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Background/aim: Tracheobronchial adenoid cystic carcinoma (ACC) is a rare type of malignancy. Although complete resection is standard treatment for localized ACC, treatment for unresectable ACC has not been established. It is unclear whether concurrent chemoradiotherapy (CCRT) followed by immune checkpoint inhibitor (ICI) therapy is effective for ACC., Case Report: A 49-year-old man was admitted to our hospital for the treatment of dyspnea and thickening of the bronchial wall from the tracheal carina to the left main bronchus, as observed on a CT scan. Systemic examinations and transbronchial biopsy led to a diagnosis of locally advanced ACC. Although radiotherapy and chemotherapy are not regarded as very sensitive for ACC, a favorable response was obtained with CCRT. Following CCRT, he received ICI therapy with durvalumab for 1 year. The patient has remained in a stable condition 18 months after therapy, with no recurrence., Conclusion: ICI after CCRT might be a promising treatment option for unresectable tracheobronchial ACC., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68 Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35)., Competing Interests: RP: Consultant: Ferring, Ipsen, Novartis, Pfizer, ViroPharma-Shire; Speaker: Novartis, ViroPharma-Shire; Research support: Corcept Therapeutics, Novartis, ViroPharma-Shire; Grant support: IBSA, Novartis, Pfizer, ViroPharma-Shire. PM: Consultant: Atlas, Alessa, EpiAxis, Rascal and AstraZeneca. MT: Consultant: HRA Pharma; Research support: Corcept Therapeutics. CS: Consultant: Ipsen, ViroPharma-Shire. UB: Consultant: Corcept Therapeutics; Employee: Sygnature Discovery, Ltd. AM: Employee: Corcept Therapeutics. The authors declare that the studies received funding from Corcept Therapeutics (Menlo Park, CA, USA). The funder had a role in study design, data collection and analysis. MA was employed by the company Corcept Therapeutics and, as an author of the manuscript and employee of Corcept Therapeutics, had a role in the study design, the decision to publish, the interpretation of clinical data, the revision of the manuscript, and approval of the final manuscript to submit. UB was employed by the company Sygnature Discovery Ltd. and, as an author of the manuscript and employee of Sygnature Discovery Ltd., supported by the funder, had a role in the preclinical data analysis and interpretation, decision to publish, revision of the manuscript, and approval of the final manuscript to submit. Open Access publication fees were paid by Corcept Therapeutics., (Copyright © 2022 Pivonello, Munster, Terzolo, Ferrigno, Simeoli, Puglisi, Bali and Moraitis.)

Sodium selenite is often given to moderate the side effects of cancer therapy to enhance the cellular defence of non-cancerous cells. To determine whether sodium selenite during radiotherapy protects not only normal cells but also cancer cells, which would imply a reduction of the desired effect of irradiation on tumour during radiotherapy, the effect of the combined treatment of irradiation and sodium selenite was investigated. Human bronchial cells from carcinoma (A549) and normal tissue (BEAS-2B) were treated with sodium selenite and effects on growth and in combination with radiation on metabolic activity and cell cycle distribution were studied. The influence on radiosensitivity was determined via colony forming assays using different solvents of sodium selenite and treatment schedules. It was shown that sodium selenite inhibits growth and influences cell cycle distribution of both normal and tumour cells. Metabolic activity of normal cells decreased more rapidly compared to that of cancer cells. The influence of sodium selenite on radiation response depended on the different treatment schedules and was strongly affected by the solvent of the agent. It could be shown that the effect of sodium selenite on radiation response is strongly dependent on the respective experimental in vitro conditions and ranges from lead to an initially suspected but ultimately no real radioprotection to radiosensitizing up to no effect in one and the same cell line. This might be a reason for controversially described cell responses to radiation under the influence of sodium selenite in studies so far.

The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope of this work is the presentation and discussion of problems encountered during this process. Briefly, the radiolabelling process and purification, as well as the quality control published, did not meet the expectations. The constant effort setting up an automated radiolabelling procedure resulted in (a) an enhanced manual method using coated glass reactors, (b) a combination of three different reliable radio thin-layer chromatography (TLC) methods instead of the published and (c) a preliminary radio high-pressure liquid chromatography (HPLC) method for identification of the compound. Additionally, an automated radiolabelling process was developed, but it requires further improvement, e.g., in terms of a reactor vessel or purification of the crude product. The published purification method was found to be unsuitable for clinical routine, and an intense screening did not lead to a satisfactory result; here, more research is necessary. To sum up, implementation of DOTA-ZOL was possible but revealed a lot of critical points, of which not all could be resolved completely yet.

Competing Interests: The authors declare that they have no conflict of interest.

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

Recurrent respiratory papillomatosis is an infrequent benign neoplasm that commonly affects the upper airway with a predilection for the larynx. Isolated tracheobronchial involvement is very rare. Diagnosis and treatment of this disease is a challenge due to its non-specific clinical manifestation and its recurrent nature. We present a 6-year-old male with a diagnosis of asthma refractory to treatment, without history or evidence of laryngeal papillomatosis. The endoscopic examination revealed extensive tracheobronchial papillomatosis and the computed tomography, pulmonary involvement. He received adjuvant therapy with intravenous Bevacizumab with very good response. We alert pediatricians to consider this rare tracheobronchial neoplasm in all children with atypical asthma symptoms or in those who do not improve with conventional medical treatment., (Sociedad Argentina de Pediatría.)

Ewing sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET), a member of the Ewing sarcoma family of tumors, is a malignant soft tissue tumor with small undifferentiated neuroectodermal cells. Primary trachea-bronchial ES/pPNET is very rare. The most common pulmonary ES is due to a metastasis. We describe a case of ES/pPNET which originated in the left basal trunk bronchus. The patient was a 30-year-old male, presenting with irritable cough and fever for 10 days. A tumor of 60 mm in diameter was found in the left basal trunk bronchus, extending to the left lower lobe. No distant metastases were detected. Histopathological examination revealed a malignancy of ES/pPNET with a diffuse proliferation of round cells, a Flexner-Wintersteiner rosette formation and positive staining for CD99. The patient was successfully treated with a combination of left lower lobectomy and adjuvant chemotherapy and has remained disease-free for approximately 18 months at follow-up. This case highlights that ES/pPNET should be considered as a differential diagnosis in cases of trachea-bronchial tumors., (Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The purpose of the present study was to develop gefitinib-loaded polymeric foams that can be used as coating of drug-eluting stents for palliative treatment of bronchotracheal cancer. Release of such an anticancer drug from such stent coating can retard tumor regrowth into the bronchial lumen. Gefitinib-loaded polyurethane (PU) foams were prepared by embedding either gefitinib micronized crystals or gefitinib-loaded poly(lactic-co-glycolic acid) microspheres in water-blown films, with up to 10% w/w loading for gefitinib microcrystals and 15% w/w for gefitinib microspheres (corresponding to 1.0% w/w drug loading). Drug-release studies showed sustained release of gefitinib over a period of nine months, with higher absolute release rates at higher drug loading content. By the end of the studied nine month release periods, 60-100% of the loaded gefitinib had been released. Foams loaded with gefitinib-PLGA microspheres at 15% w/w showed accelerated drug release after 4 months, coinciding with the degradation of PLGA microparticles in the PU foam as demonstrated by scanning electron microscopy (SEM). When applied on a nitinol braided bronchotrachial stent, PU coatings with gefitinib microspheres showed similar mechanical properties as the drug-free PU coating, which indicated that the loading of microspheres did not affect the mechnical properties of the PU foams. In conclusion, we have fabricated drug-loaded PU foams that are suitable for bronchotracheal stent coating., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Everolimus was recently approved for the treatment of neuroendocrine tumors. However, its efficacy and tolerability in hemodialysis patients with end-stage renal disease is not established., Case Presentation: We describe the case of a 47-year-old man with end-stage renal disease who received everolimus plus Lanreotide for 9 months for the management of metastatic atypical bronchial carcinoid., Conclusions: Everolimus is a treatment option for hemodialysis patients with metastatic atypical bronchial carcinoid. Based on our case report and review of literature, Everolimus does not require any dose reductions and is overall well tolerated in hemodialysis patients.

Introduction: Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%-30% of all neuroendocrine tumors and 2%-3% of all adult lung cancers. Here, they present a large case series of well-differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long-term outcomes., Methods: A retrospective review was performed of 105 patients with bronchial NETs managed in a tertiary referral center in the period between January 1998 and January 2012., Results: Bronchial NETs are commoner in females and the commonest presenting symptoms were cough (13.9%) and dyspnoea (11.6%). Octreoscan TM and Gallium-68 DOTATATE PET were found to have similar diagnostic sensitivity and FDG PET was more sensitive for higher-grade tumors. Over a median follow-up period of 35.5 months mortality rate was 5.7%. The 5-year survival was 76% and the 10-year survival was 62%. Female patients survived longer but this difference was not statistically significant (P = .59). Older age greater than 50 years (P = .027), higher levels of Chromogranin A (CgA) (P = .034), first-line treatment with surgery (P = .005), ki67 over 10% (P = .037), and tumor stage (P = .036) but not tumor grade (P = .22), were significantly associated with survival., Discussion: Several factors have been identified which are independently associated with survival including CgA levels greater than 100 pmol/L, tumor stage, age greater than 50, ki67 over 10% and having surgery as first-line treatment. There was no difference in survival between typical and atypical carcinoids., (© 2016 John Wiley & Sons Ltd.)

Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib.

The endobronchial localization of Hodgkin's disease is a rare entity which is often confused with endobronchial tuberculosis in our setting. We report the case of a 16 years old female who presented with 6 months history of dry cough, hemoptysis, dyspnea, dysphagia and dysphonia. The chest radiography showed a mediastinal and pulmonary opacity. The chest CT scan found enlarged mediastinal lymph nodes. The bronchial biopsy and peripheral lymph node biopsy confirmed Hodgkin's disease with endobronchial localization. The patient received chemotherapy (ABVD protocol) and radiotherapy with a favorable follow up.

Background: Photodynamic therapy (PDT) has several advantages. However, one of the disadvantages is its inability to be individualized according to biological characteristics of malignant tumors. The objective of this study was to investigate a strategy for individualized endobronchial PDT in the treatment of centrally located non-small cell lung cancer., Methods: New approach suggests taking fluorescence-based measurements of chlorine E6 photosensitizer (PS) accumulation in the malignant tumor tissue, and assess PS consumption rate during PDT. Two randomized groups of 45 patients took part in the comparative study of standard PDT procedure, 662nm, pulse-periodic mode, therapeutic light (reference group - RG) versus the investigated individualized approach under fluorescence control after irradiation with violet light, 408nm, diagnostic light (study group - SG). The PDT-treatment parameters and results of follow-up bronchoscopy were compared between the groups., Results: 43 (96%) of 45 patients in SG demonstrated intense fluorescence in the area of the tracheal/bronchial tumor stenosis. 4 (9%) of 45 patients (SG) demonstrated fluorescence of mucosa areas distant from the main tumor lesion after violet light irradiation. Mean fluence during the whole PDT procedure was 95±20J/cm 2 (range 60-130J/cm 2 ), which was significantly lower than in RG (p=0.01). Total exposure time was significantly lower in SG (365±65s), compared with RG (690±65s), P=0.001. According to the follow-up bronchoscopy the difference in the PDT-treatment results between the groups is statistically insignificant., Conclusions: The investigated strategy suggests using fluorescence control of the efficacy of PDT-treatment (photodynamic theranostics) to optimize and individualize the PDT procedure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Thymic carcinoma is a rare cancer, accounting for only 1% to 4% of thymic epithelial tumors. Endobronchial metastasis is a rare presentation of these tumors. A 64-year-old man presented with a cough. Lung cancer was suspected because a chest radiograph showed a 7-cm mass in the left pulmonary hilum. Computed tomography showed a mass in the anterior mediastinum and an infiltrate in the upper lobe of the left lung. Bronchoscopy demonstrated bilateral polypoid tumors in the left B bronchus and the right B bronchus. Endobronchial biopsies of both lesions resulted in a diagnosis of squamous cell carcinoma that was positive for c-KIT by immunohistochemical staining. The patient was eventually found to have thymic squamous cell carcinoma with bilateral endobronchial metastases (stage IVb according to the Masaoka-Koga staging system) by diagnostic video-assisted thoracoscopic surgery. He was subsequently treated with platinum-doublet chemotherapy and achieved a partial response for 18.8 months.

Myeloid sarcoma (MS) is an extramedullary myeloid neoplasm characterized by proliferation of myeloblasts which can occur in any organ or site. Bronchial and pulmonary involvement, however, is uncommon. We describe a case of bronchial MS in an 81-year-old female with a history of high-grade myelodysplastic syndrome; she was started on treatment few months before, and she presented with fever, cough and profuse hemoptysis. She was found to be pancytopenic with bilateral airspace consolidations, most notably in the right upper and lower lobes, on imaging studies. She was treated with broad-spectrum antibiotics and antifungals without much improvement in her clinical or radiological status. Ultimately, biopsy of the lung lesions showed myeloid sarcoma with concurrent Aspergillus fumigatus infection. Bronchial/pulmonary MS should be considered in the list of differential diagnoses in a patient with a history of myeloid neoplasm and presenting with respiratory related symptoms, as early administration of chemotherapy may help to improve survival rates.

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

There are summarized the foreign and domestic references of recent years devoted to methodology and the efficiency of the use of intraluminal high-dose radiation brachytherapy in patients with lesions of the central bronchi and trachea caused by primary and metastatic malignant tumors. It is presented own experience of applying this method in 207 patients. It is showed that in some patients to ensure the delivery of the radiation source to the area of interest it is advisable to perform firstly endotraheobronhial surgery with recanalization of the lumen of the respiratory pathways. The best is the use of intraluminal brachytherapy with high dose radiation. Palliative intraluminal irradiation of inoperable patients allowed achieving a good immediate results (65-95%), a significant reduction of the main symptoms--hemoptoe (87-95%), dyspnea (75-90%), obstructive pneumonia phenomena (50-85%), and significantly increasing survival median from 1-3 to 9-14 months. Following performance of chemoradiotherapy permitted increasing the survival median up to 15-20 months. The number of complications of intraluminal high-dose radiation brachytherapy was small, usually--pulmonary hemorrhage (2-7%) more likely developing when using large fractions--more than 10 g for 1 session.

The authors present a case of a 81-year-old non-smoker woman who was diagnosed with extended, bilateral bronchial adenocarcinoma in 2008. Two years later the tumor showed marked progression. EGFR sensitizing mutation (exon 19 deletion) was detected and gefitinib treatment was started in March 2010. After 12 months of spectacular and complete remission and 8 months of slow progression docetaxel therapy was applied and yielded partial remission. When progression redeveloped rebiopsy was performed and revealed EGFR exon 19 deletion again. Gefitinib retreatment was introduced in February 2013 and resulted in partial remission with excellent clinical status. In March, 2014 the patient is still on gefitinib treatment without any signs or symptoms of lung cancer but with very slow radiological progression. The authors overview the most important theoretical and practical questions regarding rebiopsy and retreatment in lung cancer with EGFR-TKI therapy.

A 59-year-old man was admitted to our hospital with dyspnea and cough. A large polypoid tumor was observed in the lower trachea and bronchoscopic polypectomy was performed using a snare to relieve symptoms. The tumor was diagnosed as a high grade mucoepidermoid carcinoma mainly by the histology of piecemeal specimens obtained by bronchoscopic resection. The primary lesion involved the trachea and the main bronchus, and there were multiple metastases in the lung. The patient was treated with the combination of carboplatin and paclitaxel. After four cycles of chemotherapy, the tumors were significantly reduced. He remains well without evidence of tumor progression for 25 months. This case suggests that the combination chemotherapy of carboplatin and paclitaxel can be an option for treatment of pulmonary mucoepidermoid carcinoma.

The innovation of thoracic interventions, such as endobronchial ultrasound and photodynamic ablation, has changed the interventional management of lung cancer. In this case report, we discuss the case of a successful treatment of endobronchial squamous cell carcinoma occluding the left upper lobe bronchus by a minimally invasive transbronchial approach. This case was initially planned for a sleeve left upper lobectomy. The careful assessment of radiological and ultrasonographic imaging concluded that the tumor was early-stage lung cancer. Multimodal endobronchial treatment cured the lung cancer without a thoracotomy. Pulmonary function was well preserved and no recurrence was found for more than 5 years. Even in the presence of a bulky endobronchial tumor, if there is no clear evidence of extraluminal invasion by computed tomography scan, a local bronchoscopic staging of the disease is mandatory.

Objective: To investigate the effectiveness and side effects of photofrin-photodynamic therapy (PDT) for intractable bronchial lung cancer., Methods: Thirty patients were classified as stage II-IV intractable bronchial lung cancer with lumen obstruction after they failed previous treatment regimens such as surgery, radiotherapy and chemotherapy. PDT was performed with 630 nm laser light (Diomed) delivered through cylinder diffusing tip quartz fibers that was passed through the biopsy channel of a flexible endoscope 48 h after intravenous injection of the photosensitizer photofrin (2mg/kg body weight). 72 h after the first irradiation, the endoscopic procedure was repeated, necrotic tissues were mechanically removed and the deep original lesions and newly exposed cancer lesions were re-treated, and, if necessary, the areas were cleaned repeatedly., Results: The total response rate CR+PR was 86.7%, and the mean percentage of obstruction due to tumors at different treated sites decreased from 90% to 16.7% at discharge after PDT. The KPS score was significantly improved after PDT., Conclusions: PDT of intractable bronchial lung cancer effectively reduces the amount of lumen obstruction, and improves the patient's quality of life. It may be an effective palliative treatment with minor side effects on patients with advanced bronchial lung cancer., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A study of olfactory function was performed in 15 bronchial cancer patients receiving cisplatin and 15 control subjects. Whereas odor detection and odor identification abilities were not influenced by the administration of cisplatin, a decrease in pleasantness was observed only for food odors, and not for non-food odors. Taken as a whole, these findings suggest that cisplatin therapy in bronchial cancer patients impairs the pleasure of perceived food odors, which may account for disturbances in food intake and quality of life in this population., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids., Methods: In vitro studies were used for the dose-response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase)., Results: Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0-80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content., Conclusions: The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids.

A 3-year-old neutered male Australian Shepherd mix dog presented with metastatic soft tissue sarcoma arising from a primary tumor in the left lumbar fascia. Two separate metastases to the lungs were characterized by neoplasia within bronchiolar walls, which caused obstruction of the bronchiolar lumina and atelectasis of adjacent alveoli, a characteristic feature of endobronchial metastasis. Neoplastic cells of the primary lumbar neoplasm, metastatic pulmonary lesions, and additional widespread metastatic masses identified postmortem were similarly immunoreactive for vimentin, but non-immunoreactive for cytokeratin, cluster of differentiation 18, synaptophysin, chromogranin, and desmin. The present report describes a naturally occurring case of endobronchial metastasis in a dog.

A 63-year old woman diagnosed in September 2001 with a typical bronchial carcinoid of the left upper lobe bronchus extending into the left main stem bronchus is presented. The patient was unsuitable for standard surgical treatment, and the topography was not amenable for a parenchyma-saving bronchoplastic procedure. Two cycles of bronchoscopic photodynamic therapy (PDT) were undertaken at 6 monthly intervals. The patient has now been followed up regularly for over 10 years without signs of recurrence bronchoscopically or radiologically. To our knowledge, this is the first case of a carcinoid tumour treated solely by PDT.

Currently, adenocarcinoma represents 41 % of primary lung cancers in women and 34 % in men. Thyroid metastases of lung cancer are rare and usually asymptomatic. We report the case of a patient presenting with stridor secondary to an enlarged multiple nodular thyroid accompanied by cervical lymphadenopathies accompanied by an enlarged and multiple nodular thyroid and by stridor. The final diagnosis was thyroid metastases of primary lung adenocarcinoma.

Cystic lung metastases are a rare presentation in non-small cell lung cancer and occurs mainly in squamous cell carcinoma. We present the case of a 57-year-old woman with a lung squamous cell carcinoma and cystic lung metastases, who developed bilateral metachronous pneumothorax while being administered erlotinib in third-line treatment. The apparition of a pneumothorax under chemotherapy is most often the result of tumor necrosis and formation of bronchopleural fistula. However, very few cases have been reported under targeted therapies, and to our knowledge this is the first case under erlotinib. This complication is potentially life-threatening, especially due to the possibility of pneumothorax bilateralization.

Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value., Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1., Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1)., Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients., (Copyright © 2013 S. Karger AG, Basel.)

Carcinoids are neuroendocrine malignancies characterized by their overproduction of various bioactive hormones that lead to the carcinoid syndrome. We have shown previously that AKT serves as a key regulator of growth and phenotypic expression of tumor markers in carcinoids by the genetic depletion of AKT expression. However, no small-molecule inhibitor of AKT kinase activity has been developed until recently. MK-2206, a novel allosteric inhibitor of AKT, is currently undergoing clinical trials for the treatment of solid tumors. In this study, we explored the effect of MK-2206 on carcinoid cell proliferation and bioactive hormone production in vitro in two carcinoid cell lines - pancreatic carcinoid BON and bronchopulmonary H727. Treatment with MK-2206 effectively suppressed AKT phosphorylation at serine 473 and significantly reduced cell proliferation in a dose-dependent manner. Most importantly, MK-2206 treatment resulted in a significant reduction in ASCL1, CgA, and NSE expression, collectively recognized as markers of neuroendocrine tumor malignancy. Furthermore, MK-2206-treated cells showed an increase in levels of cleaved PARP and cleaved caspase-3, with a concomitant reduction in levels of Mcl-1 and XIAP, indicating that the antiproliferative effect of MK-2206 occurs through the induction of apoptosis. In conclusion, MK-2206 suppresses carcinoid tumor growth, and alters its neuroendocrine phenotype, indicating that this drug may be beneficial for patients with carcinoid syndrome. These studies merit further clinical investigation., Competing Interests: of Potential Conflicts of Interest: No potential conflicts of interest were disclosed.

Acromegaly resulting from the ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. We present a case of acromegaly secondary to proven GHRH-secretion by a bronchial carcinoid tumor in a type 1 diabetic subject and document the clinical course pre- and post-resection of the tumor and of subsequent octreotide therapy. A 54-year-old Caucasian man was referred for evaluation of acromegalic symptoms and significantly increased insulin requirements. He had a history of left lung surgery 20 years prior for hemoptysis. Initial laboratory results indicated acromegaly. Fasting serum growth hormone (GH): 26.1 ng/mL (0-5 ng/mL), insulin-like growth factor 1 (IGF-1): 635 ng/mL (87-283 ng/mL), GH at 60 min post-ingestion of 75 grams of oral glucose during a glucose tolerance test: 8.3 ng/mL (normal <1 ng/mL). Pituitary magnetic resonance imaging (MRI) revealed diffuse pituitary enlargement without adenoma. A 4.4 cm left hilar mass was noted on chest computed tomography (CT) scan. Further evaluation for a suspected GHRH-secreting neuroendocrine tumor was pursued. Plasma GHRH level was elevated: 198 pg/mL (<50 pg/mL). Octreoscan showed radiolabelled-octreotide uptake in the left lung mass and pituitary gland. Surgical resection of the lung mass was performed. Immunohistochemical study of the tumor tissue indicated a neuroendocrine tumor secreting GHRH. Postoperatively, serum GHRH, GH and IGF-1 levels fell precipitously. At 10 months, IGF-1 levels were mildly elevated and 7 months of 10 mg long-acting octreotide therapy (Sandostatin(®) LAR(®)) was trialed. At 20 months, off octreotide, serum IGF-1 levels had normalized, acromegalic features were receding, and the patient's daily insulin requirements had decreased by 57%.

The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3α/β, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3α/β, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

Neuroendocrine tumours (NETs) are a rare and heterogeneous group of tumours whose incidence is increasing and their prevalence is now greater than that of any other upper gastrointestinal tumour. Diagnosis can be challenging, and up to 25% of patients present with metastatic disease. Following the recent FDA approval of two new molecularly targeted therapies for the treatment of advanced pancreatic NETs (pNETs), the first in 25 years, we review all systemic therapies and suggest where these newer targeted therapies fit in the treatment schedule for these challenging tumours. Clinical trial data relating to the routine use of sunitinib and everolimus in low-intermediate-grade pNETs are summarised alongside newer molecularly targeted agents undergoing clinical assessment in NETs. We particularly focus on the challenge of optimal scheduling of molecularly targeted treatments around existing systemic and localised treatment such as chemotherapy or radiotargeted therapy. We also discuss application of current evidence to subgroups of patients who have not so far been directly addressed such as those with poorer performance status or patients receiving radical surgery who may benefit from adjuvant treatment.

Objective: Endobronchial metastases (EBM) secondary to extrapulmonary solid malignant tumors are rare but may occur. The most common extrathoracic malignancies associated with EBM are colorectal, renal and breast cancer. This study aimed to evaluate the clinicopathological aspects of EBM from breast cancer and the prognosis of the patients., Methods: Clinicopathological data of 11 cases diagnosed as EBM from breast cancer treated in our hospital from 2003 to 2010 were re-evaluated. Their symptoms, recurrence interval, radiological features, histopathological properties, and prognosis were assessed., Results: Eleven cases were diagnosed by bronchoscopic bronchial biopsy. The median interval from diagnosis of breast cancer was 57 months (range: 11 - 189 mo). All patients had other proven metastases when the EBM was diagnosed. The most frequently observed symptoms were cough (8 cases). Interestingly, two patients were asymptomatic. Hilar mass (5 cases) was a common radiological finding. No disaccordance between the hormone receptor status in the primary and metastatic lesions in these patients was found. The median survival after EBM diagnosis was 21 months (range: 6 - 36) with four patients still alive and one of these four patients was surviving more than 7 years., Conclusions: On average, EBM is diagnosed about 5 years after the diagnosis of breast cancer, which is a relatively long lead time, but the median survival time is short, as 21 months in our group. The treatment plan must be individualized, because in some cases, long-term survival can be expected.

Non-Hodgkin lymphoma generally affects the thorax in nearly half of the cases, but endobronchial non-Hodgkin lymphoma is rare. A 65-year-old man presented with refractory cough and progressive dyspnea on exertion of 2 months' duration. The patient denied fever, weight loss, or night sweats. A chest x-ray revealed bilateral lower lobe infiltrates. A computed tomography scan of the chest revealed large matted mediastinal lymph nodes without clear margination. Bronchoscopic examination revealed bilateral endobronchial diffuse nodular lesions. Bronchial mucosal biopsy demonstrated B-cell lymphoma. The patient was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with near-total resolution of endobronchial and parenchymal lesions.