Carcinoid crisis: The challenge is still there.

Carcinoid crisis (CC) has classically been considered the extreme end of the spectrum of carcinoid syndrome (CS). However, this presumption and other aspects of CC remain poorly understood. Consequently, current clinical guidelines are based on a low quality of evidence. There is no standard definition of CC and its incidence is unknown. Patients with florid CS and elevated serotonin (or its derivatives) which develop CC have been reported during decades. Nevertheless, the hypothesis that CC is due to the sudden massive release of serotonin or other vasoactive substances is unproven. Many triggers of CC (surgery, anaesthesia, peptide receptor radionuclide therapy, tumour biopsy or liver-directed treatments) have been proposed. However, data from studies are heterogeneous and even contradictory. Finally, the role of octreotide in the prevention of CC has been questioned. Herein, we report a clinical case and perform a critical review of the evidence available today on this topic.

Carcinoid syndrome with right-sided valve involvement - a case report and review of the literature.

BACKGROUND: The survival of patients with neuroendocrine tumors has substantially improved with modern treatment options. Although the associated carcinoid syndrome can be diagnosed early and controlled effectively, cardiologists still encounter patients with cardiac manifestations, particularly among individuals with persistently high levels of vasoactive mediators. Treatment options have been limited to surgical valve replacement in fully manifested disease. Since surgery is not always feasible, transcatheter valve implantation is becoming an interesting alternative. CASE: A case of a 50-year-old woman with carcinoid syndrome and right-sided valvular heart disease is presented. Moderate pulmonary valve stenosis and severe tricuspid valve regurgitation were diagnosed during the evaluation and treatment of neuroendocrine tumor. The possibility of rare valve involvement and the need for interdisciplinary cooperation in the diagnosis, monitoring and treatment of patients with neuroendocrine tumors producing vasoactive substances must be emphasized. CONCLUSION: The patient had a typically presenting carcinoid syndrome with a rare cardiac manifestation. Although monitoring and treatment were carried out in accordance with recommendations and appropriate to the clinical condition, rapid progression of the metastatic disease ultimately precluded invasive cardiac intervention.

Elevated sortilin expression discriminates functional from non-functional neuroendocrine tumors and enables therapeutic targeting.

A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome.

Acetato de lanreotida e acetato de octreotida de liberação prolongada para o tratamento de pacientes com sintomas associados a tumores endócrinos gastroenteropancreáticos funcionais / Lanreotide acetate and extended-release octreotide acetate for the treatment of patients with symptoms associated with functional gastroenteropancreatic endocrine tumors

INTRODUÇÃO: Os tumores neuroendócrinos (TNE) são neoplasias, com origem mais comum no trato gastrointestinal, que podem cursar com liberação de hormônios associado a sintomas, levando a síndrome carcinoide, com incidência anual estimada em 0,25/1.000.000 na Europa (ano de 2008). As manifestações clínicas mais comuns incluem diarreia secretória e rubor súbito, mas a diarreia é considerada mais debilitante com potencial risco de morte. Quando o tratamento curativo com ressecção completa não é viável pela presença de doença metastática, o tratamento é direcionado para o controle dos sintomas da síndrome carcinoide e os análogos da somatostatina (octreotida ou lanreotida) são considerados terapia de primeira linha na SC. PERGUNTAS DE PESQUISA: O acetato de octreotida de liberação prolongada (octreotida LAR) e o acetato de lanreotida de liberação prolongada (lanreotida LP) são eficazes, seguros e custo-efetivos para o tratamento dos sintomas relacionados à SC associados ao TNE gastroenteropancreático funcional em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Foram selecionados três ensaios clínico

Comparison of Octreotide and Vasopressors as First-Line Treatment for Intraoperative Carcinoid Crisis.

BACKGROUND: Intraoperative carcinoid crisis is typically sudden onset of profound hypotension during operations on patients with neuroendocrine tumors. The crisis was thought to be due to massive release of hormones, and perioperative octreotide was recommended as a prophylaxis against the crisis and as first-line treatment. Recent studies show that octreotide does not prevent the crisis and that no massive release of hormones occurs. Therefore, the authors hypothesized that octreotide is not effective for treating the crisis. METHODS: A prospective carcinoid anesthesia database was analyzed for occurrences of crisis. Outcomes were compared between protocols when first-line therapy was bolus octreotide and when it was vasopressors without octreotide. Significance was determined by Student's t test, the Mann-Whitney U test, and Fisher's exact test. RESULTS: Among operations performed with octreotide as first-line treatment (n = 150), crisis occurred for 45 (30 %) patients, the median crisis duration was 6 min, 12 (27 %) patients had crises longer than 10 min, 42 patients (93 %) required subsequent vasopressor administration to resolve the crisis, and 3 (2 %) operations were aborted. Among operations performed with vasopressors as the first-line treatment (n = 195), crisis occurred for 49 (25 %) patients (p = 0.31), the median crisis duration was 3 min (p < 0.001), and no crisis lasted longer than 10 min (p = 0.001). Patients treated with vasopressors were less likely to have multiple crises and had a shorter total time in crisis, a shorter anesthesia time, and no aborted operations (p < 0.05 for all). CONCLUSIONS: First-line octreotide was ineffective treatment for carcinoid crisis, with patients requiring vasopressors to resolve the crisis, and many crises lasting longer than 10 min. First-line vasopressor treatment resulted in significantly shorter crisis durations, fewer crises and aborted operations, and shorter anesthesia times. Vasopressors should be used as first-line treatment for intraoperative crisis, and treatment guidelines should be changed.

Carcinoid syndrome-Symptoms and therapeutic approaches.

The carcinoid syndrome (CS) is a constellation of symptoms attributed to hypersecretion of amines, prostaglandins and polypeptides. The cardinal symptoms of CS are flushing, diarrhea and bronchospasm; however, CS may present with various symptoms and signs, as: Skin: cutaneous flushes, cyanosis, pellagra, Gastrointestinal: diarrhea, nausea, abdominal cramps, vomiting, Heart: tricuspid and pulmonic valve thickening causing right heart failure, edema, Respiratory: wheezing, dyspnea.

Carcinoid syndrome caused by a pulmonary carcinoid mimics intestinal manifestations of ulcerative colitis: A case report.

BACKGROUND: Pulmonary carcinoids are rare, low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior. Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi. Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5% of patients with neuroendocrine tumors. Due to such nonspecific presentation, most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. CASE SUMMARY: We report the case of a 48-year-old male who presented with cough, dyspnea, a history of recurrent pneumonitis, and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid. CONCLUSION: We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.

Health care resource use and costs among patients with carcinoid syndrome in France: Analysis of the National Health Insurance Database.

OBJECTIVES: Carcinoid syndrome (CS) develops in approximately 20% of patients with neuroendocrine tumours (NET). This study described healthcare resource utilization and its associated costs among patients with NET and CS, using the French national health care data system. METHODS: Patients were included if they had a hospital stay associated with the code E34.0 "CS" and at least one delivery of a somatostatin analogue (SSA) between 01/01/2012 and 31/12/2016. The end of the analysis was either 31/12/2017 or the date of death, whichever occurred first. Mean overall costs were described by item of expenditure and by periods. RESULTS: 646 patients were included: 64yo, 55% men, 64% and 15% had NET from the small-intestine or lung, respectively. Among them, 309 patients were incident and 271 died during the study period. Mean overall cost per person per month (PPPM) was €2,892: €3,273 for the first year following diagnosis, €2,574 in "middle-years" and €5,039 within the year preceding death. The two most costly expenditure items were drugs (€1,695 PPPM) and hospital stays (€870 PPPM). CONCLUSION: The first year following diagnosis and the year preceding death are the two periods representing the highest costs for CS care in France. Successful disease management may contribute to lower costs in the intermediate period.

Breakthrough Symptoms Remain an Unmet Need in Symptomatic Patients With Neuroendocrine Tumors and Carcinoid Syndrome.

OBJECTIVES: The aims of the study were to assess the effects of breakthrough carcinoid syndrome symptoms on well-being in neuroendocrine tumor (NET) patients insufficiently controlled on long-acting somatostatin analog (SSA) and to assess patient experience with treatment options, physician communication, and disease information sources. METHODS: This study surveyed US NET patients from 2 online communities, experiencing at least one symptom, by utilizing a 64-item questionnaire. RESULTS: One hundred patients participated: 73% female, 75% age 56 to 75 years, and 93% White. Primary tumor distribution was as follows: gastrointestinal NET (n = 55), pancreatic NET (n = 33), lung NET (n = 11), and other NET (n = 13). All patients were actively treated with one long-acting SSA and experiencing breakthrough symptoms: diarrhea, flushing, or other (13% experienced one, 30% two, 57% greater than two). More than one third of treated patients experienced carcinoid-related symptoms daily. Sixty percent of respondents reported not having short-acting "rescue" treatment available, impacting well-being though anxiety or depression (45%), trouble exercising (65%), sleeping (57%), employment (54%), and maintaining friendships (43%). CONCLUSIONS: Breakthrough symptoms remain an unmet need, even in treated patients with NETs. Though still relying on physicians, NET patients are now also using the Internet. Improved awareness of optimal SSA use may improve syndrome control.

Surgery Improves Patient-Reported Outcomes in Patients with Intestinal and Pancreatic NETs: A Prospective Analysis.

BACKGROUND: Incorporation of patient-reported outcomes such as health-related quality of life has become increasingly important in the management of chronic diseases such as cancer. In this prospective study, we examined the effect of surgical resection on quality of life in patients with intestinal and pancreatic neuroendocrine tumors (NETs). METHODS: Thirty-two patients underwent NET resection at our institution from January 2020 to January 2022. All patients completed the 12-item short-form quality-of-life survey prior to surgery, as well as at the 3-, 6-, and 12-month postoperative time points. The presence and severity of specific carcinoid syndrome symptoms (diarrhea, flushing, and abdominal pain) were also recorded during pre- and postoperative appointments. RESULTS: Patients experienced significant increases in both mental and physical health after surgery. Mental health scores significantly increased at all three time points (baseline: 51.33; 3-month: 53.17, p = 0.02; 6-month: 57.20, p < 0.001; 12-month: 57.34, p = 0.002), and physical health scores increased at 6 and 12 months (baseline: 50.39; 6-month: 53.16, p = 0.04; 12-month: 55.02, p = 0.003). Younger patients benefited more in terms of physical health, while older patients had more significant increases in mental health. Patients with metastatic disease, larger primary tumors, and those receiving medical therapy had lower baseline quality-of-life scores and greater improvements after surgery. The vast majority of patients in this study also experienced alleviation of carcinoid syndrome symptoms. CONCLUSIONS: In addition to prolonging survival, resection of intestinal and pancreatic NETs leads to significantly improved patient-reported quality of life.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

Outcome of carcinoid heart syndrome in patients enrolled in the SwissNet cohort.

BACKGROUND: Carcinoid heart disease is a rare disease which develops in patients with functional neuroendocrine tumors in an advanced tumor state. Patients diagnosed with carcinoid heart disease have a poor longtime prognosis with respect to morbidity and mortality and long-term data on patient outcomes are lacking. METHODS AND RESULTS: In this retrospective study, we analyzed outcomes of 23 patients with carcinoid heart disease enrolled into the SwissNet database. We observed that early diagnosis with echocardiographic surveillance of carcinoid heart disease during the course of the neuroendocrine tumor disease was beneficial to overall survival of patients. CONCLUSION: Through nationwide patient enrollment, the SwissNet registry is a powerful data tool to identify, follow-up and evaluate long-term patient outcomes in patients with rare neuroendocrine tumor driven pathologies including carcinoid heart syndrome with observational methods enabling better therapy optimization to improve patient`s long-term perspectives and survival. In line with the current ESMO recommendations, our data proposes that heart echocardiography should be included as part of the general physical assessment in patients with newly diagnosed NET.

Prescribing Characteristics of Octreotide Immediate-Release and Long-Acting Release in Patients with Neuroendocrine Tumors.

BACKGROUND: Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome (CS). High doses of LAR are commonly used in clinical practice. This study aimed to evaluate the real-world utilization of LAR and preceding IR use at the prescription and patient levels. METHODS: We used an administrative claims database (2009-2018) containing privately insured enrollees. We calculated the normalized LAR dose from pharmacy claims and the initial mean IR daily dose at the prescription level. At the patient level, we conducted a retrospective cohort study that included patients continuously enrolled with ≥1 pharmacy claim of LAR and evaluated the frequency and the clinical reason for dose escalation of LAR. The definition of the above-label maximum dose of LAR was ≥30 mg/4 weeks. RESULTS: Nineteen percent of LAR prescriptions had an above-label maximum dose. Only 7% of LAR prescriptions had preceding IR use. There were 386 patients with NETs or CS vs. 570 with an unknown diagnosis. Comparing patients with NETs or CS to those with an unknown diagnosis, 22.3% vs. 11.0 % experienced dose escalations and 29.0% vs. 26.6% had IR use before dose escalation, respectively. LAR dose escalation occurred in 50.9% vs. 39.2% for symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown groups, respectively. CONCLUSION: Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized.

Carcinoid syndrome and somatostatin analogues.

Clinical experience is herein reported with somatostatin analogues (octreotide and lanreotide) in the management of 10 CS out of a series of 14 collected cases of carcinoid syndrome (CS).

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies.

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

Fatigue and quality of life in patients with neuroendocrine neoplasia.

INTRODUCTION: Neuroendocrine Neoplasms (NEN) are rare tumours arising in the gastro-intestinal tract or lungs. Poor health related quality of life (HRQoL) is associated with the carcinoid syndrome (CS), but fatigue is also important. We aimed to quantify HRQoL and fatigue in out-patients with NEN. METHODS: In a cross-sectional study, we included 231 patients with NEN (G1-G3). We used pre-validated questionnaires MFI-20, EQ-5D-5L and 85% responded. We collected clinical, biochemical, imaging, and pathology data from Electronic Patient files. Normative values for fatigue and HRQoL were derived from background populations. RESULTS: Median age was 68 years (range 21-91) and 52% were male. Patients with NEN reported more fatigue and worse HRQoL compared to the background population (p < .05). Cured patients reported higher HRQoL than patients with current disease, and patients with high grade neoplasms (G2-G3) reported more anxiety and depression compared to patients with low grade G1 disease (p < .05). The CS resulted in a 9% relative loss in Quality Adjusted Life Years compared to patients without CS. (p < .05). More than 50% of patients with CS reported problems with usual activities, pain/discomfort, and anxiety/depression. Overall, 36% of patients with NEN were fatigued and 92% of these had psychological fatigue. Younger patients (<65 years) experienced more fatigue than older patients (p < .05). CONCLUSION: Patients with NEN report significantly lower HRQoL and more fatigue compared to the background population. Especially, patients with CS had pain, discomfort, anxiety, and depression and a relative reduction in HRQoL. However, compared to other cancer types, patients with NEN experience less fatigue.