Hypotension prediction index for prevention of intraoperative hypotension in patients undergoing general anesthesia: a randomized controlled trial.

BACKGROUND: Intraoperative hypotension is a common side effect of general anesthesia. Here we examined whether the Hypotension Prediction Index (HPI), a novel warning system, reduces the severity and duration of intraoperative hypotension during general anesthesia. METHODS: This randomized controlled trial was conducted in a tertiary referral hospital. We enrolled patients undergoing general anesthesia with invasive arterial monitoring. Patients were randomized 1:1 either to receive hemodynamic management with HPI guidance (intervention) or standard of care (control) treatment. Intraoperative hypotension treatment was initiated at HPI > 85 (intervention) or mean arterial pressure (MAP) < 65 mmHg (control). The primary outcome was hypotension severity, defined as a time-weighted average (TWA) MAP < 65 mmHg. Secondary outcomes were TWA MAP < 60 and < 55 mmHg. RESULTS: Of the 60 patients who completed the study, 30 were in the intervention group and 30 in the control group. The patients' median age was 62 years, and 48 of them were male. The median duration of surgery was 490 min. The median MAP before surgery presented no significant difference between the two groups. The intervention group showed significantly lower median TWA MAP < 65 mmHg than the control group (0.02 [0.003, 0.08] vs. 0.37 [0.20, 0.58], P < 0.001). Findings were similar for TWA MAP < 60 mmHg and < 55 mmHg. The median MAP during surgery was significantly higher in the intervention group than that in the control group (87.54 mmHg vs. 77.92 mmHg, P < 0.001). CONCLUSIONS: HPI guidance appears to be effective in preventing intraoperative hypotension during general anesthesia. Further investigation is needed to assess the impact of HPI on patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04966364); 202105065RINA; Date of registration: July 19, 2021; The recruitment date of the first patient: July 22, 2021.

Comparison of dexmedetomidine versus propofol sedation on microcirculation and organ injuries in critically ill surgical patients: A randomized controlled pilot study.

BACKGROUND: Recent studies have shown that dexmedetomidine may improve microcirculation and prevent organ failure. However, most evidence was obtained from experimental animals and patients receiving cardiac surgery with cardiopulmonary bypass. This study aimed to investigate the effect of dexmedetomidine on microcirculation and organ injuries in critically ill general surgical patients. METHODS: In this prospective randomized trial, patients admitted to the surgical intensive care unit after general surgery were enrolled and randomly allocated to the dexmedetomidine or propofol groups. Patients received continuous dexmedetomidine or propofol infusions to meet their requirement of sedation according to their grouping. At each time point, sublingual microcirculation images were obtained using the incident dark field video microscope. RESULTS: Overall, 60 patients finished the trial and were analyzed. Microcirculation parameters did not differ significantly between two groups. Heart rate at 4 h after ICU admission and mean arterial pressures at 12 h and 24 h after ICU admission were lower in the dexmedetomidine group than in the propofol group. At 24 h, serum aspartate aminotransferase (41 (25-118) vs 86 (34-129) U/L, p = 0.035) and alanine aminotransferase (50 (26-160) vs 68 (35-172) U/L, p = 0.019) levels were significantly lower in the dexmedetomidine group than in the propofol group. CONCLUSION: Microcirculation parameters did not differ significantly between the dexmedetomidine and propofol groups. At 24 h after ICU admission, serum liver enzyme levels were lower in patients receiving dexmedetomidine as compared to propofol.

Most total pancreatectomies for ductal adenocarcinoma potentially can Be replaced by whipple over the splenic artery: a before and after study.

INTRODUCTION: Recently, more and more total pancreatectomy (TP) has been performed for central-located pancreatic ductal cell adenocarcinoma (PDCA) which abuts or involves both gastroduodenal and splenic arteries and demands transaction of both of them for a complete resection. Spiked by Warshaw's procedure (spleen-preserving distal pancreatectomy with excision of splenic vessels), we developed a new procedure "Whipple over the splenic artery (WOTSA)" to replace TP by leftward extension of pancreatic parenchyma transaction line and preservation of pancreatic tail and spleen after excision of splenic artery. This uncontrolled before and after study assesses the safety and efficacy of a new technique "Whipple over the splenic artery (WOTSA)" as a treatment for PDAC which traditionally requires total pancreatectomy (TP) for a complete excision. METHODS: The study group comprised 40 consecutive patients who underwent WOTSA for PDAC between August 2019 and September 2022. Their clinicopathological characteristics and survival were compared with those of a historical control group comprising 30 consecutive patients who underwent TP between January 2016 and July 2019. RESULTS: None of the 40 patients in the WOTSA group required reoperation due to infarction of the pancreas and/or spleen remnant. DM medication after WOTSA were none in 19, oral hypoglycemic agents in 19, and insulin preparations in 2 patients. Compared with TP, patients who underwent WOTSA exhibited similar rates of major operative complications, clear pancreatic parenchyma transaction margin, and number of harvested positive lymph nodes, but higher rate of adjuvant chemotherapy completion and a trend toward better median disease free survival (14 vs. 7.5 mo, P=0.023). CONCLUSIONS: Compared to TP, WOTSA can be safely performed and have much better postoperative glycemic status without cost of higher operative risk or impaired surgical radicality. These findings indicate that most TPs for PDAC potentially can be replaced by WOTSAs.

Immunocyte profiling changes in patients received epidural versus intravenous analgesia after pancreatectomy: A randomized controlled trial.

BACKGROUND: Perioperative immunosuppressants, such as surgical stress and opioid use may downregulate anti-cancer immunocytes for patients undergoing pancreatectomy. Thoracic epidural analgesia (TEA) may attenuate these negative effects and provide better anti-cancer immunocyte profile change than intravenous analgesia using opioid. METHODS: We randomly assigned 108 adult patients undergoing pancreatectomy to receive one of two 72-h postoperative analgesia protocols: one was TEA, and the other was intravenous patient-controlled analgesia (IV-PCA). The perioperative proportional changes of immunocytes relevant to anticancer immunity-namely natural killer (NK) cells, cytotoxic T cells, helper T cells, mature dendritic cells, and regulatory T (Treg) cells were determined at 1 day before surgery, at the end of surgery and on postoperative day 1,4 and 7 using flow cytometry. In addition, the progression-free survival and overall survival between the two groups were compared. RESULTS: After surgery, the proportions of NK cells and cytotoxic T cells were significantly decreased; the proportion of B cells and mature dendritic cells and Treg cells were significantly increased. However, the proportions of helper T cells exhibited no significant change. These results were comparable between the two groups. Furthermore, there were no significant differences in progression-free survival (52.75 [39.96] and 57.48 [43.66] months for patients in the TEA and IV-PCA groups, respectively; p = 0.5600) and overall survival (62.71 [35.48] and 75.11 [33.10] months for patients in the TEA and IV-PCA groups, respectively; p = 0.0644). CONCLUSIONS: TEA was neither associated with favorable anticancer immunity nor favorable oncological outcomes for patients undergoing pancreatectomy.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Evaluation of Malignancy Risk of Ampullary Tumors Detected by Endoscopy Using 2-[18F]FDG PET/CT.

OBJECTIVE: We aimed to investigate whether 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) can aid in evaluating the risk of malignancy in ampullary tumors detected by endoscopy. MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 155 patients (79 male, 76 female; mean age, 65.7 ± 12.7 years) receiving 2-[18F]FDG PET/CT for endoscopy-detected ampullary tumors 5-87 days (median, 7 days) after the diagnostic endoscopy between June 2007 and December 2020. The final diagnosis was made based on histopathological findings. The PET imaging parameters were compared with clinical data and endoscopic features. A model to predict the risk of malignancy, based on PET, endoscopy, and clinical findings, was generated and validated using multivariable logistic regression analysis and an additional bootstrapping method. The final model was compared with standard endoscopy for the diagnosis of ampullary cancer using the DeLong test. RESULTS: The mean tumor size was 17.1 ± 7.7 mm. Sixty-four (41.3%) tumors were benign, and 91 (58.7%) were malignant. Univariable analysis found that ampullary neoplasms with a blood-pool corrected peak standardized uptake value in early-phase scan (SUVe) ≥ 1.7 were more likely to be malignant (odds ratio [OR], 16.06; 95% confidence interval [CI], 7.13-36.18; P < 0.001). Multivariable analysis identified the presence of jaundice (adjusted OR [aOR], 4.89; 95% CI, 1.80-13.33; P = 0.002), malignant traits in endoscopy (aOR, 6.80; 95% CI, 2.41-19.20; P < 0.001), SUVe ≥ 1.7 in PET (aOR, 5.43; 95% CI, 2.00-14.72; P < 0.001), and PET-detected nodal disease (aOR, 5.03; 95% CI, 1.16-21.86; P = 0.041) as independent predictors of malignancy. The model combining these four factors predicted ampullary cancers better than endoscopic diagnosis alone (area under the curve [AUC] and 95% CI: 0.925 [0.874-0.956] vs. 0.815 [0.732-0.873], P < 0.001). The model demonstrated an AUC of 0.921 (95% CI, 0.816-0.967) in candidates for endoscopic papillectomy. CONCLUSION: Adding 2-[18F]FDG PET/CT to endoscopy can improve the diagnosis of ampullary cancer and may help refine therapeutic decision-making, particularly when contemplating endoscopic papillectomy.

Placement of Nasogastric Tubes in Pancreaticoduodenectomy Patients: Switching from Immediate Intraoperative Removal to Avoiding Unnecessary Perioperative Use.

BACKGROUND: The placement of nasogastric tubes (NGTs) in abdominal surgery has been adopted for decades to attenuate ileus and prevent aspiration pneumonia. In the recent era, the guidelines recommend not using NGT routinely, and even in pancreaticoduodenectomy (PD), immediate removal of NGT in operating rooms (ORs) was suggested. However, the clinical outcome and safety of abandoning NGT during the pre-PD and intra-PD periods remain unknown. METHODS: We conducted a single-center retrospective review on adult PD patients aged between 20 and 75 years from 2013 to 2022. The study population was grouped into the NGT group (NGT was placed before PD and immediately removed in the ORs) and the non-NGT group (NGT was not placed preoperatively). Safety was evaluated by the number of adverse events. The primary aim of this study is to evaluate the need of NGT insertion in ORs among PD patients. RESULTS: The case numbers in the NGT and non-NGT groups were 391 and 578, respectively. No case in the non-NGT group needed the intraoperative insertion of NGT. The rate of pulmonary complications was 2.3% in the NGT group compared to 1.6% in the non-NGT group (P = 0.400). Furthermore, there were no significant differences in terms of rates of major complications (12.8% vs. 9.3%, P = 0.089) or mortality (1.0% vs. 1.0%, P =0.980) between the two groups. The rates of the postoperative insertion of NGT in the NGT and non-NGT groups were 2.6% and 2.8% (P = 0.840), respectively. CONCLUSION: For selected PD patients, the placement of NGT during pre-PD and intra-PD periods may be safely omitted. This primary study is considered the first foundation stone in the extension of the element of no NGT in PD.

Human liver afferent and efferent nerves revealed by 3-D/Airyscan super-resolution imaging.

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP+ varicosities in the PGP9.5+ nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1) condensed TH+ sympathetic nerves in the portal space, 2) extension of sympathetic nerves from the portal to the intralobular space, in which the TH+ nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3) the TH+ nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology.NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1) sensory nerves in the hepatoportal space; 2) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation.

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

Role of preoperative malnutrition and symptom severity in anorexia-cachexia-related quality of life in patients with operable pancreatic cancer.

PURPOSE: This study assessed the changes in malnutrition status, symptom severity, and anorexia-cachexia-related quality of life (QoL) before and after pancreatic surgery and identified significant factors associated with changes in anorexia-cachexia-related QoL in patients with operable pancreatic cancer. METHODS: In total, 76 patients with pancreatic cancer who were scheduled to undergo surgery were recruited from a medical center in northern Taiwan. The Mini Nutritional Assessment, Symptom Severity Scale, and Functional Assessment of Anorexia-Cachexia Therapy scale were used to assess the patients' nutritional status, symptom severity, and anorexia-cachexia-related QoL, respectively. Bioelectrical impedance analysis was performed using X-Scan Plus II to assess body composition. A generalized estimating equation approach was used to identify significant factors associated with anorexia-cachexia-related QoL. RESULTS: In total, 42.1% of the patients had malnutrition or were at risk of malnutrition before surgery. Preoperative malnutrition (ß = -3.857, p = .001) and higher early satiety (ß = -0.629, p = .005), insomnia (ß = -0.452, p = .025), and pain (ß = -0.779, p < .001) were associated with lower anorexia-cachexia-related QoL. CONCLUSION: Clinicians should actively assess the nutritional status of patients with pancreatic cancer before surgery and provide symptom cluster management interventions to improve nutrition, insomnia, and pain, which is crucial for enhancing patients' anorexia-cachexia-related QoL.

Transparent tissue in solid state for solvent-free and antifade 3D imaging.

Optical clearing with high-refractive-index (high-n) reagents is essential for 3D tissue imaging. However, the current liquid-based clearing condition and dye environment suffer from solvent evaporation and photobleaching, causing difficulties in maintaining the tissue optical and fluorescent features. Here, using the Gladstone-Dale equation [(n-1)/density=constant] as a design concept, we develop a solid (solvent-free) high-n acrylamide-based copolymer to embed mouse and human tissues for clearing and imaging. In the solid state, the fluorescent dye-labeled tissue matrices are filled and packed with the high-n copolymer, minimizing scattering in in-depth imaging and dye fading. This transparent, liquid-free condition provides a friendly tissue and cellular environment to facilitate high/super-resolution 3D imaging, preservation, transfer, and sharing among laboratories to investigate the morphologies of interest in experimental and clinical conditions.

Novel Non-duct-to-Mucosa Pancreaticojejunostomy Reconstruction After Pancreaticoduodenectomy: Focus on the Occurrence of Post-pancreatectomy Hemorrhage and Intra-abdominal Abscess.

BACKGROUND: Postoperative pancreatic fistulas (POPFs) are considered inevitable in some patients after pancreaticoduodenectomy (PD), and measures to minimize their clinical impact are needed. Postpancreatectomy hemorrhage (PPH) and intra-abdominal abscess (IAA) are the most severe POPF-related complications, and concomitant leakage of contaminated intestinal content is considered the main cause. An innovative method, modified non-duct-to-mucosa pancreaticojejunostomy (TPJ), was created to prevent concomitant leakage of intestinal content, and its effectiveness was compared between two periods. METHODS: All PD patients undergoing pancreaticojejunostomy from 2012 to 2021 were included. The TPJ group consisted of 529 patients recruited from January 2018 to December 2021. A total of 535 patients receiving the conventional method (CPJ) from January 2012 to June 2017 were used as a control group. PPH and POPF were defined according to the International Study Group of Pancreatic Surgery definition, but only PPH grade C was included for analysis. An IAA was defined as a collection of postoperative fluid managed by CT-guided drainage with documental culture. RESULTS: There were no significant differences in the rate of POPF between the two groups (46.0% vs. 44.8%; p = 0.700). Furthermore, the percentages of bile in the drainage fluid in the TPJ and CPJ groups were 2.3% and 9.2%, respectively (p < 0.001). Lower proportions of PPH (0.9% vs. 6.5%; p < 0.001) and IAA (5.7% vs. 10.8%; p < 0.001) were observed for TPJ than for CPJ. On adjusted models, TPJ was significantly associated with a lower rate of PPH (odds ratio [OR] 0.132, 95% confidence interval [CI] 0.051-0.343; p < 0.001) and IAA (OR 0.514, 95% CI 0.349-0.758; p = 0.001) than CPJ. CONCLUSIONS: TPJ is feasible to be performed and is associated with a similar rate of POPF but a lower percentage of concomitant bile in the drainage fluid and subsequent rates of PPH and IAA than CPJ.

Solid Pseudopapillary Neoplasms of the Pancreas Across Races Demonstrate Disparities with Comparably Good Prognosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Multimodal 3-D/2-D human islet and duct imaging in exocrine and endocrine lesion environment: associated pancreas tissue remodeling.

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC (n = 10, distal) and cadaveric donor pancreases (n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment.NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.

Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation.

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.

The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells.

BACKGROUND: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. METHODS: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. RESULTS: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. CONCLUSIONS: PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

Prognostic validity of the American joint committee on cancer eighth edition staging system for well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: The American Joint Committee on Cancer (AJCC) made improvements for staging pancreatic neuroendocrine tumors (pNETs) in its 8th Edition; however, multicenter studies were not included. METHODS: We collected multicenter datasets (n = 1,086, between 2004 and 2018) to validate the value of AJCC 8 and other coexisting staging systems through univariate and multivariate analysis for well-differentiated (G1/G2) pNETs. RESULTS: Compared to other coexisting staging systems, AJCC 7 only included 12 (1.1%) patients with stage III tumors. Patients with European Neuroendocrine Tumor Society (ENETS) stage IIB disease had a higher risk of death than patients with stage IIIA (hazard ratio [HR]: 4.376 vs. 4.322). For the modified ENETS staging system, patients with stage IIB disease had a higher risk of death than patients with stage III (HR: 6.078 vs. 5.341). According to AJCC 8, the proportions of patients with stage I, II, III, and IV were 25.7%, 40.3%, 23.6%, and 10.4%, respectively. As the stage advanced, the median survival time decreased (NA, 144.7, 100.8, 72.0 months, respectively), and the risk of death increased (HR: II = 3.145, III = 5.925, and IV = 8.762). CONCLUSION: These findings suggest that AJCC 8 had a more reasonable proportional distribution and the risk of death was better correlated with disease stage.

Distinct Survival Outcomes in Subgroups of Stage III Pancreatic Cancer Patients: Taiwan Cancer Registry and Surveillance, Epidemiology and End Results registry.

PURPOSE: Pancreatic cancer is one of the most malignant cancers with poor survival. The latest edition of the American Joint Committee on Cancer (AJCC) staging system classifies the majority of operable pancreatic cancer patients as stage-III, while dramatic heterogeneity is observed among these patients. Therefore, subgrouping is required to accurately predict their prognosis and define a treatment plan. This study conducts a cohort study to provide a more precise classification system for stage-III pancreatic cancer patients by utilizing clinical variables. METHODS: We analyzed survival using log-rank tests, univariate Cox-regression models, and Kaplan-Meier survival curves for stage-III pancreatic ductal adenocarcinoma (PDAC) patients from the Taiwan Cancer Registry (TCR). Patients were further divided into subgroups using classification and regression tree (CART) algorithm. All results were validated using the SEER database. RESULTS: Among stage-III PDAC patients, lymph node and tumor grade showed significant association with survival. Patients with N2 stage had higher mortality risks (hazard ratio [HR] = 2.30, 95% confidence interval [CI] 1.71-3.08, p < 0.0001) than N0 patients. Patients with grade 3 also had higher risk of mortality (HR = 3.80, 95% CI 2.25-6.39, p < 0.0001) than grade 1 patients. The CART algorithm stratified stage-III patients into four subgroups with significantly different survival rates. The median survival of the four subgroups was 23.5, 18.4, 14.5, and 9.0 months, respectively (p < 0.0001). Similar results were observed with SEER data. CONCLUSIONS: Lymph node involvement and tumor grade are predictive factors for survival in stage-III PDAC patients. This new precise classification system can be used to guide treatment planning in advanced-stage pancreatic cancer.