Cell Carcinoid Tumors Research Articles

Identification of Small Molecule Hes1 Modulators as Potential Anticancer Chemotherapeutics

Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.

Lung cancer in systemic lupus erythematosus

Summary Background: Evidence points to a link between systemic lupus erythematosus (SLE) and an increased risk of lung cancer. Our objective was to provide a brief report of the lung cancer cases from an SLE cohort, with respect to demographics, histology, and exposures to smoking and immunosuppressive medications. Methods: Data were obtained from a multi-site international cohort study of over 9500 SLE patients from 23 centres. Cancer cases were ascertained through linkage with regional tumor registries. Results: We analyzed information on histology subtype for 30 lung cancer cases that had occurred across five countries. Most (75%) of these 30 cases were female, with a median age of 61 (range 27—91) years. In eight cases, the histological type was not specified. In the remainder, the most common histological type reported was adenocarcinoma (N = 8; two of the adenocarcinomas were bronchoalveolar carcinoma) followed by small cell carcinoma (N = 6), and squamous cell carcinoma (N = 6) with one case each of large cell carcinoma and carcinoid tumor. Most (71%)

Thiocoraline activates transcription of notch and inhibits the proliferation of carcinoid tumor cells

Thiocoraline activates transcription of notch and inhibits the proliferation of carcinoid tumor cells

Clinicopathologic feature and outcome of appendiceal goblet cell carcinoid and neuroendocrine tumor.

e14170 Background: Goblet cell carcinoid (GCC) of the appendix is a rare tumor comprising 5% of primary appendiceal tumors. GCC shares histological features of both neuroendocrine tumor (NET) and adenocarcinoma. Clinically, GCC also has an intermediate behavior between them. The management of GCC is mostly based on small retrospective series. We report the clinicopathological features, treatments, and outcomes of patients with appendiceal GCCs and NETs from a merged database between Emory University and the Ohio State University. Methods: We identified patients with appendiceal GCCs and NETs treated at these institutions over the period of 12 years from 1999 to 2011. Chart reviews for age, gender, date of diagnosis, TNM stage, chemotherapy, intraperitoneal hyperthermic perfusion (IPHP), surgery, and survival were performed. Results: See table. In the GCC patients with stage I, II, and III, 30 received surgery alone and 1 received surgery plus IPHP. 29 out of 31 (94%) patients are alive without disease recurrence. Out of 6 GCC patients with stage IV, 5 received chemotherapy, 1 received chemotherapy plus IPHP, and 2 (33%) are alive. In the NET patients with stage I,II, and III, all 29 were treated with surgery alone. 29 out of 31 patients are alive and there was no disease-related mortality. Out of 2 NET patients with stage IV, one received chemotherapy and both are alive. Conclusions: Our data confirms the excellent prognosis of appendiceal NET regardless of stage. The outcomes of surgery for patients with stage I, II, and III in both GCCs and NETs were excellent. Patients with stage IV GCCs have higher possibility of aggressive clinical courses. Chemotherapy or IPHP should be considered in the management of stage IV GCCs. [Table: see text]

Successful treatment of duodenal carcinoid tumor by laparoscopy‐assisted endoscopic full‐thickness resection with lymphadenectomy

Reports on endoscopic full-thickness resection of the duodenum using the endoscopic submucosal dissection technique are rare. Here we present a case of a duodenal bulb carcinoid tumor successfully treated by laparoscopy-assisted endoscopic full-thickness resection (LAEFR). An asymptomatic 65-year-old woman had a 10-mm, submucosal tumor on the anterior wall of the duodenal bulb. Abdominal CT revealed an enlarged lymph node adjacent to the duodenum and pancreas. Although we informed the patient of the need for pancreatoduodenectomy with a lymphadenectomy, the patient expressly requested LAEFR. After negative nodal metastasis was confirmed by an intraoperative frozen section of the enlarged nodes, LAEFR was performed using the endoscopic submucosal dissection technique under the laparoscopic assistance. The duodenal wall defect was closed by laparoscopy with an Albert anastomosis. The entire circumferential margin of the specimen was histopathologically negative for carcinoid tumor cells. In summary, LAEFR enables en bloc and whole-layer excision of nonperiampullary duodenal lesions with a sufficient surgical margin, both vertically and laterally. LAEFR is a minimally invasive and effective treatment for selected patients with duodenal carcinoid tumor.

A Novel Case of Concurrent Renal Tumors

Renal cell carcinoma of chromophobe type is a malignant neoplasm with characteristic large cells that exhibit prominent cell membranes. Primary renal carcinoid tumors are rare tumors with the histological appearance similar to well-differentiated neuroendocrine tumors at other sites. Chromophobe renal cell carcinoma with neuroendocrine differentiation is exceedingly rare. The authors describe a case of a chromophobe renal cell carcinoma and carcinoid tumor of the kidney presenting as distinct masses in the same kidney in a 34-year-old male. The histologic and immunohistochemical features of both the tumors were characteristic with no overlapping features. The carcinoid tumor presented at a higher stage with nodal metastasis. To the best of the authors' knowledge, this is the first case of 2 morphologically distinct tumors, one chromophobe renal cell carcinoma and the other primary carcinoid tumor in the same kidney.

The evolving management of laryngeal neuroendocrine carcinomas

Laryngeal neuroendocrine neoplasms are divided into two broad categories based on their tissue of origin: epithelial and neural [1]. Laryngeal epithelial neuroendocrine neoplasms are all malignant lesions (carcinomas) and are a subset of neoplasms that share specific morphologic, histochemical, immunohistochemical, ultrastructural and molecular characteristics. The major categories of laryngeal neuroendocrine carcinomas are typical carcinoid (well differentiated neuroendocrine carcinoma), atypical carcinoid (moderately differentiated neuroendocrine carcinoma), small cell neuroendocrine carcinoma (poorly differentiated neuroendocrine carcinoma) and large cell neuroendocrine carcinoma (poorly differentiated neuroendocrine carcinoma) [2]. The neural category consists only of paraganglioma which is invariably benign [3]. Although neuroendocrine neoplasms are uncommon in the larynx, they represent the most common non-squamous neoplasms arising in this area and to date more than 700 cases of them have been reported in the literature [1]. The atypical carcinoid is the most frequent laryngeal neuroendocrine carcinoma, followed by small cell neuroendocrine carcinoma, carcinoid tumor, and large cell neuroendocrine carcinoma. However, in the past large cell neuroendocrine carcinoma was classified under the umbrella term of atypical carcinoid so it may actually be more common than previously realized [4]. Accurate classification of the laryngeal epithelial neuroendocrine carcinomas requires knowledge of specific pathologic criteria separating the major categories. Neuroendocrine carcinomas of the larynx have widely varying prognosis, clinical management, and response to therapy. Thus, accurate classification is essential. Immunohistochemistry is an important diagnostic adjunct in the evaluation of these tumors, as it allows for definitive demonstration of neuroendocrine differentiation. For typical carcinoid, conservation surgery, particularly supraglottic laryngectomy, may be suitable because the supraglottis is the most frequent site of involvement. Transoral CO2 laser surgery can be a good alternative for appropriate cases because of the functional results and lower morbidity [5]. Elective neck dissection is not warranted. Bilateral selective neck dissection (levels II and III) is only indicated for clinically or pathologically proven cervical metastases [6]. The mainstay of treatment for atypical carcinoid of the larynx is surgical resection. As most tumors are located in the supraglottis, supraglottic laryngectomy is often the procedure of choice. Transoral CO2 laser surgery has been also employed to resect these tumors with oncologically sound results and with low morbidity [7]. Elective neck dissection appears to be warranted in view of the high incidence of both early cervical metastasis and subsequent involvement of cervical lymph nodes. Bilateral dissection of sublevel IIA and level III is only adequate for elective surgical treatment of the neck in supraglottic tumors [8]. Bilateral selective neck dissection (levels II and III) should be used therapeutically for metastatic disease. Post-operative radiotherapy is indicated in the presence of cervical lymph node metastases. Painful skin metastases from an This paper was written by members of the International Head and Neck Scientific Group (www.IHNSG.com).

Abstract 2181: Tumor suppressor role of Notch3 in medullary thyroid carcinoma

Abstract Introduction: NOTCH3 is a transmembrane receptor that appears to be absent in the neuroendocrine (NE) tumors. We have previously demonstrated that transient expression of the active portion of NOTCH3 (NICD3) alters the NE phenotype and inhibits the proliferation of carcinoid tumor cells in vitro. However, the long term effect of activation this pathway is not clearly understood in Medullary Thyroid Carcinoma (MTC). To elucidate the role of Notch3 in NE, we established a doxycycline inducible NOTCH3 intracellular domain in MTC TT cells. The aim of this study was to assess the long term effect of NOTCH3 and determine the mechanism of inhibition of TT cells growth. Methods: Doxycycline inducible TT-NOTCH3 cells were created by stable transfection of Tet-On vector followed by transfection of pRevTRE-NOTCH3 plasmid. Functional analysis of NICD3 was done by measuring the degree of luciferase activity by CBF binding assay. Quantification of HES and HEY gene expression (Notch signaling mediators) was done by real time RT-PCR. Effect of Notch3 on NE markers -chromogranin A (CgA) and achaete-scute complex-like1 (ASCL1) – was assessed by Western blot analysis. The influence of NOTCH3 overexpression on TT-NOTCH cell proliferation was measured by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) rapid colorimetric assay. The mechanism of growth inhibition was determined for apoptosis markers by Western blot and flow cytometry analyses. Results: Treatment of TT-NOTCH3 cells with doxycycline led to an induction of NOTCH3 protein in a dose-dependent manner. Increase in the CBF1 binding activity showed that the NOTCH3 protein is functional and this is associated with changes in transcriptional level of HES and HEY families. More importantly, NOTCH3 activation led to a dose dependant reduction of NE markers ASCL1 and CgA. In addition, NOTCH3 activity is required to suppress MTC cell proliferation and the level of growth regression depends on the amount of NOTCH3 protein expressed. Finally, Western blot analysis and flow cytometry experiments indicated that the growth inhibition is due to apoptosis. Conclusions: We demonstrate, for the first time, that overexpression of NOTCH3 in MTC cells suppresses tumor cells growth by promoting apoptosis. Moreover, Notch3 pathway is functional as active NOTCH3 triggers the CBF-dependent transcriptional network. Finally, the activation of Notch3 in the in vitro model resulted in down-regulation of NE markers indicated that this pathway is conserved in MTC. Therefore, activation of Notch3 could be a therapeutic strategy to treat patients with MTC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2181. doi:10.1158/1538-7445.AM2011-2181

Combined Carcinoid Tumor and Squamous Cell Carcinoma of Lung: Expanding the Spectrum of Combined Tumors of Lung

Combined lung cancers containing both small cell and non-small cell carcinoma elements are uncommon but well recognized. Lung tumors with neuroendocrine differentiation form a group of histologically distinct tumors with differing clinical behavior ranging from low-grade tumors with good prognosis (typical carcinoid) to intermediate-grade tumors (atypical carcinoid) to high-grade tumors with poor prognosis (small cell carcinoma and large cell neuroendocrine tumors). The authors report clinical findings and pathologic findings in a case of combined carcinoid tumor and squamous cell carcinoma of lung. To the best of the authors' knowledge, this is the first report of such a case in the peer reviewed literature, thus broadening the spectrum of combined lung tumors.

A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum

Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10(-7)) at a Bonferroni-corrected level (<1.62×10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.

An unusual cause of carcinoid heart disease

Carcinoid heart disease (CHD) is a rare form of valvular heart disease characterized by right-sided heart valve dysfunction. Carcinoid heart disease occurs most frequently when carcinoid tumour cells metastasize from a primary site in the gut to the liver, so that vasoactive substances produced by the tumour are able to reach the systemic circulation. By contrast, in ovarian carcinoid tumours carcinoid heart disease develops in the absence of liver metastasis, because vasoactive substances can be released directly into the systemic circulation, bypassing the first-pass metabolism of the liver. There are only a few case reports in the world literature of carcinoid heart disease caused by ovarian carcinoid tumour. We report a case of an 85-year-old woman with carcinoid heart disease caused by a bilateral ovarian carcinoid tumour metastasized from a primary ileal site.

Varying Opinions on the Authenticity of a Human Midgut Carcinoid Cell Line – Letter

In 2007, our laboratory published an article in Clinical Cancer Research reporting on the development of a human midgut carcinoid tumor cell line ([1][1]). This cell line has now been shared with over 20 laboratories around the world. Investigators in the field of neuroendocrine tumor research are

Abstract 3085: Overexpression of the NOTCH3 intracellular domain alters neuroendocrine phenotype in carcinoid tumor cells

Abstract Introduction: There are four mammalian Notch receptors (Notch1-4), which exhibit unique and overlapping expression pattern and act as oncogenes or tumor suppressor genes depending on the cell and context type. We previously reported that Notch1 pathway is minimally active in neuroendocrine (NE) tumors. Furthermore, induction of the Notch1 signaling pathway by over- expression or by pharmacological treatment with valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) suppresses hormone secretion. However, the role of other Notch isoforms is not clear in carcinoid. In this study, we analyzed the presence of Notch isoforms and their regulatory role on chromogranin A (CgA), a clinically important NE marker, and achaete-scute complex-like1 (ASCL1), a known downstream target of Notch. Methods: Expression of four Notch isoforms was quantified by real time RT-PCR from parental BON cells (GI carcinoid) and VPA treated BON cells. pcDNA3.3 TOPO plasmid containing constitutively expressed human active portion of Notch3, NICD3, was transiently transfected into BON cells and the cell lysates were tested for the presence of NOTCH3. The levels of NE markers such as CgA and ASCL1 were analyzed by Western blot. Results: Gene expression analysis showed that the parental BON cells had very minimal levels of Notch1-3. Notch4 expression was not detected. In VPA treated cells, the levels of Notch1, 2 and 3 were increased significantly. Overall, the Notch3 expression level was higher than Notch1 and 2 in VPA treated cells. Importantly, there was a 60-fold induction of Notch3 expression in VPA treated cells compared to parental untreated cells. VPA treatment also resulted in a 15-fold and 20-fold increase for Notch1 and Notch2 respectively whereas Notch4 was not detected in these cells. The constitutive expression of NICD3 in BON cells resulted in a reduction in ASCL1 and CgA. Conclusions: Carcinoid tumor cells have a paucity of all Notch isoforms, including Notch3. For the first time, we demonstrate that Notch3 regulates the NE phenotype, and may play an important role in regulating carcinoid tumor progression. These findings warrant further investigation on targeting Notch3 for carcinoid cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3085.

Unique susceptibility of a human lung carcinoid tumor cell line to infection with BK virus

Carcinoid syndrome is caused by the unregulated secretion of bioactive amines from neuroendocrine tumors arising primarily in the gastrointestinal tract and lungs. The incidence of carcinoid syndrome is 1–2/100,000 and the syndrome is thought to be increasing. Carcinoid tumors are relatively slow growing but can become highly metastatic. Currently, there is no effective therapy to inhibit cell proliferation or metastasis of neuroendocrine tumor (NET) disease. Polyomaviruses are a family of viruses that are able to transform cells and promote tumor formation. In this study, the polyomaviruses SV40, JCV, and BKV were used to assess the ability of polyomaviruses to productively infect a range of human carcinoid cell lines. Infection was assessed by the immunofluorescence detection of T antigen and V antigen. Viruses and cell lines that exhibited productive infections were subsequently assayed by FACS analysis for cell binding and dual promoter luciferase assay for early and late promoter activity. Most carcinoid cell lines were not susceptible to infection by polyomaviruses. However, BKV efficiently infected the pulmonary carcinoid H727 cell line but did not infect a control, non-carcinoid lung cell line (A549). BKV was found to bind to both the susceptible H727 cells and to the non-susceptible A549 cells but viral genes were only efficiently expressed in the H727 cell line. The data demonstrate that BKV can infect human pulmonary carcinoid cells. Infection does not seem to be solely mediated by the virus’ ability to bind to cells, as the virus will also bind to non-carcinoid control cells. Both early and late gene expression are supported by the pulmonary carcinoid cells.

Effect of Y-90 SIR-Spheres Therapy for Multiple Liver Metastases in a Variety of Tumors

Objective To evaluate the outcomes of patients receiving Y- 90 SIR-Spheres in patients with multiple liver metastases from different tumors. Methods: 29 consecutive patients with multiple liver metastases from colorectal (13), Islet cell tumors (9), carcinoid tumors (4) or non-small cell lung cancer (3) who were treated with Y-90 SIR-Spheres between March, 2003 and February, 2006 were included. Only patients who had follow-up radiological exams at our institution were included. Data regarding Y-90 SIR-Spheres dose, lobe of liver treated, and chemotherapy (CTx) administered were collected. Patients’ outcomes were evaluated based on radiological evidence of change in size and number of liver metastases. Results: The study population included 8 females and 21 males at a mean age of 60y. The mean Y-90 SIR-Spheres dose administered was 39.8 mCi. Both lobes of the liver, the right lobe only or the left lobe only were treated in 26, 2, 1 patients, respectively. Sixteen patients received Y-90 SIR-Spheres after CTx failure, 5 patients as adjuvant therapy after completion of CTx, 7 patients as concurrent therapy and one patient refused repeat CTx. The mean interval between the last CTx and Y-90 SIR-Spheres was 108 days. Four patients (14%) demonstrated radiological improvement and 9 (31%) were stable for a mean interval of 2.8 mo. after Y-90 SIR-Spheres infusion. Sixteen patients (55%) demonstrated continued progress of liver metastases. Conclusion: Y-90 SIR-Spheres therapy is useful in reducing or stabilizing multiple liver metastases from a variety of tumors.

Neuroendocrine cells and associated malignancies of the oral mucosa: a review

Neuroendocrine cells of the oral mucosa constitute an under-recognized component of the diffuse neuroendocrine system with diverse subpopulations and elusive biologic roles in the oral cavity. Primary malignant oral tumors that show a neuroendocrine phenotype display histomorphologic heterogeneity thereby giving rise to a spectrum of lesions in this rare category of oral malignancy. These lesions can be divided into neuroendocrine carcinomas (NECs) of small cell or non-small cell type. The former is further subdivided into the Merkel cell type or the pulmonary type while the latter includes atypical carcinoid tumor and large cell NEC. All histologic subtypes of oral NEC appear to have a strong predilection for men in their fifth or sixth decade and arise predominantly in the non-keratinized oral mucosa. The biologic behavior of oral Merkel cell carcinomas appears to be more aggressive than those of skin. It remains to be determined whether histologic categorization of the remaining tumor subtypes is predictive of patient survival in oral neuroendocrine tumors.

Abstract A34: VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis

Abstract Carcinoid tumors are slow growing and highly vascular neuroendocrine neoplasms that have been increasing in incidence since the 1970s. Carcinoid tumors express vascular endothelial growth factor receptor 2 (VEGFR-2); however, its role is not completely understood. The aims of this study were 1) to assess the expression and regulation of VEGFR-2 in carcinoid tumors and cells and 2) to evaluate the effect of VEGFR-2 on carcinoid growth and metastasis. Methods: 1) The expression of VEGFR-2 in carcinoid tumor sections and in the novel carcinoid cell line BON, which was established and characterized in our laboratory, was assessed by immunohistochemistry andWestern blot, respectively. As VEGFR-2 signals through the PI3K/Akt pathway, signaling through Akt was adjusted chemically and through RNAi to delineate its effect on VEGFR-2 expression. 2) BON cell proliferation was measured following treatment with the VEGFR-2 inhibitor sunitinib malate to assess the effect of VEGF signaling on cell growth. A BON cell line with stably decreased VEGFR-2 expression, designated as BON shVEGFR-2, was generated by transfecting cells with shRNA to VEGFR-2. Boyden chamber and scratch assays were performed on BON shVEGFR-2 cells to assess the effect of VEGFR-2 on invasion and migration. Results: 1) Immunhistochemical analysis confirmed positive expression of VEGFR-2 in the endothelial and epithelial components of carcinoid tumor sections. Consistent with this finding, BON cells also expressed VEGFR-2. Interestingly, we noted that the regulation of VEGFR-2 expression is inversely related to PI3K/Akt signaling. Inhibition of PI3K/Akt signaling with wortmannin upregulated VEGFR-2 expression, as noted with western blot and mRNA analysis. shRNA against PTEN increased phospho-Akt, resulting in decreased expression of VEGFR-2 in BON cells. BON shPTEN cells injected into the pancreas of nude mice formed increased liver metastases, compared to BON shControl cells, and the liver metastatic cells retained decreased VEGFR-2 expression. 2) Treatment with sunitinib malate had only a modest effect on BON cell inhibition. Consistent with our in vivo studies, BON shVEGFR-2 cells have decreased expression of E-cadherin compared to BON shControl cells. Additionally, the migratory and invasive potential of BON shVEGFR-2 cells is approximately four and 1.75 times that of control BON cells, respectively, at 48 h. Conclusions: We demonstrate the expression and activity of VEGFR-2 in BON cells. The expression of VEGFR-2 on the epithelial component of carcinoid tumors and in the BON cell line, suggests an alternate role for VEGFR-2, in addition to its well-defined role in angiogenesis. The modest inhibition of BON cell growth with sunitinib malate suggests that VEGFR-2 on carcinoid tumor cells has a limited role in cell proliferation. Interestingly, we show that the level of VEGFR-2 expression in BON cells is inversely proportional to the degree of total Akt signaling, suggesting a negative feedback loop in the regulation of VEGFR-2. The finding that decreased VEGFR-2 expression results in increased invasion and migration suggests that VEGFR-2 may inhibit carcinoid metastasis. Thus, while VEGFR-2 inhibition prevents angiogenesis, it may also increase the metastatic potential of surviving carcinoid cells. Citation Information: Cancer Res 2009;69(23 Suppl):A34.

Gammagrafía con análogos de la somatostatina en el diagnóstico y el seguimiento del carcinoide bronquial pediátrico

Carcinoid tumor is a rare neuroendocrine neoplasm with different locations, the most frequent ones during the pediatric age being the appendix and lung. Scintigraphy with (111)In-DTPA-d-Phe(1)-octreotide has led to an importance advance in the diagnosis of extension in carcinoid tumor patients. We present three pediatric patients with bronchial carcinoid studied with somatostatin analogue scintigraphy (SSRS). The first patient (9 years) was studied using the SSRS after surgery due to carcinoid tumor in the right lower lobe in which tumor remains was observed (this being clearer in the tomography study). The second patient (10 years) presented due to endobronchial tumor in the left lower lobe together with atelectasis of the LUL and emphysema of the LLL. Radiology imaging techniques suggested the differential diagnosis between the endobronchial carcinoid tumor or plasma cells or foreign body gramuloma. The SSRS showed an abnormal deposit of activity in the left hemithorax consisted with carcinoid tumor. No other areas suggesting metastasis were observed. After the surgery (endobronchial resection), new controls with SSRS showed absence of disease. The third patient (12 years) came after a lobectomy (RUL) due to bronchial carcinoid. The SSRS did not show any abnormal areas of activity. In the subsequent control (3 months), a deposit of activity was observed in the middle third of the right hemithorax, after which a lobectomy was performed (RLL and ML) that showed small remains of neuroendocrine carcinoid. Subsequent controls were negative. The SSRS has demonstrated great utility in the diagnosis, follow-up and staging of pediatric patients, carriers of neuroendocrine carcinoid tumors.

Inhibition of Phosphatidylinositol 3-Kinase/Akt Signaling Suppresses Tumor Cell Proliferation and Neuroendocrine Marker Expression in GI Carcinoid Tumors

Overactivation of PI3K/Akt signaling facilitates tumor proliferation in several cancers. We have shown that various signal transduction pathways promote tumorigenesis in carcinoid tumors, which exhibit endogenously high levels of active, phosphorylated Akt. Therefore, we hypothesized that inhibition of the PI3K/Akt pathway would suppress carcinoid tumor cell growth and neuroendocrine (NE) marker production. Human carcinoid BON cells were treated in vitro with LY294002, a PI3-kinase inhibitor, or transfected with Akt1 siRNA. Tumor cell proliferation was measured by MTT for 6 days. The effect of LY294002 or Akt1 siRNA treatment was assessed by Western analysis. We examined the levels of phosphorylated Akt, total Akt, Akt1, and the NE markers human achaete-scute homolog1 (ASCL1) and chromogranin A (CgA). Treatment of BON cells with LY294002 reduced tumor cell proliferation (76%) in a dose-dependent manner. Growth also decreased in Akt1 siRNA transfected cells (26%). Levels of active, phosphorylated Akt and the NE tumor markers, ASCL1 and CgA, were diminished with both LY294002 and Akt1 siRNA treatments proportional to the degree of Akt inhibition. Total Akt, Akt2, and Akt3 levels were unaffected by these experiments. These data indicate that PI3K/Akt signaling performs a critical role in human carcinoid tumor cell survival and NE hormone generation. Furthermore, the development of novel therapeutics targeting Akt1 or components of the PI3K/Akt pathway may enhance the management of carcinoid disease.

Outcome of surgical resection for pathologic Nx and N0 non-small cell lung cancer (NSCLC)

7513 Background: Metastasis to lymph nodes (LN) connotes poor prognosis in NSCLC. Sufficient LN must be examined to accurately determine LN negativity. Patients with no LN examined (pNx) may be incompletely staged and erroneously assigned to a low risk group. To evaluate this possibility, we compared the survival of patients with node negative disease and at least 1 LN examined (pN0) to those with pNx. Methods: Retrospective analysis of all resections for NSCLC from January 1, 2004 to December 31, 2007 identified through a search of pathology databases at hospitals in the Memphis Metropolitan Area. Benign and metastatic disease, pre-operative chemo/radio therapy, bronchoalveolar cell, small cell lung, carcinoid tumors and repeat lung resection were excluded. Date of death was obtained from a National Death Index search. Variables were compared by chi-squared test, survival estimates calculated by Kaplan Meier analysis, survival estimates compared by log-rank test. Results: 746 of 809 resections met inclusion criteria. 86 (11.5%) were pNx and 510 (68.4%) pN0. Demographic and histologic characteristics were similar ( Table 1 ). 55.8% of the pNx group had sublobar resection, compared to 5.7% of pN0 (p&lt;0.0001). 179 pN0 patients (35.1%) had only hilar-intrapulmonary LN (stations 10–14), median 3 (range 1–18) examined. 46 patients (9.02%) had only mediastinal LN (stations 1–9), median 2 (1–13); 281 patients (55.1%) had both stations 10–14 and 1–9, median 7 (2–45). 85% of pN0 patients had &lt;10 LNs examined. 3-year survival estimate for the T1NxM0 vs T1N0M0 patients was 69% vs 70% (p= 0.14); for T2NxM0 vs T2N0M0 it was 25% vs 65% (p &lt;0.01). Conclusions: A high percentage of patients (11.5%) undergoing surgical resection for NSCLC had pNx. These patients were more likely to have sublobar resections. Most (85%) patients with pN0 had &lt;10 nodes examined and a large proportion (35.1%) had no mediastinal LNs, raising the possibility of understaging. Patients with pT2NxM0 did significantly worse than those with pT2N0M0. [Table: see text] [Table: see text]