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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.

BACKGROUND Many clinicians and surgeons are unfamiliar with the sclerosing angiomatoid nodular transformation (SANT), which is gaining recognition as a benign splenic tumor. We challenge that SANT is rare and whether surgical intervention could be avoided through critical imaging review. AIM To evaluate the incidence of SANT among splenic tumors and the decision-making process of SANT management. METHODS Twenty hospitalized patients who underwent splenectomy in 2018 and 2019 in a tertiary university hospital were retrospectively reviewed, and their data on imaging, diagnosis, surgical indications, and courses were recorded. All pathology results were confirmed by pathologist. Discriminative features differentiating SANT from other non-SANT splenic tumors were descriptively analyzed in this case series. RESULTS Fourteen out of 20 patients who underwent splenectomy had splenic tumors, including 3 SANTs (21% splenic tumors), 6 non-SANT benign lesions (43%), 2 metastatic tumors, and 3 lymphomas. Hypointensity on T2-weighted magnetic resonance imaging (MRI), spoke wheel enhancing pattern in contrasted computed tomography or MRI, and cold spot (low fluorodeoxyglucose uptake) in positron emission tomography (PET) scan helped establish the diagnosis of SANT. Lymphoma, presenting with a hot spot on the PET scan were differentiated from SANT. Surgical indications were reformatted for splenic tumors. Splenectomy need not be performed in patients with typical imaging features of SANT. CONCLUSION SANT is not a rare disease entity in clinical practice. Splenectomy should not be routinely indicated as the only management option for SANT with typical imaging features.

Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)–islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN–islet complex. Cadaveric donor pancreases (26–65 years old, n = 10) were fixed and sectioned (350 μm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion–islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion–islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct–islet cell contacts, forming a cluster. The duct–islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. We identify local islet remodelling associated with PanIN–islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN–islet complex is derived from tissue repair after a local injury.

Background An individual’s genetics play a role in how RNA transcripts are generated from DNA and consequently in their translation into protein. Transcriptional and translational profiling of patients furnishes the information that a specific marker is present; however, it fails to provide evidence whether the marker correlates with response to a therapeutic agent. A comparative analysis of the frequency of genetic variants, such as single nucleotide polymorphisms (SNPs), in diseased and general populations can identify pathogenic variants in individual patients. This is in part because SNPs have considerable effects on protein function and gene expression when they occur in coding regions and regulatory sequences, respectively. Therefore, a tool that can help users to obtain the allele frequency for a corresponding transcript is the need of the day. Several annotation tools such as SNPnexus and VariED are publicly available; however, none of them can use transcript IDs as input and provide the corresponding genomic positions of variants. Results In this study, we developed an R package, called transcript annotation tool (TransAT), that provides (i) SNP ID and genomic position for a user-provided transcript ID from patients, and (ii) allele frequencies for the SNPs from publicly available global populations. All data elements are extracted, collected, and displayed in an easily downloadable format in two simple command lines. TransAT is available on Windows/Linux/MacOS and is operative for R version 4.0.4 or later. It is available at https://github.com/ShihChingYu/TransAT and can be downloaded and installed using devtools::install_github("ShihChingYu/TransAT", force=T) on the R execution page. Thereafter, all functions can be executed by loading the package into R with library(TransAT). Conclusions TransAT is a novel tool that seamlessly provides genetic annotations for queried transcripts. Such easily obtainable information would be greatly advantageous for physicians, assisting them to make individualized decisions about specific drug treatments. Moreover, allele frequencies from user-chosen global ethnic populations will highlight the importance of ethnicity and its effect on patient pathogenicity.

Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare with low-grade malignancy and unclarified clinicopathological features. This study aimed to examine their characteristics and re-evaluate current treatments.Databases from three sources were screened for patients with SPNs. We compared the perioperative variables, clinical data, overall survival (OS), and prognostic factors for recurrence among the three corresponding cohorts.We identified 286 patients diagnosed with SPNs between 1988 and 2020. Patients were mostly women (81%; median age: 38 years), and peak incidence was observed in women of 20-29 years of age. SPNs had a peak incidence in Asian men at 50-59 years of age (p = 0.002) and a delayed peak incidence in Asian women at 30-39 years of age (p 0.001). Treatment strategies differed significantly across the institutions and included variations in the number of harvested lymph nodes and rates of vascular resection. Lymph node positivity was the only predictor of postoperative recurrence (odds ratio, 2.2; 95% confidence interval, 1.38-2.99; p = 0.007). Higher rates of lymphovascular invasion (p = 0.02), perineural invasion (p 0.001), and R1 margin involvement (p 0.001), as seen in one institution, did not result in poorer long-term survival in terms of the overall (p = 0.43), SPN-specific (p = 0.69), and recurrence-free survivals (p = 0.067).In contrast to previous findings that SPNs are prevalent in young women, a racial predilection for middle-aged Asian men and a delayed female peak incidence were noted. Parenchyma-preserving pancreatectomy may be an acceptable treatment. Non-radical surgery may be appropriate in patients with multiple comorbidities.

We sought to investigate whether preoperative dual-phase 2-[18F]FDG PET-CT identify predictors for poor survival in patients with ampullary carcinoma receiving pancreaticoduodenectomy. The preoperative PET-CT images of patients with resected ampullary carcinoma from June 2007 to July 2017 were analyzed. Survival curves were analyzed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard model was used to identify potential prognostic factors associated with disease-free survival (DFS) and overall survival (OS). Fifty-four subjects (26 men, 28 women) were enrolled with a median tumor size of 20 mm. All patients were followed for a median period of 36.9 months with 3- and 5-year DFS of 50.3% and 44.2%, and OS of 77.0% and 68.2%, respectively. Parameters associated with DFS in multivariate analysis were lymphovascular invasion (hazard ratio [HR]: 9.45, p < 0.001), involved margin in pathology (HR: 7.67, p < 0.001), and tumor retention index (RI) from the dual-phase PET (HR: 2.41, p = 0.03), whereas involved margin (HR: 13.14, p < 0.001), post-recurrence chemotherapy (HR: 0.10, p < 0.001), and metabolic tumor volume (MTV) (HR: 4.62, p = 0.009) emerged as independent prognostic factors for OS. Preoperative 2-[18F]FDG PET-CT offered independent prognostic biomarkers in patients with ampullary carcinoma receiving standard surgical resection. • 2-[ 18 F]FDG PET-CT offers good survival prediction before operation in primary malignant neoplasms at ampulla of Vater. • Dual-phase PET scan with bowel distention can better delineate Ampulla of Vater and characterize tumor physiology. • Preoperative risk stratification might aid in better treatment planning.

Supplemental Materials Supplemental Figures Suppl. Fig. S1 (related to Fig. 1). Multimodal imaging of islet aggregation with duct-islet cell cluster in PDAC surgical margin. (A-I) and (J-R) are two examples of the coexistence of islet aggregation, PanIN, acinar atrophy, and fibrosis in the surgical margin distal to PDAC (case No. 1628870 and 4442070). In G, H, P, Q, varying amounts of mucin were observed in the duct lesions. In I and R, the high-resolution images identify the duct (CK7+) -islet (insulin+ or glucagon+) cell cluster. Green, CK7; blue, insulin; magenta, glucagon; white, nuclei. Suppl. Fig. S2 (related to Fig. 2). Detection and confirmation of duct lesion in human donor pancreas (gallery display). Suppl. Fig. S3-1 (related to Fig. 4S). Detection and characterization of an endocrine-exocrine lesion mixture in human donor pancreas (CgA+, PGP9.5+, glucagon+ microadenoma with CK7+ epithelium in a stroma-rich environment). (A-E) Detection of glucagon+ microadenoma. A-C show microadenoma (arrow) in vibratome section. Fluorescence tissue map (D) identifies the intra-microadenoma ducts (CK7+, green; enlarged in inset i and ii, asterisk). Magenta, glucagon; blue, insulin; white, nuclei. PGP9.5 staining (E, cyan) confirms the islet/neuroendocrine lesion. Red, CD31. (F-M) Confirmation of microadenoma-duct lesion mixture with multiplex CgA, H&E, CD45, and Ki-67 signals. The endocrine-exocrine lesion mixture is associated with stromal accumulation (F-I; asterisk, enlarged area), leukocyte infiltration (J, K; asterisk/arrow, enlarged area), and prominent cell proliferation (L, M; box, enlarged area; blue arrows, Ki-67+ nuclei). An adjacent PanIN (within 2 mm) is presented in the next page. Black arrows in F, G, J, L indicate the same microenvironment. Suppl. Fig. S3-2 (related to Fig. 5). Detection of a PanIN lesion adjacent to the microadenoma in panel A-M (Suppl. Fig. S3-1). (N-P) Microadenoma and its microenvironment visualized via stereomicroscopy. N-P and A-M examine the same microenvironment (arrow). Vibratome section P is further processed for H&E histology to confirm the PanIN lesion. (Q, R) Gross view and enlarged H&E images of PanIN. The gold-standard H&E histology (cyan arrows from P to Q to R, same environment) confirms the low-grade PanIN lesion and peri-lesional stroma. Box in Q is magnified in R to specify the lesion. Suppl. Fig. S4 (related to Fig. 4O-R). False positive result in fluorescence imaging of islet cell microadenoma in human pancreas. (A-C) Gross view and side-by-side display of fluorescence and transmitted light signals of microadenoma. The three images were derived from an optically cleared microadenoma (refractive index: 1.52). A: microadenoma alongside pancreatic lobules (red, blood vessels, CD31; green, lymphatic vessels, D2-40; white, nuclei, DAPI). B: enlarged fluorescence image of vasculature (blood and lymphatic vessels). C: overlay of transmitted light and nuclear signals. Adipocytes and blood clots (black spots) are prominently seen in C via in-depth transmitted light signals. Number 1-6 indicate the adipocytes (#1-2) and blood clots (#3-6) shown in both B and C. Alphabet a-f indicate the adipocytes and blood clots appear only in C. CD31 signals of B is presented in D. B-D examine the same microenvironment. (D, E) False positive result revealed by analysis of CD31 fluorescence signals of microadenoma. Relative signals intensity along the central line of D (0-2,000 pixels) is presented in E. Both CD31-labeled blood vessels and the blood clot-induced autofluorescence create local increases in the signal intensity (E). Number 4 in E indicates the autofluorescence caused by the blood clot #4 in panel B-D. =============================================================================================== Supplemental Tables Suppl. Table S1(Related to Materials and Methods).Clinical data of pancreatic ductal adenocarcinoma cases. Suppl. Table S2(Related to Materials and Methods).Pancreas organ donor information and lesion summary. Suppl. Table S3(Related to Materials and Methods).Summary of primary antibodies used in illustrations. Suppl. Table S4(Related to Materials and Methods).Summary of color codes presented in illustrations. =============================================================================================== Supplemental Video Suppl. Video S1 (related to Fig. 3L-N). Tile scan and in-depth recording of PanIN microenvironment in human pancreas. This video shows a survey of PanIN microenvironment to identify the associated exocrine-endocrine tissue remodeling. Duct lesion and islet a- and b-cells form a complex in the peri-lobular space. Green, CK7; magenta, glucagon; blue, insulin; white, nuclei. Overlay of fluorescence and transmitted light (gray) signals is used to identify the boundaries of pancreatic lobules and CK7+ epithelium.

To analyze the effect of preoperative body composition on survival in patients with pancreatic cancer following pancreaticoduodenectomy (PD). Between October 2005 and August 2018, 116 patients (68 men, 48 women, mean age 66.2 ± 11.9 years) diagnosed with pancreatic adenocarcinoma following PD were retrospectively enrolled. The preoperative CT on vertebral level L3 was assessed for total abdominal muscle area (TAMA), visceral adipose tissue area (VAT), subcutaneous adipose tissue area (SAT), and mean skeletal muscle attenuation (SMD). The clinical data and pathological findings of tumors were collected. The impact of these factors on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan–Meier method and by univariable and multivariable Cox proportional hazards models. The 3-year DFS and OS rates were 8% and 25%, respectively. Of 116 patients, 20 (17.2%), 3 (2.6%), and 46 (39.7%) patients were classified as having sarcopenia, sarcopenic obesity, and myosteatosis, respectively. The VAT–TAMA ratio (1.2 ± 0.7 vs 0.9 ± 0.5, p = 0.01) and the visceral to subcutaneous adipose tissue area ratio (1.3 ± 0.7 vs 0.9 ± 0.5, p = 0.04) were higher in sarcopenic patients than in the nonsarcopenic group. Preoperative sarcopenia and sarcopenic obesity were associated with shorter OS (p = 0.012 and p = 0.041, respectively), but not shorter DFS. Myosteatosis was neither associated with DFS nor OS. On multivariable analysis, sarcopenia was the only significant prognostic factor for OS (p = 0.039). Preoperative sarcopenia assessed by CT is a poor prognostic factor for OS in pancreatic cancer patients after PD. • Sarcopenia and sarcopenic obesity can be evaluated by abdominal CT on L3 level. • Patients with diabetes mellitus (DM) had lower sex-standardized subcutaneous adipose tissue area index and skeletal muscle density and higher visceral to subcutaneous adipose tissue area ratio than did those without DM. • Preoperative sarcopenia, sarcopenic obesity, and new-onset diabetes mellitus may predict poor overall survival in pancreatic cancer patients following pancreaticoduodenectomy.

Background The centralization of pancreatoduodenectomy (PD) has been shown to improve patient outcomes. The scheduling of two PDs in one day is one option to shorten the waiting time for patients referred to high volume centers. The effect on the surgical team or patient outcomes of such an approach have not previously been explored. This study aimed to investigate the effect of scheduling two PDs in one day on the surgeon's workload and patient outcomes. Methods A retrospective review of patients undergoing PD by a single surgeon between 2007 and 2018 was performed. Patients were allocated into: first PD (FIRSTPD group) or second PD (SECONDPD group) according to the position on the surgical operating list. The intraoperative, postoperative outcomes, and workload (the Surgery Task Load Index; SURG-TLX) were assessed between two groups. Results A total of 967 (91%) and 101 (9%) patients were included in the FIRSTPD and SECONDPD group, respectively. There were no differences in the duration of surgery (coefficient = −9.65; 95% confidence interval: −29.26 to 9.94; P = 0.334), incidence of major complications (odds ratio = 1.08; 95% confidence interval: 0.67–1.73; P = 0.739), or 90-day mortality (odds ratio = 1.03; 95% confidence interval: 0.12–8.53; P = 0.978) for those patients in the SECONDPD group as compared to the FIRSTPD group. The mean scores of two (physical and temporal demand) of the six SURG-TLX subscales of surgical workload were recorded as significantly higher by surgeons following two PD's as compared to one PD. Conclusions Although scheduling a second PD in one day shows no association with adverse patient outcomes, there is an increase in the physical and temporal subscales of surgical workload and consideration should be given to how this could be minimized.

Background: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. Methods: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013–2015 were reviewed. Results: The median number of prior chemotherapy regimens was two (range, 1–6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51–72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6–5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9–3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. Conclusion: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy. Keywords: Chemotherapy, Nab-paclitaxel, Pancreatic cancer, Pretreated, Prognosis

Supplemental Materials Supplemental Figures Suppl. Fig. S1 (related to Fig. 1). Detection and confirmation of duct lesion in human donor pancreas (gallery display). Suppl. Fig. S2 (related to Fig. 3). False positive result in fluorescence imaging of pancreatic microadenoma. (A-C) Gross view and side-by-side display of fluorescence and transmitted light signals of microadenoma. The three images were derived from an optically cleared microadenoma (refractive index: 1.52). A: microadenoma alongside pancreatic lobules (red, blood vessels, CD31; green, lymphatic vessels, D2-40; white, nuclei, DAPI). B: enlarged fluorescence image of vasculature (blood and lymphatic vessels). C: overlay of transmitted light and nuclear signals. Adipocytes and blood clots (black spots) are prominently seen in C via in-depth transmitted light signals. Number 1-6 indicate the adipocytes (#1-2) and blood clots (#3-6) shown in both B and C. Alphabet a-f indicate the adipocytes and blood clots appear only in C. CD31 signals of B is presented in D. B-D examine the same microenvironment. (D, E) False positive result revealed by analysis of CD31 fluorescence signals of microadenoma. Relative signals intensity along the central line of D (0-2,000 pixels) is presented in E. Both CD31-labeled blood vessels and the blood clot-induced autofluorescence create local increases in the signal intensity (E). Number 4 in E indicates the autofluorescence caused by the blood clot #4 in panel B-D. Suppl. Fig. S3 (related to Fig. 4). Detection of PanIN adjacent to microadenoma. (A-C) Microadenoma and its microenvironment visualized via stereomicroscopy. A-C and Fig. 4 examine the same microenvironment (arrow). Vibratome section C is further processed for H&E histology to confirm the PanIN lesion. (D, E) Gross view and enlarged H&E images of PanIN. The gold-standard H&E histology (cyan arrows from C to D to E, same environment) confirms the low-grade PanIN lesion and peri-lesional stroma. Box in D is magnified in E to specify the lesion. =============================================================================================== Supplemental Tables Suppl. Table S1(Related to Materials and Methods).Summary of primary antibodies used in illustrations. Suppl. Table S2(Related to Materials and Methods).Summary of color codes presented in illustrations. =============================================================================================== Supplemental Video Suppl. Video S1 (related to Fig. 2). Tile scan and in-depth recording of PanIN microenvironment in human pancreas. This video shows a survey of PanIN microenvironment to identify the associated exocrine-endocrine tissue remodeling. Duct lesion and islet a- and b-cells form a complex in the peri-lobular space. Green, CK7; magenta, glucagon; blue, insulin; white, nuclei. Overlay of fluorescence and transmitted light (gray) signals is used to identify the boundaries of pancreatic lobules and CK7+ epithelium.

Tumor cells with diverse phenotypes and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. In the present study, we observe enrichment of myofibroblasts in a juxta-tumoral position with tumor cells undergoing epithelial-mesenchymal transition (EMT) that facilitates invasion and correlates with a worse clinical prognosis in PDAC patients. Direct cell-cell contacts forming heterocellular aggregates between fibroblasts and tumor cells are detected in primary pancreatic tumors and circulating tumor microemboli (CTM). Mechanistically, ATP1A1 overexpressed in tumor cells binds to and reorganizes ATP1A1 of fibroblasts that induces calcium oscillations, NF-κB activation, and activin A secretion. Silencing ATP1A1 expression or neutralizing activin A secretion suppress tumor invasion and colonization. Taken together, these results elucidate the direct interplay between tumor cells and bound fibroblasts in PDAC progression, thereby providing potential therapeutic opportunities for inhibiting metastasis by interfering with these cell-cell interactions.

BackgroundPancreatic head ductal adenocarcinoma (PHDAC) patients with the same tumor-node-metastasis (TNM) stage may share different outcomes after pancreaticoduodenectomy (PD). Therefore, a novel method to identify patients with poor prognosis after PD is urgently needed. We aimed to develop a nomogram to estimate survival in PHDAC after PD.MethodsTo estimate survival after PD, a nomogram was developed using the Tongji Pancreatic cancer cohort comprising 355 PHDAC patients who underwent PD. The nomogram was validated under the same conditions in another cohort (N = 161) from the National Taiwan University Hospital. Prognostic factors were assessed using LASSO and multivariate Cox regression models. The nomogram was internally validated using bootstrap resampling and then externally validated. Performance was assessed using concordance index (c-index) and calibration curve. Clinical utility was evaluated using decision curve analysis (DCA), X-tile program, and Kaplan–Meier curve in both training and validation cohorts.ResultsOverall, the median follow-up duration was 32.17 months, with 199 deaths (64.82%) in the training cohort. Variables included in the nomogram were age, preoperative CA 19-9 levels, adjuvant chemotherapy, Tongji classification, T stage, N stage, and differentiation degree. Harrell’s c-indices in the internal and external validation cohorts were 0.79 (95% confidence interval [CI], 0.76–0.82) and 0.83 (95% CI, 0.78–0.87), respectively, which were higher than those in other staging systems. DCA showed better clinical utility.ConclusionThe nomogram was better than TNM stage and Tongji classification in predicting PHDAC patients’ prognosis and may improve prognosis-based selection of patients who would benefit from PD.

Background We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). Method and materials We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. Results We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p Conclusion Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

Objective: To compare the metabolites of in vivo 1H- MRS in pancreatic cancer with normal pancreas, and correlate these metabolites with Positron Emission Tomography (PET) metabolic activity, clinical stages, and survival outcomes. Methods: The prospective study included 58 patients (mean age 62.7 ± 12.1 years, range 34–81 years; 36 men, 22 women) with pathological proof of pancreatic adenocarcinoma, and all of them received 18F-fluorodeoxyglucose (FDG) PET/MRI before treatment. The single-voxel MRS with a point-resolved selective spectroscopy sequence was used to measure metabolites (creatine, Glx (glutamine and glutamate), N-acetylaspartate (NAA), and lipid) of pancreatic cancer and adjacent normal parenchyma, respectively. FDG-PET parameters included SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Non-parametric tests were used to evaluate the differences of MRS metabolites between pancreatic cancer and those in normal pancreas, and their correlation with PET parameters and clinical stages. The correlation with progression-free survival (PFS) and overall survival (OS) was measured using the Kaplan–Meier and Cox proportional hazard models. Results: When compared with normal pancreas, the Glx, NAA, and lipid levels were significantly decreased in pancreatic cancer (all p < 0.05). Creatine, Glx, and lipid levels were all inversely correlated with both MTV (rho = −0.405~−0.454) and TLG (rho = −0.331~−0.441). For correlation with clinical stages, lower lipid levels were found in patients with T4 (vs. p = 0.038) and lower creatine levels were found in N1 (vs. N0, p = 0.019). Regarding survival outcomes, high TNM stage, low creatine, low Glx, and low lipid levels were associated with both poor PFS and OS (all p < 0.05). Additionally, creatine remained an independent factor for PFS and OS after adjusting for age, sex, tumor size, stages, and other metabolites levels. Conclusions: Decreased MRS metabolites in pancreatic cancer were associated with poor survival outcome, and may be used as prognostic image biomarkers for these patients.

Objectives To explore the associations among clinical characteristics, fatigue, diabetes mellitus (DM) self-care activities, and quality of life (QOL) in individuals with resectable pancreatic cancer and DM. Sample & setting 57 individuals with resectable pancreatic cancer and DM from an outpatient pancreatic surgical department in Taiwan were included in the final analysis. Methods & variables A cross-sectional, correlational design was used. QOL, fatigue, and DM self-care were measured by the European Organisation for Research and Treatment of Cancer QOL Questionnaire-Core 30, the Fatigue Symptom Inventory, and the Summary of Diabetes Self-Care Activities. Results Participants who had a shorter duration of DM and higher levels of fatigue (including intensity, duration, and interference) reported lower QOL scores. Participants who performed more DM self-care activities and physical activity per week had higher QOL scores. Fatigue, DM self-care activities, and DM duration were significant factors related to QOL. Implications for nursing Shorter DM duration, increased fatigue, and fewer DM self-care activities were determinants of worse QOL in individuals with resectable pancreatic cancer and DM.

Background Delayed postpancreatectomy hemorrhage (PPH) is a fatal complication caused by arterial erosion. This study reports a single-center experience of managing delayed PPH with different endovascular treatment approaches. Methods We reviewed the data of patients who had delayed PPH due to hepatic artery or gastroduodenal artery stump perforation and underwent endovascular treatment between 2003 and 2018. We categorized endovascular treatment approaches involving hepatic artery sacrifice, superselective pseudoaneurysm embolization with hepatic artery preservation, and covered stent placement. Technical success rates, hemorrhage recurrence rates, major and minor hepatic complication rates, and 30-day and 1-year mortality rates were assessed. Results A total of 18 patients were reviewed; 11 (61%), 4 (22%), and 3 (17%) delayed PPH cases were managed through hepatic artery sacrifice, superselective pseudoaneurysm embolization, and hepatic artery stenting, respectively. Multidetector computed tomography was performed in 14 (78%) patients. The technical success rate was 100%. The overall hemorrhage recurrence rate was 39%, with superselective pseudoaneurysm embolization having a 100% hemorrhage recurrence rate—much higher than that of hepatic artery sacrifice or stent graft placement. The overall major and minor hepatic complication rates were 56% and 83%, respectively. The overall 30-day and 1-year mortality rates were 11% and 25%, respectively. The 30-day and 1-year mortality rates and minor and major hepatic complication rates were similar in each group. Conclusion Hepatic artery sacrifice is more effective than superselective pseudoaneurysm embolization in the management of delayed PPH. Covered stent placement may be a reasonable alternative treatment to hepatic artery sacrifice.

Objectives To compare fatigue and quality of life (QOL) between individuals with pancreatogenic diabetes after total pancreatectomy (TP) and pancreaticoduodenectomy (PD). Sample & setting 50 individuals (14 after TP and 36 after PD) were recruited from a pancreatic surgical outpatient department. A final sample of 39 matched individuals (13 after TP and 26 after PD) were included in the final analysis. Methods & variables A comparative cross-sectional approach was used. Variables were fatigue and QOL. The Fatigue Symptom Inventory and European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 were used. Data went through propensity score one-to-two matching. Generalized estimating equation was used to compare fatigue and QOL. Results The groups showed no statistically significant difference in fatigue intensity and overall QOL. The TP group had significantly longer fatigue duration, perceived higher interference of functioning, lower physical function, and a higher level of insomnia. Implications for nursing Future studies with a larger sample and longitudinal design will help identify the trajectory of fatigue and QOL in individuals with pancreatogenic diabetes post-TP and PD.

Background The lymphatic system is involved in metastasis in pancreatic cancer progression. In cancer staging, lymphatic spread has been used to assess the invasiveness of tumor cells. However, from the endothelium's perspective, the analysis downplays the peri-lesional activities of lymphatic vessels. This unintended bias is largely due to the lack of 3-dimensional (3-D) tissue information to depict the lesion microstructure and vasculature in a global and integrated fashion. Methods We targeted the pancreas as the model organ to investigate lymphatic vessel remodeling in cancer lesion progression. Transparent pancreases were prepared by tissue clearing to facilitate deep-tissue, tile-scanning microscopy for 3-D lymphatic network imaging. Findings In human pancreatic ductal adenocarcinoma, we identify the close association between the pancreatic intraepithelial neoplasia (PanIN) lesions and the lymphatic network. In mouse models of PanIN (elastase-CreER;LSL-KrasG12D and elastase-CreER;LSL-KrasG12D;p53+/-), the 3-D image data reveal the peri-lesional lymphangiogenesis, endothelial invagination, formation of the bridge/valve-like luminal tubules, vasodilation, and luminal invasion. In the orthotopic mouse model of pancreatic cancer, we identify the localized, graft-induced lymphangiogenesis and the peri- and intra-tumoral lymphatic vessel invasion. Interpretation The integrated view of duct lesions and vascular remodeling suggests an active role, rather than a passive target, of lymphatic vessels in the metastasis of pancreatic cancer. Our 3-D image data provide insights into the pancreatic cancer microenvironment and establish the technical and morphological foundation for systematic detection and 3-D analysis of lymphatic vessel invasion. FUND: Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI).

Volume–outcome relationship has been demonstrated extensively for short-term outcomes for oncological surgery. However, its effect on long-term surgical outcomes or in one universal health care (UHC) system is unknown. This retrospective population-based study aims to validate the correlation between the increased hospital volume and better short- and long-term outcomes in patients who underwent total gastrectomy (TG) for gastric cancer. From the Taiwan National Health Insurance Research Database, we examined 7905 patients who underwent TG between 2000 and 2010. The surgical outcomes of this study were defined as death within 30, 60, and 180 days after TG. A total of 7905 subjects were included for analysis. The mean age was 65.8 years, and 68.8% were males. The 30-, 60-, and 180-day mortality rates after TG for gastric cancer were 2.7%, 6.2%, and 18.2%, respectively. On the multivariate analysis, TG at high-volume hospitals significantly contributed to lower 30-day (odds ratio 0.64; 95% confidence interval 0.48–0.85; P

Patients with periampullary cancer frequently suffer obstructive jaundice and commonly require preoperative biliary drainage (PBD) for relief and to avoid related complications. Although research has established a correlation between PBD and surgical wound infection, the impact of PBD on major infectious complications (intra-abdominal abscess [IAA]) and overall mortality remains debatable. We hypothesized that PBD could lead to IAA and mortality, and evaluated their correlation in patients undergoing pancreaticoduodenectomy (PD). We enrolled patients undergoing PD at an Asian academic medical center between 2007 and 2016. The types of PBD included endoscopic retrograde biliary drainage (ERBD) and percutaneous transhepatic cholangiography and drainage (PTCD). The primary outcome was IAA, defined as the presence of pus or infected fluid inside the abdominal cavity and with documented infectious pathogens. There was one (0.1%) 30-day mortality and eight (0.9%) 90-day mortalities among 899 consecutive patients examined. More than one-quarter of patients had PBD (n = 237, 26.4%; 165 ERBD, 72 PTCD). In the ERBD, PTCD, and non-PBD groups, the IAA rates were 37.0%, 16.7%, and 10.6%, respectively. On multivariate analysis, ERBD (odds ratio 3.67; 95% confidence interval 2.22–6.06; p

(4S)-4-(3-18F-Fluoropropyl)-l-glutamate (FSPG) positron emission tomography (PET) reflects system xC− transporter (xCT) expression. FSPG PET has been used to detect brain, lung, breast and liver cancer with only modest success. There is no report on the use of FSPG PET in pancreatic ductal adenocarcinoma (PDAC), presumably because of normal xCT expression in the pancreas. Nonetheless, the tissue-specific expression of xCT in the pancreas suggests that FSPG PET may be ideal for identifying metastasized PDAC. The performance of FSPG in detecting PDAC metastases was compared with that of 18F-fluorodeoxyglucose (FDG) in small-animal PET studies in seven PDAC tumour-bearing mice and in prospective PET/computed tomography (CT) studies in 23 patients with tissue-confirmed PDAC of stage III or stage IV. All PET/CT results were correlated with the results of histopathology or contrast-enhanced CT (ceCT) performed 3 and 6 months later. In the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9–14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI −1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70–4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis. FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.