Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases.

BACKGROUND: Brain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM. METHODS: Patients with newly diagnosed BM from non-small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM. RESULTS: A total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P < .001). In multivariate analysis with a diagnosis-specific graded prognostic assessment (hazard ratio, 1.41; 95% CI, 1.33-1.50 [P < .001]), the presence of neurological symptoms (hazard ratio, 1.39; 95% CI, 1.23-1.57 [P < .001]) was found to be independently associated with survival prognosis from the time of diagnosis of BM. CONCLUSIONS: Neurological symptoms at the time of BM diagnosis demonstrated a strong and independent association with survival prognosis. The results of the current study have highlighted the need for the integration of the presence of neurological symptoms into the prognostic assessment of patients with BM from non-small cell lung cancer. LAY SUMMARY: Neurological symptom evaluation is included regularly in the assessment of patients with primary brain tumors. However, to the authors' knowledge, little is known regarding the prognostic impact in patients with newly diagnosed brain metastases (BM). The current study has provided a detailed clinical characterization of the incidence, distribution, and prognostic impact of neurological symptoms in a large, real-life cohort of patients with BM from non-small cell lung cancer. In this cohort, neurological symptoms at the time of diagnosis of BM demonstrated a strong, independent prognostic impact on the survival prognosis. The results of the current study have highlighted the need for the integration of neurological symptom burden into the prognostic assessment of patients with BM from non-small cell lung cancer.

Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort.

PURPOSES: Brain metastases (BM) are a frequent complication in small cell lung cancer (SCLC), resulting in a reduced survival prognosis. Precise prognostic assessment is an important foundation for treatment decisions and clinical trial planning. METHODS: Patients with newly diagnosed SCLC BM were identified from the Vienna Brain Metastasis Registry and evaluated concerning prognostic factors. RESULTS: 489 patients (male 62.2%, female 37.8%; median age 61 years) were included. Neurological symptoms were present in 297/489 (60.7%) patients. A- to oligosymptomatic patients (5 vs. 9 months, p = 0.030) as well as patients with synchronous diagnosis of BM and primary tumor (5 vs. 9 months, p = 0.008) presented with improved overall survival (OS) prognosis. RPA (HR 1.66; 95% CI 1.44-1.91; p < 0.001), GPA (HR 1.65; p < 0.001), DS-GPA (HR 1.60; p < 0.001) and LabBM score (HR 1.69; p < 0.001) were statistically significantly associated with OS. In multivariate analysis, DS-GPA (HR 1.59; p < 0.001), neurological deficits (HR 1.26; p = 0.021) and LabBM score (HR 1.57; p < 0.001) presented with statistical independent association with OS. CONCLUSION: A- to oligosymptomatic BM as well as synchronous diagnosis of SCLC and BM were associated with improved OS. Established prognostic scores could be validated in this large SCLC BM real-life cohort.

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience.

BACKGROUND: Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT. METHODS: Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens. RESULTS: Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7-16.6). At a median time of 18.1 months (range, 6-120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month-16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5-78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46-198). CONCLUSION: This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

The Na+/K+-ATPase is the Achilles heel of multi-drug-resistant cancer cells.

We recently reported that over-expressed Na(+)/K(+)-ATPase alpha subunits are new important anti-cancer targets. Cardiotonic steroids are the natural ligands of Na(+)/K(+)-ATPase and thus potentially potent anti-cancer agents with a novel mechanism of action. We report here that the hemi-synthetic cardenolide 19-hydroxy-2''oxovoruscharin is impressively active in cancer cells expressing diverse forms of multi-drug resistance (MDR) either conferred by the over-expression of selected drug-transporter proteins or induced by a range of chemotherapeutic agents. Together with the inability of tumor cells to acquire resistance to 19-hydroxy-2''oxovoruscharin, our data suggest that this novel compound could be especially applicable to notoriously drug-resistant cancers.

Combined cervicothoracic approaches for complex mediastinal masses.

Tumors or masses occurring in the cervicothoracic region show a broad variety in their histologic origin. Accordingly, the indication for surgical resection varies, and especially in malignant lesions, surgery frequently is part of a multimodality treatment. Adequate access is important for any operation in a critical region such as the cervicothoracic junction. The anatomic location of the mass to be resected usually dictates either an anterior or posterior approach. The need for appropriate exposure is in addition paralleled by the need to preserve a maximum of important functional structures, to maintain their diligent functional interaction. Careful interdisciplinary preoperative treatment planning is necessary to achieve optimal results.

Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study.

BACKGROUND: Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies chronic thromboembolic pulmonary hypertension patients prone to develop persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and whether the degree of acute vasoreactivity affects survival or freedom from lung transplantation. METHODS AND RESULTS: Right-sided heart catheterization at baseline and after inhalation of 40 ppm nitric oxide for 20 minutes was performed in 103 patients (56.3+/-15.3 years old, 53 women). Reductions in mean pulmonary arterial pressure (DeltamPAP; -8.8+/-12.6%; P<0.0001) and pulmonary vascular resistance (-16.1+/-18.1%; P<0.0001) and an increase in mixed venous saturation during inhaled nitric oxide (9.1+/-11.6%; P<0.0001) were observed. Sixty-two patients underwent pulmonary endarterectomy after a median of 49 days (25th and 75th percentiles: 24 and 123 days). Operated patients were followed up for a median of 70.9 months (25th and 75th percentiles: 14 and 97 months). Change in mPAP during inhaled NO was identified as a predictor of persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Patients experiencing a reduction in mPAP >10.4% with nitric oxide inhalation had a better postoperative outcome. A significant correlation was found between DeltamPAP and immediate postoperative pulmonary vascular resistance (r=0.5, P<0.0001). CONCLUSIONS: A total of 80 (77.7%) of 103 patients demonstrated acute pulmonary vascular reactivity of some degree. A decrease in mPAP >10.4% under inhaled nitric oxide is a predictor of long-term survival and freedom from lung transplantation in adult patients with chronic thromboembolic pulmonary hypertension who are undergoing pulmonary endarterectomy.

Outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma is a mainly asbestos-related neoplasm that occurs with increasing frequency and is associated with a poor prognosis. Extrapleural pneumonectomy which was initially performed as a stand-alone treatment in patients with resectable disease is now currently almost uniformly applied as part of a multi-modal approach. Its value and advantage over other therapeutic strategies remain points of discussion. We therefore analysed our experience with extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. METHODS: We retrospectively reviewed our institutional experience with all consecutive patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma from 1994 to 2005. Patients were analysed with regard to hospital mortality and morbidity and long-term outcome. RESULTS: Forty-nine patients (10 female/39 male, mean age 58+12 years) underwent extrapleural pneumonectomy during the observation period. Median ICU stay was 1 day, median postoperative length of hospital stay was 13 days. After a mean follow-up of 2573 days, median survival was 376 days (mean 672+121 days, range 9-3384). One-year survival was 53%, 3-year survival 27% and 5-year survival 19%. CONCLUSION: Extrapleural pneumonectomy as part of a multi-modality treatment regimen is a good treatment option for selected patients with malignant pleural mesothelioma. The long-term results of this limited series compare favourably to non-surgical treatment regimens. Larger randomised prospective multi-centre trials are warranted to establish clear guidelines.

Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature.

Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O(2)) or normoxic (21% O(2)) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.