Does the bile duct angulation affect recurrence of choledocholithiasis?

AIM:To investigate whether bile duct angulation and T-tube choledochostomy influence the recurrence of choledocholithiasis.METHODS:We conducted a retrospective study including 259 patients who underwent endoscopic sphincterotomy and cholecystectomy for choledocholithiasis between 2000 and 2007.The imaginary line was drawn along the center of the bile duct and each internal angle was measured at the two angulation sites ofthe bile duct respectively.The values of both angles were added together.We then tested our hypothesis by examining whether T-tube choledochostomy was performed and stone recurrence occurred by reviewing each subject's medical records.RESULTS:The overall recurrence rate was 9.3% (24 of 259 patients).The mean value of sums of angles in the recurrence group was 268.3°± 29.6°,while that in the non-recurrence group was 314.8°± 19.9° (P < 0.05).Recurrence rate of the T-tube group was 15.9% (17 of 107),while that of the non T-tube group was 4.6% (7 of 152) (P < 0.05).Mean value of sums of angles after T-tube drainage was 262.5°± 24.6° and that before T-tube drainage was 298.0°± 23.9° in 22 patients (P < 0.05).CONCLUSION:The bile duct angulation and T-tube choledochostomy may be risk factors of recurrence of bile duct stones.

Delivery of nitric oxide-releasing silica nanoparticles for in vivo revascularization and functional recovery after acute peripheral nerve crush injury

Nitric oxide(NO)has been shown to promote revascularization and nerve regeneration after peripheral nerve injury.However,in vivo application of NO remains challenging due to the lack of stable carrier materials capable of storing large amounts of NO molecules and releasing them on a clinically meaningful time scale.Recently,a silica nanoparticle system capable of reversible NO storage and release at a controlled and sustained rate was introduced.In this study,NO-releasing silica nanoparticles(NO-SNs)were delivered to the peripheral nerves in rats after acute crush injury,mixed with natural hydrogel,to ensure the effective application of NO to the lesion.Microangiography using a polymer dye and immunohistochemical staining for the detection of CD34(a marker for revascularization)results showed that NO-releasing silica nanoparticles increased revascularization at the crush site of the sciatic nerve.The sciatic functional index revealed that there was a significant improvement in sciatic nerve function in NO-treated animals.Histological and anatomical analyses showed that the number of myelinated axons in the crushed sciatic nerve and wet muscle weight excised from NO-treated rats were increased.Moreover,muscle function recovery was improved in rats treated with NO-SNs.Taken together,our results suggest that NO delivered to the injured sciatic nerve triggers enhanced revascularization at the lesion in the early phase after crushing injury,thereby promoting axonal regeneration and improving functional recovery.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice:effects of 4-aminopyridine

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.

Survival outcome of patients with spontaneously ruptured hepatocellular carcinoma treated surgically or by transarterial embolization

AIM: To evaluate clinical outcomes of patients that underwent surgery, transarterial embolization (TAE), or supportive care for spontaneously ruptured hepatocellular carcinoma (HCC). METHODS: A consecutive 54 patients who diagnosed as spontaneously ruptured HCC at our institution between 2003 and 2012 were retrospectively enrolled. HCC was diagnosed based on the diagnostic guidelines issued by the 2005 American Association for the Study of Liver Diseases. HCC rupture was defined as disruption of the peritumoral liver capsule with enhanced fluid collection in the perihepatic area adjacent to the HCC by dynamic liver computed tomography, and when abdominal paracentesis showed an ascitic red blood cell count of > 50000 mm 3 /mL in bloody fluid. RESULTS: Of the 54 patients, 6 (11.1%) underwent surgery, 25 (46.3%) TAE, and 23 (42.6%) supportive care. The 2-, 4and 6-mo cumulative survival rates at 2, 4 and 6 mo were significantly higher in the surgery (60%, 60% and 60%) or TAE (36%, 20% and 20%) groups than in the supportive care group (8.7%, 0% and 0%), respectively (each, P < 0.01), and tended to be higher in the surgical group than in the TAE group. Multivariate analysis showed that serum bilirubin (HR = 1.09, P < 0.01), creatinine (HR = 1.46, P = 0.04), and vasopressor requirement (HR = 2.37, P = 0.02) were significantly associated with post-treatment mortality, whereas surgery (HR = 0.41, P < 0.01), and TAE (HR = 0.13, P = 0.01) were inversely associated with posttreatment mortality. CONCLUSION: Post-treatment survival after surgery or TAE was found to be better than after supportive care, and surgery tended to provide better survival benefit than TAE.

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA < 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels(< 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA < 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.

Prognosis of hepatocellular carcinoma expressing cytokeratin 19:Comparison with other liver cancers

AIM:To investigate whether expressing biliary phenotype predicted poor outcome after the surgical treatment in primary liver cancers. METHODS:Out of 204 patients that underwent liver resection due to hepatocellular carcinoma (HCC), liver specimens of 70 patients with HCC were evaluated for biliary components by cytokeratin (CK) 19 immunostain (CK19 - HCC and CK19 + HCC). CK19 positivity was defined as membranous and/or cytoplasmic expression in ≥ 5% of tumor cells with moderate or strong intensity. Patients with other primary liver cancers, such as com- bined HCC and cholangiocarcinoma (cHCC-CC), intrahe- patic cholangiocarcinoma (ICC) who received curative liver resection, were also included in the study. Clinical characteristics of CK19-HCC and CK19 + HCC patients, including survival outcome after curative liver resection, were compared with that of cHCC-CC and ICC patients. RESULTS: The overall survival (OS) rate of CK19 - HCC(n = 49) after the curative surgical treatment was 90.7%, and 80.4% at 1 and 5 years after the resection. OS rate of CK19 + HCC (n = 21) was 74.3%, 28.9% and OS rate of cHCC-CC (n = 22) was 66.7%, 32.2% at 1 and 5 years after the surgery. For ICC (n = 19), 1 and 5-year-OS rate was 50.2% and 14.3% after the cura-tive resection. The OS rates of CK19 + HCC and cHCC-CC were significantly lower than that of CK19-HCC, but higher than the OS rate of ICC (P = 0.000). There was no statistically significant difference in OS rate between CK19 + HCC and cHCC-CC. The disease free survival (DFS) rate of CK19-HCC was 72.0% and 54.5% at 1 and 3 years after the surgical treatment. DFS rate of CK19 + HCC was 53.3%, 34.3% and DFS rate of cHCC- CC was 51.5%, 39.2% at 1 and 3 years after the resection. For ICC, 1 and 3-year-DFS rate was 28.0% and 14.0% after the curative resection. DFS rate of CK19-HCC was significantly higher than that of ICC (P = 0.017), but marginally higher than DFS rate of either CK19 + HCC or cHCC-CC (P = 0.097, P = 0.089, respec-tively). Predictors of outcome after the surgery of primary liver cancer were pathology of the resected mass, existence of microvascular invasion and accompanying satellite nodule. CONCLUSION: Primary liver cancers with biliary components tended to show poorer surgical outcome. This suggested that immuno-phenotype of liver cancers was as important as their morphological classification.

Giant choledocholithiasis treated by mechanical lithotripsy using a gastric bezoar basket

Mechanical lithotripsy （ML） is usually considered as a standard treatment option for large bile duct stones. However, it is impossible to retrieve oversized stones because the conventional lithotripsy basket may not be able to grasp the stone. However, there is no es- tablished endoscopic extraction method for such gi- ant stone removal. We describe a case of successful extraction of a 4-cm large stone using a gastric bezoar basket. A 78-year-old woman had suffered from upper abdominal pain for 20 d. Contrast-enhanced computed tomogram revealed a 4-cm single stone in the distal common bile duct （CBD）. Endoscopic stone retraction was decided upon and endoscopic papillary balloon dilation was performed using a large balloon. An at- tempt to capture the stone using a standard lithotripsy basket failed due to the large stone size. Subsequently, we used a gastric bezoar basket to successfully capturethe stone. The stone was fragmented into small pieces and extracted. The stone was completely removed after two sessions of endoscopic retrograde cholangio- pancreatography; each of which took 30 rain. No com- plications occurred during or after the procedure. The patient was fully recovered and discharged on day 11 of hospitalization. ML using a gastric bezoar basket is a safe and effective retrieval method in select cases, and is considered as an alternative nonoperative option for the management of difficult CBD stones.

Expression of Ki-67,p53,and K-ras in chronic pancreatitis and pancreatic ductal adenocarcinoma

AIM： To examine surgical specimens of pancreas with either chronic pancreatitis or pancreatic cancer in order to study whether ductal hyperplasia and dysplasia in pancreas represent precursor lesions for pancreatic cancer. METHODS： We examined expression of Ki-67, CEA, p53, and K-ras, in the surgical specimens of pancreas with adenocarcinomas （n = 11） and chronic pancreatitis （n = 12）. Cellular proliferation was assessed by Ki-67 proliferation index using the proliferation marker Ki-67. In specimens with pancreas cancer, we divided pancreas epithelium into normal （n = 7）, ductal hyperplasia （n = 3）, dysplasia （n = 4）, and cancerous lesion （n = 11） after hematoxylin and eosin staining, Ki-67, and CEA immunohistochemical staining. In cases with chronic pancreatitis, the specimen was pathologically examined as in cases with pancreas cancer, and they were also determined as normal （n = 10）, ductal hyperplasia （n = 4）, or dysplasia （n = 5）. p53 and K-ras expression were also studied by immunohistochemical staining. RESULTS： In pancreatic cancer, the Ki-67 index was 3.73±3.58 in normal site, 6.62±4.39 in ductal hyperplasia, 13.47：1：4.02 in dysplasia and 37.03±10.05 in cancer tissue, respectively. Overall, p53 was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 14 （0%）, 0 of 7 （0%）, 7 of 9 （78%）, and 10 of 11 （91%）, respectively, and K-ras was positive in 0 of 8 （0%）, 1 of 3 （33%）, 4 of 6 （67%）, 4 of 5 （80%）, respectively. CONCLUSION： Our results favorably support the hypothesis that ductal hyperplasia and dysplasia of the pancreas might be precursor lesions for pancreas cancer. Further evaluation of oncogenes by the molecular study is needed.

Value of controlled attenuation parameter in fibrosis prediction in nonalcoholic steatohepatitis

BACKGROUND Liver stiffness measurement(LSM)tends to overestimate fibrosis stage in nonalcoholic fatty liver disease(NAFLD).Controlled attenuation parameter(CAP),provided by LSM device,has been introduced for noninvasive quantification of hepatic steatosis.AIM To determine the role of CAP values in predicting liver fibrosis stage by LSM in nonalcoholic steatohepatitis(NASH).METHODS One hundred eighty-four patients with biopsy proven NASH had LSM and CAP evaluated at baseline.Among them,130 patients had 1-year follow up LSM and analyzed for the changes of LSM after pioglitazone or ursodeoxycholic acid(UDCA)treatment.RESULTS In Kleiner fibrosis stage F0-1,LSM values increased at higher CAP tertile(P=0.001),and in F2,at middle and higher tertiles(P=0.027).No difference across CAP tertiles was noticed in F3-4(P=0.752).Receiver operating characteristic curve for LSM cutoff in diagnosis of F≥2 identified 8.05 kPa for lower CAP tertile,9.35 kPa for middle,and 10.55 kPa for high tertile.When changes in proportion of significant fibrosis(F≥2)were assessed among pioglitazone and UDCA treated patients considering CAP values,pioglitazone treated patients demonstrated decrease in proportion of high LSM.CONCLUSION In patient with NAFLD,interpretation of LSM in association with CAP scores may provide helpful information sparing unnecessary liver biopsy.

Esophageal mucosal metastasis from adenocarcinoma of the distal stomach

Dissemination of gastric cancer may usually occur by direct spread through the perigastric tissues to adjacent organ, lymphatic spread, and hematogenous spread. We report a rare case of gastric cancer with mucosal metastastic lesion on the upper esophagus that was diagnosed by endoscopy and endosonography. A biopsy of the esophageal mass was performed and the pathologic findings with immunohistochemical stain for Mucin-5AC are proved to be identical to that of gastric adenocarcinoma, suggesting metastasis from main lesion of the gastric cancer. The lesion could not be explained by lymphatic or hematogenous spread,and its metastasis mechanism is considered to be different from previous studies. We suggest that the gastroesophageal reflux of cancer cells could be one of the possible metastatic pathways for metastasis of esophagus from an adenocarcinoma of the stomach.