Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.

The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.

Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma.

BACKGROUND: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. METHODS: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. RESULTS: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. CONCLUSIONS: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

A case of preoperative embolization for a giant hypervascular pancreatic serous cystic neoplasm in pancreaticoduodenectomy.

BACKGROUND: Preoperative vascular embolization is an effective strategy for managing meningiomas, neck paragangliomas, renal cell carcinomas, and bone metastasis by reducing the intraoperative bleeding volume and operation time. Although hypervascular tumors also occur in the pancreas, preoperative embolization for these tumors is not commonly practiced. We herein present a case of a giant serous cystic neoplasm (SCN) of the pancreas with significant arterial vascularity that was managed with preoperative interventional radiology and subsequently resected via pancreaticoduodenectomy. CASE PRESENTATION: A 60-year-old man presented with an 8-cm hypervascular tumor located at the head of the pancreas, identified as an SCN on pathologic examination. The tumor had increased by 13 mm over 5 years, necessitating surgical intervention. Computed tomography revealed a substantial blood supply to the tumor from the dorsal pancreatic artery and gastroduodenal artery, both branches of the superior mesenteric artery. To mitigate the risk of severe intraoperative bleeding from this giant hypervascular tumor, branches of the dorsal pancreatic artery and gastroduodenal artery were embolized using metallic coils and further secured using a gelatin sponge 1 day prior to pancreatectomy. During the laparotomy, the tumor appeared to have decreased in size, likely because of reduced distension and congestion. Despite significant adhesions to surrounding tissues secondary to prolonged compression and inflammation, the pancreaticoduodenectomy was completed successfully in 5 h and 15 min with blood loss of 763 mL. The patient was discharged on postoperative day 15 without complications. CONCLUSIONS: Preoperative arterial embolization for hypervascular pancreatic tumors might control the risk of massive intraoperative bleeding, contributing to a favorable postoperative outcome. Utilizing interventional radiology for preoperative inflow control is one of the beneficial strategies for pancreatectomy in patients with a giant SCN.

Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

AIMS: Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. METHODS: In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. RESULTS: The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. CONCLUSIONS: For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC. Methods: EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified. Results: We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively. Conclusions: We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.

Is preoperative pancreatic juice cytology useful for determining therapeutic strategies for patients with intraductal papillary mucinous neoplasm of the pancreas?

BACKGROUND: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies. METHODS: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD < 10 mm); 61% for type 3 (MN < 5 mm and MPD ≥ 10 mm); 72% for type 4 (MN < 5 mm and MPD < 10 mm), respectively. CONCLUSIONS: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery.

Endoscopic nasobiliary drainage versus endoscopic biliary stenting for preoperative biliary drainage in patients with malignant hilar biliary obstruction: Propensity score-matched multicenter comparative study.

OBJECTIVES: For preoperative biliary drainage (PBD) of malignant hilar biliary obstruction (MHBO), current guidelines recommend endoscopic nasobiliary drainage (ENBD) due to the higher risk of cholangitis after endoscopic biliary stenting (EBS) during the waiting period before surgery. However, few studies have supported this finding. Therefore, we aimed to compare the outcomes of preoperative ENBD and EBS in patients with MHBO. METHODS: Patients with MHBO who underwent laparotomy for radical surgery after ENBD or EBS were included from retrospectively collected data from 13 centers (January 2014 to December 2018). We performed a 1:1 propensity score matching between the ENBD and EBS groups. These patients were compared for the following: cholangitis and all adverse events (AEs) after endoscopic biliary drainage (EBD) until surgery, time to cholangitis development after EBD, postsurgical AEs, and in-hospital death after surgery. RESULTS: Of the 414 patients identified, 355 were analyzed in this study (226 for ENBD and 129 for EBS). The matched cohort included 63 patients from each group. The proportion of cholangitis after EBD was similar between the two groups (20.6% vs. 25.4%, P = 0.67), and no significant difference was observed in the time to cholangitis development. The proportions of surgical site infections, bile leaks, and in-hospital mortality rates were similar between the groups. CONCLUSION: For PBD of MHBO, the proportion of AEs, including cholangitis, after EBD until surgery was similar when either ENBD or EBS was used.

Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video).

BACKGROUND: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach. METHODS: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches. RESULTS: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903). CONCLUSIONS: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.

Repeated robotic pancreatectomy for recurrent pancreatic metastasis of mesenchymal chondrosarcoma: A case report.

Mesenchymal chondrosarcoma is a rare subset of sarcomas accounting for 3%-10% of all cases of chondrosarcomas. Radical resection is the only curative strategy, even in patients with metastatic tumors. However, data regarding treatment strategies remain limited owing to the small number of cases. Herein, we report a patient who underwent repeated robotic pancreatectomy for recurrent pancreatic metastasis originating from extraskeletal mesenchymal chondrosarcoma of the pelvis. First, robotic pancreaticoduodenectomy with a reconstruction of pancreaticogastrostomy was performed for synchronous pancreatic metastasis 5 months after the primary resection of mesenchymal chondrosarcoma. Ten months after robotic pancreaticoduodenectomy, tumor recurrence was observed at the tail end of the pancreas, which was removed by reperforming robotic distal pancreatectomy. Given the precise tissue manipulation that can be achieved with robotic articulated forceps, the peripheral splenic artery and pancreas were easily isolated and divided in close proximity to the tumor. The central part of the pancreas was preserved. Robotic surgery allowed safe and effective resection of the reconstructed remnant pancreas. The patient survived for 28 months after primary tumor resection. Repeated pancreatectomy with minimally invasive techniques is a feasible and curative treatment for metastatic mesenchymal chondrosarcoma.

Prognostic Impact of Preoperative Osteosarcopenia for Patients with Pancreatic Ductal Adenocarcinoma After Curative Resection.

BACKGROUNDS: The clinical significance of preoperative osteosarcopenia in pancreatic ductal adenocarcinoma (PDAC) has not been fully studied. The purpose of this study was to evaluate the role of preoperative osteosarcopenia in predicting the survival of patients with PDAC. METHODS: We retrospectively analyzed 265 patients who underwent curative surgical resection for PDAC between 2012 and 2018 in two Japanese institutes. The skeletal muscle index at the L3 vertebrae and the bone mineral density at the Th11 vertebra were calculated for the evaluation of osteosarcopenia before surgery. The relationship between perioperative osteosarcopenia and clinicopathological factors and prognosis was analyzed. RESULTS: The median overall survival (OS) and disease-free survival (DFS) of patients with osteosarcopenia were significantly shorter than those of patients without osteosarcopenia (OS: 23 and 48 months, respectively, P < 0.001; DFS: 13.4 and 21.2 months, respectively, P = 0.004). On multivariate analysis, osteosarcopenia was found to be an independent factor associated with OS (hazard ratio [HR] 1.98; 95% confidence interval [CI] 1.40-2.80; P < 0.001) and DFS (HR 1.53; 95% CI 1.11-2.10; P = 0.009). CONCLUSIONS: Preoperative osteosarcopenia may be a useful prognostic factor in patients with PDAC who undergo surgical resection. Further studies are needed to assess whether perioperative, nutritional interventions and rehabilitation contribute to improving the prognosis of these patients.

A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament (with video).

BACKGROUND: In recent years, the number of minimally invasive pancreatoduodenectomy (MIPD) has been increasing; however, the procedure has not been widely accepted due to its complexity and difficulty. We have developed a technique to mobilize the pancreas head using a left-sided approach with a focus on the complete dissection of the Treitz ligament. METHODS: This technique focuses on the secure mobilization of the pancreas head using a left-sided approach. First, the transverse mesocolon is flipped upward and the anterior side of the mesojejunum is excised to expose the first jejunal artery (1st JA) from the distal side to its origin. During the procedure, the left sides of the SMA and Treitz ligament are exposed. The Treitz ligament is retracted to the left side and dissected anteriorly. Thereafter, the jejunum is flipped to the right side and the retroperitoneum around the origin of the jejunum and duodenum is dissected to identify the inferior vena cava (IVC). The rest of the Treitz ligament is dissected posteriorly and complete resection of the Treitz ligament releases the limitation of duodenal immobility. Thereafter, dissection proceeds along the anterior wall of the IVC, and mobilization of the pancreas head is completed from the left side. RESULTS: A total of 75 consecutive patients underwent MIPD from April 2016 to July 2022. The median operation times of laparoscopic and robotic procedures were 528 min (356-757 min) and 739 min (492-998 min), respectively. The volume of blood loss during laparoscopic and robotic procedures was 415 g (60-4360 g) and 211 g (17-1950 g), respectively. There was no mortality in any of the cases. CONCLUSION: Mobilization of the pancreas head and left-sided approach using a caudal view will be a safe and useful technique for MIPD.

Risks and benefits of pancreaticoduodenectomy in patients aged 80 years and over.

PURPOSE: The frequency of pancreaticoduodenectomy is increasing in oldest old patients owing to population aging. We aimed to clarify the clinical significance of pancreaticoduodenectomy in patients aged ≥ 80 years with multiple underlying diseases. METHODS: A total of 649 consecutive patients who underwent pancreaticoduodenectomy from April 2010 to March 2021 in our institute were divided into two groups according to their age: ≥ 80 years (51) and ≤ 79 years (598). We compared mortality and morbidity between the groups. The age-related prognosis was analyzed in 302 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma treatment. RESULTS: There were no significant differences in morbidity (Clavien-Dindo classification grade III or higher; P = 0.1300), mortality (P = 0.0786), or postoperative hospital stay (P = 0.5763) between the groups. Patients aged ≥ 80 years, who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, had shorter overall survival than those aged ≤ 79 years (median survival time, 16.7 months vs. 32.7 months; P = 0.0206). However, the overall survival of patients aged ≥ 80 years who received perioperative chemotherapy was comparable to that of patients aged ≤ 79 years (P = 0.9795). In the multivariate analysis, the absence of perioperative chemotherapy was identified as an independent prognostic factor, while age ≥ 80 years was not. Perioperative chemotherapy was the sole independent prognostic factor in patients aged ≥ 80 years who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. CONCLUSIONS: Pancreaticoduodenectomy is safe for patients aged ≥ 80 years. The survival benefits of pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma aged ≥ 80 years might be limited to those who can receive perioperative chemotherapy.

Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front.

PURPOSE: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism. METHODS: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro. RESULTS: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density. CONCLUSION: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.

Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy.

PURPOSE: To evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy. METHODS: Among 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery. RESULTS: Nineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level. CONCLUSIONS: Post-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.

Clinical Outcomes of Inside Stents and Conventional Plastic Stents as Bridge-to-Surgery Options for Malignant Hilar Biliary Obstruction.

BACKGROUND: The appropriate method of preoperative endoscopic biliary drainage (EBD) for cholangiocarcinoma with hilar biliary obstruction remains controversial. The inside-stent technique is a method of placing plastic stents entirely inside the bile duct. Several studies of patients with unresectable stage have reported longer stent patency compared with conventional endoscopic biliary stenting (EBS). Inside-stent techniques have been introduced as a bridge-to-surgery option and as an alternative to conventional EBS. AIMS: We aimed to evaluate the clinical outcomes of inside stent use and conventional EBS. METHODS: During this retrospective multicenter study, we reviewed consecutive patients with cholangiocarcinoma who underwent radical surgery after conventional EBS or inside-stent insertion. Adverse event (AE) rates after EBD and post-surgical AEs were compared. A multivariable analysis was performed to identify factors affecting cholangitis after EBD. RESULTS: Conventional EBS and inside-stent procedures were performed for 56 and 73 patients, respectively. Patient backgrounds were similar between groups, except for percutaneous transhepatic portal vein embolization. The waiting time before surgery was similar between groups (28.5 days vs. 30 days). There were no significant differences in the cholangitis rate (21.4% vs. 26.0%; P = 0.68) and all AEs (25.0% vs. 30.1%; P = 0.56) between groups. The post-surgical AE rate was similar between the groups. The multivariable analysis found that preprocedural cholangitis was a risk factor for cholangitis after EBD (odds ratio: 5.67; 95% confidence interval: 1.61-19.9). CONCLUSIONS: The outcomes of inside-stent techniques and conventional EBS for the management of preoperative EBD are comparable for patients with cholangiocarcinoma.

Clinical significance of postpancreatectomy acute pancreatitis defined by the International Study Group for Pancreatic Surgery.

Aim: The International Study Group for Pancreatic Surgery (ISGPS) developed a structured definition of postpancreatectomy acute pancreatitis (PPAP) in 2021. This study aimed to evaluate the clinical significance of PPAP as defined by the ISGPS criteria. Methods: We evaluated the medical records and postoperative computed tomography (CT) findings of 247 patients who underwent pancreaticoduodenectomy. Postoperative hyperamylasemia (POH) was defined as an elevation in serum amylase levels over the upper baseline limit (≥133 U/L) on postoperative days 1 and 3. PPAP was defined as acute pancreatitis satisfying the following three requirements: POH, clinically relevant deterioration, and radiologic features consistent with acute pancreatitis. Results: Postoperative hyperamylasemia and PPAP were prevalent in 9.7% (24/247) and 3.6% (9/247) of the patients, respectively. PPAP grade B occurred in eight patients, seven of whom experienced Clavien-Dindo grade IIIA complications, including postoperative pancreatic fistula (POPF) and extended periods of postoperative hospitalization. PPAP grade C occurred in one patient, who died from the exacerbation of underlying interstitial pneumonia following the POPF occurrence. Acute pancreatitis determined by CT was observed in 15.3% (38/247) of the patients who underwent pancreaticoduodenectomy and was strongly associated with severe morbidity (P < .0001) and longer postoperative hospitalization (P < .0001). POH preceded acute pancreatitis on CT in only 23.7% (9/38) of those cases, resulting in a low incidence rate of PPAP. Conclusion: Post-pancreatectomy acute pancreatitis is a major postoperative complication of pancreatic resection; however, based on the current ISGPS criteria, its prevalence is low. Defining PPAP promotes universal evaluation and understanding of this new concept.

Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study.

BACKGROUND/AIMS: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases. METHODS: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed. RESULTS: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week < 8 (p = 0.0285), radiological response, stable disease or progression disease (p = 0.0212), and pathological stage > IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion. CONCLUSIONS: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.

Extensive (subtotal) distal pancreatectomy for pancreatic ductal adenocarcinoma: a propensity score matched cohort study of short- and long-term outcomes compared with those of conventional distal pancreatectomy.

PURPOSE: Extensive distal pancreatectomy (ExDP) can transect the pancreatic parenchyma more from the right side than conventional distal pancreatectomy (CDP) can. This study aimed to evaluate the short- and long-term outcomes of ExDP for pancreatic ductal adenocarcinoma (PDAC) of the pancreatic body, located adjacent to the portal vein (PV). METHODS: Medical records of 98 patients who underwent ExDP (n = 15) or CDP (n = 83) for PDAC were retrospectively reviewed. Short- and long-term outcomes of the two groups were compared. Propensity score matched analysis was additionally performed to minimize the impact of treatment allocation bias. RESULTS: In the total cohort, the CDP group had a significantly higher proportion of pancreatic tail lesions (P < 0.01), higher proportion of males, and larger tumor size. Of the 15 patients who underwent ExDP, 11 could be matched. These differences of patients' characteristics were not observed after matching. Before and after matching, the duration of surgery, blood loss, rate of morbidity including pancreatic fistula, and postoperative course were comparable between the groups. The rate of recurrence and recurrence pattern were also not significantly different between the groups. ExDP for PDAC of the pancreatic body near the PV did not increase local or lymph node recurrence. The disease-free and overall survival did not differ between the groups. CONCLUSIONS: Surgical and oncological outcomes after ExDP for PDAC were acceptable and comparable to those after CDP. ExDP is a feasible procedure, and could be an option for the treatment of PDAC of the pancreatic body near PV.

Efficacy of Distal Pancreatectomy Combined With Modified DuVal Procedure in Patients With a High Risk of Postoperative Pancreatic Fistula.

BACKGROUND: The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. The present study aimed to clarify the efficacy of our modified DuVal (mDuVal) pancreatojejunostomy following DP in patients with a high risk of POPF. METHODS: The medical records of 346 consecutive patients who underwent DP between 2006 and 2016 were retrospectively reviewed. Perioperative features were compared between 24 patients undergoing mDuVal (mDuVal group) and 322 patients undergoing standard DP (standard DP group). RESULTS: Preoperative American Society of Anesthesiologists physical status 1 was more frequent in the standard group than in the mDuVal group (P = .02). The start of a solid diet after operation was significantly earlier in the mDuVal group than in the standard DP group (P = .01), while there were no significant differences between the groups for clinically relevant POPF, amylase concentration in the drainage fluid on postoperative day 1 and days 3-5, time to drain removal, additional intervention for POPF, overall complications, or postoperative hospital stay. DISCUSSION: The mDuVal procedure could be an option for patients with a high risk of POPF to improve the outcomes after DP. Further investigation involving large study populations is necessary to clarify the efficacy of this procedure.