Adrenocorticotropic Hormone-Producing Pancreatic Neuroendocrine Neoplasms: A Systematic Review.

OBJECTIVE: Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasm (ACTHoma) is an exceedingly rare type of pancreatic neuroendocrine neoplasm (pNEN) that often causes ectopic adrenocorticotropic hormone syndrome. These neoplasms have been found to be very aggressive and challenging to treat. The current systematic review aimed to analyze the clinical features, immunohistochemical characteristics, diagnosis, therapy, and prognosis of ACTHoma. METHODS: A systematic review of the English- and Chinese-language literature was performed. PubMed, EMBASE, and Wanfang databases were searched to identify articles about ACTHoma in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. RESULTS: A total of 210 studies encompassing 336 patients diagnosed with ACTHoma were selected for the systematic review, including 16 Chinese patients. CONCLUSION: ACTHoma was more common in women (66.4%), and the mean age was 44.7 years. Tumors were generally large, and the mean tumor size was 4.43 cm. The incidence of clinical manifestations was: hypokalemia, 69.3%; diabetes, 63.2%; weakness, 60.1%, hypertension, 56.4%; moon face 41.1%; and edema, 37.4%. These tumors are more commonly found in the tail of pancreas, and the most frequent site of metastasis was the liver. The pNENs or other functioning pNENs could evolve into ACTHoma. ACTHoma is a very rare disease, and the mean follow-up time was 28.3 months.

[Effects of tumor distance from anal verge and types of operations on survival outcomes for low rectal cancer after neoadjuvant chemoradiotherapy].

OBJECTIVE: To assess the effects of neoadjuvant chemoradiotherapy on survival outcomes of low rectal cancer after sphincter-preserving or removing surgery. METHODS: A total of 135 patients with rectal cancer within 10 cm from anal verge after neoadjuvant chemoradiotherapy were enrolled into this retrospective study from 2005 to 2012 at a single institute. There were 79 males and 56 females with a mean age of (58 ± 12) years and an average distance of (5.2 ± 2.1) cm from anal verge. The effects of gender, age, distance of tumor from anal verge, surgical procedure, T-stage downstaging, lateral resection margin and post-treatment lymphatic node status on 3-year disease-free survival (DFS) were examined. RESULTS: The overall 3-year DFS was 85.2% (115/135). Among 95 sphincter-preserving operations, there were anterior resection (n = 79), anterior perineal plane for ultra low anterior resection (APPEAR) technique (n = 12), Hartmann procedure (n = 3) and Parks procedure (n = 1). Among 40 sphincter-removing operations, there were abdominoperineal resection (APR) procedure (n = 39) and intersphincteric resection(ISR) (n = 1). The survival of patients undergoing sphincter-preserving or removing procedures did not differ in 3-year DFS (85.3% (81/95) vs 85.0% (34/40) , χ(2) = 0.000, P = 0.985) . Lateral resection margin and post-treatment lymphatic node status significantly affected DFS. The differential level from anal verge showed a trend of close relationship to 3-year DFS (81.5% (22/27) for 2-3 cm, 82.5% (47/57) for 4-5 cm vs 95.1% (39/41) for 6-7 cm), but without statistic significance (χ(2) = 3.111, 3.522; P = 0.078, 0.061). The survival rate for patients with sphincter-preserving at 6-7 cm from anal verge was significantly higher than that at 4-5 cm (95.0% (38/40) vs 79.5% (31/39) ,χ(2) = 4.227, P = 0.039) , but showed no differences to that with sphincter-removing at 2-3 cm from anal verge (81.0% (17/21),χ(2) = 2.864, P = 0.091) . The multivariate analysis showed that post-treatment lymphatic node status was the only prognostic factor to 3-year DFS (Wald = 4.454, P = 0.035) . CONCLUSIONS: Lateral resection margin and post-treatment lymphatic node status play an important role on DFS for patients with low rectal cancer after neoadjuvant chemoradiotherapy. The distance from anal verge is correlated with 3-year disease-free survival. Patients with tumor at 4-5 cm from annal verge can not benefit for survival when they get sphincter-preserving operations.

[Outcome of laparoscopic radical right hemicolectomy with complete mesocolic resection and D3 lymphadenectomy].

OBJECTIVE: To investigate the feasibility of laparoscopic approach for totally mesocolic resection and D3 lymphadenectomy in right colectomy. METHODS: A retrospective study was conducted to analyze the operating time, blood loss, lymph node retrieval, postoperative complications and converting rate. The relationships of 3-year disease-free survival (DFS), 3-year overall survival (OS) to gender, age, American Society of Anesthesiologists (ASA) score, body mass index (BMI), T-staging, N-staging and TNM classification were also analyzed by Kaplan-Meier surviving curve and Log-rank test. RESULTS: A total of 111 patients were enrolled in present study. There were 50 male and 61 female patients. The average operating time was (168 ± 42) minutes, blood loss was (81 ± 63) ml, lymph node retrieval was (30 ± 12). The converting rate to open surgery was 1.8%. There was no death within 30 days after operation. The 3-year DFS and 3-year OS was 86.5% and 93.7% respectively. The short-term complications occurred in 17.1% of the patients, including diarrhea (7 cases), ileus (3 cases), urinary infection (3 cases), wound dehiscence (2 cases) and so on. With the T staging progress, DFS and OS in patients showed a gradual decline, but the difference did not reach statistical significance (P > 0.05). TNM classification had relation to DFS (χ(2) = 6.985, P = 0.030), while N-staging showed significant relations both to DFS and OS (χ(2) = 14.397, P = 0.001; χ(2) = 16.699, P = 0.000). CONCLUSION: Laparascopic approach to right hemicolectomy with complete mesocolic resection and D3 lymphadenectomy is safe and has satisfied oncological outcome.

[Postoperative pathological staging correlates the prognosis of rectal cancer after neoadjuvant chemoradiotherapy].

OBJECTIVE: The present study assessed the pathological staging features of rectal cancer after neoadjuvant chemoradiotherapy, and its relation to prognosis. METHODS: Pathologic data related to TNM classification were analyzed on the surgical specimens of 135 patients with mid-low rectal cancer after neoadjuvant themoradiotherapy from 2005 to 2012. Tumor invasion, nodal status, local invasive factors (including cancer deposit, radial margin, perivascular or perineural invasion) were investigated with patients' 3-year disease-free survival (DFS). RESULTS: The overall 3-year DFS was 85.2%, with a pathological complete response (pCR) rate of 19.26%. Three out of 29 patients (10.4%) with ypT0 were found to have positive lymph nodes. There was a trend towards decreased survival as the ypT category and ypTNM staging increased (χ(2) = 14.296 and 52.643, P = 0.006 and 0.000). ypT0-T2 in T category and yp0-I in TNM staging showed a favorable survival above 92%, while the patients with ypT3, or ypIIIB had a comparable lower DFS of 70.2% and 46.7%. DFS in patients with negative lymph node were significantly improved than those with positive nodes (93.5% vs. 66.7%, χ(2) = 34.125, P = 0.000). Patients with or without local invasive factor significantly differed in DFS (42.9% vs. 90.1%, χ(2) = 32.666, P = 0.000) . Cox regression analyze showed that the nodal status (RR = 12.312, 95%CI: 2.828-39.258, P = 0.000) and local invasive factors (RR = 5.422, 95%CI: 1.202-8.493, P = 0.020) were independent risk factors to 3-year survival. As the concept of clinical complete response (cCR) is obscure, there were 27.6% of patients with ypT0 had normal mucosa or no evidence of tumor by EUS or MRI tests before surgery. CONCLUSION: Postoperative pathologic staging features were closely associated with patient's prognosis. The increasing of ypT or ypTNM staging was correlated to decreasing of DFS. Nodal status, positive radial margin, perivascular and perineural invasion were independent risk factors to DFS. Since cCR did not correlate and could not predict pCR, the ongoing radical surgery could not be avoided even there was no evidence of tumor existing before operation.

The ratio of skeletal muscle mass to body mass index combined with inflammatory immune markers to stratify survival of pancreatic cancer after pancreatoduodenectomy.

BACKGROUND: We sought to combine skeletal muscle index and inflammatory immune markers to stratify long-term survival in patients with pancreatic cancer after pancreatoduodenectomy (PD). METHODS: A total of 581 patients with pancreatic cancer underwent PD were included, and divided into the training and validation cohort. Image analysis of computed tomography scans was used to calculate the ratio of skeletal muscle (SM) area to body mass index (BMI). Naples prognostic score (NPS) was calculated from blood-test inflammatory immune markers. Propensity score matching (PSM) analysis was performed to minimize biases of clinicopathological characteristics. To estimate the overall survival (OS), a nomogram was developed using the training cohort. The predictive accuracy of nomogram was estimated by concordance index (C-index), calibration curve, and receiver operating characteristics (ROC) curve. RESULTS: After PSM analysis, SM/BMI ratio, NPS, lymph node metastasis, TNM stage, surgical margin, tumor grade and adjuvant therapy were independent predictors of OS, which were all assembled into nomogram. The SM/BMI ratio was the best single-predictor for 3- and 5-year OS, with an AUC of 0.805 (95% CI: 0.755-0.855) and 0.812 (95% CI: 0.736-0.888), respectively. Harrell's c-index of the nomogram in the training cohort was 0.786 (95% CI: 0.770-0.802), and the area under ROC curve of 1-year, 3- and 5-year OS prediction were 0.869 (95%CI: 0.837-0.901), 0.846 (95%CI: 0.810-0.882) and 0.849 (95%CI: 0.801-0.896). CONCLUSIONS: The nomogram based on SM/BMI ratio and NPS had excellent predictive performance, which should be incorporated to conventional risk scores to stratify survival of patients with PDAC after PD.

MiR-200b-3p elevates 5-FU sensitivity in cholangiocarcinoma cells via autophagy inhibition by targeting KLF4.

Cholangiocarcinoma is one of the most lethal human cancers, and chemotherapy failure is a major cause of recurrence and poor prognosis. We previously demonstrated that miR-200 family members are downregulated in clinical samples of cholangiocarcinoma and inhibit cholangiocarcinoma tumorigenesis and metastasis. However, the role of differentially expressed miR-200b-3p in 5-fluorouracil chemosensitivity remains unclear. Here, we examined how miR-200b-3p modulates 5-fluorouracil chemosensitivity in cholangiocarcinoma. We observed that miR-200b-3p was associated with 5-fluorouracil sensitivity in cholangiocarcinoma and increased 5-fluorouracil-induced mitochondrial apoptosis in cholangiocarcinoma cells. Mechanistically, miR-200b-3p suppressed autophagy in cholangiocarcinoma cells to mediate 5-fluorouracil sensitivity. Further, we identified KLF4 as an essential target of miR-200b-3p in cholangiocarcinoma. Notably, the miR-200b-3p/KLF4/autophagy pathway augmented the chemosensitivity of cholangiocarcinoma cells to 5-fluorouracil. Our findings underscore the key role of miR-200b-3p in chemosensitivity to 5-fluorouracil and highlight the miR-200b-3p/KLF4/autophagy axis as a potential therapeutic target for cholangiocarcinoma.

[Acquiring laparoscopic skill for colorectal surgery: based on the experience of a colorectal surgeon].

OBJECTIVE: Laparoscopic colorectal surgery is a skill-dependent procedure. The present study aims to analyze the learning curve of a properly trained surgeon, with basic laparoscopic techniques, to become skillful in performing laparoscopic colorectal operations. METHODS: A series of non-selective, consecutive 189 cases of laparoscopic colorectal surgery were accomplished, from December 2009 to February 2012, by one surgeon with years of skilled technique in laparoscopic cholecystectomy, rich experience in assisting laparoscopic colorectal surgery, and experience of approximately 180 procedures of gastric and colorectal surgery annually. 170 out of 189 procedures were radical operations for colorectal neoplasma, including right colectomies in 28 cases, left colectomies in 5 cases, sigmoidectomies in 28 cases, high Dixon procedures in 45 cases, low Dixon (total mesorectal excision, TME) procedures in 41 cases and Miles procedure in 23 cases. 19 other patients underwent combined procedures for multi-primary tumors or inflammatory enteritis. All these procedures were analyzed according to time span (the earlier half and later half) in respect to length of surgery, intraoperative blood loss, number of lymph nodes retrieved, intraoperative events and postoperative complications. RESULTS: For radical right colectomy, the D2 dissection conducted in the earlier phase (n = 8) had the similar length of surgery, more blood loss and less LN retrieval, compared with the D3 dissection conducted in recent phase (n = 20). The earlier performed high Dixon procedures (n = 22) consumed longer time than the later procedures (n = 23) consumed, but with similar blood loss and LN retrieval. Low Dixon (TME) procedures showed significant differences in length of surgery and blood loss relative to time span. Recently performed simoidectomy and Miles procedures showed a trend of shorter time consumed compared with earlier performed procedures. Conversion ratio to open surgery was 1.05%. Adverse effects occurred in 8 cases of surgeries, including intestinal injury (3/189), insufficient distal margin (2/189), intraoperative bleeding (2/189) and vaginal injury (1/76). There was no operative death. Chief complications included urinary retention 5.82%, ileus 4.76%, anastomotic leak 4.24%, perineal infection 23.08% (6/26), wound dehiscence 2.65%, gastrointestinal bleeding 1.59%, peritoneal infection 1.06%. Surgery for distal rectum tended to have more complications, such as urinary retention, anastomotic leak and perineal infection. The later performed low Dixon procedures produced insignificantly fewer anastomotic leaks than those in the earlier phase. CONCLUSIONS: For a trained surgeon with basic laparoscopic techniques, there are at least 15 - 25 cases of different procedures needed for him/her to become skilled to perform laparoscopic surgery. The learning curve should also depend on the annual number of colorectal surgeries.

Targeting the alterations of ARID1A in pancreatic cancer: tumorigenesis, prediction of treatment, and prognostic value.

The chromatin remodeling gene AT-rich interactive domain 1A (ARID1A), encoding a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is one of the most frequently mutated chromatin regulators across a broad spectrum of cancers. Most of the ARID1A alterations are inactivating, leading to the loss or reduced expression of the protein. Recently, ARID1A has been demonstrated as a tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC), as its inactive alterations attribute to carcinogenesis. Importantly, ARID1A alterations are revealed as predictive biomarkers for the selection of targeted therapy and immune checkpoint blockade (ICB) therapy. In PDAC, the application of ARID1A alterations in stratifying patients for precise treatment has also been widely explored in preclinical and early clinic studies with encouraging preliminary results. Furthermore, the prognostic value of ARID1A mutations in PDAC has been suggested by various studies. In this review, we focus on the functions of ARID1A alterations in PDAC, particularly their functions during carcinogenesis and their predictive value in treatment selection and prognosis, to provide a comprehensive overview on our current understanding of ARID1A alterations in PDAC.

The Impact of Preoperative and Postoperative Malnutrition on Outcomes for Ampullary Carcinoma After Pancreaticoduodenectomy.

PURPOSE: The aim of this study was to investigate the effect of preoperative and postoperative malnutrition on postoperative short- and long-term outcomes for ampullary carcinoma after pancreatoduodenectomy (PD). METHODS: Data were collected retrospectively from 511 patients with ampullary carcinoma who underwent PD between June 2012 and June 2019. Nutritional status before and at 3, 6, and 12 months after operation was assessed by the scored Patient-Generated Subjective Global Assessment (PG-SGA). The patients were classified into well-nourished, moderately malnourished, and severely malnourished group according to the PG-SGA score. Propensity score matching (PSM) was performed to adjust baseline characteristics between preoperative group A (well-nourished and moderately malnourished group) and group B (severely malnourished group). After PSM, clinicopathological variables and postoperative complications were compared between the two groups. Univariate and multivariate Cox analysis was also conducted to investigate the prognostic factors of overall survival of patients with ampullary carcinoma who underwent PD. RESULTS: Preoperatively, 122 (23.9%) patients were classified into well-nourished group, 189 (37.0%) into moderately malnourished group, and 200 (39.1%) into severely malnourished group. After PSM analysis, the incidence of overall postoperative complications was higher in group B than that in group A (50.5% vs. 32.5%, p < 0.001). Multivariate Cox proportional hazards regression model showed that severe malnutrition (PG-SGA score >9 scores) before operation [hazard ratio (HR) = 1.508; 95% CI, 1.103-2.061; p = 0.01] and at 6 months (HR = 4.148; 95% CI, 2.523-6.820; p < 0.001) and 12 months (HR = 5.272; 95% CI, 3.630-7.656; p < 0.001) after operation was an independent prognostic factor of patients who underwent PD for ampullary carcinoma. CONCLUSIONS: Severe malnutrition before and at 6 and 12 months after operation significantly affects the long-term survival of patients with ampullary carcinoma who underwent PD. Additionally, the preoperative malnutrition was closely related to postoperative complications.

Long Noncoding Competing Endogenous RNA Networks in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial-mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.

Predictive factors of postoperative pancreatic fistula after laparoscopic pancreatoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) continues to be a major contributor to morbidity after pancreaticoduodenectomy (PD), but it remains unclear what risk factors can precisely predict the development of CR-POPF after laparoscopic pancreatoduodenectomy (LPD). We thus aimed to identify the risk factors for predicting CR-POPF after LPD. METHODS: A total of 388 consecutive patients who underwent LPD at our institution between July 2014 and December 2018 were identified. All data, including pre-, intra-, and postoperative risk factors associated with CR-POPF defined by the International Study Group of Pancreatic Fistula, were collected retrospectively. To evaluate the predictive performance of the risk factor models, areas under the receiver operating characteristic curve (ROC) were determined. RESULTS: CR-POPF was observed in 31 patients (8.0%) with significant association observed with body mass index (BMI), visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA), intra-abdominal fat thickness, main pancreatic duct width, soft pancreatic texture, operative time, underlying pathology, and albumin (Alb) on postoperative days (POD) 1--3. Multivariate analyses revealed that VFA >82 cm2 [odds ratio (OR) =11.088; P=0.029], main pancreatic duct width <3 mm (OR =7.701; P=0.001), soft pancreatic texture (OR =12.543; P=0.022), and operative time >320 min (OR =6.061; P<0.001) were independent risk factors for CR-POPF after LPD. Areas under the ROC curve (AUC) analysis revealed the pancreatic texture was the strongest single predictor (AUC =0.854) of CR-POPF, and pancreatic texture + pancreatic duct width was the best two-predictor model (AUC =0.904). Meanwhile, our findings indicated an association between the TFA >221 cm2 (OR =8.637; P=0.001) and VFA >82 cm2 (OR =7.009; P<0.001) with soft pancreatic texture. CONCLUSIONS: Soft pancreatic texture, VFA >82 cm2, main pancreatic duct width <3 mm, and operative time >320 min were independent predictive risk factors of CR-POPF for LPD.

Prognostic significance of preoperative Naples prognostic score on short- and long-term outcomes after pancreatoduodenectomy for ampullary carcinoma.

BACKGROUND: The Naples prognostic score (NPS) is an effective and objective tool to assess the immune-nutritional status of patients with malignant tumors. The aim of this study was to investigate the clinical significance of preoperative NPS on short- and long-term outcomes after pancreatoduodenectomy (PD) for ampullary carcinoma. METHODS: We retrospectively analyzed 404 consecutive patients with ampullary carcinoma who underwent PD between January 2012 and June 2018. Preoperative NPS was calculated from serum albumin and total cholesterol concentrations, and the neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio (LMR). Patients were then divided into three groups according to their NPS. Clinicopathological variables, postoperative outcomes, and survival data were compared between the three groups. Univariate and multivariate Cox analysis of overall survival (OS) and recurrence-free survival (RFS) were also conducted, and time-dependent receiver operating characteristic (ROC) curves were created to evaluate the discriminatory ability of the prognostic scoring systems. RESULTS: Patients with higher NPS had worse prognosis, and significant OS difference (group 0 vs. 1, P=0.02; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001) and RFS difference (group 0 vs. 1, P=0.088; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001). Multivariate analysis revealed that NPS was an independent significant predictor of OS (grade 2 vs. grade 1 or 0, hazard ratio: 3.067; P<0.001) and RFS (grade 2 vs. grade 1 or 0, hazard ratio: 2.732; P<0.001). The time-dependent receiver operating curve analysis showed that NPS had better prognostic performance for OS and RFS than other prognostic models. Additionally, significant differences in the incidence of postoperative morbidity were observed between the three groups, and the NPS was an independent risk factor of overall postoperative complications (grade 2 vs. grade 1 or 0, odds ratio: 1.692; P=0.02). CONCLUSIONS: The NPS was an independent predictor of overall- and RFS in patients undergoing PD for ampullary carcinoma, and was independently associated with the incidence of postoperative complications.

A randomised, multicentre trial of somatostatin to prevent clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.

BACKGROUND: Prophylactic somatostatin to reduce the incidence of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy remains controversial. We assessed the preventive efficacy of somatostatin on clinically relevant postoperative pancreatic fistula in intermediate-risk patients who underwent pancreaticoduodenectomy at pancreatic centres in China. METHODS: In this multicentre, prospective, randomised controlled trial, we used the updated postoperative pancreatic fistula classification criteria and cases were confirmed by an independent data monitoring committee to improve comparability between centres. The primary endpoint was the rate of clinically relevant postoperative pancreatic fistula within 30 days after pancreaticoduodenectomy. RESULTS: Eligible patients (randomised, n = 205; final analysis, n = 199) were randomised to receive postoperative intravenous somatostatin (250 µg/h over 120 h; n = 99) or conventional therapy (n = 100). The primary endpoint was significantly lower in the somatostatin vs control group (n = 13 vs n = 25; 13% vs 25%, P = 0.032). There were no significant differences for biochemical leak (P = 0.289), biliary fistula (P = 0.986), abdominal infection (P = 0.829), chylous fistula (P = 0.748), late postoperative haemorrhage (P = 0.237), mean length of hospital stay (P = 0.512), medical costs (P = 0.917), reoperation rate (P > 0.99), or 30 days' readmission rate (P = 0.361). The somatostatin group had a higher rate of delayed gastric emptying vs control (n = 33 vs n = 21; 33% vs 21%, P = 0.050). CONCLUSIONS: Prophylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy. TRIAL REGISTRATION: NCT03349424.

Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models.

PURPOSE: Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. EXPERIMENTAL DESIGN: In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA-based high-content screening was implemented to validate the function of the deregulated genes. RESULTS: The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. CONCLUSIONS: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.

OLR1 Promotes Pancreatic Cancer Metastasis via Increased c-Myc Expression and Transcription of HMGA2.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, the mechanisms of metastasis in pancreatic cancer remain unclear. Oxidized low-density lipoprotein receptor 1 (OLR1), a lectin-like scavenger receptor that recognizes several ligands, such as oxidized low-density lipoprotein, was previously reported in cardiovascular and metabolic diseases. The role and mechanism of OLR1 in pancreatic cancer is unclear. In this study, we found that OLR1 expression was significantly higher in pancreatic cancer tissues than that in adjacent normal tissues and closely associated with reduced overall survival. OLR1 promoted proliferation and metastasis of pancreatic cancer cells in vitro and in vivo. Mechanistically, OLR1 increased HMGA2 transcription by upregulating c-Myc expression to promote the metastasis of pancreatic cancer cells. In addition, patients with pancreatic cancer with high expression of OLR1-c-Myc-HMGA2 axis showed worse prognosis compared with patients with low expression of OLR1-c-Myc-HMGA2 axis. IMPLICATIONS: Our findings suggested that the OLR1-c-Myc-HMGA2 axis promotes metastasis of pancreatic cancer cells and may serve as potential therapeutic targets and prognosis markers for patients with pancreatic cancer.

Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer.

BACKGROUND: Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. METHODS: Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. RESULTS: Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. CONCLUSION: Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

Glucagonoma and the glucagonoma syndrome.

Glucagonoma is an extremely rare pancreatic α-islet cell tumor and is often accompanied by certain clinical symptoms including necrotizing migratory erythema (NME), diabetes, weight loss and anemia. The objectives of the current review were to discern the clinical features, diagnosis, treatment and prognosis of glucagonoma by evaluating 623 reported cases. A 1998 study reviewed 407 cases and 216 cases were reported in studies published after 1998. The current review consisted of 268 males and 339 females, with an average age of 52.4 years. The male-to-female ratio was 0.79. The incidence of typical clinical findings were as follows: NME, 82.4% (350/425); diabetes, 68.5% (291/425); weight loss, 60.2% (256/425); anemia, 49.6% (211/425); and glossitis or stomatitis or cheilitis, 41.2% (175/425). A total of 499 cases reported the location of the tumor as the pancreas and 64.1% (320/499) involved the pancreatic tail. Tumor size was recorded in 58.3% (126/216) cases reported after 1998 and average tumor size was 5.0 cm. Metastasis was detected in 49.2% of patients (293/595 for whom metastasis or no metastasis were recorded) upon diagnosis. These patients were older than those without metastasis (average age, 54.0 years old vs. 50.8 years old). The average time between symptoms and diagnosis of glucagonoma was 31.4 months. Glucagonoma is a very rare disease. It is important for clinicians to learn more about this disease to be able to diagnose and treat it as early as possible, thus improving patient prognosis.

MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.

BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.

BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.