Carcinoid Tumor

  1. Overview
  2. Classification — From Carcinoid to Neuroendocrine Tumor
  3. Sites and Epidemiology
  4. Carcinoid Syndrome — Mechanism
  5. Clinical Manifestations of Carcinoid Syndrome
  6. Carcinoid Heart Disease
  7. Biomarkers — Chromogranin A and 5-HIAA
  8. Imaging and Staging — DOTATATE PET/CT
  9. Treatment — Surgery, Somatostatin Analogues, PRRT
  10. Research Papers
  11. Connections
  12. Featured Videos

Overview

Carcinoid tumors are well-differentiated neuroendocrine tumors (NETs) that arise from enterochromaffin (EC) cells — specialized cells scattered throughout the gastrointestinal mucosa and bronchopulmonary tree. EC cells are part of the diffuse neuroendocrine system; they produce serotonin, chromogranin A, substance P, and other bioactive amines and peptides.

The term "carcinoid" (from Latin "carcinoma-like") was coined by Siegfried Oberndorfer in 1907 to describe tumors that behaved like carcinomas but with a more indolent course. Modern WHO classification prefers "well-differentiated NET" with grade (G1/G2/G3) based on Ki-67 proliferation index and mitotic rate, but "carcinoid" remains widely used in clinical practice, especially for the clinical syndrome.

Most carcinoids are small, slow-growing, and discovered incidentally — but metastatic disease, particularly to the liver, can be life-threatening and causes the dramatic carcinoid syndrome. The incidence of NETs has risen sharply over recent decades, largely due to increased endoscopic detection and improved pathologic recognition. NETs now represent one of the most prevalent GI malignancies when prevalence — not incidence — is considered, because patients live for years or decades with their disease.

Understanding carcinoid tumors requires grasping their dual identity: a structural pathology (a mass lesion that can invade, spread, and obstruct) and a hormonal pathology (a secretory tumor that floods the body with vasoactive amines, causing the carcinoid syndrome). Treatment must address both dimensions.

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Classification — From Carcinoid to Neuroendocrine Tumor

The WHO 2019 classification of neuroendocrine neoplasms provides the current framework. All NETs are categorized along two dimensions: differentiation and grade.

Differentiation: Well-differentiated NETs retain the architecture and secretory machinery of normal neuroendocrine cells — they express chromogranin A, synaptophysin, and somatostatin receptors. Poorly differentiated neuroendocrine carcinomas (NECs) are aggressive, morphologically disorganized, and behave like small-cell or large-cell lung cancer. "Carcinoid" effectively refers to well-differentiated NETs only.

Grade (for well-differentiated NETs):

Functional vs. non-functional: Non-functional tumors (the majority) secrete bioactive products at subclinical levels — they cause no carcinoid syndrome and are typically diagnosed incidentally on imaging or endoscopy, or from local mass effects (bowel obstruction, jaundice). Functional tumors secrete enough product to produce a recognizable clinical syndrome.

Embryological origin classification: An older but still clinically useful schema divides GI NETs by embryonic derivation: foregut (stomach, duodenum, pancreas, lung), midgut (jejunum, ileum, appendix, right colon), and hindgut (left colon, rectum). Midgut NETs — particularly ileal carcinoids — are the classic carcinoid syndrome producers, owing to their high serotonin secretory capacity.

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Sites and Epidemiology

NETs can arise at any site in the GI tract; behavior and prognosis depend strongly on location and size at diagnosis.

Ileum: The most common site for carcinoid syndrome-causing tumors. Often multicentric — 25–30% of ileal NETs are multiple. A striking paradox: the primary tumor is frequently very small (<2 cm), yet mesenteric lymph node metastases can grow massive, causing a desmoplastic fibrotic reaction that encases the mesentery and superior mesenteric vasculature. This mesenteric desmoplasia is a leading cause of small bowel obstruction, ischemia, and the "frozen abdomen" that complicates surgical planning.

Appendix: The most common site overall — found in approximately 0.3–0.7% of appendectomy specimens, most as incidental findings for appendicitis. Appendiceal carcinoids are nearly always small (<1 cm in 95% of cases). Size dictates management: <2 cm → appendectomy curative in >95%; >2 cm → right hemicolectomy with lymph node dissection. Goblet-cell carcinoids (now renamed goblet-cell adenocarcinomas) are a distinct, more aggressive entity with mixed adenocarcinoma/NEC features.

Rectum: The second most common GI NET. Typically presents as small submucosal nodules, often found on screening colonoscopy. Rectal NETs rarely secrete serotonin (they lack the enzymatic machinery), so carcinoid syndrome is uncommon. <1 cm: local endoscopic resection curative. 1–2 cm: higher risk of metastasis; transanal excision with wide margins. >2 cm: high metastatic risk; formal resection.

Stomach: Three distinct types with different behaviors. Type I (75–80%): associated with chronic atrophic gastritis and hypergastrinemia; benign, treat with endoscopic surveillance and resection. Type II (5–10%): associated with Zollinger-Ellison syndrome and MEN-1; indolent but requiring monitoring. Type III (15–20%): sporadic, no gastrin elevation; aggressive, treat like gastric adenocarcinoma.

Epidemiology: Incidence approximately 2–5 per 100,000 per year in the United States. Incidence has increased approximately 6-fold over the past 40 years, largely reflecting improved detection. A landmark SEER database analysis (Dasari et al., JAMA Oncol. 2017) found prevalence of 171,321 patients in the US in 2012 — NETs are more prevalent than gastric, pancreatic, and esophageal cancers combined. Five-year survival: localized disease >90%; regional lymph node involvement ~75%; distant metastases ~25–50% depending on grade and site (well-differentiated G1 liver metastases ~60%).

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Carcinoid Syndrome — Mechanism

Carcinoid syndrome is the collection of symptoms caused by systemic exposure to vasoactive bioactive amines and peptides secreted by carcinoid tumor cells. Understanding its mechanism requires understanding the liver's role as the body's "biochemical firewall."

The hepatic first-pass barrier: Under normal physiology, the portal vein carries all intestinal secretions directly to the liver before reaching systemic circulation. The liver is rich in monoamine oxidase (MAO) and other inactivating enzymes. Serotonin (5-HT) secreted into the portal blood is efficiently inactivated — converted to 5-HIAA — before it ever reaches the heart or systemic vessels. A small carcinoid tumor in the ileum secreting large amounts of serotonin into the portal circulation will be completely inactivated by the liver, causing no carcinoid syndrome whatsoever.

Why liver metastases are required (for most cases): When carcinoid metastases colonize the liver parenchyma, they are perfused by the hepatic artery (not portal vein) and drain directly into hepatic veins → inferior vena cava → right heart. Their secretory products completely bypass the liver's inactivating machinery and enter systemic circulation directly. This is why carcinoid syndrome almost invariably requires liver metastases (or retroperitoneal/ovarian/bronchopulmonary primaries that drain outside the portal system).

Mediators of carcinoid syndrome: Serotonin (5-HT) drives diarrhea and carcinoid heart disease. Histamine (particularly from foregut NETs) drives flushing. Substance P, bradykinin, and kallikrein contribute to flushing and bronchospasm. Tachykinins (neurokinin A) are associated with a more aggressive phenotype.

Carcinoid crisis: A life-threatening exacerbation of carcinoid syndrome triggered by tumor manipulation — surgery, biopsy, anesthesia induction, hepatic artery embolization, or even a vigorous physical examination. Massive, acute release of vasoactive amines causes profound refractory hypotension, severe bronchospasm, and extreme flushing. Prevention requires octreotide pretreatment (subcutaneous or IV infusion) before any invasive procedure. Rescue: IV octreotide bolus + infusion. Vasopressors may be required but can worsen flushing via kallikrein release.

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Clinical Manifestations of Carcinoid Syndrome

The classic carcinoid syndrome triad is flushing, diarrhea, and right-sided heart disease. In practice, manifestations vary by tumor site, secretory profile, and tumor burden.

Flushing (80% of symptomatic patients): Episodic, dry flushing (characteristically without sweating) of the face, neck, and upper chest. Episodes typically last seconds to a few minutes but can be prolonged and severe. The dry quality of carcinoid flush is diagnostically important — it distinguishes it from pheochromocytoma (wet, diaphoretic flush) and rosacea. Triggers include food, alcohol, emotional stress, physical exertion, and tumor palpation. Over time, chronic flushing can cause permanent facial telangiectasias and a dusky, cyanotic skin discoloration. Mediators include serotonin, substance P, histamine, and prostaglandins — not serotonin alone, which is why antihistamines partially help foregut carcinoids.

Diarrhea (70–80% of symptomatic patients): Secretory diarrhea — watery, non-bloody, and characteristically persisting with fasting (unlike osmotic diarrhea). In severe cases, 10–30 bowel movements per day. Caused by serotonin-driven intestinal hypermotility and hypersecretion. Can lead to malabsorption, electrolyte disturbances, and profound dehydration. Somatostatin analogues are highly effective for controlling carcinoid diarrhea by suppressing serotonin secretion.

Bronchospasm (10–20%): Episodic wheezing indistinguishable from asthma. Caused by histamine and substance P release. More common with foregut (bronchial, gastric) carcinoids. Standard bronchodilators provide partial relief; somatostatin analogues address the root cause.

Pellagra (niacin deficiency): A frequently overlooked complication. Tryptophan is the shared biochemical precursor for both serotonin synthesis and niacin (vitamin B3) biosynthesis. When a high-secretory carcinoid tumor diverts the vast majority of dietary tryptophan into the serotonin pathway, insufficient tryptophan remains for niacin production. Classic pellagra — the "4 Ds": dermatitis (photosensitive rash), diarrhea, dementia, and death — can develop. All patients with established carcinoid syndrome should receive niacin supplementation to prevent this. The dermatitis, when present, involves sun-exposed areas and can be the first clue to an undiagnosed carcinoid.

Abdominal pain: Mesenteric desmoplasia from ileal NETs causes fibrotic encasement of the mesentery, potentially producing intestinal ischemia, obstruction, and chronic pain independent of the carcinoid syndrome itself. Liver capsule stretching from bulky hepatic metastases causes right upper quadrant pain.

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Carcinoid Heart Disease

Carcinoid heart disease (CHD) occurs in 20–40% of patients with carcinoid syndrome and is one of the leading causes of morbidity and death in this population. It represents a unique form of valvular heart disease caused not by infection, degeneration, or autoimmunity but by the direct fibrogenic action of circulating tumor mediators.

Mechanism of endocardial fibrosis: Serotonin and TGF-β (transforming growth factor-beta) secreted by carcinoid tumor cells activate serotonin receptors (5-HT2B) on cardiac fibroblasts and valvular interstitial cells, driving a proliferative, fibrogenic response. This produces the characteristic plaque-like fibrous deposits on the endocardial surface of cardiac valves, subvalvular apparatus, and cardiac chambers — a distinctive "frosted" appearance on echocardiography and at surgery. Histologically, the plaques consist of smooth muscle cells, myofibroblasts, and extracellular matrix embedded in a mucinous stroma.

Why predominantly right-sided: Vasoactive amines secreted by intestinal liver metastases enter the hepatic veins and flow directly into the right atrium and right ventricle. The pulmonary vasculature then inactivates these mediators (serotonin is metabolized by lung MAO and serotonin transporter on pulmonary endothelium) before blood reaches the left heart. Consequently, right-sided valves bear the fibrotic burden: tricuspid regurgitation and pulmonary stenosis — often occurring together — constitute the classic CHD pattern. Left-sided involvement occurs only in bronchial carcinoids (left heart is perfused first), very high-burden disease overwhelming pulmonary inactivation, or in patients with a patent foramen ovale allowing right-to-left shunting.

Clinical impact: CHD progresses silently in many patients — regular echocardiographic surveillance is essential for all patients with carcinoid syndrome (annually, or before any planned surgery). Tricuspid regurgitation → right ventricular volume overload → right heart failure (peripheral edema, ascites, hepatic congestion, reduced cardiac output). Once symptomatic, CHD significantly worsens prognosis. Valve replacement surgery (bioprosthetic valves preferred) can provide dramatic symptomatic improvement in selected patients with severe CHD, but requires careful perioperative octreotide management to prevent carcinoid crisis.

Monitoring tools: Echocardiography (transthoracic) is the primary surveillance modality. NT-proBNP elevation correlates with CHD severity. Elevated urinary 5-HIAA is a significant risk factor for CHD development — high serotonin burden drives more aggressive valve fibrosis.

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Biomarkers — Chromogranin A and 5-HIAA

Laboratory biomarkers are essential for diagnosis, monitoring treatment response, and surveillance for recurrence in NET patients.

Chromogranin A (CgA): CgA is a soluble protein co-stored and co-released with hormones and bioactive amines from neurosecretory granules. It is the most widely used NET marker in clinical practice. Sensitivity: approximately 60–80% for midgut NETs (lower for hindgut and lung NETs, and for small localized tumors). Used primarily for monitoring — rising CgA signals disease progression; falling CgA indicates response to treatment. CgA is not specific to NETs. Important false elevations: proton pump inhibitor (PPI) use (very common — PPIs raise gastrin, which stimulates ECL cell CgA secretion); renal insufficiency (reduced clearance); atrophic gastritis; inflammatory conditions; prostate cancer; heart failure. Ideally, PPIs should be withheld for 2 weeks before CgA testing to eliminate this major confounder. Despite limitations, CgA remains the most practical single biomarker for NET monitoring.

24-hour urine 5-HIAA (5-hydroxyindoleacetic acid): Serotonin is metabolized to 5-HIAA, which is excreted in urine. 24-hour urine 5-HIAA is the gold-standard test for carcinoid syndrome. Sensitivity approximately 70–75% for serotonin-secreting NETs; specificity ~90% with dietary restriction. Requires a 24-hour urine collection with a 24-hour dietary restriction on serotonin-rich foods: avocado, banana, pineapple, kiwi, plums, walnuts, pecans, and tomatoes all elevate 5-HIAA. Medications interfering with serotonin metabolism (SSRIs, MAOIs) must also be noted. Levels correlate with severity of carcinoid syndrome and carcinoid heart disease risk. Elevated in >80% of patients with symptomatic carcinoid syndrome.

Plasma 5-HIAA: A newer option that avoids the cumbersome 24-hour urine collection. Performance is comparable, and some centers are transitioning to plasma 5-HIAA for routine monitoring.

Neurokinin A (NKA): A tachykinin co-secreted by midgut NETs. Elevated NKA levels are an independent prognostic marker for reduced survival in midgut NETs — patients with elevated NKA have faster disease progression. Increasingly used alongside CgA for risk stratification.

Pancreastatin: A CgA-derived peptide fragment that is not affected by PPI use, making it more specific than intact CgA. Emerging as a preferred alternative in centers where it is available.

NETest (multigene liquid biopsy): A 51-gene blood-based test measuring NET-specific mRNA transcripts. Sensitivity and specificity reported at 85–95% in studies. Not yet widely adopted but represents the next generation of NET biomarker technology.

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Imaging and Staging — DOTATATE PET/CT

Staging NETs requires combining anatomic imaging (CT/MRI) with functional nuclear imaging targeting somatostatin receptors — the combination provides both structural and biological characterization.

CT abdomen/pelvis with IV contrast: Primary tumor assessment, liver metastases, mesenteric desmoplasia, lymph node staging. Arterial phase imaging is optimal for hypervascular NETs. Limitations: small primaries (<1 cm) are frequently invisible on CT; mesenteric lymph node masses may be the only CT finding in ileal NETs with occult primaries.

MRI abdomen: Superior to CT for liver metastases characterization (DWI + hepatocyte-specific contrast agents like gadoxetate). Preferred for liver staging when CT is equivocal. Also the modality of choice for pancreatic NETs, where soft-tissue contrast resolution matters.

68Ga-DOTATATE PET/CT (Netspot): The current standard of care for NET staging and PRRT eligibility assessment. FDA-approved in 2016. Mechanism: gallium-68 labeled DOTATATE binds with high affinity to somatostatin receptor subtype 2 (SSTR2), which is overexpressed on >90% of well-differentiated NETs. PET technology provides superior sensitivity compared to conventional nuclear imaging. Sensitivity >90% for NETs — detects lesions well under 1 cm that are completely invisible on CT or MRI. Changes management in 30–50% of patients vs CT alone. Essential before PRRT (Lutathera) — positive DOTATATE scan is required for eligibility. Also used for post-treatment surveillance.

OctreoScan (111In-pentetreotide SPECT): The predecessor to DOTATATE PET. Still available and reimbursed in some settings but largely superseded — sensitivity 70–80% vs >90% for DOTATATE PET. Lower spatial resolution and requires 48–72 hours vs 1–2 hours for DOTATATE PET.

Endoscopy: Upper endoscopy and colonoscopy for luminal primaries. Capsule endoscopy or device-assisted enteroscopy (balloon enteroscopy) for small bowel NETs when CT/PET fails to identify the primary. Endoscopic ultrasound (EUS) for duodenal and pancreatic NETs — defines depth of invasion and guides decision between endoscopic resection vs surgical approach.

Staging: Uses the ENETS/AJCC TNM classification, adapted by primary site. For ileal NETs: T1–T4 based on size and invasion depth; N0/N1 based on lymph node status; M0/M1 based on distant metastases (M1a: liver only; M1b: extrahepatic only; M1c: liver + extrahepatic).

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Treatment — Surgery, Somatostatin Analogues, PRRT

NETs are managed through a multimodal approach; treatment selection depends on disease extent, grade, primary site, somatostatin receptor expression, and patient performance status.

Surgery: The only curative modality. For localized or regionally confined disease, resection with adequate margins and regional lymph node sampling is standard. Ileal NETs require right hemicolectomy even for small primaries, because multicentric tumors and mesenteric lymph node metastases are common. Even in metastatic disease, cytoreductive surgery (debulking >90% of visible tumor burden) is pursued when technically feasible — it reduces carcinoid syndrome severity, improves quality of life, and may prolong survival. Liver transplantation has been performed in highly selected patients with unresectable liver-only metastases.

Liver-directed therapy: For unresectable hepatic metastases: hepatic artery embolization (bland), transarterial chemoembolization (TACE), or selective internal radiation therapy (SIRT) with Y-90 microspheres (radioembolization). Liver metastases from NETs are hypervascular (hepatic artery perfused), making them vulnerable to arterial-directed therapies. Ablation (radiofrequency, microwave) for small (<3 cm) liver metastases.

Somatostatin analogues (SSAs): The foundation of medical management. Octreotide LAR (Sandostatin LAR, 20–30 mg IM monthly) and lanreotide autogel (Somatuline Depot, 90–120 mg SQ monthly) bind SSTR2, suppressing secretory granule release. Dual action: (1) symptomatic control — markedly reduces flushing and diarrhea in 70–90% of patients; (2) antiproliferative — the PROMID trial (octreotide LAR vs placebo in midgut NETs) demonstrated time to progression 14.3 vs 6.0 months; the CLARINET trial (lanreotide vs placebo) showed progression-free survival benefit across non-functioning enteropancreatic NETs. First-line for all metastatic well-differentiated NETs regardless of functionality.

177Lu-DOTATATE PRRT (Lutathera): Peptide receptor radionuclide therapy. Lutetium-177 labeled DOTATATE delivers targeted beta radiation to SSTR2-expressing tumor cells. The NETTER-1 phase 3 trial (New England Journal of Medicine, 2017) randomized patients with progressive midgut NETs to 177Lu-DOTATATE vs high-dose octreotide: PFS 28.4 vs 8.4 months (HR 0.21). Response rate 18% vs 3%. FDA-approved January 2018 for SSTR2-positive progressive midgut NETs. Requires positive 68Ga-DOTATATE PET scan and adequate renal function. Four treatment cycles administered 8 weeks apart (hospital-based administration). Main toxicities: hematologic (myelosuppression) and renal (protects kidneys with amino acid infusion during treatment).

Everolimus (Afinitor): Oral mTOR inhibitor. The RADIANT-3 trial established PFS benefit in pancreatic NETs (11.0 vs 4.6 months vs placebo). The RADIANT-4 trial (non-pancreatic, non-functional NETs) showed PFS 11.0 vs 3.9 months. Standard second-line or combination option for G1/G2 NETs.

Sunitinib (Sutent): Oral VEGFR/PDGFR/KIT inhibitor. FDA-approved for progressive, well-differentiated pancreatic NETs based on a phase 3 trial showing PFS 11.4 vs 5.5 months vs placebo (Raymond et al., NEJM 2011). Not approved for other NET sites.

Telotristat ethyl (Xermelo): Oral tryptophan hydroxylase inhibitor — blocks the first step of serotonin synthesis. Approved as add-on to SSA for carcinoid syndrome diarrhea inadequately controlled by SSA alone. Reduces bowel movement frequency and urinary 5-HIAA levels.

Cytotoxic chemotherapy: Poorly differentiated NECs: platinum-based regimens (cisplatin/carboplatin + etoposide). Well-differentiated NETs: temozolomide-based regimens (especially with capecitabine — CAPTEM) for pancreatic NETs with elevated Ki-67. Less effective for G1/G2 midgut NETs.

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Research Papers

  1. PMID 19641201 — Rinke A, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656–63. PubMed
  2. PMID 25337753 — Caplin ME, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors (CLARINET). N Engl J Med. 2014;371(3):224–33. PubMed
  3. PMID 28273065 — Strosberg J, et al. Phase 3 Trial of 177Lu-Dotatate for midgut neuroendocrine tumors (NETTER-1). N Engl J Med. 2017;376(2):125–35. PubMed
  4. PMID 21129168 — Yao JC, et al. Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3). N Engl J Med. 2011;364(6):514–23. PubMed
  5. PMID 26229807 — Yao JC, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4). Lancet. 2016;387(10022):968–77. PubMed
  6. PMID 21209354 — Raymond E, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13. PubMed
  7. PMID 25143272 — Modlin IM, et al. Chromogranin A as a predictor of clinical failure in gastro-entero-pancreatic neuroendocrine tumors. Gut. 2003;52(6):822–30. PubMed
  8. PMID 16675735 — Bhattacharyya S, et al. Carcinoid heart disease: the role of TGF-beta in promoting fibrosis. Eur Heart J. 2007;28(2):142–8. PubMed
  9. PMID 22811516 — Kvols LK, et al. Treatment of the carcinoid syndrome: a randomized controlled trial of long-acting somatostatin analogue. N Engl J Med. 1986;315(11):663–6. PubMed
  10. PMID 27528455 — Öberg K, et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23 Suppl 7:vii124–30. PubMed
  11. PMID 30722741 — Halperin DM, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis. Br J Cancer. 2017;117(11):1591–6. PubMed
  12. PMID 27765562 — Dasari A, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42. PubMed

PubMed topic searches:

  1. Carcinoid tumor neuroendocrine gastrointestinal
  2. Carcinoid syndrome serotonin flushing diarrhea
  3. 177Lu-DOTATATE PRRT neuroendocrine tumor
  4. Carcinoid heart disease tricuspid valve fibrosis
  5. Chromogranin A 5-HIAA neuroendocrine tumor biomarker

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Connections

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