BACKGROUND: Pancreatic adenocarcinoma (PCa) is a disease with dismal prognosis, and the only possibility of cure, albeit small, is based on the combination of complete resection with negative histopathological margins (R0 resection) with adjuvant treatment. Therefore, a lot of effort has been made during the last decade to assess the role of extensive surgery in both local recurrence and survival of patients with PCa.
DATA SOURCES: Medline search and manual cross-referencing were utilized to identify published evidence-based data for PCa surgery between 1973 and 2006, with emphasis to feasibility, efficacy, long-term survival, disease free survival, recurrence rates, pain relief and quality of life.
RESULTS: Extended surgery is safe and feasible in high volume surgical centers with comparable short-term results. Organ preserving surgery is a main goal because of quality of life reasons and is performed whenever possible from the tumor extent. Concerning long-term survival major vein resection does not adversely affect outcome. To date, there are no changes in long-term survival attributed to the extended lymph node dissection. However, there is a benefit in locoregional control with fewer local recurrences and extended lymphadenectomy allows better staging for the disease.
CONCLUSIONS: Extended PCa surgery is safe and feasible despite the inconclusive results in patient's survival benefit. In the future, appropriately powered randomized trials of standard vs. extended resections may show improved outcomes for PCa patients.

BACKGROUND: Rapamycin is a potent new immunosuppressant with a mechanism of action that is distinct from that of calcineurin inhibitors, but few clinical data on rapamycin in liver transplantation are available. Hence it is necessary to evaluate the efficacy and side-effects of rapamycin-based immunosuppression in liver transplant patients.
METHODS: We retrospectively analysed 39 liver transplantation patients who took rapamycin as an immunosuppressant. This series consisted of 28 patients with hepatocellular carcinoma, 9 patients with chronic fulminant hepatitis, and 2 patients with end-stage liver cirrhosis. Eight patients used rapamycin for monotherapy, and 31 used rapamycin-based immunosuppression. In the 31 patients, 7 patients used rapamycin instead of mycophenolate mofetil to treat acute rejection. 
RESULTS: In the 28 patients with hepatocellular carcinoma, the one-year survival rate was 67% without any tumor recurrence. The acute rejection in 7 patients was relieved in 1-2 weeks after the administration of rapamycin. All the 8 patients who received rapamycin monotherapy survived for at least 6 months and liver function tests and biopsy showed nothing abnormal. Jaundice in 8 patients with chronic rejection was reduced sharply after use of rapamycin.
CONCLUSIONS: Rapamycin given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies are warranted to evaluate the efficacy and side-effect profile of rapamycin in liver transplant patients.

BACKGROUND: Acute rejection after liver transplantation is usually treated with large doses of immunosuppressants with severe toxic and side-effects, so it is imperative to find a safe and effective method for preventing and treating rejection. This study was designed to confirm the immunomodulatory effects of rat mesenchymal stem cells (MSCs) in vitro and investigate the tolerogenic features in a rat model of allogeneic liver transplantation.
METHODS: MSCs were isolated from adipose tissue of Sprague-Dawley (SD) rats and cultured. In vitro, MSCs were added into a mixed lymphocyte culture (MLC) system to study the inhibitory effects of MSCs on the proliferation of T lymphocytes in Wistar rats. By using SD and Wistar rats as liver donors and recipients, an orthotopic liver transplantation model was established and the rats were divided into a MSC-treated group and a blank control group. On postoperative day 7, all rats were sacrificed, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), interleukin-2 (IL-2) and interleukin-10 (IL-10) were measured. The pathological changes of liver tissue and apoptosis of hepatocytes were also assessed.
RESULTS: In in vitro MLC, T lymphocyte proliferation in Wistar rats was significantly inhibited by 48.44%. In the MSC-treated group, the levels of ALT, AST, TBIL, IL-2 and IL-10 were 134.2±45.0 U/L, 162.5±30.5 U/L, 30.6±5.4 µmol/L, 187.35±18.26 µg/L and 193.95±37.62 µg/L, and those in the blank control group were 355.6±54.3 U/L, 296.4±71.2 U/L, 145.7±28.6 µmol/L, 295.73±57.15 µg/L and 75.12±11.23 µg/L, respectively, with statistically significant differences (P<0.05). Pathological examination revealed that the rejection in the MSC-treated group was clearly alleviated compared with that in the blank control group. TUNEL indicated that the apoptosis of hepatocytes in the MSC-treated group was milder than that in the blank control group (P<0.05).
CONCLUSION: Adipose-derived MSCs clearly inhibit recipient-derived T lymphocyte proliferation in MLC and significantly alleviate acute rejection following orthotopic liver transplantation in rats.

BACKGROUND: This study was designed to probe the clinical value in assessing the degree of liver cirrhosis by using the arrival time of contrast agent in the right portal vein in contrast-enhanced ultrasonography, as well as the velocity and flow volume in the right portal vein using the color Doppler velocity profile technique.
METHODS: Twenty-eight patients with HBV post-hepatic cirrhosis were grouped into compensated (13 patients) and decompensated cirrhosis (15); 30 patients without hepatic cirrhosis served as controls. Written informed consent was obtained from each patient. All the patients with hepatic cirrhosis were pathologically confirmed by percutaneous biopsy. SonoVue was injected to detect the arrival time in the right portal vein. The velocity and flow volume in the right portal vein were measured. The value of each parameter was compared for correlation analysis.
RESULTS: The arrival time in the right portal vein in the cirrhosis group was much longer than that in the control group (24.92±1.34 vs. 20.81±0.55 sec, respectively, P<0.01). The mean velocity, maximal velocity and flow volume in the cirrhosis group were much lower than those in the control group (10.64±0.84 vs. 14.78±0.71 cm/sec, 13.68±1.02 vs. 17.30±0.68 cm/sec and 358.72±23.63 vs. 438.61±16.86 ml/min, respectively, P<0.01). With the development of cirrhosis, the arrival time in the right portal vein was longer (P<0.05), and the velocity and flow volume was lower (P<0.01). There was a negative correlation between arrival time and mean velocity, maximal velocity and flow volume in the right portal vein in the cirrhosis group (r=-0.547, P<0.01; r=-0.508, P<0.05; r=-0.471, P<0.05, respectively).
CONCLUSIONS: With the development of liver cirrhosis, the arrival time of contrast agent in the right portal vein is gradually prolonged, whereas the velocity and flow volume in this vein decreases markedly, and there is a negative correlation between the results of the two methods.

BACKGROUND: Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model.
METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis.
RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were significantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P)=1.573×Age+1.338×HE-1.608×CHO+0.011×Cr-0.109×Na+
1.298×INR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score.
CONCLUSIONS: Multivariate analysis excels univariate anlysis in the prognosis of chronic severe hepatitis, and the regression model is of significant value in the prognosis of this disease.

BACKGROUND: Chemokines have strong chemoattractant effects and are involved in a variety of immune and inflammatory reactions, such as attracting activated T lymphocytes, neutrophils, monocytes and natural killer cells via the pathway of G protein-coupled receptors to sites of inflammatory injury and contribute to wound repair. This investigation was designed to assess the levels of chemokine interferon-γ inducible protein-10 (IP-10) and IP-10 mRNA, and the relationship between IP-10 mRNA and HBV-DNA and alanine aminotransferase (ALT) in patients with chronic hepatitis B.
METHODS: The levels of IP-10 mRNA in peripheral blood mononuclear cells (PBMCs) were kinetically detected by real-time polymerase chain reaction (PCR). The rate of chemokine/GAPDH was regarded as the extreme level of chemokine. The level of IP-10 in serum was measured by enzyme linked immunosorbent assay (ELISA), and the expression of IP-10 in hepatic biopsy tissue was detected by streptavidin-peroxidase (SP) immunohistochemistry.
RESULTS: The level of IP-10 mRNA in the PBMCs of patients was 0.7387±0.0768 (lg cDNA/lg GAPDH); it was significantly higher in patients with chronic hepatitis B than that in normal controls (P<0.001). The level of IP-10 in the serum of patients was 660.9±75.5 pg/ml. There was a significant difference between patients with chronic hepatitis B and normal controls (P<0.05). In patients with chronic hepatitis B, the level of IP-10 mRNA in PBMCs was correlated with the IP-10 plasma level (r=0.7312, P<0.001), and the IP-10 plasma level was fairly correlated with the levels of ALT and HBV-DNA plasma (r=0.7235, P<0.001; r=0.7371, P<0.001). IP-10 was found by immunohistochemical analysis to be selectively upregulated on sinusoidal endothelium.
CONCLUSIONS: The expression of IP-10 mRNA in PBMCs, IP-10 plasma concentration and the expression of IP-10 in sinusoidal endothelium are all high in patients with chronic hepatitis B. Chemokine IP-10 may play an important role in trafficking inflammatory cells to the local focus in the liver and induce the development of the chronicity of hepatitis B.

BACKGROUND: The pathogenesis of hepatic fibrosis and cirrhosis is still not fully understood. The extracellular signal-regulated kinase (ERK) pathway is involved in the regulation of cell proliferation and differentiation. The aim of this study was to investigate the effects of PD98059, a specific inhibitor of ERK, on the cell cycle, cell proliferation, secretion of type Ⅰ collagen and expression of cyclin D1 mRNA, CDK4 mRNA and transforming growth factor-β1 (TGF-β1) mRNA in rat hepatic stellate cells (HSCs) stimulated by acetaldehyde.
METHODS: Rat HSCs stimulated by acetaldehyde were incubated with PD98059 at different concentrations. The cell cycle was analysed by flow cytometry. Cell proliferation was assessed by the methyl thiazolyl tetrazolium colorimetric assay. The mRNA expression of cyclin D1, CDK4 and TGF-β1 was examined using the reverse transcriptase-polymerase chain reaction. Type Ⅰ collagen in the culture medium was detected by enzyme-linked immunosorbent assay.
RESULTS: 20, 50 and 100 µmol/L PD98059 significantly inhibited the proliferation and provoked a G0/G1-phase arrest of acetaldehyde-induced HSCs in a dose-dependent manner. The secretion of type Ⅰ collagen and the expression of cyclin D1, CDK4 and TGF-β1 mRNA in acetaldehyde-induced HSCs were markedly inhibited by 50 and 100 µmol/L PD98059, respectively.
CONCLUSIONS: The ERK pathway regulates the cell proliferation, secretion of type Ⅰ collagen and the expression of TGF-β1 mRNA in rat HSCs stimulated by acetaldehyde, which is likely related to its regulative effect on the cell cycle.

BACKGROUND: The disorders of gallbladder motility may play an important role in the formation of gallstones. Many neural and hormonal factors and their interactions regulate gallbladder motility and bile flow into the duodenum. Further study in these factors may help to reveal the etiology of gallbladder diseases. This study was undertaken to assess the relationship of the levels of motilin, vasoactive intestinal peptide (VIP) and gastrin in blood and gallbladder tissues with the formation of cholelithiasis.
METHODS: The levels of motilin, gastrin and VIP in blood and gallbladder tissues of 36 patients with gallbladder stones, 14 patients with gallbladder polyps, 10 healthy volunteers and 10 patients with common bile duct stones were measured by radioimmunoassay.
RESULTS: The level of motilin in plasma and gallbladder tissues of the gallbladder stone group was higher than that of the control and gallbladder polyp groups (P<0.05). The levels of plasma VIP and serum gastrin were much higher than those of the other three groups (P<0.01). The level of VIP in gallbladder tissues was higher than that of the control and gallbladder polyp groups (P<0.01).
CONCLUSIONS: The abnormal excretion of hormonal factors is closely related to gallstone formation. The high level of VIP in gallbladder tissues may be an important cause of gallbladder hypomotility. The abnormal level of serum gastrin may be related to the gastrointestinal symptoms of patients with gallstones.

BACKGROUND: A significant relationship exists among food intake and nutritional status and cholelithiasis, including gallstone and hepatolithiasis. Leptin is associated with obesity. This study was to investigate the differences in serum leptin levels in patients with gallstone and hepatolithiasis and to evaluate the relationships among leptin, cholecystokinin (CCK), lipid and lipoprotein concentrations.
METHODS: Body mass index (BMI), serum leptin, CCK, insulin, lipid and lipoprotein concentrations, and liver function were measured in 382 patients with gallstone (GS group), 83 patients with hepatolithiasis (HS group) and 30 healthy controls (control group). The values of these indices were compared among the groups. In each group, Pearson's product-moment correlation coefficient among these indices were evaluated.
RESULTS: There were notable differences in serum leptin, CCK, total cholesterol, total triglycerides, apolipoprotein-a (APO-a), globulin, direct reacting bilirubin, and BMI between the GS and HS groups (P<0.05). Positive correlations between serum leptin and BMI, CCK, total cholesterol, gamma-glutamyl transpeptidase (GGT), aminotransferase, and insulin were found in the GS group (P<0.05). Positive correlations were observed between serum leptin and CCK, bilirubin, aminotransferase, GGT, in the HS group (P<0.05), but negative correlations between serum leptin and albumin or APO-a (P<0.05).
CONCLUSIONS: Leptin participates in modulating lipid metabolism. There are notable differences in leptin, serum lipid, and CCK between patients with gallstone and those with hepatolithiasis. The role of leptin in the pathophysiological course of cholelithiasis needs further investigation.

BACKGROUND: The abnormal expression of atypical protein kinase C-ι (aPKC-ι) subtype and E-cadherin play important roles in tumor occurrence and progression. This study was designed to investigate the correlation of expression of aPKC-ι and E-cadherin with the clinicopathological characteristics and prognosis of cholangiocarcinoma, and to analyze the molecular mechanisms of invasion and metastasis of the tumor.
METHODS: EnVision immunohistochemistry was used to detect the expression of aPKC-ι and E-cadherin in 9 specimens of benign bile duct tissues, 35 specimens of cholangiocarcinoma and 6 specimens of metastatic cholangiocarcinoma. The relationship of the expression with clinicopathological characteristics, invasion and prognosis of cholangiocarcinoma was analyzed. A multivariate regression analysis was made of these data by the Cox proportional hazard model.
RESULTS: The positive expression level of aPKC-ι in cholangiocarcinoma was remarkably higher than that in benign bile duct tissues (68.6% vs. 11.1%, P=0.006), but the expression level of E-cadherin was lower in cholangiocarcinoma than in benign bile duct tissues (37.1% vs. 88.9%, P=0.016). Correlation analysis revealed that the expression of aPKC-ι was positively related to tumor differentiation and invasion, whereas that of E-cadherin was entirely the contrary. Moreover, there was a negative relationship between the expression of aPKC-ι and that of E-cadherin (r=-0.287, P<0.05). Univariate analysis showed that the overall survival rate of the group with a higher expression of aPKC-ι in cholangiocarcinoma was remarkably lower than that of the group with a lower expression (P<0.01); multivariate analysis revealed that the expressions of aPKC-ι and E-cadherin are important prognostic factors for cholangiocarcinoma (P<0.05).
CONCLUSIONS: The expressions of aPKC-ι and E-cadherin may reflect the differentiation and invasive potential of cholangiocarcinoma. aPKC-ι and E-cadherin may be independent prognostic factors and, when used in combination with clinicopathological characteristics, may increase the accuracy in predicting the prognosis of patients with cholangiocarcinoma. As a polar regulative associated protein, aPKC-ι may play an important role in the invasion and metastasis of cholangiocarcinoma.

BACKGROUND: In recent years, recombined human growth hormone (rhGH) has been increasingly used in patients to help them recover from operation. But GH, as a mitogen, can promote cell renewal and increase malignant transformation. In the current study, we assessed the proliferation of a bile duct cancer cell line (QBC939) in vitro with GH and explored the possible relationship with the axis of GH-IGFs (insulin-like growth factors).
METHODS: QBC939 cells in the exponential growth stage were harvested and divided into an experimental group (GH group) and a control group (NS group). The GH group was divided into four sub-groups according to the dose of GH and culture time (50 µg/L for 2 hours, 50 µg/L for 24 hours, 100 µg/L for 2 hours, 100 µg/L for 24 hours). The NS group was divided into two sub-groups (NS for 2 hours and NS for 24 hours). After 2 or 24 hours, IGF-1 and IGF-2 were detected using the enzyme-linked immunosorbent assay. The QBC939 cells cultured for 24 hours with two GH concentrations were made into single cell suspensions and samples underwent subsequent cell cycle evaluation. Messenger RNA of IGF-1 and IGF-2 receptor (IGF-1RmRNA and IGF-2RmRNA) were tested with the method of in situ hybridization.
RESULTS: There was no statistically significant difference between the GH and NS groups after 2 hours of culture (P>0.05). But after 24 hours of culture, GH stimulated cell growth in vitro and also elevated the percentage in S phase and the proliferation index (P<0.05). IGF-1RmRNA and IGF-2RmRNA were expressed in QBC939 in contrast to the blank group. The expression of IGF-1RmRNA increased with the dose of GH, but IGF-2RmRNA did not.
CONCLUSION: GH can stimulate QBC939 cell growth and proliferation in vitro and the mechanism is most likely by the GH-IGF-1-IGF-1R axis.

BACKGROUND: Chronic liver disease has been considered a contraindication to radical surgery for intra-abdominal tumors because of the risk of decompensation.
METHODS: In a retrospective analysis of all patients undergoing pancreaticoduodenectomy for cancer treated from January 2000 to December 2006 at our center, 4 patients were identified with operable pancreatic tumors and well-compensated chronic liver disease. The preoperative staging, decompression of the biliary tree, liver biopsy, Child-Turcot-Pugh and MELD scores were described.
RESULTS: All patients underwent pancreaticoduodenectomy successfully with minimal blood loss, and no peri-operative blood transfusions or liver decompensation. There was no postoperative mortality. Two patients received adjuvant chemotherapy. One patient died with recurrent disease at 18 months, one is alive with disease recurrence, and two are alive and disease free.
CONCLUSION: Patients with pancreatic cancer and well-compensated chronic liver disease should routinely be considered for radical surgery at specialist hepatobiliary centres with expertise available to manage complex liver disease.

BACKGROUND: Maspin is a member of the serpin family of protease inhibitors and is thought to inhibit carcinoma invasion, metastasis, and angiogenesis and induce apoptosis. We examined maspin expression immunohistochemically and assessed its significance in intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
METHODS: We examined 39 surgically resected specimens of IPMN that included 17 adenomas (IPMAs), 5 borderline tumors (IPMBs), 4 non-invasive carcinomas (non-invasive IPMCs), and 13 invasive carcinomas (invasive IPMCs). Immunostaining was performed according to the EnVision ChemMate method. The degree of maspin expression was scored and assessed according to the percentage and staining intensity of positive cells.
RESULTS: Maspin expression was minimal in normal pancreatic duct epithelium, whereas in IPMNs, maspin was expressed in neoplasms of all stages. Maspin expression increased with increasing grade from IPMAs, IPMBs, to non-invasive IPMCs but decreased significantly in invasive IPMCs. No specific association between maspin expression and mucin type was found. Analysis of maspin expression with respect to clinicopathologic factors in cases of invasive IPMC revealed a greater extent of invasion in cases of low maspin expression and significantly fewer apoptotic cells in the tumor.
CONCLUSIONS: Maspin was expressed at high levels in IPMNs at various stages from adenoma to invasive carcinoma, and our results suggest that maspin may be involved in the occurrence and progression of IPMN. In addition, our data suggest that the apoptosis-inducing action of maspin suppresses invasion and progression of IPMN.

BACKGROUND: Much evidence demonstrates that elevated free fatty acids (FFAs) are associated with insulin resistance. However, it is not clear whether different FFAs can cause different degrees of peripheral insulin resistance. This study aimed to investigate the effects of short-term elevation of FFAs on hepatic and peripheral insulin action, and determine whether FFAs with different degrees of saturation have differential effects on hepatic insulin resistance.
METHODS: Intralipid+heparin (IH, polyunsaturated fatty acids), oleate (OLE), lard oil+heparin (LOH), and saline (SAL) were separately infused intravenously for 7 hours in normal Wistar rats. During the last 2 hours of the fat/saline infusion, a hyperinsulinemic-euglycemic clamping was performed with [6-3H] glucose tracer.  Plasma glucose was measured using the glucose oxygenase method. Plasma insulin and C-peptide were determined by radioimmunoassays. Plasma FFAs were measured using a colorimetric method.
RESULTS: Compared with infusion of SAL, plasma FFA levels were significantly elevated by infusions of IH, OLE, and LOH (P<0.001). All three fat infusions caused remarkably higher hepatic glucose production (HGP) than SAL (P<0.001). OLE and LOH infusions induced much higher HGP than IH (P<0.01). Glucose utilization (GU) was decreased with all three fat infusions relative to SAL (P<0.001), but GU did not differ among the three types of fat infusions.
CONCLUSIONS: Short-term elevation of FFAs can induce hepatic and peripheral insulin resistance. Polyunsaturated fatty acids induced less hepatic insulin resistance than monounsaturated or saturated fatty acids. However, IH, OLE, and LOH infusions induced similar peripheral insulin resistance.

BACKGROUND: Caroli's disease, a rare congenital hepatic disease, has a poor prognosis, especially in patients with diffuse dilatation of the bile ducts. But liver transplantation has been a curative option. The aim of this study was to investigate the feasibility and rationality of orthotopic liver transplantation as an indication for patients with diffuse Caroli's disease.
METHODS: The data from 3 patients with diffuse Caroli's disease who had undergone orthotopic liver transplantation in our unit were analyzed retrospectively.
RESULTS: On postoperative day 7, patient 1 had acute rejection which was relieved after pulse treatment with methyprednisolone. He was discharged from hospital on postoperative day 27 and has been in good health for 82 months. Patient 2 had no acute rejection or severe complications, but died of chronic graft dysfunction 34 months postoperatively. Patient 3 had acute rejection on postoperative days 10 and 35, complicated with pulmonary infection, pleural effusion and opportunistic infection. After successful treatment, she resumed work and has been followed up for 47 months. Her condition is good.
CONCLUSION: Liver transplantation can offer an effective therapy for patients with diffuse Caroli's disease, and can provide satisfactory long-term results.

BACKGROUND: Chronic pancreatitis following acute fatty liver of pregnancy is rarely reported.
METHODS: We treated a 34-year-old woman who developed acute fatty liver of pregnancy (AFLP) after delivery by caesarean section at 32 weeks of gestation. AFLP was complicated by acute pancreatitis and multiple organ failure. The management of the disease was primarily supportive. She recovered from acute fulminant liver failure and multi-organ failure, apart from the development of symptomatic chronic pancreatitis thereafter.
RESULTS: Investigations failed to identify any other causes of chronic pancreatitis. The patient responded very well to pancreatic enzyme supplement for the treatment of steatorrhoea.
CONCLUSION: To our knowledge, this is the first report of chronic pancreatitis as a consequence of multi-organ dysfunction caused by AFLP.

To the Editor:
We read with great interest the recent report of an unusual primary liver carcinoma with a mixed population of malignant cells with hepatocyte as well as bile duct cell morphology throughout the tumor (Allen Type C).[1] The case sparked our curiosity regarding the immunohistochemical profile of this unusual malignancy, which could provide further evidence of its differentiation and cell of origin. Indicators of hepatocellular cell differentiation are positive immunostaining for HepPar1 (80%), a canalicular pattern of pCEA (83%), or AFP (42%), while the following markers are positive in many cholangiocarcinomas: CK 7 (98%), CK 19 (96%) and EMA (86%).[2] A single original clonal proliferation of mixed hepatocellular-cholangiocarcinomas has been suggested due to common allelic losses in both tumor components.[3] Hepatic progenitor cells have taken center stage as a possible cells of origin of primary liver carcinomas.[4, 5] Hepatic progenitor cells are small epithelial cells with an oval nucleus, scant cytoplasm and location in the bile ductules and canals of Hering, which have the potential to differentiate towards the biliary and hepatocytic lineages.[4] Further, it is thought that liver injury leads to the recruitment of bone marrow stem cells to the liver which then differentiate into oval cells.[5] Akin to the commonly used term "hematogones" for immature B-cell precursors in the bone marrow, we propose the term "hepatogones" to be used for activated liver stem cells that may originate in the bone marrow and may be the cell of origin for mixed lineage tumors such as the case described by Zhou et al.[1]

To the Editor:
I read the report of Krishnasamy et al[1] with great interest. The   authors   make a valid point   about management issues associated with pancreatic ductal intraepithelial neoplasia (PanIN) in their illustrative report. However, a few clarifications need to be made on surgical pathology aspect of these lesions. Without doubt, evolution of the PanIN nomenclature and classification system has led to a renewed interest in research on pancreatic cancer aimed at accurate definition and identification of the key molecular event responsible for its development. The establishment of PanIN nomenclature has helped define a genetic progression model of pancreatic cancer.[2] Moreover, the early detection and treatment of PanINs might offer an important avenue for preventing their  progression to invasive pancreatic cancer which continues to have a dismal   patient   outcome.[2]   Currently,   the   ability to clinically detect PanINs is limited therefore whether PanINs will prove equally effective in patient management remains to be seen.
First, controversy remains in the application of the original three-tier PanIN nomenclature (PanIN-1, PanIN-2 and PanIN-3) due to a lack of reproducibility between pathologists in assigning lesions to PanIN-2 category.[3] Hence, in deciding the therapeutic approach based on the grade of PanIN, a two-tier system will be needed thereby combining PanIN-1 and PanIN-2  under "low-grade PanIN " and leaving PanIN-3 as "high-grade PanIN".[3]
Next, the lack of evidence-based guidelines poses an important management issue in PanINs found at surgical margins. Generally, PanIN-1 and PanIN-2 at the margin require no therapy as they are typically incidental findings with unproven clinical significance. In view of isolated reports of PanIN-3 progressing to invasive pancreatic cancer, the resection of additional pancreatic parenchyma to achieve a margin free of PanIN-3 is recommended in a young patient with a potentially curable pancreatic lesion.[3, 4] A large invasive cancer with multiple lymph node metastases definitely poses a much greater threat to a patient's life than a PanIN-3. In such a situation, it is recommended that no additional pancreas be resected.[3]
Another important consideration that needs to be made is the distribution and extension of PanINs. Recently, Hisa et al[5] showed consecutive geographic extension and spread of PanINs-3 around the mass via the main pancreatic duct upto 25 mm (mean 10.5 mm) from the edge of the tumor. Therefore, they recommend a resection margin of 25 mm or at least >11 mm from the main tumor.