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Background This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines. Methods Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] ≥ 10 mm, and obstructive jaundice) and worrisome features (cyst size ≥ 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5–9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically. Results Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; ΔAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79. Conclusion Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased.

Background Potential benefits of local extirpation of benign pancreatic head tumors are tissue conservation of pancreas, stomach, duodenum and common bile duct (CBD) and maintenance of pancreatic functions. Methods Medline/PubMed, Embase and Cochrane Library databases were searched to identify studies applying duodenum-preserving total or partial pancreatic-head resection (DPPHRt/p) and reporting short- and long-term outcomes. Twenty-four studies, including 416 patients who underwent DPPHRt/p, were identified for systematic analysis. The meta-analysis was based on 10 prospective controlled and 4 retrospective controlled cohort studies, comparing 293 DPPHRt/p resections with 372 pancreato-duodenectomies (PD). Results, systematic analysis Of 416 patients, 75.7% underwent total and 24.3% partial head resection, while 47.1% included segmentectomy of duodenum and CBD. The most common pathology was cystic neoplasm (65.8%) and endocrine tumors (13.4%). The frequencies of severe postoperative complications of 8.8%, pancreatic fistula of 19.2%, re-operation of 1.7% and hospital mortality of 0.48%, indicate a low level of early post-operative complications. Meta-analysis DPPHRt/p significantly preserved the level of exocrine (IV = −0.67, 95% CI −0.98 to −0.35, p = 0.0001) and endocrine (IV = 18.20, fixed, 95% CI −0.92 to 25.48, p = 0.0001) pancreatic functions compared to PD when the pre- and postoperative functional status in both groups are analyzed. There were no significant differences between DPPHRt/p and PD in frequency of pancreatic fistula, delayed gastric emptying or hospital mortality. Conclusion DPPHRt/p for benign neoplasms and neuro-endocrine tumors of the pancreatic head is associated with a low level of early-postoperative complications and a better conservation of exocrine and endocrine functions.

Background Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer. Methods Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed. Results There was a significant correlation between EMT status and CA19-9 levels ( P = .020); peritoneal washing cytology ( P = .025); portal vein invasion ( P = .038); and lymph node metastasis ( P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion ( P = .024); lymph node metastasis ( P = .033); and EMT status ( P P = .002); however, no significant difference was seen in patients with epithelial tumors. Conclusion EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis.

Background After pancreatoduodenectomy in patients with celiac axis stenosis or obstruction, it becomes problematic to maintain the upper abdominal organ blood flow, especially to the liver. The aim of this study was to investigate the celiac axis stenosis caused by median arcuate ligament (MAL) compression and to classify it according to preoperative image findings. Methods From January 1989 to November 2010, 562 patients underwent operations for diseases of the pancreatic head region in our department. To diagnose celiac artery compression by the MAL, angiography was used in the early period and 3-dimensional image reconstruction of multidetector-row computed tomography was used from 2004. The morphologic characteristics of the celiac axis stenosis were analyzed during intraoperative treatment. Results Twelve (2.1%) patients were diagnosed with MAL compression, and 8 of these patients only underwent MAL division to restore the celiac artery blood flow. One patient required conservation of the collateral circulation, and 2 patients needed arterial reconstruction. In the analysis of the level of origin of the celiac axis, there were no remarkable differences between nonstenotic and stenotic cases, or between mild and severe stenotic cases. Morphologic grades were defined based on the preoperative image findings and consequent intraoperative treatments. Conclusion Preoperative grading of celiac axis stenosis could make pancreatoduodenectomy safer with maintenance of the upper abdominal organ blood flow in patients with MAL compression.

Background Wrapping is thought to prevent pancreatic fistula and postoperative hemorrhage for pancreaticoduodenectomy (PD), and we analyzed whether omentum/falciform ligament wrapping decreases postoperative complications after PD. Methods This is a retrospective study of wrapping using the omentum/falciform ligament in patients that underwent PD between January 2006 and June 2008 in 139 institutions that were members of the Japanese Society of Pancreatic Surgery. Results Ninety-one institutions responded to the questionnaires, and data were accumulated from 3,288 patients. The data from 2,597 patients were acceptable for analysis; 918 (35.3%) patients underwent wrapping and 1,679 patients did not. A pancreatic fistula occurred in 623 patients (37.3%) in the nonwrapping group, in comparison to 393 patients (42.8%) in the wrapping group (P = .006). The incidence of a grade B/C pancreatic fistula was lower in the nonwrapping group than the wrapping group (16.7% vs 21.5%; P = .002). An intra-abdominal hemorrhage occurred in 54 patients (3.2%) in the nonwrapping group, which was similar to the incidence in the wrapping group (32 patients; 3.5%). The mortality was 1.3% and 1.0% in nonwrapping and wrapping groups, respectively. A multivariate analysis revealed 7 independent risk factors for pancreatic fistula; male, hypoalbuminemia, soft pancreas, long operation time, extended resection, pylorus preservation, and omentum wrapping. There were 4 independent risk factors for early intra-abdominal hemorrhage and 2 independent risk factors for late intra-abdominal hemorrhage. Conclusion This retrospective study revealed that omentum wrapping did not decrease the incidence of pancreatic fistula. An additional validation study is necessary to evaluate the efficacy of wrapping for PD.

To assess the prognostic effect of intraoperative radiotherapy (IORT) in unresectable pancreatic cancer.We reviewed 198 patients with unresectable pancreatic cancer, which was found during experimental laparotomy. Liver metastasis was observed in 70 patients, peritoneal metastasis in 44, liver and peritoneal metastasis in 23 and locally advanced tumor in 61. Treatment consisted of IORT with or without postoperative chemotherapy. Overall survival (OS) and prognostic factors were evaluated for each pattern of disease spread.IORT was performed in 120 patients, and chemotherapy was administered in 80. Sixty patients did not receive either treatment. OS in the untreated group was significantly inferior to that for IORT alone and IORT plus gemcitabine (GEM)-based chemotherapy. IORT and GEM-based chemotherapy were identified as independent prognostic factors [hazard ratio (HR) = 0.51, p0.001; HR = 0.43, p0.001]. IORT was an independent prognostic determinant for patients with peritoneal metastasis (HR = 0.24, p = 0.011) but not for those with liver metastasis (HR = 0.78, p = 0.381).IORT followed by GEM-based chemotherapy is the recommended treatment strategy in unresectable pancreatic cancer. and IAP.

Protein production within the secretory pathway is accomplished by complex but organized processes. Here, we demonstrate that the growth factor midkine interacts with LDL receptor-related protein 1 (LRP1) at high affinity (K(d) value, 2.7 nm) not only at the cell surface but also within the secretory pathway during biosynthesis. The latter premature ligand-receptor interaction resulted in aggregate formation and consequently suppressed midkine secretion and LRP1 maturation. We utilized an endoplasmic reticulum (ER) retrieval signal and an LRP1 fragment, which strongly bound to midkine and the LRP1-specialized chaperone receptor-associated protein (RAP), to construct an ER trapper. The ER trapper efficiently trapped midkine and RAP and mimicked the premature ligand-receptor interaction, i.e. suppressed maturation of the ligand and receptor. The ER trapper also diminished the inhibitory function of LRP1 on platelet-derived growth factor-mediated cell migration. Complementary to these results, an increased expression of RAP was closely associated with midkine expression in human colorectal carcinomas (33 of 39 cases examined). Our results suggest that the premature ligand-receptor interaction plays a role in protein production within the secretory pathway.

Background Pancreaticoduodenectomy and distal pancreatectomy for lesions of the neck or body of the pancreas sacrifice a large amount of normal pancreatic tissue. Middle pancreatectomy (MP) is a parenchyma sparing technique that reduces the risk of postoperative endocrine and exocrine insufficiency. This study aims to evaluate the perioperative and long-term results of MP and to clarify whether MP can be performed with outcomes comparable with traditional pancreatectomies. Method Twenty-six patients who underwent MP for benign or low-grade malignant tumor of the pancreas between 1991 and 2006 at the Department of Surgery II, Nagoya University Graduate School of Medicine, were identified. Their outcomes were compared with 2 separate control groups, 35 left-side pancreatectomies (LSP) and 60 right-side pancreatectomies (RSP). Results The mean operating time of the MP group was 295 minutes, which was significantly shorter than that for RSP (P = .0001). The rate of pancreatic fistula formation was higher in the MP group than in the 2 control groups, although the differences did not reach statistical significance. After a mean follow-up of 71 months, postoperative endocrine function was equivalent to the pre-operative values in the MP group, and none of the patients developed diabetes mellitus postoperatively. Only 1 patient in the MP group required enzyme substitution postoperatively for exocrine insufficiency. The MP group was inclined to be superior to the other 2 control groups in terms of postoperative nutritional status. Conclusion Middle pancreatectomy is a reasonable technique that is indicated for selected patients with benign or low malignant tumors in the neck and body of the pancreas. Middle pancreatectomy seems to result in better preservation of exocrine and endocrine functions as well as in better nutritional status postoperatively.

Background ABO incompatibility in organ transplantation is still a high risk factor for antibody-mediated rejection, despite the progress in effective treatments. We have explored the possibility of using the enzyme to remove the blood type A/B antigen in organs. Methods Recombinant endo-s-galactosidase (ABase), which releases A/B antigen, was produced in E. coli BL-21. Human A/B red blood cells (RBC) were digested with ABase, and subjected to flow cytometric analysis after incubation with human sera. Purified recombinant ABase was intravenously administered to a baboon. Biopsies were taken from kidney and liver before and 1, 4 and 24 h after in vivo administration. Excised baboon kidneys were perfused with cold UW solution +/− purified recombinant ABase and preserved at 4 °C. Biopsies were taken before and 1 and 4 h after ex vivo perfusion. The change in A/B antigen expression was analyzed by immunohistochemical study. Results ABase removed 82% of A antigen and 95% of B antigen in human A/B red blood cells, and suppressed anti-A/B antibody binding and complement activation effectively. ABase was also found to remain active at 4 °C. In vivo infusion of ABase into a blood type A baboon demonstrated a marked reduction of A antigen expression in the glomeruli of kidney (85% at 1 h, 9% at 4 h and 13% at 24 h) and the sinusoids of liver (47% at 1 h, 1% at 4 h and 3% at 24 h) without serious adverse effects. After ex vivo perfusion and cold storage of excised baboon kidney (blood type B) with ABase, the expression levels of B antigen in glomeruli were reduced to 49% at 1 h and 6% at 4 h. Conclusions This alternative approach might be useful for minimizing antibody removal and anti-B cell immunosuppression as an adjuvant therapy in ABO-incompatible kidney, liver and possibly heart transplantation.

To recognize “normal” hepatic hemodynamics after live donor liver transplantation (LDLT), we analyzed Doppler parameters on recipients with a right liver graft and donors after extended left hepatectomy. Theoretically these values should be the same. From April 2000 to October 2004, 20 LDLTs were performed using a right liver graft. The 10 recipients without postoperative complications and their donors were included in this study. Portal venous velocity (PVV; cm/s), hepatic arterial peak systolic velocity (cm/s), and hepatic venous peak velocity (HVPV; cm/s) were measured during the first 2 weeks. In donors PVV and HVPV after LDLT were significantly higher after than before left hepatectomy: 19.2 ± 4.2 vs. 31.5 ± 13.0 cm/s ( P = .013) and 23.0 ± 7.2 vs. 41.8 ± 10.3 cm/s respectively ( P = .010). However, there were mild degrees of increased PVV and HVPV. In recipients, a markedly increased PVV (106.3 ± 45.2 cm/s on day 1) was significantly higher than that in donors on each postoperative day. The hepatic arterial resistive index in recipients was also significantly higher than that in donors on each postoperative day, for example, 0.72 ± 0.11 vs 0.62 ± 0.04 on day 1 ( P = .0326). In conclusion, we have shown “abnormal” hepatic hemodynamics in even those recipients without complications during the early postoperative period after LDLT.

Background In renal hyperparathyroidism, in which basically all parathyroid glands are hyperplastic, overlooking one undescended parathyroid gland becomes important. Methods Between July 1973 and December 2004, 1750 patients in our department underwent parathyroidectomy for severely advanced renal hyperparathyroidism. We evaluated the frequency and location of undescended parathyroid glands and the clinical findings and the prognosis of patients with such glands. Results Undescended parathyroid glands in our series of renal hyperparathyroidism numbered 16 of 1750 cases (0.91%). In 9 patients, the glands were removed at the initial parathyroidectomy in our hospital. Two of these glands were detected by preoperative imaging; 6 glands were removed with an undescended thymus. The mean weight of the undescended parathyroid glands that were removed at initial operations was 470 mg (30 to 1392 mg). In 7 other patients, unrecognized undescended glands were responsible for persistent hyperparathyroidism in 6 patients and recurrent disease in 1 patient. In 4 of these 7 patients, the initial parathyroidectomy was performed at our hospital; in the other 3 patients, the initial parathyroidectomy had been done at another hospital, and the glands were removed on reoperation. The mean weight of these glands was 1295 mg (range, 444-2396 mg). In 12 of a total of 16 patients with undescended glands, there appeared to be an inferior parathyroid gland, and the other 4 glands appeared to be a superior gland. No glands were detected by sestamibi scans. Conclusion In operations for renal hyperparathyroidism, an undescended parathyroid gland can be readily overlooked, which leads to persistent or recurrent hyperparathyroidism. Because an undescended parathyroid gland is not always an inferior gland, in surgery for persistent and/or recurrent renal hyperparathyroidism, it is very important to examine carefully the submandibular portion to detect such an undescended gland.

Aims In the current study, we investigated possible correlations of the mtDNA copy number in hepatocellular carcinoma (HCC) with the pathological findings and prognosis. Methods We studied 31 HCC specimens using quantitative real-time polymerase chain reaction analysis, and the correlation between the mtDNA copy number and the clinicopathologic parameters and mutations in the D-loop region of the mitochondrial genome. Results The mtDNA copy number was reduced in HCCs compared with the corresponding non-cancerous liver tissues ( p =0.002), and significantly correlated with tumour size ( p =0.014) and cirrhosis ( p =0.048). Patients with a low mtDNA copy number tended to show shorter 5-year survival rates than patients with a high mtDNA copy number when assessed by Kaplan–Meier curves, but not a significant (overall survival rate, 63 vs 83%; p =0.19). The copy number of HCC with mtDNA D-loop mutation or deletion was lower, but not significantly so ( p =0.656, p =0.590, respectively). Conclusions Our results indicated that a reduced copy number of mtDNA is correlated with HCC and associated with malignant potential.

Gastrointestinal stromal tumours (GIST) are thought to derive from interstitial cells of Cajal (ICCs), which are putative pacemaker cells for gut motility. Isolated cells were obtained by enzymatic treatment of human duodenum GIST tissue having a frequent gain-of-function gene mutation. After cell culturing, c-Kit immunoreactivity was preserved and the cells developed long processes. Whole cell patch clamp recordings revealed voltage-dependent outward currents, without transient inward currents. Intracellular Ca 2+ measurements showed oscillation-like spontaneous activity in some GIST cells. RT-PCR revealed expression of ion channels (Kv1.1, Kv1.6 and KCNH2; IP3R1, and IP3R2; TRPC1, 3, 6 and 7; Cx43), which have been suggested to play important roles in pacemaker activity. However, SCN5A, a TTX-resistant Na + channel known to be expressed in human ICCs, was below detectable levels. These data suggest that GIST cells appear to preserve some, but not all ionic mechanisms underlying pacemaker activity in ICC.

Pancreatic cancer remains a lethal disease. Although there are many reports on the survival rates of pancreatic cancer patients after surgical resection, the clinicopathological characteristics that influence long‐term survival over 5 years remain controversial. Here, we clarify the favourable prognostic factors for long‐term survival. One hundred and eighty‐two patients with pancreatic cancer underwent surgical resections from 1981 to 1997 in our department. Among them, eight patients survived for at least 5 years after the surgery. The clinicopathological characteristics of the eight long‐term survivors who underwent radical resections were studied retrospectively. R0 surgical resections, including five combined with portal vein resections (62.5%), were achieved in these eight patients. Negative invasions of the major regional artery (seven of eight, 87.5%) and to the extrapancreatic nerve plexus (seven of eight, 87.5%), and N0 or N1 lymph node metastasis (7 of 8, 87.5%) were detected as clinicopathological features of long‐term survivors in our study. No exposure of carcinoma at the dissected surface and cut end (seven of eight, 87.5%) was characteristically confirmed by pathology. Portal vein invasion was seen in three of the eight patients (37.5%). For long‐term survival in cases of pancreatic cancer, complete R0 resections should be performed and negative invasions in the major regional arteries and to the extrapancreatic plexus of the nerve were necessary. No invasion to the portal vein was not necessarily required if R0 was achieved by combined resection of the portal vein.

Background/Aims The development of human malignancies can be attributed to aberrant regulation of intracellular signal transduction pathways. In the current study, we aimed to evaluate focal adhesion kinase (FAK), a non-receptor tyrosine kinase, expression in hepatocellular carcinoma (HCC), and to explore the prognostic significance of FAK. Methods We investigated FAK mRNA expression in 60 HCC specimens using quantitative real-time reverse transcription polymerase chain reaction analysis, and the correlation between FAK expression and clinicopathologic parameters. FAK protein expression was examined using Western blot analysis and an immunohistochemical study. Results We found that FAK mRNA was overexpressed in HCCs compared with the corresponding non-cancerous liver tissues ( P =0.0008). The FAK overexpression correlated significantly with tumor size ( P =0.034) and serum AFP level ( P =0.030). Univariate and multivariate analyses revealed that FAK mRNA expression was an independent prognostic factor for disease-free (risk ratio 3.83; P =0.024) and overall (risk ratio 7.14; P =0.015) survival. Besides, we confirmed immunohistochemically that the FAK protein was detectable in cancer cells despite non-expression in corresponding non-cancerous tissues. Conclusions Our results suggest that FAK mRNA expression has prognostic significance for the survival of patients with HCC.

ObjectivesWe investigated the utility of the peak negative myocardial velocity gradient (MVG) derived from tissue Doppler imaging (TDI) for evaluation of diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM).BackgroundHypertrophic cardiomyopathy is characterized by impaired diastolic function with abnormal stiffness and prolonged relaxation. However, it remains difficult to evaluate these defects noninvasively.MethodsBoth TDI and conventional echocardiography were performed in 36 patients with HCM and in 47 control subjects. Left ventricular (LV) pressure was measured simultaneously in all HCM patients and in 26 controls.ResultsThe peak negative MVG occurred soon after the isovolumic relaxation period during the initial phase of rapid filling (auxotonic relaxation). It was significantly smaller in HCM patients than in control subjects (2.32 ± 0.52/s vs. 4.82 ± 1.15/s, p < 0.0001); the cutoff value for differentiation between all HCM patients and 47 normal individuals was determined as 3.2/s. Both the left ventricular end-diastolic pressure (LVEDP) (19.6 ± 6.1 mm Hg vs. 6.5 ± 1.7 mm Hg, p < 0.0001) and the time constant of LV pressure decay during isovolumic diastole (tau) (44.0 ± 6.7 ms vs. 32.1 ± 5.5 ms, p < 0.0001) were increased in HCM patients compared with controls. The peak negative MVG was negatively correlated with both LVEDP (r= −0.75, p < 0.0001) and tau (r= −0.58, p < 0.0001).ConclusionsA reduced peak negative MVG reflects both prolonged relaxation and elevated LVEDP. The peak negative MVG might thus provide a noninvasive index of diastolic function, yielding unique information about auxotonic relaxation in patients with HCM.

Background/Aims: Several lines of experimental data suggest that acinar cells have the potential to differentiate into ductular-like cells, and these newly formed acinoductular cells may act as (facultative) stem cells. The purpose of this study was to test this hypothesis in a model of pancreatic regeneration in rats. Methods: In the current study, using a 90% pancreatectomy as a rat model for pancreatic regeneration, we serially examined the pancreatic tissues in a time-dependent manner by conventional histology and immunostaining. Cell proliferation was assessed by in vivo bromodeoxyuridine (BrdU) labeling. Results: By 24 h after surgery, acini showed depleted granules with more dilated lumens (acinar ectasia). By day 2, focal regions of regeneration appeared which were separated by fibrosis and composed of ductular-like cells (tubular complexes) and acinar cells with dilated lumina. Double immunofluorescent staining revealed that both amylase and CK19 were positive in the same cells localized to the focus of regeneration from the animals on day 2, the phenotype of cells from those regions apparently reverted to acinar cells, and the regions completely disappeared by day 7. By 48 h after surgery, the number of BrdU-positive cells increased 4.3fold in ductular cells, and 2.5-fold in acinar cells compared with control tissue. Conclusion: Acinar cells through acinoductular metaplasia may be a source of pancreatic regeneration.

We performed simultaneous bilateral laparoscopic total adrenalectomy in two patients with Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Preoperative serum cortisol in the patients was 29.5 and 53.2 microg/dl, respectively. The clinical symptoms of the latter patient were advanced, and respiration was labored with orthopnea. Laparoscopic adrenalectomies were performed transabdominally in the sequential lateral decubitus positions with extension of the lateral abdominal wall of the affected side. Three 12-mm and three 5-mm trocars were positioned, and two trocar sites in the midline were used on both sides. The flexible fiberscope was inserted through the umbilical port. The adrenal glands were large, fragile, and multinodular. The maximal diameters of the removed glands were 7.8 and 8.7 cm, respectively. In both patients, the adrenal glands were successfully removed without fragmentation. The operation times were 505 and 320 min, and the estimated blood loss was 150 and 5 ml, respectively. Neither intraoperative nor postoperative complications occurred, although the latter patient required muscle training before ambulation on postoperative day 42. The procedures resulted in marked clinical improvements. Compliance with the substitutive therapy remained excellent, and the patients expressed a very high degree of satisfaction with the laparoscopic adrenal surgery. The procedures of bilateral laparoscopic adrenalectomy were successful, and provided increased experience with the laparoscopic techniques.

Non-invasive diagnosis of cirrhosis by transit-time analysis of an ultrasound contrast agent has been reported, even though the mechanism by which contrast arrives to the hepatic vein earlier in cirrhosis than in normal controls is unknown. The aim of this study is to assess whether the earlier appearance of contrast in the hepatic vein depends on intrahepatic or extrahepatic causes.There were 15 participants: six volunteers, three patients with hepatitis, and six with cirrhosis. The contrast agent was given intravenously, and transit-time analysis of the hepatic artery, portal vein and hepatic vein was performed. The time-acoustic intensity curves in the three vessels were analyzed by an image and cineloop display and quantification software package.The hepatic artery and portal vein arrival times were not significantly different among the three groups. On the other hand, hepatic vein arrival times were significantly earlier in cirrhosis (median 18 seconds) compared with arrival times in hepatitis patients (median 30 seconds, P0.001) and in healthy volunteers (median 31 seconds, P0.001). These results give support to a previous pilot study and indicate that most of the time delay in hepatic vein arrival time between cirrhosis and the other groups originated from intrahepatic circulation abnormalities.This study confirms that the earlier appearance of contrast in the hepatic vein observed in cirrhosis is due to intrahepatic, and not extrahepatic, hemodynamic changes.

We applied novel real-time reverse transcriptase-polymerase chain reaction (RT-PCR) with a LightCycler for quantitative detection of carcinoembryonic antigen (CEA) mRNA expressing tumor cells in the peripheral blood of colorectal cancer patients. Analysis of peripheral blood samples from 99 potentially curative colorectal cancer patients revealed a significantly higher mean CEA mRNA value in post-operative bloods (18.71) than in pre-operative blood (1.03) (P=0.003). Kaplan-Meier analysis demonstrated disease free survival of patients with positive CEA mRNA in post-operative blood to be significantly shorter than in cases negative for CEA mRNA (P=0.03). These results suggest that tumor cells could be shed into the bloodstream during surgical procedures, and these free tumor cells are accompanied by a poor patient outcome. Real-time quantitative RT-PCR is a useful technique for quantitative assessment of free tumor cells in the peripheral blood of colorectal cancer patients.

Background. The indocyanine green (ICG) clearance test has been used to estimate liver functional reserve before hepatectomy. However, changes in ICG clearance after hepatectomy have not been investigated, and their extent remains unknown. Patients and methods. The ICG(K) value, signifying the ICG elimination rate constant, was measured with pulse-dye densitometry before operation and 1, 2, 3, 5, and 7 days postoperatively in 22 patients who underwent liver resection of various extent. CT volumetry was used to calculate the residual liver volume ratio. The relationship between the pre- and postoperative ICG(K) value and the residual liver volume ratio was examined statistically. Results. There was a significant drop in ICG(K) value, from 0.193 ± 0.011 before operation to 0.160 ± 0.013 on Postoperative Day 1, and then it remained significantly low at the postoperative examination times. The residual liver volume ratio was 70.2 ± 5.4%. The estimated ICG(K) value, calculated by the preoperative ICG(K) value and the residual liver volume ratio, showed a significant correlation with the actual postoperative value (r = 0.859 on Postoperative Day 1, P < 0.0001). In five patients with prolonged jaundice, the estimated ICG(K) value was significantly lower than in those without it (0.077 ± 0.028 versus 0.153 ± 0.012, P = 0.0136). Conclusions. The perioperative ICG(K) value measured by pulse-dye densitometry revealed a significant decrease in ICG(K) after operation depending on the reduction in liver volume, and the estimated ICG(K) based on the residual liver volume was useful in predicting postoperative morbidity.

The HLA class I and class II mediated antigen presentation plays a major role in the initiation of immune response and the development of acute rejection after transplantation. The purpose of this study was to examine whether MHC-encoded antigen processing (TAP1, TAP2, LMP2, DMA and DMB) gene polymorphisms were associated with the incidence and the severity of acute rejection after renal transplantation. We studied a selected population of 112 pairs of donors and recipients who underwent living-related renal transplantation. They were divided into 3 groups: rejection-free (Group A, n = 51), steroid-sensitive rejection (Group B, n = 31) and steroid-resistant rejection (Group C, n = 30). The frequency of TAP2*0103 (41.2%) was significantly higher in the donors of Group A than that of Group B (12.9%, p = 0.0070, pc = 0.0280) or Group C (16. 7%, p = 0.0225, pc = 0.0900). No significant difference was observed in the allelic frequencies of the TAP1, LMP2, DMA, and DMB genes in the donors or recipients among Groups A, B, and C. This result supported the idea that the TAP2 gene polymorphism might be functionally related to antigen presentation. It also suggested that donor's antigen presenting cells with the TAP2*0103 allele would have the attenuated efficacy in the presentation of allospecific antigens to recipient's T cells.

Galalpha1-3Gal is the major xenoantigenic epitope responsible for hyperacute rejection upon pig to human xenotransplantation. Endo-beta-galactosidase C from Clostridium perfringens destroys the antigenic epitope by cleaving the beta-galactosidic linkage in the Galalpha1-3Galbeta1-4GlcNAc structure. Based on partial peptide sequences of the enzyme, we molecularly cloned the enzyme gene, which encodes a protein with a predicted molecular mass of about 93 kDa. The deduced protein sequence of the enzyme has limited homology in the C-terminal half with endo-beta-galactosidase from Flavobacterium keratolyticus and beta-1,3-glucanases. The enzyme expressed in Escherichia coli removed the alpha-galactosyl epitope nearly completely from pig erythrocytes and from pig aortic endothelial cells. The enzyme-treated endothelial cells in culture were greatly reduced in cell surface antigens, which were recognized by IgM, IgG, or IgA in human sera, and became much less susceptible to complement-mediated cytotoxicity caused by human sera. When the pig kidney was perfused with the enzyme, the vascular endothelial cells became virtually devoid of the alpha-galactosyl epitope, with concomitant decrease in binding to IgM in human plasma. These results demonstrated that the recombinant endo-beta-galactosidase C is a valuable aid in xenotransplantation.

Patients with Cushing's syndrome (137 total) who underwent adrenalectomy from 1957 through 1999 were reviewed for survival and complications. Of the 137 patients, 83 had adrenocortical adenoma, 30 Cushing's disease, seven primary pigmented nodular adrenocortical disease (PPNAD), eight adrenocorticotropin (ACTH)-independent macronodular hyperplasia, five adrenocortical carcinoma, and four ectopic ACTH syndromes. Seventy-eight patients with adrenocortical adenoma are alive, and their survival rate was equal to the age-matched control population, when patients who died of postoperative complications were excluded. Of the patients with Cushing's disease, 20 are alive, and ten of 16 patients (63%) who were followed and evaluated, had skin pigmentation. Four of 16 patients (25%) developed Nelson's syndrome. Five PPNAD patients and six with ACTH-independent macronodular hyperplasia are alive. All five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within two years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid disappearance of signs and symptoms of glucocorticoid excess after total adrenalectomy is assured, and the prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease.

To evaluate the effects of chronic liver diseases on mitochondrial DNA (mtDNA) transcription and replication, nuclear respiratory factor-1 (NRF-1) mRNA, mitochondrial transcription factor A (mtTFA) mRNA, a RNA component of ribonuclease (RNase) for mitochondrial RNA processing (MRP), mitochondrial cytochrome b mRNA, and mtDNA were measured in normal, chronically viral-hepatitic and cirrhotic human livers. The mRNA levels of the regulatory factors for mitochondrial gene (NRF-1 and mtTFA) and cytochrome b were significantly increased by chronic hepatitis (160, 280, and 175%, respectively) compared with those in normal livers, but were not different between cirrhotic and normal livers. On the other hand, concentrations of mtDNA and RNA component of RNase MRP were not different among normal, chronically hepatitic, and cirrhotic livers. These results suggest that either persistent hepatitis viral infection or repeated cell necrosis and regeneration in chronically hepatitic liver may be associated with increase in mtDNA transcription.

We measured the populations of mutated mitochondrial DNAs with the 7,436 bp or the 4,977 bp deletion from apparently normal human liver and human livers with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The amount of the mutated mitochondrial DNA was at the same level between normal and chronically hepatitic livers but was significantly lower in human livers with cirrhosis and hepatocellular carcinoma, especially the latter, suggesting that the mutated mitochondrial DNAs may be decreased with the progress of liver disease from chronic hepatitis to cirrhosis and hepatocellular carcinoma. This phenomenon is opposite to that occuring in the ageing process.

Background: This study was performed to investigate the diagnostic accuracy of intraportal endovascular ultrasonography (IPEUS) in assessing vascular invasion by biliary tract cancer. Methods: A prospective study of 31 consecutive patients with biliary tract cancer was performed. All patients underwent surgery. The sonographic criterion for right hepatic artery invasion was interruption of the hyperechoic layer or encasement by tumor. The sonographic criterion for portal vein invasion was obliteration of the echogenic band of the portal vein. IPEUS findings were confirmed by surgical exploration and pathologic examination of resected specimens. Results: Right hepatic artery invasion was confirmed in resected specimens in seven patients and by operative findings in four patients. Portal vein invasion was confirmed in resected specimens in six patients and by operative findings in five patients. For diagnosis of right hepatic artery invasion, the sensitivity, specificity, and overall accuracy of IPEUS were all 100%; respective values were 63.6%, 84.2%, and 76.7% for angiography. For diagnosis of portal vein invasion, the sensitivity, specificity, and overall accuracy of IPEUS were 100%, 95%, and 96.8%, respectively. The corresponding values were 63.6%, 89.5%, and 80% for portography and 54.5%, 85%, and 74.2%, respectively, for CT. Conclusion: IPEUS will improve the assessment of vascular invasion at the hepatic hilum by biliary tract cancer. (Gastrointest Endosc 1998; 47:33-41.)

BACKGROUND: The significance of pTNM staging of hepatocellular carcinoma (HCC) as a prognostic factor after hepatic resection was evaluated. PATIENTS AND METHODS: The prognoses were analyzed in 262 patients treated with hepatic resection for HCC. RESULTS: As a whole, the pTNM stages correlated well with the survival rates. The survival rates of stage I and II patients were significantly higher than those of stages III and IV. However, there was no significant difference in survivals between stage I and II, and between stage III and IV-A. The survival rates of the patients treated with segmentectomy or lobectomy in stages I and II were significantly higher than those with subsegmentectomy or smaller resection. Multivariate analysis revealed that tumor size greater than 2 cm, multiple gross tumors, surgical margin less than 1 cm, and Child C classification were independently significant factors of poor survival. CONCLUSIONS: The results of hepatic resection for HCC should be stratified by pTNM staging and by Child classification of hepatic function before comparison.

This study was designed to clarify effects of gamma-glutamylcysteine ethyl ester, a prodrug of glutathione, on doxorubicin-induced changes in liver energy metabolism after hepatectomy. Rats were divided into two major groups dependent on whether hepatectomy had been performed. Rats undergoing hepatectomy were subdivided into three groups: the control group, 70% of the liver was resected; the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was administered intraperitoneally; and the doxorubicin + gamma-glutamylcysteine group, 30 min before hepatectomy 50 mg/kg body weight of gamma-glutamylcysteine ethyl ester was injected intravenously and other procedures were performed as in the doxorubicin group. In the group not undergoing hepatectomy, 2 mg/kg body weight doxorubicin was administered intraperitoneally after a sham operation. Rats in each group were sacrificed 24, 72, and 120 hr after hepatectomy or sham operation, and the remnant liver was isolated. Liver mitochondrial function, adenine nucleotide concentrations, and glutathione and glutathione peroxidase activities were determined. Doxorubicin did not show any significant effects on parameters measured in rats not undergoing hepatectomy. Liver mitochondrial function was increased significantly 24 hr after hepatectomy, and significant decreases in adenine nucleotide concentrations were observed 24 and 72 hr after hepatectomy. Doxorubicin inhibited the increase in mitochondrial function associated with hepatectomy and delayed recovery of liver adenine nucleotide concentrations. Significant increases in tissue glutathione concentrations were observed 24 and 72 hr after hepatectomy. These significant increases in glutathione concentrations were not observed in rats treated with doxorubicin 72 hr after hepatectomy. Furthermore, doxorubicin decreased glutathione peroxidase activity after hepatectomy. Administration of gamma-glutamylcysteine ethyl ester lessened these doxorubicin-induced changes. These results indicate that changes in the glutathione redox system might be involved in the doxorubicin-induced deterioration of the remnant liver energy metabolism. Clinical application of gamma-glutamylcysteine ethyl ester might be expected.

Evidence has accumulated that oxygen-derived free radicals contribute to the cellular damage induced by ischemia-reperfusion. It has been suggested that nitric oxide (NO) may act as a protective factor in ischemia-reperfusion injury since NO increases blood flow and may scavenge oxyradicals. Nevertheless, controversy exists as to the role of NO. This study was designed to clarify the role of endogenous NO in ischemia-reperfusion-induced liver injury in rats in vivo. Wistar rats weighing 250-300 g were divided into three groups: (1) untreated group (Control); (2) NG-nitro-L-arginine, a specific inhibitor of NO production (L-NNA); and (3) L-arginine-pretreated L-NNA group (AR+L-NNA). Occlusion of all vessels to the median and left hepatic lobes (60 min) was followed by reperfusion for 1 or 24 hr. L-NNA was administered before ischemia as a 10 mg/kg bolus. L-Arginine was given just before L-NNA administration as a 100 mg/kg bolus. Administration of L-NNA resulted in endothelial cell injury characterized by the elevation of serum hyaluronic acid as well as the reduction of hepatic tissue blood flow, and the recovery of hepatic adenosine triphosphate was depressed compared with the control after both 1 and 24 hr of reperfusion. Furthermore, the leakages of various liver enzymes and lipid peroxide were also increased, associated with histological damage. This effect of L-NNA was completely abolished by pretreatment with L-arginine. These results suggest that endogenous NO provides a protective effect against ischemia-reperfusion injury in rat liver.

Background. We evaluated the role of intravascular ultrasonography in the diagnosis of intravascular tumor thrombi. Methods. During the past 2 years intracaval endovascular ultrasonography was performed in 26 selected patients to diagnose inferior vena cava invasion. Results of positive intracaval endovascular ultrasonogram were correlated with the pathologic findings of resected specimens and autopsy and with other imaging technologies such as computed tomography and angiography. Results. Six patients had positive studies of intracaval tumor thrombus. In all cases detailed horizontal images perpendicular to the inferior vena cava axis were studied. Five of the six patients underwent resection. Intravascular ultrasonography correctly predicted, the extent of the tumor thrombus, the degree of tumor adherence to the vessel wall, and the intraluminal movement of the tumor thrombus. Floating thrombi were visualized as an intraluminal to-and-fro movement. Thrombus adhesion to the vessel wall appeared as an absence of space between the tumor and the wall, with no respiratory movement of the thrombus. Conclusions. Intravascular ultrasonography was useful for the accurate diagnosis of intravascular tumor thrombi and aided in formulating the operative strategy.

OBJECTIVES The objective of this study was to identify the most appropriate endoscopic biliary drainage method in patients with pancreatic head cancer. METHODS A prospectively collected database comprising 122 consecutive patients who underwent pancreatoduodenectomy, including 72 patients treated by endoscopic retrograde biliary drainage (ERBD) and 50 patients treated by endoscopic nasobiliary drainage (ENBD) procedures, was analyzed. RESULTS All bile cultures collected intraoperatively were positive in the ERBD group, and the positive rates of drainage fluid cultures on postoperative days 1, 3, and 5 and the incidence of postoperative abdominal abscess formation were significantly higher than those in the ENBD group. Moreover, ERBD was identified as an independent predictive factor for postoperative pancreatic fistula (POPF) formation (hazards ratio, 11.81; P < 0.001). The receiver operating characteristic curve analysis for the preoperative drainage period in the ERBD group revealed that the determined cutoff level for the onset of POPF was 29 days. CONCLUSIONS Endoscopic retrograde biliary drainage resulted in more frequent postoperative complications, including POPF, compared with ENBD. Postoperative pancreatic fistula is more likely to occur if the ERBD period exceeds 1 month in patients scheduled to undergo pancreatoduodenectomy.

Background: Limited vascular access could be encountered in an obese or re-transplant patient. Aims: An en bloc SPK composite graft transplant in an obese diabetic patient under hemodialysis was described. Patients & methods: At the back-table, SMA and SA of the pancreas graft were reconstructed with a long "Y" artery graft. The smaller left renal artery is anastomosed to thelonger common limb of the arterial Y graft and the shorter portal vein is to the longer graft left renal vein. This en bloc composite graft allowed to facilitate “real” SPK transplant using single common graft artery and vein for anastomosis to one recipient arterial and venous site. The en bloc pancreas and kidney composite graft was implanted by suturing the graft left renal vein to IVC and graft common iliac artery the recipient distal aorta. Results: The operative time was 7 hours with cold ischemic time of 6 hours and 25 min. and warm ischemic time of 47 min. The patient was discharged on postoperative day 20, with a serum creatinine level of 1.4 ng/ ml and a blood glucose level of 121 mg/dL. He has not had any rejection episodes or postoperative complications in the following 12 months after the en bloc SPK transplant. Conclusion: En bloc pancreas and kidney composite graft might be an option for patients with limited vascular access. This technique (1) facilitates “real” simultaneous pancreas and kidney (SPK) transplant with only single common artery and vein for implanting the composite graft; (2) minimizes dissection of vessels and conserves recipient vessels.

Thirty clinical tests on PVC drain tubes coated with hydrophilic copolymer with long poly(ethylene oxide) chains (PEO-COAT®) were carried out. Controls were non-coated PVC drain tubes. Thrombogenesis was observed in 24 out of 30 non-coated PVC drain tubes (80%) and in only 4 out of 30 PEO-COAT drain tubes (13%). PEO-COAT drain tubes significantly suppressed absorption of plasma proteins and adhesion of platelets. The excellent antithrombogenic property of this hydrophilic polymer, already suggested by in vitro and in vivo experiments, was demonstrated here clinically.

s / Pancreatology 13 (2013) e1–e94 e76 Conclusion: Our study confirmed that IL-6, IL-8, IL-10, and sTNFr measured on admission, and CRP and pancreatic elastase measured on third day of admission represent valuable prognostic factors in the determination of severity in patients with AP.