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Background: Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data., Methods: The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity., Results: Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9 months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6 months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4 + (p = 0.015) and CD8 + (p = 0.017) T cells and a lower CD8 + /Foxp3 + ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression., Conclusions: The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors., (© 2024. Society of Surgical Oncology.)

Background: The management of malignant ascites is critical for treating patients with advanced pancreatic cancer. The purpose of this study was to assess the safety of cell-free and concentrated ascites reinfusion therapy (CART) and its impact on the prognosis of patients with advanced pancreatic cancer who have massive malignant ascites., Methods: This study analyzed 47 procedures in 29 patients who underwent CART for ascites caused by pancreatic cancer between 2015 and 2022. Among them, 7 patients who received chemotherapy following CART were classified as the chemotherapy group, while 22 patients without chemotherapy after CART were classified as the palliative care group., Results: Among the 47 procedures, adverse events (AEs) were observed in 9 procedures (19 %). Grade 2 adverse events were observed only in one procedure, manifested as fever. There were no grade 3 or 4 AEs, nor were there any treatment-related deaths. The median survival time was 4.0 months in the chemotherapy group and 0.7 months in the palliative care group (p = 0.004). The albumin level in the chemotherapy group was significantly higher than that in the palliative care group., Conclusion: CART is feasible and might be the optimal option to enable prolonged use of chemotherapy to improve the prognosis for late-stage pancreatic cancer patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: PDAC cells upregulate carbonic anhydrase 9 (CA9) expression in order to survive in hypoxic tumor environments, which plays a key role in tumor progression. However, the relationship between CA9 expression and preoperative treatment has not been clarified. We evaluated the clinical impact of CA9 expression on the efficacy of neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC)., Methods: We investigated CA9 expression in 273 surgical specimens and 20 serum samples obtained from patients with PDAC and evaluated their clinical outcomes. We analyzed the function of CA9 using human pancreatic cancer cell lines., Results: CA9 was positively expressed in 36.2 % of patients who underwent NACRT, which was significantly lower than those who underwent upfront surgery (US) (58.9 %, p < 0.001). Interestingly, patients who were CA9-positive in the US group had a significantly poorer prognosis than that of those in the NACRT group (median survival time [MST], 21.5 months vs. 49.2 months, p < 0.001), while there was no significant difference between patients who were CA9-negative in the US and NACRT groups (MST, 45.8 months vs. 46.3 months, p = 0.357). Moreover, serum CA9 levels tended to correlate positively with CA9 expression in cancer tissues. In-vitro experiments demonstrated that CA9 expression was reduced after treatments with radiation and chemoradiation therapy (RT/CRT), and that CA9 knockdown suppressed the impact of RT/CRT on cancer cell proliferation., Conclusions: CA9 may act as a target molecule for RT/CRT, highlighting its clinical importance as a valuable biomarker for more stringent indications for NACRT., Competing Interests: Declaration of competing interest The authors declare that they have no confict of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs., Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models., Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Elevated autophagy activity enhances the malignancy of pancreatic cancer (PaCa), and autophagy is recognized as a novel therapeutic target. Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) is a transcription factor that suppresses autophagy, but its association with PaCa is unknown. We analyzed the function of ZKSCAN3 in PaCa and investigated whether autophagy regulation through ZKSCAN3 could become a new therapeutic target for PaCa. Using reverse transcription-quantitative polymerase chain reaction and western blotting, we observed that ZKSCAN3 expression was upregulated in several PaCa cell lines compared with normal pancreatic ductal epithelial cells. Additionally, comparing ZKSCAN3 expression with the prognosis of PaCa patients using web databases, we found that higher ZKSCAN3 expression in PaCa was associated with extended overall survival. Knocking down ZKSCAN3 promoted the proliferation of PaCa cells. Moreover, following ZKSCAN3 knockdown, PaCa cells exhibited significantly enhanced migratory and invasive properties. Conversely, overexpression of ZKSCAN3 significantly suppressed the proliferation, migration and invasion of PaCa cells. Additionally, the knockdown of ZKSCAN3 increased the expression of LC3-II, a marker of autophagy, whereas ZKSCAN3 overexpression decreased LC3-II expression. In a xenograft mouse model, tumors formed by MIA PaCa-2 cells in which ZKSCAN3 was knocked down significantly increased in size compared with the control group. In conclusion, ZKSCAN3 expression was upregulated in several pancreatic cancer cells. Additionally, it was revealed that ZKSCAN3 is negatively correlated with the malignancy of PaCa through autophagy. These results suggest that autophagy regulation via ZKSCAN3 may be a new therapeutic target for PaCa., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Both geometric and dosimetric components are commonly considered when determining the margin for planning target volume (PTV). As dose distribution is shaped by controlling beam aperture in peripheral dose prescription and dose-escalated simultaneously integrated boost techniques, adjusting the margin by incorporating the variable dosimetric component into the PTV margin is inappropriate; therefore, geometric components should be accurately estimated for margin calculations., Purpose: We introduced an asymmetric margin-calculation theory using the guide to the expression of uncertainty in measurement (GUM) and intra-fractional motion. The margins in fiducial marker-based real-time tumor tracking (RTTT) for lung, liver, and pancreatic cancers were calculated and were then evaluated using Monte Carlo (MC) simulations., Methods: A total of 74 705, 73 235, and 164 968 sets of intra- and inter-fractional positional data were analyzed for 48 lung, 48 liver, and 25 pancreatic cancer patients, respectively, in RTTT clinical trials. The 2.5th and 97.5th percentiles of the positional error were considered representative values of each fraction of the disease site. The population-based statistics of the probability distributions of these representative positional errors (PD-RPEs) were calculated in six directions. A margin covering 95% of the population was calculated using the proposed formula. The content rate in which the clinical target volume (CTV) was included in the PTV was calculated through MC simulations using the PD-RPEs., Results: The margins required for RTTT were at most 6.2, 4.6, and 3.9 mm for lung, liver, and pancreatic cancer, respectively. MC simulations revealed that the median content rates using the proposed margins satisfied 95% for lung and liver cancers and 93% for pancreatic cancer, closer to the expected rates than the margins according to van Herk's formula., Conclusions: Our proposed formula based on the GUM and motion probability distributions (MPD) accurately calculated the practical margin size for fiducial marker-based RTTT. This was verified through MC simulations., (© 2023 American Association of Physicists in Medicine.)

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although the overall survival rate of patients with resectable pancreatic cancer has gradually improved, some patients relapse early and have a poor prognosis. This study aimed to identify the preoperative risk factors for early recurrence after neoadjuvant chemoradiotherapy in patients with resectable pancreatic cancer., Methods: This study analyzed patients who underwent pancreatectomy after receiving neoadjuvant chemoradiotherapy for resectable pancreatic cancer between January 2009 and June 2021 and excluded those with borderline resectable and unresectable pancreatic cancers. Early recurrence was defined as recurrence within 6 months after surgery., Results: This study included 203 patients, of whom 22 experienced early recurrence. The median survival time of patients with early recurrence was 18.3 months, which was significantly worse than that of patients with late recurrence (44.0 months, p < 0.001) or no recurrence (not reached, p < 0.001). Logistic regression analysis revealed that a carbohydrate antigen 19-9 level of >100 units/mL and a T status of ≥T2 after neoadjuvant chemoradiotherapy were independent predictive risk factors for early recurrence. The median recurrence-free survival time of patients with two risk factors was 9.7 months and significantly worse than that of those with either risk factors (20.5 months, p = 0.024) and those with no risk factor (26.2 months, p < 0.001)., Conclusions: A combination of a high-level carbohydrate antigen 19-9 and a T status of ≥T2 after neoadjuvant chemoradiotherapy are predictors of early recurrence and may be helpful for selecting patients who require a stronger preoperative treatment., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

The patient described herein was diagnosed with left breast, endometrial, and early gastric cancers at 49, 53, and 57 years of age, respectively. Magnetic resonance cholangiopancreatography performed when she was undergoing treatment for cholecystitis at 50 years of age showed local pancreatic duct dilatation in the pancreatic head. She was followed in the Department of Gastroenterology at our hospital for an intraductal papillary mucinous neoplasm(IPMN). An abdominal computed tomography scan obtained at 59 years of age revealed dilation of the main pancreatic duct in the pancreas body and tail, therefore an endoscopic ultrasound-guided fine needle aspiration was performed. She was diagnosed with pancreatic cancer and underwent a laparoscopic distal pancreatectomy. The postoperative course was uneventful; however, the pancreatic cancer recurred and she died approximately 14 months postoperatively. Reports of multiple cancers associated with IPMNs are rare, yet we managed a patient with a pancreatic head IPMN complicated by metachronous quadruple carcinomas( breast, endometrial, gastric, and pancreatic cancers).

Background: Although patient-risk stratification is important for selecting individualized treatment for pancreatic ductal adenocarcinoma (PDAC), predicting the oncologic outcomes after surgery remains a challenge. In this study, we identified a nectin family gene panel (NFGP) that can accurately stratify oncologic outcomes in patients with PDAC., Study Design: Comprehensive analysis of the expression of 9 nectin family genes identified the NFGP, which was assessed for predictive performance in 2 independent public cohorts (The Cancer Genome Atlas [TCGA] n = 176; International Cancer Genome Consortium [ICGC] n = 89). It was subsequently trained and validated for the in-house training cohort without neo-adjuvant therapy (NAT, n = 213) and the validation cohort with NAT (n = 307)., Results: Using the Cox regression model, NFGP derived from 9 nectin family genes accurately stratified overall survival (OS) in TCGA (p = 0.038) and ICGC (p = 0.005). We subsequently optimized NFGP, which robustly discriminated postoperative prognosis, OS (p = 0.014) and relapse-free survival ([RFS] p = 0.006) in the training cohort. The NFGP was successfully validated in an independent validation cohort (OS: p < 0.001; RFS: p = 0.004). Multivariate analysis demonstrated the NFGP was an independent prognostic factor for OS and RFS in the training (p = 0.028 and 0.008, respectively) and validation (p < 0.001 and 0.013, respectively) cohorts. The subcohort analyses showed that the predictive performance of NFGP is applicable to the patients' subcohort according to resectability or adjuvant therapy status. Additionally, a combination model of NFGP score and CA19-9 level emerged with improved accuracy for predicting prognosis., Conclusions: This study established the predictive significance of NFGP for oncologic outcomes after surgery in PDAC. Our data demonstrate its clinical impact as a potent biomarker for optimal patient selection for individualized treatment strategies., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Pancreatic cancer (PaCa) tends to be resistant to chemotherapy and is associated with a very poor prognosis. It has been previously reported by the authors that integrin‑linked kinase (ILK) is a prognostic factor in PaCa. ILK expression was examined in a newly established gemcitabine (Gem)‑resistant (Gem‑R) PaCa cell line and it was demonstrated that ILK expression was upregulated compared with that in Gem‑sensitive (Gem‑S) cells. In the present study, the effects of increased ILK expression in Gem‑R PaCa cells were evaluated and it was examined whether compound 22 (Cpd22), an ILK inhibitor, exerted antitumor effects not only in Gem‑S cells but also in Gem‑R cells. Reverse transcription‑quantitative polymerase chain reaction and western blotting revealed that ILK expression was higher in Gem‑R PaCa cells than in Gem‑S PaCa cells. Cpd22 inhibited the growth of PaCa cells in a concentration‑dependent manner. Cpd22 also inhibited the growth of Gem‑R PaCa cells. The invasive and angiogenic potential of Gem‑R PaCa cells was enhanced compared with that in Gem‑S cells; however, ILK small interfering RNA and Cpd22 treatment suppressed this enhancement of invasive potential compared with that in Gem‑S cells. The addition of Cpd22 to Gem also improved the sensitivity of Gem‑R cell lines to Gem. Furthermore, enhanced Akt signaling was associated with increased malignancy in Gem‑R cell lines. In conclusion, ILK was upregulated with resistance and may be involved in tumor angiogenesis, invasive potential, and chemotherapy resistance, which were all suppressed by Cpd22 treatment. Thus, Cpd22 may be a novel therapeutic agent for the treatment of PaCa.

Background: This study aimed to evaluate the significance of multiple tumor markers (TMs) measurements in determining the indications for conversion surgery (CS) in the management of unresectable locally advanced pancreatic cancer (UR-LAPC)., Methods: A total of 103 patients with UR-LAPC, treated between 2008 and June 2021, were enrolled in this study. Three TMs, including carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and Duke pancreatic monoclonal antigen type 2 (DUPAN-2), were measured., Results: Twenty-five patients (24%) underwent CS. The median preoperative treatment period was 9.5 months. The median survival time (MST) from the initial treatment for patients with CS was significantly longer than that for patients without surgery (34.6 vs. 18.9 months, P < 0.001). The number of elevated TMs before CS was one in five patients and two in five patients, while 15 patients had normal levels of all three TMs. Notably, the MST from the initial treatment for patients with all three preoperative normal TMs levels was favorable for 70.5 months. In contrast, patients with one or two preoperatively elevated TMs levels had a significantly worse prognosis (25.4 and 21.0 months, respectively, P < 0.001). Furthermore, the relapse-free survival of patients with three preoperative normal TMs levels was significantly longer than those with one or two elevated TMs levels (21.9 vs. 11.3 or 3.0 months, respectively, P < 0.001). Non-normal values of all TMs before CS were identified as independent poor prognostic factors., Conclusions: Simultaneous measurement and assessment of the three TMs levels may help determine the surgical indications for UR-LAPC after systemic anticancer treatment., Competing Interests: Declaration of competing interest Authors declare no conflict of interest for this article., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Girdin, an actin‑binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse‑free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin‑knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF‑A) was significantly decreased in Girdin‑knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen‑forming ability of vascular endothelial cells was also decreased in Girdin‑knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF‑A. These results suggested that Girdin is involved in EGF signaling‑mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular‑targeted drugs for Girdin may improve the prognosis of PaCa in the future.

Background: Long-term outcomes and prognostic factors of proton radiotherapy for locally advanced pancreatic cancer (LAPC) in the body and tail are still unknown. The aim of this study was to determine the prognostic factors after proton radiotherapy in a large group of patients with LAPC in the body and tail., Methods: The medical records of 200 patients with LAPC in the body and tail who underwent proton radiotherapy between February 2009 and January 2021 at the Hyogo Ion Beam Medical Center were retrospectively reviewed to identify prognostic factors that contribute to long-term survival., Results: The overall survival rate at 1- and 2-year after PT was 69.6% and 35.4% with a median overall survival of 18.4 months. The 1- and 2-year local progression-free, and progression-free survival rates were 84.3% and 68.0%, and 44.3% and 19.4%, respectively. In multivariate analysis, superior mesenteric artery (SMA) invasion (SMA only invasion vs. celiac artery only invasion; P = 0.049: SMA and celiac artery invasion vs. celiac artery only invasion; P = 0.017), carbohydrate antigen 19-9 (CA 19-9) level ≥ 231.9 U/mL (P = 0.001), anterior peripancreatic invasion (P = 0.006), and incomplete scheduled concurrent chemotherapy (P = 0.009) were statistically significant prognostic factors for overall survival. There was no significant difference in local progression-free survival; however, distant metastasis-free survival was statistically worse in patients with prognostic factors than in those without., Conclusions: Proton radiotherapy for LAPC in the body and tail may be a valuable multidisciplinary treatment option. Patients with SMA invasion, higher pre-proton radiotherapy serum CA 19-9 level, anterior peripancreatic invasion, or incomplete scheduled concurrent chemotherapy had worse overall survival because of worse distant metastasis-free survival, suggesting that distant metastases have a significant impact on overall survival in such patients., Trial Registration: Retrospectively registered., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Ischemic gastropathy is one of the unique postoperative complications associated with distal pancreatectomy with celiac axis resection for locally advanced pancreatic cancer. Therefore, it is essential to evaluate blood flow to the stomach following a resection; however, no intraoperative procedures have been established to assess this issue. Herein we describe two cases in which intraoperative evaluation of real-time blood flow in the residual stomach was performed using indocyanine green fluorescence and da Vinci Firefly technology during a robot-assisted distal pancreatectomy with celiac axis resection., Methods: Robot-assisted distal pancreatectomy with celiac axis resection was performed using a da Vinci Xi surgical system on two patients with locally advanced pancreatic cancer and suspected invasion of the celiac artery. Indocyanine green (ICG) (0.5 mg/kg) was injected intravenously after resection to evaluate real-time blood flow of the stomach using the da Vinci Firefly system. Blood flow of the stomach was evaluated 60 seconds after the intravenous injection of ICG., Results: All cases were confirmed that there was sufficient blood flow in the residual stomach. Therefore, reconstruction of the left gastric artery was not performed, and the surgery was completed with preservation of the stomach. Good postoperative outcomes were achieved and there was no evidence of ischemic gastropathy or delayed gastric emptying in both cases., Conclusion: This method is very useful in determining whether or not to perform reconstruction of the left gastric artery and/or additional resection of the remnant stomach during a robot-assisted distal pancreatectomy with celiac axis resection., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background: /Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications., Methods: Twenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences., Results: Of the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and β-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01)., Conclusions: The diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to declare., (Copyright © 2023 IAP and EPC. All rights reserved.)

Background: Adenosquamous carcinoma of the pancreas is a rare variant, with a worse prognosis than pancreatic ductal adenocarcinoma; moreover, it has characteristic clinical and histopathological features. Studies have mentioned the differentiation of intraductal papillary mucinous neoplasms into mucinous/tubular adenocarcinomas; however, their transdifferentiation into adenosquamous carcinoma remains unclear., Case Presentation: An 80-year-old Japanese woman was referred to our hospital for further examination of multiple pancreatic cysts. Enhanced computed tomography after close follow-up for 6 years revealed a new nodule with poor enhancement on the pancreatic body. Distal pancreatectomy and splenectomy were performed. Histopathological examination revealed an adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms; moreover, the intraductal papillary mucinous neoplasms lacked continuity with the adenosquamous carcinoma. Immunohistochemical analysis revealed squamous cell carcinoma and differentiation from adenocarcinoma to squamous cell carcinoma. Gene mutation analysis revealed KRAS G12D and KRAS G12R mutations in adenosquamous carcinoma components and intraductal papillary mucinous neoplasm lesions, respectively, with none showing the mutation of GNAS codon 201. The final histopathological diagnosis was adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms of the pancreas., Conclusions: This is the rare case of adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms of the pancreas. To investigate the underlying transdifferentiation pathway of intraductal papillary mucinous neoplasms into this rare subtype of pancreatic cancer, we explored gene mutation differences as a clinicopathological parameter., (© 2023. The Author(s).)

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

Objective: The aim of this study is to evaluate the utility of adjuvant radiotherapy (intraoperative radiotherapy, IORT; postoperative radiotherapy, PORT), and definitive radiotherapy for non-metastatic pancreatic cancer., Methods: Ninety-nine patients were analyzed. Thirty patients underwent IORT with surgery, 31 underwent PORT after surgery, and 38 underwent definitive radiotherapy. Tumor stage [Union for International Cancer Control (UICC) 2009] was as follows: Stage I, 7; IIA, 16; IIB, 31; III, 45. The doses for IORT, PORT, and definitive radio therapy were 20 to 30, 40 to 64.6, and 50.4 to 61.2 Gy, respectively. Associations between clinical parameters including age, gender, tumor site, stage, performance status, surgical margin, and use of chemotherapy and local control (LC) or overall survival (OS) were analyzed., Results: Follow-up periods for all patients were 1.1-145 months (median, 11). OS rate in the IORT, PORT, and definitive radiotherapy groups was 22%, 16%, and 6%, respectively, at 2 years. The 5-year OS rate was 13%, 3.2%, and 0%, respectively. Local control rate at 2 years was 33%, 35%, and 0%, respectively. No Grade ≥ 3 tox icities were observed. Distant metastasis was less common in the IORT group. Stage and surgical margin were sig nificant factors for OS after IORT. Performance status and chemotherapy were significant factors for OS after PORT and definitive radiotherapy., Conclusions: The present study showed the safety of the three treatment modalities, but the outcomes were not satisfactory. More intensive strategies including radiotherapy should be investigated.

Immune checkpoint blockade (ICB) treatment improves the prognosis of several types of solid tumors, however, responsiveness to ICB therapy remains low in pancreatic ductal adenocarcinoma (PDACs), which has a rich tumor microenvironment (TME). The TME is composed of various stromal cells, including cancer-associated fibroblasts (CAFs), which contribute to the establishment of an immunosuppressive microenvironment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate immune pathway that results in the upregulation of immune cell recruiting-cytokines and anti-tumor efficacy. In this study, we aimed to investigate the impact of cGAS-STING expression and the presence of CAFs upon immune cell infiltration in PDACs. cGAS and STING co-expressing PDAC cases showed favorable survival, with many cytotoxic CD8 + T cell infiltrations from the stromal component adjacent to the cancer cells toward cancer cells, but not in cGAS-STING signaling defected PDAC cases. The signatures of tumor-restrain CAFs were expressed in tumors with cGAS-STING signaling. Finally, transwell co-culture experiments demonstrated that immune cell infiltration was impeded by the presence of CAFs, but not by activation of cGAS-STING signaling. In conclusion, pro-infiltration signals, such as cGAS-STING, and characterization of CAFs are crucial in defeating CAF barricades and encouraging immune cell infiltration in PDACs., (© 2022. The Author(s).)

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells., (© 2022. The Author(s).)

Background: Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup., Methods: We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features., Results: We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites., Conclusion: We identified that lung metastasis revealed an immunologically "hot" tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Pancreatic cancer (PaCa) exhibits one of the poorest prognoses among all gastrointestinal cancers due to the rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. However, the mechanisms through which PaCa becomes resistant to radiotherapy are unknown. Here, we established radiation‑resistant PaCa cell lines to investigate the factors involved in radiation resistance. The role of the C‑X‑C motif chemokine ligand 12 (CXCL12)/C‑X‑C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effects of a CXCR4 antagonist on radiation‑resistant PaCa cell lines were investigated. As confirmed by immunofluorescence staining, reverse transcription quantitative polymerase chain reaction, and western blotting, the expression of CXCR4 was higher in radiation‑resistant PaCa cell lines than that noted in normal PaCa cell lines. The invasion ability of radiation‑resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation‑resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.

10Z‑Hymenialdisine is a natural product derived from the marine sponge Axinella carteri . 10Z‑Hymenialdisine has anti‑inflammatory effects exerted through NF‑κB; however, it is unclear whether 10Z‑Hymenialdisine has anti‑angiogenic effects in cancer cells. In the present study, both the anti‑angiogenic and antimetastatic effects of this compound in pancreatic cancer were investigated. It was initially confirmed that 10Z‑Hymenialdisine significantly inhibited the proliferation of pancreatic cancer cells. Next, using both reverse transcription‑quantitative PCR and ELISA, it was demonstrated that 10Z‑Hymenialdisine significantly suppressed the expression of VEGF and IL‑8 mRNAs and proteins in pancreatic cancer. Immunohistochemical analysis revealed that 10Z‑Hymenialdisine inhibited NF‑κB activity in pancreatic cancer cell lines. It was also identified that 10Z‑Hymenialdisine inhibited tube formation in EA.hy926 cells. In vivo , 10Z‑Hymenialdisine significantly inhibited the growth of BxPC‑3 pancreatic cancer cells that were subcutaneously injected into model mice. In conclusion, the present study demonstrated that 10Z‑Hymenialdisine exerted anti‑angiogenic effects by suppressing NF‑κB activity and angiogenic factors, such as VEGF and IL‑8, in pancreatic cancer cell lines. 10Z‑Hymenialdisine has potential applications as a novel therapeutic agent for the treatment of pancreatic cancer.

Background: In infrared reflective (IR) marker-based hybrid real-time tumor tracking (RTTT), the internal target position is predicted with the positions of IR markers attached on the patient's body surface using a prediction model. In this work, we developed two artificial intelligence (AI)-driven prediction models to improve RTTT radiotherapy, namely, a convolutional neural network (CNN) and an adaptive neuro-fuzzy inference system (ANFIS) model. The models aim to improve the accuracy in predicting three-dimensional tumor motion., Methods: From patients whose respiration-induced motion of the tumor, indicated by the fiducial markers, exceeded 8 mm, 1079 logfiles of IR marker-based hybrid RTTT (IR Tracking) with the gimbal-head radiotherapy system were acquired and randomly divided into two datasets. All the included patients were breathing freely with more than four external IR markers. The historical dataset for the CNN model contained 1003 logfiles, while the remaining 76 logfiles complemented the evaluation dataset. The logfiles recorded the external IR marker positions at a frequency of 60 Hz and fiducial markers as surrogates for the detected target positions every 80-640 ms for 20-40 s. For each logfile in the evaluation dataset, the prediction models were trained based on the data in the first three quarters of the recording period. In the last quarter, the performance of the patient-specific prediction models was tested and evaluated. The overall performance of the AI-driven prediction models was ranked by the percentage of predicted target position within 2 mm of the detected target position. Moreover, the performance of the AI-driven models was compared to a regression prediction model currently implemented in gimbal-head radiotherapy systems., Results: The percentage of the predicted target position within 2 mm of the detected target position was 95.1%, 92.6% and 85.6% for the CNN, ANFIS, and regression model, respectively. In the evaluation dataset, the CNN, ANFIS, and regression model performed best in 43, 28 and 5 logfiles, respectively., Conclusions: The proposed AI-driven prediction models outperformed the regression prediction model, and the overall performance of the CNN model was slightly better than that of the ANFIS model on the evaluation dataset., (© 2022. The Author(s).)

Background: Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy (GPT) for non-metastatic, locally advanced pancreatic cancer (LAPC) remain unclear. This study aimed to determine the factors associated with long-term survival in GPT for non-metastatic LAPC., Methods: The medical records of 123 patients with LAPC treated with GPT between February 2009 and December 2019 at Hyogo Ion Beam Medical Center were retrospectively reviewed to assess the factors associated with long-term survival outcomes., Results: The median overall survival of the total cohort treated with GPT was 18.7 months. The 1- and 2-year overall, local progression-free, and progression-free survival rates were 70.4% and 35.7%, 78.2% and 59.0%, and 38.6% and 20.8%, respectively. Multivariate analysis revealed that LAPCs at the pancreatic body-tail and those without anterior peripancreatic invasion were independently associated with longer overall survival (P = 0.040 and P = 0.015, respectively). The median overall survival of patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion were 24.1 and 28.1 months, respectively. LAPCs at the pancreatic body-tail had a higher volume ratio irradiated over 60 Gy equivalents at gross tumor volume than those at the pancreatic head (P < 0.001). LAPCs with anterior peripancreatic invasion had more peritoneal recurrence within 6 months after GTP than those without anterior peripancreatic invasion (P = 0.039)., Conclusions: GPT is a promising treatment option for patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion., (© 2022. The Author(s).)

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r =  - 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis., (© 2022. The Author(s).)

The 5-year survival rate of pancreatic ductal carcinoma (PDAC) patients is <10% despite progress in clinical medicine. Strategies to prevent the development of PDAC are urgently required. The flavonoids Luteolin (Lut) and hesperetin (Hes) may be cancer-chemopreventive, but effects on pancreatic carcinogenesis in vivo have not been studied. Here, the chemopreventive effects of Lut and Hes on pancreatic carcinogenesis are assessed in the BOP-induced hamster PDAC model. Lut but not Hes suppressed proliferation of pancreatic intraepithelial neoplasia (PanIN) and reduced the incidence and multiplicity of PDAC in this model. Lut also inhibited the proliferation of hamster and human pancreatic cancer cells in vitro. Multi-blot and microarray assays revealed decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) on Lut exposure. To explore the relationship between DPYD and STAT3 activity, the former was silenced by RNAi or overexpressed using expression vectors, and the latter was inactivated by small molecule inhibitors or stimulated by IL6 in human PDAC cells. DPYD knock-down decreased, and overexpression increased, pSTAT3 and cell proliferation. DPYD expression was decreased by inactivation of STAT3 and increased by its activation. The frequency of pSTAT3-positive cells and DPYD expression was significantly correlated and was decreased in parallel by Lut in the hamster PDAC model. Finally, immunohistochemical analysis in 73 cases of human PDAC demonstrated that DPYD expression was positively correlated with the Ki-67 labeling index, and high expression was associated with poor prognosis. These results indicate that Lut is a promising chemopreventive agent for PDAC, targeting a novel STAT3-DPYD pathway., (© The Author(s) 2021. Published by Oxford University Press.)

Pancreatic cancer (PaCa) is one of the most aggressive types of cancer. Thus, the development of new and more effective therapies is urgently required. Escin, a pentacyclic triterpenoid from the horse chestnut, has been reported to exhibit antitumor potential by reducing cell proliferation and blocking the nuclear factor‑κB (NF‑κB) signaling pathway in several types of cancer. Our previous study reported that NF‑κB enhanced the secretion of interleukin (IL)‑8 and vascular endothelial growth factor (VEGF), thereby inducing angiogenesis in PaCa cell lines. In the present study, it was examined whether escin inhibited angiogenesis by blocking NF‑κB activation in PaCa. It was initially confirmed that escin, at concentrations >10 µM, significantly inhibited the proliferation of several PaCa cell lines. Next, using immunocytochemical staining, it was found that escin inhibited the nuclear translocation of NF‑κB. Furthermore, ELISA confirmed that NF‑κB activity in the escin‑treated PaCa cells was significantly inhibited and reverse transcription‑quantitative PCR showed that the mRNA expression levels of tumor necrosis factor‑α‑induced IL‑8 and VEGF were significantly suppressed following escin treatment in the PaCa cell lines. ELISA also showed that escin decreased the secretion of IL‑8 and VEGF from the PaCa cells. Furthermore, tube formation in immortalized human endothelial cells was inhibited following incubation with the supernatants from escin‑treated PaCa cells. These results indicated that escin inhibited angiogenesis by reducing the secretion of IL‑8 and VEGF by blocking NF‑κB activity in PaCa. In conclusion, escin could be used as a novel molecular therapy for PaCa.

Background: Particle radiotherapy has increasingly gained acceptance for locally advanced pancreatic cancers owing to superior tumor conformity and dosimetry compared to conventional photon radiotherapy. However, the close proximity of the pancreas to the stomach and duodenum leads to radiation-induced gastrointestinal toxicities, which hinder the delivery of curative doses to the tumor. To overcome this problem, a surgical spacer was placed between the tumor and gastrointestinal tract, and subsequent proton radiotherapy was performed in this study., Methods: Data from 9 patients who underwent surgical spacer placement and subsequent proton radiotherapy were analyzed. The safety and feasibility of the spacer placement surgery were evaluated; the impact of the spacer on dosimetry was also assessed using dose volume histogram (DVH) analyses, before and after surgical spacer placement., Results: Surgical spacer placement and subsequent proton radiotherapy were successfully completed in all cases. Surgical spacer placement significantly improved the dose intensity covering 95%, mean, and minimum doses for the gross tumor volume, and the clinical and planning target volume based on the DVH, while respecting the dose constraints of the gastrointestinal tract. Based on the Common Terminology Criteria for Adverse Events, two patients (22.2%) developed gastrointestinal ulcer (Grade 2) at 1 and 35 months, and one patient (11.1%) developed gastric perforation (Grade 4) at 4 months after proton radiotherapy., Conclusions: Surgical spacer placement in the locally advanced pancreatic body and tail cancers is relatively safe and technically feasible. Comparing radiation plans, surgical spacer placement seems to improve the dose distribution in the locally advanced pancreatic body and tail cancers, which are close to the gastrointestinal tract.

Objectives: There is no standard chemotherapy for advanced pancreatic cancer (APC) after gemcitabine plus nab-paclitaxel (GP) failure. The aim of this study was to evaluate the efficacy and safety of FOLFIRINOX (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (FFX) and modified FFX (mFFX) for APC patients after GP failure., Methods: We retrospectively evaluated the efficacy and safety of FFX in APC patients who were refractory or intolerant of GP., Results: Between July 2014 and October 2018, 23 patients received FFX after failure of GP. The overall response rate (RR) was 23%, and the disease control rate (DCR) was 68%. The median progression-free survival (PFS) was 5.3 months (95% confidence interval, 2.5-8.9), and the median overall survival (OS) was 12.1 months (95% confidence interval, 4.0-14.2). Twelve patients received FFX, and 11 patients received mFFX. In the FFX group, the RR was 9%, the DCR was 73%, the PFS was 5.3 months, and the OS was 6.9 months. In the mFFX group, the RR was 23%, the DCR was 64%, the PFS was 4.3 months, and the OS was 12.8 months. There was no significant difference between the groups., Conclusions: FOLFIRINOX has potential activity for patients with APC in whom GP failed.

Pancreatic serous cystic neoplasms (SCNs), such as serous cystadenoma (SCA), are generally recognized as benign because malignant counterparts of SCNs have been extremely rare. In clinical practice, pancreatic cystic neoplasms diagnosed as SCNs have been managed by conservative observation, as long as the patients remained asymptomatic. We herein report a case of metachronous ductal adenocarcinoma that was discovered during long-term follow-up of SCN and review the related literature. To our knowledge, this was the first reported case of the local presence of ductal adenocarcinoma adjacent to SCA that was preoperatively diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

We developed a synchrotron-based real-time-image gated-spot-scanning proton-beam therapy (RGPT) system and utilized it to clinically operate on moving tumors in the liver, pancreas, lung, and prostate. When the spot-scanning technique is linked to gating, the beam delivery time with gating can increase, compared to that without gating. We aim to clarify whether the total treatment process can be performed within approximately 30 min (the general time per session in several proton therapy facilities), even for gated-spot-scanning proton-beam delivery with implanted fiducial markers. Data from 152 patients, corresponding to 201 treatment plans and 3577 sessions executed from October 2016 to June 2018, were included in this study. To estimate the treatment process time, we utilized data from proton beam delivery logs during the treatment for each patient. We retrieved data, such as the disease site, total target volume, field size at the isocenter, and the number of layers and spots for each field, from the treatment plans. We quantitatively analyzed the treatment process, which includes the patient load (or setup), bone matching, marker matching, beam delivery, patient unload, and equipment setup, using the data obtained from the log data. Among all the cases, 90 patients used the RGPT system (liver: n = 34; pancreas: n = 5; lung: n = 4; and prostate: n = 47). The mean and standard deviation (SD) of the total treatment process time for the RGPT system was 30.3 ± 7.4 min, while it was 25.9 ± 7.5 min for those without gating treatment, excluding craniospinal irradiation (CSI; head and neck: n = 16, pediatric: n = 31, others: n = 15); for CSI (n = 11) with two or three isocenters, the process time was 59.9 ± 13.9 min. Our results demonstrate that spot-scanning proton therapy with a gating function can be achieved in approximately 30-min time slots., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

We report a case of conversion surgery for a locally advanced unresectable(UR-LA)pancreatic cancer that was radically resected after S-1 therapy. A 65-year-old man visited a referral physician because of fatigue and liver dysfunction. A CT scan revealed a mass in the pancreatic uncinate process that was suspected to be superior mesenteric artery(SMA)infiltration and was diagnosed as UR-LA pancreatic cancer. GEM nab-PTX therapy was initiated but was discontinued after 2 courses because of adverse events. The treatment was switched to S-1 monochemotherapy. After that, the tumor did not progress for around 1.5 years, and the patient was referred to our hospital for surgical treatment. As the contact between the tumor and the SMA was considered to be less than half-round, we made a diagnosis of borderline resectable(BR-A)pancreatic cancer. Subsequently, we performed a pancreaticoduodenectomy with partial resection of the portal vein and achieved R0 resection. The patient received adjuvant chemotherapy with S-1 and showed no signs of recurrence for 10 months after surgery.

A 56-year-old man underwent distal pancreatectomy due to pancreatic body carcinoma in 2009, at the age of 46. There had been no sign of metastasis and recurrence until levels of tumor markers began to increase in January 2014. PET scan, CT scan, and other examinations showed a possible carcinoma in the pancreas head. The patient underwent total remnant pancreatectomy. The tumor was located in the uncinate process of the pancreas with infiltration of the portal vein. The pathological diagnosis of the tumor was moderately differentiated adenocarcinoma. The ductal lumen structure was relatively maintained and the cytoplasm was comparatively clear. Since its pathological findings were similar to those observed in 2009, the tumor appeared to be a recurrence of the tumor resected at that time. The patient had received postoperative chemotherapy and remains alive in 2019 without recurrence. While there is evidence that surgical resection for the recurrence of other cancers such as colon cancer may improve patient survival, it remains unclear if surgical resection of recurrence in the remnant pancreas after pancreatectomy of pancreatic cancer is feasible. We report a case with long survival after surgical resection of a pancreatic carcinoma recurrence in the remnant pancreas.

Background: The optimal treatment for isolated local recurrence (ILR) of pancreatic adenocarcinoma (PDAC) after surgical resection remains unclear. This study aimed to evaluate the safety and efficacy of proton radiotherapy (PRT) for ILR of PDAC after surgery., Methods: The medical records of patients with ILR of PDAC after surgery who underwent proton beam therapy between 2011 and 2015 at Hyogo Ion Beam Medical Center were retrospectively studied., Results: The study analyzed 30 patients (14 women and 16 men) with a median age of 65 years (range 38-81 years) who had initially undergone pancreatoduodenectomy (n = 23) or distal pancreatectomy (n = 7) for their primary tumors. Upon ILR, PRT was administered with a median total cumulative dose of 67.5 gray equivalent (GyE) (range 50-67.5 GyE) using 19 to 25 fractions. For 25 patients, concurrent chemotherapy was administered using gemcitabine (n = 18) or S-1 (n = 7). Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months (range 2.1-50.4 months), 23 patients had experienced tumor progression and 10 had died. Nine patients (30%) experienced local tumor progression. The median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months, respectively. Pre-PRT serum levels of cancer antigen 19-9 higher than 100 U/mL and duke pancreatic monoclonal antigen type 2 higher than 150 U/mL were significantly associated with shorter progression-free survival rates., Conclusions: Proton radiotherapy for ILR of PDAC after surgery is well tolerated and produces good locoregional control and should be considered for eligible patients.

Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem‑R). To elucidate the mechanism of Gem‑R, two Gem‑R PaCa cell lines were established from AsPC‑1 and MIA PaCa‑2 cells. It was demonstrated that expression of interleukin‑8 (IL‑8) mRNA was significantly upregulated in Gem‑R PaCa cells by cDNA microarray and RT‑qPCR analyses. Increased IL‑8 secretion by Gem‑R cells was confirmed by cytokine array and enzyme‑linked immunosorbent assay. Moreover, we found that co‑culture with Gem‑R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti‑CXCR2 (main receptor for IL‑8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL‑8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem‑R increased IL‑8 production and consequently increased tumor angiogenesis, the IL‑8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem‑R.

BACKGROUND Mucinous cystic neoplasm (MCN) of the pancreas is a rare mucin-producing cystic neoplasm that has a characteristic histological feature referred to as ovarian-type stroma (OS) underlying the epithelium. Pancreatic ductal carcinoma arises from MCN as a precursor lesion, but data on progression pathways are limited. CASE REPORT A 40-year-old female was referred to our hospital for further investigation of a pancreatic cyst. Further examination showed a 7.0 cm multilocular cyst in the pancreatic tail and a solid mass in the thick septum of the cystic tumor. Distal pancreatectomy and splenectomy were performed. Histological examination revealed a moderately differentiated invasive ductal carcinoma (IDC) with a diameter of 0.5 cm in the thick septum of the cystic lesion and a cyst wall composed of epithelium with low-grade to severe dysplasia. The epithelium covered an OS. Pathological diagnosis was IDC arising in MCN of the pancreas. Immunohistochemical examination showed that MUC1 expression was negative in MCN but positive in IDC. KRAS mutation was observed in both MCN and IDC regions. CONCLUSIONS We present a rare case of moderately differentiated pancreatic IDC arising in MCN. To elucidate the underlying progression pathway, we explored the correlation between KRAS mutation and MUC expression as a clinicopathological parameter.

Intensity-modulated radiotherapy (IMRT) is now regarded as an important treatment option for patients with locally advanced pancreatic cancer (LAPC). To reduce the underlying tumor motions and dosimetric errors during IMRT as well as the burden of respiratory management for patients, we started to apply a new treatment platform of the dynamic tumor dynamic tumor-tracking intensity-modulated radiotherapy (DTT-IMRT) using the gimbaled linac, which can swing IMRT toward the real-time tumor position under patients' voluntary breathing. Between June 2013 and March 2015, ten patients were treated, and the tumor-tracking accuracy and the practical benefits were evaluated. The mean PTV size in DTT-IMRT was 18% smaller than a conventional ITV-based PTV. The root-mean-squared errors between the predicted and the detected tumor positions were 1.3, 1.2, and 1.5 mm in left-right, anterior-posterior, and cranio-caudal directions, respectively. The mean in-room time was 24.5 min. This high-accuracy of tumor-tracking with reasonable treatment time are promising and beneficial to patients with LAPC.

Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor-κB (NF-κB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF-κB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF-κB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC-3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC-3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki-67 expression, CD31-positive microvessel density, NF-κB p65 expression, and VEGF and IL-8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF-κB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: The purpose of this study was to evaluate the usefulness of respiratory-gated positron emission tomography (4D-PET) in pancreatic cancer radiotherapy treatment planning (RTTP)., Materials and Methods: Fourteen patients with 18F-fluorodeoxyglucose (FDG)-avid pancreatic tumours were evaluated between December 2013 and March 2015. Two sets of volumes were contoured for the pancreatic tumour of each patient. The biological target volume in three-dimensional RTTP (BTV3D) was contoured using conventional respiratory un-gated PET. The BTV3D was then expanded using population-based margins to generate a series of internal target volume 3D (ITV3D) values. The ITV 4D (ITV4D) was contoured using 4D-PET. Each of the five phases of 4D-PET was used for 4D contouring, and the ITV4D was constructed by summing the volumes defined on the five individual 4D-PET images. The relative volumes and normalized volumetric overlap were computed between ITV3D and ITV4D., Results: On average, the FDG-avid tumour volumes were 1.6 (range: 0.8-2.3) fold greater in the ITV4D than in the BTV3D. On average, the ITV3D values were 2.0 (range: 1.1-3.4) fold larger than the corresponding ITV4D values., Conclusion: The ITV generated from 4D-PET can be used to improve the accuracy or reduce normal tissue irradiation compared with conventional un-gated PET-based ITV., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The CXCL12-CXCR4 signaling axis in malignant tumor biology has increased in importance, and these peptides are implicated in tumor growth, invasion and metastasis. The aim of our study was to examine the important role of the axis in pancreatic cancer (PaCa) cells' relationship with stromal cells in gemcitabine-resistant (GEM-R) tumors and to confirm the effectiveness of CXCR4 antagonists for the treatment of GEM-R PaCa cells., Methods: We established two GEM-R PaCa cell lines using MIA PaCa-2 and AsPC-1 cells. The expression of CXCR4 mRNA in PaCa cells and the expression of CXCL12 mRNA in fibroblasts were examined by reverse transcription polymerase chain reaction (RT-PCR). The expression of CXCR4 protein in PaCa cells was examined by immunosorbent assay (ELISA) and immunocytochemistry. Using Matrigel invasion assays and animal studies, we then examined the effects of two CXCR4 antagonists, AMD11070 and KRH3955, on the invasiveness and tumorigenicity of GEM-R PaCa cells stimulated by CXCL12., Results: We found that the expression of CXCR4 in GEM-R PaCa cells was significantly enhanced by GEM but not in normal GEM-sensitive (GEM-S) PaCa cells. In RT-PCR and ELISA assays, the production and secretion of CXCL12 from fibroblasts was significantly enhanced by co-culturing with GEM-R PaCa cells treated with GEM. In Matrigel invasion assays, the invasiveness of GEM-R PaCa cells treated with GEM was significantly activated by fibroblast-derived CXCL12 and was significantly inhibited by CXCR4 antagonists, AMD11070 and KRH3955. In vivo, the tumorigenicity of GEM-R PaCa cells was activated by GEM, and it was significantly inhibited by the addition with CXCR4 antagonists., Conclusions: Our findings demonstrate that the CXCL12-CXCR4 signaling axis plays an important role in PaCa cells' resistance to GEM. CXCR4 expression was significantly enhanced by the exposure to GEM in GEM-R PaCa cells but not in GEM-S PaCa cells. Furthermore, CXCR4 antagonists can inhibit the growth and invasion of GEM-R PaCa cells. These agents may be useful as second-line chemotherapy for GEM-R PaCa in the future.

Background and Purpose: To evaluate the treatment outcomes of radiotherapy and prognostic factors for recurrent pancreatic cancer., Patients and Methods: The study comprised 30 patients who developed a locoregional recurrence of primarily resected pancreatic cancer and received radiotherapy between 2000 and 2013 with a median dose of 54 Gy (range, 39-60 Gy). Concurrent chemotherapy included gemcitabine for 18 patients and S-1 for seven patients. The treatment outcomes and prognostic factors were retrospectively analyzed., Results: The median follow-up after radiotherapy was 14.6 months. The 1-year overall survival, local control, and progression-free survival rates were 69%, 67%, and 32%, respectively. The median overall survival and progression-free survival rates were 15.9 and 6.9 months, respectively. Tumor marker reduction and ≥ 50% reduction were observed in 18 and two patients, respectively. Of the seven patients who exhibited pain symptoms, four and two patients were partly and completely relieved, respectively. Late grade 3 ileus and gastroduodenal bleeding were observed in one patient each. Among the clinicopathological factors evaluated, only a disease-free interval of greater than 18.9 months exhibited a significant association with improved overall survival (p = 0.017)., Conclusions: Radiotherapy for isolated locally recurrent pancreatic cancer resulted in encouraging local control, overall survival, and palliative effects with mild toxicity, particularly in patients with a prolonged disease-free interval. This treatment strategy should be prospectively evaluated.

Background: Hypoxia is an important condition to promote angiogenesis that is essential to tumor progression, including pancreatic ductal adenocarcinoma (PDAC). We evaluated whether the immunohistochemistry for hypoxia inducible factor-1α (HIF-1α) was correlated with hepatic metastases in PDAC., Methods: We examined the expression of HIF-1α, vascular endothelial growth factor-A (VEGF-A), thymidine phosphorylase (TP) and basic fibroblast growth factor (bFGF) in a total of 100 paraffin-embedded PDAC primary tumors using immunohistochemical staining, and assessed their clinicopathological correlations. We determined microvessel count (MVC) and apoptotic index (AI), and assessed their correlations with hepatic metastases. Student's t-test, the Mann-Whitney U-test, and Spearman correlation coefficients were used to validate the model, and regression analysis was used to test the model., Results: Hypoxia inducible factor-1α expression induced the expression of multiple angiogenic factors, leading to a higher MVC and a lower AI. HIF-1α expression (P = 0.0087) and angiogenic factors (P = 0.0079) were significantly associated with not only the microvessel status (P = 0.022) but also the high incidence of hepatic metastasis (P = 0.02), resulting in the worse survival of PDAC patients (P < 0.05)., Conclusions: Hypoxia inducible factor-1α plays a pivotal role in hepatic metastasis through its association with the expression of angiogenic factors in PDAC patients. These results may contribute future therapeutic strategies to prevent pancreatic cancer metastasis., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be an intriguing therapeutic strategy in PaCa., (© 2013.)

In patients with pancreatic cancer, intensity-modulated radiotherapy (IMRT) under breath holding facilitates concentration of the radiation dose in the tumor, while sparing the neighboring organs at risk and minimizing interplay effects between movement of the multileaf collimator and motion of the internal structures. Although the breath-holding technique provides high interportal reproducibility of target position, dosimetric errors caused by interportal breath-holding positional error have not been reported. Here, we investigated the effects of interportal breath-holding positional errors on IMRT dose distribution by incorporating interportal positional error into the original treatment plan, using random numbers in ten patients treated for pancreatic cancer. We also developed a treatment planning technique that shortens breath-holding time without increasing dosimetric quality assurance workload. The key feature of our proposed method is performance of dose calculation using the same optimized fluence map as the original plan, after dose per fraction in the original plan was cut in half and the number of fractions was doubled. Results confirmed that interportal error had a negligible effect on dose distribution over multiple fractions. Variations in the homogeneity index and the dose delivered to 98%, 2%, and 50% of the volume for the planning target volume, and the dose delivered to 1 cc of the volume for the duodenum and stomach were ±1%, on average, in comparison with the original plan. The new treatment planning method decreased breath-holding time by 33%, and differences in dose-volume metrics between the original and the new treatment plans were within ± 1%. An additional advantage of our proposed method is that interportal errors can be better averaged out; thus, dose distribution in the proposed method may be closer to the planned dose distribution than with the original plans.

Purpose: This study aims to evaluate the interfractional dose variations in the organs-at-risk (OARs) during pancreatic breathhold intensity-modulated radiotherapy (IMRT) and to assess the impacts of "planning organs-at-risk volume" (POV) structures generated by isotropically expanding the dose-limiting OARs, based on the comparison of the interfractional doses to the OARs between IMRT plans and conventional three-dimensional-conformal radiotherapy (3D-CRT) plans., Methods: Thirty repeat CT scans were acquired from ten consecutive patients who were receiving chemoradiotherapy for pancreatic cancer. Six IMRT plans for each patient with two levels of prescription (45 and 51 Gy in 15 fractions) and 3 POV margin sizes (5, 7, and 10 mm) were generated based on the initial CT scan under predetermined constraints. Two 3D-CRT plans (39 and 42 Gy in 15 fractions) were simultaneously generated. The dose distribution of all of the treatment plans was recalculated with the repeat CT scans. The interfractional dose variations in the three OARs (stomach, duodenum, and small intestine) were evaluated, and the absolute volumes ≥39 Gy (V39Gy) of the OARs in the IMRT plans were compared to those in the 3D-CRT plans. Regression analyses were performed to assess the relative impact of the factors of interest on the interfractional dose variations of the OARs., Results: Substantial dose excesses to the three OARs were observed at all of the prescription dose levels and the POV margin sizes on the repeat CT scans. The safety threshold based on the mean stomach V39Gy on the recalculated 39 Gy-3D-CRT plans was 1.9 ml. Statistically significant and marginally insignificant mean V39Gy values above the safety thresholds were observed in the stomach in the 51 Gy-IMRT plans (2.6 and 2.1 ml with the 5- and 7-mm PRV margins, respectively (P = 0.015 and 0.085)). Only in the case of the 10-mm POV margin did the metric fall below the safety threshold to 1.5 ml (P = 0.634). The duodenum and the small intestine did not violate the safety thresholds (1.4 and 3.8 ml, respectively). From the multiple regression analyses, only the margin size (P < 0.001) and the POV V39Gy (P < 0.001) were significantly associated with the distribution of recalculated V39Gy for the stomach. Multiple factors, including the margin size (P = 0.020) and the POV V39Gy (P < 0.001) were associated with the recalculated V39Gy for the duodenum. However, none of the POV parameters for the small intestine were associated with the recalculated V39Gy., Conclusions: Considerable interfractional dose variation was observed in three critical OARs. At the escalated prescription dose of breathhold IMRT, the dose variations could exceed the dose variations using 3D-CRT at the safe prescription dose level, indicating that a dose-escalation strategy based solely on the initial advantageous dose distribution in a breathhold IMRT can be problematic. Given the current limitations for predicting or coping with variation throughout the treatment course, the use of POV should be considered for safely delivering escalated doses to patients with pancreatic cancer.

Purpose: To identify the dosimetric parameters associated with gastrointestinal (GI) toxicity in patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based chemoradiotherapy., Methods and Materials: The data from 40 patients were analyzed retrospectively. Chemoradiotherapy consisted of conventional fractionated three-dimensional radiotherapy and weekly gemcitabine. Treatment-related acute GI toxicity and upper GI bleeding (UGB) were graded according to the Common Toxicity Criteria Adverse Events, version 4.0. The dosimetric parameters (mean dose, maximal absolute dose which covers 2 cm(3) of the organ, and absolute volume receiving 10-50 Gy [V(10-50)]) of the stomach, duodenum, small intestine, and a composite structure of the stomach and duodenum (StoDuo) were obtained. The planning target volume was also obtained. Univariate analyses were performed to identify the predictive factors for the risk of grade 2 or greater acute GI toxicity and grade 3 or greater UGB, respectively., Results: The median follow-up period was 15.7 months (range, 4-37). The actual incidence of acute GI toxicity was 33%. The estimated incidence of UGB at 1 year was 20%. Regarding acute GI toxicity, a V(50) of ≥ 16 cm(3) of the stomach was the best predictor, and the actual incidence in patients with V(50) <16 cm(3) of the stomach vs. those with V(50) of ≥ 16 cm(3) was 9% vs. 61%, respectively (p = 0.001). Regarding UGB, V(50) of ≥ 33 cm(3) of the StoDuo was the best predictor, and the estimated incidence at 1 year in patients with V(50) <33 cm(3) of the StoDuo vs. those with V(50) ≥ 33 cm(3) was 0% vs. 44%, respectively (p = 0.002). The dosimetric parameters correlated highly with one another., Conclusion: The irradiated absolute volume of the stomach and duodenum are important for the risk of acute GI toxicity and UGB. These results could be helpful in escalating the radiation doses using novel techniques, such as intensity-modulated radiotherapy, for the treatment of pancreatic cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate the interfractional dose variations for intensity-modulated radiotherapy (RT) combined with breath-hold (BH) at end-exhalation (EE) for pancreatic cancer., Methods and Materials: A total of 10 consecutive patients with pancreatic cancer were enrolled. Each patient was fixed in the supine position on an individualized vacuum pillow with both arms raised. Computed tomography (CT) scans were performed before RT, and three additional scans were performed during the course of chemoradiotherapy using a conventional RT technique. The CT data were acquired under EE-BH conditions (BH-CT) using a visual feedback technique. The intensity-modulated RT plan, which used five 15-MV coplanar ports, was designed on the initial BH-CT set with a prescription dose of 39 Gy at 2.6 Gy/fraction. After rigid image registration between the initial and subsequent BH-CT scans, the dose distributions were recalculated on the subsequent BH-CT images under the same conditions as in planning. Changes in the dose-volume metrics of the gross tumor volume (GTV), clinical target volume (CTV = GTV + 5 mm), stomach, and duodenum were evaluated., Results: For the GTV and clinical target volume (CTV), the 95th percentile of the interfractional variations in the maximal dose, mean dose, dose covering 95% volume of the region of structure, and percentage of the volume covered by the 90% isodose line were within ±3%. Although the volume covered by the 39 Gy isodose line for the stomach and duodenum did not exceed 0.1 mL at planning, the volume covered by the 39 Gy isodose line for these structures was up to 11.4 cm(3) and 1.8 cm(3), respectively., Conclusions: Despite variations in the gastrointestinal state and abdominal wall position at EE, the GTV and CTV were mostly ensured at the planned dose, with the exception of 1 patient. Compared with the duodenum, large variations in the stomach volume receiving high-dose radiation were observed, which might be beyond the negligible range in achieving dose escalation with intensity-modulated RT combined with BH at EE., (Copyright © 2012 Elsevier Inc. All rights reserved.)