Unique Biology of Pancreatic Ductal Adenocarcinoma Accompanied by Rapidly Impaired Diabetes: A Favorable Long-Term Survival Following Curative Resection.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are sometimes diagnosed accompanied by rapidly impaired diabetes (PDAC-RID). Although this type of PDAC may have unusual biological features, these features have not been explained. METHODS: Patients with PDAC who underwent upfront pancreatectomy between 2010 and 2018 were retrospectively reviewed. PDAC-RID was defined as a glycated hemoglobin (HbA1c) value of ≥ 8.0% of newly diagnosed diabetes, and acute exacerbation of previously diagnosed diabetes. Other patients were classified as PDAC with stable glycometabolism (PDAC-SG). Clinicopathological factors, long-term survival rates, and recurrence patterns were evaluated. RESULTS: Of the 520 enrolled patients, 104 were classified as PDAC-RID and 416 as PDAC-SG. There was no significant difference regarding TNM staging, resectability, or adjuvant chemotherapy rate between the groups. However, 5-years cancer-specific survival (CSS) was significantly higher in the PDAC-RID group than in the PDAC-SG group (45.3% vs. 31.1%; p = 0.02). This survival difference was highlighted in relatively early-stage PDAC (≤ pT2N1) (CSS: 60.8% vs. 43.6%; p = 0.01), but the difference was not significant for advanced-stage PDAC. A multivariate analysis of early-stage PDAC showed that PDAC-SG was an independent risk factor of shorter CSS (hazard ratio 1.76; p = 0.02). The hematogenous metastatic rate in early-stage PDAC was lower in the PDAC-RID group than in the PDAC-SG group (18.3% vs. 35.8%; p = 0.01). CONCLUSIONS: PDAC-RID showed a favorable long-term survival rate after curative resection with low hematogenous metastases, which may be due to its unique biology.

Utilization of the modified Kama scoring system for predicting bail-out cholecystectomy: a valuable tool in the era of rising laparoscopic surgery prevalence.

PURPOSE: Recently, bail-out cholecystectomy (BOC) during laparoscopic cholecystectomy to avoid severe complications, such as vasculobiliary injury, has become widely used and increased in prevalence. However, current predictive factors or scoring systems are insufficient. Therefore, in this study, we aimed to test the validity of existing scoring systems and determine a suitable cutoff value for predicting BOC. METHODS: We retrospectively assessed 305 patients who underwent laparoscopic cholecystectomy and divided them into a total cholecystectomy group (n = 265) and a BOC group (n = 40). Preoperative and operative findings were collected, and cutoff values for the existing scoring systems (Kama's and Nassar's) were modified using a prospectively maintained database. RESULTS: The BOC rate was 13% with no severe complications. A logistic regression analysis revealed that the Kama's score (odds ratio, 0.93; 95% confidence interval 0.91-0.96; P < 0.01) was an independent predictor of BOC. A cutoff value of 6.5 points gave an area under the curve of 0.81, with a sensitivity of 87% and a specificity of 67%. CONCLUSIONS: Kama's difficulty scoring system with a modified cutoff value (6.5 points) is effective for predicting BOC.

Introduction of robotic pancreatoduodenectomy following phase 2a IDEAL guidelines.

BACKGROUND: Robotic pancreatoduodenectomy (RPD) is a newly introduced procedure, which is still evolving and lacks standardization. An objective assessment is essential to investigate the feasibility of RPD. The current study aimed to assess our initial ten cases of RPD based on IDEAL (Idea, Development, Exploration, Assessment, and Long-term study) guidelines. METHODS: This was a prospective phase 2a study following the IDEAL framework. Ten consecutive cases of RPD performed by two surgeons with expertise in open procedures at a single center were assigned to the study. With objective evaluation, each case was classified into four grades according to the achievements of the procedures. Errors observed in the previous case were used to inform the procedure in the next case. The surgical outcomes of the ten cases were reviewed. RESULTS: The median total operation time was 634 min (interquartile range [IQR], 594-668) with a median resection time of 363 min (IQR, 323-428) and reconstruction time of 123 min (IQR, 107-131). The achievement of the whole procedure was graded as A, "successful", in two patients. In two patients, reconstruction was performed with a mini-laparotomy due to extensive pneumoperitoneum, probably caused by insertion of a liver retractor from the xyphoid. Major postoperative complications occurred in two patients. One patient, in whom the jejunal limb was elevated through the Treitz ligament, had a bowel obstruction and needed to undergo re-laparotomy. CONCLUSIONS: RPD is feasible when performed by surgeons experienced in open procedures. Specific considerations are needed to safely introduce RPD.

Indocyanine green-fluorescent imaging for a detection of accessory pancreatic duct in pancreas-preserving duodenectomy.

Pancreas-preserving duodenectomy is indicated for select patients with a duodenal tumor in the second portion. In this procedure, identification and closure of the accessory pancreatic duct is important to prevent postoperative pancreatic fistula. A 63-y-old man was diagnosed with duodenal mucosal carcinoma in the second portion, with invasion of the major ampullary. We performed pancreas-preserving duodenectomy. Intraoperatively, indocyanine green-fluorescent imaging identified the accessory pancreatic duct clearly and it was successfully closed. Postoperative pancreatic fistula did not occur. Indocyanine green-fluorescent imaging is effective in identifying the accessory pancreatic duct in pancreas-preserving duodenectomy.

Sequential therapy of portal vein embolization and systemic chemotherapy for locally advanced perihilar biliary tract cancer.

BACKGROUND: Curative resection is the only potential treatment for cure in patients with perihilar biliary tract cancer (PBTC). However, post hepatectomy liver failure (PHLF) due to insufficient future liver remnant volume (FRLV) remains a lingering risk even after portal vein embolization (PVE). This study aimed to investigate the feasibility and efficacy of a sequential treatment strategy consisting of PVE followed by preoperative chemotherapy before surgery. METHODS: Between April 2019 and December 2021, 15 patients with locally advanced PBTC (LA-PBTC) underwent sequential treatment consisting of PVE followed by preoperative chemotherapy. The feasibility and efficacy, including resection rate, changes of FRLV, and chemotherapeutic effect, were investigated retrospectively. RESULTS: Thirteen of 15 patients (86.6%) underwent curative resection. The median duration time between PVE and surgery was 144 days. FRLV/TLV ratio was 31.3% at prePVE, 38.4%, at two weeks after PVE, and 45.7% before surgery, respectively. There was significant increase in FRLV/TLV ratio two weeks after PVE. Additional increase in FRLV/TLV ratio was significantly achieved before surgery. PHLF occurred in 5 patients (38.4%). Pathological complete response was found in 2 of 13 patients (15.3%). CONCLUSIONS: Sequential PVE and systemic chemotherapy contribute to the sufficient hypertrophy of FRLV without compromising resectability in patients with LA-PBTC.

Young Adult Case of Fontan-associated Liver Disease with Hepatocellular Carcinoma During the Transition from Pediatric to Internal Medicine Care and Follow-up.

In recent years, the outcomes of the Fontan procedure have been good, but Fontan-associated liver disease (FALD), which causes congestive hepatopathy due to elevated central venous pressure (CVP), has become a serious problem when considering patients' long-term prognosis. A 28-year-old woman with Emanuel syndrome was admitted to our hospital for the treatment of hepatocellular carcinoma (HCC). She was diagnosed with pulmonary atresia and underwent a bidirectional pulmonary artery shunt at the age of 1 year and 10 months and the Fontan procedure at 4 years of age. Blood tests showed an increase in γ-glutamyltransferase in her early 20s and a marked increase in alfa-fetoprotein levels at age 27 years. She was diagnosed as having HCC in the S7 region by contrast-enhanced computed tomography and underwent hepatectomy. There were no serious adverse events, and the patient has survived 18 months after surgery without recurrence. In this report, the optimal time for the transition from the pediatrics department to adult healthcare units is also discussed, along with the management system for FALD in our hospital.

Wilms' tumor 1 peptide-loaded dendritic cell vaccination in patients with relapsed or refractory acute leukemia.

INTRODUCTION: The prognosis of patients with relapsed or refractory acute leukemia is poor. In the present pilot study, we treated relapsed or refractory acute leukemia patients with Wilms' tumor 1 (WT1) peptide-loaded dendritic cells (DCs) and examined safety, clinical and immunological responses. METHODS: Eleven eligible patients were enrolled. DCs were administered every 2-3 weeks with OK-432 adjuvant. RESULTS: The treatment was well tolerated. The reduction of leukemia cells or the expression of WT1 mRNA was observed in four patients which was maintained for a significant period of time. All the responding patients manifested immune responses against WT1 which might be related to clinical outcome. Decreases in the absolute number of regulatory T cells were observed following vaccination, indicating that DC vaccinations may contribute to the reversal of immunosuppression. CONCLUSION: These results indicate that DC-based immunotherapy is safe and feasible for patients with acute leukemia.

Baseline immunity predicts prognosis of pancreatic cancer patients treated with WT1 and/or MUC1 peptide-loaded dendritic cell vaccination and a standard chemotherapy.

The prognosis of patients with advanced pancreatic cancer is poor despite the recent introduction of immune checkpoint inhibitors. Therefore, the development of new therapeutic approaches is urgently required. In the present phase I/II study, we have evaluated the safety, the efficacy and the prognostic factors of Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded dendritic cell (DC) vaccination in combination with a chemotherapy employing gemcitabine plus nab-paclitaxel or a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Forty-eight eligible patients were enrolled and received the vaccinations approximately every 2-4 weeks at least seven times. No severe adverse events related to the vaccinations were observed. Median progression free survival and overall survival were 8.1 months and 15.1 months, respectively. DC vaccinations augmented tumor specific immunity which might be related to clinical outcome. The multivariate analyses demonstrated that WT1 or MUC1-specific interferonɤ enzyme-linked immunospot number prior to DC vaccination was an independent prognostic factor related to overall survival. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and has clinical benefits for patients in advanced stage of PDAC. The precise evaluation of the baseline antitumor specific immunity is critical to predict clinical outcome.

Dendritic cell vaccination combined with a conventional chemotherapy for patients with relapsed or advanced pancreatic ductal adenocarcinoma: a single-center phase I/II trial.

The prognosis of patients with advanced pancreatic cancer is poor. In the present phase I/II study, we have evaluated the safety and the feasibility of Wilms' tumor 1 (WT1) and/or mucin1 (MUC1) peptide-pulsed dendritic cell (DC) vaccination in combination with chemotherapy in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Sixty-five eligible patients were enrolled. No severe adverse events related to the vaccinations were observed. Objective response rate and disease control rate was 12.3% and 50.8%, respectively. Median progression-free survival and overall survival were 4.9 and 9.6 months, respectively. DC vaccinations augmented WT1- and MUC1-specific immunity which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of PDAC.

Immunotherapy employing dendritic cell vaccination for patients with advanced or relapsed esophageal cancer.

The prognosis of patients with advanced esophageal cancer is poor despite the recent introduction of immune checkpoint inhibitors. In the present pilot study, we have evaluated the safety and the feasibility of Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination in combination with OK-432 in patients with advanced or relapsed esophageal cancer. Fifteen eligible patients were enrolled. No severe adverse events related to the vaccinations were observed. Objective response rate and disease control rate were 20% and 40%, respectively. Median progression free survival and overall survival was 4.1 months and 7.0 months, respectively. WT1 peptide-pulsed DC vaccinations augmented WT1specific immunity, which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of esophageal cancer.

Repeat hepatectomy for liver metastases from bile duct neuroendocrine tumor: a case report.

BACKGROUND: Primary neuroendocrine tumor (NET) originating from the extrahepatic bile duct is rare, although liver metastasis from gastroenteropancreatic NET is frequently observed. We herein report a case who successfully underwent repeat hepatectomy for liver metastases from bile duct NET grade 2 (G2). CASE PRESENTATION: A 75-year-old man presented with jaundice and was suspected of perihilar cholangiocarcinoma by computed tomography (CT) and magnetic resonance imaging (MRI). He underwent extended left hepatectomy, extrahepatic bile duct resection, and hepaticojejunostomy. Pathological findings showed a NET G2 of the biliary tract arising from the common bile duct. Two years and 11 months after surgery, a liver metastasis was detected and hepatectomy was performed. During the surgery, another liver metastasis was detected, and limited liver resection for the two lesions was performed. Pathological findings showed four liver metastases of NET G2. Five years and 4 months after the first surgery (2 years and 5 months after the second hepatectomy), four liver metastases were detected. Thereafter, he received somatostatin analogues for 1 year. Although the size of tumors increased slightly, the number did not change. He underwent limited liver resections and was diagnosed with 7 liver metastases of NET G2. Finally, another hepatectomy (fourth hepatectomy) was performed and long-term survival without recurrence was obtained for as long as 8 years after the first surgery. CONCLUSIONS: Repeat hepatectomy is a good option to obtain long-term survival for liver metastases from bile duct NET G2 in select patients.

Phase I/II Pilot Study of Wilms' Tumor 1 Peptide-Pulsed Dendritic Cell Vaccination Combined With Conventional Chemotherapy in Patients With Head and Neck Cancer.

The prognosis of metastatic or relapsed head and neck squamous cell carcinoma (HNSCC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with Wilms' tumor 1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with conventional chemotherapy. Eleven eligible patients with metastatic or relapsed HNSCC were enrolled. No severe adverse events related to a vaccination were observed. Five patients had durable stable disease and six other patients had disease progression after DC vaccination. Median progression-free survival and overall survival was 6.4 months and 12.1 months, respectively. DC vaccination augmented Wilms' tumor 1-specific immunity which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of HNSCC.

Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.

The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC.

Immunological Analysis and Generation of Dendritic Cells From Lavage Fluid Obtained by Cell-Free and Concentrated Ascites Reinfusion Therapy.

Cell-free and concentrated ascites reinfusion therapy (CART) is an effective treatment for patients with refractory ascites. Cellular components such as cancer cells and blood cells are removed and discarded. The aim of this study was to investigate the alteration of immune cells in lavage fluid and the generation of dendritic cells (DCs) from lavage fluid obtained by CART. Flow cytometry analysis showed a trend toward immunosuppression and impairment in innate immunity in lavage fluid. Immature DCs with downregulation of CD14 and increased antigen-uptake were generated by culturing monocytes obtained from lavage fluid with GM-CSF and IL4. Following the culture with proinflammatory mediators, mature DCs with upregulation of CD83 and potent ability of T cell activation were induced. There were no significant phenotypical or functional differences between these DCs and DCs derived from peripheral blood, indicating lavage fluid might be employed for an alternative cellular source for the generation of DCs.