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.

[Long-Term Survival of a Case with Peritoneal Dissemination from Appendiceal Goblet Cell Carcinoid Treated with Systemic Chemotherapy].

A 64-year-old man complained of lower abdominal pain and vomiting. The CT scan showed adhesional ileus; therefore, small bowel resection procedure was performed. Histological findings showed signet-ring cell carcinoma and poorly differentiated adenocarcinoma. We performed ileocecal resection as an additional surgery. The operative findings revealed peritoneal nodules. The histological findings suggested goblet cell carcinoid with peritoneal dissemination. mFOLFOX+bevacizumab was administered, and no progression was observed for 30 months after the surgery. Appendiceal goblet cell carcinoid is rare and its prognosis is poor. Here, we report a case of appendiceal GCC that achieved a relatively long-term survival despite peritoneal dissemination.

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.

Iridociliary Body Metastasis of Atypical Carcinoid: Case Management with Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

We report a rare case involving a 52-year-old female diagnosed with an atypical bronchial carcinoid tumor with metastases to the mediastinum, hilar lymph nodes, breast, and pancreas. In additional, the patient had metastases to the iris and ciliary body, resulting in progressive vision loss in her left eye. Treatment was successful by intravitreal injections of anti-vascular endothelial growth factor.

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).

Lung Neuroendocrine Tumors: How Does Molecular Profiling Help?

PURPOSE OF REVIEW: Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs. RECENT FINDINGS: There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft.

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.

Peptide receptor radionuclide therapy induced carcinoid crisis: A case report.

Peptide receptor radionuclide therapy (PRRT) is a therapeutic option in inoperable or metastatic neuroendocrine tumours (NETs). PRRT proved to be promising in prolonging survival and delaying disease progression in patients with advanced bronchopulmonary carcinoid. However, it may lead to worsening of carcinoid symptoms or even precipitate carcinoid crises. The incidence of PRRT induced carcinoid crisis would be between 1-10%. This usually takes place during the first PRRT cycle, either during the tracer infusion or 12-48 hours' post-administration. We report a 62-year-old man with underlying metastatic lung carcinoid tumour who developed carcinoid crisis at 10 hours after receiving PRRT. The carcinoid crisis was successfully treated with intravenous octreotide infusion, corticosteroid, a selective 5-HT3 receptor antagonist, parenteral ranitidine and chlorpheniramine for H1 and H2 antagonism respectively.

The Role of Adjuvant Chemotherapy in Non-Metastatic Goblet Cell Carcinoid of the Appendix: An 11-Year Experience from the National Cancer Database.

BACKGROUND: Goblet cell carcinoids (GCC) are an aggressive, albeit rare, subtype of appendiceal tumors that exhibit distinct histologic features and lack clear treatment guidelines. We aimed to ascertain the impact of adjuvant chemotherapy (AC) for GCC in a national cohort of patients. METHODS: Patients who underwent a right hemicolectomy for stage I-III GCC of the appendix between 2006 and 2016 were selected from the National Cancer Database (NCDB). Stratification based on AC receipt was performed. Kaplan-Meier survival estimates and Cox proportional hazard regression were used to identify predictors of overall survival (OS). RESULTS: A total of 867 patients were identified, of whom 124 (14%) received AC. Patients in the AC group were significantly younger (54 vs. 57 years; p = 0.006) and were predominantly of male sex (60 vs. 48%; p = 0.012). On histopathology, patients in the AC group had a higher proportion of poorly/undifferentiated grade (27 vs. 5%; p < 0.001), T4 disease (35 vs. 11%; p < 0.001), and lymph node-positive disease (45 vs. 7%; p < 0.001) than patients who did not receive AC. After excluding patients diagnosed in 2016 due to a lack of follow-up data (n = 162), a survival advantage for the AC group was detected only after stratification for lymph node-positive disease (p = 0.007). On Cox proportional hazard regression, AC demonstrated an independent association with improved OS (hazard ratio 0.24, 95% confidence interval 0.084-0.683; p = 0.007). CONCLUSION: The current analysis from the NCDB supports the role of AC for GCC of the appendix, chiefly for patients with lymph node metastatic disease.

Long-term effect of everolimus in recurrent thymic neuroendocrine neoplasia.

PURPOSE: Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. PATIENTS AND METHODS: Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. RESULTS: We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. CONCLUSION: Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

Primary malignant ovarian carcinoid; management and outcomes.

OBJECTIVE: To investigate the clinicopathological characteristics and survival of patients with malignant ovarian carcinoid tumor (OC). MATERIALS AND METHODS: The National Cancer Database was accessed and patients diagnosed between 2004 and 2015 with a OC who did not have a personal history of a tumor at another site were selected. Overall survival (OS) was assessed for patients who had ≥1 month of follow-up. OS rates were estimated following generation of Kaplan-Meier curves and compared with the log-rank test. RESULTS: A total of 588 patients with a median age of 51.5 years were identified. The majority were White (71.6%), had unilateral tumors (94.2%) with a median size of 3.8 cm that were confined to the ovary (88%). Patients with early stage disease (n = 431) had excellent OS compared to those with advanced stage (II-IV) disease (n = 51), p < 0.001; 5-yr OS rates were 95.4% and 53.1% respectively. For patients with stage I disease, there was no difference in OS between those who did (n = 211) and did not (n = 175) have hysterectomy, p = 0.92. For patients with advanced stage disease, administration of adjuvant chemotherapy was not associated with better survival, p = 0.093. CONCLUSIONS: OCs are typically small, unilateral tumors confined to the ovary arising in perimenopausal patients. Survival outcomes are excellent for patients with early stage disease and unilateral salpingo-oophorectomy appears to be curative.

A Phase II Study of Ibrutinib in Advanced Neuroendocrine Neoplasms.

BACKGROUND: Ibrutinib is an orally administered inhibitor of Bruton's tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited within neuroendocrine neoplasms (NENs) where they stimulate angiogenesis and tumor growth. Ibrutinib inhibits mast cell degranulation and has been associated with regression of tumors in a mouse insulinoma model. METHODS: A prospective, phase II trial evaluated patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs) who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560 mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. The primary endpoint was objective response rate. RESULTS: Twenty patients were enrolled on protocol from November 2015 to December 2017 (15 advanced GI/lung NENs and 5 pNENs). No patient reached an objective response. Median PFS was 3.0 months. A total of 44 drug-related adverse events (AEs) were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs, and 1 patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment. CONCLUSIONS: Ibrutinib does not show significant evidence of activity in well-differentiated gastroenteropancreatic and lung NENs.

Capecitabine and Temozolomide in Patients with Advanced Pulmonary Carcinoid Tumours.

BACKGROUND: Temozolomide and capecitabine (CAPTEM) chemotherapy is known to be active in patients with pancreatic neuroendocrine tumours. OBJECTIVE: This retrospective analysis set out to describe the efficacy and toxicity of CAPTEM in patients with advanced pulmonary carcinoids (PCs). METHODS: Patients were included with advanced PC who had been treated with a maximum of 6 cycles of oral temozolomide 200 mg/m2 on days 10-14 and capecitabine 750 mg/m2 b.i.d. on days 1-14, repeated every 28 days, -followed by monthly intramuscular injection of octreotide 30 mg long-acting release as maintenance treatment. RESULTS: Of the 33 patients, all with well-differentiated PC, 61% had atypical carcinoid, 36% had Ki-67 index >10% and 42% had ≥3 organs involved by metastasis. CAPTEM was administered as first-line treatment in 42% of patients, and 17% had received prior somatostatin analogue treatment. Six patients (18%) achieved a partial response, 19 (58%) had stable disease and 8 (24%) developed progressive disease. After a median time of follow-up of 34.8 months, median progression-free survival (PFS) was 9.0 months and median overall survival 30.4 months. Median duration of disease response was 21.7 months and median duration of disease control 9.7 months. Patients with multi-organ metastasis had shorter PFS, but only when treated as second or third line with CAPTEM (p = 0.023). CONCLUSIONS: CAPTEM induced a modest response and PFS rate, comparable to other studies with temozolomide in patients with advanced PC. The efficacy of CAPTEM should be compared to that of monotherapy with temozolomide in a prospective clinical trial.

[Appendiceal Goblet Cell Carcinoid Successfully Treated with Bevacizumab plus mFOLFOX6 Regimen-A Case Report].

A 67-year-old man presented with abdominal distention and vomiting.Computed tomography revealed bowel obstruction due to a cecal tumor.We performed laparoscopic ileocecal resection after decompression with an ileus tube. Intraoperative findings included multiple disseminated nodules on the mesenterium surrounding the cecal tumor.The histopathologic diagnosis was poorly differentiated adenocarcinoma, which consisted of glandular proliferation of atypical epithelial cells and dispersed infiltration of goblet cells. Immunohistochemistry showed positively stained neuroendocrine markers, such as CD56, chromogranin, and synaptophysin.The patient was diagnosed with goblet cell carcinoid of the appendix and treated with combination chemotherapy of bevacizumab, fluorouracil, folinic acid, and oxaliplatin.He remained free from progression for over 1 and half years with this treatment.Subsequent chemotherapy was ineffective, and he passed away.There is no established chemotherapy regimen for goblet cell carcinoid, which has the aspects of both adenocarcinoma and neuroendocrine tumors.However, the present case suggested the efficacy of the mFOLFOX6 regimen in combination with bevacizumab for appendiceal goblet cell carcinoid.

Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.

BACKGROUND: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. PATIENTS AND METHODS: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. RESULTS: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. CONCLUSION: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. IMPLICATIONS FOR PRACTICE: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane.

BACKGROUND: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. METHODS: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. RESULTS: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. CONCLUSIONS: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms.

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.