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.
Systemic administration of IL-18 induces polyclonal IgE responses by causing NKT cells to express CD40 ligand and to produce IL-4. Administration of IL-33 also induces IgE response, although the ...mechanism underlying IgE response is unclear. Here, we compared the effects of IL-18 and IL-33 on bone marrow-derived mast cells and basophils as well as non-polarized and Th2-polarized CD4+ T cells in vitro. Basophils, comprising IL-18Rα+ cells (14.2%) and IL-33Rα+ cells (34.6%), and mast cells, comprising IL-18Rα+ cells (2.0%) and IL-33Rα+ cells (95.6%), produce IL-4, IL-6, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF) and chemokines (RANTES, MIP-1α, MIP-1β and MCP-1), upon stimulation with IL-18 and/or IL-33 in the presence of IL-3. Only basophils strongly produce IL-4. Furthermore, compared with mast cells, basophils produce larger amounts of the above cytokines and chemokines in response to IL-33. Level of IL-33Rβ-mRNA expression in basophils is higher than that in mast cells. Effect of IL-33 is dependent on ST2 binding, and its signal is transduced via MyD88 in vitro. We also found that IL-2 plus IL-18 or IL-33 alone stimulates non-polarized or Th2-polarized CD4+ T cells to produce IL-4 and IL-13 or IL-5 and IL-13, respectively. We finally showed that administration of IL-33 into mice ST2/MyD88 dependently induces airway hyperresponsiveness (AHR) and goblet cell hyperplasia by induction of IL-4, IL-5 and IL-13 in the lungs. Furthermore, same treatment of RAG-2−/− mice, lacking T and B cells, more strikingly induced AHR with marked goblet cell hyperplasia and eosinophilic infiltration in the lungs. Thus, IL-33 induces asthma-like symptom entirely independent of acquired immune system.
Background
Gemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been ...able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S‐1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC.
Methods
We performed a mulitcenter, randomized phase III trial across 39 centers. Enrolled patients were randomly allocated (1:1) to either the GCS or GC arm. The GCS regimen comprised gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) infusion on day 1 and 80 mg/m2 of S‐1 on days 1–7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression‐free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778.
Results
Between July 2014 and February 2016, 246 patients were enrolled. The median OS and 1‐year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio HR 0.79, 90% confidence interval CI: 0.628–0.996; P = .046 stratified log‐rank test). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577–0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms.
Conclusions
GCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first‐line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.
Ioka and colleagues present the results of a phase III study comparing gemcitabine and cisplatin plus S‐1 (GCS) with gemcitabine and cisplatin for unresectable or recurrent biliary tract cancer. GCS demonstrated survival benefits and a higher response rate, and could be the new standard chemotherapy for advanced biliary tract cancer.
Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-γ-promoted fibrin ...deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood. We found that myofibroblasts of the adhesion predominantly expressed signature molecules of mesothelial cells that line the serosa. Microarray analysis revealed IL-6 as a key underlying player, supported by elevated IL-6 levels in the peritoneal fluid of post-laparotomy human subjects. Injured serosa of cecum-cauterized mice also exhibited induction of Il6, which was followed by Tnf, concomitant with rapid accumulation of neutrophils, substantial population of which expressed TGF-β1, a master regulator of fibrosis. Besides, neutrophil-ablated mice showed reduction in induction of the adhesion, suggesting that TGF-β1
neutrophils triggered the adhesion. Human neutrophils expressed TGFB1 in response to TNF-α and TNF in response to IL-6. Moreover, anti-IL-6 receptor monoclonal antibody abrogated neutrophil recruitment and adhesion formation. Thus, IL-6 signaling represents a potential target for the prevention of postoperative adhesions.
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.
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.
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).
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).
PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure.
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.
Background
Accurate assessment of resection volume and vascular anatomy is mandatory in preoperative planning for safe and curative hepatectomy to treat cancer. Accordingly, we examined feasibility ...and accuracy of a preoperative three‐dimensional (3D) computed tomography (CT) scan based simulation in patients with impaired liver function undergoing hepatectomy for hepatocellular carcinoma (HCC).
Methods
Hepatectomy simulation software was programmed to reconstruct detailed 3D vascular structure and calculate liver volume based on hepatic circulation. In 113 patients with HCC, liver resection volume was estimated preoperatively by both simulation and conventional planimetry. For validation, predicted resection volumes were compared with actual resected specimen weights. The resection margin as estimated by the simulation was compared with the margin in the specimen.
Results
Simulation showed higher correlation and smaller discrepancy (r = 0.96; 9.3 ml) between predicted and actual liver resection volume than conventional planimetry (r = 0.74; 174 ml). Simulation showed correlation (p < 0.01) between estimated and actual segmental volume, which was not measurable by planimetry. Simulation showed a correlation (r = 0.84) between predicted and actual margin, with a difference of 1.6 mm.
Conclusions
Hepatectomy simulation in 3D predicted segmental liver volume and the resection margin accurately. This virtual method should contribute to preoperative planning to achieve safe, curative resection in HCC patients, whose hepatic function is compromised.
Background
We investigated safety‐related outcomes of hepatobiliary pancreatic (HBP) surgeries performed after establishment of the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery (JSHBPS) ...board certification system for expert surgeons.
Methods
We analyzed post‐HBP surgery mortality data obtained from annual safety reports provided by board‐certified training institutions between 2012 and 2015.
Results
The 90‐day mortality rate for the 53,929 high‐level HBP surgeries performed at board‐certified training institutions was 1.7%. The 30‐day mortality rates for 2012, 2013, 2014, and 2015 were 0.9%, 0.7%, 0.6%, and 0.6%, respectively, and the 90‐day mortality rates were 2.1%, 1.8%, 1.6%, and 1.3%, respectively, with significant decreases in both. The surgeries with high 4‐year cumulative mortality rates were left hepatic trisectionectomy (10.3%), hepatopancreatectomy (7.6%), liver transplant recipient surgery (6.7%), hepatectomy with extrahepatic bile duct resection (4.6%), and right hepatic trisectionectomy (4.5%). Over the 4‐year period, the number of operations increased, but the 90‐day mortality rates for these surgeries, with the exception of right trisectionectomy, decreased.
Conclusions
The JSHBPS board certification system for expert surgeons has significantly decreased mortality subsequent to high‐level HBP surgeries. Reducing mortality associated with high‐risk HBP surgeries will be our next challenge.
HighlightOn behalf of the JSHBPS Safety Management Committee, Otsubo and colleagues report the results of their first analysis of safety‐related outcomes of the recently established JSHBPS board certification system for expert surgeons. Data spanning 2012–2015 indicate that the board certification system has significantly decreased mortality subsequent to high‐level hepato‐biliary‐pancreatic surgery.
Almost all mature cells that undergo apoptosis in an age-dependent or an accidental manner are completely recovered in tissue-specific microenvironments without any physiological changes. After ...peripheral blood leukocytes are released into the local region, fibroblast cells and new blood vessels commonly proliferate during wound healing. Inducible repair tools mainly supplied from blood vessels are cleared by peripheral blood phagocytic macrophages. Finally, hematopoietic stem cell (HSC)-derived precursor cells migrate from bone marrow (BM) to the microenvironment to rebuild damaged tissues (the mature immune system). In contrast to the mature immune system, the effects of aging on HSCs (long-term HSCs) and peripheral blood lymphocytes (long-term PBLs) are not clearly understood in the BM and thymus niches with tissue-specific microenvironments with some physiological changes (the aged BM niche) for incomplete rebuilding of damaged tissues (the aged immune system). In this review, the roles of the aged immune system in both a delay of acute inflammation and the development of chronic inflammation or fibrosis are discussed.
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.
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