Carbon Ion Irradiation Activates Anti-Cancer Immunity.

Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes. Thus, carbon ion radiation therapy (CIRT) activates anti-cancer immunity. However, cancer is protected by the tumor microenvironment (TME), which consists of pro-cancerous immune cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The TME is too robust to be destroyed by the CIRT-mediated anti-cancer immunity. Various modalities targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages have been developed. Preclinical studies have shown that CIRT-mediated anti-cancer immunity exerts its effects in the presence of these modalities. In this review article, we provide an overview of CIRT-mediated anti-cancer immunity, with a particular focus on recently identified means of targeting the TME.

Autophagy Inhibition Increased Sensitivity of Pancreatic Cancer Cells to Carbon Ion Radiotherapy.

BACKGROUND/AIMS: Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer. METHODS: We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone. RESULTS: CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining. CONCLUSION: CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities.

[Morphological Features of Cancer Stem-Like Cells Derived from a Mouse Tumor].

In 21 of 47 mice, tumor development was initiated by intraperitoneal injection of one side population(SP)cell derived from a mouse ascites tumor and the host mice died of the ascites tumor. The SP cells were thought to be cancer stem-like cells. Examination by differential interference contrast microscopy revealed that the SP cells were smaller in size(ϕ 27.5µm), and had a higher N/C ratio, sparser and shorter microvilli on the cell surface, and significantly fewer mitochondria, as compared to the non-SP cells(ϕ 30.0µm). These findings could be related to the stemness of the SP cells.

Antithrombin Together with NETs Inhibitor Protected Against Postoperative Adhesion Formation in Mice.

BACKGROUND/AIMS: Postoperative adhesions may induce adverse outcomes in patients. Adhesion formation is initiated by fibrin accumulation at the surgical site which is followed by local neutrophilia and the establishment of neutrophil extracellular traps (NET). Previous reports have suggested that the preventive efficacy of reagents designed to reduce postoperative adhesion is inversely correlated with neutrophilia and NET production. Antithrombin (AT) is a natural inhibitor of thrombin, a key factor in coagulation. Here, we evaluate whether treatment with AT and/or NET inhibitors prevent or reduce postoperative adhesion formation in mice. METHODS: Mice were treated with AT and/or NET inhibitors before and/or after cecum cauterization and their adhesion scores were evaluated on day 7 post-operation. Immunochemistry/ immunofluorescence analyses were also performed and we used GSK484, an inhibitor of peptidyl arginine deiminase 4 (PAD4), as the NET inhibitor. RESULTS: AT or GSK484 partially rescued postoperative adhesion formation in mice. AT prevented thrombin-induced plasminogen activator inhibitor 1 and interleukin-6 expression in mesothelial cells in vitro. However, AT could not prevent neutrophilia or NETs formation around the injured serosa. Finally, we investigated a combination of AT and a PAD4 inhibitor and found that this could inhibit almost all adhesion formation in these animals. Since AT-inactivating proteases are liberated following NET release, they might dampen the biological action of the AT treatment. This suggests that NET inhibitors might allow AT to exert its full action in the surgically injured serosa. CONCLUSION: Combined treatment with AT and GSK484 may effectively attenuate postoperative adhesion production in mice.

Blockade of Tumor Necrosis Factor by Etanercept Prevents Postoperative Adhesion Formation in Mice.

BACKGROUND/AIMS: Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation. METHODS: Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). RESULTS: Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercept-treated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band. CONCLUSION: Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation.

Proposed model for the prediction of intrahepatic covalently closed circular DNA level in patients with chronic hepatitis B.

AIM: We sought to create a prediction model for intrahepatic covalently closed circular DNA (IH-cccDNA) level in chronic hepatitis B (CHB) patients and to validate the model's predictive accuracy. METHODS: Patients who did not receive previous nucleoside analogue (NA) therapy were assigned to the training cohort (n = 57), and those who received previous NA therapy were assigned to the validation cohort (n = 69). Factors linked to IH-cccDNA levels in the training cohort were analyzed and a formula to predict IH-cccDNA levels was constructed. Next, the reproducibility of that formula was assessed. RESULTS: In the multivariate analysis for the prediction of IH-cccDNA level in the training cohort, fasting blood sugar (FBS) (P = 0.0227), hepatitis B e antigen (HBeAg) (P = 0.0067) and log10 (HB surface antigen [HBsAg]) (P = 0.0497) were significant, whereas HB core-related antigen (HBcrAg) tended to be significant (P = 0.0562). The formula was constructed and named the FBS-cres score based on the variables used (FBS, HBcrAg, HBeAg, and HBsAg). The FBS-cres score was calculated as: 3.1686 - (0.0148 × FBS) + (0.1982 × HBcrAg) + (0.0008168 × HBeAg) + (0.1761 × log10 (HBsAg)). In the training cohort, a significant correlation was noted between HBcrAg and IH-cccDNA levels (P < 0.0001, r = 0.67), whereas the FBS-cres score was more closely correlated to IH-cccDNA level (P < 0.0001, r = 0.81). In the validation cohort, significant correlation was found between HBcrAg and IH-cccDNA levels (P = 0.0012, r = 0.38), whereas the FBS-cres score was more closely linked to IH-cccDNA levels (P < 0.0001, r = 0.51). Similar tendencies were observed in all subgroup analyses. CONCLUSION: Our proposed model for the prediction of IH-cccDNA level could be helpful in CHB patients.

Liver fibrosis markers as assessed by ultrasound elastography and serum samples: A large comparative study in hepatitis virus B and C liver diseases.

AIM: We aimed to compare the well-established liver fibrosis (LF) markers in Japanese patients with chronic hepatitis B (CHB, n = 331) and chronic hepatitis C (CHC, n = 886) and to discuss possible causes of differences in results between CHB patients and CHC patients. METHODS: Virtual touch quantification (VTQ) in acoustic radiation force impulse, Fibrosis-4 (Fib-4) index, aspartate aminotransferase to platelet ratio index (APRI), and hyaluronic acid (HA) were compared between the two cohorts. As an additional investigation, total collagen proportional area (TCPA, %) was tested using liver pathological samples (n = 83). RESULTS: Significant LF (F2 or greater) and advanced LF (F3 or greater) were identified in 153 (46.2%) and 76 (23.0%) patients in the CHB cohort and 579 (65.3%) and 396 (44.7%) patients in the CHC cohort. The median VTQ, Fib-4 index, APRI, and HA values in the CHB cohort were 1.20 m/s, 1.36, 0.44, and 25 ng/mL; those in the CHC cohort were 1.32 m/s, 2.60, 0.74, and 65.5 ng/mL (P-values, all <0.0001). Similar tendencies were noted by F stage-based stratification. The median TCPA in the CHB cohort and the CHC cohort were 8.5% and 12.7% (P < 0.0006). The TCPA values in the CHC cohort were higher than those in the CHB cohort regardless of LF stage. CONCLUSION: Values of LF markers in CHB patients can differ from those in CHC patients even in the same LF stage. Difference in total amount of collagen fiber in CHB and CHC appears to be linked to the difference.

Comparison of liver stiffness assessment by transient elastography and shear wave elastography using six ultrasound devices.

AIM: Transient elastography (TE) is the gold standard for measurement of liver stiffness. The usefulness of shear wave elastographies (SWE) is well accepted. However, the measurement values cannot be equivalently compared because cut-off values for the diagnosis of liver fibrosis are different among those devices. We aimed to clarify correlations, to generate the regression equations between TE and SWEs, and to compare the diagnostic ability of each device to diagnose liver fibrosis. METHODS: A total of 109 patients with chronic liver disease who underwent liver biopsy and same-day evaluation of liver stiffness using six ultrasound devices were analyzed. The diagnostic ability of liver stiffness from each ultrasound device and correlations between TE and each SWE were analyzed. RESULTS: Liver stiffness measured by all six ultrasound devices increased significantly as liver fibrosis stage advanced (P < 0.001). Receiver operating characteristic (ROC) curve analysis for predicting significant fibrosis (≥F2) and cirrhosis yielded area under the ROC curve (AUROC) values based on TE of 0.830 (95% confidence interval [CI], 0.755-0.905) and 0.959 (95% CI, 0.924-0.995), respectively. The AUROCs for predicting significant fibrosis (≥F2) and cirrhosis (F4) based on SWE from all five ultrasound devices were over 0.8 and 0.9, respectively. Furthermore, the correlation coefficients between TE values and SWE values from five ultrasound devices were all over 0.8, indicating a strong relationship. CONCLUSION: Our study showed strong correlations between TE and SWEs with high correlation coefficients. The regression equations between TE and SWEs demonstrated the ability to compare the measurement values in each device equivalently.

The Effect of Daikenchuto, Japanese Herbal Medicine, on Adhesion Formation Induced by Cecum Cauterization and Cecum Abrasion in Mice.

Daikenchuto (DKT) has been widely used for the treatment of postsurgical ileus in Japan. However, its effect on postsurgical adhesion formation has been obscure. In this study, the effect of DKT on postsurgical adhesion formation induced by cecum cauterization or cecum abrasion in mice was investigated. First, the expression of adhesion-related molecules in damaged ceca was investigated by quantitative (q)RT-PCR. During 24 h after surgery, mRNA expressions of interferon-γ (IFN-γ), plasminogen activator inhibitor-1 (PAI-1), interleukin-17 (IL-17), and Substance P (SP) in cauterized ceca and those of PAI-1 and IL-17 in abraded ceca were significantly up-regulated. Next, the effect of DKT on adhesion formation macroscopically evaluated with adhesion scoring standards. DKT (22.5-67.5 mg/d) was administered orally for 7 d during the perioperative period, and DKT did not reduce adhesion scores in either the cauterization model (control : DKT 67.5 mg/d, 4.8 ± 0.2 : 4.8 ± 0.2) or in the abrasion model (control : DKT 67.5 mg/d, 4.9 ± 0.1 : 4.5 ± 0.3). Histologically, collagen deposition and leukocyte accumulation were found at the adhesion areas of control mice in both models, and DKT supplementation did not alleviate them. Last, effect of DKT on expression of proadhesion moleculs was evaluated. DKT also failed to down-regulate mRNA expression levels of them in damaged ceca of both models. In conclusion, PAI-1 and IL-17 may be key molecules of postsurgical adhesion formation. Collagen deposition and leukocytes accumulation are histological characteristic feature of post-surgical adhesion formation. DKT may not have any preventive effect on postsurgical adhesion formation in mice.

Pathological findings that contribute to tissue stiffness in the spleen of liver cirrhosis patients.

AIM: Spleen stiffness is increased in liver cirrhosis (LC). We attempted to characterize the pathological features of spleen in LC. METHODS: We compared pathological findings of resected spleen tissues of 28 LC patients and those of six healthy controls. In addition, we measured spleen stiffness before splenectomy by shear wave elastography in nine LC patients. After splenectomy, we examined the relationship between spleen stiffness and pathological findings. RESULTS: Passive congestion of the spleen was more frequently observed in LC patients than in controls (P < 0.01). The sinus was wider in LC patients than in controls (P < 0.01). In the spleens of the LC patients, diffuse α-smooth muscle actin (αSMA) expression of sinusoidal mesenchymal cells and deposition of collagen fibers on the perisinusoidal wall were observed. In nine LC patients whose spleen stiffness was examined, the width of the sinus increased along with spleen stiffness (r = 0.89, P < 0.01). Spleen stiffness was higher in the spleen tissues with diffuse αSMA expression of sinusoidal mesenchymal cells than in those with partial αSMA expression of sinusoidal mesenchymal cells (P = 0.01). The degree of fibrosis was higher in the LC patients with diffuse αSMA expression of the red pulp than in those with partial αSMA expression of the red pulp (P = 0.03). CONCLUSION: In the LC patients, spleen tissues showed passive congestion with a dilated sinus, diffuse αSMA expression of sinusoidal mesenchymal cells, and deposition of collagen fibers on the perisinusoidal wall. This contributed to spleen stiffness.

Risk factors for surgical site infection after major hepatobiliary and pancreatic surgery.

Major hepatobiliary and pancreatic (HP) surgeries are complex procedures associated with a high incidence of surgical site infection (SSI) and are commonly performed in patients with cancer in Japan. This study was performed to investigate the risk factors for SSI, including incisional and organ/space SSI, in HP surgery. The following procedures were included in the study: hepatectomy with and without biliary tract resection, pancreatectomy [pancreaticoduodenectomy (PD), others], and open cholecystectomy. In total, 735 patients were analyzed. The incidence of SSI was 17.8% (incisional, 5.2%; organ/space, 15.5%; both 2.9%). The highest incidence of SSI was observed in patients who underwent hepatectomy with biliary tract resection (39.1%), followed by pancreatectomy (PD, 28.8%; others, 29.8%). Almost all SSIs after these three procedures were classified as organ/space (39.1%, 25.0%, and 27.7%, respectively), and these procedures were risk factors for not only total SSI but also organ/space SSI in the multivariate analysis. An American Society of Anesthesiologists physical status of ≥3 was a risk factor for incisional SSI. Preoperative biliary drainage, prolonged surgery, concomitant surgery, and massive intraoperative bleeding were associated with SSI. In conclusion, the main type of SSI was organ/space SSI after HP surgery, and different risk factors were identified between organ/space and incisional SSI. Procedure-related factors and preoperative biliary drainage were independent risk factors for SSI. To prevent SSI, the indication for preoperative biliary drainage should be carefully evaluated in patients undergoing HP surgery.

Impaired Value of 99m Tc-GSA Scintigraphy as an Independent Risk Factor for Posthepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

BACKGROUND: Posthepatectomy liver failure (PHLF) was recently defined with the corresponding recommendations as follows: grade A, no change in clinical management; grade B, clinical management with noninvasive treatment; and grade C, clinical management with invasive treatment. In this study, we identified the risk factors for grade B and C PHLF in patients with hepatocellular carcinoma (HCC). METHODS: Of 339 HCC patients who underwent curative hepatic resection, 218 were included for analysis. The LHL15 index (uptake ratio of the liver to that of the liver and heart at 15 min) was measured by 99m Tc-GSA (99m technetium-labelled galactosyl human serum albumin); remnant LHL15 was calculated as LHL15 × [1 - (resected liver weight - tumor volume)/whole liver volume without tumor]. RESULTS: A total of 163 patients were classified as having no PHLF, whereas 17, 37, and 1 patient had PHLF grade A, B, and C, respectively. There were significant differences in indocyanine green R15, serum albumin, prothrombin time, Child-Pugh classification, LHL15 and remnant LHL15 between patients with grades B/C PHLF and patients with grade A or no PHLF. Only remnant LHL15 was identified as an independent risk factor for grades B/C PHLF (p = 0.023), with a cut-off value of 0.755. CONCLUSIONS: Remnant LHL15 was an independent risk factor for grades B/C PHLF. Patients with impaired remnant LHL15 value of <0.755 should be carefully monitored for PHLF.

Short- and long-term outcomes of the Frey procedure for chronic pancreatitis: a single-center experience and summary of outcomes in Japan.

PURPOSE: To evaluate the short- and long-term outcomes of the Frey procedure for chronic pancreatitis (CP). METHODS: The subjects of this study were 12 patients who underwent the Frey procedure for CP between January, 2000 and December, 2016. We assessed pain relief, weight gain, and exocrine/endocrine insufficiency during follow-up. RESULTS: The study population comprised 11 men and 1 woman (91.7% vs. 8.3%; mean age, 50.3 ± 6.8 years; range 39-61 years). Pancreatitis was caused by alcohol in 9 (75%) patients and was idiopathic in 3 (25%) patients. The mean follow-up period was 82.5 ± 46.5 months (range 16.9-152.1 months). There was no operative mortality, but three patients (25%) suffered postoperative morbidity. All patients were pain-free at the time of discharge. There was no case of new-onset diabetes mellitus after surgery, although one patient (8.3%) suffered exocrine insufficiency. The body weight and body mass index of all patients improved during follow-up. Only one patient continued to suffer pain in the long term. CONCLUSION: The findings of this long-term follow-up of patients who underwent the Frey procedure suggest that it offers effective pain relief and is a safe technique for the management of CP.

Reinforced staplers for distal pancreatectomy.

PURPOSE: The safety and efficacy of reinforced staplers during distal pancreatectomy (DP) remain controversial because of the small sample size. This multicenter single-arm prospective study aims to evaluate the safety and efficacy of reinforced staplers with bioabsorbable material during DP. METHODS: Between October 2014 and August 2015, 121 patients scheduled for DP were enrolled in this study at 11 institutions in Japan. The primary endpoint was the incidence of clinically relevant pancreatic fistula. Protocol treatment was defined as "distal pancreatectomy using reinforced staplers." RESULTS: Per-protocol analysis of 105 patients was performed; 16 of the patients were excluded based on discontinuation of protocol treatment criteria. Clinically relevant pancreatic fistula occurred in 13 (12.4%) of 105 patients. The overall morbidity rate was 29.5% (31 of 105 patients) and severe complication (Clavien classification IIIa or more) was 10.5% (11/105). Mortality rate was 0%, although reoperations were performed on two patients (1.9%). Multivariate logistic regression analysis of independent risk factors for clinically relevant pancreatic fistula after DP using reinforced stapler closure was operative time more than 240 min (P = 0.047, odds ratio 5.79), registration numbers less than 10 (P = 0.046, odds ratio 13.01), and staple line hemorrhage (P = 0.003, odds ratio 16.34). CONCLUSION: This study confirms the safety of reinforced staplers for pancreatic stump closure during DP. However, the efficacy of reinforced staplers for decreasing clinically relevant pancreatic fistula could not be drawn from this study. TRIAL REGISTRATION: This prospective study was registered with ClinicalTrials.gov (NCT02270554) and UMIN Clinical Trial Registry (UMIN000015384).

11C-Choline positive but 18F-FDG negative pancreatic metastasis from renal cell carcinoma on PET.

Choline is a new PET tracer, which uptake may occur via a choline-specific transporter protein and be accelerated during the proliferation of tumor cells. We report a 61-year-old woman with a metastatic pancreatic tumor from renal cell carcinoma, measuring 35×40 mm. PET scans demonstrated accumulation of 11C-choline in the metastatic pancreatic tumor, but no accumulation of 18F-FDG. Choline PET/CT may play a useful and complementary imaging modality, especially when FDG-PET/CT does not show expected findings or when the evaluation of tumor viability is needed, in patients with renal cell carcinoma.

Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula.

OBJECTIVES: The aim of this study was to evaluate in a multicenter randomized controlled trial (RCT) whether pancreaticojejunostomy (PJ) of pancreatic stump decreases the incidence of pancreatic fistula after distal pancreatectomy (DP) compared with stapler closure. BACKGROUND: Several studies reported that PJ of pancreatic stump reduces the incidence of pancreatic fistula after DP. However, no RCT has confirmed the efficacy of PJ of pancreatic stump. METHODS: One hundred thirty-six patients scheduled for DP were enrolled in this study between June 2011 and March 2014 at 6 high-volume surgical centers in Japan. Enrolled patients were randomized to either stapler closure or PJ. The primary endpoint was the incidence of pancreatic fistula based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01384617). RESULTS: Sixty-one patients randomized to stapler and 62 patients randomized to PJ were analyzed by intention-to-treat. Pancreatic fistula occurred in 23 patients (37.7%) in the stapler closure group and 24 (38.7%) in the PJ group (P = 0.332) in intention-to-treat analysis. The incidence of clinically relevant pancreatic fistula (grade B or C) was 16.4% for stapler closure and 9.7% for PJ (P = 0.201). Mortality was zero in both groups. In a subgroup analysis for thickness of pancreas greater than 12 mm, the incidence of clinically relevant pancreatic fistula occurred in 22.2% of the patients in the stapler closure group and in 6.2% of the PJ group (P = 0.080). CONCLUSIONS: PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure.

Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages.

BACKGROUND & AIMS: Splenectomy in cirrhotic patients has been reported to improve liver function; however the underlying mechanism remains obscure. In the present study, we investigated the mechanism using a murine model, which represents well the compensated liver cirrhosis. METHODS: C57BL/6 male mice were allowed to drink water including thioacetamide (TAA: 300 mg/L) ad libitum for 32 weeks. After splenectomy at 32 weeks, mice were sacrificed on days one, seven, and 28, respectively, while TAA-administration was continued. Perioperative changes in peripheral blood and liver tissues were analyzed. RESULTS: TAA treatment of mice for 32 weeks reproducibly achieved advanced liver fibrosis with splenomegaly, thrombocytopenia, and leukocytopenia. After splenectomy, liver fibrosis was attenuated, and macrophages/monocytes were significantly increased in peripheral blood, as well as in the liver. Progenitor-like cells expressing CK-19, EpCAM, or CD-133 appeared in the liver after TAA treatment, and gradually disappeared after splenectomy. Macrophages/monocytes accumulated in the liver, most of which were negative for Ly-6C, were adjacent to the hepatic progenitor-like cells, and quantitative RT-PCR indicated increased canonical Wnt and decreased Notch signals. As a result, a significant amount of ß-catenin accumulated in the progenitor-like cells. Moreover, relatively small Ki67-positive hepatic cells were significantly increased. Protein expression of MMP-9, to which Ly-6G-positive neutrophils contributed, was also increased in the liver after splenectomy. CONCLUSIONS: The hepatic accumulation of macrophages/monocytes, most of which are Ly-6C(lo), the reduction of fibrosis, and the gradual disappearance of hepatic progenitor-like cells possibly play significant roles in the tissue remodeling process in cirrhotic livers after splenectomy.

Hemodynamic analysis and treatment of an enlarging extrahepatic portal aneurysm: report of a case.

Aneurysms in the portal venous system are relatively rare. We report the case of an extrahepatic portal venous aneurysm, detected incidentally by ultrasonography. The patient, a 75-year-old woman, was initially observed over 18 months, during which time, the aneurysm grew from 36 mm × 32 mm to 51 mm × 37 mm in size, without symptoms. Hemodynamic analysis employing computational flow dynamics technique showed obvious turbulence in the aneurysm, and the wall shear stress (WSS) against that part of the aneurysmal wall was greater than in other sites. To prevent complications such as spontaneous rupture and portal vein thrombosis, the aneurysm was resected, with reconstruction of the portal trunk. While careful follow-up is sufficient for most portal venous aneurysms, its enlargement could indicate possible spontaneous rupture. The increased WSS against part of the aneurysmal wall most likely accounts for the aneurysm enlargement in this case.

Primary adenocarcinoma of the minor duodenal papilla with mass-forming chronic pancreatitis: report of a case.

A 70-year-old male was treated for gastric ulcers. Follow-up upper gastrointestinal endoscopy revealed an irregular, elevated tumor in the second portion of the duodenum. Upon pathological inspection of a biopsy specimen, a diagnosis of adenocarcinoma was made, and the patient was admitted to our hospital. Computed tomography showed an irregular mass in the pancreatic head and dilatation of the main pancreatic duct and bile duct. Pancreatic head carcinoma with infiltration of the duodenum was diagnosed, and pylorus-preserving pancreaticoduodenectomy was performed. A histopathological examination of the resected specimen showed moderately differentiated adenocarcinoma in the minor duodenal papilla and chronic pancreatitis in the pancreatic head. Therefore, primary adenocarcinoma of the minor duodenal papilla with mass-forming chronic pancreatitis was diagnosed. Currently, the patient is alive without recurrence 17 months after the surgery. Primary adenocarcinoma of the minor duodenal papilla is extremely rare. We herein report this case, and also provide a review of the literature.

Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice.

UNLABELLED: Concanavalin A (Con A) treatment induces severe hepatitis in mice in a manner dependent on T cells, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Treatment with the anticoagulant heparin protects against hepatitis, despite healthy production of IFN-γ and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge, liver of wild-type (WT) mice showed prompt induction of Ifnγ and Tnf, followed by messenger RNA expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), which initiate blood coagulation and inhibit clot lysis, respectively. Mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifnγ(-/-) mice and Ifnγ(-/-) Tnf(-/-) mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti-TF monoclonal antibody protected against Con A-induced hepatitis, whereas Pai1(-/-) mice were not protected. Both hepatic macrophages and sinusoidal endothelial cells (ECs) expressed Tf after Con A challenge. Macrophage-depleted WT mice reconstituted with hematopoietic cells, including macrophages deficient in signal transducer and activator of transcription-1 (STAT1) essential for IFN-γ signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1(-/-) mice reconstituted with WT macrophages. Exogenous IFN-γ and TNF rendered T-cell-null, Con A-resistant mice deficient in recombination-activating gene 2, highly susceptible to Con A-induced liver injury involving TF. CONCLUSIONS: Collectively, these results strongly suggest that proinflammatory signals elicited by IFN-γ, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation-mediated hepatitis.