Removal of gemcitabine-induced senescent cancer cells by targeting glutaminase1 improves the therapeutic effect in pancreatic ductal adenocarcinoma.

Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated ß-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.

KLK10 derived from tumor endothelial cells accelerates colon cancer cell proliferation and hematogenous liver metastasis formation.

Tumor endothelial cells (TECs), which are thought to be structurally and functionally different from normal endothelial cells (NECs), are increasingly attracting attention as a therapeutic target in hypervascular malignancies. Although colorectal liver metastasis (CRLM) tumors are hypovascular, inhibitors of angiogenesis are a key drug in multidisciplinary therapy, and TECs might be involved in the development and progression of cancer. Here, we analyzed the function of TEC in the CRLM tumor microenvironment. We used a murine colon cancer cell line (CT26) and isolated TECs from CRLM tumors. TECs showed higher proliferation and migration than NECs. Coinjection of CT26 and TECs yielded rapid tumor formation in vivo. Immunofluorescence analysis showed that coinjection of CT26 and TECs increased vessel formation and Ki-67+ cells. Transcriptome analysis identified kallikrein-related peptide 10 (KLK10) as a candidate target. Coinjection of CT26 and TECs after KLK10 downregulation with siRNA suppressed tumor formation in vivo. TEC secretion of KLK10 decreased after KLK10 downregulation, and conditioned medium after KLK10 knockdown in TECs suppressed CT26 proliferative activity. Double immunofluorescence staining of KLK10 and CD31 in CRLM tissues revealed a significant correlation between poor prognosis and positive KLK10 expression in TECs and tumor cells. On multivariate analysis, KLK10 expression was an independent prognostic factor in disease-free survival. In conclusion, KLK10 derived from TECs accelerates colon cancer cell proliferation and hematogenous liver metastasis formation. KLK10 in TECs might offer a promising therapeutic target in CRLM.

High N6-methyladenosine-activated TCEAL8 mRNA is a novel pancreatic cancer marker.

N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.

ASO Author Reflections: Potential of Peripheral Plasma Exosomal miRNA: miR-6855-5p Could Predict Radiosensitivity in Patients with Pancreatic Cancer, and Enhances Radioresistance.

The efficacy of preoperative treatment for pancreatic cancer (PC) has been reported in randomized controlled trials, but the optimal regimen and the appropriateness of combining radiotherapy remain controversial. Therefore, predicting the efficacy of preoperative treatment using biomarkers and determining whether to combine chemotherapy or radiotherapy based on the biology of individual tumors could help personalize treatment and maximize therapeutic outcomes. In this study, a microRNA (miRNA) microarray analysis was performed using peripheral blood plasma exosomes from 10 PC patients who underwent neoadjuvant chemoradiotherapy, leading to the identification of miR-6855-5p as a candidate miRNA. miR-6855-5p was found to induce radioresistance in PC cells. In another cohort of 28 patients, it was observed that those with higher expression levels of miR-6855-5p in peripheral blood plasma exosomes tended to have increased radioresistance (r = - 0.5964). In future, measuring plasma exosomal miR-6855-5p before treatment could potentially lead to precision medicine by personalizing the decision of whether to include radiotherapy in the treatment plan.

Skeletal Muscle-Derived Irisin Enhances Gemcitabine Sensitivity and Suppresses Migration Ability in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.

miR-6855-5p Enhances Radioresistance and Promotes Migration of Pancreatic Cancer by Inducing Epithelial-Mesenchymal Transition via Suppressing FOXA1: Potential of Plasma Exosomal miR-6855-5p as an Indicator of Radiosensitivity in Patients with Pancreatic Cancer.

BACKGROUND: Whether radiation should be added to neoadjuvant treatment remains controversial, and liquid biopsy has not been reported to predict radioresistance in pancreatic cancer (PC). We aimed to identify microRNAs (miRNAs) governing radioresistance in PC by utilizing peripheral plasma exosome samples and to verify their usefulness as biomarkers. METHODS: miRNA microarray analysis was conducted using pretreatment peripheral plasma exosomes from 10 patients with PC receiving neoadjuvant chemoradiotherapy (NACRT) in the discovery cohort. Patients were categorized into two groups (good and poor responders) based on treatment responses, and candidate miRNAs exhibiting differential expression between the two groups were identified. The radiosensitivity of PC cells was examined after miR-6855-5p overexpression. Next-generation sequencing (NGS) and TargetScan were used to explore the mechanisms of radioresistance. We investigated the correlation between miR-6855-5p expression levels in the pretreatment peripheral plasma exosomes of 28 patients in the validation cohort and the response to NACRT. RESULTS: miR-6855-5p expression was higher in poor responders than in good responders. miR-6855-5p induces radioresistance in PC cells. NGS showed that epithelial-mesenchymal transition (EMT) was involved in miR-6855-5p-related radioresistance. Forkhead box protein A1 (FOXA1) was identified as a direct target of miR-6855-5p using NGS and TargetScan. Clinical examination of samples from the validation cohort revealed a tendency for patients with higher expression of miR-6855-5p in peripheral plasma exosomes to exhibit increased radioresistance (r = -0.5964). CONCLUSIONS: miR-6855-5p regulates the radioresistance of PC by inducing EMT via suppressing FOXA1, and miR-6855-5p in peripheral plasma exosomes may be a biomarker for radioresistance of PC.

Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel Versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015).

BACKGROUND: The optimal neoadjuvant chemotherapy (NAC) regimen for patients with localized pancreatic ductal adenocarcinoma (PDAC) remains uncertain. This trial aimed to evaluate the efficacy and safety of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), in patients with resectable/borderline-resectable (R/BR) PDAC. PATIENTS AND METHODS: Treatment-naïve patients with R/BR-PDAC were enrolled and randomly allocated. They received two cycles (2 months) of each standard protocol, followed by radical surgery for those without tumor progression in general hospitals belonging to our intergroup. The primary endpoint was to determine the superior regimen on the basis of achieving a 10% increase in the rate of patients with progression-free survival (PFS) at 2 years from allocation. RESULTS: A total of 100 patients were enrolled, with 94 patients randomly assigned to the GS arm (N = 46) or GA arm (N = 48). The 2-year PFS rates did not show the stipulated difference [GA, 31% (24-38%)/GS, 26% (18-33%)], but the Kaplan-Myer analysis showed significance (median PFS, GA/GS 14 months/9 months, P = 0.048; HR 0.71). Secondary endpoint comparisons yielded the following results (GA/GS arm, P-value): rates of severe adverse events during NAC, 73%/78%, P = 0.55; completion rates of the stipulated NAC, 92%/83%, P = 0.71; resection rates, 85%/72%, P = 0.10; average tumor marker (CA19-9) reduction rates, -50%/-21%, P = 0.01; average numbers of lymph node metastasis, 1.7/3.2, P = 0.04; and median overall survival times, 42/22 months, P = 0.26. CONCLUSIONS: This study found that GA and GS are viable neoadjuvant treatment regimens in R/BR-PDAC. Although the GA group exhibited a favorable PFS outcome, the primary endpoint was not achieved.

Prognostic Significance of Biologic Factors in Patients with a Modest Radiologic Response to Neoadjuvant Treatment for Resectable and Borderline Resectable Pancreatic Cancers: Impact of the Combination Index of Sialyl-Lewis Antigen-Related Tumor Markers.

BACKGROUND: Appropriate re-evaluation after neoadjuvant treatment (NAT) is important for optimal treatment selection. Nonetheless, determining the operative eligibility of patients with a modest radiologic response remains controversial. This study aimed to assess the prognostic significance of biologic factors for patients showing a modest radiologic response to NAT and investigate the tumor markers (TMs), CA19-9 alone, DUPAN-II alone, and their combination, to create an index that combines these sialyl-Lewis antigen-related TMs associated with treatment outcomes. METHODS: This study enrolled patients deemed to have a "stable disease" by RECIST classification with slight progression (tumor size increase rate, ≤20%) as their radiologic response after NAT. A sialyl-Lewis-related index (sLe index), calculated by adding one fourth of the serum DUPAN-II value to the CA19-9 value, was created. The prognostic significances of CA19-9, DUPAN-II, and the sLe index were assessed in relation to postoperative outcomes. RESULTS: An sLe index lower than the cutoff value (45.25) was significantly associated with favorable disease-free survival. Moreover, the post-NAT sLe index had a higher area under the curve value for recurrence within 24 months than the post-NAT levels of CA19-9 or DUPAN-II alone. Multivariable analysis showed that a post-NAT sLe index higher than 45.25 was the single independent predictive factor for recurrence within 24 months. CONCLUSIONS: Additional evaluation of biologic factors can potentially enhance patient selection, particularly for patients showing a limited radiologic response to NAT. The authors' index is a simple indicator for the biologic evaluation of multiple combined sialyl-Lewis antigen-related TMs and may offer a better predictive significance.

Preoperative treatment response prediction for pancreatic cancer by multiple microRNAs in plasma exosomes: Optimization using machine learning and network analysis.

BACKGROUND/OBJECTIVES: MicroRNAs (miRNAs) are involved in chemosensitivity through their biological activities in various malignancies, including pancreatic cancer (PC). However, single-miRNA models offer limited predictability of treatment response. We investigated whether a multiple-miRNA prediction model optimized via machine learning could improve treatment response prediction. METHODS: A total of 20 and 66 patients who underwent curative resection for PC after gemcitabine-based preoperative treatment were included in the discovery and validation cohorts, respectively. Patients were classified according to their response to preoperative treatment. In the discovery cohort, miRNA microarray and machine learning were used to identify candidate miRNAs (in peripheral plasma exosomes obtained before treatment) associated with treatment response. In the validation cohort, miRNA expression was analyzed using quantitative reverse transcription polymerase chain reaction to validate its ability to predict treatment response. RESULTS: In the discovery cohort, six and three miRNAs were associated with good and poor responders, respectively. The combination of these miRNAs significantly improved predictive accuracy compared with using each single miRNA, with area under the curve (AUC) values increasing from 0.485 to 0.672 to 0.909 for good responders and from 0.475 to 0.606 to 0.788 for poor responders. In the validation cohort, improved predictive performance of the miRNA combination over single-miRNA prediction models was confirmed, with AUC values increasing from 0.461 to 0.669 to 0.777 for good responders and from 0.501 to 0.556 to 0.685 for poor responders. CONCLUSIONS: Peripheral blood miRNA profiles using an optimized combination of miRNAs may provide a more advanced prediction model for preoperative treatment response in PC.

Prognostic impact of aberrant right hepatic artery involvement in patients with pancreatic cancer: A multicenter retrospective cohort study.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the prognostic value of aberrant right hepatic artery (A-RHA) involvement in patients with pancreatic cancer (PC). METHODS: This study enrolled 474 patients who underwent upfront pancreatectomy or neoadjuvant treatment for resectable (R) or borderline resectable (BR) PC from four institutions. The patients were divided into three groups: A-RHA involvement group (n = 12), patients who had sole A-RHA involvement without major arterial involvement; BR-A group (n = 104), patients who had major arterial involvement; R/BR-PV group (n = 358), others. RESULTS: All patients in the A-RHA involvement group underwent margin-negative resection. The median overall survival of the entire cohort in the A-RHA involvement, R/BR-PV, and BR-A groups was 41.2, 33.5, and 25.2 months, respectively. Although survival in the R/BR-PV group was significantly more favorable than that in the BR-A group (p = 0.0003), no significant difference was observed between the A-RHA involvement group and the R/BR-PV (p = 0.7332) and BR-A (p = 0.1485) groups. CONCLUSIONS: The prognosis of patients with PC and sole A-RHA involvement was comparable to that of patients with R/BR-PV.

Apparent diffusion coefficient in intrahepatic cholangiocarcinoma diffusion-weighted magnetic resonance imaging noninvasively predicts Ki-67 expression.

AIM: Tumor Ki-67 expression reflects prognosis and cancer grade, and biopsy-based preoperative assessment of Ki-67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki-67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki-67 expression in intrahepatic cholangiocarcinoma (ICC). METHOD: We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki-67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n = 18) and low (n = 21) Ki-67 expression. To assess the diagnostic performance of the ADC values for Ki-67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). RESULTS: The mean and minimum ADC values were significantly lower in the group with high Ki-67 expression. For predicting high Ki-67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki-67 expression level in ICC. CONCLUSION: Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki-67 expression.

Application of a laparoscopic device for cell-derived sheet transplantation on the liver in a porcine model.

BACKGROUND: Cell-derived sheets are of global interest for regenerative therapy. Transplanting a sheet for abdominal organs requires a device for laparoscopic delivery to minimize invasiveness. Here, using a porcine model, we aimed to confirm the feasibility of a device developed to deliver sheets to the thoracic cavity in a laparoscopic transplantation procedure. MATERIAL AND METHODS: We used the device to transplant human skeletal myoblast cell sheets onto the liver and measured extra-corporeal, intra-abdominal, and total procedure times for sheet transplantation. Tissues, including the liver and the sheet, were collected two days after transplantation and analyzed histologically. RESULTS: In all experiments (n = 27), all sheets were successfully placed at target locations. The mean (± standard deviation) extra-corporeal, intra-abdominal, and total procedure times were 44 ± 29, 33 ± 12, and 77 ± 36 s, respectively. We found no difference between the two surgeons in procedure times. Histological analyses showed no liver damage with the transplantation and that sheets were transplanted closely onto the liver tissue without gaps. CONCLUSION: We confirmed the feasibility of a simple universal device to transplant cell-derived sheets via laparoscopic surgery. This device could support a minimally invasive procedure for sheet transplantation.

Prognostic Impact of Gastroduodenal Artery Involvement in Cancer of the Pancreatic Head.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) contacting major arteries such as the celiac, common hepatic, and superior mesenteric artery is linked to poor prognosis and classified as borderline resectable. Although PDAC involving the gastroduodenal artery (GDA) is considered resectable, the prognostic impact of GDA involvement remains unclear. Here we investigated the prognostic impact of GDA involvement in PDAC after resection. METHODS: This study included 105 patients with resectable PDAC or borderline resectable with portal vein involvement. Patients were divided into two groups: those with tumor-GDA contact ≤ 180° and those with GDA contact > 180°. We evaluated the prognostic impact of GDA involvement between these groups. RESULTS: Both recurrence-free and overall survival after the surgery were significantly poorer with GDA contact > 180° than ≤ 180°. The poorer prognosis with GDA contact > 180° was verified by multivariate analysis and propensity score matching analysis to match patient backgrounds between the groups. The frequency of postoperative distant metastasis was also significantly higher in patients with GDA contact > 180°. CONCLUSIONS: GDA involvement is an independent factor significantly associated with postoperative survival in PDAC, and the poorer prognosis with GDA involvement may be linked to the development of postoperative distant metastasis.

Automated Analysis for the Prevalence of Cancer-Associated Fibroblasts in Resected Specimens of Intrahepatic Cholangiocarcinoma is a Simple and Reliable Evaluation System.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) has a high recurrence rate and poor prognosis, and chemotherapy options are limited. The prevalence of cancer-associated fibroblasts (CAFs) in iCCA has recently emerged as a prognostic marker and therapeutic target. A method to quantify the expression of CAFs is needed; however, a simple and reliable quantification method has not yet been established. OBJECTIVE: The aim of this study was to establish a simple and reliable method of quantifying CAFs. METHODS: A total of 71 patients with iCCA who underwent curative resection from November 2006 to October 2020 in our hospital were investigated. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) was performed and α-SMA-positive cells were quantified by an automated analysis system (new method) and visually counted (conventional method). The times required for measurement and the prognosis were compared. RESULTS: The results of the quantification of CAFs by the new method were significantly correlated with the results by the conventional method, and the time required for measurement was significantly shorter with the new method. Patients with high-intensity CAFs showed a significantly poorer prognosis in terms of overall survival (OS) and the cumulative hepatic recurrence rate. In addition, high α-SMA levels were a significant risk factor for OS in multivariate analysis. CONCLUSIONS: This new method may contribute to the management of patients with iCCA, not only for the prediction of prognosis of patients with iCCA, but also for the indication of targeted therapy against CAFs.

Change Impact of Body Composition During Neoadjuvant Chemoradiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma Undergoing Pancreatectomy.

BACKGROUND: The change impact of body composition during neoadjuvant therapy on clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. The aim of this study was to investigate the association between changes in body composition during neoadjuvant chemoradiotherapy (NACRT) and postoperative outcomes in patients with PDAC undergoing pancreatectomy, using three-dimensional images. METHODS: We reviewed 66 consecutive patients with resectable/borderline resectable PDAC receiving gemcitabine and S-1 with radiotherapy between April 2010 and June 2016. Body compositions were evaluated pre- and post-NACRT. All patients were hospitalized and supplied with regulated diet during NACRT treatment. RESULTS: Psoas major muscle volume index (PMI), abdominal fat volume index, and visceral fat volume index decreased significantly after NACRT (P < 0.0001, P < 0.0001, P < 0.0001, respectively). The post-NACRT CA19-9 level decreased significantly in the small-PMI-decrease group compared with the large-PMI-decrease group (P = 0.046). Recurrence-free survival (RFS) and overall survival (OS) of the large-PMI-decrease group were significantly poorer than those of the small-PMI-decrease group (P = 0.002, P = 0.006, respectively). On the other hand, there were no significant differences in RFS and OS between groups with high and low PMI, at the point of either pre-NACRT (P = 0.117, P = 0.123, respectively) or post-NACRT (P = 0.065, P = 0.064, respectively). Multivariate analysis identified a large percentage decrease in PMI as an independent risk factor for recurrence and death (P = 0.003, P = 0.002, respectively). CONCLUSIONS: Loss of skeletal muscle mass during NACRT was an independent risk factor for survival in patients with PDAC.

DUPAN-II normalisation as a biological indicator during preoperative chemoradiation therapy for resectable and borderline resectable pancreatic cancer.

BACKGROUND: Duke pancreatic mono-clonal antigen type 2 (DUPAN-II) is a famous tumour maker for pancreatic cancer (PC) as well as carbohydrate antigen 19-9 (CA19-9). We evaluated the clinical implications of DUPAN-II levels as a biological indicator for PC during preoperative chemoradiation therapy (CRT). METHODS: This retrospective analysis included data from 221 consecutive patients with resectable and borderline resectable PC at diagnosis who underwent preoperative CRT between 2008 and 2017. We focused on 73 patients with elevated pre-CRT DUPAN-II levels (> 230 U/mL; more than 1.5 times the cut-off value for the normal range). Pre- and post-CRT DUPAN-II levels and the changes in DUPAN-II ratio were measured. RESULTS: Univariate analysis identified normalisation of DUPAN-II levels after CRT as a significant prognostic factor (hazard ratio [HR] = 2.06, confidence interval [CI] = 1.03-4.24, p = 0.042). Total normalisation ratio was 49% (n = 36). Overall survival (OS) in patients with normalised DUPAN-II levels was significantly longer than that in 73 patients with elevated levels (5-year survival, 55% vs. 21%, p = 0.032) and in 60 patients who underwent tumour resection (5-year survival, 59% vs. 26%, p = 0.039). CONCLUSION: Normalisation of DUPAN-II levels during preoperative CRT was a significant prognostic factor and could be an indicator to monitor treatment efficacy and predict patient prognosis.

Pancreatic cancer near the splenic hilum has a higher likelihood of splenic vessel invasion and unfavorable survival.

PURPOSE: This study aimed to investigate whether clinical outcomes varied based on the tumor location within the pancreatic body and tail in patients with pancreatic cancer (PC). METHODS: Ninety-five patients who had undergone a distal pancreatectomy for resectable (R) or borderline resectable (BR) PC within the pancreatic body or tail region were retrospectively investigated and divided into four groups (three subgroups of R-PC according to tumor location, and BR-PC): R-PC in the pancreatic body region (group A, n = 24), R-PC on the right side of the pancreatic tail region (group B, n = 17), R-PC on the left side of the pancreatic tail region (group C, n = 29), and BR-PC located in any region within the pancreatic body and tail (group BR, n = 25). RESULTS: Group C patients showed a higher incidence of pretreatment splenic artery and vein involvement than group A and B patients (splenic artery: 8.3/11.8/41.4%, p < 0.010; splenic vein: 25.0/23.5/79.3%, p < 0.010, in groups A/B/C, respectively). The overall survival of group C patients was significantly unfavorable compared to that of group A and B patients (median: 3.9/4.2/2.3 years in groups A/B/C, p = 0.029, respectively). Pretreatment clinical factors were comparable between group C and group BR. Median survival rates were comparable between group C and BR patients (2.3 and 2.0 years, respectively) (p = 0.93). CONCLUSIONS: Differences in anatomical location within the pancreatic body and tail characterize the unfavorable outcomes of PC near the splenic hilum.

Investigation of the variation of vessels around the pancreatic head based on the first jejunal vein anatomy at pancreaticoduodenectomy.

PURPOSE: Pancreaticoduodenectomy (PD) for pancreatic cancer carries a high risk of massive intraoperative blood loss. The artery first approach (AFA) prevents blood loss during PD, but the optimal approach is unclear. The first jejunal vein (FJV) often comprises multiple veins and broadly supports venous drainage of the proximal jejunum. Its ligation carries a risk of proximal jejunum congestion. Here we investigated the anatomical characteristics of PD-associated vessels and AFA approach selection based on FJV anatomy. METHODS: This study included 148 Japanese living donors for liver transplantation. We reviewed their computed tomography images and assessed the anatomical pattern of PD-associated vessels in terms of FJV anatomy. RESULTS: The FJV traveled posterior to the superior mesenteric artery in 128 patients (86.5%, dorsal group) and anterior in 20 (13.5%, ventral group). The predominant draining vein of the inferior pancreaticoduodenal vein was the superior mesenteric vein in the ventral group (87.5%) and the FJV in the dorsal group (97.9%). Compared with the dorsal group, the ventral group had a significantly greater percentage with the superior mesenteric vein ventral to the superior mesenteric artery (30.0% versus 10.9%) and a significantly larger posterior superior pancreaticoduodenal vein diameter (3.2 ± 0.9 versus 2.7 ± 0.6 mm, p = 0.0029). These results were validated in patients with pancreatic head cancer. CONCLUSIONS: The anatomical characteristics of PD-associated vessels differed significantly between groups defined by FJV anatomy. Understanding the venous anatomy, especially the FJV, could support selection of the best approach in AFA for PD.

Rubicon can predict prognosis in patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy.

BACKGROUND: Despite previous therapeutic studies on autophagy in cancer, its role in the treatment of pancreatic ductal adenocarcinoma remains controversial, especially regarding its effect on chemotherapy, radiotherapy, and both combined. We focused on RUN domain Beclin-1 interacting and cysteine-rich-containing protein (Rubicon) to reveal its contribution to pancreatic ductal adenocarcinoma after chemoradiotherapy. METHODS: To evaluate the clinical significance of Rubicon, immunohistochemistry was performed, and Rubicon expression was analyzed across 81 specimens resected from patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. A gemcitabine-resistant pancreatic ductal adenocarcinoma cell line was established followed by Rubicon expression and autophagy flux estimation. Finally, gemcitabine sensitivity, invasion ability, and cell viability were evaluated using Rubicon-targeting small interfering RNA. RESULTS: Rubicon expression in resected pancreatic ductal adenocarcinoma samples after chemoradiotherapy revealed significantly worse overall survival and recurrence-free survival in the Rubicon-high expression group than in the Rubicon-low expression group (overall survival: median [years] 2.02 vs. 3.21, p = 0.0359; recurrence-free survival: median [years] 0.90 vs. 1.90, p = 0.0146). In vitro, gemcitabine-resistant pancreatic ductal adenocarcinoma cell lines exhibited higher Rubicon expression and lower autophagy flux than the parental cell line (p < 0.01). Transduction with small interfering RNA downregulated the expression without affecting gemcitabine sensitivity, but it reduced invasion ability and cell viability (p < 0.01) in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line. CONCLUSIONS: High Rubicon expression is a significant, unfavorable prognostic factor in pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. Downregulation of Rubicon expression improves invasion ability and cell viability in gemcitabine-resistant pancreatic ductal adenocarcinoma.

A novel prediction model of pancreatic fistula after pancreaticoduodenectomy using only preoperative markers.

BACKGROUND: Since clinically relevant postoperative pancreatic fistula (CR-POPF) can cause intra-abdominal hemorrhage and abscesses, leading to surgery-related deaths after pancreaticoduodenectomy (PD), its preoperative prediction is important to develop strategies for surgical procedures and perioperative management. This study aimed to establish a novel prediction model for CR-POPF using preoperative markers. METHODS: On a training set of 180 patients who underwent PD at the Yamaguchi University Hospital, a combination of CR-POPF predictors were explored using the leave-one-out method with a unique discrete Bayes classifier. This predictive model was confirmed using a validation set of 366 patients who underwent PD at the Osaka University Hospital. RESULTS: In the training set, CR-POPF occurred in 60 (33%)　of 180 patients and 130 (36%)　of 366 patients in the validation set using selected markers. In patients with pancreatic ductal adenocarcinoma (PDAC), the main pancreatic duct (MPD) index showed the highest prognostic performance and could differentiate CR-POPF with 87% sensitivity and 81% specificity among 84 patients in the training set. In the validation set, the sensitivity and specificity of the MPD index-based model for 130 PDAC samples were 93% and 87%, respectively. In patients with non-PDAC, the MPD index/body mass index (BMI) combination showed the highest prognostic performance and could differentiate CR-POPF with 84% sensitivity and 57% specificity among 96 patients in the training set. In the validation set, the sensitivity and specificity of the MPD index/BMI-based model for 236 non-PDAC samples were 85% and 53%, respectively. CONCLUSION: We developed a novel prediction model for pancreatic fistulas after PD using only preoperative markers. The MPD index and MPD index/BMI combination will be useful for CR-POPF assessment in PDAC and non-PDAC samples, respectively.