Histone methyltransferase SUV420H1/KMT5B contributes to poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high rate of recurrence and poor prognosis, even after curative surgery. Multikinase inhibitors have been applied for HCC patients, but their effect has been restricted. This study aims to clarify the clinical impact of SUV420H1/KMT5B, one of the methyltransferases for histone H4 at lysine 20, and elucidate the novel mechanisms of HCC progression. We retrospectively investigated SUV420H1 expression using HCC clinical tissue samples employing immunohistochemical analysis (n = 350). We then performed loss-of-function analysis of SUV420H1 with cell cycle analysis, migration assay, invasion assay and RNA sequence for Gene Ontology (GO) pathway analysis in vitro, and animal experiments with xenograft mice in vivo. The SUV420H1-high-score group (n = 154) had significantly poorer prognosis for both 5-year overall and 2-year/5-year disease-free survival than the SUV420H1-low-score group (n = 196) (p < 0.001 and p < 0.05, respectively). The SUV420H1-high-score group had pathologically larger tumor size, more tumors, poorer differentiation, and more positive vascular invasion than the SUV420H1-low-score group. Multivariate analysis demonstrated that SUV420H1 high score was the poorest independent factor for overall survival. SUV420H1 knockdown could suppress cell cycle from G1 to S phase and cell invasion. GO pathway analysis showed that SUV420H1 contributed to cell proliferation, cell invasion, and/or metastasis. Overexpression of SUV420H1 clinically contributed to poor prognosis in HCC, and the inhibition of SUV420H1 could repress tumor progression and invasion both in vitro and in vivo; thus, further analyses of SUV420H1 are necessary for the discovery of future molecularly targeted drugs.

Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system.

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

Circulating Tumor DNA as a Potential Prognostic Marker in Patients with Borderline-Resectable Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy Followed by Pancreatectomy.

BACKGROUND: Circulating tumor DNA (ctDNA) might be a promising biomarker for pancreatic cancer in liquid biopsy. This study aimed to evaluate the usefulness of liquid biopsy for patients with borderline-resectable pancreatic cancer (BR-PC). METHODS: Patients with BR-PC according to the National Comprehensive Cancer Network guidelines (2017) and eligible for neoadjuvant chemotherapy (NAC) followed by pancreatectomy were recruited at Wakayama Medical University Hospital (UMIN000026647) between March 2017 and April 2020. The study enrolled 55 patients with locally advanced PC, and each patient consented to inclusion in the study. The study investigated the relationship between KRAS status in ctDNA and clinicopathologic features, analyzing ctDNA at three time points: pretreatment, post-NAC, and post-operation. RESULTS: Of the 55 enrolled patients with a diagnosis of BR-PC, 34 were scheduled to undergo pancreatectomy. From 27 patients with resected BR-PC, 81 blood samples were analyzed in triplicate for ctDNA. The patients with positive pretreatment and post-NAC ctDNA status had no significant decrease in median relapse-free survival (RFS) or overall survival (OS). However, the patients with positive postoperation ctDNA status had a significantly shorter median OS (723 days) than the patients with negative ctDNA results (not reached; P = 0.0148). A combined analysis of postoperative ctDNA and CA19-9 values showed the cumulative effect on both RFS (P = 0.0066) and OS (P = 0.0046). The adjusted hazard ratio for risk of survival computed for the patients carrying risk factors (either detectable ctDNA or CA19-9 > 37 U/ml) increased from 4.13-fold to 17.71-fold (both P = 0.0055) compared with the patients who had no risk factors. CONCLUSION: Positive ctDNA predicts poor survival for patients with BR-PC who undergo NAC followed by pancreatectomy.

Radiographic Splenic Artery Involvement Is a Poor Prognostic Factor in Upfront Surgery for Patients with Resectable Pancreatic Body and Tail Cancer.

PURPOSE: The prognostic impact of radiographic splenic vessel involvement in pancreatic cancer remains unclear. We evaluate its oncological significance in resectable pancreatic body/tail cancer. PATIENTS AND METHODS: We retrospectively review 102 cases of resectable pancreatic cancer and 51 of borderline resectable pancreatic cancer (BRPC) who underwent pancreatectomy for pancreatic body/tail cancer. Resectable pancreatic body/tail cancer was classified into one of three categories based on radiographic splenic vessel involvement. RESULTS: Among 102 cases of resectable pancreatic cancer, 37 (36.3%), 35 (34.3%), and 30 cases (29.4%) were classified as no splenic vessel involvement (Rnone), splenic vein involvement (RV), and splenic artery involvement (RA), respectively. Disease-free survival (DFS) among patients with Rnone, RV, RA, and BRPC was 58.5, 18.4, 10.8, and 9.2 months, respectively. Patients with RV and RA had significantly poorer DFS than patients with Rnone (P = 0.010, P < 0.001, respectively). Median survival among Rnone, RV, RA, and BRPC was 80.6, 23.4, 15.1, and 21.3 months, respectively. Patients with RV and RA had significantly poorer survival than patients with Rnone (P = 0.001, P < 0.001, respectively) and had short survival similar to that of those with BRPC. Multivariate Cox proportional hazard analysis detected preoperative CA19-9 ≥ 37 IU/L, radiologic splenic vein involvement, radiologic splenic artery involvement, intraoperative bleeding ≥ 500 ml, transfusion, positive washing cytology, and noncompletion of adjuvant therapy as independent prognostic factors. CONCLUSIONS: Radiographic splenic artery involvement is a poor prognostic factor in resectable pancreatic body/tail cancer and may have a role in stratification of treatment strategy.

Division of the pancreas at the neck reduces postoperative pancreatic fistula in laparoscopic distal pancreatectomy: Comparison of pancreatic division at the body.

BACKGROUND: objectives: During laparoscopic distal pancreatectomy (LDP), the optimal site for pancreatic division with consideration of postoperative pancreatic fistula (POPF) is unclear. We evaluate which site of pancreatic division, neck or body, has better outcomes after LDP. METHODS: This was a retrospective, observational study. LDP was performed in 102 consecutive patients between December 2009 and May 2020. After excluding 14 patients with pancreatic division at tail, 88 patients (pancreatic division at neck n = 46, at body n = 42) were included in this study. Short- and long-term outcomes after LDP were compared between pancreatic division at neck and body. RESULTS: The pancreatic transection site was thicker at body than at neck (17.5 vs. 11.9 mm, P < 0.001), although there were no significant differences of pancreatic texture and pancreatic duct size. The Grade B/C POPF rate was significantly higher when the pancreas was divided at body than when divided at neck (21.4 vs. 6.5%, P = 0.042). We found no significant differences between pancreatic division at neck and body in residual pancreatic volume (34.0 vs. 34.8 ml, P = 0.855), incidence of new-onset or worsening diabetes mellitus more than six months after LDP (P = 0.218), or body weight change (six-month: P = 0.116, one-year: P = 0.108, two-year: P = 0.195, tree-year: P = 0.131, four-year: P = 0.608, five-year: P = 0.408). CONCLUSION: This study suggests that the pancreatic division at neck might reduce the Grade B/C POPF incidence after LDP, compared to division at body. A potential reason is that the pancreas at body is thicker than that at neck. However, further large-scale studies are necessary to confirm our results.

Covered self-expandable metal stents versus plastic stents for preoperative biliary drainage in patient receiving neo-adjuvant chemotherapy for borderline resectable pancreatic cancer: Prospective randomized study.

OBJECTIVES: This single-center comparative randomized superiority study compared biliary stenting using fully covered self-expandable metal stents (FCSEMS) and biliary stenting using plastic stents (PS) in preoperative biliary drainage of patients with borderline resectable pancreatic cancer (BRPC) who are planned to undergo a single regimen of neo-adjuvant chemotherapy (NAC). METHODS: Twenty-two patients with BRPC who required preoperative biliary drainage before NAC (Gemcitabine plus Nab-paclitaxel) were randomly assigned 1:1 to the FCSEMS or PS group. The primary endpoint was the rate of stent dysfunction until surgery or tumor progression. Secondary endpoints were stent patency, number of re-interventions, adverse events of endoscopic retrograde biliary drainage (EBD), operation time, volume of intraoperative bleeding, postoperative hospitalization, postoperative adverse events and medical costs. RESULTS: Eleven patients in each of the groups reached the primary endpoint. The FCSEMS group showed a significantly lower rate of stent dysfunction (18.2% vs. 72.8%, P = 0.015), longer stent patency (P = 0.02), and lower number of re-interventions for stent dysfunction (0.27 ± 0.65 vs. 1.27 ± 1.1, P = 0.001) than the PS group. The adverse events of EBD, operation time, volume of intraoperative bleeding, postoperative hospitalization, postoperative adverse events and medical costs did not significantly differ between the two groups. CONCLUSIONS: In patients with BRPC for preoperative biliary drainage, stent dysfunction occurred less frequently with FCSEMSs than with PSs. In addition, FCSEMS and PS provided similar preoperative management of BRPC in terms of the safety of surgery and medical costs. (UMIN ID000030473).

Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade.

BACKGROUND: Cancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1+ DCs), with high ability to support CD8+ T-cell responses. METHODS: We have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice. RESULTS: The fusion protein was delivered to XCR1+ DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8+ T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab. CONCLUSIONS: Cancer Ag targeting to XCR1+ DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.

Complete REtraction of the StomaCh using pEnrose draiN and liver reTractor (CRESCENT) during laparoscopic distal pancreatectomy.

PURPOSE: Laparoscopic distal pancreatectomy (LDP) is a well-accepted procedure for benign and malignant diseases of the pancreatic body and/or tail. To perform it safely, a wide operative field is crucial. For the maintenance of a good surgical field during LDP, we developed an original technique for stomach retraction: "Complete REtraction of the StomaCh using pEnrose draiN and liver reTractor, CRESCENT." METHODS: In CRESCENT technique, the body and antrum of the stomach are suspended by two Penrose drains, and the fundus and/or upper body of the stomach are retracted upward using a liver retractor. After complete retraction, the stomach is well attached to the abdominal wall and forms a crescent-like shape. Before we developed the CRESCENT technique, we pulled the antrum of the stomach laterally by suture and hanged the body of the stomach upward using a Penrose drain (control method). We evaluated perioperative outcomes of the 87 consecutive patients who underwent LDP and compared outcomes of CRESCENT technique (n = 24) and previously used technique as a control (n = 63). RESULTS: Operative time was significantly shorter in the CRESCENT technique than in control method (median, 234 vs. 303 min, P < 0.001). We found no significant differences in incidences of overall morbidity (16.7 vs. 20.6%, P = 0.677), including grade B/C postoperative pancreatic fistula (8.3 vs. 7.9%, P = 0.455), between CRESCENT technique and control method. There was no mortality by either method. CONCLUSIONS: Our original technique, CRESCENT, is a simple procedure in which the stomach is completely retracted during LDP.

Diffusion-weighted MRI predicts the histologic response for neoadjuvant therapy in patients with pancreatic cancer: a prospective study (DIFFERENT trial).

PURPOSE: Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. METHODS: We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. RESULTS: Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P < 0.001/< 0.0001). The post-treatment cutoff value of ADC at the site of vascular contact for discriminating histological response of tumor destruction of ≤ 50% and tumor destruction of > 50% was determined at 1.42 × 10-3 mm2/s. It predicts R0 with 88% sensitivity, 50% specificity, and 61% accuracy. For histological response, the post-treatment whole-tumor ADC cutoff value for discriminating between tumor destruction of ≤ 50% and tumor destruction of > 50% was determined at 1.40 × 10-3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. CONCLUSIONS: Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.

Preoperative In-Hospital Rehabilitation Improves Physical Function in Patients with Pancreatic Cancer Scheduled for Surgery.

Low preoperative physical function in cancer patients is associated with postoperative complications; however, there have been no reports on the benefits of in-hospital preoperative rehabilitation on preoperative physical function in patients with pancreatic cancer. Therefore, the aim of this study was to quantitatively determine the effects of preoperative in-hospital rehabilitation provided under the supervision of a physiotherapist, on preoperative physical function in patients with pancreatic cancer. The study subjects were 26 patients (15 males, 11 females; age 71.2 ± 8.5 years, range: 51-87 years), including four patients with preoperative chemotherapy, scheduled for surgery for pancreatic cancer. Muscle strengthening exercises and aerobic exercises were conducted 11.9 ± 5.1 days prior to surgery. Cardiopulmonary exercise testing, 6-minute walk distance, and the Functional Independence Measure score were measured before and after the rehabilitation program. We also investigated the relation between the rehabilitation program and incidence of postoperative complications. All 26 study patients completed the preoperative rehabilitation program and no adverse events were noted. Peak oxygen uptake during cardiopulmonary exercise testing and 6-minute walk distance increased significantly after the rehabilitation program. The Functional Independence Measure score remained constant throughout the intervention. No wound infection, delirium, deep vein thrombosis, or respiratory complications were encountered postoperatively. In-hospital preoperative rehabilitation under the supervision of a physiotherapist significantly improved physical function and maintained physical activity in patients with pancreatic cancer. Such improvements may contribute toward preventing serious postoperative complications, resulting in better outcomes.

Impact of Ninjin'Yoeito on Fatigue in Patients Receiving Nab-Paclitaxel Plus Gemcitabine Therapy: A Prospective, Single-Arm, Phase II Open Label, Nonrandomized, Historically-Controlled Study.

BACKGROUND: Ninjin'yoeito, a traditional Japanese herbal medicine, is used to prevent fatigue, loss of appetite, and coldness of limbs. Fatigue is an especially common issue during chemotherapy and can affect quality of life and the ability to complete scheduled treatment. OBJECTIVES: This prospective exploratory trial evaluates the efficacy of ninjin'yoeito for fatigue in patients undergoing nab-paclitaxel plus gemcitabine therapy for unresectable pancreatic cancer. The primary end point was evaluation of fatigue according to Functional Assessment of Chronic Illness Therapy-Fatigue score during 2 courses of nab-paclitaxel plus gemcitabine therapy. Secondary end points included evaluation of dose intensity, appetite loss using numerical rating scale, and peripheral neuropathy using a patient neurotoxicity questionnaire. METHODS: We compared data from this interventional trial with a prior observational trial without administration of ninjin'yoeito with identical definition of end points (UMIN000021758). Thirty patients were required by the study. RESULTS: Threshold mean of Functional Assessment of Chronic Illness Therapy-Fatigue score across 8 weeks during chemotherapy was under 5.3 (P = 0.002). Secondary end points did not reveal any specific patterns in appetite loss or degree of pain. No significant changes in patient neurotoxicity questionnaire concerning sensory/motor disorders were observed, but the mean (SD) incidence of patients with sensory disturbance was higher between the fifth and eighth weeks (8.8 [1.26]) than during the first and fourth weeks (4.8 [0.96]) (P = 0.003). Clinically significant adverse reactions of ninjin'yoeito were not observed. CONCLUSIONS: Ninjin'yoeito may be useful for improving the symptoms of fatigue caused by nab-paclitaxel plus gemcitabine in patients with unresectable pancreatic cancer. UMIN Clinical Trials Registry identifier: UMIN000025606. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Modified Blumgart Mattress Suture Versus Conventional Interrupted Suture in Pancreaticojejunostomy During Pancreaticoduodenectomy: Randomized Controlled Trial.

OBJECTIVE: This study used a randomized controlled trial (RCT) to evaluate whether mattress suture of pancreatic parenchyma and the seromuscular layer of jejunum (modified Blumgart method) during pancreaticojejunostomy (PJ) decreases the incidence of clinically relevant postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD). BACKGROUND: Several studies reported that mattress suture of Blumgart anastomosis in PJ could reduce POPF rate. This, however, is the first RCT. METHODS: Between June, 2013 and May, 2017, 224 patients scheduled for PD were enrolled in this study in Wakayama Medical University Hospital. Enrolled patients were randomized to either interrupted suture or modified Blumgart mattress suture. The primary endpoint was the incidence of grade B/C POPF based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01898780). RESULTS: Patients were randomized to either interrupted suture (103 patients) or modified Blumgart mattress suture (107 patients) and were analyzed by intention-to-treat. Grade B/C POPF occurred in 7 patients (6.8%) in the interrupted suture group and 11 (10.3%) in the mattress suture group (P = 0.367). Mortality within 90 days was 0 in both groups. There were no significant differences in all postoperative complications between the interrupted suture group and the modified Blumgart mattress suture group. CONCLUSIONS: Mattress suture of pancreatic parenchyma and the jejunal seromuscular layer during PJ (modified Blumgart technique) did not reduce clinically relevant POPF compared with interrupted suture.

Ischemic gastropathy after distal pancreatectomy with en bloc celiac axis resection for pancreatic body cancer.

PURPOSE: Risk factors of ischemic gastropathy (IG) following distal pancreatectomy with en bloc celiac axis resection (DP-CAR) remain unclear. METHODS: Fifty consecutive patients with pancreatic cancer who underwent DP-CAR were retrospectively reviewed for possible risk factors for IG. This study was registered on the UMIN Clinical Trials Registry (UMIN 000028732). RESULTS: Complications higher than grade 3 were observed in 21 patients (42%) and mortality in 4 (8%). Left gastric artery (LGA) resection (P = 0.046) and a combination of left inferior phrenic artery (IPA) with LGA resection (P = 0.012) were risk factors of IG, and an elevated creatine kinase (CK) value ≥ 1005 IU/L (P = 0.025) was associated with IG. Among prognostic factors, IG (OR, 5.997; 95% CI, 1.543-23.309; P = 0.010), completion of adjuvant chemotherapy (OR, 0.282; 95% CI, 0.121-0.654; P = 0.003), longer operative time (OR, 2.261; 95% CI, 1.084-4.714; P = 0.030), and higher age (OR, 2.212; 95% CI, 1.081-4.524; P = 0.030) remained independent predictors of survival. Comparison at 2 and 3 months postoperatively showed nutritional values were higher in patients who underwent LGA-preserving DP-CAR than those with LGA-resecting DP-CAR: total protein (7.17 ± 0.56 vs 6.65 ± 0.66 g/dl, P = 0.007), albumin (4.04 ± 0.45 vs 3.43 ± 0.43 g/dl, P < 0.001), and total cholesterol (162.3 ± 34.7 vs 141.6 ± 27.2 mg/dl, P = 0.044). CONCLUSIONS: The poorer prognosis in patients who undergo DP-CAR may be related to more advanced tumors. A combination of left IPA and LGA resection was a significant risk factor for IG. IG, completion of adjuvant chemotherapy, longer operative time, and higher age remain good independent predictors of survival.

Intensive perioperative rehabilitation improves surgical outcomes after pancreaticoduodenectomy.

PURPOSE: Although the mortality rate for pancreaticoduodenectomy (PD) has decreased to around 2.8-5% in high-volume centers, postoperative complications are still common in 30-50% of cases. Preoperative exercise, called "prehabilitation," has been recently reported to reduce the frequency of complications after surgery. This study aims to evaluate the impact of the intensive perioperative rehabilitation on improvement of surgical outcomes for patients undergoing PD. METHODS: Between 2003 and 2014, 576 consecutive patients underwent PD in Wakayama Medical University Hospital. Of these, 331 patients received perioperative rehabilitation combined with prehabilitation and postoperative rehabilitation between 2009 and 2014. Previously, 245 patients underwent PD without perioperative rehabilitation between 2003 and 2008. We compared surgical outcomes between the patients undergoing PD with and without perioperative rehabilitation to evaluate the efficacy of our rehabilitation program. RESULTS: The frequency of pulmonary complications was significantly lower in patients undergoing PD with perioperative rehabilitation than those without (0.9% vs. 4.3%, P = 0.011). There were no significant differences in other complication or mortality rates. Length of hospital stay was also shorter in patients receiving perioperative rehabilitation than that of those not receiving it (16 vs. 24 days, P < 0.001). CONCLUSIONS: Intensive perioperative rehabilitation might reduce postoperative pulmonary complications and shorten postoperative hospital stay after PD. Therefore, we suggest that perioperative rehabilitation should be included as part of enhanced recovery after surgery for patients undergoing PD, although further large-scale studies are necessary to confirm our results.

Successful removal of an internal pancreatic stent that migrated into the bile duct using double-balloon enteroscopy after pancreaticoduodenectomy.

PURPOSE: Internal stents used during pancreaticoduodenectomy (PD) are generally spontaneously passed through the rectum by defecation. However, we encountered six patients with internal stents that migrated into the bile duct after PD. We herein report the outcomes of these six patients and the usefulness of double-balloon enteroscopy (DBE) for removal of such stents from the bile duct. METHODS: An internal stent was placed across pancreaticojejunostomy in 416 (68.8%) of 605 consecutive patients undergoing PD between 2005 and 2015. This study evaluated the characteristics and outcomes of the six patients whose internal stent migrated into the bile duct. RESULTS: Migration of an internal stent into the bile duct was found during follow-up computed tomography (CT) in 6 (1.4%) of 416 patients who had an internal stent placed during PD. Three patients developed stent-induced cholangitis, and two had bile duct stones. Excluding one patient whose internal stent spontaneously slipped out and disappeared from the bile duct, all patients underwent successful removal of a stent from the bile duct by a single instance of biliary intervention involving DBE. CONCLUSIONS: Removal of a stent from the bile duct using DBE is a feasible and useful procedure that should be considered if an internal stent is detected during follow-up CT after PD.

[In Vivo Antigen Delivery to Dendritic Cells-A Novel Peptide Vaccine for Cancer Therapy].

Tumor-derived peptides can induce antitumor cytotoxic T lymphocyte(CTL)response. However, the effects are limited. We aimed to overcome this limitation by selectively delivering antigen peptides to an XC chemokine receptor 1-expressing dendritic cell subset(XCR1+DC)that is notable for its exceptional ability to generate CTL response. To do that, we designed a vaccine(mXCL1-OVA peptide vaccine)that consisted of a murine XCR1 ligand(XCL1)and an ovalbumin(OVA)-derived MHC class I-restricted antigen. When co-injected with the immune adjuvant polyinosinic-polycytidylic acid(poly[I: C]), mXCL1-OVA peptide vaccine showed much greater antigen-specific cytotoxic T cell(CTL)response than either OVA protein plus poly(I: C)or OVA peptide plus poly(I: C). Furthermore, mXCL1-OVA peptide vaccine plus poly(I: C)showed more prominent antitumor effects against OVA-expressing melanoma(B16-OVA)than other vaccines with regard to growth inhibition. Thus, our results suggest that chemokine-directed antigen delivery to DC subsets with high CTL-inducing ability is a promising method for generating effective antitumor immunity.

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients.

We investigated peptide cocktail vaccine OCV-C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single-arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28-day treatment cycle, patients received weekly subcutaneous injection of OCV-C01 for 48 weeks and gemcitabine was administered intravenously at 1,000 mg/m2 on days 1, 8 and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease-free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide-specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months [95% confidence interval (CI), 11.1-20.6] and the DFS rate at 18 months was 34.6% (95% CI, 18.3-51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8-82.5). The administration of OCV-C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A-specific CTL responses and without (p = 0.027), and between patients with KIF20A expression and without (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A-specific CTL responses. OCV-C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer.

[Cancer Immunotherapy Using Human Induced Pluripotent Stem Cell-Derived Dendritic Cells(iPSDCs)Expressing Carcinoembryonic Antigen].

The difficulty in obtaining a sufficient number of functional dendritic cells(DCs)is a well-known serious problem in DCbased immunotherapy. Therefore, we used induced pluripotent stem cell-derived DCs(iPSDCs). We have reported that mouse iPSDCs are equivalent to BMDCs, in terms of maturation and antigen presentation. In this study, the antitumor immune response of human iPSDCs expressing the carcinoembryonic antigen was examined, to determine its clinical application in gastrointestinal cancer. Human iPS cells were established from healthy human fibroblasts using a Sendai virus vector, and human iPSDCs were differentiated under a feeder-free culture. Additionally, the surface marker expression, cytokine production, and migratory capacity of human iPSDCs were equivalent to those of monocyte-derived DCs(MoDCs). After 3 cycles of stimulation of autologous PBMCs by genetically modified DCs, the 51Cr-release assay was performed. The lymphocytes stimulated by iPSDCs-CEA showed cytotoxic activity against LCL-CEA and CEA652-pulsed LCL, but showed no cytotoxicity against LCL-LacZ. In addition, they showed cytotoxic activity against CEA-positive human cancer cell lines, MKN45 and HT29, but showed no cytotoxicity against CEA-negative human cancer cell line MKN1. In conclusion, CEA-specific CTLs responses could be induced by iPSDCs-CEA. This vaccination strategy may be useful in future clinical applications of cancer vaccines.

Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

A replaced right hepatic artery adjacent to pancreatic carcinoma should be divided to obtain R0 resection in pancreaticoduodenectomy.

BACKGROUND: The aim of the present study was to clarify the optimal surgical strategy in the patients with right hepatic artery (RHA) variation undergoing pancreaticoduodenectomy (PD) based on the tumor position and the R1 resection rate. METHODS: A total of 180 consecutive patients who underwent PD for pancreatic ductal adenocarcinoma between January 2000 and May 2013 were evaluated for RHA variation, surgical outcome, and the R1 resection rate retrospectively. In this study, we defined three types of tumors: (i) the resectable type, where tumors were situated more than 10 mm away from the root of the replaced right hepatic artery (rRHA)/replaced common hepatic artery (rCHA); (ii) the adjacent type, where tumors were situated within 10 mm from the root of the rRHA/rCHA without tumor abutment of the superior mesenteric artery (SMA); and (iii) the borderline resectable type, where the tumor abuts the SMA, but does not to exceed 180° of the circumference of the vessel wall. RESULTS: Twenty-five patients were identified to have a RHA variation in preoperative imaging studies. There were 16 patients with resectable type tumors, five with adjacent type tumors, and four with borderline resectable tumors. The rRHA/rCHA was preserved in 14 (88 %) patients with the resectable type, all of the patients with the adjacent type and none of the patients with the borderline type pancreatic carcinomas. The R1 resection rates were significantly higher in patients with adjacent/borderline resectable type tumors (78 %) compared to those with resectable type tumors (6 %) (p = 0.001). CONCLUSION: The rRHA of the adjacent type pancreatic carcinoma should be divided to improve the rate of R0 resection.