Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis.

BACKGROUND: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. PATIENTS AND METHODS: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. RESULTS: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). CONCLUSIONS: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.

External Validation of the FSAC Model Using On-Therapy Changes in Noninvasive Fibrosis Markers in Patients with Chronic Hepatitis B: A Multicenter Study.

Antiviral therapy (AVT) induces the regression of non-invasive fibrosis markers (NFMs) and reduces hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients. We externally validated the predictive performance of the FSAC prediction model for HCC using on-therapy NFM responses. Our multicenter study consecutively recruited treatment-naïve CHB patients (n = 3026; median age, 50.0 years; male predominant (61.3%); cirrhosis in 1391 (46.0%) patients) receiving potent AVTs for >18 months between 2007 and 2018. During follow-up (median 64.0 months), HCC developed in 303 (10.0%) patients. Patients with low FIB-4 or APRI levels at 12 months showed significantly lower HCC risk than those with high NFM levels at 12 months (all p < 0.05). Cumulative 3-, 5-, and 8-year HCC probabilities were 0.0%, 0.3% and 1.2% in the low-risk group (FSAC ≤ 2); 2.1%, 5.2%, and 11.1% in the intermediate-risk group (FSAC 3-8); and 5.2%, 15.5%, and 29.8% in the high-risk group (FSAC ≥ 9) (both p < 0.001 between each adjacent pair). Harrell's c-index value for FSAC score (0.770) was higher than those for PAGE-B (0.725), modified PAGE-B (0.738), modified REACH-B (0.737), LSM-HCC (0.734), and CAMD (0.742). Our study showed that the FSAC model, which incorporates on-therapy changes in NFMs, had better predictive performance than other models using only baseline parameters.

Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis.

This study aimed to evaluate the predictive performance of pre-existing well-validated hepatocellular carcinoma (HCC) prediction models, established in patients with HBV-related cirrhosis who started potent antiviral therapy (AVT). We retrospectively reviewed the cases of 1339 treatment-naïve patients with HBV-related cirrhosis who started AVT (median period, 56.8 months). The scores of the pre-existing HCC risk prediction models were calculated at the time of AVT initiation. HCC developed in 211 patients (15.1%), and the cumulative probability of HCC development at 5 years was 14.6%. Multivariate Cox regression analysis revealed that older age (adjusted hazard ratio [aHR], 1.023), lower platelet count (aHR, 0.997), lower serum albumin level (aHR, 0.578), and greater LS value (aHR, 1.012) were associated with HCC development. Harrell's c-indices of the PAGE-B, modified PAGE-B, modified REACH-B, CAMD, aMAP, HCC-RESCUE, AASL-HCC, Toronto HCC Risk Index, PLAN-B, APA-B, CAGE-B, and SAGE-B models were suboptimal in patients with HBV-related cirrhosis, ranging from 0.565 to 0.667. Nevertheless, almost all patients were well stratified into low-, intermediate-, or high-risk groups according to each model (all log-rank p < 0.05), except for HCC-RESCUE (p = 0.080). Since all low-risk patients had cirrhosis at baseline, they had unneglectable cumulative incidence of HCC development (5-year incidence, 4.9−7.5%). Pre-existing risk prediction models for patients with chronic hepatitis B showed suboptimal predictive performances for the assessment of HCC development in patients with HBV-related cirrhosis.

Novel Liver Stiffness-Based Nomogram for Predicting Hepatocellular Carcinoma Risk in Patients with Chronic Hepatitis B Virus Infection Initiating Antiviral Therapy.

Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0-304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88-222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 (internal validity: 0.805), higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir.

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESCAVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB-4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC-ESCAVT category (0-1, 2-4 and 5 for the low-, intermediate- and high-risk groups, respectively) (overall P < .001, log-rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC-ESCAVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC-ESCAVT model for HCC development, which includes male sex, cirrhosis and FIB-4 of >3.25 as constituent variables.

An observational study on long-term renal outcome in patients with chronic hepatitis B treated with tenofovir disoproxil fumarate.

In patients with chronic hepatitis B (CHB), long-term effects of tenofovir disoproxil fumarate (TDF) on renal function have been controversial. This study aimed to analyse the real-world long-term effects of TDF on renal function in Korean patients with CHB. We analysed a cohort of 640 treatment-naïve patients with CHB who were treated with TDF between May 2012 and December 2015 at Severance Hospital, Seoul, Republic of Korea. The mean age was 48.3 years old, and 59.5% were male. The proportions of hypertension and diabetes mellitus (DM) were 11.6% and 14.2%, respectively, and that of liver cirrhosis was 20.8%. During the 5-year follow-up, using a linear mixed model, serum creatinine increased from 0.77 ± 0.01 mg/dL to 0.85 ± 0.02 mg/dL (P < .001), and eGFR decreased from 102.6 ± 0.6 mL/min/1.73 m2 to 93.4 ± 1.4 mL/min/1.73 m2 (P < .001). In subgroup analysis, eGFR was statistically more decreased in patients with age > 60 than ≦60 years old (P = .027), and in patients with diuretic use than without diuretic use (P = .008). In multivariate analysis, the independent risk factors for eGFR decrease > 20% were baseline eGFR < 60mL/min/1.73 m2 (P = .034) and the use of diuretics (P < .001). CHB patients on TDF experienced greater reduction in renal function with age > 60 and with diuretic use compared to those without these characteristics. Baseline eGFR < 60 mL/min/1.73 m2 and use of diuretics were independent risk factors of eGFR decline of more than 20% on TDF therapy.

Establishment and validation of a risk prediction model in patients with hepatocellular carcinoma treated with transarterial radioembolization.

BACKGROUND/AIMS: Few studies have reported the treatment outcomes of transarterial radioembolization (TARE) using yttrium-90 (Y) for hepatocellular carcinoma (HCC). We established and validated a new risk prediction model for patients with HCC treated with TARE. METHODS: Between 2010 and 2017, 113 and 35 patients with intrahepatic HCC treated with TARE were selected for the training and validation cohorts, respectively. The modified response evaluation criteria in solid tumors (mRECIST) were used for response evaluation. RESULTS: In the training cohort, the median age was 64.1 years (92 males and 21 females) and the mean survival after TARE was 50.3 months. The cumulative survival rates at six and 12 months were 92.0 and 84.0%, respectively. A new risk prediction model for patients with HCC treated with TARE (Y-scoring system) was established from the training cohort using five independent baseline variables [serum albumin < 3.5 g/dL, hazard ratio = 5.446; alpha-fetoprotein > 200 ng/mL (hazard ratio = 5.071); tumor number ≥ 3 (hazard ratio = 2.933); portal vein thrombosis (hazard ratio = 4.915); and hepatic vein invasion (hazard ratio = 8.500)] and two on-treatment variables [no des-gamma-carboxy prothrombin response (hazard ratio = 15.346) and progressive disease at three months (hazard ratio = 4.154)] for mortality (all P < 0.05). The predictive accuracy of the Y-scoring system was acceptable to predict six [area under the curve (AUC) = 0.845], nine (AUC = 0.868), and 12-month mortality (AUC = 0.886) (all P < 0.05). The predictive accuracy of the system was similarly maintained in the validation cohort (AUC 0.737-0.901 at 6-12 months). CONCLUSION: Our new risk prediction model can be used to stratify different prognoses in patients with HCC treated with TARE. Validation studies are required.

Alpha-Fetoprotein, Des-Gamma-Carboxy Prothrombin, and Modified RECIST Response as Predictors of Survival after Transarterial Radioembolization for Hepatocellular Carcinoma.

PURPOSE: To evaluate the prognostic role of alpha-fetoprotein (AFP), des-gamma-carboxy protein (DCP), and modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with hepatocellular carcinoma after transarterial radioembolization (TARE). MATERIALS AND METHODS: During 2009-2016, 63 patients with AFP >20 ng/mL, DCP >20 mAU/mL, and Child-Pugh class A who were treated with TARE were evaluated using landmark and risk-of-death method after TARE. Both resin microspheres (n = 46) and glass microspheres (n = 17) were used. AFP or DCP response was defined as more than 50% decrease from baseline. mRECIST response was defined as complete or partial response. Median age was 60 years, and the proportion of male sex was 77.8% (n = 49). The proportions of patients with Barcelona Clinic Liver Cancer stages A, B, and C were 7.9% (n = 5), 46.0% (n = 29), and 46.0% (n = 29), respectively. RESULTS: At the 3-month landmark, AFP, DCP, and mRECIST responders lived longer than nonresponders (median overall survival, 75.8 vs 7.6 months for AFP; 75.8 vs 7.1 months for DCP; and 75.8 vs 10.0 months for mRECIST; all P < .05). The 6-month risk of death at the 3-month landmark was statistically different only between DCP responders and nonresponders (P = .002). In multivariate analysis, age less than 70 years (P = .024), absence of distant metastasis (P = .049), DCP response (P = .003), and mRECIST response (P = .003) were independent predictors for overall survival at the 3-month landmark after TARE. CONCLUSIONS: AFP, DCP, and mRECIST responders showed better prognosis than nonresponders after TARE, and DCP response was a more potent predictor than AFP response. Tumor marker response, as well as radiologic response, may be useful to predict post-TARE survival.

Transarterial Chemoembolization in Treatment-Naïve and Recurrent Hepatocellular Carcinoma: A Propensity-Matched Outcome Analysis.

OBJECTIVES: Transarterial chemoembolization (TACE) improves the survival of patients with hepatocellular carcinoma (HCC); however, TACE treatment outcomes of patients with treatment-naïve HCC (TN-HCC) and those with recurrent HCC after curative resection (R-HCC) have not yet been compared. METHODS: We recruited 448 patients with TN-HCC, and 275 patients with R-HCC treated with TACE as first-line anti-cancer treatment. RESULTS: At first TACE, patients with TN-HCC showed a significantly lower proportion of male gender (74.9% vs. 84.3%), higher proportion of liver cirrhosis (61.9% vs. 49.3%), higher aspartate aminotransferase (median 48 vs. 31 IU/L), alanine aminotransferase (median 38 vs. 26 IU/L), alpha-fetoprotein (AFP) (median 96.6 vs. 7.7 ng/mL), and total bilirubin (mean 1.0 vs. 0.8 mg/dL) levels, longer prothrombin time (median 1.05 vs. 1.01 international normalized ratio), higher tumor number (mean 2.1 vs. 1.7), larger tumor size (median 3.1 vs. 1.6 cm), and lower proportion of Barcelona Clinic Liver Cancer stage 0-A (55.6% vs. 71.9%) than patients with R-HCC (all P < 0.05). Multivariate analysis showed that TACE for TN-HCC (vs. R-HCC) was an independent predictor of mortality (hazard ratio, 1.328; P = 0.024) with AFP level and tumor number (all P < 0.05). However, treatment outcomes between TN-HCC and R-HCC became statistically similar after propensity score-matched (PSM) analysis using liver cirrhosis, tumor size, and multiple tumors (P < 0.05). CONCLUSIONS: Based on the similar TACE treatment outcomes observed with the PSM analysis, the current TACE treatment guideline for patients with TN-HCC might similarly be applied for patients with R-HCC.

Refractoriness to transarterial chemoembolization in patients with recurrent hepatocellular carcinoma after curative resection.

BACKGROUND/AIMS: It is important to identify patients who are refractory to transarterial chemoembolization (TACE), which is performed for the treatment of hepatocellular carcinoma (HCC). We investigated the predictors of poor treatment outcomes in patients with recurrent HCC treated who were treated with TACE after curative resection. METHODS: 428 patients with recurrent HCC after curative resection who were treated with TACE were enrolled. RESULTS: The median age of the study population was 59.2 years. On multivariate analysis, ≥2 TACE procedures within 6 months (hazard ratio [HR] = 1.898), and the des-gamma carboxyprothrombin level (HR = 1.000) independently predicted the progression to Barcelona Clinic Liver Cancer (BCLC) stage C in patients with BCLC stage 0-B HCC (both P<0.05). In addition, ≥2 and ≥3 TACE procedures within 6 months independently predicted mortality in the entire study population (HR = 1.863 and 1.620, respectively). The probability of progression to BCLC stage C in patients with BCLC stage 0-B HCC and the mortality rate in the entire study population were significantly higher in patients treated with ≥2 TACE within 6 months than in those who underwent fewer procedures (P = 0.002 and P<0.001, respectively). CONCLUSIONS: More than 2 TACE procedures within 6 months might be associated with the refractoriness to TACE in patients with recurrent HCC after curative resection.

Conditional Survival Estimates Improve Over Time for Patients with Hepatocellular Carcinoma: An Analysis for Nationwide Korea Cancer Registry Database.

PURPOSE: Conditional survival estimates (CSE) can provide additional useful prognostic information on the period of survival after diagnosis, which helps in counseling patients with cancer on their individual prognoses. This study aimed to analyze conditional survival (CS) for hepatocellular carcinoma (HCC) using a Korean national registry. MATERIALS AND METHODS: Patients with HCC, registered in the Korean cancer registry database, were retrospectively reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method. The 1-year CS at X year or month after diagnosis were calculated as CS1=OS(X+1)/OS(X). CS calculations were performed in each Barcelona Clinic Liver Cancer stage, after which patients at stage 0, A, and B underwent subgroup analysis using initial treatment methods. RESULTS: A total of 4,063 patients diagnosed with HCC from January 2008 to December 2010, and 2,721 who were diagnosed from January 2011 to December 2012, were separately reviewed. In 2008-2010, the 1-year CS of 1, 2, 3, 4, and 5-year survivors was 82.9%, 85.1%, 88.3%, 88.0%, and 88.6%, respectively. Patients demonstrated an increase in CSE over time in subgroup analysis, especially in the advanced stages. In 2011-2012, the 1-year CS of 6, 12, 18, 24, 30, and 36 months was 81.5%, 83.8%, 85.3%, 85.5%, 86.5%, and 88.8%, respectively. The subgroup analysis showed the same tendency towards increased CSE in the advanced stages. CONCLUSION: Overall, the CS improved with each additional year after diagnosis in both groups. CSE may therefore provide a more accurate prognosis and hopeful message to patients who are surviving with or after treatment.

Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma.

Background The pivotal RESORCE trial showed that regorafenib was effective as second-line therapy for patients with advanced HCC who progressed on first-line sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Methods Between April 2017 and August 2017, the Named Patient Program (NPP) was activated to provide controlled, pre-approval access of regorafenib in Korea. This analysis is a multicenter retrospective study of patients who received regorafenib under the NPP. Results A total of 49 patients entered into this NPP, and 40 patients received regorafenib in five Korean institutions. All but one patient received regorafenib as second-line therapy after progression on sorafenib, and 36 (90%) and 34 (85%) patients were classified as Child-Pugh A and BCLC stage C, respectively. The response rate was 10% (n = 4). The median progression-free survival (PFS) was 3.7 months (95% CI, 2.5-4.9 months), and the median overall survival (OS) was not reached. The 1 year OS rate was 54.6%. The time-to-progression (TTP) on prior sorafenib was significantly associated with PFS and OS. The most common grade 3-4 toxicities were hand-foot skin reaction (n = 3, 8%), hypertension (n = 2, 5%), and increased aspartate aminotransferase (n = 2, 5%). Conclusion Regorafenib was well-tolerated and effective in patients with advanced HCC who progressed on first-line sorafenib, with efficacy and safety outcomes consistent with those of the previous RESORCE trial. TTP on first-line sorafenib may predict the efficacy of subsequent regorafenib.

Combined use of AFP, PIVKA-II, and AFP-L3 as tumor markers enhances diagnostic accuracy for hepatocellular carcinoma in cirrhotic patients.

OBJECTIVE: As data on the effectiveness of tumor markers in detecting hepatocellular carcinoma (HCC) in cirrhotic patients are limited, we investigated the diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3). MATERIAL AND METHODS: This retrospective study enrolled 361 cirrhotic patients with HCC, and 276 cirrhotic patients without HCC occurrence. RESULTS: Most patients were men (n = 431, 67.7%); the median age was 57.0 years. The main etiology of chronic liver disease was chronic hepatitis B (n = 467, 73.3%). The sensitivity and specificity of combined three biomarkers was 87.0 and 60.1% in overall HCC, and 75.7 and 60.1% in early HCC, respectively (cutoff: 20 ng/mL for AFP, 40 mAU/mL for PIVKA-II, and 5% for AFP-L3). The area under the receiver operating characteristic curve (AUROC) for HCC diagnosis was 0.765 (95% confidence interval [CI], 0.728-0.801) for AFP; 0.823 (95% CI, 0.791-0.854) for PIVKA-II; and 0.755 (95% CI, 0.718-0.792) for AFP-L3. The AUROC for early HCC diagnosis was 0.754 (95% CI, 0.691-0.816) for AFP, 0.701 (95% CI, 0.630-0.771) for PIVKA-II, and 0.670 (95% CI, 0.596-0.744) for AFP-L3. Combining the three tumor markers increased the AUROC to 0.877 (95% CI, 0.851-0.903) for HCC diagnosis, and 0.773 (95% CI, 0.704-0.841) for early HCC diagnosis. CONCLUSION: Diagnostic accuracy improved upon combining the AFP, PIVKA-II, and AFP-L3 tumor markers compared to each marker alone in detecting HCC and early HCC in cirrhotic patients.

[A case of alpha-cell nesidioblastosis and hyperplasia with multiple glucagon-producing endocrine cell tumor of the pancreas].

Nesidioblastosis is a term used to describe pathologic overgrowth of pancreatic islet cells. It also means maldistribution of islet cells within the ductules of exocrine pancreas. Generally, nesidioblastosis occurs in beta-cell and causes neonatal hyperinsulinemic hypoglycemia or adult noninsulinoma pancreatogenous hypoglycemia syndrome. Alpha-cell nesidioblastosis and hyperplasia is an extremely rare disorder. It often accompanies glucagon-producing marco- and mircoadenoma without typical glucagonoma syndrome. A 35-year-old female was referred to our hospital with recurrent acute pancreatitis. On radiologic studies, 1.5 cm sized mass was noted in pancreas tail. Cytological evaluation with EUS-fine-needle aspiration suggested serous cystadenoma. She received distal pancreatectomy. The histologic examination revealed a 1.7 cm sized neuroendocrine tumor positive for immunohistochemical staining with glucagon antibody. Multiple glucagon-producing micro endocrine cell tumors were scattered next to the main tumor. Additionally, diffuse hyperplasia of pancreatic islets and ectopic proliferation of islet cells in centroacinar area, findings compatible to nesidioblastosis, were seen. These hyperplasia and almost all nesidioblastic cells were positive for glucagon immunochemistry. Even though serum glucagon level still remained higher than the reference value, she has been followed-up without any evidence of recurrence or hormone related symptoms. Herein, we report a case of alpha-cell nesidioblastosis and hyperplasia combined with glucagon-producing neuroendocrine tumor with literature review.

Therapeutic strategies for well-differentiated papillary mesothelioma of the peritoneum.

OBJECTIVE: Well-differentiated papillary mesothelioma is an uncommon subtype of mesothelioma with a frequently indolent course, although it occasionally manifests in a more aggressive form. To establish a treatment strategy for this rare disease, we report the clinical characteristics and outcomes of 15 patients with well-differentiated papillary mesothelioma. METHODS: All pathologically diagnosed well-differentiated papillary mesothelioma cases were reviewed between 1998 and 2012. RESULTS: Of the 15 cases, 8 and 7 presented with single and multiple lesions, respectively. All cases with single lesions were asymptomatic, while 4 out of the 7 cases with multiple lesions were symptomatic. After tumor excision, none of the eight single-lesion cases experienced tumor recurrence. Among the other seven cases with multiple lesions, only one patient with disseminated lesions died due to disease burden. Five patients with multiple lesions received cisplatin-based intravenous or intraperitoneal chemotherapy, with a mix of complete (n= 2) and partial (n= 2) responses observed. Of particular note, one patient receiving cisplatin and pemetrexed combination chemotherapy experienced complete tumor resolution without any serious toxicity. CONCLUSIONS: We recommend different treatment strategies based on the disease status. If the tumor is completely resectable, an excisional biopsy seems to be sufficient. If complete resection is unavailable for the asymptomatic patient with a localized tumor extent, close follow-up is an appropriate option. When the tumor is extensive or accompanied by symptoms, chemotherapy should be strongly considered.