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Abstract

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single‐cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno‐ and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single‐cell level are yet completely unknown. To study the cellular composition and single‐cell gene expression profiles in lung carcinoids, we applied single‐cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single‐cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in non‐inflammatory monocyte‐derived myeloid cells. Tumor‐associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer‐associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFβ and JAK/STAT signaling. Moreover, single‐cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single‐cell gene expression profiles in lung carcinoids, demonstrating the non‐inflammatory and vessel‐rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets. This article is protected by copyright. All rights reserved.

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... Of note, there was not a statistically significant difference in survival rates between patients with and without simultaneous pathological findings. It has been reported that monocyte-derived myeloid cells in lung carcinoid tissues have equal to slightly lower expression scores of numerous gene profiles associated with inflammation and the immune response when compared to normal tissues, indicating that the lung carcinoid immune microenvironment is predominated by non-inflammatory monocyte-derived myeloid cells, without mentioning if this finding is associated with better outcomes (43). However, it remains to be determined whether this finding is associated with improved outcomes. ...
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... The best performing classifier combined the colorectal cancer dataset from Lee et al. [29] with the lung cancer from Laughney et al. [27], and achieved a minimal balanced accuracy of 0.97 on the validation data. The performance of the best performing gene set was tested on the hepatocellular carcinoma [32] (balanced accuracy of 0.93), and the lung carcinoid dataset [33] (balanced accuracy of 0.99). ...
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Abstract Macrophages express several lysosomal cysteine proteases such as cathepsins and legumain. In this study, we assessed the expression, activity and secretion of legumain in cellular models of monocytes/macrophages. Macrophages were derived from M-CSF- or GM-CSF/IFNγ-stimulated human primary monocytes (M2 and M1, respectively), PMA-treated human THP-1 cells, or murine RAW264.7 macrophages. In both primary monocytes and THP-1 cells, monocyte-to-macrophage differentiation caused highly increased cellular expression and activity of legumain. Also, secretion of legumain from macrophages, but not from monocytes, was observed. Notably, M2 macrophages expressed significantly higher levels of active legumain than M1 macrophages, which are not previously reported. Legumain mRNA has been shown to be down-regulated in monocytes isolated from patients treated with the HMG-CoA reductase inhibitor atorvastatin. Interestingly, in our study, the active legumain produced by M2 macrophages was found to be inhibited by atorvastatin, which was reflected in aberrant cellular expression and processing.
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Pulmonary carcinoids comprise a well-differentiated subset of neuroendocrine tumors (NETs) usually associated with a favorable prognosis, but mechanisms underlying disease progression are poorly understood. In an explorative approach to identify pathways associated with progression, we compared gene expression profiles of tumors from 5 patients with a favorable and 5 with a poor disease outcome. Differentially expressed genes were validated using quantitative RT-PCR on 65 carcinoid tumors, in combination with survival analysis. One of the identified pathways was further examined using immunohistochemistry.As compared to other chromosomal locations, a significantly higher number of genes downregulated in carcinoids with a poor prognosis were located at chromosome 11q (P=0.00017), a region known to be frequently lost in carcinoids. In addition, a number of upregulated genes were found involved in the mitotic spindle checkpoint, the chromosomal passenger complex (CPC), mitotic kinase CDC2 activity, and the BRCA-Fanconi Anemia pathway. At the individual gene level, BIRC5 (survivin), BUB1, CD44, IL20RA, KLK12 and OTP were independent predictors of patient outcome. For survivin the number of positive nuclei was also related to poor prognosis within the group of carcinoids. Aurora B kinase and survivin, major components of the CPC, were particularly upregulated in high-grade carcinomas, and may therefore comprise therapeutic targets for these tumors.To our knowledge, this is the first expression profiling study focusing specifically on pulmonary carcinoids and progression. We have identified novel pathways underlying malignant progression and validated several genes as being strong prognostic indicators, some of which could serve as putative therapeutic targets.
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The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
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Background Lung cancer is made up of distinct subtypes, including non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information. Methods Using data from Surveillance, Epidemiology, and End Results (SEER) areas, we assessed lung-cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific subtypes (incidence-based mortality). We also evaluated lung-cancer incidence and survival according to cancer subtype, sex, and calendar year. Joinpoint software was used to assess changes in incidence and trends in incidence-based mortality. Results Mortality from NSCLC decreased even faster than the incidence of this subtype, and this decrease was associated with a substantial improvement in survival over time that corresponded to the timing of approval of targeted therapy. Among men, incidence-based mortality from NSCLC decreased 6.3% annually from 2013 through 2016, whereas the incidence decreased 3.1% annually from 2008 through 2016. Corresponding lung cancer–specific survival improved from 26% among men with NSCLC that was diagnosed in 2001 to 35% among those in whom it was diagnosed in 2014. This improvement in survival was found across all races and ethnic groups. Similar patterns were found among women with NSCLC. In contrast, mortality from SCLC declined almost entirely as a result of declining incidence, with no improvement in survival. This result correlates with limited treatment advances for SCLC in the time frame we examined. Conclusions Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances — particularly approvals for and use of targeted therapies — is likely to explain the reduction in mortality observed during this period.
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Purpose: Combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across several tumour types. Neuroendocrine tumors (NETs) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs. Experimental design: CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3mg/kg and ipilimumab at 1mg/kg every three weeks for four doses, followed by nivolumab 3mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate. Results: Twenty-nine patients with advanced NETs received treatment. Three patients (10%) had low, 13 (45%) intermediate and 13 (45%) high grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NENs) and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression free survival was 4.8 months (95% CI: 2.7, 10.5) and overall survival 14.8 months (95% CI: 4.1,21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events. Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high grade pancreatic NENs.
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Chapter
CCL4, a CC chemokine, previously known as macrophage inflammatory protein (MIP)-1β, has diverse effects on various types of immune and nonimmune cells by the virtue of its interaction with its specific receptor, CCR5, in collaboration with related but distinct CC chemokines such as CCL3 and CCL5, which can also bind CCR5. Several lines of evidence indicate that CCL4 can promote tumor development and progression by recruiting regulatory T cells and pro-tumorigenic macrophages, and acting on other resident cells present in the tumor microenvironment, such as fibroblasts and endothelial cells, to facilitate their pro-tumorigenic capacities. These observations suggest the potential efficacy of CCR5 antagonists for cancer treatment. On the contrary, under some situations, CCL4 can enhance tumor immunity by recruiting cytolytic lymphocytes and macrophages with phagocytic ability. Thus, presently, the clinical application of CCR5 antagonists warrants more detailed analysis of the role of CCL4 and other CCR5-binding chemokines in the tumor microenvironment.
Chapter
Within the tumor microenvironment, chemokines play a key role in immune cell trafficking regulation and immune landscape formulation. CCL3 or macrophage inflammatory protein-1α (MIP-1α), an important chemokine implicated in both immune surveillance and tolerance, has emerged as a prognostic biomarker in both solid and hematological malignancies. CCL3 exerts both antitumor and pro-tumor behavior which is context dependent highlighting the complexity of the underlying interrelated signaling cascades. Current CCL3-directed therapeutic approaches are investigational and further optimization is required to increase efficacy and minimize adverse events.
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Background: Pulmonary carcinoids (PCs) represent only a minority of all primary pulmonary malignancies but they are the most common type of pulmonary malignancy diagnosed in children and adolescents. In this nationwide study, we analyzed data on all PC tumours in the Icelandic population over a 60-year period and concentrated especially on incidence and patient outcomes. Methods: We studied all cases of PCs diagnosed in Iceland in the period 1955‒2015. Histological specimens were re-evaluated and the tumours were staged according to the TNM system (seventh edition). Survival was estimated using the Kaplan-Meier method, with a mean follow-up of 15.7 years. Results: Altogether, 88 patients (median age 51.0 years, 65.9% women) were diagnosed with PCs in the study period. The incidence increased from 0.19/100,000/year in the first decade (1955‒1964) to 0.58/100,000/year in the last decade (2005‒2015), with a mean increase of 29.0% per decade of the study period (p < 0.001). The rise in incidental detection was, however, not significant. The median tumour diameter was 2.2 cm (range 0.4‒7.0) and typical histology was seen in 74 patients (84.1%). The other 14 patients (15.9%) had atypical histology. In all, 90.9% of the patients underwent pulmonary resection, 81.2% of them with lobectomy, with all of them surviving at least 30 days postoperatively. Most patients (n = 52, 62.7%) were stage IA at diagnosis, 15 (18.1%) were stage IB, nine (10.8%) were stage IIA, and three were stage IIIA (3.6%). Four patients (4.8%) had distant metastases (stage IV), two of whom had typical histology. Five-year survival was 89.8% for all patients: 93.2% for patients with typical histology and 70.7% for those with atypical histology. Conclusion: The incidence of PCs in Iceland has increased significantly over the last six decades, which cannot be explained by a rise in incidental detection at chest imaging. Most patients have localized disease and a favourable histology, where the long-term outcome is excellent.
Article
Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.
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Carcinoids and large-cell neuroendocrine carcinomas (LCNEC) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g. MEN1), and few affect genes of the PI3K-AKT-mTOR pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of OTP/CD44, and upregulation of RET gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with bi-allelic inactivation of TP53 and RB1, a hallmark of small-cell lung cancer (SCLC); and the other one with bi-allelic inactivation of TP53 and STK11/KEAP1, genes that are frequently mutated in non-small cell lung cancer (NSCLC). These data, together with the identification of common mutations in the different components of combined LCNEC-NSCLC tumors, provides further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mTOR pathway mutations and response to mTOR inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, DLL3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.
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In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labelled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration (p<0.001), as well as with the severity of tumor-associated inflammation (p<0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator (p<0.01, hazard ratio 0.4 for overall survival, p<0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas and in this tumor entity PD-L1 expression in inflammatory cells is positively correlated to patient survival.
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To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies.
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In contrast to a prior emphasis on the finality of cell fate decisions in developmental systems, cellular plasticity is now emerging as a general theme in the biology of multiple adult organ systems. In the lung, lineage tracing has been used to identify distinct epithelial stem and progenitor cell populations. These cells, together with their differentiated progeny, maintain a stable identity during steady state conditions, but can display remarkable lineage plasticity following injury. This Review summarizes our current understanding of the different cell lineages of the adult mammalian lung and their responses to injury. In the lung, which is constantly exposed to infection and aerosolized toxins, epithelial plasticity might be more of a rule than an exception, and it is likely that different injuries elicit different facultative responses.
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The tyrosine kinome and phosphatome harbor oncogenes and tumor suppressor genes and important regulators of angiogenesis and tumor stroma formation. To provide a better understanding of their potential roles in cancer, we analyzed the expression of 85 tyrosine kinases and 42 tyrosine phosphatases by in situ hybridization in a total of 36,576 human normal and tumor tissue specimens. Nine-tenths of the assessed transcripts had tumor cell expression concordant with expression array databases. Further, pan-cancer expression of AATK, PTPRK, and PTPRU and expression of PTPRS in a subset of tumors were observed. To demonstrate tumor subcompartment resolution, we validated the predicted tumor stroma-specific markers HTRA1, HTRA3, MXRA5, MXRA8, and SERPING1 in situ. In addition, to known vascular and stromal markers such as PDGFRB, we observed stromal expression of PTK6 and TNS1 and vascular expression of INSR, PTPRF, PTPRG, PTPRU, and TNS1, of which INSR emerged as a tumor-specific vessel marker. This study demonstrates the feasibility of large-scale analyses to chart the transcriptome in situ in human cancers and their ability to identify novel cancer biomarkers. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Article
Pulmonary carcinoid tumors are rare low-grade malignant neoplasms and constitute 2-5% of all lung tumors. In this study, we aimed to determine the clinical presentations, types of surgery, long-term treatment outcomes and survival rates of patients diagnosed with carcinoid tumor treated surgically in our clinic. Patients operated in our clinic between 1992 and 2008 with confirmed or suspected diagnoses of carcinoid tumors were included in our study. Patients' hospital records were retrospectively analyzed. A total of 104 patients (age 19-71 years, mean 44±13 years, 2 SD) with pathologically confirmed carcinoid tumor were analyzed. A total of 84 patients (81%) were diagnosed as typical and the remaining 20 (19%) being atypical carcinoid tumor. As many as 24 patients (23%) were asymptomatic. The most frequent symptom was recurrent respiratory infection (35%). The most used surgical procedures were lobectomy (47%) and bilobectomy (16%). Mean postoperative follow-up period was 72 months (6-190 months). No surgery related mortality was noticed. As many as 15 (14%) patients died during the follow-up period. Overall 5- and 10-year survival rates were 89% and 72%, respectively. For typical carcinoid tumors, the 5- and 10-year survival rates were 92% and 83%, and for atypical carcinoids 73% and 46%, respectively (p<0.001). In our study, we noticed histological subtype, stage of the disease and the type of surgery performed to be prognostic factors of carcinoid tumors. Atypical carcinoid tumors tend to be more metastatic and had worse prognosis when compared with typical carcinoid tumors. We conclude that surgery is the best treatment of choice for carcinoid tumors, especially parenchyma-sparing procedures, because of their good mid- and long-term survival rates.
Article
Few published reports have examined the incidence and outcomes for patients with carcinoid lung tumors. The aim of the current study was to explore incidence, type of surgical treatment given, and outcome for patients with typical (TC) and atypical (AC) lung carcinoids in a national cohort (Norway). All lung-cancer patients diagnosed in the period 1993-2005 and who were reported to the Cancer Registry of Norway were identified. Biopsies or resection specimens were reviewed and reclassified according to the World Health Organization (WHO) 2004 classification. Surgically treated patients were staged according to the seventh edition of the pathological tumor-node-metastasis (pTNM) staging system. Of 26665 lung cancers registered during the period, 265 (1%) had carcinoid tumors, of which 11 were diagnosed coincidentally at autopsy. In the remaining 254 patients, TCs were found in 188 cases, and ACs were found in 59 cases; seven cases had unclassifiable carcinoids. Of the 217 resected tumors, 173 (80%) were TCs. General surgeons performed 94 resections, including 11 of 17 pneumonectomies. All six bronchial resections were performed by thoracic surgeons. Of the 33 operated patients who died during follow-up, 18 had metastatic carcinoid tumors, of which 10 (56%) were ACs. In 37 non-resected patients (15 with AC and seven with unclassifiable histology), metastatic or locally advanced disease (N=21, 12 of which were ACs) was the main cause of inoperability and death. Five-year survival for all patients was 92% for TC and 66% for AC; for resected patients, the survival rates were 96% and 79%, respectively. Carcinoids are rare malignant tumors and are, in most cases, resectable; the TC subgroup had better prognosis than the AC in univariate analyses. The main cause of death was metastasis/locally advanced tumor at presentation or recurrent disease following resection; both situations were three times more common in patients with AC.
Article
Typical pulmonary carcinoid tumors are well-differentiated neuroendocrine tumors that are associated with good patient survival rates, while atypical carcinoid tumors are more aggressive and have worse patient survival rates. Because these tumors rarely involve the thoracic lymph nodes at presentation, it is currently unknown to what extent the presence of thoracic lymph node metastases at the time of diagnosis influences patient survival. A computerized search of the medical records for pulmonary carcinoid tumor at the Mayo Clinic from 1976 to 1997 revealed 517 patients, from which we identified 36 patients with pulmonary carcinoid tumors involving regional thoracic lymph nodes but without distant disease. For each patient, we reviewed the tumor histology, stage, and outcome. In addition, because the histologic criteria for the diagnosis of carcinoid tumors had changed significantly during the time of the study, we reexamined all of the histologic specimens using the current World Health Organization (WHO) criteria for classifying pulmonary neuroendocrine tumors. After reclassification with the WHO criteria for neuroendocrine tumors, 23 patients had typical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, 19 patients had no evidence of disease (NED), 2 patients had developed systemic metastases (SM) and are still alive, and 2 patients had died. Eleven patients had atypical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, four patients had NED, seven patients had developed SM within a median time of 17 months, and six patients with SM died shortly thereafter (median survival time, 25.5 months), while one is still alive. Two patients had been reclassified with large cell neuroendocrine carcinoma at the time of this review; both of these patients had developed SM (at 4 months and 21 months after diagnosis) and had died (at 15 months and 21 months after diagnosis, respectively). These data suggest that patients with atypical pulmonary carcinoid tumors with regional lymph node metastases have a high likelihood of developing recurrent disease if treated with surgical resection alone and have significantly worse outcome (p < 0.001) compared to those patients with typical carcinoid tumors with thoracic lymph node involvement.
Article
RGS proteins finely tune heterotrimeric G-protein signaling. Implying the need for such fine-tuning in the developing vascular system, in situ hybridization revealed a striking and extensive expression pattern of Rgs5 in the arterial walls of E12.5-E17.5 mouse embryos. The distribution and location of the Rgs5-positive cells typified that of pericytes and strikingly overlapped the known expression pattern of platelet-derived growth factor receptor (PDGFR)-beta. Both E14.5 PDGFR-beta- and platelet-derived growth factor (PDGF)-B-deficient mice exhibited markedly reduced levels of Rgs5 in their vascular plexa and small arteries. This likely reflects the loss of pericytes in the mutant mice. RGS5 acts as a potent GTPase activating protein for Gi(alpha) and Gq(alpha) and it attenuated angiotensin II-, endothelin-1-, sphingosine-1-phosphate-, and PDGF-induced ERK-2 phosphorylation. Together these results indicate that RGS5 exerts control over PDGFR-beta and GPCR-mediated signaling pathways active during fetal vascular maturation.
Article
To evaluate type of surgery, long-term survival and factors influencing outcome in pulmonary carcinoid tumors. We reviewed data of 252 patients who underwent surgery for carcinoid tumor in 1968-1989 (Group A) and in 1990-2005 (Group B). All cases were reviewed and classified as typical (TC) or atypical carcinoid (AC) according to WHO criteria (1999). There were 174 (69%) patients with TC (167 N0, 6 N1 and 1 N2) and 78 (31%) with AC (56 N0, 13 N1, 9 N2). Surgery consisted of 163 (64.7%) formal lung resections (121 lobectomies, 18 bilobectomies, 14 segmentectomies, 10 pneumonectomies), 76 (30.1%) sleeve or bronchoplastic resections and 13 (5.2%) wedge resections. No perioperative mortality occurred, 17 (6.7%) patients experienced complications. Overall 5, 10 and 15-year survival rate was 90%, 83% and 77%. TC showed a more favourable prognosis than AC (10-year survival rate 93% and 64%; p=0.00001) as well as N0 patients in comparison with N1-2 patients (10-year survival rate 87% and 50%; p=0.00005). Group A received lymph-node sampling, Group B received a systematic lymphadenectomy. No difference was found between Group A and B in detection of nodal metastases (10.9% versus 11.9%; p=0.79), but in Group A we observed 2 lymph-node relapses. In Group B number of sleeve resections significantly increased (2.7% versus 20.4%; p=0.0001) and number of pneumonectomies showed a significant reduction (7.2% versus 1.4%; p=0.01). Typical histology and N0 status were important prognostic factors in carcinoid tumors. Parenchyma-sparing procedures must be considered the treatment of choice with systematic lymphadenectomy.