Bronchial Tumors Research Articles

Signalling with retinoids in the human lung: validation of new tools for the expression study of retinoid receptors

BackgroundRetinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumors have failed. Therefore, the pertinence of new clinical trials using second generation retinoid requires prior better understanding of retinoid signalling. This is our aim when validating extensively research tools, focused on Retinoic Acid Receptor beta, whose major role in lung cancer is documented.MethodsBiocomputing was used to assess the genomic organization of RAR beta. Its putative RAR-beta1' promoter features were investigated experimentally. Specific measures realized, with qRT-PCR Syber Green assays and a triplex of Taqman probes, were extensively validated to establish Retinoid Receptors mRNAs reference values for in vivo normal human bronchial cells, lung tumors and cell lines. Finally, a pan-RAR-beta antibody was generated and extensively validated by western-blot and immunoprecipitation.ResultsNo promoter-like activity was found for RAR-beta1'. RAR-beta2 mRNAs increase signs the normal differentiation of the human bronchial epithelium while a decrease is observed in most lung cancer cell lines. Accordingly, it is also, along with RXR beta, down-regulated in lung tumors. When using nuclear extracts of BEAS-2B and normal lung cells, only the RAR-beta2 long protein isoform was recognized by our antibody.ConclusionRigorous samples processing and extensive biocomputing, were the key factors for this study. mRNA reference values and validated tools can now be used to advance researches on retinoid signalling in the lung.

Functional imaging in differentiating bronchial masses: an initial experience with a combination of 18F-FDG PET-CT scan and 68Ga DOTA-TOC PET-CT scan

To evaluate the role of combination of (18)F-FDG PET-CT scan and (68)Ga DOTA-TOC PET-CT scan in differentiating bronchial tumors observed in contrast enhanced computed tomography scan of chest. Prospective observational study. Place of study: All India Institute of Medical Sciences, New Delhi, India. 7 patients with bronchial mass detected in computed tomography scan of the chest were included in this study. All patients underwent (18)F-FDG PET-CT scan, (68)Ga DOTA-TOC PET-CT scan and fiberoptic bronchoscope guided biopsy followed by definitive surgical excision. The results of functional imaging studies were analyzed and the results are correlated with the final histopathology of the tumor. Histopathological examination of 7 bronchial masses revealed carcinoid tumors (2 typical, 1 atypical), inflammatory myofibroblastic tumor (1), mucoepidermoid carcinoma (1), hamartoma (1), and synovial cell sarcoma (1). The typical carcinoids had mild (18)F-FDG uptake and high (68)Ga DOTA-TOC uptake. Atypical carcinoid had moderate uptake of (18)F-FDG and high (68)Ga DOTA-TOC uptake. Inflammatory myofibroblastic tumor showed high uptake of (18)F-FDG and no uptake of (68)Ga DOTA-TOC. Mucoepidermoid carcinoma showed mild (18)F-FDG uptake and no (68)Ga DOTA-TOC uptake. Hamartoma showed no uptake on either scans. Synovial cell sarcoma showed moderate (18)F-FDG uptake and mild focal (68)Ga DOTA-TOC uptake. This initial experience with the combined use of (18)F-FDG and (68)Ga DOTA-TOC PET-CT scan reveals different uptake patterns in various bronchial tumors. Bronchoscopic biopsy will continue to be the gold standard; however, the interesting observations made in this study merits further evaluation of the utility of the combination of (18)F-FDG PET-CT scan and (68)Ga DOTA-TOC PET-CT scan in larger number of patients with bronchial masses.

Stimulatory effect of growth hormone–releasing hormone (GHRH(1-29)NH2) on the proliferation, VEGF and chromogranin A secretion by human neuroendocrine tumor cell line NCI-H727 in vitro

Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in a variety of cellular processes like cell survival, proliferation, apoptosis, angiogenesis and neoplastic transformation of various non-pituitary tissues. Here, we investigated for the first time the in vitro effect of GHRH(1-29)NH2 on the proliferation and the secretion of vascular endothelial growth factor (VEGF) and chromogranin A by the human bronchial neuroendocrine tumor cells NCI-H727. GHRH(1-29)NH2 at the concentrations of 10(-8)-10(-6)M increased the proliferation of these cells and this effect was associated with a statistically significant increase in VEGF and chromogranin A secretion into the supernatants of the tested cells. Our findings indicate that GHRH functions as a trophic hormone for bronchial neuroendocrine (NET) tumors.

Bronchial atypical carcinoid tumor without invasion but with marked intraluminal growth like branchial tree cast

Pulmonary carcinoid tends to show intraluminal growth. However, pulmonary atypical carcinoid showing bronchial tree-like cast is extremely rare. A 63-year-old man was admitted to our hospital because of cough and sputum. Imaging modalities including XP, US, CT, and MRI showed bronchial tree-like tumor shadow in the right middle and lower lobes. Transbronchial biopsy revealed atypical carcinoid. A lobectomy of the right middle and lower lobe and lymph node dissection were performed. Grossly, the resected specimens showed cast-like tumor within the bronchial tree. It contained necrotic areas. Microscopically, the tumor cells were arranged in trabecular, ribbon, and insular patterns. There were many necrotic areas. The tumor cells showed hyperchromatic nuclei, and mitotic figures were recognized in 4 per 2 mm 2 . Parenchymal invasion was not recognized. Lymphovascular permeation was absent. Immunohistochemically, the tumor cells were positive for cytokeratins, synaptophysin, chromogranin, CD56, and neuron-specific enolase, but negative for S100 protein, melanosome, p53 protein, and KIT. The Ki-67 labeling was 15%. The tumor cells were stained with Grimelius stains. The lymph nodes showed no metastatic lesions. Therefore, atypical carcinoid was diagnosed. The patient was followed up with adjuvant chemotherapy, and is now alive free from tumor 7 years after the operation. In summary, clinicians and pathologists should be aware that atypical carcinoid can show branchial tree-like casts within the bronchial lumens but without parenchyma invasion. Such atypical carcinoids may have favorable prognosis.

Sialadenoma papilliferum of the bronchus: Rare tracheobronchial tumor of salivary gland type

Presented herein is the second case of sialadenoma papilliferum of the bronchus in a 75-year-old man. The bronchial tumor had an exophytic papillary lesion protruding into the lumen of the ostial region of the right superior lobe bronchus on chest CT and bronchoscopy. Grossly, the resected tumor was pedunculated, 5 x 3 x 3 mm in size and consisted of both an exophytic papillary lesion protruding into the bronchial lumen and a glandular component in the bronchial submucosa. Histologically, the papillary structures were lined by ciliated or non-ciliated columnar epithelium and metaplastic non-keratinizing stratified squamous epithelium. The submucosal glandular components were well circumscribed beneath and in continuity with the papillary lesion. The glandular components of cysts and duct-like structures were lined by a double-layer epithelium composed of luminal cells and basal cells. Sialadenoma papilliferum is a rarely recognized salivary gland tumor, mostly occurring at intraoral mucosal sites including the hard and soft palate and buccal mucosa. There have been sporadic cases of sialadenoma papilliferum of the esophagus, nasopharynx and nasal cavity. To the authors' knowledge only one case of sialadenoma papilliferum of the bronchus has been reported previously.

Pulmonary neuroendocrine/carcinoid tumors

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well-differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors.

Bronchial Carcinoid Tumours in Children: Surgical Treatment and Outcome in a Single Institution

Carcinoid tumors are low grade, malignant, neuroendocrine neoplasms. Although rare, they represent the most common primary bronchial tumours in childhood. The aim of our study was to analyse the long-term survival and surgical treatment outcome in our young patients operated for carcinoid tumour. We retrospectively reviewed the data of 15 paediatric patients who underwent surgery at our Institution. There were 11 male and 4 female patients with a median age of 15 years (range 8-18). All carcinoids were centrally located and symptomatic. We performed 10 (66.7%) parenchyma-saving procedures (5 sleeve lobectomies, 3 sleeve resections of the main bronchus, 2 bronchoplasties associated with lung resection) and 5 (33.3%) standard resections (3 bilobectomies and 2 lobectomies). There were 13 typical and 2 atypical carcinoids. Three patients (20%) had nodal metastases. There were no surgery-related deaths or complications. At long-term follow-up all patients presented with regular growth and all but one are alive. Two (13.3%) patients needed re-operation. Results suggest that, in experienced and skilled hands, conservative procedures are the treatment of choice for the management of paediatric bronchial carcinoids. Relapses can be successfully treated with re-operation and they can occur even after many years, underlining the importance of long-term follow-up.

Incidence and Outcomes of Malignant Pediatric Lung Neoplasms

We sought to define current incidence trends and outcomes for children with lung and bronchus tumors. The SEER registry was queried from 1973 to 2004 for all patients with pulmonary tumors less than 20 y of age. Overall, 160 patients were identified. The age-adjusted incidence has remained stable at 0.049 per 100,000 persons. The median age at diagnosis was 16 y. Whites had the highest age-adjusted population incidence at 0.056 per 100,000. Most tumors arose in the lower lobe (37%), followed by the upper lobe (31.2%). The most common histology was endocrine tumor (51.6%), followed by sarcoma (11%), and mucoepidermoid tumor (9%). Overall survival was greater than 381 mo with a 15-y survival of 65%. Males had better survival (>381 versus 288 months). Endocrine and mucoepidermoid tumors had the best survival. Small cell carcinoma had the worst median survival at less than 5 mo. Squamous cell carcinoma and adenocarcinoma both had a 14-mo median survival. Median survival for nonsurgically treated patients was 14 mo with a 10-y survival rate of 32%. Surgery improved the 10-y survival to 75% (P<0.0001). Multivariate analysis demonstrated nonsurgical treatment and nonendocrine tumor histology to be independent prognostic factors of death. The incidence of pediatric lung cancer remains stable. Several factors, including nonsurgical treatment and nonendocrine tumors confer a poor prognosis. Early diagnosis and surgical therapy provide the best chance for survival.

Neuroendocrine bronchial and thymic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up

The annual incidence of typical and atypical bronchial carcinoid tumors has been reported to be 0.6/100 000 and the overall age adjusted incidence for thymic carcinoids 0.01/100 000/year. Of all carcinoid tumors, ∼25% are located in the respiratory tract. The pulmonary carcinoids comprise 1–2% of all lung tumors. Both bronchial and thymic carcinoids may be part of multiple endocrine neoplasia type I syndrome (MEN-I).

Carinal wedge resection for lipoma combined with bronchoplastic lobectomy for lung cancer

A carinal tumor was detected in a 65-year-old male patient by preoperative bronchoscopic examination but was not diagnosed on simultaneous transbronchial biopsy. Also, a right lower bronchial tumor was diagnosed as squamous cell carcinoma. Resection of the carinal tumor and right lower lobectomy were performed simultaneously. We performed a modified one-stomatype carinal reconstruction and flap bronchoplasty to prevent complications on anastomosis. This case report illustrates that these procedures represent useful options for carinal-bronchial reconstruction.

Langerhans Cell Sarcoma with Pulmonary Manifestation, Mediastinum Involvement and Bronchoesophageal Fistula. A Rare Location and Difficulties in Histopathological Diagnosis

Langerhans cell sarcoma, a neoplastic proliferation of Langerhans cells with malignant cytologic features, is a very rare disease. Only a few cases have been documented in the English-language literature. Special methods, like immunohistochemistry and/or ultrastructural examination, are indispensable for appropriate diagnosis. Correct diagnosis is difficult. In fact, the disease is often misdiagnosed. We present the case of a 47 year-old man with a large mass in the middle lobe of the lung, infiltrating anterior mediastinum, with multiple pulmonary round lesions and enlargement of local lymph nodes, and with bronchoesophageal fistula. Clinical examination indicated the possibility of advanced primary lung cancer. However, the first histological diagnosis was Langerhans cell histiocytosis. In spite of treatment, the progression of pulmonary lesions was observed. Therefore, upper- and middle-lobectomy was performed. The diagnosis of Langerhans histiocytosis was confirmed microscopically again. Nevertheless, the patient's condition deteriorated progressively and he was admitted to the National Tuberculosis and Lung Diseases Research Institute in order to establish a final diagnosis. Revision of earlier resected specimens, as well as an immunohistochemical and ultrastructural examination of samples, taken once again from a bronchial tumor, led to the establishment of a diagnosis of a unique form of Langerhans cell sarcoma with rare pulmonary manifestation.

Surgical treatment of primary malignant tumors of the trachea and main bronchus

To explore the clinical experience of surgical treatment of primary malignant tumors of the trachea and main bronchus. The clinicopathological data of 18 patients with primary malignant tumors of the trachea and main bronchus surgically treated from February 1994 to August 2007 were reviewed retrospectively. The surgical management included sleeve tracheal resection in 8 cases, lower trachea and carina resection with carina reconstruction in 4 cases, local enucleation of the tumor in 4 cases, left or right carino-pneumonectomy and carina reconstruction in 2 cases, and resection of the tracheal or bronchial tumor and reconstruction of the airway under cardiopulmonary bypass in 6 cases. Among the 18 cases, there were 7 adenoid cystic carcinomas, 9 squamous cell carcinomas, 1 lymphoepithelial-like carcinoma and 1 follicular non-Hodgkin lymphoma. All the cases recovered well except one who died of endotracheal bleeding and asphyxia at the 10(th) postoperative day. Surgical resection is the most effective treatment for primary malignant tumors of the trachea and main bronchus. The selection of operation modes should be individualized according to patients' condition. Both complete resection and safety should be taken into consideration simultaneously.

Lipome endobronchique : apport de l’imagerie. À propos d’un cas

Endobronchial lipoma is a rare benign bronchial tumour. A search should be carried out on submillimetre MDCT scan slices in patients presenting segmental or lobar collapse or recurrent pulmonary infection in the same bronchial territories. The authors report MDCT and MR imaging in a patient with endobronchial lipoma discovered on an MDCT scan.

Bronchial Mucoepidermoid Carcinoma

We report a case of a minimally fluoro-2-deoxy-D-glucose avid bronchial mucoepidermoid tumor in a young male heavy smoker who presented with hemoptysis and a normal chest x-ray.

Cytology of mixed germ cell tumor with mediastinal metastasis

Nonseminomatous germ cell tumors of the testis are common and are very aggressive malignant tumors. Most of the cases have metastases at the time of diagnosis, and involvement of the posterior mediastinum in particular is well known. A 33 year-old male patient presented with complaints of a swelling on the right side of the neck that had been growing for the last month, as well as shortness of breath and cough. His thoracic computed tomography (CT) showed a 1.5 cm lymph node on the anterior mediastinum and a mass of about 11 × 10 × 8 cm extending from the right lung apex to the right hilus, with regular contours and without contrast enhancement. The patient, who was given the preliminary diagnosis of a mixture metastatic bronchial tumor plus lymphoma, was subjected to transthoracic fine needle aspiration cytology (FNAC). His abdominal CT revealed a hypodense, heterogeneous and cystic necrotic mass of about 10 × 7 × 5 cm that was para-aortic at the infrarenal level (initially predicted as a lymphoma). The patient, who could not be typed in his cytopathological examination, was diagnosed with malignant epithelial tumor and was recommended to undergo a genitourinary system examination. Upon finding a high alpha fetoprotein (AFP) value, a scrotal ultra sonography was performed which showed a mass filling the right testis. Histopathological examination of the orchiectomy material resulted in the diagnosis of mixed germ cell tumor (60% mature teratoma and 40% yolk sac tumor). Even though metastatic lesions are mostly seen in the posterior mediastinum, our findings reveal that specimens obtained with FNAC from the anterior mediastinum bear discohesive, pleomorphic, small nuclei in epithelial cells with microvacoules in the cytoplasm. These cytopathological alterations in specimens from the anterior mediastinum might promote germ cell and yolk sac tumors.

Surgical management and palliative treatment in bronchial neuroendocrine tumours: A clinical study of 45 patients

Bronchial neuroendocrine tumours account for 1–2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. The majority of the literature available comprises surgical series and there is a scarcity of data available for the management of patients with inoperable disease. We present a series of 45 patients referred to our institution from 1998 to 2006, with a mean follow-up of 54 months. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell neuroendocrine carcinoma in 4 and 1 case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Twenty-six of these 45 cases had unresectable disease, whilst the remainder were treated with surgical resection. Initial therapy with surgical resection was performed in 19 patients, 2 of whom had undergone neo-adjuvant chemotherapy. Recurrence occurred in 7 (36.8%), average duration of disease-free survival post-surgery was 61 months. Chemotherapy was first line therapy in five cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in six patients, for symptom control and anti-tumour effect. Peptide receptor radionuclide therapy, with Yttrium-90 DOTA-Octreotate, was given in two cases, both of whom achieved disease stabilization for 9–12 months respectively. There was a significant difference between Stage 4 and Stage 1 disease at presentation and survival. In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy offers palliation improving both symptoms and mortality.

ADAMTS-1 Metalloproteinase Promotes Tumor Development through the Induction of a Stromal Reaction In vivo

ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1-overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor beta (TGF-beta), and interleukin-1beta (IL-1beta). Neutralizing antibodies against TGF-beta and IL-1beta blocked the chemotactic effect of medium conditioned by ADAMTS-1-expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1-induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling.

Accuracy of 18F‐FDG‐PET/CT for staging of oral squamous cell carcinoma

This study prospectively assessed 2-[F18]-fluoro-2-deoxy-D-glucose-positron emission tomography (18F-FDG-PET)/CT (PET/CT) in oral squamous cell carcinoma. Twenty-three patients completed preoperative TNM staging (CT, MR, whole-body fusion imaging PET/CT). In patients who underwent surgical therapy (19 of 23), TNM staging based on PET/CT scan was compared with pTNM. PET/CT correctly staged 16 of 19 primary tumors (accuracy 84.2%, sensitivity 84.2%, positive predictive value 100%) and correctly ruled out bone invasion in 3 patients with false-positive results according to CT and/or MR. PET/CT incorrectly identified neck involvement in 5 of 15 patients (3 false positives, 2 false negatives) who underwent neck dissection (accuracy 66.7%, specificity 76.9%, negative predictive value 83.3%). False-negative cases showed a nodal size not exceeding 10 mm. One patient with a bronchial synchronous primary tumor was identified. PET/CT scan showed good accuracy in determining the extension and/or depth of invasion of the primary tumor. Nevertheless, PET/CT was not accurate to rule out nodal metastases.

Epidermal Growth Factor Receptor Abnormalities in the Pathogenesis and Progression of Lung Adenocarcinomas

To identify the characteristics and sequence of epidermal growth factor receptor (EGFR) abnormalities relevant to the pathogenesis and progression of lung adenocarcinoma, we performed a precise mapping analysis of EGFR mutation, gene copy number, and total and phosphorylated EGFR protein expression for the same tissue sites. We examined normal bronchial and bronchiolar epithelium (NBE) and tumor tissues obtained from 50 formalin-fixed lung adenocarcinomas, including 24 EGFR-mutant primary tumors with nine corresponding lymph node metastases and 26 wild-type primary tumors. NBE in 12 of 24 (50%) mutant and 3 of 26 (12%) wild-type tumors harbored EGFR mutations; these NBE also showed a lack of EGFR copy number increase and frequent EGFR (69%) and phosphorylated EGFR (33%) overexpression. EGFR mutation and protein overexpression were more frequent in NBE sites within tumors than in NBE sites adjacent to and distant from tumors, suggesting a localized field effect. Sites with high and low EGFR copy numbers were heterogeneously distributed in six of nine primary tumors and in one of eight metastases. EGFR protein overexpression was significantly higher in metastasis sites than in primary tumors. We conclude from our findings that EGFR mutations and protein overexpression are early phenomena in the pathogenesis of lung adenocarcinoma and that EGFR mutation precedes an increase in gene copy number. In EGFR-mutant adenocarcinoma metastases, the higher levels of EGFR overexpression and more homogeneously distributed high gene copy numbers suggest tumor progression. Our findings have important implications for the development of new strategies for targeted chemoprevention and therapy in lung adenocarcinoma using EGFR inhibitors.

Bronchial carcinoid tumours: Clinical features and management in a series of 45 patients

19076 Background: Bronchial neuroendocrine tumours account for 1–2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. Management of bronchial carcinoids has evolved over recent years with the advent of new treatment modalities. To identify the optimal treatment pathway for patients with bronchial neuroendocrine tumours. Methods: We present a series of 45 patients referred to our institution from1998–2006. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell nenuroendocrine carcinoma in 4 and one case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Results: Initial therapy with surgical resection was performed in 19 patients, 2 of which underwent pre-operative chemotherapy. Recurrence occurred in 8 (42%), of which 4 were in patients with atypical carcinoids. Average duration of disease free survival post surgery was 61 months. Chemotherapy was first line therapy in 5 cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in 6 patients, for either symptom control and anti-tumour effect, the average time to disease progression was 10.5 months. Peptide receptor radiotargetted therapy, with Y-90 DOTA Octreotate, was given in 2 cases, both of whom achieved disease stabilization for 9 to 12 months respectively. There was no significant difference in survival based on histological classification between typical, atypical, large non-small neuroendocrine carcinoma. There was a significant difference between stage 4 and stage 1 disease at presentation and survival (p= 0.028). 5 year survival for bronchial carcinoids is better than that for most other lung cancers. Conclusions: In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somastostatin analogues and peptide receptor radiotargetted therapy offers numerous palliative treatments for improving both symptoms and mortality. No significant financial relationships to disclose.