small molecules

2026-09-16 | New and emerging somatostatin therapies for neuroendocrine tumors: “what is in the pipeline”

Introduction Somatostatin receptors (SSTRs) have played a central role in all aspects of the management of neuroendocrine/endocrine neoplasms (NENs). This includes in diagnosis of NENs with the widespread use of radiolabeled SSTR ligands to localize both the primary tumor location and extent of the tumors, as well as confirm its NEN nature. In NEN management non-radiolabeled SSTR agonists are the first line for control of the hormone-excess state for most functional NENs (F-NENs) as well as for the initial cytotoxic treatment of advanced tumor growth, and more recently, the use of radiolabeled SSTR ligands for the treatment of more aggressive advanced disease, as well as the assessment of tumor location, tumor extent and response to therapies. While somatostatin analogs (SSTA) have been successful in all of the above areas, there is increasing need for improvement, because not all patients respond to existing SSTAs therapies, others become resistant with time to existing SSTA treatment, current imaging with radiolabeled SSTAs is negative in some patients and ease of use/availability of ligand can be a problem and lastly, newer groups of patients are being considered for possible SSTA treatment with newer SSTA related compounds.Areas covered In this perspective, the authors briefly review recent advances which are resulting or may result in new and emerging SSTAs that show promise in future use in NEN patients. It includes identification of both new or promising non-radioactive SSTA (cold SSTA) and radiolabeled SSTAs which could replace existing SSTAs now currently used, as well as new protocols for the new/promising SSTAs, or for existing SSTAs. These new/promising SSTAs/ or new/promising uses of these SSTAs include both chemically completely new SSTAs; pharmacologically new in their actions such as nonpeptide in nature; antagonist rather than agonist; longer acting in duration; and oral rather than parenteral administration. For peptide receptor radionuclide therapy (PRRT)/ imaging with radiolabeled SSTAs new developments covered include new promising SSTAs coupled to beta-emitters, alpha emitters, administered with radio-sensitizing agents, and new, promising protocols for PRRT retreatment, personalized treatment, adjuvant treatment or treatment of pediatric patients. They also include combinations of new/promising/exiting SSTAs both radiolabeled for PRRT or non-radiolabeled for tumor cytotoxic /and/or inhibitory effects formed by administration of the SSTA with other cytotoxic agents such as mTor inhibitors, chemotherapeutic agents, Tyrosine Kinase Inhibitors (TKIs), angiogenesis inhibitors, nonradioactive-SSTAs with PRRT or with immune therapy.Expert Opinion This review of new and promising SSTR therapies involving both radiolabeled and non-radiolabeled for the future treatment of NENs strongly supports the conclusion that in the future SSTR- based drugs will continue to play prominent roles in all aspects of the management of NENs. This conclusion extends to the use of SST ligands to image these tumors to establish the location of the primary, location and extent of metastatic disease and the presence of SSTRs on the tumor for possible PRRT therapy; to the control of hormonal symptoms in F-NENs such as the carcinoid syndrome, vasoactive-intestinal-peptide- secreting (VIPomas)/ Adrenocortotropin-secreting(ACTHomas), etc. and to anti-proliferative roles for the treatment of advanced disease with both non-radioactive SSTAs, as well with PRRT with radiolabeled SSTAs and likely with novel new non-radiolabeled cytotoxic SSTAs. Numerous recent studies firmly establish these conclusions, all of which are reviewed here; and they will likely be further supported by additional studies that are in progress and also cited here.

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2026-07-07 | Severe hypokalaemia and secretory diarrhoea secondary to a vasoactive intestinal peptide-secreting tumour (VIPoma).

A woman in her 60s presented to the emergency department with an 18-month history of chronic secretory diarrhoea and 8 kg weight loss. She had multiple previous presentations to healthcare for dehydration, weakness and severe hypokalaemia (serum potassium <2.5 mmol/L) over the preceding 18 months. Previous colonoscopy and workup for infectious and inflammatory causes had not yielded a diagnosis. At presentation, her serum potassium was 2.1 mmol/L (reference 3.5-5 mmol/L) with evidence of muscle weakness and volume depletion. A CT of the abdomen and pelvis demonstrated an 8 cm mass in the pancreatic tail. Endoscopic biopsy demonstrated well-differentiated pancreatic neuroendocrine tumour. Serum vasoactive intestinal peptide (VIP) was elevated eightfold above the upper limit of normal, in keeping with the diagnosis of VIPoma. Long-acting somatostatin analogue (SSA) was initiated. The patient underwent surgical resection of the primary tumour for symptom control. Following surgery and ongoing SSA use, diarrhoea and hypokalaemia have resolved.

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2025-11-06 | Severe Idiopathic Secretory Diarrhoea With a Profound Sustained Response to Somatostatin Analogues: A Case Report.

Chronic secretory diarrhoea is a diagnostic challenge with a broad differential and significant impact on patient's quality of life. While common causes include microscopic colitis, bile acid diarrhoea, and laxative use, rarer aetiologies such as vasoactive intestinal peptide (VIP)-secreting neuroendocrine tumours (VIPomas) must be considered when standard investigations fail. We present a 35-year-old woman with a two-year history of progressively worsening, fasting-persistent, high-volume watery diarrhoea leading to severe electrolyte abnormalities and weight loss requiring resuscitation in intensive care. Extensive biochemical, endoscopic, and radiological investigations-including faecal analysis, colonoscopy, neuroendocrine markers, multiphase CT, endoscopic ultrasound, and Ga-68 Dotatate PET imaging-failed to identify an underlying cause. Serum VIP levels remained within the normal range. Despite the absence of a definitive diagnosis, empirical treatment with the somatostatin analogue octreotide led to rapid and sustained symptom resolution. The patient was subsequently maintained on long-acting lanreotide with complete remission. Notably, diarrhoea recurred upon cessation of therapy, again resolving with reinitiation. After 4 years, the patient self-ceased lanreotide without symptom recurrence, and follow-up imaging remained unremarkable. This case highlights a diagnostic dilemma: clinical and biochemical features were highly suggestive of a VIPoma, yet no tumour was identified despite repeated advanced imaging and biochemical workup. The patient's remarkable therapeutic response to somatostatin analogue therapy, in the absence of confirmed neuroendocrine neoplasia, suggests that somatostatin analogues may have a broader role in the management of idiopathic secretory diarrhoea than currently appreciated. We present a rare case of chronic secretory diarrhoea with suspected but unproven VIPoma, demonstrating sustained and reproducible response to somatostatin analogue therapy. This case supports the consideration of therapeutic trials of somatostatin analogues in refractory secretory diarrhoea of unknown origin.

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2025-10-01 | S5329 When Common Diagnoses Overshadow the Rare: A Case Revealed by EUS After Multiple Admission

Introduction: Chronic diarrhea is a common complaint with a broad differential diagnosis, often attributed to infections, medications, or inflammatory conditions. Rarely, it may signal an underlying neuroendocrine tumor such as a VIPoma—a pancreatic tumor that secretes vasoactive intestinal polypeptide and causes watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Due to its rarity and nonspecific presentation, VIPoma is often misdiagnosed. We present a case of a 61-year-old woman with 2 years of unexplained diarrhea and recurrent hypokalemia, ultimately diagnosed with a pancreatic VIPoma after extensive evaluation. Case Description: A 61-year-old woman with a medical history of hypertension, type 2 diabetes, microscopic colitis, hyperlipidemia, and obesity presented with chronic diarrhea lasting 2 years. Her symptoms included frequent, clear, odorless stools, weakness, and muscle cramps. Despite multiple hospitalizations for hypokalemia and diarrhea, initially attributed to gastroenteritis, Ozempic side effects, or microscopic colitis, her condition persisted. On this admission, stool analysis was negative for pathogens, and a CT scan revealed a fluid-filled colon with pneumobilia. Gastroenterology consultation led to an endoscopic ultrasound (EUS), which identified a 9 mm × 7 mm mass in the uncinate process of the pancreas. A biopsy confirmed a grade 1 VIPoma, and her serum vasoactive intestinal polypeptide (VIP) levels were elevated at 280 pg/ml. Discussion: This case emphasizes the diagnostic challenge of VIPomas in patients with chronic diarrhea and hypokalemia, particularly when more common causes have been excluded. Early identification through advanced imaging like EUS and appropriate treatment with cryoablation and octreotide led to a favorable outcome. This case underscores the need for clinicians to maintain a high index of suspicion for rare endocrine tumors in such patients, as timely diagnosis and intervention can significantly improve prognosis.

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2025-09-06 | Stereotactic Body Radiation Therapy Facilitating Debulking Surgery in Metastatic VIPoma with Severe Diarrhea and Hypovolemic Shock.

BACKGROUND Treatment of metastatic vasoactive intestinal peptide tumors (VIPoma) is challenging and requires a careful multidisciplinary approach to achieve optimal disease control. We present a case of metastatic VIPoma with recurring episodes of life-threatening diarrhea necessitating multiple intensive care unit (ICU) admissions. CASE REPORT A 54-year-old man presented with severe watery diarrhea and metabolic acidosis with MRI showing a necrotic pancreatic body mass, and multiple liver lesions. Histopathologic and biochemical findings were consistent with VIPoma. Due to the multifocal liver lesions, he was deemed unsuitable for curative surgical intervention, shifting focus to other therapies. Initial treatments over 7 months included octreotide, transarterial chemoembolization, yttrium-90 radioembolization, and systemic therapy with everolimus, with decreases in serum vasoactive intestinal peptide (VIP) levels from a peak of 3180 pg/mL to undetectable levels corresponding to temporary relief of diarrhea. However, the temporary relief was followed by a rapid increase in VIP levels into the 200s and 300s and recurrence of 3-11 liters of diarrhea per day. He had multiple ICU admissions due to severe diarrhea/hypovolemic shock until he was treated with stereotactic body radiation therapy (SBRT). SBRT of the pancreatic site immediately yielded long-term hemodynamic stability, prevented further ICU admissions, and enabled the patient to receive debulking surgery. CONCLUSIONS Although radiation is not typically a primary treatment modality for VIPoma, in this case, the high dose per fraction delivered with stereotactic technique to a pancreatic mass played a crucial role in alleviating his catastrophic volume loss through intravenous octreotide-refractory diarrhea, making the patient a suitable candidate for debulking surgery. This case highlights the importance of considering all available treatment options, even those not traditionally employed, when managing complex cases with refractory symptoms.

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proteins

2026-08-01 | EP939 - ECE_2703 - When you hear hoofbeats think horses but remember zebras: a case of life-threatening VIPoma

Abstract Introduction Vasoactive intestinal peptide-secreting tumor (VIPoma) is a rare neuroendocrine neoplasm (NEN), with an annual incidence of 1 per million. It is usually located in the pancreatic tail. VIPoma syndrome, caused by excessive unrestricted VIP secretion, presents as severe fasting-persistent watery diarrhea, hypokalemia, and achlorhydria, known as “WDHA syndrome” or Verner-Morrison syndrome. Management of VIPoma includes symptom-oriented pharmacotherapy, conservative treatment options such as somatostatin analogs (SSAs), and surgery. Case Report A 69-year-old woman was admitted to the emergency department (ED) in hypovolemic shock due to massive watery diarrhea up to 10 liters per day. The physical examination revealed generalized flushing and marked dehydration, with an initial blood pressure of 80/38 mmHg and a heart rate of 122 beats per minute. Venous blood gas showed metabolic acidosis with pH of 7.12 and hypokalemia of 2.8 mmol/L. The gastroenteritis PCR panel was negative. After initial treatment (intravenous fluids, hydrocortisone, vasopressors) and stabilization of vital parameters in the ED, the patient was transferred to the Department of Endocrinology for suspected rare WDHA syndrome. Continuous infusion of octreotide resulted in resolution of diarrhea; the patient also started lanreotide. Blood tests confirmed elevated VIP—180 pmol/L (N < 24 pmol/L), calcitonin—941 pg/mL (N < 11.5), and chromogranin A 253.8 ng/mL (N < 102). Approximately 2 months earlier, the patient was hospitalized due to similar symptoms associated with hyperglycemia and hypercalcemia. A CT scan of the abdomen showed a solitary, irregular, polycystic mass measuring 70 × 38 × 65 mm located in the pancreatic area. Tumor biopsy in an outpatient setting revealed low-grade NEN, but no further procedures followed. PET/CT with 68Ga-DOTATATE confirmed three pancreatic lesions with high expression of the somatostatin receptor, the largest measuring 48 × 32 mm with SUVmax 26.5. After a multidisciplinary team meeting, the patient was qualified for surgery. Subtotal pancreatectomy and splenectomy with partial gastrectomy and partial colectomy was performed, the surgery was uneventful. The resected NEN was G2 with Ki67 4%. Since the procedure, the patient has been asymptomatic with good biochemical control. Discussion Although VIPoma is a rare disease, the characteristic clinical course can facilitate an initial diagnosis. Fasting-persistent watery diarrhea with severe electrolyte disturbances should prompt the idea of rare neuroendocrine causes, the so-called “zebras”. Elevated calcitonin, a biomarker more easily accesible than VIP, may contribute to secretory diarrhea. Early recognition and initiation of appropriate therapy can save lives and, in the long term, can preserve the quality of life of patients.

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2026-07-14 | Distal pancreatectomy for neuroendocrine neoplasms in patients with multiple endocrine neoplasia type 1.

To analyze the outcomes of multiple endocrine neoplasia type 1 (MEN1) patients after distal pancreatectomy (DP) for pancreatic neuroendocrine neoplasm (P-NENs) with a specific attention to postoperative complications and long-term survival. MEN1 patients from the French MEN1 cohort who underwent DP for P-NENs between 1990 and 2022 were included in the study. Early and late postoperative complications, secretory control, pancreatic disease-free and overall survival were assessed. Out of 62 patients included, 41 (66%) underwent DP for a non-functioning P-NENs, 14 (23%) for insulinomas, 4 (6%) for a VIPoma and 3 (5%) for a glucagonoma. Median follow-up was 84 months (range: 12-335). No death within the 90 postoperative days was observed. Clavien-Dindo grade III-V postoperative complications occurred in 16% of the patients (n=11). Fourteen patients (23%) developed pancreatic fistulas. Twenty-four patients (39%) developed diabetes mellitus and 8 patients (13%) developed pancreatic exocrine insufficiency. The secretory control rate was 90%. Mean age at death was 56±10.9years. Five-year and ten-year overall survival was 93.0% [CI (85-100)], and 86.7% [CI (76.2-98.5)]. Ten-year liver metastasis-free survival was significantly shorter when DP was performed for non-functioning P-NENs compared to insulinomas 60.4% [CI (47-79)] versus 83.3% [CI (68-87)] (P=0.007). Distal pancreatectomy in MEN1 patients is a safe surgical procedure with an acceptable morbidity and a very low postoperative mortality. Further studies are needed to standardize the extent of lymph node removal when distal pancreatectomy is performed in MEN-1 patients.

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2026-06-24 | Characteristics, management, and outcomes of patients with VIPoma-A retrospective analysis of the ENETS database.

VIPoma is an extremely rare functioning pancreatic neuroendocrine tumor. Therefore, data regarding treatment and outcome are very limited. Aim (s): This multicenter study aimed to analyze clinical characteristics, real-world management, and outcomes of patients with VIPoma. Patients with VIPoma treated in a 20-year period at 14 referral centers for neuroendocrine tumors (NET) were collected in the ENETS Database. Clinical characteristics, therapeutic interventions, and outcomes were analyzed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Of 70 patients, 59 (54% male) with a median age of 55 years were included. Forty-six (78%) patients were diagnosed due to the classical watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome, and 40 (68%) presented with distant metastases at diagnosis. Fifty-two (88%) had serum VIP levels >2 times the upper normal limit and the median Ki-67 index was 5% (range 1%-40%). Surgery of the primary VIPoma was performed in 32 (54%), with curative intent in 22 (37%). In patients with stage I-III disease (n = 19), long-term cure was achieved in only 26% (5/19), with a median DFS of 81 (95%-CI: 1-215) months and 10-year OS of 78% (95%-CI: 61%-100%). In stage IV patients (n = 53, 40 at diagnosis, 13 disease progression), the sequence and type of 354 treatment lines varied, while SSA (n = 77, 22%), loco-regional liver-directed therapy (n = 72, 20%), and chemotherapy (n = 69, 19%) were most often applied. Median OS for patients with stage IV at diagnosis was 142 (95%-CI: 87-not available (NA)) months with 10-year survival of 50% (95%-CI: 35%-73%). Patients with VIPoma treated at NET centers have relatively favorable survival, even with distant metastases at diagnosis, although long-term cure rates remain low.

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2025-10-01 | S6233 Chronic Diarrhea in a Patient With Exocrine Pancreatic Insufficiency: Unmasking a VIPoma

Introduction: Among the rare but important causes of chronic diarrhea is vasoactive intestinal peptide-secreting tumor (VIPoma). We present a case of chronic diarrhea ultimately diagnosed as VIPoma, highlighting key diagnostic considerations and the importance of early recognition. Case Description/Methods: A 54-year-old man with gastroesophageal reflux disease and exocrine pancreatic insufficiency (EPI) presented with chronic, watery diarrhea occurring more than 10 times daily, predominantly postprandial, and associated with nocturnal fecal incontinence and a 27 kg weight loss over 6 months. Previous bidirectional endoscopies were non-diagnostic, and trials of pancreatic enzyme replacement, antimotility agents, rifaximin, and bile acid sequestrants provided no relief. A comprehensive evaluation for infectious, inflammatory, osmotic, and secretory causes was unrevealing. An initial chromogranin A (CgA) level was elevated at 380.5 ng/mL while the patient was on a proton pump inhibitor (PPI) for severe esophagitis; a repeat level increased further to 2,413 ng/mL while still on PPI therapy. Repeat bidirectional endoscopies were performed to evaluate for maldigestion, celiac disease, amyloidosis, and atypical infections, with negative findings. He was referred to the gastrointestinal motility clinic for ongoing symptoms and concern for irritable bowel syndrome with diarrhea (IBS-D). Stool osmolality was 346 mOsm/kg, with an osmolar gap of 104 mOsm/kg, in the setting of EPI. Persistent diarrhea despite total parenteral nutrition and the absence of oral intake raised concern for a secretory process. Cross-sectional imaging of the chest, abdomen, and pelvis was unremarkable, but serum vasoactive intestinal peptide was elevated at 84.6 pg/mL (reference: 0.0–58.8), prompting Gallium-68 DOTATATE PET/computed tomography to localize a VIP-secreting tumor. Discussion: Given their rarity, VIPomas are often overlooked in the differential diagnosis of chronic diarrhea, particularly in patients with coexisting gastrointestinal comorbidities, as in this case. Although elevated serum CgA levels can be seen in VIPomas, they may be falsely elevated by PPI use. However, in this case, there was a sixfold increase in CgA level on repeat testing despite this consideration, further supporting the suspicion of a VIPoma. This case underscores the importance of considering VIPomas in the workup of chronic secretory diarrhea, particularly when symptoms are refractory to standard therapies and associated with significant malnutrition.

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2025-10-01 | S3212 An Occult Pancreatic Neuroendocrine Tumor Diagnosed by Endoscopic Ultrasound After Normal Imaging

Introduction: Functional pancreatic neuroendocrine tumors (PNETs) are a rare cause of chronic diarrhea, particularly vasoactive intestinal peptide-producing tumors (VIPomas). These tumors usually present with severe, symptomatic diarrhea and are often associated with widespread and aggressive metastases. However, the following case demonstrated a more indolent disease course, highlighting the variability in clinical presentation. Case Description/Methods: A 78-year-old man with a past medical history of hypertension and hyperlipidemia was referred for evaluation in the gastroenterology clinic for chronic diarrhea interfering with his quality of life. Two years prior, the patient had undergone a cholecystectomy, and his diarrhea was initially attributed to bile salt malabsorption. As part of the diagnostic process, bile salt binders were prescribed, but further evaluation for chronic diarrhea continued. By the time of his clinic visit, the patient’s symptoms had resolved. However, initial lab work revealed an elevated vasoactive intestinal peptide (VIP) level of 1200 pg/mL. Additional investigations showed no abnormalities, including a complete blood count, comprehensive metabolic panel, infectious stool studies, and abdominal Magnetic Resonance Imaging with intravenous contrast. Given the elevated VIP level, the patient underwent a PET DOTATATE scan, which revealed an area of kerning 3 at the pancreatic uncinate process concerning for PNET. Subsequently, endoscopic ultrasound (EUS) was performed, which identified a round hypoechoic mass measuring 7 × 5 mm in the head of the pancreas. Fine Needle Biopsy (FNB), which showed cells positive for CAM5.2 and synaptophysin, suspicious for PNET. The patient’s case was discussed at pancreas board, and options offered were surveillance, EUS-guided radiofrequency ablation, and surgery. Given his age and well controlled symptoms, he elected to pursue a surveillance strategy. Discussion: The case highlights the role of EUS in identifying small PNETs, which may not be identifiable on cross-sectional imaging studies such as computed tomography and magnetic resonance imaging. Surveillance, ablation, and surgery are all reasonable treatment options for well-differentiated PNETs less than 2 cm in size that are causing minimal symptoms. Our case demonstrates the importance of multidisciplinary management and individualized treatment decision making.

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antibodies

2026-06-15 | Robust response to pembrolizumab in temozolomide-associated hypermutated and microsatellite instability-high functional pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.

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2020-11-04 | Evaluation of Outcomes Following Surgery for Locally Advanced Pancreatic Neuroendocrine Tumors

Importance

Although outcome of surgical resection of liver metastases from pancreatic neuroendocrine tumors (PNETs) has been extensively studied, little is known about surgery for locally advanced PNETs; it was listed recently by the European neuroendocrine tumor society as a major unmet need.

Objective

To evaluate the outcome of patients who underwent surgery for locally aggressive PNETs.

Design, Setting, and Participants

This retrospective single-center case series reviewed consecutive patients who underwent resection of T3/T4 PNETs at a single academic institution. Data collection occurred from 2003 to 2018. Data analysis was performed in August 2019.

Main Outcomes and Measures

Disease-free survival (primary outcome) and overall mortality (secondary outcome) were assessed with Kaplan-Meier analysis. Recurrence risk (secondary outcome, defined as identification of tumor recurrence on imaging) was assessed with Cox proportional hazard models adjusting for covariates.

Results

In this case series, 99 patients with locally advanced nondistant metastatic PNET (56 men [57%]) with a mean (SEM) age of 57.0 (1.4) years and a mean (SEM) follow-up of 5.3 (0.1) years underwent surgically aggressive resections. Of those, 4 patients (4%) underwent preoperative neoadjuvant treatment (including peptide receptor radionuclide therapy and chemotherapy); 18 patients (18%) underwent pancreaticoduodenectomy, 68 patients (69%) had distal or subtotal pancreatic resection, 10 patients (10%) had total resection, and 3 patients (3%) had other pancreatic procedures. Additional organ resection was required in 86 patients (87%): spleen (71 patients [71%]), major blood vessel (17 patients [17%]), bowel (2 patients [2%]), stomach (4 patients [4%]), and kidney (2 patients [2%]). Five-year disease-free survival was 61% (61 patients) and 5-year overall survival was 91% (91 patients). Of those living, 75 patients (76%) had an Eastern Cooperative Oncology Group score of less than or equal to 1 at last followup. Lymph node involvement (HR, 7.66; 95% CI, 2.78-21.12;P < .001), additional organ resected (HR, 6.15; 95% CI, 1.61-23.55;P = .008), and male sex (HR, 3.77; 95% CI, 1.68-8.97;P = .003) were associated with increased risk of recurrence. Functional tumors had a lower risk of recurrence (HR, 0.23; CI, 0.06-0.89;P = .03). Required resection of blood vessels was not associated with a significant increase recurrence risk.

Conclusions and Relevance

In this case series, positive lymph node involvement and resection of organs with tumor involvement were associated with an increased recurrence risk. These subgroups may require adjuvant systemic treatment. These findings suggest that patients with locally advanced PNETs who undergo surgical resection have excellent disease-free and overall survival.

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2015-08-14 | Hormone and Receptor Candidates for Target and Biotherapy of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) produce various hormones and bioactive substances and are known to express a large variety of peptide hormone receptors. While these hormones and receptors play a role in the pathophysiology of this heterogeneous group of tumors, they also form an important target for treatment and diagnosis. One of the most well-known target receptors in NETs are somatostatin receptors. On the basis of the expression of functional somatostatin receptors on the cell surface of NET cells, somatostatin analogs have already been used for decades to control symptoms related to hormonal overproduction in patients with NETs. Recent placebo-controlled studies have also demonstrated a significant antitumor activity, both in functioning and nonfunctioning NETs. Moreover, other peptide hormone receptors (e.g. receptors for GLP-1, CCK, GRP, secretin and dopamine) can be expressed at a high density in NETs. As such, these classes of receptors may also form potential targets for diagnosis and treatment. Finally, in recent years novel biotherapies targeting several growth factor systems have been introduced in the treatment of patients with NETs and are being explored for their efficacy in this setting, either as monotherapy or in combination treatment. This chapter aims to give an overview on the above topic.

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1996-04-01 | Monoclonal Antibody to VIP: Production, Characterization, Immunoneutralizing Activity, and Usefulness in Cytochemical Staining

A very stable cell line has been generated that produces monoclonal antibody to VIP designated as CURE.V55. This hybridoma was produced by fusion of spleen cells from an immunized Robertsonian mouse containing the translocated 8.12 chromosome with FOX-NY myeloma cells that are APRT deficient. VIP monoclonal antibody producing cell line #55 was selected by limiting dilutions using thymocytes as feeder layers. Ascites fluid containing high concentration of VIP monoclonal antibody was produced from pristane-primed BALB/c mice. Ascites fluid contained approximately 20 mg/ml IgG and bound 50% of 2 fmol 125I-VIP at a final dilution of 1:50,000. Binding of this IgG1 antibody was inhibited by 50% at 5 nM concentration of either VIP 1-28 or VIP 7-28. Protein-A purified IgG of this antibody, used in a concentration of 30 mg/kg per rat (IV), completely reversed the inhibitory effect of gastric corpus contractions induced by intravenous injection of VIP (10 nmol/kg) in sodium pentothal-anesthetized rats. A control anti-keyhole limpet hemocyanin monoclonal antibody did not alter the stimulatory effect of VIP on gastric corpus contractions. Immunohistochemistry showed that this VIP monoclonal antibody stains neurons, and nerve fibers in human and rat gallbladder and the sphincter of Oddi as previously described with our polyclonal antiserum.

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1994-03-31 | Clinical and biochemical effects in vivo of monoclonal antitumor antibody in Verner-Morrison's syndrome.

Monoclonal antibodies have not been evaluated in metastasizing endocrine tumors, even though these lesions may induce severe morbidity of hormone excess in absence of considerable tumor burden. A murine monoclonal antibody of the IgG2a subtype was generated by immunization with dispersed tumor cells from an endocrine pancreatic carcinoma associated with liver and peritoneal metastases as well as a therapy-resistant Verner-Morrison's syndrome. Immunohistochemical staining disclosed selective tissue reactivity of the antibody and conspicuous immunostaining on the surface of the tumor cells. Infusion of 100 mg antibody over 2 days into the common hepatic artery of the patient was accompanied by reduced diarrhea volume until death 6 weeks later and transient elevation of total plasma immunoreactivity for vasoactive intestinal peptide due to large molecular forms of the peptide. Postmortem examination demonstrated disappearance of peritoneal metastases as well as absence of immunostaining for the injected antibody and the transferrin receptor within residual hepatic tumors. The results substantiate that symptomatic alleviation and perhaps interference with tumor cell mass may be obtained with monoclonal antibodies in patients with endocrine tumors and that the antiidiotypic immunoglobulin response may play a role herein.

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cell therapies

2024-11-05 | Modulating the Vasoactive Intestinal Peptide (VIP) Pathway Reprograms Superior CAR T Cells

Chimeric antigen receptor (CAR) T cell therapy is a highly potent cellular immunotherapy that still faces significant obstacles that limit clinical success. Novel immunomodulatory approaches to improve the CAR T cell phenotype, metabolic fitness, and the engagement of endogenous immunity are necessary to create effective CAR T products. Vasoactive intestinal peptide (VIP) is a neuropeptide that dampens adaptive immune responses and is abundantly produced by several hematologic malignancies. Here, we have engineered CAR T cell therapies that secrete a synthetic short peptide drug that antagonizes VIP receptors (CAR/VIPRa). CAR/VIPRa T cells are less activated and less exhausted by the manufacturing process, which lends to better viability and preservation of memory phenotypes. Furthermore, VIPR antagonism increases the number of mitochondria and enriches the utilization of oxidative phosphorylation. This metabolic reprogramming results in quiescent CAR/VIPRa T cells that have greater potential and plasticity to achieve improved energetic profiles after antigen stimulation. In vivo, CAR/VIPRa T cells demonstrate significantly greater expansion with less exhausted phenotypes and are enriched for memory phenotypes in xenograft tumor models. Additionally, the small peptide drug produced by CAR/VIPRa T cells increases the number of endogenous tumor-infiltrating T cells in syngeneic tumor models. To investigate clinical relevance, CAR/VIPRa T cells manufactured from patient-derived T cells recapitulated lower activation profiles and enrichment for memory phenotypes. Collectively, this approach to antagonize the VIP/VIPR pathway serves to improve CAR T cell phenotype and function before and after tumor engagement to drive enhanced anti-tumor efficacy. Therefore, CAR/VIPRa T cells are uniquely equipped to overcome many key obstacles that are required for success of CAR T therapy in the clinic.

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2024-06-03 | Successful liver transplantation as rescue therapy in a patient with metastases from a vasoactive intestinal peptide producing neuroendocrine tumor.

This case report presents a 40-year-old patient with a vasoactive intestinal peptide (VIP) secreting high grade (Ki-67 39%) neuroendocrine tumor (NET) from the pancreas, for whom successful liver transplantation (LT) was carried out 8 years after resection of the primary tumor due to massive liver metastases. The transplantation was done as rescue therapy due to rapid progression and a devastating clinical condition requiring intravenous supplementation for 20 hours daily. The latest imaging carried out 18 months after transplantation is without signs of recurrence, and the patient is in good health with undetectable levels of VIP. According to the guidelines, LT is only recommended if Ki-67 is <20% and if there has been tumor control for more than 6 months prior to transplantation. Our case illustrates that LT is an option that should be considered for selected NET patients without extrahepatic involvement regardless of tumor grade and clinical condition.

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2010-12-03 | Vasoactive intestinal polypeptide secreting pancreatic tumour with hepatic metastases: long term survival after orthotopic liver transplantation.

VIPomas are rare neuroendocrine tumours, with metastases often confined to the liver. Orthotopic liver transplantation may be considered in patients with metastases confined to the liver, however the long term benefits have yet to be shown. To discuss the role of orthotopic liver transplantation for neuroendocrine tumours including VIPomas. We describe the case of a very rare pancreatic VIPoma, the therapeutic modalities employed, including orthotopic liver transplantation, and present the results of a relevant literature search. This case is the longest (25 years) reported in the literature for survival from a VIPoma after initial diagnosis and long term survival after liver transplantation (9 years). Liver transplantation for metastatic VIPomas confined to the liver may be justified in selected patients to provide symptomatic hormonal control and pain from tumour bulk, provided there is no extra hepatic disease and medical treatment has been exhausted.

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2008-02-01 | QS427. Multivisceral Transplantation for Non-Resectable Slow-Growing Tumors of the Mesenteric Root

Introduction: Slow growing tumors of the mesenteric root present a formidable surgical challenge. These tumors are generally comprised of neuroendocrine tumors and desmoid tumors, and respond poorly to radiation therapy, chemotherapy, or local embolic treatments. Frequently, patients with neuroendocrine tumors will additionally present with liver metastases which are also slow growing. Surgical resection of the primary tumor and the liver metastases, or primary tumor resection with transplantation of the liver, have been described. We report 5 cases of non-resectable tumors of the mesenteric root in which each patient received definitive treatment with multivisceral transplantation. Methods: Patients were referred for evaluation for transplantation after determination by experienced hepatobiliary surgeons that the primary tumor was not resectable and involved the mesenteric root, including the superior mesenteric artery (SMA) and celiac axis. The involved tumors included VIPoma, insulinoma, carcinoid tumor, desmoid tumor and gastrointestinal stromal tumor. Two of the patients had known liver metastases at the time of evaluation. A thorough work-up was completed to assure that there was no evidence of extrahepatic spread of the disease. Each of the patients was then listed for multivisceral transplantation which included simultaneous transplantation of all organs with blood supply provided by the SMA and celiac axis, including the stomach, duodenum, pancreas, small intestine and liver. Indiana University is one of seven Medicaid approved centers of excellence for intestinal transplantation. Results: Six patients were referred for evaluation, and 5 patients received standard multivisceral transplantation. One patient died during the evaluation period after local embolic therapy for liver metastases resulted in fulminant hepatic failure. Surgery included complete resection of the native organs, with removal of the SMA and celiac axis at the level of the aorta, and resection of the periaortic lymph nodes. Patient ages ranged from 21 to 51. Post-transplant survival is 100% with survival time ranging from 2 months to 25 months. No patient currently has evidence of recurrent disease. All patients are fully functional, living at home and tolerating a regular diet. Maintenance immunosuppression therapy includes tacrolimus and low dose steroids. Conclusions: Multivisceral transplantation may offer a reasonable therapeutic alternative to patients with non-resectable slow-growing tumors involving the SMA and celiac axis, with or without metastases to the liver.

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2001-08-01 | Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma

OBJECTIVE Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell‐based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin‐producing pancreatic carcinoma. DESIGN Autologous dendritic cells (DCs) were generated from peripheral blood monocytes in the presence of granulocyte/macrophage colony‐stimulating factor, interleukin‐4 and tumour necrosis factor α. DCs were loaded with tumour‐derived lysate (TL), and were delivered by subcutaneous injections in 4‐week intervals. RESULTS Three weeks after first treatment, the patient developed a strong delayed‐type hypersensitivity (DTH) skin reaction with an erythema and induration after the challenge with TL‐pulsed DCs, which indicates the efficient generation of antigen‐specific memory T‐cells. Immunohistochemical analysis of skin biopsy demonstrated a strong perivascular and epidermal infiltration by T‐helper (CD4 positive) and cytotoxic T cells (CD8 positive). Stimulation with TL revealed a dose‐dependent T‐cell proliferation with a stimulation index of 1·1–5·7 compared to 1·1–1·4 before vaccination ( P < 0·01). Most strikingly, DC‐based vaccination was accompanied by a steady decrease of the tumour marker chromogranin A from 2.93 umol/l initially to below the detection limit of 0.15 umol/l within 9 months of therapy. The ultrasound examination revealed a tumour regression of the metastasis in the right lobe of the liver. CONCLUSIONS Our data indicate that vaccination with tumour lysate‐pulsed DCs induced a significant antitumour immune response in a neuroendocrine carcinoma of the pancreas. This approach represents an alternative strategy for the treatment of advanced neuroendocrine carcinomas that are resistant to conventional therapy.

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