Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2.

Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01. Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL-1; doses in the MAD cohort were 2.5 and 5 mg·mL-1. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed. Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration (Cmax) values after single and multiple doses of 5 mg·mL-1 APN01 were 1.88 and 6.61 ng·mL-1, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5. Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases.

Clinical characteristics, treatment, and outcome of patients with large cell neuroendocrine carcinoma of the lung and brain metastases - data from a tertiary care center.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms.

Clinical characteristics, treatment, and long-term outcome of patients with brain metastases from thyroid cancer.

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9-24), 4 years for FTC (range 2.1-41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8-57), 26 months for FTC (range 3.9-188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.

Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer.

PURPOSE: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design. EXPERIMENTAL DESIGN: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. RESULTS: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. CONCLUSIONS: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.

Prophylactic treatment with oral azithromycin in cancer patients during the COVID-19 pandemic (OnCoVID): a randomized, single-blinded, placebo-controlled phase 2 trial.

BACKGROUND: Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. METHODS: This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. RESULTS: In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III-IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. CONCLUSION: Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. CLINICALTRIALS: gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.

Changing characteristics, treatment approaches and survival of patients with brain metastasis: data from six thousand and thirty-one individuals over an observation period of 30 years.

BACKGROUND: An accurate classification of patients with brain metastases (BMs) is an important foundation to guide individualised treatment decisions and to formulate BM cohorts for modern clinical trials. METHODS: Six thousand and thirty-one patients with newly diagnosed BM from different solid tumours treated between 1986 and 2020 were identified from the Vienna Brain Metastasis Registry. RESULTS: A rising fraction of patients presented with asymptomatic BM during the observation period (1986-1999: 20.2% vs 2010-2020: 30.6%; p < 0.001). Especially, oncogene-addicted non-small-cell lung cancer (NSCLC) and BRAF (v-Raf murine sarcoma viral oncogene homolog)-positive melanoma had a higher rate of asymptomatic BM presentation compared with wild-type tumours (p < 0.05). Significant changes of initial BM treatment approaches were observed with a decrease of neurosurgical procedures (1986-1999: 30.8% vs 2010-2020: 19.5%) and an increase of radiation treatments (1986-1999: 65.0% vs 2010-2020: 73.3%) and systemic therapies (1986-1999: 1.0% vs 2010-2020: 2.0%; p < 0.001). Median overall survival (OS) was heterogeneous between primary tumour entities but with an overall increase over the decades (median OS 1986-1999: 5 months vs 2010-2020: 7 months; p = 0.001). Survival times were longer in patients with oncogene-addicted NSCLC, BRAF-positive melanoma and hormone receptor-positive breast cancer compared with the other cancer subtypes (p > 0.05). CONCLUSION: Our data highlight shifting trends in the symptomatic presentation and in treatment strategies of patients with BM over the last decades. Entity specific aspects and, in particular, the presence of targetable driver mutation impact the clinical presentation and prognosis. Future BM specific trials need to address the modern composition of BM cohorts and the distinct clinical course of patients with targetable driver mutations.

Humoral Immune Response in Hematooncological Patients and Health Care Workers Who Received SARS-CoV-2 Vaccinations.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles.

Brain metastases (BM) present a common cause of mortality and morbidity in several metastatic cancer entities. New therapeutic developments during the last decades, including targeted and immune-related therapies, have shown considerable extra- and intracranial response rates in specific subgroups of BM patients. However, differences in the molecular alteration in the BM tumor tissue compared to extracranial tumors leads to heterogeneous therapeutic responses. Therefore, an accurate molecular analyzation of BM tissue, if possible, has become an essential part in therapeutic decision making in BM patients. The concordance of predictive molecular biomarkers between multiple sites including extracranial and intracranial tumor tissue have been analyzed for some but not all biomarkers routinely applied in modern precision medicine approaches. In the present review, we summarize the current evidence of predictive biomarkers for personalized therapy approaches in the treatment of parenchymal BM.

Thyroid Hormone Replacement Therapy Is Associated with Longer Overall Survival in Patients with Resectable Gastroesophageal Cancer: A Retrospective Single-Center Analysis.

INTRODUCTION: As thyroid hormones modulate proliferative pathways it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. MATERIAL AND METHODS: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria, including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS). RESULTS: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n = 647: median OS 29.7 months; hyperthyroid, n = 50: 23.1 months; hypothyroid, n = 70: 47.9 months; p = 0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n = 53: median OS 30.6 months; with, n = 67: 51.3 months; p = 0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within the limit of normal: 23.4, above: 32.4, below: 9.6 months; p = 0.045). CONCLUSIONS: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.

Androgen Receptor is Expressed in Breast Cancer Brain Metastases.

BACKGROUND: Androgen receptor (AR) expression is a potential therapeutic target in breast cancer (BC) as it is frequently expressed in the luminal A and B subtypes and in approximately one third of basal-like cancers. As AR-positive BC displays a distinct biological behavior, we aimed to analyze AR expression in the particular context of BC brain metastases (BM). MATERIALS AND METHODS: Patients with newly diagnosed BC BM treated with neurosurgical resection were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, biological tumor subtypes and overall survival were obtained by retrospective chart review. Formalin-fixed and paraffin-embedded specimen containing BM tissue were retrieved from the Neuro-Biobank. Immunohistochemical staining of AR was performed and AR expression in the tumor-cell nucleus was evaluated. RESULTS: Fifty-seven BM samples from 57 individual patients with BC were available for this analysis. AR expression of ≥1% tumor cells was evident in 20/57 (35.1%) BM specimens; the median AR-expression rate was 10% (range: 1% to 60%). AR expression was observed in 11/21 (52.4%) BM of the luminal/human epidermal growth factor receptor 2 (HER2)-negative subtype, 3/13 (23.1%) of the luminal/HER2-positive subtype, 2/7 (28.6%) of the HER2-positive subtype and 4/16 (25.0%) of the triple-negative subtype (P=0.247). Median survival from diagnosis of BM was 10 months (range: 0 to 104 mo) in the entire cohort. No significant association of overall survival and AR expression ≥1% was observed (15 vs. 13 mo; P>0.05). CONCLUSION: AR is expressed in more than one third of BC BM with the highest rates among the luminal/HER2-negative BC subtype and may therefore be a potential prognostic and predictive biomarker in this particular BC population.

Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases.

BACKGROUND: Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer. METHODS: One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry. RESULTS: PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; padj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32-1.59; padj = 1.62e - 13), NLR (HR 1.55; 95% CI: 1.38-1.75; padj = 1.92e - 11), LLR (HR 1.57; 95% CI: 1.39-1.77; padj = 1.96e - 11), PLR (HR 1.60; 95% CI: 1.39-1.85; padj = 2.87955e - 9), MLR (HR 1.41; 95% CI: 1.14-1.75; padj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54-2.18; padj = 2.73e - 10) remained independent factors associated with OS at BM diagnosis. CONCLUSIONS: Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.

Brain metastases in metastatic cancer: a review of recent advances in systemic therapies.

Introduction: Brain metastases (BM) are a frequent complication of metastatic cancer. Due to the wider availability and application of screening procedures, an increasing fraction of patients are diagnosed at the asymptomatic stage. The introduction of immune checkpoint inhibitors and targeted therapies has revolutionized treatment in several frequently BM-causing entities like metastatic lung cancer, melanoma and breast cancer. However, registered trials of new targeted and immunotherapy mostly excluded patients with BM resulting in limited knowledge of the intracranial efficacy of new systemic agents.Areas covered: The present review highlights recent advances in systemic therapies for the treatment and prophylaxis of the three leading BM causing tumors: NSCLC, melanoma and breast cancer.Expert opinion: High intracranial efficacy was observed for several next-generation tyrosine kinase inhibitors as well as immune checkpoint inhibitors, especially in patients with asymptomatic disease. Ongoing discussions addressed the need for local therapies in patients with asymptomatic BM and the availability of systemic therapy with high intracranial efficacy. Further BM-specific studies as well as BM-specific endpoints in registered trials are needed to define the role of systemic monotherapies in patients with BM.

Soluble PD-L1 is associated with local and systemic inflammation markers in primary and secondary brain tumours.

BACKGROUND: Immune-modulatory treatments have so far shown limited clinical activity in primary brain tumours. We aimed to investigate soluble programmed death receptor ligand 1 (sPD-L1) as systemic inflammation parameter in patients with brain tumour. METHODS: EDTA plasma was collected from 81 glioma (55 glioblastoma (GBM), 26 lower-grade glioma (LGG)), 17 meningioma and 44 brain metastasis (BM) patients and 24 controls. sPD-L1 concentrations were determined by ELISA. Correlations with the local tumour microenvironment were assessed by immunohistochemical analysis for PD-L1, CD3 and CD8. RESULTS: sPD-L1 was detected in 62 out of 166 (37.7%) patients (glioma: 41/81, 50.6%; meningioma: 5/17, 29.4%; BM: 7/44, 15.9%; controls: 9/24, 37.5%; p=0.002). sPD-L1 concentrations were lower in BM than in LGG (p=0.003) or GBM (p<0.001). Membranous PD-L1 expression on tumour cells was not associated with sPD-L1 concentrations (p=0.953). sPD-L1 concentration was inversely correlated with the density of CD8+ (r=-0.713, p=0.001) and CD3+ (r=-0.484, p=0.042) tumour-infiltrating lymphocytes in LGG. sPD-L1 is correlated with neutrophil counts (r=-0.318, p=0.045) and C reactive protein levels (r=-0.363, p=0.008) in GBM. sPD-L1+ patients had longer overall survival in GBM (p=0.006) and worse OS in LGG (p=0.028). CONCLUSIONS: sPD-L1 is detectable in a fraction of patients with brain tumour. Although it is not correlated with tissue PD-L1 expression, correlations with other local and systemic inflammation parameters could be detected in LGG and GBM.

SARS-CoV-2 seroprevalence in oncology healthcare professionals and patients with cancer at a tertiary care centre during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 outbreak, healthcare professionals (HCP) are at the frontline of clinical management and at increased risk for infection. The SARS-CoV-2 seroprevalence of oncological HCP and their patients has significant implications for oncological care. METHODS: HCP and patients with cancer at the Division of Oncology, Medical University of Vienna were included between 21 March and 4 June and tested for total antibodies against SARS-CoV-2 employing the Roche Elecsys Anti-SARS-CoV-2 immunoassay. Reactive samples were confirmed or disproved by the Abbott SARS-CoV-2 IgG test. Additionally, a structured questionnaire regarding basic demographic parameters, travel history and COVID-19-associated symptoms had to be completed by HCP. RESULTS: 146 subjects (62 HCP and 84 patients with cancer) were enrolled. In the oncological HCP cohort, 20 (32.3%) subjects were medical oncologists, 28 (45.2%) nurses at our ward and 14 (22.6%) fulfil other functions such as study coordinators. In the patient cohort, most individuals are on active anticancer treatment (96.4%). 26% of the HCP and 6% of the patients had symptoms potentially associated with COVID-19 since the end of February 2020. However, only in 2 (3.2%) HCP and in 3 (3.6%) patients, anti-SARS-Cov-2 total antibodies were detected. The second assay for anti-SARS-Cov-2 IgG antibodies confirmed the positive result in all HCP and in 2 (2.4%) patients, suggesting an initial assay's unspecific reaction in one case. In individuals with a confirmed test result, an active COVID-19 infection was documented by a positive SARS-CoV-2 RNA PCR test. CONCLUSION: Specific anti-SARS-CoV-2 antibodies were found solely in persons after a documented SARS-CoV-2 viral infection, thus supporting the test methods' high sensitivity and specificity. The low prevalence of anti-SARS-CoV-2 antibodies in our cohorts indicates a lack of immunity against SARS-CoV-2. It highlights the need for continued strict safety measures to prevent uncontrolled viral spread among oncological HCPs and patients with cancer.

Postoperative Magnetic Resonance Imaging After Surgery of Brain Metastases: Analysis of Extent of Resection and Potential Risk Factors for Incomplete Resection.

BACKGROUND: Extent of resection (EOR) constitutes a crucial factor for patient prognosis in surgery of brain metastases (BMs). According to early studies using postoperative magnetic resonance imaging (MRI), an unexpected residual tumor was not uncommon. Knowledge of potential risk factors for incomplete BM resection would be of major importance to optimize surgical strategies. The aim of this study was to evaluate EOR in a large cohort and analyze potential risk factors for incomplete BM resection. METHODS: Patients with BM resection and available postoperative MRI were included. Intraoperative estimation of EOR by the neurosurgeon was noted. Additionally, EOR was determined by postoperative MRI. Potential risk factors for incomplete resection were investigated. RESULTS: There were 145 patients with 163 BMs included. According to postoperative MRI, complete resection was achieved in 103 (63%) BMs, and resection was incomplete in 44 (27%) BMs. Postoperative MRI detected unexpected residual tumor in 32 (25%) BMs, and a misjudgment of the EOR by the neurosurgeon was found in 29% of cases. Regarding risk factors for incomplete resection, preoperative tumor volume was significantly larger in incompletely resected BMs compared with completely resected BMs (P = 0.011). All other analyzed risk factors had no significant influence on EOR. CONCLUSIONS: Our data indicate that postoperative MRI is able to detect a high portion of unexpected residual tumors after surgery of BMs. Preoperative tumor volume in particular represents an important risk factor for incomplete resection, and hence neurosurgeons should pay special attention to avoid residual tumor tissue.

Hypothyroidism correlates with favourable survival prognosis in patients with brain metastatic cancer.

BACKGROUND: Several preclinical and epidemiologic studies have indicated tumour-promoting effects of thyroid hormones (THs). However, very limited knowledge exists on the prognostic impact of thyroid function in metastatic cancer. METHODS: We compiled a discovery cohort of 1692 patients with newly diagnosed brain metastases (BMs) of solid cancers treated at the Medical University of Vienna and an independent validation cohort of 191 patients with newly diagnosed BMs treated at the University Hospital Zurich. RESULTS: Hypothyroidism before diagnosis of cancer was evident in 133 of 1692 (7.9%) patients of the discovery, and in 18 of 191 (9.4%) patients of the validation cohort. In the discovery cohort, hypothyroidism was statistically significantly associated with favourable survival prognosis from diagnosis of cancer (31 vs. 21 months; p = 0.0026) and with survival prognosis from diagnosis of BMs (12 vs. 7 months; p = 0.0079). In multivariate analysis including the diagnosis-specific graded prognostic assessment score, primary tumour type and sex, hypothyroidism was an independent factor associated with survival after diagnosis of BMs (hazard ratio: 0.76; 95% confidence interval [CI]: (0.63; 0.91; p = 0.0034). In the validation cohort, the association of hypothyroidism and favourable survival prognosis from diagnosis of cancer (55 vs. 11 months; p = 0.00058), as well as from diagnosis of BMs (40 vs. 10 months; p = 0.0036) was confirmed. CONCLUSION: Pre-existing hypothyroidism was strongly and independently associated with prognosis in patients with newly diagnosed BMs, supporting the evidence from preclinical data that THs may indeed have a tumour-promoting effect. Further investigation of the underlying pathobiological mechanism and potential therapeutic implications are required.

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.

Sarcopenia in Neurological Patients: Standard Values for Temporal Muscle Thickness and Muscle Strength Evaluation.

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, ρ = 0.746; p < 0.001; prospective cohort, ρ = 0.649; p < 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20; p < 0.001; prospective cohort, ρ = -0.199; p = 0.023), or BMI (retrospective cohort, ρ = 0.116; p = 0.042; prospective cohort, ρ = 0.227; p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia.

Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

PURPOSE: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns. EXPERIMENTAL DESIGN: TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays. RESULTS: TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases. CONCLUSIONS: TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.