Symptoms Of Carcinoid Syndrome Research Articles

Plasma tryptophan pathway metabolites quantified by liquid chromatography-tandem mass spectrometry as biomarkers in neuroendocrine tumor patients.

A good and accessible biomarker is of great clinical value in neuroendocrine tumor (NET) patients, especially considering its frequently indolent nature and long-term follow-up. Plasma chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are currently used as biomarkers in NET, but their sensitivity and specificity are restricted. 5-HIAA is the main metabolite of serotonin, an important neurotransmitter of the tryptophan pathway. The aim of this study is to estabish a sensitive and accurate method for the quantification of tryptophan pathway metabolites in plasma. We further aimed to evaluate its utility as a clinical tool in NET disease. We obtained plasma samples from NET patients and healthy controls recruited from the University Hospital of North Norway, Tromsø. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and eight metabolites of the tryptophan pathway were quantified. We included 130 NET patients (72/130 small intestinal [SI] NET, 35/130 pancreatic NET, 23/130 other origin) and 20 healthy controls. In the SI-NET group, 26/72 patients presented with symptoms of carcinoid syndrome (CS). We found that combining tryptophan metabolites into a serotonin/kynurenine pathway ratio improved diagnostic sensitivity (92.3%) and specificity (100%) in detecting CS patients from healthy controls compared with plasma 5-HIAA alone (sensitivity 84.6%/specificity 100%). Further, a clinical marker based on the combination of plasma serotonin, 5-HIAA, and 5OH-tryptophan, increased diagnostic capacity identifying NET patients with metastasized disease from healthy controls compared with singular plasma 5-HIAA, serotonin, or CgA. In addition, this marker was positive in 61% of curatively operated SI-NET patients compared with only 10% of healthy controls (p < .001). Our results indicate that simultaneous quantification of several tryptophan metabolites in plasma, using LC-MS/MS, may represent a clinically useful diagnostic tool in NET disease.

Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature

RationaleWhen compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. MethodsFecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. Results87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p < 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. ConclusionMidgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.

What Is Carcinoid Syndrome? A Critical Appraisal of Its Proposed Mediators.

Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and improved overall survival of patients with NEN over recent decades, patients are increasingly suffering from chronic and refractory CS symptoms. At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. This systematic review is the first to critically appraise the available evidence for the various hormonal mediators considered to play a causative role in CS. Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.

Appendiceal Neuroendocrine Neoplasms: A Comprehensive Review.

Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered.

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

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). 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. 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 12months (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. In addition to prolonging survival, resection of intestinal and pancreatic NETs leads to significantly improved patient-reported quality of life.

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

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. 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. 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. Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis

Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

Ileal Neuroendocrine Tumour Causing Carcinoid Syndrome in Absence of Hepatic Metastasis

Carcinoid syndrome consists of the classic symptom triad of flushing, diarrhoea, and valvular heart disease. It occurs in the majority of patients with liver metastases. This report presents a 68-year-old female who suffered from chronic diarrhoea with a history of multiple admissions for the same. On evaluation, a Computed Tomography (CT) scan showed a terminal ileal lesion and bulky ovaries. Suspecting Neuroendocrine Tumour (NET) with carcinoid syndrome, a Gallium 68 DOTANOC (DOTA-1-Nal3- octreotide) scan was done which revealed somatostatin receptor expression in enhancing soft tissue lesion in terminal ileum as well as in bilateral adnexa. This confirmed the diagnosis of NET of the ileum and bilateral ovarian metastases. The patient underwent laparoscopic curative resection of the primary tumour along with bilateral oophorectomy. The patient was diagnosed with ileal NET and presented with clinical symptoms of carcinoid syndrome, yet did not have evidence of hepatic metastasis, but instead had bilateral ovarian metastasis which itself is a rare entity.

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

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. This study surveyed US NET patients from 2 online communities, experiencing at least one symptom, by utilizing a 64-item questionnaire. 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%). 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.

S3514 A Case of Symptomatic Ileal Non-Secretory Neuroendocrine Tumor Successfully Treated With Octreotide

Introduction: Neuroendocrine tumor incidence is steadily increasing, likely from detection due to better imaging, routine colonoscopies, and endoscopies. Most NETs, 55%, are found in the GI tract and only 0.1-1% found on routine colonoscopy. About 40% of NETs are hormone producing leading to the clinical diagnosis of carcinoid syndrome. One of the most common symptoms of carcinoid syndrome is diarrhea occuring in 80% percent of cases, however diarrhea can be present in non-secretory NETs. Here we report a case of GNET presenting as diarrhea that responded to octreotide injections despite having normal 5-HIAA and chromogranin A levels. Case Description/Methods: Our patient is an 80 year old female with past medical history of hypertension, renal stones, and IBS with baseline diarrhea of about 2-4 pasty stools a day. In November she developed two days of severe diarrhea with 10 watery stools a day and multiple episodes of incontinence which prompted patient to go to the ED. The inpatient workup was negative for acute causes, CT showed diverticulosis, and stools returned to baseline. The patient was discharged with outpatient GI follow up. At home the severe diarrhea retuned so outpatient GI planned for colonoscopy. Results of the procedure included a 2cm submucosal non-obstructing mass in the terminal ileum. Pathology showed a G1 well differentiated neuroendocrine tumor. Patient was referred to oncology and workup revealed no metastasis on PET/CT and negative 5-HIAA and chromogranin A levels. During initial oncology visit patient was started on octreotide injections which greatly improved the diarrhea. Even with negative carcinoid workup the decision was made to continue octreotide injections and not to pursue surgical options. (Figure) Discussion: The terminal ileum is the most common GI location for NETs. Terminal ileum intubation on coloscopy is attempted 30-80% and greatly aids in diagnosis, as with our patient. Once diagnosed, there is limited guidance on treatment of diarrhea in patients with NETs and negative carcinoid workup. There are no abstracts or research on treatment of diarrhea with negative carcinoid syndrome. One treatment for carcinoid syndrome is somatostatin analogues but no guidelines with non-carcinoid NETs and therapeutic value in octreotide. However, with our patient, treatment with monthly octreotide injections resolved their symptoms. Our case emphasizes importance of ileal intubation in coloscopy and that somatostatin analogue treatment should be considered in non carcinoid NETs.Figure 1.: Small bowel (terminal ileum): well-differentiated neuroendocrine tumor (G1).

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.

Neuroendocrine neoplasms of the small intestine and the appendix - update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [Nowotwory neuroendokrynne jelita cienkiego i wyrostka robaczkowego - uaktualnione zasady diagnostyki i leczenia (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)

Updated Polish recommendations for the management of patients with neuroendocrine neoplasms (NENs) of the small intestine (SINENs) and of the appendix (ANENs) are presented here. The small intestine, and especially the ileum, is one of the most common locations for these neoplasms. Most of them are well-differentiated and slow-growing tumours; uncommonly - neuroendocrine carcinomas. Their symptoms may be untypical and their diagnosis may be delayed or accidental. Najczęściej pierwszą manifestacją ANEN jest jego ostre zapalenie. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of SINENs patients with distant metastases. In laboratory diagnostics the assessment of 5-hydroxyindoleacetic acid concentration is helpful in the diagnosis of carcinoid syndrome. The most commonly used imaging methods are ultrasound examination, computed tomography, magnetic resonance imaging, colonoscopy and somatostatin receptor imaging. Histopathological examination is crucial for the proper diagnosis and treatment of patients with SINENs and ANENs. The treatment of choice is a surgical procedure, either radical or palliative. Long-acting somatostatin analogues (SSAs) are essential in the medical treatment of functional and non-functional SINENs. In patients with SINENs, at the stage dissemination with progression during SSAs treatment, with high expression of somatostatin receptors, radioisotope therapy should be considered first followed by targeted therapies - everolimus. After the exhaustion of the above available therapies, chemotherapy may be considered in selected cases. Recommendations for patient monitoring are also presented.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

What Gastroenterologists Should Know about Carcinoid Syndrome

Carcinoid syndrome (CS) is the most common functional syndrome associated with neuroendocrine neoplasia (NEN), particularly in intestinal NEN with extensive liver metastases. Owing to the heterogenous symptomatic scenario present in CS, recognition of these patients may be challenging. In this review, we explore some key clinical factors used to identify patients affected by CS, with particular focus on differential diagnoses of diarrhea, which is the main symptom of CS. Moreover, we highlight the importance of nutritional screening as a clinical indication to prevent malnutrition and to manage the most common nutrient deficiencies present in these patients.

Carcinoid Crisis: A Misunderstood and Unrecognized Oncological Emergency.

Simple SummaryIn this review, the Authors are going to discuss the main highlights of the Carcinoid Crisis, an uncommon manifestation related to neuroendocrine tumors, focusing on the potential etiopathogenetic mechanisms, clinical implications, potential treatments and prophylaxis.Carcinoid Crisis represents a rare and extremely dangerous manifestation that can occur in patients with Neuroendocrine Tumors (NETs). It is characterized by a sudden onset of hemodynamic instability, sometimes associated with the classical symptoms of carcinoid syndrome, such as bronchospasm and flushing. Carcinoid Crisis seems to be caused by a massive release of vasoactive substances, typically produced by neuroendocrine cells, and can emerge after abdominal procedures, but also spontaneously in rare instances. To date, there are no empirically derived guidelines for the management of this cancer-related medical emergency, and the available evidence essentially comes from single-case reports or dated small retrospective series. A transfer to the Intensive Care Unit may be necessary during the acute setting, when the severe hypotension becomes unresponsive to standard practices, such as volemic filling and the infusion of vasopressor therapy. The only effective strategy is represented by prevention. The administration of octreotide, anxiolytic and antihistaminic agents represents the current treatment approach to avoid hormone release and prevent major complications. However, no standard protocols are available, resulting in great variability in terms of schedules, doses, ways of administration and timing of prophylactic treatments.

Recent Advances in the Diagnosis and Management of Carcinoid Syndrome

Carcinoid syndrome, a paraneoplastic condition linked with the release of multiple humoral factors, affects around 30-40% of patients with well-differentiated neuroendocrine tumours. Carcinoid syndrome has a major and unfavourable impact on patients' quality of life; it raises costs when compared to non-functioning neuroendocrine tumours; and it causes patients' lifestyles to alter, such as food, job, physical activity, and social life. Somatostatin analogues have been the first-line therapy for individuals with neuroendocrine tumours and carcinoid disease for decades. While these drugs give considerable relief from carcinoid syndrome symptoms, clinical progression is unavoidable, necessitating further research into newer treatment measures.Carcinoid tumours are sometimes difficult to diagnose because of their vague or nonspecific symptoms. There have been several advancements in all aspects of carcinoid syndrome, as well as novel therapeutics, in the previous few years. New epidemiological studies show that it is becoming more common; increasing insights into the pathogenesis of its various clinical manifestations and its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history, and management of the disease.An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till November 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: “Recent advances”, “Carcinoid syndrome”, “Neuroendocrine Neoplasms” and “Carcinoid heart disease”. We comprehensively reviewed the literature on the pathogenesis, clinical features, and newer treatment modalities for Carcinoid Syndrome.Recent advancements in research and management have resulted from advances in our understanding of the aetiology of carcinoid syndrome. The development of molecular indicators of aggressiveness improved serum tumour markers, and the molecular aetiology of carcinoid heart disease are all possible because of advances in molecular biology. We conducted a comprehensive review to update knowledge regarding the pathophysiology, diagnostic protocols, and current and newer treatments for carcinoid syndrome, which presently requires a multidisciplinary approach, due to the complexity of the illness's aetiology, diagnosis, and therapy.

Principles of Surgical Management of Small Intestinal NET.

Simple SummarySmall-intestinal neuroendocrine tumors (siNETs) account for 25% of gastroenteropancreatic NETs. A total of 89% of multiple tumors are located in the ileum, often within 100 cm of the ileocecal valve. According to current guidelines, all localized siNETs should be considered for radical resection with lymphadenectomy. The preoperative workout should focus on symptoms of carcinoid syndrome (flush, diarrhea, and cardiac failure). Morphological evaluation should include a CT scan with a thin-slice arterial CT, a PET/CT with 68 Ga, and a hepatic MRI. Levels of 24 h urinary 5-hydroxyindoleacetic acid are needed. Regarding surgery, the limiting component is the number of free jejunal branches allowing a resection without risk of short small bowel syndrome. In case of emergency surgery, there is expert agreement that it is not reasonable to initiate resection of the mesenteric mass without comprehensive workup and mapping. The challenge lies in the ability to propose a resection without imposing short small bowel syndrome on the patients.Introduction: Small-intestinal neuroendocrine tumors (siNETs) account for 25% of gastroenteropancreatic NETs. Multiple siNETs appear to develop in a limited segment of the small bowel (SB), 89% of them being located in the ileum, most often within 100 cm of the ileocecal valve (ICV). According to the European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC), all localized siNETs should be considered for radical surgical resection with adequate lymphadenectomy irrespective of the absence of lymphadenopathy or mesenteric involvement. Surgical management of siNETs: The preoperative workout should include a precise evaluation of past medical and surgical history, focusing on the symptoms of carcinoid syndrome (flush, diarrhea, and cardiac failure). Morphological evaluation should include a CT scan including a thin-slice arterial CT, a PET/CT with 68 Ga, and a hepatic MRI in cases of suspected metastasis. Levels of 24 h urinary 5-hydroxyindoleacetic acid are needed. Regarding surgery, the limiting component is the number of free jejunal branches allowing a resection without risk of short small bowel syndrome. The laparoscopic approach has been poorly studied, and open laparotomy remains the gold standard to explore the abdominal cavity and entirely palpate the small bowel through bidigital palpation and compression. An extensive lymphadenectomy is required. A prophylactic cholecystectomy should be performed. In case of emergency surgery, current recommendations are not definitive. However, there is expert agreement that it is not reasonable to initiate resection of the mesenteric mass without comprehensive workup and mapping. Conclusion: The surgery of siNETs is in constant evolution. The challenge lies in the ability to propose a resection without imposing short small bowel syndrome on the patients. The oncological benefits supported in the literature led to recent changes in the recommendations of academic societies. The next steps remain the dissemination of reproducible quality criteria to perform these procedures.

S3682 Management of Right-Sided Carcinoid Heart Failure

Introduction: Carcinoid heart disease is a rare disease affecting around 20% of patients with carcinoid syndrome. It is considered a result of high circulating serotonin levels depositing into heart valves. The characterized symptoms of carcinoid syndrome are vasomotor flushing, gastrointestinal hypermotility and cardiac involvement. Right heart valve disorders increase morbidity and mortality due to right heart failure complications of fluid overload. This case presents a 48 year old woman with new findings on echocardiogram compatible with right heart failure. Case Description/Methods: A 48 year old woman with a past medical history of hypothyroidism presented with shortness of breath for the last month. No productive cough, no sick contacts, no fevers or chills. Endorses diffuse redness on her face and right arm. Antistreptolysin A returned positive and completed a 10 day course of cephalexin without relief. Other related symptoms were abdominal distress, nonbloody diarrhea and tachycardia. She lost approximately 30 pounds in the last 2 months due to chronic diarrhea. Recent celiac serology testing has been negative. CT Abdomen and Pelvis with contrast shows a prominent, speculated nodal mass at the root of the mesentery with focal nodular thickening of the duodenal wall. 5-HIAA returned at 40mg/24h (Reference < 30 mg/24hr). Echocardiogram revealed grade 1 diastolic dysfunction, preserved ejection fraction and moderate tricuspid regurgitation. Lasix was started for diuresis along with octreotide to calm down the systemic 5-HIAA surge. She will be followed up outpatient for surgical evaluation. Discussion: Carcinoid heart disease is caused by the deposition of pearly fibrotic plaques into the endocardium of right sided valves leading to multiple patterns of severe valve dysfunction. Plaque formation causes leaflet thickening, and fusion of the valves. Echocardiography remains a reliable method for the definitive diagnosis. Valve replacement is currently the gold standard treatment for symptomatic carcinoid valve disease. However, debates remain in terms of the choice of heart valve prosthesis. The surgical indications of carcinoid heart disease are symptomatic right ventricular failure, severe valvular dysfunction and systemic venous pressure elevation. Contraindications are end-stage metastatic disease poorly controlled carcinoid symptoms despite octreotide therapy medical management. This case highlights the rare syndrome of carcinoid heart disease with follow up surgery in the outpatient..

Changes in Carcinoid Syndrome Symptoms Among Patients Receiving Telotristat Ethyl in US Clinical Practice: Findings from the TELEPRO-II Real-World Study.

BackgroundInadequately controlled symptoms incur a substantial burden on patients with neuroendocrine tumors and carcinoid syndrome (CS). The effectiveness of telotristat ethyl (TE) with a somatostatin analog for uncontrolled CS diarrhea has been demonstrated in clinical trials and observational studies. TELEPRO-II was a prospective observational study evaluating TE’s effectiveness in clinical practice over the first 3 months of treatment.MethodsPatients initiating TE in 2018 participated in an optional nurse support program reporting CS symptoms during interviews at baseline and 1, 2, and 3 months after TE initiation. Eligible patients received TE for ≥3 months and reported symptom burden at baseline and ≥1 follow-up visit within the first 3 months. Daily bowel movement (BM) frequency and flushing episodes were reported as events/episodes per day. Stool consistency, nausea severity, urgency severity, and abdominal pain were reported on a severity scale (1–10). Symptom changes were evaluated using paired-sample t-tests and Wilcoxon signed-rank tests. Analysis of symptoms based on achievement of <30% or ≥30% reduction in daily BM frequency was conducted using a cumulative distribution function.ResultsA total of 684/1603 (43%) patients were eligible for analysis. At baseline, patients reported a mean of 6.3 BM/day, nausea severity of 8.4/10 and stool urgency of 8.2/10. Significant improvements in all CS symptoms were observed after 3 months of TE. Mean daily BMs were reduced 64% after 3 months of TE (mean reduction [SD], –3.99 [3.8]; P<0.0001). Most patients (74%, n=503) reported ≥30% reduction in daily BM frequency; these patients also reported improvements in other symptoms (76–87%). Patients with <30% reduction in daily BMs also reported improvements in nausea severity (62%, n=24), daily flushing episodes (66%, n=98), abdominal pain (50%, n=60), urgency severity (38%, n=64), and stool consistency (24%, n=44).ConclusionPatients treated with TE in a real-world setting experienced significant, clinically meaningful improvements in CS symptoms.

Telotristat in the management of Carcinoid diarrhoea – A real world experience of patients from ENETs centre of excellence in Neuroendocrine tumours

Background and Aims Diarrhoea is a common and debilitating symptom of Carcinoid syndrome. Effective control of symptoms is achieved with somatostatin analogues (SSAs) and additional loperamide and/or codeine phosphate. Symptom control is lost with time and disease progression. There is, therefore, a strong need for additional and more effective therapies. Telotristat-ethyl is a peripheral tryptophan-hydroxylase inhibitor approved for treatment of diarrhoea. Here, we present our experience of Telotristat for treating carcinoid diarrhoea in a large cohort of patients outside of clinical trials. The primary outcome was reduction in stool frequency of >30%, as defined in most studies. Methods Patients were identified from a prospective database and information collected retrospectively from the hospital's electronic patient records. We included 31 patients (25 males, 6 females; Median age 69 years) on Telotristat and 10 patients on fortnightly high-dose SSA (6 males, 4 females; Median age 67 years). Results The mean (range) duration of treatment in telotristat and 2 weekly SSA groups was 258 (15-479) and 689 (219-1446) days respectively. Primary endpoint was achieved in 82% (23/28) patients on Telotristat with median percentage reduction in stool frequency of 60% (IQR 50-69), compared to 28% (2/7) (22 (−30 to 55) %) in the control group. Odds ratio for reduction in stool frequency >30% was −11, (95% CI 1.71-77.1). Conclusion This real world experience supports the effectiveness and safety of Telotristat to treat carcinoid diarrhoea not adequately controlled by standard treatment with SSA.