenal metastasis.

We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel associated with irradiation of 60 Gy shrunk the lung tumor. However, soon after,the para-aortic lymph node became swollen. Esophagogastroduodenoscopy revealed three duodenal tumors. Differential diagnosis between malignant lymphoma and metastatic duodenal cancer was endoscopically difficult. The histology of biopsied specimens was poorly differentiated adenocarcinoma. Immunohistochemical analysis revealed a positive reaction for thyroid transcription factor-1 (TTF-1). Thus, we concluded that these were metastatic duodenal tumors from lung adenocarcinoma. Two courses of gemcitabine led to a complete remission in this duodenal metastasis and para-aortic lymph node swelling with only scarring remaining in computed tomography. He is now on the continuous generalized chemotherapy. In conclusion, duodenal metastasis from primary lung adenocarcinoma is rare and hard to diagnose. In such an instance, TTF-1 immunostaining is crucial to obtain the correct diagnosis.

[Case of visceral varicella-zoster virus infection after autologous peripheral blood stem cell transplantation in which severe abdominal pain preceded the skin rash].

We report a 54-year-old man who developed visceral varicella-zoster virus (VZV) infection after autologous peripheral blood stem cell transplantation (auto-PBSCT) without using immunosuppressive agents for multiple myeloma. He suffered from severe abdominal pain 2 months after auto-PBSCT, and morphine chloride was needed to control it. Since the characteristic skin rash of VZV infection appeared over his entire body on the seventh hospital day, aciclovir was immediately started with favorable results. It is extremely difficult to diagnose VZV infection when severe abdominal pain proceeds and the eruptions characteristic of VZV infections are absent. This may also result in devastating delays in effective antiviral treatment. The increase in fat density around the celiac trunk and the root of the superior mesenteric artery on computed tomography shown in this case may has contributed to the correct diagnosis of visceral VZV infection.

Hepatocellular carcinoma, with portal thrombus after viral eradication, disappeared by 5-fluorouracil and interferon.

Hepatocarcinogenesis after a sustained virological response (SVR) in type C chronic hepatitis and cirrhosis is an important issue in endemic areas; hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) therapy is especially very hard. We herein report a first case in which combination therapy with interferon-α and continuous intra-arterial infusion of 5-fluorouracil (designated as FAIT) provided a complete response in HCC with PVTT after SVR. Therefore, we think that FAIT is a good option to treat HCC with or without PVTT, even after SVR.

A Fatal Aortoesophageal Fistula Caused by Critical Combination of Double Aortic Arch and Nasogastric Tube Insertion for Superior Mesenteric Artery Syndrome.

Double aortic arch (DAA) is a rare vascular congenital abnormality. Since a vascular ring surrounds bronchus and esophagus, any oral or nasal intubation can physically cause fatal aortoesophageal fistula (AEF). We report herein the first case of association of DAA and superior mesenteric artery (SMA) syndrome and the second case of AEF caused by nasogastric intubation in an adult with DAA. A 19-year-old woman visited our hospital for nausea and vomiting. She was diagnosed with SMA syndrome by computed tomography (CT). Nasogastric intubation relieved her symptoms in 4 days. Extramural compression with top ulceration was found in esophagogastroduodenoscopy on the 5th hospital day. She suddenly showed massive hematemesis on the 12th hospital day. AEF was found by CT. Soon, she died despite of intensive care. Retrospective interview disclosed the fact that DAA was pointed out in her childhood. We conclude that intubation must be avoided in DAA and a detailed clinical interview about DAA is mandatory to avoid AEF.

[An elderly hemodialytic case of recurrent esophageal cancer given combination chemotherapy with docetaxel and nedaplatin who showed temporal relief of swallowing disturbance].

An 82-year-old man was admitted for recurrent and unresectable esophageal cancer. His performance status was grade 2, although he was on hemodialysis due to chronic renal failure since 2003. Esophagogastroduodenoscopy revealed stenosis of esophagus by the recurrent tumor. After percutaneous endoscopic gastrostomy, he received biweekly combination chemotherapy with docetaxel (18 mg/m(2)) and nedaplatin (16 mg/m(2)). Hemodialysis was carried out one hour after termination of nedaplatin infusion. As severe adverse reactions due to anticancer-chemotherapy were not encountered, he could receive four courses of chemotherapy in our outpatient clinic. Difficulty in swallowing improved after the second course was finished. Finally, he died of acute myocardial infarction. In conclusion, combination chemotherapy with docetaxel and nedaplatin can be safely carried out for a patient with recurrent and unresectable esophageal cancer even on hemodialysis by appropriate down-dosing of anticancer agents.

Intestinal anisakiasis can cause intussusception in adults: an extremely rare condition.

We report an extremely rare case of adult intussusception caused by anisakiasis. A 41-year-old man was admitted into our hospital for right lower abdominal colicky pain. Ultrasonography and computed tomography revealed the presence of intussusception. As pneumo-dynamic resolution by colonoscopy failed, surgery was performed. The anisakis body was found in the submucosal layer of the resection specimen. The patient was discharged 9 d after the operation. Anisakiasis may cause intussusception in any country where sushi or sashimi now exists as a popular food. If suspicious, detailed clinical interview as to food intake prior to symptom development is crucial.

[A case of intestinal tuberculosis associated with ileo-ileal fistula].

A 25-year-old woman was admitted with fever and right lower abdominal pain that had started 3 days after the administration of antituberculosis agents for pulmonary tuberculosis. She was given a diagnosis of intestinal tuberculosis with ileo-ileal fistula formation on computed tomography, colonoscopy and laboratory test findings. She was kept on anti-tuberculosis agents. Soon after, ileus and a micro abscess appeared near the fistula. Ileocecal resection with partial ileal resection resulted in a good postoperative clinical course. Tuberculosis is still a major infectious disease. Intestinal tuberculosis is very rarely associated with fistula formation, and when it occurs, is difficult to differentiate from Crohn disease. Our case strongly suggests that typical intestinal tuberculosis findings can help in differential diagnosis between intestinal tuberculosis and Crohn disease.

[Retrospective analysis of generalized chemotherapy for unresectable advanced gastric cancer].

In Japan where the incidence of gastric cancer is high, the standard regimens for unresectable advanced gastric cancer are the S-1 single or S-1/CDDP combined therapies that are evidenced by the JCOG9912 and SPIRITS trial. We performed retrospective analysis on chemotherapy for unresectable advanced gastric cancer in our division from 2003 to 2008. Seventy-six patients were subjected to this study. Among them, 66 patients (86.8%) received S-1-containing regimens. Mean survival time (MST) of all patients was 309 days. MST of S-1/Paclitaxel (PTX), S-1/CPT-11 and S-1/CDDP regimens were 289, 339 and 411 days, respectively. MST of S-1/CPT-11 was significantly longer than that of S-1/PTX (p<0. 01). Next, we compared the MST among different performance statuses (PS). The respective MST of PS 0, 1, 2 cases (361, 289 and 161 days) evidenced no statistically significant difference, although the MST was shorter depending on the progression of PS. Considering the histology, the MST of patients with well- and moderately-differentiated adenocarcinoma was significantly longer than that of poorly-differentiated adenocarcinoma and signet-ring cell carcinoma (p=0. 04). The call is for more effective chemotherapy in the future based on results we will obtain from controlled studies that may also deal with the second-line chemotherapy regimens, chemotherapy for aged people and molecular-targeting cancer agents.

Thyroid Metastasis of Gastric Cancer: A Rare Occasion With Poor Prognosis.

A 68-year-old man was diagnosed as having advanced gastric cancer. Computed tomography showed a thyroid tumor with trachea deviation. This tumor exhibited mosaic echogenecity in ultrasonography. Signet-ring cell carcinoma was found by means of fine needle aspiration biopsy. This tumor gradually became swollen and the thyroid hormone levels in blood were increased without any clinical symptom. Shortly, he died from his illness in the 29th hospital day. Autopsy disclosed that the left lobe of the thyroid gland was highly invaded by malignant cells and that lymphogenic rather than angiogenic metastasis was highly probable. Thyroid metastasis of gastric cancer is extremely rare. The prognosis is very poor. Ultrasonography is a very useful modality especially when coupled with recently developed fine needle aspiration biopsy in differential diagnosis of thyroid tumors once malignancy is suspected. Therapeutic strategy largely depends on the nature of primary malignant tumor. If the tumor is slowly progressive such as renal cell carcinoma and breast cancer, extirpation of thyroid tumors may extend life expectancy. In conclusion, the metastatic thyroid tumor of gastric cancer is rare and shows poor prognosis. Fine needle aspiration biopsy under ultrasonography is strongly recommended as a useful diagnostic tool.

[A pregnant woman with inoperable advanced gastric cancer who received systemic anti-cancer chemotherapy after the non-full term fetus delivery by cesarean section].

A 28-year-old pregnant woman at 26 weeks and 2 days gestation visited a local outpatient clinic complaining of a tender abdominal mass. Examinations revealed an advanced gastric cancer with multiple liver, bone, lymph node metastasis and mesenteric dissemination, thus she was transferred to our division at 27 weeks and 1 day-gestation. With her consent we decided to maintain her pregnancy until 28 weeks when the delivered fetus could be kept alive an incubator, avoiding the adverse effect on the fetus by anti-cancer chemotherapy to mother. Rapid fetus delivery by cesarean section was carried out at 28 weeks and 1 day gestation, yielding a 958-gram baby. The mother complained of respiratory distress and suffered from lymphangitis carcinomatosa on the 3 postoperative day. We began combination chemotherapy with S-1 and paclitaxel (S-1 100 mg/day, 3 weeks on, 2 weeks off and paclitaxel 70 mg/day on 1, 8 and 15) was started on the 4th postoperative day. Although temporary regression of lymphangitis carcinomatosa was seen with a relief of symptoms, her condition deteriorated on the 24th days. The second course chemotherapy was started on the 28th days without any relief of symptoms. Her general status deteriorated and she died on the 33rd postoperative day. The association of pregnancy and gastric cancer is rare but such cases are often in an advanced clinical stage, with bad prognosis. It is necessary to determine the treatment strategy on the basis of comprehensive consideration of the status of both the mother and fetus. Upper gastrointestinal endoscopy when gastric cancer is suspected is recommended in any pregnant woman with long-term morning sickness.

[A case of interstitial pneumonia induced by gemcitabine hydrochloride for unresectable bile duct cancer].

A 78-year-old man was admitted for obstructive jaundice and unresectable bile duct cancer on March 4, 2008. Since biliary drainage was extremely difficult, he began 2 treatment courses of gemcitabine hydrochloride (GEM 800 mg/m(2) on days 1, 8, 15 every 4 weeks). He suffered from dry cough and dyspnea on May 13, 2008. He was diagnosed as GEM-induced interstitial pneumonia with severe hypoxemia by CT scan and arterial blood gas examination. He recovered with two courses of steroid pulse therapy, diuretics and antibiotics. Alternatively, he was given oral S-1 ( 80 mg/m(2) 4 weeks on and 2 weeks off) from June 12, 2008. His QOL was well kept without jaundice for as long as a half year. This is the first report of GEM-induced interstitial pneumonia in bile duct cancer. In conclusion, interstitial pneumonia must be taken into consideration as a rare adverse reaction when GEM is used for biliary neoplasms.

[A case of hepatocellular carcinoma with liver cirrhosis type C surviving over 2 years by repeated transarterial infusion therapy using cisplatinum].

A 58-year-old man with hepatocellular carcinoma (HCC) with liver cirrhosis type C was admitted to our division in April, 2004 to receive transarterial chemo-embolization (TACE) as a first-line chemotherapy for HCC. Thereafter, he had TACE twice for multicentric HCC. In December, 2005, TACE was thought to have become ineffective since his multicentric HCC progressed. So, we employed transarterial injection therapy (TAI) with fine powder cisplatinum (IAC) as a second-line chemotherapy. Stable disease was accomplished by the 22 sessions of TAI with IAC. After February 2008, IAC was given in combination with degradable starch microspheres (DSM) to reinforce the anti-cancer effect. The total therapeutic sessions using IAC became 26 in number. Total IAC amount used reached to more than 2,200 mg without any serious adverse reaction. In conclusion, TAI using IAC is thought to be effective in the chemotherapy of HCC, safely controlling the tumor progression.