Role of the intratumoral microbiome in tumor progression and therapeutics implications.

Microbes are widely present in various organs of the human body and play important roles in numerous physiological and pathological processes. Nevertheless, owing to multiple limiting factors, such as contamination and low biomass, the current understanding of the intratumoral microbiome is limited. The intratumoral microbiome exerts tumor-promoting or tumor-suppressive effects by engaging in metabolic reactions within the body, regulating signaling cancer-related pathways, and impacting both host cells function and immune system. It is important to emphasize that intratumoral microbes exhibit substantial heterogeneity in terms of composition and abundance across various tumor types, thereby potentially influencing diverse aspects of tumorigenesis, progression, and metastasis. These findings suggest that intratumoral microbiome have great potential as diagnostic and prognostic biomarkers. By manipulating the intratumoral microbes to employ cancer therapy, the efficacy of chemotherapy or immunotherapy can be enhanced while minimizing adverse effects. In this review, we comprehensively describe the composition and function of the intratumoral microbiome in various human solid tumors. Combining recent advancements in research, we discuss the origins, mechanisms, and prospects of the clinical applications of intratumoral microbiome.

The characteristics of serum lipid spectrum in PanNENs and its correlation with clinicopathological features and prognosis.

Background: The role of dyslipidemia in pancreatic neuroendocrine tumors (PanNENs) is unclear. The aim of this study is to analyze the characteristics of serum lipid spectrum in PanNENs, and the effect of the variation in lipid profile on the development of PanNENs clinicopathological features and prognosis. Methods: All PanNENs patients between November 2012 and September 2020 in the authors' research center were identified from patient medical records and databases. A total of 185 with PanNENs patients were ultimately included in this study, including 100 nonfunctional PanNENs and 85 insulinomas. Clinicopathologic features, serum lipid level and overall survival results were retrospectively analyzed using statistical methods. Results: In 185 PanNENs, 95 (51.4%) patients appear to have dyslipidemia. Patients with insulinoma had a lower proportion of abnormal HDL than those with nonfunctional PanNENs (10.6% vs 23%, P=0.026). The mean serum HDL levels of insulinomas were 0.131 mmol/L higher than the NF-PanNENs (1.306 ± 0.324 vs 1.175 ± 0.315, P=0.006). In multivariate logistic analysis, high levels of HDL are negatively correlated to tumor size (OR 0.233, 95% CI: 0.069-0.790, P=0.019), but HDL was not associated with pathological grade or metastasis. And a correlation has been found between hypercholesterolemia and the original location of the tumor (OR:0.224, 95%CI: 0.066-0.753, P =0.016). In addition, the outcome of the survival analysis revealed that dyslipidemia did not influence the prognosis of PanNENs patients (P>0.05). Conclusions: HDL was negatively correlated with the tumor size of PanNENs. The serum HDL level of insulinoma patients is higher than nonfunctional PanNENs.

Cancer-associated fibroblast-secreted miR-421 promotes pancreatic cancer by regulating the SIRT3/H3K9Ac/HIF-1α axis.

This study was designed to explore the effects of exosomal miR-421 secreted by cancer-associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF-derived exos (CAF-exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR-421, sirtuin-3 (SIRT3), and hypoxia duciblefactors-1 alpha (HIF-1α) levels. Cell counting kit-8 (CCK-8), wound-healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual-luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR-421 and SIRT3. Chromatin immunoprecipitation (f)-verified H3K9Ac enrichment in the HIF-1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR-421 from CAFs on PC. CAFs and exos were successfully isolated. CAF-exo-treated PC cells highly expressed miR-421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR-421 increased the expression of SIRT3. SIRT3 is a target of miR-421, and inhibiting the expression of SIRT3 reversed the negative effects of miR-421 knockdown on PC cell. Knocking down miR-421 in CAF-exo inhibited the expression of HIF-1α in PC cells. Moreover, SIRT3-mediated HIF-1α expression by regulating H3K9Ac. HIF-1α overexpression reversed the inhibiting effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR-421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR-421 attenuated CAF-exo induced tumor growth. Exosomal miR-421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF-1α axis. This study provided insights into the molecular mechanism of PC.

LINC00960 regulates cell proliferation and glycolysis in pancreatic cancer through the miR-326-3p/TUFT1/AKT-mTOR axis.

Pancreatic cancer (PC) is a common malignant cancer characterized by high mortality and poor prognosis. LINC00690 was involved in the occurrence and progression of PC, but the underlying mechanisms require further investigation. The goal of this study was to figure out how LINC00960 mediates glycolysis in PC. LINC00960, miR-326-3p, and Tuftelin 1 (TUFT1) expression levels were detected in PC cell lines. LINC00960 and TUFT1 expression levels were increased in PC cells when compared with normal pancreatic cells, whereas miR-326-3p expression levels were decreased. The expression levels of LINC00690 affected glycolysis in PC, and inhibition of LINC00960 inhibited tumor growth in vivo. LINC00690 targeted and suppressed the expression of miR-326-3p. MiR-326-3p bound to TUFT1, and miR-326-3p inhibited AKT-mTOR pathway activation via TUFT1. In conclusion, the depletion of LINC00960 repressed cell proliferation and glycolysis in PC by mediating the miR-326-3p/TUFT1/AKT-mTOR axis. Thus, we present a novel mechanism underlying the progression of PC that suggests LINC00960 is a potential therapeutic target for this cancer.

Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms.

Despite advances in therapy and achievements in translational research, pancreatic cancer (PC) remains an invariably fatal malignancy. Risk factors that affect the incidence of PC include diabetes, smoking, obesity, chronic pancreatitis, and diet. The growing worldwide obesity epidemic is associated with an increased risk of the most common cancers, including PC. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironment are involved in the association of obesity with PC. Herein, we systematically review the epidemiology of PC and the biological mechanisms that may account for this association. Included in this review is a discussion of adipokine-mediated inflammation, lipid metabolism, and the interactions of adipocytes with cancer cells. We consider the influence of bariatric surgery on the risk of PC risk as well as potential molecular targets of therapy. Our review leads us to conclude that targeting adipose tissue to achieve weight loss may represent a new therapeutic strategy for preventing and treating PC.

Warshaw Technique in Laparoscopic Spleen-Preserving Distal Pancreatectomy: Surgical Strategy and Late Outcomes of Splenic Preservation.

Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) can be accomplished with either the preservation or the resection of splenic vessels; the latter is also known as Warshaw technique. Our study is designed to investigate the operation selection strategy when proceeding LSPDP and to evaluate the long-term outcomes of patients undergoing Warshaw surgery. The medical records and follow-up data of patients who underwent LSPDP in Qilu Hospital, Shandong University, were reviewed retrospectively. A total of thirty-five patients were involved in this study, including 17 cases of patients who were treated with Warshaw procedure (WT) while the other 18 cases had splenic vessels preserved (SVP). Compared with the SVP group, the operative time and intraoperative blood loss in WT group were improved significantly. The incidence of early postoperative splenic infarction was higher in WT group. However, there was no report of splenic abscess or second operation. Follow-up data confirmed that there was no significant difference in spleen phagocytosis and immune function compared with normal healthy population. Our study confirms that LSPDP-Warshaw procedure is a safe and efficient treatment for the benign or low grade malignant tumors in distal pancreas in selected patients. The long-term spleen function is normal after Warshaw procedure. Preoperative assessment and intraoperative exploration are recommended for the selection of operation approaches.

Cystic pancreatic neuroendocrine tumors: A distinctive subgroup with indolent biological behavior? A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The clinicopathological features and biological behaviors of cystic pancreatic neuroendocrine tumors (pNETs) are unclear and controversial. Here we performed a systematic review and meta-analysis to investigate the unique characteristics of cystic pNETs, to determine whether they represent a distinct clinical entity. METHODS: We selected comparative studies published since January 2000 that explore the differences between clinicopathological features of cystic and solid pNETs. Demographic information, pathological characteristics, and survival information were analyzed. RESULT: The 12 selected studies comprised 355 and 1530 patients diagnosed with cystic and solid pNETs, respectively. Compared with solid pNETs, cystic pNETs were less likely to be functional (odds ratio, OR = 0.31, 95% confidence interval (CI) 0.19-0.50, p < 0.00001), more likely to affect males (OR = 1.56, 95% CI 1.22-2.00, p = 0.0005), and significantly associated with multiple endocrine neoplasia type 1 (OR = 2.71). Cystic pNETs were more likely to present with G1 and G2 rather than G3 (OR = 1.66). Cystic pNETs were associated with less frequent distant organs and lymph node metastasis, microvascular invasion, perineural invasion, and a low Ki-67 index and mitotic count. There were no significant differences between 5- and 10-year overall survival. However, the 5-year disease-free survival (DFS) and 10-year DFS rate of patients with cystic pNETs was significantly higher compared with those with solid pNETs (94.6% vs 83.5%, OR = 3.00; 92.7% vs 63.6%, OR = 5.92, respectively). CONCLUSIONS: Cystic pNETs represent a distinct subgroup of pNETs that present with an indolent biological behavior, and patients experience better DFS. Observation and surveillance should be considered in some selected cases.

Immunotherapy for pancreatic cancer: A long and hopeful journey.

Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer.

Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies.

There is a strong rationale and many theoretical advantages for neoadjuvant therapy in pancreatic cancer (PC). However, study results have varied significantly. In this study, a systematic review and meta-analysis of prospective studies were performed in order to evaluate safety and effectiveness of neoadjuvant therapy in PC. Thirty-nine studies were selected (n = 1458 patients), with 14 studies focusing on patients with resectable disease (group 1), and 19 studies focusing on patients with borderline resectable and locally advanced disease (group 2). Neoadjuvant chemotherapy was administered in 97.4% of the studies, in which 76.9% was given radiotherapy and 74.4% administered with chemoradiation. The complete and partial response rate was 3.8% and 20.9%. The incidence of grade 3/4 toxicity was 11.3%. The overall resection rate after neoadjuvant therapy was 57.7% (group 1: 73.0%, group 2: 40.2%). The R0 resection rate was 84.2% (group 1: 88.2%, group 2: 79.4%). The overall survival for all patients was 16.79 months (resected 24.24, unresected 9.81; group 1: 17.76, group 2: 16.20). Our results demonstrate that neoadjuvant therapy has not been proven to be beneficial and should be considered with caution in patients with resectable PC. Patients with borderline resectable or locally advanced disease may benefit from neoadjuvant therapy, but further research is needed.

Early detection of pancreatic cancer: Where are we now and where are we going?

Pancreatic cancer (PC) is one of the most lethal malignancies. Recent studies indicate that patients with incidentally diagnosed PC have better prognosis than those with symptoms and that there is a sufficient window for early detection. However, effective early diagnosis remains difficult and depends mainly on imaging modalities and the development of screening methodologies with highly sensitive and specific biomarkers. This review summarizes recent advances in effective screening for early diagnosis of PC using imaging modalities and novel molecular biomarkers discovered from various "omics" studies including genomics, epigenomics, non-coding RNA, metabonomics, liquid biopsy (CTC, ctDNA and exosomes) and microbiomes, and their use in body fluids (feces, urine and saliva). Although many biomarkers for early detection of PC have been discovered through various methods, larger scale and rigorous validation is required before their application in the clinic. In addition, more effective and specific biomarkers of PC are urgently needed.

Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology.

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease.

LincRNA-ROR promotes invasion, metastasis and tumor growth in pancreatic cancer through activating ZEB1 pathway.

Pancreatic cancer (PC) remains one of the most lethal malignant tumors; early distant metastasis commonly results in poor prognosis. Recent studies confirmed the pivotal role of the long non-coding RNAs (lncRNAs) in tumorigenesis and metastasis of malignant tumors, including PC. However, little is known about the role of LincRNA-ROR (linc-ROR) in PC. In the present study, we found that linc-ROR was upregulated in PC tissues. Overexpression of linc-ROR promoted cells proliferation, migration, invasion and metastasis both in vitro and in a mouse model. Contrarily, knockdown of linc-ROR attenuated proliferation, invasion and distant metastasis. Mechanistically, we confirmed that linc-ROR up-regulates ZEB1 and then induces epithelial-mesenchymal transition (EMT), which promotes the aggressive biological behaviors of PC. Together, these results indicate that linc-ROR acts as an important regulator of ZEB1, can promote invasion and metastasis in PC, and may represent a novel therapeutic target.

Lymph node ratio is an independent prognostic factor for patients after resection of pancreatic cancer.

BACKGROUND: The prognostic value of lymph node ratio (LNR) in pancreatic cancer remains controversial. In the current retrospective study, we assessed the value of LNR on predicting the survival of postoperative patients with pancreatic cancer. METHODS: Medical records of patients who underwent pancreatic resection for pancreatic cancer in the department of general surgery, Qilu Hospital, Shandong University were reviewed retrospectively. Demographic, clinicopathological, tumor-specific data, and histopathological reports were collected. Univariate and multivariate survival analyses were performed. RESULTS: A total of 83 patients with pancreatic cancer were collected. The mean number of examined LN was 8.2 ± 6.1 (0 to 26). Differential degree (low) (P = 0.019, hazard ratio (HR) = 2.276, 95% confidence interval (CI): 1.171 to 4.424) and LNR >0.2 (P = 0.018, HR = 2.685, 95% CI: 1.253 to 5.756) were independent adverse prognostic factors according to the multivariate survival analysis. CONCLUSIONS: Our study indicated that LNR >0.2 was an independent adverse prognostic factor for pancreatic cancer, which may provide important information for prognostic assessment.

Pancreatic cancer stem cells: new insight into a stubborn disease.

Resistance to conventional therapy and early distant metastasis contribute to the unsatisfactory prognosis of patients with pancreatic cancer. The concept of cancer stem cells (CSCs) brings new insights into cancer biology and therapy. Many studies have confirmed the important role of these stem cells in carcinogenesis and the development of hematopoietic and solid cancers. Recent studies have shown that CSCs regulate aggressive behavior, recurrence, and drug resistance in pancreatic cancer. Here, we review recent advances in pancreatic cancer stem cells (PCSCs) research. Particular attention is paid to the regulation mechanisms of pancreatic cancer stem cell functions, such as stemness-related signaling pathways, microRNAs, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment, and the development of novel PCSCs targeted therapy. We seek to further understand PCSCs and explore potential therapeutic targets for pancreatic cancer.

[Pancreatic acinar cell carcinoma: diagnostic and surgical treatment strategy].

OBJECTIVE: To investigate the clinical features, diagnostic and therapeutic strategy of pancreatic acinar cell carcinoma. METHODS: The data of pancreatic acinar cell carcinoma patients who underwent surgical operations from January 2002 to January 2012 were retrospectively reviewed. RESULTS: Six cases of pancreatic acinar cell carcinoma, identified with pathology were collected, including 3 males and 3 females with the average of 47.8 yeas old. Upper abdominal pain was present in 5 cases, weight loss was present in 4 cases with the average of 12.5 kg. Other symptoms included nausea/vomiting, back pain and obstructive jaundice. The serum CA19-9 and CA24-2 level were significantly elevated in 2 cases. CT scan, MRI and DSA were the main imaging methods to diagnose this disease. However, no case was diagnosed as pancreatic acinar cell carcinoma before operation. All cases were confirmed by the pathological examination. Relatively high rates of surgical resection, long operative time, more blood loss and combined multi-organ resection were the characteristics of this disease's operative surgical procedures. The average period of postoperative follow-up process was 60 months, and the mean survival time was (32 ± 8) months. CONCLUSIONS: The clinical features and biological behavior of pancreatic acinar cell carcinoma are different from those of ductal adenocarcinoma, while the relatively specific clinical manifestations and imaging changes will be helpful for qualitative diagnosis before operation. As it has high rate of resection and better prognosis, more radical surgical strategies should be carried out for patients of this disease.

Risk factors for the occurrence of insulinoma: a case-control study.

BACKGROUND: The etiology of insulinoma is poorly understood. Few studies investigated the possible roles of environmental factors and lifestyle in the pathogenesis of insulinoma. The aim of this study is to identify risk factors associated with occurrence of insulinoma in the Chinese population. METHODS: This study consisted of 196 patients with insulinoma and 233 controls. Demographic information of the patients and controls and risk factors of the disease were analyzed. Univariate and unconditional multivariable logistic regression analyses were made to estimate odds ratios (ORs) and possible risk factors. RESULTS: Approximately 68.88% (135/196) of the patients were from rural areas in contrast to 10.30% (24/233) of the controls (P<0.0001). This difference was confirmed by the multivariate analysis (OR=4.950; 95% CI: 2.928-8.370). Family history of pancreatic endocrine tumor (OR=16.754; 95% CI: 2.125-132.057) and other cancers (OR=2.360; 95% CI: 1.052-5.291) was also related to a high-risk population of insulinoma. CONCLUSION: Rural residents or people who have a family history of pancreatic endocrine tumor and other cancers are a high-risk population of insulinoma.

Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis.

BACKGROUND: Insulinoma was a rare tumor and its pathogenesis was poorly understood. There had no study that focused on the role of mTOR signaling pathway in insulinoma tumorigenesis. MATERIALS AND METHODS: Expression of p-mTOR and its downstream p-P70S6K in insulinoma and normal pancreatic tissue was evaluated by immunohistochemical staining and Western blotting. In vitro study, an insulinoma cell line (INS-1) was treated with inhibitors of mTOR (rapamycin) or dual PI3K/mTOR inhibitor (NVP-BEZ235), RT-PCR, and Western blotting were applied to evaluate their influence on the expression of mTOR and P70S6K. Cell proliferation was evaluated by MTT test, cell cycle and apoptosis were analyzed by flow cytometry, insulin secretion level was evaluated by GSIS method. RESULTS: Positive expression of p-mTOR and p-P70S6K was much higher in insulinoma tumor specimens than the normal pancreatic islet (P < 0.05). mTOR inhibitors can induce decreased expression of mTOR and P70S6K, which resulting in inhibiting INS-1 cell proliferation, insulin secretion and inducing apoptosis. NVP-BEZ235 had better influence on inhibiting the cell proliferation and inducing apoptosis than rapamycin. CONCLUSION: mTOR/P70S6K signaling pathway is involved in tumorigenesis of insulinoma, NVP-BEZ235 and rapamycin offer a promising role as novel drugs in treatment of insulinoma.

Risk factors for postoperative pancreatic fistula in patients with insulinomas: analysis of 292 consecutive cases.

BACKGROUND: Pancreatic fistula (PF) remains the most challenging complication in pancreatic surgery, yet few published studies have focused on the risk factors for postoperative PF in patients undergoing surgery for insulinomas. METHODS: From January 1990 to February 2010, a total of 292 patients with insulinomas underwent surgery at Peking Union Medical College Hospital. Demographic data, intraoperative procedures, and postoperative data were collected. Particular attention was paid to variables associated with PF as defined by the International Study Group of Pancreatic Fistula (ISGPF). Univariate and multivariate analyses were used to identify possible risk factors for PF. RESULTS: PF was found in 132 (45.2%) patients, of whom 90 were classified into ISGPF grade A, 33 grade B, and 9 grade C. Multivariate analysis showed that male patients (OR=2.56; P=0.007) and operative time >180 minutes (OR=3.756; P<0.0001) were independent risk factors for clinical PF. Pancreatic resection with stapler was a protective factor for both total PF (OR=0.022; P=0.010) and clinical PF (OR=0.097; P=0.007). CONCLUSIONS: Male gender and operative time >180 minutes were independent risk factors for clinical PF, while pancreatic resection with a stapler was a protective factor. Whether body mass index (BMI) and other variables during operation are risk factors of PF needs further study.

Prognostic factors after pancreatoduodenectomy for distal bile duct cancer.

Prognostic factors influencing long-term survival after radical resection for distal bile duct cancer have not been well established because of the rarity of this malignancy. The goal of this study was to identify main prognostic factors in patients undergoing pancreatoduodenectomy for distal bile duct carcinoma. A retrospective study consisting of 122 patients with distal bile duct cancer who underwent pancreatoduodenectomy in three major university hospitals was performed to identify the main prognostic factors. Major surgical complications occurred in 40 patients (32.8%), of whom eight died (6.6%) in the hospital. Overall actuarial survival (excluding hospital deaths) at 1-, 3-, and 5-year follow-up was 82.9, 49.4, and 32.7 per cent, respectively, with a median survival of 36 months. Univariate analysis showed that papillary tumor (P = 0.045), negative surgical margin (R0 resection, P = 0.005), earlier pT (P = 0.005), pTNM stage (P < 0.001), and absence of lymph node involvement (P < 0.0001) were significant predictors of survival. On multivariate analysis, only lymph node metastasis was shown to be an independent prognostic factor of survival (P = 0.036). Lymph node involvement was the most important survival predictor after a Whipple resection in patients with distal cholangiocarcinoma.

Surgical management of patients with insulinomas: Result of 292 cases in a single institution.

BACKGROUND: Insulinoma is rare tumor with an incidence of approximately four cases per million per year. There are few large sample, single-center series that focus on the surgical management strategy of insulinomas. PATIENTS AND METHODS: Medical records of patients diagnosed as insulinoma from 1990 to 2010 in Peking Union Medical College Hospital were reviewed retrospectively. Clinical data were collected and statistically analyzed. RESULTS: A total of 328 patients were diagnosed with insulinomas; 292 of them underwent 320 operations, which included 46 laparoscopic surgeries. Tumor enucleation was the most common operative procedure. Multiple tumors were found in 30 cases; 17 cases were multiple endocrine neoplasia-1 syndrome. Thirteen patients with malignant insulinomas underwent tumor resection. Pancreatic fistula (PF) was the most frequent complication, and the incidence of clinical PFs (Grades B and C) was 14.4%. There was no significant statistical difference between open and laparoscopic surgery in blood loss, operative time, and complications. Metachronous tumors were noted in 11 patients. CONCLUSION: Surgery is the best treatment of choice for insulinoma patients. Surgical approach depends on tumor size, location, and its pathological characters. Laparoscopic management of insulinomas is feasible and safe for tumors located in the body or tail of the pancreas. Open surgery combined with intraoperative ultrasonography is recommended to avoid omission of lesions in patients with multiple insulinomas. An aggressive surgical approach is indicated for malignant insulinoma patients.