Lung Carcinoid Research Articles

NTRK and ALK rearrangements in mesothelioma and lung carcinoid.

e20558Background: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK result in oncogenic fusion proteins that have been identified in many tumor types, including lung, colorectal, sali...

Clinical and Pathologic Characteristics of Pulmonary Carcinoid Tumors in Central and Peripheral Locations

Pulmonary carcinoid tumors occur in both central and peripheral locations, and some differences in clinico-pathological features have long been observed. We investigated a large number of resected carcinoid tumors with the aim to further define the characteristics of tumors from both locations. One hundred sixty-six resected carcinoid tumors of the lung were analyzed for a variety of clinical and pathologic features, including histology subtype, mitotic rate, Ki67 index, necrosis, invasive pattern, architectural pattern, cell morphology, sustentacular cells, neuroendocrine hyperplasia, and orthopedia homeobox protein (OTP) and TTF-1 immunohistochemical expressions. Unsupervised hierarchical cluster analysis suggested three clusters as the best solution using TTF-1 and OTP expression: TTF-1-positive and OTP-positive tumors as cluster 1, TTF-1-positive but OTP-negative as cluster 2, and TTF-1-negative and OTP-negative as cluster 3. Cluster 1 was characterized by peripheral location, presence of spindle cell component, presence of sustentacular cells, female predominance, and strong association with neuroendocrine hyperplasia. Cluster 2 was characterized by central location, polygonal cell morphology, acinar growth pattern in a subset of tumors, and only rare association with neuroendocrine hyperplasia. Cluster 3 consisted of more aggressive tumors with more heterogeneous pathologic features. Tumors showed polygonal cell morphology and acinar growth pattern. Occurrence of neuroendocrine hyperplasia was exceptional. Our study confirmed distinct characteristics of central and peripheral type carcinoid. An important difference was a strong association of the peripheral tumor with neuroendocrine hyperplasia while such an association in central tumors was negligible. The tumor location might be relevant for pathobiology of lung carcinoid tumors.

Advances on systemic treatment for lung neuroendocrine neoplasms.

Lung well-to-moderately differentiated neuroendocrine tumors (also known as carcinoids) and large cell neuroendocrine lung carcinoma (poorly differentiated neuroendocrine tumor) are rare neuroendocrine neoplasms, which account for less than 4% of all lung neoplasms. Due to their low incidence, their systemic treatment is greatly influenced by therapeutic evidence derived from the more frequent gastroenteropancreatic neuroendocrine neoplasms and/or small cell lung carcinoma leading to significant bias. Currently, employed systemic therapies for lung carcinoids, aiming at controlling tumor growth include long acting somatostatin analogues (SSAs), peptide receptor radionuclide therapy, chemotherapy and molecular-targeted therapy. In this review, each of those treatments is presented based upon available clinical evidence from retrospective and prospective studies particularly focused on the role of everolimus in the advanced setting and on ongoing clinical trials reflecting our expectations in the near future. In addition, we critically analyse currently employed treatment of large cell neuroendocrine carcinoma where the appropriate chemotherapeutic regimen is still a matter of debate.

Orthopedia homeobox is preferentially expressed in typical carcinoids of the lung.

Twenty-seven percent of neuroendocrine tumors (NETs) are associated with distant metastases, and in some patients, the primary site is unknown. Orthopedia homeobox protein (OTP) has been described as a useful marker for lung carcinoids (LCs) and for separating low-grade typical carcinoids (TCs) from intermediate-grade atypical carcinoids (ACs) in resection specimens. This study evaluated OTP, thyroid transcription factor 1 (TTF-1), and Ki-67 expression in fine-needle aspiration (FNA) samples of various NETs. A search for NETs diagnosed via FNA with subsequent resection was performed. Cell block sections were stained for OTP, TTF-1, and mindbomb E3 ubiquitin protein ligase 1 (Mib-1). Nuclear expression for OTP and TTF-1 was considered positive. Nuclear Ki-67 staining was reported as a percentage. Results were correlated with the grade and primary site for resection specimens. Sixty-three FNA samples of NETs were identified: 14 liver samples, 14 pancreatic samples, 13 lymph node samples, 12 lung samples, 3 retroperitoneum samples, 2 small intestine samples, and 5 other samples. OTP was positive in 12 of 63 NETs (19%) from the following sites: lung (n = 8), liver (lung primary; n = 2), skin (n = 1), and lymph node (lung primary; n = 1). In well-differentiated NETs, only LCs were OTP-positive, whereas TTF-1 was positive in LCs and nonlung NETs (67% vs 7%). Within the LC category, OTP was positive in 100% of the TCs versus 17% of the ACs. OTP is specific for LCs because well-differentiated nonlung NETs are negative for OTP. OTP preferentially stains TCs over ACs. In well-differentiated NETs, OTP staining is highly specific for LCs, and in combination with a low Ki-67 index, it suggests a pulmonary TC. Cancer Cytopathol 2018;126:236-42. © 2018 American Cancer Society.

Uveal Metastasis: Clinical Features and Survival Outcome of 2214 Tumors in 1111 Patients Based on Primary Tumor Origin.

PURPOSE:The purpose of this study is to evaluate patients with uveal metastasis based on primary tumor site.METHODS:Retrospective analysis from Wills Eye Hospital, Philadelphia, PA, USA, for uveal metastasis clinical features and outcomes based on the primary tumor site.RESULTS:There were 2214 uveal metastases diagnosed in 1111 consecutive patients. The demographics included mean age of 60 years (median 61 years), Caucasian race (88%), and female gender (64%). The tumor was unilateral (82%) and primary site was established before uveal metastasis (67%). The primary tumor originated in the breast (37%), lung (26%), kidney (4%), gastrointestinal (GI) tract (4%), cutaneous melanoma (2%), lung carcinoid (2%), prostate (2%), thyroid (1%), pancreas (1%), other sites (3%), and unknown (16%). Comparative analysis of the 5 most common primary sites (breast, lung, kidney, GI tract, and cutaneous melanoma), revealed metastasis at mean age (57, 62, 66, 61, 59 years), as unilateral tumor (74%, 86%, 85%, 93%, 85%), with mean number of metastasis/eye (1.9, 1.7, 1.0, 1.1, 2.0), and in females (99%, 46%, 26%, 25%, 30%). Choroidal metastases measured mean base (9.3, 10.2, 9.1, 11.0, 7.3 mm), mean thickness (2.4, 3.6, 4.4, 4.0, 2.9 mm), and demonstrated predominant color yellow (94%, 91%, 56%, 97%, 36%). Of the 769 patients with documented follow-up, mean patient survival was poor (22.2, 11.5, 8.6, 12.4, 11.4 months) and Kaplan–Meier analysis revealed 3-year survival (33%, 19%, 0%, 14%, 21%) and 5-year survival (24%, 13%, 0%, 14%, 21%). The worst survival was found in patients with pancreatic metastasis (mean 4.2 months) and best survival with lung carcinoid (92% at 5 years).CONCLUSION:In a tertiary referral service, uveal metastasis originates from cancer in the breast, lung, kidney, GI tract, cutaneous melanoma, or others. Overall prognosis is poor with 5-year survival at 23% and worst survival with pancreatic metastasis whereas best survival with lung carcinoid metastasis.

A Rare Case of Metastasis of Lung Carcinoid to Breast

Metastases to the breast from non-mammary primary tumors are uncommon. We present a rare, but typical, case of metastasis to the breast from lung carcinoid tumor, 20 years after the primary cancer was treated.

A Case of Lung Carcinoid with Non-tuberculous Mycobacteriosis of the Lung Diagnosed by Bronchoscopy and Resected in the Early Stage

A Case of Lung Carcinoid with Non-tuberculous Mycobacteriosis of the Lung Diagnosed by Bronchoscopy and Resected in the Early Stage

Case Report: Transection of Radial Arterial Catheter Requiring Surgical Intervention

We report a case in which a radial arterial line was placed prior to induction of general anaesthesia in a 76 year old male with prostate cancer and multiple co-morbidities who presented for thoracoscopic resection of a right lower lobe carcinoid lung tumor. The patient's intra-operative course was complicated by acute blood loss requiring conversion to an open procedure. A subsequent injury to the superior vena cava resulted in the need for immediate re-exploration at the conclusion of surgery. While the arterial line was still indicated in this patient's postoperative course in the ICU, malfunction on post-operative day one resulted in removal of the catheter. The catheter was secured by stay sutures and during the attempt to cut these sutures, the arterial catheter was inadvertently severed and a fragment remained within the patient's radial artery. Surgical intervention was required to remove the retained catheter and the patient recovered without evidence of residual injury or deficit to the artery and extremity. Literature review reveals only one other case report of a retained catheter in a radial artery caused by accidental transection during removal. We review indications for arterial line placement, complications, as well as methods for securing arterial catheters.

Nationwide multicenter study on the management of pulmonary neuroendocrine (carcinoid) tumors.

Background and aimTo analyze the management and outcome of patients with primary typical (TC) and atypical lung carcinoids (AC) in Switzerland.MethodsRetrospective analysis of patients selected from a neuroendocrine tumor (NET) registry. Patients were divided into TC and AC according to pathology reports, and surgical procedures were grouped as wedge/segmentectomy, lobectomy/bilobectomy and pneumectomy. Survival analysis was performed using the Kaplan–Meier method and log-rank test.ResultsOver 7 years, 113 pulmonary carcinoids (61.9% females, mean age 59.4 years) were included from 19 hospitals, with pathology data on Ki67 and necrosis incomplete in 16 cases. Eighty-three TC and 14 AC underwent surgical resection with a primary tumor size of median 14.5 (range 1–80) mm and diagnosis was established in 55.8% at surgery. Mean follow-up was 30.2 ± 23.1 months. Lobectomy was performed in 54.2% and wedge resection in 17.7% of cases. Six patients received additional systemic therapy. There was a trend for larger primary lesion size and a significantly higher rate of N2–N3 status in AC. Mean survival tended to be increased in patients with TC compared to AC (86.1 vs 48.4 months, P = 0.06) and mean disease-free interval after surgical resection was 74.1 and 48.3 months for TC and AC, respectively (P = 0.74).ConclusionAC of the lung has a more malignant behavior and a trend to a worse outcome. The results of this registry reinforce the need for standardized histological diagnosis and inter-disciplinary therapeutic decision making to improve the quality of care of patients with TC and AC.

P3.15-002 Molecular Profiling and Networks Relevant to Disease Mechanisms in Small Cell Lung Cancer and Lung Carcinoid Tumor

Small Cell lung cancer (SCLC), which belongs to neuroendocrine tumor (NT), is known for its highly aggressive clinical features and poor prognosis. The molecular underpinnings that may prognosticate survival and could increase our understanding of tumor development and progression are still poor understood in its highly aggressive malignancies. We aimed to describe the proteomic characteristics and biomarker profiling of high-grade NT, SCLC versus low-grade NT, carcinoid tumor (CT) by the state-of-the-art proteomics techniques utilizing clinical specimens.

Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial

There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. Novartis Pharma AG.

Surgical Resection for Pulmonary Carcinoid: Long-Term Results of Multicentric Study-The Importance of Pathological N Status, More Than We Thought.

Histological subdivision into typical (TC) and atypical (AC) is crucial for treatment and prognosis of lung carcinoids but can be also very challenging, even for experts. In this study, we aimed to strengthen or reduce the prognostic value of several pathological, clinical, or per-operative factors some of which are still controversial. We retrospectively reviewed clinical records related to 195 patients affected by TC (159) or AC (36) surgically treated between 2000 and 2014, in three different centers. Survival and subtypes comparison analyses were performed to identify potential prognostic factors. TCs showed a lower rate of nodal involvement than ACs (N0=94.9%; N1=1.9%; N2=3.2% in typical and N0=63.8%; N1=16.6%; N2=19.4% in atypical carcinoids, respectively, p<0.0001). Long-term oncological results of resected carcinoids were significantly better in TCs than ACs with higher 5- and 10-year overall survival rates (97.2 and 88.2% vs. 77.9 and 68.2%, respectively; p=0.001) and disease-free survival rates (98.2 and 90.3% in typical and 80.8 and 70.7% atypical carcinoids, respectively; p=0.001). Risk factors analysis revealed that AC subtype [HR 4.33 (95% CI 1.72-8.03), p=0.002], pathological nodal involvement [HR 3.05 (95% CI 1.77-5.26), p<0.0001], and higher SUVmax [HR 4.33 (95% CI 1.03-7.18), p=0.002] were independently and pejoratively associated with overall survival. Factors associated with a higher risk of recurrence were AC subtype [HR 6.13 (95% CI 1.13-18.86), p=0.002]; nodal involvement [HR 5.48 (95% CI 2.85-10.51), p<0.0001]; higher Ki67 expression level [HR 1.09 (95% CI 1.01-1.20), p=0.047]; and SUVmax [HR 1.83 (95% CI 1.04-3.23), p=0.035]. Surgery for lung carcinoids allows satisfactory oncological results which mainly depend on carcinoid subtype dichotomy, pathological nodal status, and SUVmax.

Unilateral pulmonary artery pre-operative occlusion test: technical feasibility and safety prior to pneumonectomy or pleuropneumonectomy for malignancy.

The aim of the present study was to assess the technical feasibility and safety of the unilateral pulmonary artery occlusion (UPAO) test in pre-operative evaluation of pneumonectomy or pleuropneumonectomy for lung or pleural tumours. The UPAO test was performed on 91 patients who were scheduled to undergo or were being considered for pneumonectomy or pleuropneumonectomy between June 2003 and July 2016. There were 74 males and 17 females, with a median age of 65 years (range, 23-80). The technical success rate, procedure time and complication rate were evaluated. Technical success was defined as completion of the UPAO test. The diagnoses of the 91 patients were as follows: lung cancer in 63, malignant pleural mesothelioma in 21, thymoma in 5, lung metastasis in 1 and lung carcinoid in 1. The UPAO test was performed successfully on 88 out of 91 patients (technical success rate: 97%). The median procedure time was 57 min (range, 34-120). Cardiac arrest due to migration of the balloon catheter to the pulmonary trunk occurred in 1 patient (complication rate: 1.1%). The UPAO test in pre-operative evaluation of pneumonectomy or pleuropneumonectomy for lung or pleural tumours appears to be technically feasible. However, it needs to be performed with care in order to avoid severe complications. Advances in knowledge: The UPAO test can be safely performed and is helpful in evaluating patients for pneumonectomy or pleuropneumonectomy.

Atypical lung carcinoid metastasis to the pituitary gland

Objective To study clinicopathological features, diagnosis and differential diagnosis of atypical lung carcinoid metastasis to the pituitary gland based on clinical data of one patient. Methods and Results A 81-year-old female presented headache and sudden blindness, and head MRI showed that there was a lesion at the saddle area. The tumor was detected at intrasellar and in grayish red during surgery. The diameter of tumor was 2 cm. The tumor was soft with no envelop at and well-defined margins, and insufficiency in blood supply. The tumor was removed completely along its edge. Under optical microscopy, the tumor was consisted of small round cells of the same size. Tumor cells were distributed around blood vessels in a nest manner or diffuse manner with brisk mitotic activity and focal necrosis. By using immunohistochemical staining, the tumor cells were diffusely positive for synaptophysin (Syn), CD56 and thyoid transcription factor - 1 (TTF - 1), focal positive for cytokeratin (CK) and P53, and negative for growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), S-100 protein (S-100), thyroglobulin (TG) and calcitonin. Ki?67 labeling index was about 33%. Conclusions Pituitary metastasis is a rare tumor, and only a few cases of atypical lung carcinoid metastasis to the pituitary gland have been reported. Definite diagnosis could be made by history, typical histopathological characteristics and immunohistochemical expressions. DOI: 10.3969/j.issn.1672-6731.2017.09.010

Chemotherapy in NETs: When and how.

The majority of neuroendocrine tumours (NETs) are well-differentiated tumours that follow an indolent course, in contrast to a minority of poorly differentiated neuroendocrine carcinomas (NECs) which exhibit an aggressive course and assocaited with an overall short survival. Although surgery is the only curative treatment for NETs it is not always feasible,necessitating the application of other therapies including chemotherapy. Streptozotocin (STZ)-based regimens have long been used for advanced or metastatic well-to-moderately differentiated (G1-G2) NETs, especially those originating from the pancreas (pNETs). In poorly differentiated grade 3 (G3) tumours, platinum-based chemotherapy is recommended as first-line therapy, albeit without durable responses. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in pNETs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In lung and thymic carcinoids, chemotherapy is reserved for patients with progressive metastatic disease in whom other treatment options are unavailable. Overall, chemotherapy is indicated in patients who have progressed on first-line treatment with somatostatin analogues, have extensive tumour load or exhibit rapid growth following a period of follow-up, and/or have a high proliferative rate; it may occasionally can be used in a neo-adjuvant setting. Prospective randomised studies are awaited to substantiate the role of chemotherapy in the therapeutic algorithm of NETs along with other evolving treatments.

An abscopal effect in a case of neuroendocrine atypical carcinoid lung cancer

An abscopal effect in a case of neuroendocrine atypical carcinoid lung cancer

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study

Background: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. Methods: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. Results: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. Conclusions: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Instructions to Authors

Neuroendocrine tumors (NETs) are originating from neuroendocrine cells in diffuse endocrine systems. NETs are diagnosed by characteristic histologic features and immunoprofiles. Recent 2010 WHO classification for gastroenteropancreatic NETs introduced grading system based on mitotic count and Ki-67 proliferation index. Gastroenteropancreatic NETs are classified as NET grade 1, NET grade 2, and neuroendocrine carcinoma (NET grade 3). However, the carcinoid is still used in classification of NETs of the lung and uterine cervix. Some issues with grading system such as methodologies for evaluation of Ki-67 index and subclassification of neuroendocrine carcinoma (NET grade 3) are arising. The importance of Ki-67 labeling index is emerging in differential diagnosis of lung carcinoids. In this review, we focus on recent grading and classification of NETs and related issues in various organs, including gastrointestinal tract, pancreas, lung, and female reproductive organs.

Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver.

Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial.

Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design.Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks.Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277-84. ©2016 AACR.