Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: Islet amyloid deposition and reduced ß-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects. To date, the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma (PDAC) have not been specifically addressed. AIM: To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences (proximal vs distal residual pancreas) are associated with islet amyloid deposition. METHODS: We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients, including 14 patients with normal glucose tolerance (NGT), 16 patients with prediabetes and 15 new-onset diabetes (NOD) patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020. Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans. Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows: (1) Hematoxylin and eosin for general histological appearance; (2) hematoxylin and insulin for the determination of fractional ß-cell area (immunohistochemistry); and (3) quadruple insulin, glucagon, thioflavin T and DAPI staining for the determination of ß-cell area, α-cell area and amyloid deposits. RESULTS: Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition, fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions, especially in the prediabetes and NOD groups. Consistent with this finding, the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group (37.35 ± 12.16 cm3 vs 69.79 ± 18.17 cm3, P < 0.001). As expected, islets that stained positive for amyloid (islet amyloid density) were found in the majority of PDAC cases. The proportion of amyloid/islet area (severity of amyloid deposition) was significantly higher in both prediabetes and NOD patients than in NGT patients (P = 0.002; P < 0.0001, respectively). We further examined the regional differences in islet amyloid deposits. Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups (3.98% ± 3.39% vs 0.50% ± 0.72%, P = 0.01; 12.03% vs 1.51%, P = 0.001, respectively). CONCLUSION: In conclusion, these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation, which may be associated with the pathogenesis of NOD secondary to PDAC.

A double-cannula pancreatic gastrostomy method for pancreatic duct stenosis due to disconnected pancreatic duct syndrome: A surgical case report.

INTRODUCTION AND IMPORTANCE: Disconnected Pancreatic Duct Syndrome (DPDS) without peripancreatic fluid collections are relatively difficult for endoscopists to manage and usually treated with distal pancreatectomy or pancreaticojejunostomy. However, these procedures are risky for patients with severe edema of pancreatic tissue. We report an original one-stage surgical approach for these patients, namely, the "double-cannula pancreatic gastrostomy method". CASE PRESENTATION: A 38-year-old man was admitted with recurrent acute pancreatitis. ct images suggest pancreatic duct discontinuity syndrome. Intraoperative exploration revealed that pancreas inflammation was severe and distal pancreatectomy or pancreaticojejunostomy were risky. Therefore, we decided to perform a double-cannula pancreatic gastrostomy. A 16F type catheter penetrated the front and back walls of the stomach for gastrostomy, and a 6F catheter was inserted into the pancreatic duct for drainage. We placed the drainage tube of pancreatic duct into the gastrostomy tube to ensure the drainage tube of pancreatic duct could reach the gastric cavity. The gastrostomy tube is led out of the body through the abdominal wall. CLINICAL DISCUSSION: Both endoscopic and surgical approaches have been reported in treating DPDS patients. Internal drainage and excision are common surgical methods. CONCLUSIONS: The double-cannula pancreatic gastrostomy was a safe and effective method in this patient. CORE TIP: In this case, the patient suffered recurrent acute pancreatitis due to disconnected pancreatic duct syndrome. This patient without peripancreatic fluid collections was relatively difficult for endoscopists to manage. However, intraoperative exploration revealed a high risk of distal pancreatectomy or pancreaticojejunostomy. Therefore, we used A double-cannula pancreatic gastrostomy method and successfully treated the complications of pancreatic duct stenosis.

The differential effects of sarcopenia and cachexia on overall survival for pancreatic ductal adenocarcinoma patients following pancreatectomy: A retrospective study based on a large population.

OBJECTIVES: Both cachexia and sarcopenia have been considered adverse predictors for prognosis in patients with pancreatic cancer; although sarcopenia and cachexia share some similarities, they are still defined as distinct nutritional conditions. We aimed to explore the differential impacts of sarcopenia and cachexia on prognosis for pancreatic ductal adenocarcinoma (PDAC) patients following radical excision. METHODS: From January 2015 to May 2022, 614 patients undergoing surgery for PDAC were retrospectively included. Sarcopenia was defined as the L3 total skeletal muscle index below 52.4 cm2 /m2 (men) and 38.5 cm2 /m2 (women). Cachexia was classified according to the following criteria: involuntary weight loss >5% over the past 6 months, or weight loss >2% and BMI <20 kg/m2 , or weight loss >2% and sarcopenia. RESULTS: Of the 614 patients included in the analysis, 62% and 48% were diagnosed with sarcopenia and cachexia, respectively. Kaplan-Meier analysis showed that sarcopenia and/or cachexia were significantly associated with worse overall survival (OS) rather than worse recurrence-free survival (RFS). Moreover, Cox regression analysis revealed that cachexia rather than sarcopenia was an adverse factor for OS in all PDAC patients. For poorly differentiated PDAC, both cachexia and sarcopenia were significantly associated with shorter OS. However, for moderately/well-differentiated PADC, cachexia was an independent factor for adverse OS, but not sarcopenia. CONCLUSIONS: Sarcopenia and cachexia have different effects on OS for PDAC patients undergoing radical excision. This difference may provide some important information for preoperative management.

Clinicopathological features and long-term prognosis of purely cystic pancreatic neuroendocrine tumors: A single-center experience.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are heterogenous neoplasms, of which the prognosis varies widely. Purely cystic pancreatic neuroendocrine tumors (C-pNETs) are a small subset of pNETs in which data are extremely rare. This study aimed to compare clinicopathological and long-term survival differences between C-pNETs and solid pNETs (S-pNETs). METHODS: A retrospective review of 242 patients with pNETs underwent resection in our institution from 2009 to 2019 was conducted. Demography characteristics, clinicopathological features and long-term outcomes of them were analyzed. RESULTS: Sixteen out of 242 patients (6.6%) were identified as C-pNETs. Compared with S-pNETs, C-pNETs were more frequently non-functional (75% vs 45%, P = 0.02), and the median tumor diameter of C-pNETs was smaller (36 mm vs. 47 mm, P = 0.001). And the accuracy of preoperative diagnosis of C-pNETs was significantly lower (31% vs 78%, P = 0.001). Of note, the majority of C-pNETs were well-differentiated with G1 (81% vs 35%, P = 0.001). And there were no G3 (0 vs 7%, P = 0.001) in C-pNETs. No T4 stage or R1/R2 surgical margin detected in C-pNETs. And only one C-pNETs (6%) had regional lymph node metastasis (N) or synchronous distant metastasis (M). Additionally, only one patient with C-pNETs (6%) suffered tumor recurrence, compared with 24 (13%) for S-pNETs. And survival analysis showed the patients with C-pNETs seemed to be with better disease-free survival (P = 0.26). CONCLUSION: C-pNETs are rare subtype with possibly less aggressive behavior comparing with their solid counterparts. Recurrence and tumor-related death still occurs in patients with resected C-pNETs, although they tend to be with more favorable prognosis.

Neoadjuvant therapy in resectable pancreatic cancer: A promising curative method to improve prognosis.

Currently, 15 randomized controlled trials (RCTs) have been designed to investigate whether neoadjuvant therapy (NAT) benefits patients with resectable pancreatic adenocarcinoma (R-PA) compared to surgery alone. Five of them have acquired results so far; however, corresponding conclusions have not been obtained. We speculated that the reason for this phenomenon could be that some prognostic factors had proven to be adverse through upfront surgery curative patterns, but some of them were not regarded as independent baseline characteristics, which is important to obtaining comparability between the NAT and upfront surgery groups. This fact could cause bias and lead to the difference in the outcomes of RCTs. In this review, we collate data about risk factors (such as tumor size, resection margin, and lymph node status) influencing the prognoses of patients with R-PA from five RCTs and discuss the possible reasons for the varying outcomes.

Prospects and applications of enucleation in solid pseudopapillary neoplasms of the pancreas.

Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare, low-grade, malignant neoplasms that are mostly seen in young women in the second and third decades of life and are quite uncommon in children. Standard resection for benign and borderline neoplasms of the pancreas is associated with a substantial risk of postoperative morbidity and long-term functional impairment, whereas enucleation leads to less morbidity and preserves healthy parenchyma as well as exocrine and endocrine function. Enucleation of SPNs has been increasingly reported to be feasible and safe for preserving the normal physiological function of the pancreas, especially in teenagers and children. This review summarizes findings published in recent years on the enucleation of SPNs as well as potential future developments and directions. Enucleation has undoubtedly come to stay as an alternative surgical procedure for SPNs. However, many questions remain unresolved, and future directions toward the best surgical indication, the prevention and intervention of complications, especially pancreatic fistula, intraoperative resection margin safety assessment, and long-term oncology prognosis remain to be evaluated and should be explored in future clinical trials.

Analysis of invasiveness and tumor-associated macrophages infiltration in solid pseudopapillary tumors of pancreas.

BACKGROUND: Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor. Considering its malignant behaviors, SPT has been classified as a low-grade malignant tumor. Indeed, only 9.2% of all SPT patients are initially diagnosed as malignant with invasion or metastasis. Thus, one of the challenges in managing SPT patients is predicting malignant behavior. AIM: To investigate the malignant behavior and tumor-associated macrophage (TAM) infiltration between different histopathologic features of SPT patients. METHODS: Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study. Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylin-eosin (HE)-stained sections. Based on the histopathological features, the SPT patients were divided into two groups: capsule or invasion. Clinical features, malignant behavior, and TAM infiltration were compared between the two groups. RESULTS: Among the 22 SPT patients, 11 were identified for each group, having either a capsule or invasion histopathologic feature. Malignant behavior was more frequent in the invasion group, including 2 patients who had peripheral organ invasion, 3 with liver metastasis, and 1 with both lymph node and spleen metastases (P= 0.045). Ki-67 index of more than 3% was also more frequent in the invasion group (P = 0.045). Immunohistochemical analysis showed that the invasion group had a significant increase of CD68-positive TAMs in intratumor and peritumor sites in comparison with the capsule group (all P < 0.0001). Similarly, CD163-positive M2-like macrophages were also markedly increased in the intratumor and peritumor sites in the invasion group (all P < 0.0001). At the liver metastasis site, both intratumor and peritumor tissues showed relatively high-level CD68-positive TAMs and CD163-positive M2-like macrophages infiltration. However, the differences between the intratumor, peritumor and normal hepatic tissues did not reach statistical significance (all P > 0.05). CONCLUSION: SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration, especially M2-like macrophages. This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.

Development and Validation of a Novel Radiomics-Based Nomogram With Machine Learning to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors.

Backgroud: Tumor grade is the determinant of the biological aggressiveness of pancreatic neuroendocrine tumors (PNETs) and the best current tool to help establish individualized therapeutic strategies. A noninvasive way to accurately predict the histology grade of PNETs preoperatively is urgently needed and extremely limited. Methods: The models training and the construction of the radiomic signature were carried out separately in three-phase (plain, arterial, and venous) CT. Mann-Whitney U test and least absolute shrinkage and selection operator (LASSO) were applied for feature preselection and radiomic signature construction. SVM-linear models were trained by incorporating the radiomic signature with clinical characteristics. An optimal model was then chosen to build a nomogram. Results: A total of 139 PNETs (including 83 in the training set and 56 in the independent validation set) were included in the present study. We build a model based on an eight-feature radiomic signature (group 1) to stratify PNET patients into grades 1 and 2/3 groups with an AUC of 0.911 (95% confidence intervals (CI), 0.908-0.914) and 0.837 (95% CI, 0.827-0.847) in the training and validation cohorts, respectively. The nomogram combining the radiomic signature of plain-phase CT with T stage and dilated main pancreatic duct (MPD)/bile duct (BD) (group 2) showed the best performance (training set: AUC = 0.919, 95% CI = 0.916-0.922; validation set: AUC = 0.875, 95% CI = 0.867-0.883). Conclusions: Our developed nomogram that integrates radiomic signature with clinical characteristics could be useful in predicting grades 1 and 2/3 PNETs preoperatively with powerful capability.

The Role of Primary Tumor Resection in Patients With Pancreatic Neuroendocrine Tumors With Liver Metastases.

Background: Liver metastases (LMs) are common in advanced pancreatic neuroendocrine tumor (PNET) patients. Currently, the benefit of primary tumor resection (PTR) in the setting of PNET patients with liver metastases is still controversial in several guidelines. Methods: Data were extracted from the Surveillance, Epidemiology and End Results (SEER) database to evaluate this issue. The main index of interest in our study was overall survival time. Results: Information on 536 PNET patients with liver metastases from the SEER database was identified. A total of 214 patients (PTR group) received primary tumor resection, and more than half of them (132 patients) had synchronous LM resection. The other 322 PNET patients (non-PTR group) with liver metastases did not receive primary tumor resection. A significant survival benefit was gained from PTR when compared with non-PTR patients, both in OS (72.93 ± 2.7 vs. 36.80 ± 2.22 months) and 3- or 5-year survival rates (75.1% vs. 28.9% and 67.9% vs. 22.3%, respectively). No difference was found between PTR alone and PTR with synchronous LM resection. From univariate and multivariate analyses, younger age (<65 years) and good or moderate tumor differentiation may be more important when considering primary tumor resection. However, we found that all grades of tumor differentiation could result in a better overall survival time after primary tumor resection. Conclusion: Our study suggested that primary tumor resection in pancreatic neuroendocrine patients with liver metastases could result in a longer survival time. Primary tumor resection with synchronous liver metastasis resection was not related to a better survival benefit. This treatment strategy may routinely be taken into consideration in these patients.

A comprehensive validation of the novel 8th edition of American Joint Committee on Cancer staging manual for the long-term survivals of patients with non-functional pancreatic neuroendocrine neoplasms.

Histologically, the World Health Organization has classified pancreatic neuroendocrine neoplasms (p-NENs) into well-differentiated pancreatic neuroendocrine tumors (G1/G2 p-NETs) and poorly-differentiated pancreatic neuroendocrine carcinoma (G3 p-NECs) based on tumor mitotic counts and Ki-67 index. Recently, the 8th edition of American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging manual has incorporated some major changes in 2017 that the TNM staging system for p-NENs should only be applied to well-differentiated G1/G2 p-NETs, while poorly-differentiated G3 p-NECs be classified according to the new system for pancreatic exocrine adenocarcinomas. However, this new manual for p-NENs has seldom been evaluated.Data of patients with both G1/G2 and G3 non-functional p-NENs (NF-p-NENs) from our institution was retrospectively collected and analyzed using 2 new AJCC 8th staging systems. We also made survival comparisons between the 8th and 7th edition system separately for different subgroups.For G1/G2 NF-p-NETs, there were 52 patients classified in AJCC 8th edition stage I, 40 in stage II, 41 in stage III and 19 in stage IV. As for G3 NF-p-NECs, 17, 19, 24, and 18 patients were respectively defined from AJCC 8th edition stage I to stage IV. In terms of the AJCC 7th staging system, the 230 patients with NF-p-NENs were totally distributed from stage I to stage IV (94, 63, 36, 37, respectively). For the survival analysis of both G1/G2 NF-p-NETs and G3 NF-p-NECs, the AJCC 7th edition system failed to discriminate the survival differences when compared stage III with stage II or stage IV (P > .05), while the 8th edition ones could perfectly allocate patients into 4 statistically different groups (P < .05). The HCIs of AJCC 8th stage for G1/G2 NF-p-NETs [HCI=0.658, 95% confidence interval (CI)=0.602-0.741] and stage for G3 NF-p-NECs (HCI=0.704, 95% CI=0.595-0.813) was both statistically larger than those of AJCC 7th stage for different grading NF-p-NENs [(HCI=0.578, 95% CI=0.557-0.649; P=.031), (HCI=0.546, 95% CI=0.531-0.636; P = .019); respectively], indicating a more accurate predictive ability for the survivals of NF-p-NENs.Our data suggested the 2 new AJCC 8th staging systems were superior to its 7th edition for patients with both G1/G2 NF-p-NETs and G3 NF-p-NECs.

World Health Organization grading classification for pancreatic neuroendocrine neoplasms: a comprehensive analysis from a large Chinese institution.

BACKGROUND: Pancreatic neuroendocrine neoplasms (p-NENs) are a group of highly heterogeneous tumors with distinct clinicopathological features and long-term prognosis. In 2017, in order to better stratify patients into prognostic groups and predicting their outcomes, World Health Organization (WHO) officially updated its grading system for p-NENs which distinguished these neoplasms among Grading 1 (G1) pancreatic neuroendocrine tumors (p-NETs), G2 p-NETs, G3 p-NETs and G3 pancreatic neuroendocrine carcinomas (p-NECs). However, this new grading classification for p-NENs has not yet been rigorously validated. METHODS: Data of patients who were surgically treated and histopathologically diagnosed as p-NENs at West China Hospital of Sichuan University from January 2002 to December 2018 were retrospectively collected and analyzed according the novel WHO 2017 grading classification. RESULTS: We eventually enrolled 480 eligible patients with p-NENs in our present study, in which 150 patients with WHO 2017 G1 p-NETs, 158 with G2 p-NETs, 64 with G3 p-NETs and 108 with G3 p-NECs were identified. The estimated 5-year overall survival for patients with G1 p-NETs, G2 p-NETs, G3 p-NETs and G3 p-NECs was 75.8, 58.4, 35.1 and 11.1%, with a median survival time of 85.3mons, 67.4mons, 51.3mons and 26.8mons, respectively. Patients with G2 p-NETs present notably worse survival than those with G1 p-NETs (P = 0.03). Survival of G3 p-NETs were significantly worse than that of G1 p-NETs or G2 p-NETs (P < 0.001, P = 0.023, respectively), as well as that when comparing G3 p-NECs with G1 p-NETs or G2 p-NETs (P < 0.001, P < 0.001, respectively). Patients with G3 p-NECs showed statistically shorter survival than those with G3 p-NETs (P < 0.001). Both WHO 2017 and 2010 grading criteria could be independent predictor for the OS of p-NENs (P = 0.016, P = 0.022; respectively). The 95% confidence intervals of WHO 2017 grading classification (0.983-9.454) was slightly smaller than that of WHO 2010 criteria (0.201-13.374), indicating a relatively more accurate predicting ability for the prognosis of p-NENs. CONCLUSION: The WHO 2017 grading classification for p-NENs could successfully allocate patients into four groups with distinct clinical features and significant survival differences, which might be superior to the WHO 2010 criteria for its better prognostic stratification and more accurate predicting ability.

Functionality is not an independent prognostic factor for pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) that produce hormones leading to symptoms are classified as functional tumors, while others are classified as nonfunctional tumors. The traditional view is that functionality is a factor that affects the prognosis of pNEN patients. However, as the sample sizes of studies have increased, researches in recent years have proposed new viewpoints. AIM: To assess whether functionality is an independent factor for predicting the prognosis of pNEN patients. METHODS: From January 2004 to December 2016, data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance, Epidemiology, and End Results (SEER) database and West China Hospital database were retrospectively analyzed. RESULTS: Contemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis. From the SEER database, age (P = 0.006) and T stage (P < 0.001) were independent risk factors affecting the survival. From the West China Hospital database, independent prognostic factors were age (P = 0.034), sex (P = 0.032), and grade (P = 0.039). The result of the cohort consisting of the combined populations from the two databases showed that race (P = 0.015), age (P = 0.002), sex (P = 0.032) and T stage (P < 0.001) were independent prognostic factors. In the West China Hospital database and in the total population, nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma. However, functionality was not associated with the survival time of patients with pNETs in the multivariate analysis. CONCLUSION: Functionality is not associated with prognosis. Race, age, sex, and T stage are independent factors for predicting the survival of patients with pNETs.

Analysis of recurrence after resection of well-differentiated non-functioning pancreatic neuroendocrine tumors.

Although pancreatic neuroendocrine tumors (PNETs) are generally considered to have a favorable overall prognosis after resection, disease recurrence has been observed. Few studies have specifically addressed recurrence after resection of PNETs, especially for non-functioning PNETs (NF-PNETs). The aim of our study is to analyze the recurrence of resected well-differentiated NF-PNETs.Patients who underwent surgical resection for grade 1 and 2 NF-PNETs without synchronous metastasis were identified for analysis. Patients were treated from January 2009 to December 2017 in our institution. Univariate and multivariate cox regression analysis were conducted to identify prognostic factors.Of the 88 patients, 46 were men (52%) and the mean age was 52 years. With a median follow-up of 49.1 months (range, 8-122 months), there were 12 recurrences (14%). Liver was the most common recurrence site (7/12, 58%). The 1-, 3-, and 5-year recurrence-free survival was 99%, 90%, and 88%, respectively. Univariate analysis identified that age >52 years, positive lymph nodes, tumor grade 2, and Ki67 index ≥5% were statistically significant. Multivariate analysis identified that Ki67 index ≥5% (hazard ratio [HR], 4.69; 95% confidence interval [CI], 1.36-16.75, P = .015), positive lymph nodes (HR, 6.75; 95% CI, 1.73-24.43, P = .006) were independently associated with recurrence. The 5-year disease-free survival rate was 53% (95% CI, 14.20-91.81%) for patients with Ki-67 ≥5% or (and) positive lymph nodes, while 95% (95% CI, 82.26-100%) for the patients without these 2 factors.Ki67 index and lymph node status are independently associated with recurrence after resection of well-differentiated NF-PNETs in this study.

Predicting survival in non-functional pancreatic neuroendocrine tumours.

BACKGROUND: Owing to the limited prevalence and heterogeneity, it is difficult to predict long-term survival of non-functional pancreatic neuroendocrine tumours (NF-PNETs).This study aimed to evaluate the factors predicting disease-specific survival (DSS) for well-differentiated NF-PNETs. METHODS: Data were collected retrospectively from 256 patients with pancreatic neuroendocrine tumours who underwent surgical resection between January 2009 and December at our institution. Of these, 103 NF-PNETs (40%) were identified for analysis. RESULTS: Of the 103 patients, 54 were male (52%) and the mean age was 52 years (range 21-75 years). Most patients (60/103, 58%) in our series were symptomatic. Seventeen patients (16%) died during follow-up, with a median period of 47 months. There were 88 patients with well-differentiated tumours and 10 of them (10/88, 11%) died of tumour progression. Median DSS after primary resection was 58.8 months (range 16-122 months). Multivariate analysis identified age >52 years (P = 0.038) and tumour grade G2 (P = 0.001) as statistically significant predictors of DSS. There was no association between gender, tumour size, symptoms, surgical procedure, severe complications, tumour location, tumour size, resection margin, positive lymph nodes and vascular invasion with DSS. CONCLUSION: Tumour grade, age, presence of symptoms and distant metastasis were related to poor DSS of NF-PNETs. Age >52 years and tumour grade G2 might be independent predictors of poor DSS for patients with well-differentiated NF-PNETs.

MEX3A knockdown inhibits the development of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the most serious causes of death in the world due to its high mortality and inefficacy treatments. MEX3A was first identified in nematodes and was associated with tumor formation and may promote cell proliferation and tumor metastasis. So far, nothing is known about the relationship between MEX3A and PDA. METHODS: In this study, the expression level of MEX3A in PDA tissues was measured by immunohistochemistry. The qRT-PCR and western blot were used to identify the constructed MEX3A knockdown cell lines, which was further used to construct mouse xenotransplantation models. Cell proliferation, colony formation, cell apoptosis and migration were detected by MTT, colony formation, flow cytometry and Transwell. RESULTS: This study showed that MEX3A expression is significantly upregulated in PDA and associated with tumor grade. Loss-of-function studies showed that downregulation of MEX3A could inhibit cell growth in vitro and in vivo. Moreover, it was demonstrated that knockdown of MEX3A in PDA cells promotes apoptosis by regulating apoptosis-related factors, and inhibits migration through influencing EMT. At the same time, the regulation of PDA progression by MEX3A involves changes in downstream signaling pathways including Akt, p-Akt, PIK3CA, CDK6 and MAPK9. CONCLUSIONS: We proposed that MEX3A is associated with the prognosis and progression of PDA,which can be used as a potential therapeutic target.

Prognostic impact of lymph node status in patients after total pancreatectomy for pancreatic ductal adenocarcinoma: A strobe-compliant study.

The optimal number of examined lymph nodes (ELN) for staging and impact of nodal status on survival following total pancreatectomy (TP) for pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim of this study was to evaluate the prognostic impact of different lymph node status after TP for PDAC.The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients who underwent TP for PDAC from 2004 to 2015. We calculated overall survival (OS) of these patients using Kaplan-Meier analysis and Cox proportional hazards model.Overall, 1291 patients were included in the study, with 869 node-positive patients (49.5%). A cut-off points analysis revealed that 19, 19, and 13 lymph nodes best discriminated OS for all patients, node-negative patients, and node-positive patients, respectively. Higher number of ELN than the corresponding cut-off points was an independent predictor for better prognosis [all patients: hazard ratios (HR) 0.786, P = .002; node-negative patients: HR 0.714, P = .043; node-positive patients: HR 0.678, P < .001]. For node-positive patients, 1 to 3 positive lymph nodes (PLN) correlated independently with better survival compared with those with 4 or more PLN (HR 1.433, P = .002). Moreover, when analyzed in node-positive patients with less than 13 ELN, neither the number of PLN nor lymph node ratio (LNR) was associated with survival. However, when limited node-positive patients with at least 13 ELN, univariate analyses showed that both the number of PLN and LNR were associated with survival, whereas multivariate analyses demonstrated that only number of PLN was consistently associated with survival (HR 1.556, P = .004).Evaluation at least 19 lymph nodes should be considered as quality metric of surgery in patients who underwent TP for PDAC. For node-negative patients, a minimal number of 19 lymph nodes is adequate to avoid stage migration. For node-positive patients, PLN is superior to LNR in predicting survival after TP, predominantly for those with high number of ELN.

Mesenterico-portal vein invasion should be an important factor in TNM staging for pancreatic ductal adenocarcinoma: Proposed modification of the 8th edition of the American Joint Committee on Cancer staging system.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC) excludes extrapancreatic extension from the assessment of T stage and restages tumors with mesenterico-portal vein (MPV) invasion into T1-3 diseases according to tumor size. However, MPV invasion is believed to be correlated with a poor prognosis. AIM: To analyze whether the inclusion of MPV invasion can further improve the 8th edition of the AJCC staging system for PDAC. METHODS: This study retrospectively included 8th edition AJCC T1-3N0-2M0 patients undergoing pancreaticoduodenectomy/total pancreatectomy from two cohorts and analyzed survival outcomes. In the first cohort, a total of 7539 patients in the surveillance, epidemiology, and end results database was included, and in the second cohort, 689 patients from the West China Hospital database were enrolled. RESULTS: Cox regression analysis showed that MPV invasion is an independent prognostic factor in both databases. In the MPV- group, all pairwise comparisons between the survival functions of patients with different stages were significant except for the comparison between patients with stage IIA and those with stage IIB. However, in the MPV+ group, pairwise comparisons between the survival functions of patients with stage IA, stage IB, stage IIA, stage IIB, and stage III were not significant. T1-3N0 patients in the MPV+ group were compared with the T1N0, T2N0, and T3N0 subgroups of the MPV- group; only the survival of MPV-T3N0 and MPV+T1-3N0 patients had no significant difference. Further comparisons of patients with stage IIA and subgroups of stage IIB showed (1) no significant difference between the survival of T2N1 and T3N0 patients; (2) a longer survival of T1N1 patients that was shorter than the survival of T2N0 patients; and (3) and a shorter survival of T3N1 patients that was similar to that of T1-3N2 patients. CONCLUSION: The modified 8th edition of the AJCC staging system for PDAC proposed in this study, which includes the factor of MPV invasion, provides improvements in predicting prognosis, especially in MPV+ patients.