Tracheobronchial Adenoid Cystic Carcinoma Treated Successfully With Chemoradiotherapy Followed by Durvalumab: A Case Report.

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.

Mucoepidermoid carcinoma cured by a combination of high-frequency snare and photodynamic therapy: A case report.

Mucoepidermoid carcinoma (MEC) is a rare salivary gland tumor, accounting for 0.2% of all lung tumors. The standard treatment for MEC of the primary bronchus is surgery, although intraluminal bronchoscopic treatment has recently become an option. A 68-year-old man presented with an asymptomatic bronchial tumor in the right intermediate bronchus. The tumor was resected using a high-frequency snare (HFS) during bronchoscopy, and the specimen was pathologically diagnosed as low-grade MEC. A residual lesion was detected in the resected area by autofluorescence imaging. The tumor appeared to be localized within the subepithelial layer without metastases, and photodynamic therapy (PDT) was performed as a local treatment. The patient had no recurrence for 18 months. PDT is effective and safe for patients with centrally located early-stage lung cancer, but there are few reports of its use for rare tumors, such as MEC. In this case, PDT allowed for local control and avoided surgery, including bronchoplasty, for MEC. Combined treatment of tumor reduction by HFS and PDT of the residual lesion may be an optimal treatment for MEC of the bronchus.

Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant.

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 68Ga-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).

The solvent and treatment regimen of sodium selenite cause its effects to vary on the radiation response of human bronchial cells from tumour and normal tissues.

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.

DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis-Challenges and Critical Points in Implementation into Clinical Routine.

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.

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane.

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.

[Tracheobronchial and pulmonary papillomatosis without involvement of the larynx treated with intravenous Bevacizumab in a child]. / Papilomatosis traqueobronquial y pulmonar sin compromiso de la laringe tratada con bevacizumab endovenoso en un niño.

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.

La papilomatosis respiratoria recurrente es una neoplasia benigna infrecuente que, comúnmente, afecta la vía aérea superior con predilección por la laringe. El compromiso traqueobronquial aislado es muy raro. El diagnóstico y el tratamiento de esta enfermedad constituyen un desafío, debido a su manifestación clínica inespecífica y su naturaleza recurrente. Se presenta a un varón de 6 años con diagnóstico de asma refractario al tratamiento, sin historia ni evidencia de papilomatosis laríngea. El examen endoscópico reveló papilomatosis traqueobronquial extensa, y la tomografia computada, compromiso pulmonar. Recibió terapia adyuvante con bevacizumab endovenoso, con muy buena respuesta.Se alerta a los pediatras para considerar esta rara neoplasia traqueobronquial en todo niño con síntomas de asma atípicos o que no mejoran con el tratamiento médico convencional.

Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumors in Bronchus.

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.

Efficacy and safety of everolimus treatment in a hemodialysis patient with metastatic atypical bronchial carcinoid: case report and literature review.

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.

Well-differentiated bronchial neuroendocrine tumors: Clinical management and outcomes in 105 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%). OctreoscanTM 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.

Erlotinib for coexisting typical bronchial carcinoid and advanced lung adenocarcinoma: does the epidermal growth factor receptor mutation status matter?

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.

Fabrication and characterization of gefitinib-releasing polyurethane foam as a coating for drug-eluting stent in the treatment of bronchotracheal cancer.

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.

Endobronchial localization of Hodgkin's disease.

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.

Endobronchial photodynamic therapy under fluorescence control: Photodynamic theranostics.

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/cm2 (range 60-130J/cm2), 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.

Thymic Carcinoma With Endobronchial Metastasis: A Case Report.

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.