Aberrant phosphorylation of human LRH1 at serine 510 is predictable of hepatocellular carcinoma recurrence.

We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen receptor α regulate their activity independently of the ligands. Since this site is conserved at S510 in human liver receptor homolog 1 (hLRH1), we developed a monoclonal antibody (mAb) that recognized the phosphorylation form of hLRH1S510 (hLRH1pS510) and verified its clinicopathological significance in hepatocellular carcinoma (HCC). We generated the anti-hLRH1pS510 mAb and assessed its selectivity. We then evaluated the hLRH1pS510 signals in 157 cases of HCC tissues by immunohistochemistry because LRH1 contributes to the pathogenesis of diverse cancers. The developed mAb specifically recognized hLRH1pS510 and worked for immunohistochemistry of formalin-fixed paraffin-embedded tissues. hLRH1pS510 was exclusively localized in the nucleus of HCC cells, but the signal intensity and positive rates varied among the subjects. According to the semi-quantification, 45 cases (34.9%) showed hLRH1pS510-high, and the remaining 112 cases (65.1%) exhibited hLRH1pS510-low. There were significant differences in the recurrence-free survival (RFS) between the two groups, and the 5-year RFS rates in the hLRH1pS510-high and hLRH1pS510-low groups were 26.5% and 46.1%, respectively. In addition, high hLRH1pS510 was significantly correlated with portal vein invasion, hepatic vein invasion, and high levels of serum alpha-fetoprotein (AFP). Furthermore, multivariable analysis revealed that hLRH1pS510-high was an independent biomarker for HCC recurrence. We conclude that aberrant phosphorylation of hLRH1S510 is a predictor of poor prognosis for HCC. The anti-hLRH1pS510 mAb could provide a powerful tool to validate the relevance of hLRH1pS510 in pathological processes such as tumor development and progression.

Tissue-Engineered Hepatocyte Sheets Supplemented with Adipose-Derived Stem Cells.

The ability to engineer biologically viable hepatocytes and tissue matrices with long-term functional maintenance has attracted considerable interest in the fields of hepatocyte transplantation and liver tissue engineering. Here, newly developed hepatocyte sheets supplemented with adipose-derived stem cells (ADSCs) were evaluated to assess the effects of ADSCs on hepatocyte function and engraftment into the subcutaneous space. Eight-week-old male C57BL/6J mice were used as donors, and 6-week-old male C.B-17/Icr-scid/scid mice were used as recipients. Hepatocyte-ADSC composite sheets were developed using temperature-responsive culture dishes. Hepatocyte viability in the hepatocyte-ADSC composite sheets was evaluated in an in vitro assay, and the outcome of subcutaneous transplantation of the sheet was evaluated. Hepatocyte viability was sustained in the hepatocyte-ADSC composite sheets in vitro. Albumin secretion was significantly higher (p = 0.015) in the hepatocytes of the hepatocyte-ADSC composite sheets (70.5 µg/mL) than in hepatocyte-only sheets (24.0 µg/mL). Cytokine assays showed that hepatocyte growth factor and interleukin-6 were contributed by ADSCs and not hepatocytes, which were not capable of constitutively secreting them. Immunohistochemically, phosphorylated STAT3 and c-MET expression in hepatocytes in the hepatocyte-ADSC composite sheets was significantly higher than that in the hepatocyte-only sheets. Engraftment of the transplanted hepatocyte-ADSC composite sheets was significantly enhanced without pretreatment of the subcutaneous tissue to induce a vascular network. In the hepatocyte-ADSC composite sheets, the viability of the hepatocytes was significantly maintained as the co-cultured ADSCs provided cytokines, enhancing pivotal cell signaling necessary for hepatocyte activity. Impact statement Hepatocyte transplantation is a safe, less invasive bridge treatment for liver transplantation, but its effectiveness is low and transitory. Herein, we introduce newly developed hepatocyte-adipose-derived stem cell composite sheets with improved strength, easier transplantation, and increased hepatocyte viability in the subcutaneous transplantation compared with hepatocyte-only sheets.

Achieving clinically optimal balance between accuracy and simplicity of a formula for manual use: Development of a simple formula for estimating liver graft weight with donor anthropometrics.

In developing a formula for manual use in clinical settings, simplicity is as important as accuracy. Whole-liver (WL) mass is often estimated using demographic and anthropometric information to calculate the standard liver volume or recommended graft volume in liver transplantation. Multiple formulas for estimating WL mass have been reported, including those with multiple independent variables. However, it is unknown whether multivariable models lead to clinically meaningful improvements in accuracy over univariable models. Our goal was to quantitatively define clinically meaningful improvements in accuracy, which justifies an additional independent variable, and to identify an estimation formula for WL graft weight that best balances accuracy and simplicity given the criterion. From the Japanese Liver Transplantation Society registry, which contains data on all liver transplant cases in Japan, 129 WL donor-graft pairs were extracted. Among the candidate models, those with the smallest cross-validation (CV) root-mean-square error (RMSE) were selected, penalizing model complexity by requiring more complex models to yield a ≥5% decrease in CV RMSE. The winning model by voting with random subsets was fitted to the entire dataset to obtain the final formula. External validity was assessed using CV. A simple univariable linear regression formula using body weight (BW) was obtained as follows: WL graft weight [g] = 14.8 × BW [kg] + 439.2. The CV RMSE (g) and coefficient of determination (R2) were 195.2 and 0.548, respectively. In summary, in the development of a simple formula for manually estimating WL weight using demographic and anthropometric variables, a clinically acceptable trade-off between accuracy and simplicity was quantitatively defined, and the best model was selected using this criterion. A univariable linear model using BW achieved a clinically optimal balance between simplicity and accuracy, while one using body surface area performed similarly.

[A Case of Pancreatic Cancer That Developed Peritoneal Recurrence after Radical Surgery following Neoadjuvant Chemoradiation Therapy(NACRT)with Pathological Complete Response(pCR)].

A 71-year-old woman was diagnosed with a tumor in the pancreatic head on CT imaging, which was performed as a close examination of an exacerbation of diabetes mellitus. The pancreatic tumor was diagnosed as resectable pancreatic cancer, and after preoperative adjuvant chemoradiotherapy, pancreatoduodenectomy was performed as a radical surgery. There were no residual tumor cells in the resected specimen histopathologically, and the patient was judged to have a pathological complete response(pCR). Six months of postoperative adjuvant chemotherapy was administered, but peritoneal recurrence was observed at 20 months postoperatively, and the patient is currently undergoing treatment for recurrence. There have been other reports of recurrence even after pCR was achieved with preoperative treatment, so it is important to follow up carefully, keeping in mind that pancreatic cancer is a latent systemic disease.

How is transfusion-associated graft-versus-host disease similar to, yet different from, organ transplantation-associated graft-versus-host disease?

Graft-versus-host disease (GVHD) is a rare, usually fatal complication following blood transfusion or organ transplantation, namely transfusion-associated GVHD (TA-GVHD) and organ transplantation-associated GVHD (OA-GVHD). The dominant mechanism of GVHD is exposure to viable donor lymphocytes that are not recognized as foreign by, but able to respond to, the recipient. The clinical features and relative risk factors of either TA-GVHD or OA-GVHD are yet to be fully understood. The current review article aims to discuss and summarize the similarities and differences between TA-GVHD and OA-GVHD to gain a deeper understanding of the pathogenesis. It is evident that the shared human leukocyte antigens (HLA) between donor and recipient and immunocompromised status of the recipient are the two main risk factors for the development of both TA-GVHD and OA-GVHD. In particular, the homozygous donor with donor-dominant one-way matching at the three loci HLA-A, -B, and -DR has a high risk of developing GVHD following liver transplantation, and such donors should be excluded to prevent it. However, the development of GVHD is thought to be related to a combination of several risk factors, and the contribution of each risk factor remains unknown. Further studies are warranted to determine the important contributing factors that lead to an accurate prediction of GVHD development.

What is the optimal surgical treatment for hepatocellular carcinoma beyond the debate between anatomical versus non-anatomical resection?

The optimal type of hepatectomy for hepatocellular carcinoma (HCC)-anatomical or non-anatomical resection-remains controversial despite numerous comparative studies. There are common fundamental issues in published studies comparing anatomical resection with non-anatomical resection: (1) confounding by indication, (2) setting primary outcomes, and (3) a lack of a clear definition of non-anatomical resection. This degrades the quality of the comparison of the two types of surgery. To measure the therapeutic effect of hepatectomy, it is essential to understand the accumulated knowledge underlying these issues, such as the mechanism of hepatocellular carcinoma spread, tumor blood flow drainage theory, and the three patterns of hepatocellular carcinoma recurrence: (1) local intrahepatic metastasis, (2) systemic metastasis, and (3) multicentric carcinogenesis recurrence. Based on evidence that the incidence of local intrahepatic metastasis was so low it was almost negligible, the therapeutic effect of anatomical resection on the oncological survival was determined to be similar to that of non-anatomical resection. Recent research progress demonstrating the clinical impact of subclinical dissemination of HCC after surgery may stimulate new debate on the optimal surgical treatment for HCC beyond the comparison of anatomical and non-anatomical resection.

Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes.

Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. Several studies have suggested that the clonal depletion, anergy, and expansion of the antigen-specific regulatory immune network are the mechanisms for donor-specific tolerance with ADLs, which act synergistically to induce robust transplant tolerance. This achievement represents a huge step forward toward the clinical application of immune tolerance induction. We herein summarize the reported operational induction therapies in islet transplantation using the ADLs. Moreover, a few obstacles for the engraftment of transplanted islets, such as islet immunogenicity and instant blood-mediated response, which need to be resolved in the future, are also discussed.

Predicting Post-Hepatectomy Liver Failure Using Intra-Operative Measurement of Indocyanine Green Clearance in Anatomical Hepatectomy.

BACKGROUND: Prediction of post-hepatectomy liver failure (PHLF) based on remnant liver function reserve is important for successful hepatectomy. The aim of this study was to investigate whether intraoperative indocyanine green (ICG) clearance in a future remnant liver was a predictor of PHLF. METHODS: This prospective study enrolled 31 consecutive patients who underwent anatomical hepatectomy between June 2016 and August 2019. Intraoperative ICG plasma disappearance rate (ICG-PDR) and ICG retention rate at 15 min (ICG-R15) were measured after clamping the selective hepatic inflow to the liver to be resected. The discriminative performance of the ICG-associated variables for the prediction of PHLF grade B/C was evaluated by receiver operator curve (ROC) analysis. RESULTS: Of the operations performed, 87.1% were major hepatectomy. PHLF Grade B/C was observed in eight patients (25.8%) with no mortality. The concordance indices of intraoperative ICG-PDR and ICG-PDR for predicting PHLF were 0.834 (95% CI, 0.69-0.98) and 0.834 (95% CI, 0.69-0.98), respectively. A subgroup analysis of patients with preoperative biliary drainage (BD) (n = 17) showed that the concordance indices of intraoperative ICG-PDR increased to 0.923 (95% CI, 0.79-1.00). CONCLUSIONS: Intraoperative ICG clearance in the remnant liver was a promising predictor for PHLF in patients undergoing anatomical hepatectomy, especially in patients with BD.

Comprehensive analysis of gene expression of isolated pancreatic islets during pretransplant culture.

BACKGROUND: The aim of this study was to investigate the effect of pretransplant culture on the survival of pancreatic islet grafts, and to determine the biological characteristics of isolated islets during pretransplant culture. METHODS: The survival of islets from Wistar rats, transplanted to diabetic C57BL/B6 mice, was compared between fresh islets and cultured islets. A comprehensive gene expression analysis was employed to investigate biological processes during pretransplant culture, and in vitro validation studies were performed. RESULTS: Survival of cultured xenografts was significantly prolonged as compared to that of fresh islets (fresh:12.5 ± 1.9 days, 1-day cultured:16.0 ± 1.3 days (p= 0.017), 3-day cultured:17.0 ± 2.6 days (p= 0.014)). Comprehensive gene expression analysis identified significant upregulation of annotated functions associated with inflammation in cultured groups. Six proinflammatory genes, including heme oxygenase 1 (HO-1) and IL-6, were significantly upregulated during culture.　Validation studies revealed significantly higher levels of IL-6 in the supernatant of cultured islets and HO-1 in the cultured islets when compared with fresh islets. CONCLUSION: Transplantation of cultured islets induced significant but minimal prolongation of graft survival in xenogeneic combinations. Comprehensive analysis of gene expression in cultured islets showed biological processes associated with proinflammation during culture.

Accuracy comparison of MR elastography and biological markers in detecting liver fibrosis and predicting postoperative ascites.

BACKGROUND: This retrospective study aimed to compare the discriminative performance between magnetic resonance elastography (MRE) and biological markers in detecting liver fibrosis and in predicting postoperative ascites (PA). METHODS: We enrolled 77 patients consecutively who underwent hepatectomy between March 2017 and June 2019. Liver fibrosis was histopathologically graded using the METAVIR scoring system as reference. Discriminative performance of non-invasive assessments in detecting different stages of liver fibrosis and predicting PA was evaluated by receiver-operator curve analysis. RESULTS: The concordance indices (C-indices) for MRE and biological markers for detecting significant fibrosis (≥F2) and cirrhosis (F4) were: MRE, 0.84 and 0.86; Wisteria floribunda agglutinin + Mac-2 binding protein (WM2BP), 0.63 and 0.71; Hyaluronic acid (HA), 0.72 and 0.75; 7 S-type 4 collagen (T4C), 0.61 and 0.66; APRI, 0.76 and 0.83; and Fib-4, 0.75 and 0.76. Univariable logistic analysis for predicting PA showed that C-indices were 0.751 (p = 0.007), 0.798 (p = 0.106), 0.771 (p = 0.050), 0.674 (p = 0.855), 0.655 (p = 0.263), and 0.560 (p = 0.640) for MRE, WM2BP, Fib-4, HA, APRI, and T4C, respectively. CONCLUSION: MRE has a higher diagnostic performance than biological markers in detecting the stages of liver fibrosis and is a predictor for PA after hepatectomy.

Early intra-abdominal infection following pancreaticoduodenectomy:associated factors and clinical impact on surgical outcome.

Early intra-abdominal infection (IAI) following pancreaticoduodenectomy (PD) is an initial event relating to morbidities caused by postoperative pancreatic fistula (POPF). The aims of this study were to determine factors associated with IAI, and to investigate its impact on postoperative outcome.Consecutive patients, 113 in total, who underwent PD at Fukushima Medical University Hospital between January 2012 and September 2017 were included in this retrospective study. IAI was defined by positive bacterial culture from intra-abdominal drainage fluid any time through postoperative day 3 (POD3). Logistic regression analysis was used to identify the relevant factors associated with IAI. The clinical impact of the POD3 infection indicators related to POPF were assessed by multivariate analysis.The incidence of IAI, POPF, and mortality were 36.1%, 36.1%, and 0%, respectively. Independent factors associated with IAI were preoperative biliary drainage (PBD) (OR = 2.91, CI = 1.16-7.33, p = 0.023) and soft pancreas (OR = 8.67, CI = 2.37-31.77, p = 0.001). Among infection markers on POD3, the significant factors for POPF were CRP (OR = 1.18, CI = 1.08-1.30, p < 0.001), IAI (OR = 7,37, CI = 2.53-21.5, p < 0.001), and drain amylase (OR = 1.00, CI = 1.00-1.01, p = 0.001).In conclusion, PBD, soft pancreas, and higher age were associated with IAI. IAI has a significantly negative impact on postoperative outcome.

Invasion of human microvascular endothelial cells by Mycobacterium leprae through Mce1A protein.

In patients with lepromatous leprosy, Mycobacterium leprae is often observed inside the human microvascular endothelial cells (HMVEC) surrounding Schwann cells (SC) at the site of lesions in the peripheral nerves. Based on this observation, it is considered that the nasal mucous may be the invasion pathway for M. leprae and HMVEC serve as an important reservoir for the bacteria before they invade SC. In light of previous research which revealed that Mce1A protein mediates bacterial invasion into nasal epithelial cells and HMVEC, we conducted a study to determine whether the invasion of M. leprae into HMVEC can be suppressed by blocking the Mce1A protein. In this study, we analyzed bacterial invasive activity by adding recombinant Escherichia coli, which express the active region (InvX:72 a.a.) of Mce1A protein on their external membrane, into cultured HMVEC, using the adhesin involved in the diffuse adherence mechanism. The number of bacteria that invaded into the cells was then measured by a colony counting method. The active region of Mce1A was divided into four sections, and hyperimmune antisera was prepared for each section for analyzing the inhibitory effect against invasion. The invasive activity was suppressed by antibodies against InvX regions 1-24 a.a., 25-46 a.a. and 58-72 a.a. This suggests that the InvX regions 1-24 a.a., 25-46 a.a. and 58-72 a.a. of Mce1A protein play an important role in the invasion of M. leprae into HMVEC and that it may be possible to suppress entry of M. leprae in HMVEC with antibodies against these regions.

[FOLFIRINOX for Locally Advanced and Recurrent Pancreatic Cancer with UGT1A1 *6 and or UGT1A1*28 Polymorphisms-A Report of Two Cases].

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

The unique tropism of Mycobacterium leprae to the nasal epithelial cells can be explained by the mammalian cell entry protein 1A.

Leprosy is a chronic infection where the skin and peripheral nervous system is invaded by Mycobacterium leprae. The infection mechanism remains unknown in part because culture methods have not been established yet for M. leprae. Mce1A protein (442 aa) is coded by mce1A (1326 bp) of M. leprae. The Mce1A homolog in Mycobacterium tuberculosis is known to be associated with M. tuberculosis epithelial cell entry, and survival and multiplication within macrophages. Studies using recombinant proteins have indicated that Mce1A of M. leprae is also associated with epithelial cell entry. This study is aimed at identifying particular sequences within Mce1A associated with M. leprae epithelial cell entry. Recombinant proteins having N-terminus and C-terminus truncations of the Mce1A region of M. leprae were created in Escherichia coli. Entry activity of latex beads, coated with these truncated proteins (r-lep37 kDa and r-lep27 kDa), into HeLa cells was observed by electron microscopy. The entry activity was preserved even when 315 bp (105 aa) and 922 bp (308 aa) was truncated from the N-terminus and C-terminus, respectively. This 316-921 bp region was divided into three sub-regions: 316-531 bp (InvX), 532-753 bp (InvY), and 754-921 bp (InvZ). Each sub-region was cloned into an AIDA vector and expressed on the surface of E. coli. Entry of these E. coli into monolayer-cultured HeLa and RPMI2650 cells was observed by electron microscopy. Only E. coli harboring the InvX sub-region exhibited cell entry. InvX was further divided into 4 domains, InvXa-InvXd, containing sequences 1-24 aa, 25-46 aa, 47-57 aa, and 58-72 aa, respectively. Recombinant E. coli, expressing each of InvXa-InvXd on the surface, were treated with antibodies against these domains, then added to monolayer cultured RPMI cells. The effectiveness of these antibodies in preventing cell entry was studied by colony counting. Entry activity was suppressed by antibodies against InvXa, InvXb, and InvXd. This suggests that these three InvX domains of Mce1A are important for M. leprae invasion into nasal epithelial cells.

Pancreaticobiliary maljunction diagnosed long after laparotomy in the neonatal period for annular pancreas: report of a case.

BACKGROUND: Although annular pancreas concurrent with pancreaticobiliary maljunction has rarely been reported, some reports have pointed out a possibility that both anomalies have a common pathogenesis in pancreatic development. We herein report a case with pancreaticobiliary maljunction diagnosed long after surgical treatment for annular pancreas. CASE PRESENTATION: A 34-year-old female, with a surgical history of duodenal obstruction due to annular pancreas in the neonatal period, was referred to our hospital for further examination of chronic pancreatitis. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed choledocholithiasis, pancreatic lithiasis, and pancreaticobiliary maljunction without biliary dilatation. Choledocholithotomy and cholecystectomy were performed, and highly elevated levels of amylase in bile from the common bile duct were found intraoperatively. CONCLUSION: The present case highlights a possible association of pancreaticobiliary maljunction in a patient with annular pancreas.

Prognostic impact of soluble intercellular adhesion molecule-1 in hepatocellular carcinoma.

The identification of novel biomarkers for hepatocellular carcinoma (HCC) is of great importance in improving the outcome of patients with HCC. The present study aimed to determine the prognostic significance of the soluble intercellular adhesion molecule (sICAM)-1 in patients with HCC. The present study prospectively collected clinicopathological data from 36 patients with HCC who had undergone successful hepatectomy. An analysis using a receiver operating characteristic (ROC) curve was performed to determine the cut-off value for predicting prognosis. Overall survival (OS), recurrence-free survival (RFS) and potential prognostic factors were analyzed. The ROC curve analysis revealed a sICAM-1 cut-off value of 440 ng/ml. HCC patients with sICAM-1 ≥440 ng/ml exhibited a poorer OS and RFS than those with sICAM-1 <440 ng/ml (P=0.002). sICAM-1 ≥440 ng/ml (hazard ratio=3.623; 95% confidence interval: 1.145-11.458; P=0.028) and Child B (hazard ratio=1.514; 95% confidence interval: 1.066-2.150; P=0.021) were independent prognostic factors for OS, and sICAM-1 ≥440 ng/ml was an independent prognostic factor for RFS (hazard ratio=3.625; 95% confidence interval: 1.233-10.659; P=0.019). Serum sICAM-1 may be a promising predictor for the overall and recurrence-free survival of patients with HCC.

Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

[A Case of Long-Term Survival of Metastatic and Recurrent Duodenal Gastrointestinal Stromal Tumor Treated with Multimodality Managements].

We hereby report a case of long-term survival of metastatic and recurrent duodenal gastrointestinal stromal tumor(GIST) treated with multimodality managements. A 59-year-old man was diagnosed with duodenal GIST and underwent surgical resection of a primary lesion of the duodenum. Since the pathological findings on mitotic rate indicated its high risk of recurrence, the systemic treatment by imatinib mesylate was given shortly after the surgery. Six months later, metastatic lesions being considered to be imatinib-resistant were observed in the remnant liver. Since there were no other drugs available for GISTs in clinic at that time, surgery of central bisegmentectomy with partial resection of the liver was performed to eliminate all metastatic lesions. However, recurrences had been repeatedly diagnosed afterward. In response to them, four more surgery for recurrent liver or peritoneal tumors, two transcatheter arterial chemoembolizations(TACE)and one radiofrequency ablation(RFA)were performed on the basis of its resectability. Sunitinib malate had been given since it was approved for imatinib-resistant GISTs in clinic. Eventually, as long as 99 months had passed since we observed the first evidence of the resistance to imatinib mesylate when he died from the GIST.

[A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis].

We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed.