Practical Role of Mutation Analysis for Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: A Meta-Analysis

Background

Imatinib has become the standard first line treatment of gastrointestinal stromal tumors (GIST) in the advanced phase and adjuvant setting. We carried out an up-to-date meta-analysis to determine the practical role of mutation analysis for imatinib treatment in patients with advanced GIST.

Methods

Eligible studies were limited to imatinib treatment for patients with advanced GIST and reported on mutation analysis. Statistical analyses were conducted to calculate the odds ratio (OR), hazard ratio (HR) and 95% confidence interval (CI) using fixed-effects and random-effects models.

Results

A total of 2834 patients from 3 randomized controlled trials and 12 cohort studies were included. The ORs of response rates in KIT exon 11-mutant GISTs were 3.504 (95% CI 2.549-4.816, p<0.001) and 3.521 (95% CI 1.731-7.165, p=0.001) compared with KIT exon 9-mutant and wild type GISTs, respectively. The HRs of progression-free survival in KIT exon 11-mutant GISTs were 0.365 (95% CI 0.301-0.444, p<0.001) and 0.375 (95% CI 0.270-0.519, p<0.001) compared with KIT exon 9-mutant and wild type GISTs. The HRs of overall survival in KIT exon 11-mutant GISTs were 0.388 (95% CI 0.293-0.515, p<0.001) and 0.400 (95% CI 0.297-0.538, p<0.001) compared with KIT exon 9-mutant and wild type GISTs. No statistical significant differences were found between KIT exon 9-mutant and wild type. The overall response rate in KIT-exon 11-mutant GISTs were 70.5% (65%-75.9%) compared with 57.1% (51%-63.2%) in KIT-positive GISTs. No evidence of publication bias was observed.

Conclusion

Patients with advanced GIST harboring a KIT exon 11 mutation have the best response rate and long-term survival with imatinib treatment. Mutation analysis would be more helpful than KIT expression analysis to decide appropriate therapy for a specific patient.     

Prognostic Indicators for Gastrointestinal Stromal Tumors: A Review

Gastrointestinal stromal tumors (GISTs) are potentially malignancies that can occur anywhere in the digestive tract. Tyrosine kinase inhibitors (TKIs) such as imatinib have proven effective since the discovery of KIT and PDGFRA. The current version of NCNN, ESMO and EURACAN guidelines recognized that the three main prognostic factors are the mitotic rate, tumor size and tumor site. In addition, tumor rupture is also recognized as an independent risk factor. However, recent evidence shows that various types of gene mutations are associated with prognosis, and influencing factors such as gastrointestinal bleeding and high Ki67 index have been associated with poor prognosis. It shows that the current risk classification is still insufficient and controversial. With the emergence of more and more lack mutation in KIT/PDGFRA GISTs (KIT/PDGFRA wild-type GISTs) or drug resistance genes, primary and secondary drug resistance problems are caused, which makes the treatment of late or metastatic GIST face challenges. Therefore, this article will review the clinicopathological characteristics of GIST, the special molecular subtypes and other factors that may affect prognosis. We will also explore reliable prognostic markers for better postoperative management and improve the prognosis of patients with GIST.     

Selecting Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumor with Secondary KIT Activation-Loop Domain Mutations

Advanced gastrointestinal stromal tumors (GIST), a KIT oncogene-driven tumor, on imatinib mesylate (IM) treatment may develop secondary KIT mutations to confer IM-resistant phenotype. Second-line sunitinib malate (SU) therapy is largely ineffective for IM-resistant GISTs with secondary exon 17 (activation-loop domain) mutations. We established an in vitro cell-based platform consisting of a series of COS-1 cells expressing KIT cDNA constructs encoding common primary±secondary mutations observed in GISTs, to compare the activity of several commercially available tyrosine kinase inhibitors on inhibiting the phosphorylation of mutant KIT proteins at their clinically achievable plasma steady-state concentration (Css). The inhibitory efficacies on KIT exon 11/17 mutants were further validated by growth inhibition assay on GIST48 cells, and underlying molecular-structure mechanisms were investigated by molecular modeling. Our results showed that SU more effectively inhibited mutant KIT with secondary exon 13 or 14 mutations than those with secondary exon 17 mutations, as clinically indicated. On contrary, at individual Css, nilotinib and sorafenib more profoundly inhibited the phosphorylation of KIT with secondary exon 17 mutations and the growth of GIST48 cells than IM, SU, and dasatinib. Molecular modeling analysis showed fragment deletion of exon 11 and point mutation on exon 17 would lead to a shift of KIT conformational equilibrium toward active form, for which nilotinib and sorafenib bound more stably than IM and SU. In current preclinical study, nilotinib and sorafenib are more active in IM-resistant GISTs with secondary exon 17 mutation than SU that deserve further clinical investigation.     

Treating Adrenal Tumors in 26 Patients with CyberKnife: A Mono-Institutional Experience

Background

CyberKnife (CK) is a novel stereotactic radiosurgery system for treating tumors in any part of the body. It is a non-invasive or minimally invasive tumor treatment modality that can deliver high doses of spatially precise radiation and minimize exposure to neighboring healthy tissues or vital organs. The purpose of this study was to investigate the safety and efficacy of CK in the treatment of adrenal tumors.

Methods and Results

We performed a retrospective analysis of 26 patients with adrenal tumors who had been treated with CK in the radiotherapy center of our hospital between March 2009 and March 2012. Eight patients had primary adrenal tumors and 18 patients had metastatic adrenal tumors. In addition to CK, 4 patients received chemotherapy and 2 patients received immunotherapy. The average tumor volume was 72.1 cm³ and the prescribed radiation dosage ranged from 30 to 50 Gy and was fractionated 3 to 5 times with a 58% to 80% isodose line. Abdominal CT was performed between 1 to 3 months after the CK treatment to evaluate the short-term efficacy with follow-up examinations once every 3 months. Three patients had complete remission, 12 patients had partial remission, 5 patients had stable disease, and 6 patients had progressive illness. The effective rate of pain relief was 93.8% and the disease control rate was 77% with a median overall survival of 17 months and a median progression-free survival of 14 months. Treatment Related toxicity was well-tolerated, but preventative measure need to be taken for radiation enteritis.

Conclusions

CK is safe and effective for treating adrenal tumors with few adverse reactions. Nonetheless, its long-term effects requires further follow-up.     

Fractioned Dose Regimen of Sunitinib for Patients with Gastrointestinal Stromal Tumor: A Pharmacokinetic and Treatment Efficacy Study

AIM: Sunitinib has shown benefit in patients with imatinib (IM)–resistant gastrointestinal stromal tumor (GIST). However, its advantages are somewhat diminished because of associated toxicities. Herein, we clarify the efficacy and safety of fractioned dose regimen of sunitinib by a pharmacokinetic and efficacy study. MATERIALS AND METHODS: Between 2001 and March 2013, a total of 214 patients with metastatic GIST was treated at Chang Gung Memorial Hospital. Among them, 55 (11.6%) patients who received sunitinib were investigated. One group of patients was administered with standard dose of once-daily sunitinib (standard dose group) and the other group was administered with standard total daily dose of sunitinib in fractioned doses (fractioned dose group). RESULTS: Thirty-two male and 23 female patients with a median age of 55 years received sunitinib. The median duration of sunitinib administration was 9.2 months. The clinical benefit was 65.2%. The mean peak blood level of sunitinib in patients with fractioned doses was significantly lower than that in those with once-daily dose (83.4 vs 50.1 ng/ml, P = .01). The rates of adverse effects of hand-foot syndrome, mucositis, and yellow skin were significantly decreased by fractioned doses of sunitinib. However, the progression-free and overall survival did not differ between patients with different treatment regimens. CONCLUSION: The fractioned dose regimen of sunitinib appears to be a safe and effective treatment for patients with IM-resistant/intolerant GISTs. Significantly decreased toxicity of this regimen could be explained by significantly lower peak sunitinib blood level. However, the treatment efficacy is not reduced by this regimen.     

Circulating Tumor Cells in Patients with Recurrent or Metastatic Head and Neck Carcinoma: Prognostic and Predictive Significance

Introduction

We investigated the frequency of detection and the prognostic and predictive significance of circulating tumor cells (CTCs) in patients with recurrent/metastatic (R/M) head and neck carcinoma (HNC) before starting systemic therapy.

Patients and methods

Using the CellSearch technology, CTCs were assessed prospectively in peripheral blood of 53 R/M-HNC patients. We performed spiking experiments to test the diagnostic performance of the CellSearch platform in identifying squamous carcinoma cells.

Results

CTCs were identified in 14 (26%) and 22 (41%) patients at baseline and at any time point, respectively. In univariate analysis ≥2 CTCs had a poorer prognostic role than 0–1 CTC. In multivariate analysis, the presence of one CTC or more was associated with a poor prognosis both in terms of progression-free survival (PFS) [Hazard Ratio (HR): 3.068, 95% confidence interval (CI): 1.53–6.13, p 0.002] and overall survival (OS) [HR: 3.0, 95% CI: 1.48–6.0, p 0.002]. A disease control after systemic therapy was obtained in 8% of CTC-positive patients as opposed to 45% in CTC-negative ones (p 0.03). The epidermal growth factor receptor (EGFR) expression was identified in 45% of CTC-positive patients.

Discussion

In conclusion, CTCs are detected in one out of three patients with RM-HNC. CTC detection is a strong prognostic parameter and may be predictive of treatment efficacy. The frequency of EGFR expression in CTCs seems to be lower than that expected in the primary tumor.     

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program

Background

Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.

Methods

Adverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) “gastrointestinal (GI) perforation”, “embolic and thrombotic events, venous (VTE)”, and “embolic and thrombotic events, arterial (ATE)”, and the Adverse Event Group Term (AEGT) “edema.” The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis.

Results

A total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1–2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4−65.7% for all grades and from 1.2−14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0−5.6% (grade ≥3, 0−5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0−6.2%) and grade ≥3 (0−6.2%).

Conclusions

The frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.     

Results of Neurosurgical Microvascular Extracranial-Intracranial Bypass for Stroke: A Decade of Experience

In 400 patients who have had neurosurgical microvascular bypass operations by one surgeon for problems of cerebrovascular occlusion disease, the results are encouraging, particularly in those who had transient ischemic attacks with hemodynamic lesions previously considered inoperable or inaccessible. The permanent neurologic morbidity rate is 2 percent and the present operative mortality is 2.5 percent. The incidence of stroke to date on the side of a functioning bypass is 0.9 percent per year. Average duration of follow-up is 43 months.     

胃肠道间质瘤组织S100A4、CD55的表达及与临床病理参数及预后的关系研究

摘要 目的：探讨胃肠道间质瘤组织S100A4、衰变加速因子（CD55）的表达及与临床病理参数及预后的关系。方法：选取2011年1月-2015年12月在陆军军医大学附属西南医院江北院区/陆军第958医院行手术切除并经术后病理确诊的124例GIST组织和对应的瘤旁正常组织病理蜡块,采用免疫组化法检测S100A4、CD55在GIST组织及瘤旁正常组织中的表达,分析其表达与GIST患者临床病理参数及预后的关系。结果：S100A4、CD55在GIST组织中的高表达率明显高于瘤旁正常组织,差异有统计学意义（P<0.05）。S100A4、CD55表达与GIST患者肿瘤大小、核分裂相、NIH分级及远处转移有关（P<0.05）,与GIST患者年龄、性别、发生部位、组织学类型无关（P>0.05）。S100A4、CD55低表达的GIST患者术后复发率和转移率低于S100A4、CD55高表达的GIST患者,差异有统计学意义（P<0.05）;S100A4、CD55低表达组患者5年中位无进展生存期明显高于S100A4、CD55高表达组,差异有统计学意义（P<0.05）。结论：S100A4、CD55在GIST组织存在高表达, 二者可能参与了GIST的侵袭与转移,并与患者术后的预后有关。     

非小细胞肺癌脑部转移瘤适形与调强放疗的剂量研究

为探讨NSCLC脑部转移瘤调强放疗与适形放疗的剂量特点,本研究选取57例非小细胞肺癌脑转移瘤患者,其中单个脑转移灶患者5例,多个脑转移灶患者52例,分别设计全脑放疗+适形放疗与调强放疗计划,用均匀指数(HI)和适形指数(CI)评价靶区剂量,危及器官(OAR)剂量用近似最大剂量D_2%(串联)和中位剂量D_50%(并联)进行评价。研究发现,单个脑转移灶IMRT与WBRT+CRT比较中,CI为(PTV,(0.80±0.15) cGy,(0.34±0.19) cGy, p=0.00),HI为(PTV,(0.52±0.03) c Gy,(0.71±0.12) cGy, p=0.24),两者OARs剂量比较:脑干为((4 348±236) cGy,(4 593±149) cGy, p=0.01),脑垂体为((4 258±166) cGy,(4 581±123) cGy, p=0.02);在多个脑转移灶中,IMRT与WBRT+CRT比,较CI为(PTV,(0.59±0.33) cGy,(0.49±0.27) cGy, p=0.03),HI为(PTV,(0.93±0.01) cGy,(0.58±0.03) cGy, p=0.19),两者OARs剂量比较:脑干为((4 946±132) cGy,(4 843±196) cGy, p=0.51),脑垂体为((4 597±180) cGy,(4 705±149) cGy, p=0.70)。本研究的结果说明,单个脑转移灶患者,IMRT较WBRT+CRT有更好的靶区适形性、稍差的靶区异质性,脑干和垂体的IMRT剂量低于WBRT+CRT,而眼球、晶体的剂量两者差别不明显。多个脑转移灶患者,IMRT较WBRT+CRT有更好的靶区适形性、稍差的靶区异质性,而OARs剂量,IMRT较WBRT+CRT差异不明显。在临床实践过程中,应当根据患者不同的病灶情况选择合适的放疗方案,以获取更优的临床治疗效果。     

Long-Term Outcomes of Patients with Acute Cholecystitis after Successful Percutaneous Cholecystostomy Treatment and the Risk Factors for Recurrence: A Decade Experience at a Single Center

Background

Percutaneous cholecystostomy tube (PCT) has been effectively used for the treatment of acute cholecystitis (AC) for patients unsuitable for early cholecystectomy. This retrospective study investigated the recurrence rate after successful PCT treatment and factors associated with recurrence.

Methods

We reviewed patients treated with PCT for AC from October 2004 through December 2013. Patients with successful PCT treatment were those who were free from persistent PCT drainage. We used multivariable logistic regression analysis sequentially to identify factors associated with each outcome.

Results

The study included 184 patients (mean age: 70.1 years). The average duration for parenteral antibiotics was 14.4 days and 20.0 days for PCT drainage. The one-year recurrence rate was 9.2% (17/184) with most recurrences occurring within two months (6.5%, 12/184) of the procedure. Complicated cholecystitis (odds ratio [OR]: 4.67; 95% confidence interval [CI]: 1.44–15.70; P = 0.01) and PCT drainage duration >32 days (OR: 4.92; 95% CI: 1.03–23.53; P = 0.05) positively correlated with one-year recurrence; parenteral antibiotics duration >10 days (OR: 0.21; 95% CI: 0.05–0.68; P = 0.01) was inversely associated with one-year recurrence.

Conclusions

The recurrence rate was low for patients after successful PCT treatment. Predictors for recurrence included the severity of initial AC and subsequently provided treatments.     

The Clinical Effectiveness of Patient Initiated Clinics for Patients with Chronic or Recurrent Conditions Managed in Secondary Care: A Systematic Review

Background

Missed or inappropriate hospital appointments cost the UK National Health Service millions of pounds each year and delay treatment for other patients. Innovative methods of appointment scheduling that are more flexible to patient needs, may improve service quality and preserve resources.

Methods

A systematic review of the evidence for the clinical effectiveness of patient initiated clinics in managing long term care for people with chronic or recurrent conditions in secondary care. Seven databases were searched including MEDLINE, Embase and PsycINFO (using the OVID interface), the Cochrane Library of Systematic Reviews and CENTRAL, Science Citation Index Expanded, Social Sciences Citation Index, and Conference Proceedings Citation Index (via the Web of Science interface) from inception to June 2013. Studies comparing patient initiated clinics with traditional consultant-led clinics in secondary care for people with long term chronic or recurrent diseases were included. Included studies had to provide data on clinical or resource use outcomes. Data were extracted and checked by two reviewers using a piloted, standardised data extraction form.

Results

Eight studies (n = 1927 individuals) were included. All were conducted in the UK. There were few significant differences in clinical outcomes between the intervention and control groups. In some instances, using the patient initiated clinics model was associated with savings in time and resource use. The risk of harm from using the patient initiated clinic model of organising outpatient care is low. Studies with longer follow-up periods are needed to assess the long term costs and the ongoing risk of potential harms.

Conclusions

The UK policy context is ripe for evidence-based, patient-centred services to be implemented, especially where the use of health care resources can be optimised without reducing the quality of care. Implementation of patient initiated clinics should remain cautious, with importance placed on ongoing evaluation of long term outcomes and costs.     

S100P Expression Is a Novel Prognostic Factor in Hepatocellular Carcinoma and Predicts Survival in Patients with High Tumor Stage or Early Recurrent Tumors

The calcium-binding protein S100P is expressed in a variety of human cancer cells and is important in cancer cell growth and invasion. Using differential display, we found S100P is overexpressed in human hepatocellular carcinoma (HCC). We examined the expression of 305 unifocal, primary HCC tumors using immunohistochemistry. The S100P protein was expressed in 173 of the 305 (56.7%) HCC tumors. The expression of S100P correlated with female sex (P = 0.0162), high serum α-fetoprotein level (P = 0.0001), high tumor grade (P = 0.0029), high tumor stage (P = 0.0319), the presence of the p53 mutation (P = 0.0032), and the absence of the β-catenin mutation (P = 0.0489). Patients with HCC tumors that expressed S100P were more likely to have early tumor recurrence (ETR) (P = 0.0189) and lower 5-year survival (P = 0.0023). The multivariate analysis confirmed that S100P expression was an independent prognostic factor in HCC. The combinatorial analysis showed an additive unfavorable prognostic interaction between S100P expression and the p53 mutation. In contrast, the β-catenin mutation was associated with better prognosis in both S100P-positive and -negative HCCs. Furthermore, S100P expression was a predictor of survival in HCC patients with high tumor stage or ETR (P = 0.0026 and P = 0.0002, respectively). Our study indicates the expression of the S100P protein is a novel independent predictor for poor prognosis in HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage or ETR.     

Aerosolized Lipid Amphotericin B for Complementary Therapy and/or Secondary Prophylaxis in Patients with Invasive Pulmonary Aspergillosis: A Single-Center Experience

Mycopathologia - Experience with aerosolized lipid amphotericin B (aeLAB) as therapy or secondary prophylaxis in patients with invasive pulmonary aspergillosis (IPA) is anecdotal. We performed a...     

Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients

Background

The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome.

Methods

Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7–79.9 years) with a follow-up greater than five years (median 11 years, range 5.3–22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11–20 Gy) and the median tumor volume was 9.5 ml (range 2.8–51 ml).

Results

Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively.

Conclusions

Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy.     

培美曲塞联合长春瑞滨治疗复发转移性宫颈癌患者对疾病控制及预后随访研究

摘要 目的：探讨培美曲塞联合长春瑞滨治疗复发转移性宫颈癌对疾病控制及预后的影响。方法：选择2018年5月~2019年6月收治的100例复发转移性宫颈癌患者,按照随机数表法分观察组和对照组,每组50例。对照组采用紫杉醇联合顺铂化疗,观察组则采用培美曲塞联合长春瑞滨治疗。比较2组疾病控制效果,记录患者化疗前后Karnofsky评分变化,统计2组患者毒副反应及生存率、生存期。结果：观察组的疾病控制率为84.00%,明显高于对照组的62.00%,差异显著（P<0.05）;治疗后,2组患者的Karnofsky评分均升高,且观察组[（86.25±3.02）分]明显高于对照组[（81.15±3.11）分],差异显著（P<0.05）; 2组患者胃肠道反应、骨髓抑制、血小板计数减少、恶心呕吐等毒副反应发生率比较,无明显差异（P>0.05）;观察组患者的1年生存率70.00%、2年生存率58.00%、3年生存率26.00%均高于对照组的50.00%、38.00%、10.00%,观察组的生存期[（18.12±3.21）月]长于对照组[（14.18±2.81）月],差异显著（P<0.05）。结论：培美曲塞联合长春瑞滨治疗复发转移性宫颈癌效果显著,可有效提高患者的生存质量及生存率,延长生存期,毒副反应低,患者耐受性好,可在临床推广运用。     

Clinical Presentation and Long-Term Outcome of Patients With Ectopic Acth Syndrome Due to Bronchial Carcinoid Tumors: A One-Center Experience

Objective: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department.Methods: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure.Results: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 ± 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin-releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 ± 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases.Conclusion: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence.Abbreviations: ACTH = adrenocotricotropic hormone BC = bronchial carcinoid BIPSS = bilateral inferior petrosal sinus sampling CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome CT = computed tomography EAS = ectopic ACTH syndrome HDDST = high-dose dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal IPS:P = inferior petrosal sinus to periphery ratio MRI = magnetic resonance imaging