small molecules

2026-08-09 | Cutaneous Manifestations of Carcinoid Tumor and Syndrome.

Carcinoid syndrome refers to the signs and symptoms a patient experiences secondary to a carcinoid tumor or another well-differentiated neuroendocrine tumor, which secretes serotonin and other peptides that enter the bloodstream; only 10% of patients with carcinoid tumors experience carcinoid syndrome. Common findings include facial flushing, tachycardia, and shortness of breath. Carcinoid tumors usually originate in the gastrointestinal (G.I.) tract. They are slow growing but can metastasize to the liver, lymph nodes, and elsewhere. Primary or metastatic cutaneous carcinoid tumors present as pink, fast-growing dermal or subcutaneous nodules. The diagnostic workup includes a thorough history and physical examination of the entire body, including a urinary 24-hour 5-hydroxyindoleacetic acid (5-HIAA) and serum chromogranin A. Management of carcinoid syndrome initially includes the use of somatostatin analogs, diet, medication regulation, and clinical monitoring. More aggressive treatment, such as peptide receptor radionuclide therapy or everolimus, an mTOR inhibitor, may be required.

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2026-07-01 | Hepatic arterial embolization procedures in neuroendocrine tumors with carcinoid heart disease: a retrospective single-center study on safety and feasibility

Abstract Hepatic arterial embolization reduces liver tumor burden and hormonal secretion in neuroendocrine tumors, but its safety in patients with carcinoid heart disease is underexplored, and current guidelines suggest managing the cardiac disease first. We assessed the safety and efficacy of hepatic arterial embolization in patients with neuroendocrine tumors and concomitant carcinoid heart disease in a single-center retrospective study including patients with liver metastases and carcinoid heart disease confirmed on expert transthoracic echocardiography between 2001 and 2025. The primary endpoint was procedural safety; secondary endpoints were symptom control, biochemical response, and overall survival. Twenty-seven patients (median age: 58.6 years) underwent 69 embolization procedures using bland, conventional, and drug-eluting bead techniques. Severe carcinoid heart disease was present in 52% of patients, and right-sided valvular disease was found in 96%, with tricuspid regurgitation predominating. No procedure-related or cardiovascular death occurred. Two cardiac complications (7%) arose, both in patients with severe pre-existing valvular disease, together with four extra-cardiac complications. Carcinoid syndrome symptoms and urinary 5-hydroxyindoleacetic acid levels decreased significantly after treatment, whereas cardiac symptoms remained stable. The median overall survival was 6.25 years, with a 5-year survival of 60%. Hepatic arterial embolization appears feasible with an acceptable safety profile in patients with neuroendocrine tumors and concomitant carcinoid heart disease when performed in expert centers with multidisciplinary management and may contribute to carcinoid syndrome control. Prospective multicenter studies are warranted to confirm these findings and define the optimal sequencing of hepatic arterial embolization and cardiac valve surgery. Key findings

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2026-06-27 | Transcatheter Tricuspid Valve Replacement in Carcinoid Heart Disease With Transjugular 3D Intracardiac Echocardiography Guidance.

Transcatheter tricuspid valve replacement (TTVR) with the EVOQUE system was the first Food and Drug Administration-approved TTVR therapy for clinical use in patients with symptomatic severe tricuspid regurgitation. Successful implantation is largely dependent on both fluoroscopic and transesophageal echocardiography (TEE) guidance. Imaging by TEE may be inadequate for confident and successful TTVR, which has led to adjunctive imaging with intracardiac echocardiography (ICE). We present a unique case of TTVR with the EVOQUE system using transjugular 3-dimensional (3D) ICE guidance in symptomatic severe tricuspid regurgitation due to carcinoid syndrome in the setting of cardiogenic shock. Transjugular 3D ICE is an effective adjunctive imaging modality for TTVR in patients who have inadequate imaging on TEE. A transjugular approach for 3D ICE offers an alternative route compared with transfemoral for real-time visualization of the tricuspid valve leaflets with no interference with the valve delivery system.

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2026-06-18 | Isolated Tricuspid Valve Dysplasia in a Patient with Behçet's Disease: An Unusual Mimic of Carcinoid Heart Disease and Arrhythmogenic Right Ventricular Cardiomyopathy

Isolated tricuspid valve dysplasia (ITVD) is a rare congenital abnormality of the tricuspid valve that may remain clinically silent until adulthood and can resemble acquired causes of severe tricuspid regurgitation. This case report describes a 28-year-old man with established Behçet's disease who presented with progressive exertional dyspnoea, palpitations, and bilateral lower-limb oedema. Clinical examination showed features of right-sided heart failure and a pansystolic murmur consistent with severe tricuspid regurgitation. Electrocardiography demonstrated complete right bundle branch block, and 48-hour Holter monitoring showed frequent premature atrial contractions without sustained supraventricular or ventricular tachycardia. Transthoracic echocardiography revealed severe tricuspid regurgitation caused by diffuse thickening, retraction, and malcoaptation of the tricuspid valve leaflets, with marked right atrial and right ventricular dilatation and mildly reduced right ventricular systolic function. The initial differential diagnosis included carcinoid heart disease, arrhythmogenic right ventricular cardiomyopathy, Ebstein's anomaly, and Behçet's-related inflammatory valvulopathy. Mild biochemical abnormalities were not accompanied by clinical features of carcinoid syndrome, and 18F-FDG PET-CT and 68Ga-DOTATATE PET-CT showed no neuroendocrine tumour or hepatic metastases. Cardiac magnetic resonance imaging demonstrated severe right ventricular dilatation and apical aneurysms but no evidence supporting arrhythmogenic right ventricular cardiomyopathy. The absence of apical leaflet displacement excluded classic Ebstein's anomaly. After multidisciplinary evaluation, isolated tricuspid valve dysplasia was diagnosed, and the patient underwent successful bioprosthetic tricuspid valve replacement. Recovery was uneventful, and discharge occurred on postoperative day 10. This case highlights the need for structured multimodality assessment of primary severe tricuspid regurgitation in young adults with systemic inflammatory disease, particularly when congenital and acquired right-sided valvular disorders have overlapping clinical and imaging features.

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2026-05-24 | A Combination of the Tryptophan Hydroxylase Inhibitor Telotristat with the mTOR Inhibitor Everolimus as an Effective Strategy Against Neuroendocrine Tumors.

Neuroendocrine tumors are a rare and heterogeneous group of neoplasms that frequently cause carcinoid syndrome, characterized by diarrhea, flushing, and carcinoid heart disease. A recent therapy for carcinoid syndrome involves inhibition of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, using telotristat ethyl. Telotristat has demonstrated clinical control of carcinoid syndrome; however, its potential antitumoral effects remain unclear. This study aimed to evaluate the antitumor activity of telotristat ethyl alone and in combination with everolimus in neuroendocrine tumor models. Cell viability was assessed in three neuroendocrine tumor cell lines of pancreatic (BON-1, QGP-1) and intestinal (HROC57) origin following treatment with telotristat ethyl. Combination treatments with telotristat ethyl and everolimus or other antitumoral agents were evaluated for effects on cell viability, apoptosis, and cell cycle distribution. In vivo efficacy was examined in nude mice bearing BON-1-derived xenografts treated with telotristat ethyl, everolimus, or the combination. Tumor growth, toxicity, proliferation (Ki67), and apoptosis (active caspase-3) were analyzed. Telotristat ethyl reduced cell viability in all three neuroendocrine tumor cell lines. Combination with everolimus, but not with other antitumoral treatments, synergistically decreased cell viability, induced apoptosis, and reduced the proportion of cells in the G2/M phase. In nude mice bearing BON-1 xenografts, combined treatment with telotristat ethyl and everolimus arrested tumor growth without signs of toxicity compared with single treatments. At the end of treatment, tumors from combination-treated mice showed a reduction in proliferation (Ki67) comparable to single-treated groups and an increase in apoptosis as indicated by active caspase-3. Telotristat ethyl exhibits antitumoral activity in neuroendocrine tumor models in vivo. Moreover, the combination of telotristat ethyl and everolimus, two therapies already used in clinical practice, may represent a safe and effective therapeutic strategy for neuroendocrine tumors.

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cell therapies

2026-06-15 | Acute and midterm outcomes of patients undergoing right-sided heart valve surgery for carcinoid heart valve disease.

Carcinoid heart syndrome is a rare manifestation of metastatic neuroendocrine tumor that causes right heart valve dysfunction and subsequent symptomatic right heart failure, reducing long-term survival. In addition to symptomatic treatment, therapeutic strategies include surgical or interventional valve replacement for tricuspid and pulmonary valve regurgitation. Between 2011 and 2022, 12 patients with symptomatic right heart failure and carcinoid heart syndrome underwent elective valve surgery at our institution and were retrospectively included in this study. Procedural data, early clinical outcomes, survival, and time to reintervention were analyzed. The median follow-up period was 33 months, ranging from 2 to 131 months. All patients underwent tricuspid bioprosthetic valve replacement with concomitant pulmonary valve replacement in 4 patients. A 3-dimensional endoscopic approach via right anterolateral minithoracotomy was conducted in 33.3% (4 out of 12) of cases, whereas a full median sternotomy was performed in 66.7% (8 out of 12). Beating-heart technique without crossclamping of the aorta was used in 58.3% (7 out of 12) of cases. Postoperative rethoracotomy for bleeding was required in 2 patients, and 1 patient developed acute kidney injury. No patients experienced permanent pacemaker implantation or stroke. One patient died during hospitalization due to acute hepatic failure in the presence of a preoperatively elevated Model for End-Stage Liver Disease score of 13, resulting in an in-hospital mortality rate of 8.3%. At final follow-up, overall survival was 41.7% (5 out of 12). Five patients required valve reintervention due to bioprosthetic degeneration associated with progression of the underlying neuroendocrine tumor, occurring 11 to 44 months after the index procedure. Two patients underwent surgical redo procedures (1 repeat tricuspid valve replacement and 1 repeat pulmonary valve replacement). One patient underwent pulmonary balloon valvuloplasty followed by 2 valve-in-valve procedures using balloon-expandable transcatheter heart valves. In addition, 2 patients underwent combined valve-in-valve interventions of both the tricuspid and pulmonary valves. Four of the 5 patients undergoing reintervention died during subsequent follow-up. The results from our single-center study provide descriptive information on current treatment approaches for this rare cardiovascular disease. Surgical valve replacement for carcinoid heart syndrome is technically feasible and associated with satisfactory early clinical outcomes. However, reinterventions are frequently required, largely driven by progression of neuroendocrine tumor disease. Consequently, the influence of valve intervention on long-term survival remains uncertain, and valve durability appears limited, as reflected by the high rate of repeat procedures. These findings underscore the necessity for close follow-up with dedicated heart valve units, enabling early detection of disease progression and bioprosthetic valve degeneration and ensuring optimized care through a multidisciplinary treatment approach.

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2023-07-17 | LIVER TRANSPLANT FOR METASTATIC NEUROENDOCRINE TUMORS: A SINGLE-CENTER REPORT

Neuroendocrine tumors are rare neoplasms of uncertain biological behavior. The liver is one of the most common sites of metastases, occurring in 50% of patients with metastatic disease.To analyze a clinical series in liver transplant of patients with neuroendocrine tumors metastases.A retrospective descriptive study, based on the review of medical records of patients undergoing liver transplants due to neuroendocrine tumor metastases in a single center in northeast Brazil, over a period of 20 years (January 2001 to December 2021).During the analyzed period, 2,000 liver transplants were performed, of which 11 were indicated for liver metastases caused by neuroendocrine tumors. The mean age at diagnosis was 45.09±14.36 years (26-66 years) and 72.7% of cases were females. The most common primary tumor site was in the gastrointestinal tract in 64% of cases. Even after detailed investigation, three patients had no primary tumor site identified (27%). Overall survival after transplantation at one month was 90%, at one year was 70%, and five year, 45.4%. Disease-free survival rate was 72.7% at one year and 36.3% at five years.Liver transplantation is a treatment modality with good overall survival and disease-free survival results in selected patients with unresectable liver metastases from neuroendocrine tumors. However, a rigorous selection of patients is necessary to obtain better results and the ideal time for transplant indication is still a controversial topic in the literature.

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2023-02-09 | Liver transplantation in gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors are part of a heterogeneous group of tumors located in organs such as the gastrointestinal tract (GIT), lungs, thymus, thyroid, and adrenal glands. The most prevalent sites are the small intestine, cecal appendix, and pancreas. More than 50% of these tumors are associated with metastases at the time of diagnosis. Neuroendocrine tumors are classified according to the degree of cell differentiation and the histopathological proliferation index of the lesion. Neuroendocrine tumors can be well differentiated or poorly differentiated. G3 tumors are characterized by Ki-67 expression greater than 20% and can be either well differentiated (G3 NET) or poorly differentiated (G3 NEC). Neuroendocrine carcinoma (NEC G3) is subdivided into small-cell and large-cell types. When neuroendocrine tumors present clinical and compressive symptoms, carcinoid syndrome is evident. Carcinoid syndrome occurs when the tumor produces neuroendocrine mediators that cannot be metabolized by the liver due to either the size of the tumor or their secretion by the liver itself. Several therapeutic strategies have been described for the treatment of metastatic neuroendocrine tumors, including curative or palliative surgical approaches, peptide receptor radionuclide therapy, percutaneous therapy, systemic chemotherapy, and radiotherapy. Liver surgery is the only approach that can offer a cure for metastatic patients. Liver metastases must be completely resected, and in this context, orthotopic liver transplantation has gained prominence for yielding very promising outcomes in selected cases. The aim of this study is to review the literature on OLT as a form of treatment with curative intent for patients with gastroenteropancreatic neuroendocrine tumors with liver metastasis.

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2020-06-01 | Liver transplantation in the treatment of unresectable hepatic metastasis from neuroendocrine tumors

: Neuroendocrine tumors (NET) are rare neoplasms with generally indolent growth behavior. The liver is the most common site of NET metastasis. The NET metastatic spread to the liver are usually multiple tumors involving bilateral hemilivers. For patients with isolated NET metastasis to the liver, a complete extirpation (R0) resection of both the primary NET and liver metastasis provide the best chance of tumor recurrence-free patient survival. Orthotopic liver transplantation (OLT) presents a viable treatment option for patients with unresectable liver metastasis from NET. Post-OLT outcomes for the patients of NET with liver metastasis (5-year overall survival rate 47–71%) are comparable to those for other indications. However, the high rate of recurrence after OLT (31–57%) remains a clinical obstacle. As such, it is imperative to consider each patient individually and identify prognostic factors that would impact post-OLT outcomes. This article focuses on the role of OLT in the definitive treatment of metastatic liver NET, review patient selection criteria predictive of survival outcomes and post-OLT outcomes for patients.

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2018-05-10 | Resection of the Primary Gastrointestinal Neuroendocrine Tumor Improves Survival With or Without Liver Treatment

Objective: The aim of this study was to determine outcomes of primary tumor resection in metastatic neuroendocrine tumors across all primary tumor sites. Background: Primary tumor resection (PTR) may offer a survival benefit in metastatic gastrointestinal neuroendocrine tumors (GI-NETs); however, few studies have examined the effect of primary site and grade on resection and survival. Methods: This is a retrospective study of patients with metastatic GI-NETs at presentation between 2005 and 2011 using the California Cancer Registry (CCR) dataset merged with California Office of Statewide Health Planning and Development (OSHPD) inpatient longitudinal database. Primary outcome was overall survival (OS). Univariate and multivariate (MV) analyses were performed using the Pearson Chi-squared tests and Cox proportional hazard, respectively. OS was estimated using the Kaplan-Meier method and log-rank test. Results: A total of 854 patients with GI-NET metastases on presentation underwent 392 PTRs. Liver metastases occurred in 430 patients; 240 received liver treatment(s). PTR improved OS in patients with untreated metastases (median survival 10 vs 38 months, P < 0.001). On MV analysis adjusted for demographics, tumor stage, grade, chemotherapy use, Charlson comorbidity index, primary tumor location, or treatment of liver metastases, PTR with/without liver treatment improved OS in comparison to no treatment [hazard ratio (HR) 0.50, P < 0.001 and 0.39, P < 0.001, respectively]. PTR offered a survival benefit across all grades (low-grade, HR 0.38, P = 0.002 and high-grade, HR 0.62, P = 0.025) Conclusion: PTR in GI-NET is associated with a better survival, with or without liver treatment, irrespective of grade. This study supports the resection of the primary tumor in patients with metastatic GI-NETs, independent of liver treatment.

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proteins

2026-08-03 | Effective treatment of carcinoid syndrome with peptide receptor radionuclide therapy

CLINICAL VIGNETTEThe severity of symptoms intensified over the following months; therefore, we decided to increase the frequency and escalate doses of lanreotide (120mg once every 2 weeks).However, adequate symptom control was not achieved, as complaints persisted despite partial improvement.Although imaging studies [computed tomography (CT) scans] still described the disease as stable, we observed clinical and biochemical progression, with a substantial rise in chromogranin A levels (Fig. 2).Next available treatment options were discussed, and peptide receptor radionuclide therapy 69-year-old male patient diagnosed with a midgut neuroendocrine tumor (NET) was admitted to the hospital due to aggravating symptoms of carcinoid syndrome (CS).The patient has a history of emergency laparotomy with segmental resection of the small intestine (end-to-end anastomosis) due to gangrenous perforated inflammation of Meckel's diverticulum in September 2015.Histopathological examination revealed a NET G1 of Meckel's diverticulum, with immunohistochemistry showing: synaptophysin positive, chromogranin positive, and Ki67 positive in < 2% of cell nuclei.Due to high somatostatin receptor expression demonstrated on [99mTc] HYNIC-TOC scans (Krenning score 3-4) and the presence of peritoneal implants, as well as metastases in lymph nodes, bones, and liver, the patient began therapy with long-acting somatostatin analogs in 2016 -initially octreotide 30 mg every 4 weeks; later, we switched to lanreotide 120 mg every 4 weeks.The treatment was well tolerated, and a radiological response [stable disease (SD)] was achieved according to RECIST 1.1 criteria.At the end of 2022, the patient began experiencing periodic symptoms of CS -initially sporadically, then progressively intensifying over the following months.He reported intermittent abdominal pain, diarrhea (up to 12 bowel movements per day), and facial flushing with telangiectasias (Fig. 1).We performed 24-hour urine collections for 5-hydroxyindoleacetic acid (5-HIAA), the results of which were significantly elevated.As the next step, we measured NT-proBNP to evaluate for carcinoid heart disease; the level was slightly increased -205.6 pg/mL (cut off 125) -so we did not extend the diagnostics with echocardiography, in accordance with Polish Network of Neuroendocrine Tumors and European Neuroendocrine Tumor Society recommendations [1,2].

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2026-02-27 | Oxalate nephropathy from untreated pancreatic insufficiency in a neuroendocrine tumour patient.

Pancreatic exocrine insufficiency (PEI) is an under-recognised cause of chronic diarrhoea in patients with neuroendocrine tumours (NETs). If left untreated or undertreated, PEI can lead to complications such as oxalate nephropathy (ON), which may result in loss of kidney function and potentially limit oncologic treatment options, including peptide receptor radionuclide therapy (PRRT). We present a man in his late 60s with a small bowel NET who developed persistent, uncontrolled diarrhoea for several years. The diarrhoea was attributed to multiple factors, including secretory NET (ie, carcinoid syndrome), bile acid diarrhoea and PEI secondary to somatostatin analogue therapy. Due to financial constraints, the patient was unable to consistently take pancreatic enzyme replacement therapy (PERT). Years after the diagnosis of NET, the patient developed a new onset worsening of kidney function. Further work-up, including a kidney biopsy, confirmed ON, which significantly limited subsequent treatment options, including PRRT. Routine screening for PEI and early initiation of PERT should be considered in all NET patients with chronic diarrhoea to prevent ON and preserve future treatment options.

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2025-10-10 | Ectopic Cushing's syndrome in a patient with DIPNECH and metastatic lung carcinoid.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare precursor to lung carcinoids. We report a case of ACTH-dependent Cushing's syndrome in a 73-year-old female patient with metastatic lung carcinoid arising on a background of DIPNECH. She presented with lower limb oedema, hypokalaemia, hypertension, and de novo diabetes. Clinical suspicion for hypercortisolism was confirmed by abnormal cortisol tests. A thoracic CT scan showed multiple lung nodules suggestive of DIPNECH and biopsy of one of the nodules identified an ACTH-expressing carcinoid tumour. A PET-Ga-68-DOTATOC revealed pulmonary and multiple tumour lesions in the ganglia, bone and liver with overexpression of somatostatin receptors. A liver biopsy demonstrated involvement by a well-differentiated neuroendocrine neoplasia, consistent with metastasis. Hypercortisolism was managed with octreotide and metyrapone, but the patient succumbed to complications 14 months post-diagnosis. This case suggests DIPNECH's potential to progress to hyperfunctioning, metastatic carcinoids and highlights the necessity for vigilant long-term surveillance and early intervention.

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2025-10-01 | S3462 The Largest Known Case of a Solid Pseudopapillary Neoplasm Presenting as Acute Pancreatitis

Introduction: Carcinoid syndrome, the most common ectopic hormonal syndrome associated with neuroendocrine tumors (NETs), results from unfiltered systemic release of vasoactive amines like serotonin due to hepatic metastases. Hallmark symptoms include flushing, diarrhea, and wheezing. Somatostatin analogs (SSAs) such as lanreotide are first-line therapy. Case Description/Methods: We present a man in his 60s with alcohol use disorder, prostate cancer on androgen deprivation, and metastatic small bowel NET on long-term lanreotide. He presented with anasarca, orthostatic presyncope, muscle wasting, and chronic diarrhea (2–3 episodes/day for over 4 years despite antidiarrheals). Tumor burden appeared stable, but chromogranin A was markedly elevated, raising concern for persistent carcinoid activity contributing to malabsorption. Labs revealed fat-soluble vitamin deficiencies (A, D, E, K), INR > 10 (corrected with vitamin K), and fecal elastase <10 µg/g, confirming exocrine pancreatic insufficiency (EPI). Imaging showed pancreatic atrophy and calcifications suggestive of chronic pancreatitis. This raised the question of chronic SSA exposure versus long-standing alcohol use disorder as contributing etiologies. CREON, a pancreatic enzyme replacement therapy (PERT), was initiated, leading to improved diarrhea, nutritional repletion, and successful diuresis. Discussion: Although EPI is rarely reported in SSA trials for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), its prevalence in clinical practice is significantly higher—up to 20% in some series. Despite this, EPI remains under-recognized, as demonstrated here where it was not considered even after 14 years of disease. Among patients with well-differentiated NETs treated with SSAs, EPI occurs in approximately 1 in 4 cases. Screening with fecal elastase-1 (FE1) in symptomatic patients should be part of a guideline-based approach, as up to 92% of affected patients benefit from PERT. Routine screening for malnutrition should be implemented in all GEP-NEN patients. Treatment of diarrhea should be guided by its etiology. Early involvement of gastroenterology, oncology, and endocrinology is recommended to co-manage chronic diarrhea, a frequent yet multifactorial symptom. Portions of this case report were edited with the assistance of AI-based language tools.

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2025-07-28 | A Royal Flush: Carcinoid Heart Disease Complicated by Severe Tricuspid and Pulmonic Valve Regurgitation.

Carcinoid heart disease (CHD) is a severe complication of metastatic neuroendocrine tumors (NETs), leading to fibrotic degeneration of right-sided heart valves. A 38-year-old male presented with progressive dyspnea, fatigue, abdominal bloating, diarrhea, and facial flushing. Imaging revealed hepatic metastases and mesenteric lymphadenopathy, and biochemical markers confirmed a NET of likely gastrointestinal origin. Echocardiography showed torrential tricuspid regurgitation, severe pulmonary insufficiency, right ventricular dilation, and a patent foramen ovale (PFO). The patient was started on long-acting lanreotide for carcinoid syndrome and optimized on heart failure therapy. Due to severe valvular dysfunction, he underwent tricuspid and pulmonic valve replacement with bioprosthetic valves and PFO closure under perioperative octreotide infusion. The patient also underwent transthoracic liver debulking and ablation, small bowel resection, and mesenteric dissection. Postoperatively, he showed symptomatic improvement and remains under multidisciplinary surveillance. This case highlights the importance of early recognition, multidisciplinary management, and surgical intervention in CHD to optimize outcomes. Early initiation of somatostatin analog therapy, guideline-directed medical therapy for heart failure, and timely surgical intervention can significantly improve symptom burden and survival.

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antibodies

2026-08-07 | Clinical Responses to Tarlatamab Among Patients with Pulmonary Carcinoid.

Pulmonary carcinoid (PC) is a rare, well-differentiated neuroendocrine tumor of the lung. In patients with metastatic disease, systemic therapies typically have low response rates, and long-term survival is poor. PC frequently expresses DLL3, but whether it responds to the DLL3-targeted bispecific T-cell engager tarlatamab is unknown. We analyzed 11 patients with DLL3-high PC treated with tarlatamab at Memorial Sloan Kettering. Tumor response was assessed using RECIST v 1.1. Response rate was 8/11 (73%), including one patient with central nervous system-only disease, and disease control rate was 11/11 (100%). All patients experienced reduction of their measurable disease. One patient had progressed at time of data cutoff and median progression-free survival was not reached. Cytokine release syndrome (CRS) occurred in cycle 1 in 9/11 (82%) patients including 2 with grade 3 CRS. Tarlatamab demonstrated a high response rate in PC. Cytokine release syndrome was common. Tarlatamab is a promising treatment option for patients with PC.

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2026-04-03 | Surgical resection of an adrenocorticotropic hormone-producing pulmonary typical carcinoid with mediastinal lymph node metastasis and high programmed death-ligand 1 expression.

The programmed death-ligand 1 positivity rate in typical carcinoid is generally low; however, cases with programmed death-ligand 1 expression are more frequently associated with lymph node metastasis and have a poorer prognosis. While immune checkpoint inhibitors were incorporated into adjuvant chemotherapy regimens for programmed death-ligand 1-positive non-small cell lung cancer, their efficacy in pulmonary carcinoids remains unclear. A 47-year-old woman presented to a local clinic with moon face. Laboratory testing revealed elevated levels of adrenocorticotropic hormone and cortisol and adrenocorticotropic hormone-dependent Cushing's syndrome was suspected. For further evaluation, the patient was referred to our hospital. Computed tomography revealed a nodule in the left lower lobe of the lung and enlargement of the left hilar lymph node, suggesting ectopic Cushing's syndrome. Left lung cancer (cT1bN1M0, cStage IIB) was suspected, and the patient underwent robot-assisted thoracoscopic left lower lobectomy with ND2a-2 lymph node dissection for diagnostic and therapeutic purposes. Pathological examination confirmed a diagnosis of typical carcinoid (pT1bN2M0, pStage IIIA) with high programmed death-ligand 1 expression. Considering the presence of mediastinal lymph node involvement and programmed death-ligand 1 expression, the patient received four courses of cisplatin and vinorelbine, followed by treatment with atezolizumab. Postoperatively, her adrenocorticotropic hormone levels normalized, and the patient has been alive 18 months postoperatively without recurrence. Programmed death-ligand 1-positive typical carcinoids are associated with a higher frequency of lymph node metastasis and poorer prognosis. Additional case investigations are required to assess the efficacy of immune checkpoint inhibitors in typical carcinoid.

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2025-03-31 | Exploring the association between 91 circulating inflammatory proteins and the risk of carcinoid syndrome: a Mendelian randomization analysis.

This study aims to explore the potential correlation between circulating inflammatory proteins and carcinoid syndrome (CS). Using summary data from genome-wide association studies (GWAS), we conducted a Mendelian randomization (MR) analysis with two samples, treating 91 circulating inflammatory proteins as exposure factors and CS as the outcome. Based on genetic loci closely associated with circulating inflammatory proteins selected as instrumental variables, we primarily employed the inverse-variance weighted (IVW) method for analysis, combined with the weighted median method (WM), simple median method (SM), weighted mode estimation (WME), and MR-Egger regression for comprehensive analysis. Initial IVW results revealed significant causal effects of six circulating inflammatory proteins on CS. Specifically, Interleukin-17C levels were negatively correlated with CS risk, indicating a protective effect; whereas beta-nerve growth factor, C-C motif chemokine 20, Natural killer cell receptor 2B4, C-X-C motif chemokine 5, and Leukemia inhibitory factor levels were positively correlated with CS risk, suggesting detrimental effects. In heterogeneity tests, the selected single-nucleotide polymorphisms (SNPs) did not show heterogeneity, and analysis using Egger intercept and MR-PRESSO test did not detect pleiotropy of SNPs, thus validating the reliability of the study. Furthermore, sensitivity analysis using the leave-one-out method further confirmed the robustness of the results. In summary, this study identified significant causal relationships between six inflammatory proteins-Interleukin-17C, beta-nerve growth factor, C-C motif chemokine 20, Natural killer cell receptor 2B4, C-X-C motif chemokine 5, and Leukemia inhibitory factor-and CS risk through MR analysis. This finding not only emphasizes the important role of inflammation in the pathogenesis of CS but also suggests the potential value of inflammatory proteins as targets for early diagnosis and therapeutic interventions.

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2023-10-22 | Clinical manifestation of neuroendocrine tumor – carcinoid heart disease

Carcinoid heart disease (CHD) is a rare manifestation of the carcinoid syndrome, but eventually occurs in most patients and is a major cause of cardiovascular mortality. The development of CHD is known to be a negative prognostic factor in patients with advanced neuroendocrine tumors. The mechanism of CHD pathophysiology remains poorly understood. Progress in early diagnosis and improvement of therapeutic approaches over the last decade has reduced hospital mortality in this cohort of patients. In this clinical case we summarize clinical features of the examination, treatment of and demonstrate modern pathogenetic aspects of the development of this condition.

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2023-03-31 | Data from Development and Characterization of a Novel <i>In vivo</i> Model of Carcinoid Syndrome

<div>Abstract<p><b>Purpose:</b> Carcinoid syndrome, characterized by flushing, diarrhea, and valvular heart disease, can occur following carcinoid tumor metastasis to the liver and systemic release of bioactive hormones into the systemic circulation. Treatment of this devastating disease is hampered by the lack of an <i>in vivo</i> model that recapitulates the clinical syndrome.</p><p><b>Experimental Design:</b> Here, we have injected BON cells, a novel human carcinoid cell line established in our laboratory, into the spleens of athymic nude mice to establish liver metastases.</p><p><b>Results:</b> The majority of mice injected intrasplenically with BON cells developed significant increases in plasma serotonin and urine 5-hydroxyindoleacetic acid, and several mice exhibited mesenteric fibrosis, diarrhea, and fibrotic cardiac valvular disease reminiscent of carcinoid syndrome by both echocardiographic and histopathologic evaluation. Mice pretreated with octreotide, a long-acting somatostatin analogue, or bevacizumab, a vascular endothelial growth factor inhibitor, developed fewer liver metastases and manifestations of carcinoid syndrome, including valvular heart disease.</p><p><b>Conclusion:</b> We have provided an important <i>in vivo</i> model to further delineate novel treatment modalities for carcinoid syndrome that will also be useful to elucidate the factors contributing to the sequelae of carcinoid disease (e.g., mesenteric fibrosis and valvular heart disease).</p></div>

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other

2025-10-01 | SUN-265 Lung Carcinoid Tumor as an Unusual Presentation in a Puerto Rican Patient with MEN1

Abstract Disclosure: A.C. Cotto-Vazquez: None. L. Rodriguez-Franco: None. O. Mora-Osoria: None. K.N. Yelton Torres: None. L. Salgado-Romero: None. A. Nieves-Rivera: None. C. Rosario-Martinez: None. J.M. Garcia-Mateo: None. Background:Multiple Endocrine Neoplasia 1 (MEN1) is a rare autosomal dominant syndrome with predominance for specific endocrine tumors associated with parathyroid glands, anterior pituitary, and pancreatic islet cells. Lung carcinoid tumors are uncommon and typically develop on their own. They rarely occur in connection with MEN1. Case:We present a case of a 50-year-old male that comes for an evaluation of persistent hypercalcemia. The patient's medical history indicated a diagnosis of an unspecified lung tumor and asthma. After the evaluation of laboratory workup and imaging, primary hyperparathyroidism (PHPT) was established with confirmation of right inferior parathyroid adenoma after minimally invasive parathyroidectomy. At follow up, the patient continued with persistent PHPT. Exploratory neck surgery revealed left superior parathyroid adenoma. The recurrence of PHPT instigated closer inspection into the history of his pulmonary tumor with suspicion of a neuroendocrine etiology. Following a pathology review, a lung carcinoid tumor was confirmed indicating an association with MEN1. Family history assessment revealed his mother had been treated for PHPT, pituitary tumor and pancreatic/liver cancer, with genetic confrimation of MEN1. In addition, the patient’s son presented at the age of 23 with parathyroid adenoma. Because of concerns related to medical insurance and costs, the patient did not undergo MEN1 genetic testing at this time. Over the following years, he was regularly monitored for MEN1-related tumors with imaging and laboratory tests, though the results remained negative. 8 years later, SPECT-CT was recommended for follow up of hypercalcemia with high normal i-PTH which demonstrated abnormal foci of radiotracer retention. He underwent parathyroidectomy, once again, with pathology confirming left inferior parathyroid hyperplasia. After continued recommendations for family screening of MEN1, genetic testing identified a pathogenic variant of MEN1 c.95C&gt;G (p.Pro32Arg). Our patient demonstrates an unusual presentation of this syndrome with an initial case of lung carcinoid tumor and a 9 year history of isolated hyperparathyroidism. Conclusion:This case contributes information about the variants of MEN1 in which a Hispanic mother and son had two different presentations of the same inherited syndrome. These results point to a variant mutation in this particular case. Further genetic analysis of the patient's family may offer insights into the inheritance of MEN1 variants and whether other mutations impact its clinical presentation, thereby enhancing our understanding of related syndromes associated with MEN1. In addition, it might contribute to the knowledge of gene therapy and its potential benefits for MEN1 patients. Presentation: Sunday, July 13, 2025

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2024-10-01 | PD15-12 Single-Nuclei Multiomic Analysis of Small Intestinal Neuroendocrine Tumors and Matched Liver Metastases Reveals Gene Expression Changes Associated With Disease Progression

Abstract S.G. Andrews: None. S. Rajhans: None. T. Truongvo: None. J.P. Madigan: None. S.D. Forsythe: None. M. Kelly: None. J. Del Rivero: None. J.M. Hernandez: None. N. Nilubol: None. E. Arda: None. S.M. Sadowski: None. Metastatic lesions of small intestinal neuroendocrine tumors (siNETs) cause detrimental health effects, including carcinoid syndrome, hepatic injury, and impact survival. siNETs are rare and understudied. Limited studies have shown low mutational burden relative to other cancers; therefore, other mechanisms governing gene expression likely affect tumor progression and metastasis formation. Gene expression changes driving siNET progression are largely unknown and may be due to epigenomic alterations and structural variants. In the first assessment of both transcriptomic and epigenomic changes in siNET metastasis, we analyzed matched patient primary and liver metastases samples to assess intertumoral heterogeneity, elucidate epigenetic mechanisms, and investigate possible drivers of tumor progression, with the goal of discovering novel targets for therapy. Nuclei were isolated via homogenization and density gradient separation, then captured via 10X Genomics Chromium. Single-nuclei RNA-Seq and ATAC-seq libraries were generated and sequenced using Illumina NovaSeq instruments. After read alignment and quality control, 3,300-7,000 nuclei were analyzed per sample. Data analysis was completed via Trinity CTAT inferCNV, Seurat, ClusterProfiler, and Signac. Tumor cells were labeled via enriched copy number variation. Accessory cells were labeled via biomarker expression. Our cohort consisted of three patient-matched primary siNETs and liver metastases, one patient normal liver sample, and one healthy duodenal sample. Upon dimensionality reduction, all tumor samples clustered separately from normal controls. Inferred copy number variation analysis of matched lesions from each patient demonstrated aberrant copy number alterations (CNA); these somatic CNA signatures demonstrated varied clonal trajectories from primary to metastasis among the three patients. Gains of segments of chromosome 2 were common among all three sets of tumors. After cluster profiling of each patient, transition clusters that included cells from matched primary and metastatic tumors demonstrated transcriptomic alterations of alpha- and beta-catenin, syntaxin, and cadherin-binding pathways, as well as pathways governing lipoprotein particle receptor and tyrosine phosphatase activities. Following differential gene expression analysis, transition clusters showed silencing of oncogene RAB3C, oncogenic transcription factor SOX5, cell adhesion factor PTPRT and phosphodiesterase PDE10A, with an upregulation of these genes within clusters representing the invasive and progressive liver metastases. This study demonstrates multiple processes associated with tumor progression in siNETs. This research may provide new insights for targeted therapy of this rare and understudied disease, which currently faces limited treatment options and poor prognosis in advanced stages. Sunday, June 2, 2024

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2015-04-08 | Neuroendocrine gastro-enteropancreatic tumors – from eminence based to evidence-based medicine – A Scandinavian view

Neuroendocrine tumors (NETs) comprise a heterogenous group of neoplasms with variable clinical expression and progression. The primary tumors most frequently occur in the lungs, intestine and the pancreas. The NET incidence is approximately 6.1/100,000 per year with a prevalence higher than 35/100,000 per year. A NET may be functioning with symptoms related to hormone overproduction or non-functioning, not presenting any hormone-related symptoms. From the early 1980s and onwards, Uppsala University Hospital has contributed significantly to diagnosis, just to mention immunohistochemistry, radio-immunoassays for hormones and peptides and molecular imaging. On the therapeutic side, treatments with cytotoxics as well as biologicals such as, somatostatin analogs and interferons have been evaluated. We have furthermore been involved in important phase III trials for registration of so called, new targeted agents such as, RADIANT-3 and RADIANT-2. Our group were also the first to localize the gene for MEN I on chromosome 11 locus q13. Most recent developments have been the establishments of new biomarkers such as, olfactory receptor E51E1 as well as micro-RNAs in carcinoid tumors of the intestine and lung. A new oncolytic virus, Ad-Vince, for treatment of most NETs has been developed and is ready for the clinic. Furthermore, we have been involved in establishing Nordic and international collaborations. Today, NETs is an area with rapid development and recognized by international organizations at conferences, with large attendance. The Nordic countries continue to be significant contributors to the field.

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2013-08-22 | Oncolytic vesicular stomatitis virus as a treatment for neuroendocrine tumors

Background-Therapeutic goals for neuroendocrine tumors (NETs) not amenable to surgical cure are limited to relieving symptoms and slowing progression.However, many cancers acquire defective antiviral responses as they undergo unregulated proliferation.Therefore, we explored the abilities of recombinant wild-type vesicular stomatitis virus (rwt-VSV) and an attenuated Matrix protein mutant (M51R-VSV) to exploit defective antiviral pathways in NETs.Methods-Viral infectivity and lethality were evaluated in a panel of human NET cell lines H727, UMC-11, and CNDT2.5.We evaluated β-interferon pathways in these cells to define the acquired defect.Murine xenografts were treated with a single intratumoral injection of M51RVSV to study viral efficacy in vivo.Results-VSV infected >99% of cells within 24 hours and killed >95% within 72 hours.NET cells did not produce significant amounts of β-interferon after infection, but exogenous βinterferon protected cells from oncolysis.Treatment with M51R-VSV resulted in significantly suppressed tumor growth compared with mock-infected xenografts for H727 (87±72% vs. 2197±335%, p<0.001),UMC-11 (12±59% vs. 1471±324%, p<0.001), and CNDT2.5 (81±121% vs. 1576±349%, p=0.001). Conclusions-VSV infects and kills humanNETs by exploiting their inability to produce a type I antiviral response.Therefore, M51R-VSV is an excellent candidate for the treatment of advanced NETs. BackgroundNeuroendocrine tumors (NETs), otherwise known as carcinoids, arise from enterochromaffin cells located throughout the body, but are most commonly found in the gastrointestinal tract and tracheobronchial tree. 1;2 While both historical and modern

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2011-05-30 | Oncolytic Viruses for the Treatment of Neuroendocrine Tumors

Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.

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