Preoperative pancreatic stent placement before the enucleation of insulinoma located in the head and neck of the pancreas in proximity to the main pancreatic duct: study protocol for a multicentre randomised clinical trial in Chinese tertiary medical centres.

INTRODUCTION: The surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct. METHODS AND ANALYSIS: This is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests. ETHICS AND DISSEMINATION: The study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05523778.

Outcomes of endoscopic ultrasound-guided ablation and minimally invasive surgery in the treatment of pancreatic insulinoma: a systematic review and meta-analysis.

Background and aims: Most pancreatic insulinomas can be treated by minimally invasive modalities. The aim of this meta-analysis was to assess the clinical outcomes of endoscopic ultrasound (EUS)-guided ablation and minimally invasive surgery (MIS) in the treatment of pancreatic insulinoma. Materials and methods: Online databases were searched for relevant studies. The primary aim was to compare the rates of adverse events (AEs) and the secondary aims were to compare the clinical and technical success rates, length of hospital stays, and symptom recurrence rates between EUS and MIS approaches. Results: Eight studies with 150 patients were identified that reported EUS-guided ablation outcomes, forming the EUS group, and 9 studies with 236 patients reported MIS outcomes, forming the MIS group. The pooled median age of the included patients in the EUS group was greater than that of the MIS group (64.06 vs. 44.98 years old, p < 0.001). Also, the technical success rate was significantly higher in the EUS group (100% vs. 96.6%, p = 0.025), while the clinical success was significantly higher (6%) in the MIS group (94% vs. 98.7%, p = 0.021). The AE rates (18.7% vs. 31.1%, p = 0.012) and severe AE rates (1.3% vs. 7.9%, p = 0.011) were significantly lower in the EUS group. The median length of hospital stay in the EUS group (2.68 days, 95% CI: 1.88-3.48, I2 = 60.3%) was significantly shorter than in the MIS group (7.40 days, 95% CI: 6.22-8.58, I2 = 42.2%, p < 0.001). The recurrence rate was significantly higher in the EUS group (15.3% vs. 1.3%, p < 0.001). Conclusions: EUS-guided ablation is associated with a lower AE rate and a shorter length of hospital stay, but a higher recurrence rate for the treatment of insulinoma compared with MIS. The EUS approach may be an alternative, even first-line, treatment for poor surgery candidates.

[Current views on the treatment of insulinoma].

RELEVANCE: Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma. AIM: Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used. MATERIALS AND METHODS: Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science. RESULTS: The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used. CONCLUSION: The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma: a state of the art review.

INTRODUCTION: Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs) that lead to incapacitating hypoglycemia. Guidelines recommend surgical resection as the mainstay of management. However, surgery is fraught with complications, causing significant peri/post-operative morbidity. Since insulinomas are usually benign, solitary, small (<2 cm), and do not need lymphadenectomy, hence, in this regard, endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is now being increasingly performed, to circumvent these adverse events and impairment of pancreatic function. AREAS COVERED: A comprehensive literature search was undertaken across various databases (PubMed/MEDLINE, Embase, Scopus), with no language restriction, for relevant articles (case series, reviews, case reports) pertaining to EUS-RFA for insulinoma and PNETs, till October 2023. In this review, we have explicated the role of EUS-RFA for insulinoma management, detailing thoroughly its mechanism of action, EUS-RFA devices with data on its safety and efficacy, and an algorithmic approach for its management. EXPERT OPINION: EUS-RFA is being advocated as a 'mini-invasive' option with the potential to replace surgery as a first-line approach for benign, sporadic, solitary, and small (<2 cm) insulinomas. Under real-time guidance, EUS-RFA has immense precision, is safe, predictable, with acceptable safety profile. Presently, it is being frequently performed for high-risk or inoperable candidates. Current need-of-the-hour is a randomized controlled trial to substantiate its role in the therapeutic algorithm for insulinoma management.

Intraoperative segmental pancreatic occlusion and insulin assay combination optimizes the localization of lesions and confirmation of complete resection in pancreatic hypoglycemia patients.

AIM: To evaluate the efficacy of the application of intraoperative segmental pancreatic occlusion and insulin assay in surgical procedures for pancreatic hypoglycemia. METHODS: We retrospectively analyzed the clinical data of 11 pancreatic hypoglycemia cases treated in the China-Japan Friendship Hospital between September 2015 and August 2021. Intraoperative segmental pancreatic occlusion and insulin assay were used to enhance hypersecretory pancreatic tissues' localization and to achieve a complete resection. Intraoperative testing of insulin levels (peripheral venous blood) was carried out at several time points starting from before the resection of hypersecretory tissues (base value) and at 1 minute, 5 minutes, 15 minutes, 30 minutes, and 60 minutes after resection. Additional testing every 30 minutes until the end of the operation was carried out when necessary. RESULTS: A total of 11 pancreatic hypoglycemia cases were included; 9 cases were insulinomas (all with single pancreatic lesions, with 4 located in the head, 1 in the body, and 4 in the tail), 1 MEN-1, and 1 nesidioblastosis. The insulin assay (30 minutes after the resection of hypersecretory tissues) enhanced the ability to locate target tissues and the accuracy of complete resection to 100%. As for intraoperative blood glucose monitoring, the accuracy 30 minutes after resection was as low as 36.6%. Postoperative levels of insulin and glucose were normal in all patients, with no recurrence of hypoglycemic symptoms during postoperative follow-up visits (9 to 72 months). CONCLUSION: Intraoperative segmental pancreatic occlusion and insulin assay in pancreatic hypoglycemia is a simple, accurate, and fast approach that enhances the localization and complete resection of hypersecretory tissues. Such a combination is highly significant in challenging cases of hypoglycemia.

[Individualized approach for MEN1-associated duodenopancreatic neuroendocrine neoplasms]. / Individualisiertes Vorgehen bei MEN1-assoziierten duodenopankreatischen neuroendokrinen Neoplasien.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. OBJECTIVE: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. MATERIAL AND METHODS: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. RESULTS: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. CONCLUSION: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers.

Robotic Enucleation of Pancreatic Head Insulinomas in Close Proximity to the Pancreatic Duct.

BACKGROUND: Insulinomas are rare pancreatic neuroendocrine tumors for which the main curative treatment is surgical resection. Enucleation is preferred over pancreatoduodenectomy to minimize morbidity and function loss.1 Robotic-assisted surgery offers improved versatility and less blood loss than laparoscopic surgery for pancreatic enucleation.2-4 Our video describes the technique for robotic enucleation of pancreatic head insulinomas in close proximity to the pancreatic duct. PATIENTS AND METHODS: The video describes the presentation, diagnostic imaging, and technical aspects of the surgical approach in two patients with pancreatic head insulinomas that underwent robotic enucleation. RESULTS: Case one was a 76-year-old woman who experienced syncope for 2 months. Case two was a 61-year-old man, previously treated for renal cancer, who had documented hypoglycemic symptoms. Computed tomography (CT) scan and magnetic resonance imaging (MRI) identified a 1.5 cm and 1.2 cm pancreatic head mass, respectively. Both patients presented with low glucose levels, and elevated C-peptide and proinsulin. In both cases, endoscopic retrograde cholangiopancreatography (ERCP) and pancreatic duct stent placement were performed the same day of surgery for intraoperative identification and preservation of the duct. Robotic enucleation of the masses was performed, and an ultrasound was used to identify the masses and relation with main pancreatic duct. Pathology revealed a well-differentiated neuroendocrine tumor in both cases. The patient's postoperative course was uneventful, and they were discharged on day 5. Successful resolution of hypoglycemic events occurred in both patients. CONCLUSION: Robotic enucleation is a safe and feasible option for treating pancreatic head tumors in challenging locations. Intraoperative ultrasound is an essential tool for the successful robotic enucleation of pancreatic head tumors.

Diagnostic work-up and surgical management of insulinoma: A retrospective analysis from a tertiary referral center.

Insulinoma is a multifaceted disease that poses several challenges in terms of clinical presentation, diagnostic work-up, and surgical management. The aim of this study was to describe diagnostic work-up, surgical management, and postoperative outcomes of patients with insulinoma. All consecutive patients who underwent surgery for insulinoma at San Raffaele Hospital (Milan, Italy) between January 2008 and January 2022 were included. Overall, 98 patients were considered. The median delay between presenting symptoms and insulinoma diagnosis was 10 months (IQR, 4-21). Insulinoma diagnosis was made at our Institution in 45 patients, 20 of whom referred within 6 months from symptoms onset. In this subgroup, the median interval between symptoms presentation and insulinoma diagnosis was 4 months (IQR, 2-6), as compared to 14 months (IQR, 10-26) in patients (n = 25) who referred to our institution after 6 months from symptoms onset (p < .001). The insulinoma was localized preoperatively in all the cases. All patients underwent ≥1 high-quality imaging: computed tomography (CT: n = 87, sensitivity 84%), magnetic resonance imaging (MRI: n = 55, sensitivity 85%) and endoscopic ultrasound (EUS: n = 79, sensitivity 100%). MRI identified the tumor in eight patients with negative CT. EUS localized the insulinoma in three patients with negative CT and negative MRI. Parenchyma-sparing resections were performed in 41 patients. Contact with major vessels, lesion close to Wirsung duct and suspect of malignancy were the main reasons to perform a formal resection. An early referral to high-volume centers is important for reducing diagnostic delay in patients with insulinoma. The diagnostic work-up of insulinoma frequently requires several imaging modalities to be performed, with EUS being the most sensitive one. Parenchyma-sparing surgery for insulinoma should be performed whenever technically and oncologically feasible.

18F-labeled PEGylated exendin-4 imaging noninvasively differentiates insulinoma from an accessory spleen: the first case report of [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography for insulinoma.

Background: Insulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operator-dependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization. Case description: This is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT. Conclusion: In this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization.

Diagnosis and Surgical Management of Insulinomas-A 23-Year Single-Center Experience.

Background and Objectives: Insulinoma is a rare tumor of the Langerhans islets of the pancreas. It produces insulin and causes severe hypoglycemia with neuroglycopenic symptoms. The incidence is low, at about 1-2 per 1 million inhabitants per year. The diagnosis is based on the presence of Whipple's triad and the result of a fasting test. Surgery is the treatment of choice. Objectives: A retrospective observational study of patients operated on for insulinoma in our hospital focused on the diagnosis, the type of surgery, and complications. Materials and Methods: We retrospectively reviewed patients operated on due to insulinoma. There were 116 surgeries between 2000 and 2022. There were 79 females and 37 males in this group. A fasting test and a CT examination were performed on all the patients. Results: The average duration of the fasting test was 18 h. Insulinoma was found in the body and tail of the pancreas in more than half of the patients. Enucleation was the most frequent type of surgery. Complications that were Clavien Dindo grade III or more occurred in 18% of the patients. The most frequent complications were abscesses and pancreatic fistula. Five patients had malignant insulinoma. Conclusions: Surgery is the treatment of choice in the case of insulinomas. The enucleation of the tumor is a sufficient treatment for benign insulinomas, which are not in contact with the main pancreatic duct. Due to the low incidence of the condition, the centralization of patients is recommended.

Unmasked insulinoma occasioned by severe hypoglycemic coma immediately postpartum: a case report.

BACKGROUND: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. CASE PRESENTATION: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. CONCLUSIONS: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia.

Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma.

BACKGROUND: Insulinoma is the most common functional pancreatic neuroendocrine tumor and treatment is required to address symptoms associated with insulin hypersecretion. Surgical resection is effective but burdened by high rate of adverse events (AEs). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) demonstrated encouraging results in terms of safety and efficacy for the management of these tumors. However, studies comparing surgery and EUS-RFA are lacking. AIMS: The primary aim is to compare EUS-RFA with surgery in term of safety (overall rate of AEs). Secondary endpoints include: (a) severe AEs rate; (b) clinical effectiveness; (c) patient's quality of life; (d) length of hospital stay; (e) rate of local/distance recurrence; (f) need of reintervention; (g) rate of endocrine and exocrine pancreatic insufficiency; (h) factors associated with EUS-RFA related AEs and clinical effectiveness. METHODS: ERASIN-RCT is an international randomized superiority ongoing trial in four countries. Sixty patients will be randomized in two arms (EUS-RFA vs surgery) and outcomes compared. Two EUS-RFA sessions will be allowed to achieve symptoms resolution. Randomization and data collection will be performed online. DISCUSSION: This study will ascertain if EUS-RFA can become the first-line therapy for management of small, sporadic, pancreatic insulinoma and be included in a step-up approach in case of clinical failure.

Right-Side Acquired Diaphragmatic Hernia in an Adult 15 Years After Living Donor Liver Transplant.

Cases of adult liver transplant recipients with a postoperative right-side acquired diaphragmatic hernia are extremely rare. In this report, we describe an adult case of right-side acquired diaphragmatic hernia 15 years after living donor liver transplant. A 27-year-old woman was diagnosed with pancreatic insulinoma with multiple metastases in the liver. To treat the liver failure, she underwent left lobe living donor liver transplant and distal pancreatectomy with splenectomy 3 years after the transcatheter arterial chemoembolization. As a result of the liver abscesses that reached the diaphragm, the delicate diaphragm was injured, which required repair during the transplant surgery. At the age of 46 years, she developed a cough and intermittent abdominal pain. One month later, she went to another hospital's emergency room with complaints of epigastric pain. The computed tomography scan revealed colon and small intestine prolapse into the right thoracic cavity. She was referred to our hospital and underwent surgery the next day. Two adjacent right diaphragm defects were successfully sutured with nonabsorbable sutures. The patient was discharged on postoperative day 11.

INSULINOMA OF THE TAIL OF THE PANCREAS - A CASE REPORT.

Insulinoma is a rare neuroendocrine functional tumor of the pancreas of unknown etiology which manifests itself through hypoglycemic symptoms which resolve by administering glycose. Common autonomic symptoms of insulinoma include diaphroresis, tremor, and palpitations, whereas neuroglycopenenic symptoms include confusion, behavioural changes, personality changes, visual disturbances, seizure, and coma. In most cases, these are benign solitary tumors of the pancreas, and in 5% of the cases they are associated with MEN1 syndrome. A characteristic of the diagnosis is the presence of hypoglycemia, and increased levels of C-peptide and insulin. Further radiological verification (non-invasive imaging procedures: computed tomography and magnetic resonance imaging; and invasive modalities, such as endoscopic ultrasonography and arterial stimulation venous sampling) of the tumor are required as well as its surgical extraction. We present a case of a middle-aged male with history of recurrent hypoglycemic episodes with vertigo, sweating, tremors, anxiety, fatigue, and loss of consciousness, all of which resolved after eating food. The diagnoses were confirmed after we performed non-invasive imaging procedure, such as Computed Tomography and Magnetic Resonance Imaging. The patient underwent successful resection of the tumor, and his symptoms showed complete resolution. Despite the low incidence of these tumors, they should be suspected, in cases where the patient presents with repetitive hypoglycemic episodes, with symptoms, which resolve after eating a meal. Timely diagnosis and adequate treatment in most cases equals to complete withdrawal of symptoms.

Changes in diagnosis and operative treatment of insulinoma over two decades.

PURPOSE: Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades. METHODS: Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000-2010 (group 1) and 2011-2020 (group 2). RESULTS: Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1-249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease. CONCLUSION: Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Effective strategies for adequate control of hormonal secretion in functioning neuroendocrine neoplasms.

Neuroendocrine neoplasms are a unique form of malignancies as they can be accompanied by specific functioning hormonal syndromes that can impair survival and quality of life in patients. Functioning syndromes are defined by the combination of specific clinical signs and symptoms in combination with inappropriately elevated circulating levels of hormones. Clinicians should remain vigilant for the presence of functioning syndromes in neuroendocrine neoplasm patients at presentation as well as during follow-up. The correct diagnostic work-up should be initiated in cases of clinical suspicion of a neuroendocrine neoplasm-associated functioning syndrome. Management of a functional syndrome includes options from supportive, surgical, hormonal and antiproliferative treatment modalities. Here, we review the patient and tumour characteristics for each functioning syndrome that should be taken into account when deciding the optimum treatment strategy in neuroendocrine neoplasm patients.

Case Report: Giant insulinoma, a very rare tumor causing hypoglycemia.

Insulinomas, with an incidence of 4 cases per million individuals per year, remain amongst the most frequent functional neuroendocrine tumors. The usual diameter of insulinomas usually remains under 3 cm of major axis. However, 44 exceptional cases of "giant insulinomas", have been reported worldwide, generally exceeding 9 cm in major axis. In this article, we report the case of a 38-year-old woman whom suffered from chronic hypoglycemia despite treatment with diazoxide. Abdominal CT-scan revealed a 88 x 73 mm mass located at the tail of the pancreas. Following surgical excision, histopathological analysis confirmed G1 neuroendocrine tumor, with focal cytoplasmic expression of insulin in tumor cells. After a 16-month follow-up period, the patient didn't address any specific complaint, and no disease recurrence and/or metastasis were observed. A 68Ga-DOTATATE-PET scan was performed 6 months after surgery, which came back normal. Genetic evaluation has not been performed in our patient. The physiopathology of giant insulinomas remain unexplained, however with possible relationship with type 1 multiple endocrine neoplasia, sporadic somatic YY1 mutations and possible transformation of bulky non-functional pancreatic neuroendocrine tumors to a functional phenotype, with slow insulin secretion. While giant insulinomas remain rare in the literature, multicentric genetic analysis of tumor samples might reveal unique features of this rare subtype of neuroendocrine pancreatic tumors. Insulinomas of large size tend to have greater malignancy and higher rates of invasiveness. Careful follow-up, especially for liver and lymph node metastases, must be performed using functional imaging techniques to avoid disease relapse.

Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic insulinoma: A single-center experience.

BACKGROUND/OBJECTIVES: Insulinomas are rare, functioning pancreatic neuroendocrine neoplasms (pNEN), whose gold standard therapy is surgical resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a recent technique that has emerged as a minimally invasive therapeutic option for patients with pancreatic lesions not eligible for surgery. In this study, we aimed to describe a series of patients with unresectable pancreatic insulinoma treated with EUS-RFA. METHODS: This is a single-center, retrospective study including all consecutive patients with functioning pancreatic insulinoma undergoing EUS-RFA for surgical unfitness or surgery refusal, between March 2017 and September 2021. Technical success (i.e., complete mass ablation), adverse event rate and severity, clinical and radiologic outcomes (i.e., symptom remission with a normal concentration of blood glucose, and the presence of intralesional necrosis), and post-procedural follow-up were assessed. RESULTS: A total of 10 patients (mean age: 67.1 ± 10.1years; F:M 7:3) were included. The mean size of insulinoma was 11.9 ± 3.3 mm. Technical success and clinical remission were achieved in 100% of patients. Only one (10%) patient was successfully treated with two RFA sessions. Two procedure-related early adverse events occurred, including two (20%) cases of mild abdominal pain. No major complications were observed. The complete radiologic response within 3 months after EUS-RFA was observed in all patients (100%). After a median follow-up of 19.5 (range12-59) months, symptom remission and persistent euglycemia were assessed in all the patients. CONCLUSIONS: Data from this case series suggest that EUS-RFA is a feasible and safe therapeutic approach for pancreatic insulinomas in patients unwilling or unable to undergo surgery with medium-term efficacy.

Indocyanine green fluorescence imaging to localize insulinoma and provide three-dimensional demarcation for laparoscopic enucleation: a retrospective single-arm cohort study.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging is a new technology that can improve the real-time location of tumor edges and small nodules during surgery. However, no study has investigated its application in laparoscopic insulinoma enucleation. This study aimed to evaluate the feasibility and accuracy of this method for intraoperative localization of insulinomas and margin assessment during laparoscopic insulinoma enucleation. MATERIALS AND METHODS: Eight patients who underwent laparoscopic insulinoma enucleation from October 2016 to June 2022 were enrolled. Two methods of ICG administration, ICG dynamic perfusion and three-dimensional (3D) demarcation staining, were utilized in the laparoscopic insulinoma enucleation. Tumor-to-background ratio (TBR) and histopathologic analysis were used to evaluate the feasibility and accuracy of these novel navigation methods in laparoscopic insulinoma enucleation. RESULTS: All eight enrolled patients underwent both ICG dynamic perfusion and 3D demarcation staining. ICG dynamic perfusion images were available for six of them, among which five tumors could be recognized by TBR (largest TBR in each case 4.42±2.76), while the other could be distinguished by the disordered blood vessels in the tumor area. Seven out of eight specimens had successful 3D demarcation staining (TBR 7.62±2.62). All wound bed margins had negative frozen sections and final histopathologic diagnoses. CONCLUSIONS: ICG dynamic perfusion may be helpful in observing the abnormal vascular perfusion of tumors, providing similar functionality to intraoperative real-time angiography. ICG injection under the tumor pseudocapsule may be a useful method for acquiring real-time, 3D demarcation for the resection of insulinoma.