Continuity of care for patients with de novo metastatic cancer during the COVID-19 pandemic: A population-based observational study.

During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1-12 2020: pre-COVID-19, weeks 12-20 2020: 1st peak, weeks 21-41 2020: recovery, weeks 42-53 2020: 2nd peak, weeks 1-20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77-0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72-0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p < .001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.

Prognostic Implication of KRAS G12C Mutation in a Real-World KRAS-Mutated Stage IV NSCLC Cohort Treated With Immunotherapy in The Netherlands.

Introduction: With the approval of G12C inhibitors as the second line of treatment for KRAS G12C-mutated NSCLC, and the expanding research regarding targeting KRAS, it is key to understand the prognostic implication of KRAS G12C in the current first line of treatment. We compared overall survival (OS) of patients with stage IV KRAS G12C-mutated NSCLC to those with a KRAS non-G12C mutation in a first-line setting of (chemo)immunotherapy. Methods: This nationwide population-based study used real-world data from The Netherlands Cancer Registry. We selected patients with stage IV KRAS-mutated lung adenocarcinoma diagnosed in 2019 to 2020 who received first-line (chemo-)immunotherapy. Primary outcome was OS. Results: From 28,120 registered patients with lung cancer, 1185 were selected with a KRAS mutation, of which 494 had a KRAS G12C mutation. Median OS was 15.5 months (95% confidence interval [CI]: 13.6-18.4) for KRAS G12C versus 14.0 months (95% CI:11.2-15.7) for KRAS non-G12C (p = 0.67). In multivariable analysis, KRAS subtype was not associated with OS (hazard ratio = 0.95, 95% CI: 0.82-1.10). For the subgroup with programmed death-ligand 1 at 0% to 49% who received chemoimmunotherapy, median OS was 13.3 months (95% CI: 10.5-15.2) for G12C and 9.8 months (95% CI: 8.6-11.3) for non-G12C (p = 0.48). For the subgroup with programmed death-ligand 1 more than or equal to 50% who received monoimmunotherapy, the median OS was 22.0 months (95% CI: 18.4-27.3) for G12C and 18.9 months (95% CI: 14.9-25.2) for non-G12C (p = 0.36). Conclusions: There was no influence of KRAS subtype (G12C versus non-G12C) on OS in patients with KRAS-mutated stage IV NSCLC treated with first-line (chemo)immunotherapy.

Survival of patients with KRAS G12C mutated stage IV non-small cell lung cancer with and without brain metastases treated with immune checkpoint inhibitors.

INTRODUCTION: Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). METHODS: Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 - June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM- groups were compared using log-rank tests. RESULTS: Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM-, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0-15.9) and 6.7 (95% CI 5.1-8.5) months for BM+ and BM- (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2-27.3) and 17.8 (95% CI 13.4-22.0) months for BM+ and BM- (p = 0.77), respectively. CONCLUSION: Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS.

[Current and future therapeutic options for COVID-19]. / Recente en toekomstige behandelingen bij covid-19.

The anti-inflammatory agents dexamethasone (corticosteroid), and tocilizumab and sarilumab (IL6-inhibitors) are effective in the treatment of late COVID-19. Other anti-inflammatory agents, like anakinra (IL1-inhibitor), baricitinib and tofacitinib (JAK-inhibitors) and lenzilumab (GM-CSF-inhibitor) have also shown positive results in late COVID-19. For the treatment of early COVID-19, the inhalation corticosteroid budesonide is regarded as an off-label treatment option. Virus-inhibitors, like remdesivir, molnupiravir and nirmatrelvir/ritonavir decrease the risk of hospitalization and the development of severe COVID-19 by patients with early symptoms. Monoclonal antibodies have shown limited or no efficacy against the omicron-variant of SARS-CoV-2. Fluvoxamine, l-arginine, AT-527 and ensovibep are considered as potential promising new therapies for the treatment of early COVID-19.

Use of potentially inappropriate medication in older patients with lung cancer at the end of life.

OBJECTIVES: Medications at the end of life should be used for symptom control. Medications which potential adverse effects outweigh their expected benefits are called 'potentially inappropriate medications' (PIMs). PIMs are related with adverse drug events and reduced quality of life. In this study, we investigated to what extent PIMs are dispensed to older patients with lung cancer in the last month of life. METHODS: We selected patients with lung cancer, aged 65+, diagnosed between 2009 and 2014, and who died before April 1st 2015 from the population-based Netherlands Cancer Registry (NCR). The NCR is linked to the PHARMO Database Network, that includes medications dispensed by community pharmacies in the Netherlands. The eight PIM groups were based on the OncPal Deprescribing Guideline: aspirin, dyslipidaemia medications, antihypertensives, osteoporosis medications, peptic ulcer prophylaxis, oral hypoglycaemics, vitamins and minerals. RESULTS: Data of 7864 patients with lung cancer were analyzed. Median age was 74 year (IQR = 70-79) and 67% was male. 45% of all patients received at least one PIM in their last month of life. Taking into account all dispensed medications, patients receiving PIMs received more different medications compared to those receiving no PIMs, respectively 10 (SD = 5) vs. 3 (SD = 4) different medications (P < 0.001). CONCLUSION: Almost half of the older patients with lung cancer in the Netherlands received PIMs in their last month of life. Since PIM use is associated with reduced quality of life, it is important that health care professionals continue to critically assess which medication can be discontinued at the end of life.

Experiences of healthcare professionals with support for mesothelioma patients and their relatives: Identified gaps and improvements for care.

OBJECTIVE: To assess perspectives and experiences of healthcare professionals and other relevant stakeholders regarding psychosocial support and palliative care in mesothelioma patients and their relatives, to identify gaps and to explore potential improvements in current healthcare. METHODS: Individual, semi-structured interviews were conducted with healthcare professionals and other relevant stakeholders. Interviews were transcribed verbatim and analysed thematically using ATLAS.ti. RESULTS: In total, 16 respondents participated in an interview (69% women; mean age: 51.8 years (SD 12.41; range 28-75)). Four key themes were identified: (1) availability of tailored psychosocial and palliative care, (2) timely integration and organisation of psychosocial support and palliative care, (3) differences in provided support and care between healthcare professionals and hospitals and (4) training of healthcare professionals and stakeholders on psychosocial problems. CONCLUSION: Our study showed that psychosocial support and palliative care for patients with mesothelioma could be improved. A more fluent transition between primary and secondary cancer care and early integration of psychosocial support and palliative care is advised. Lastly, more attention is needed for psychosocial and palliative care in the basic medical training of healthcare professionals.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Chest computed tomography and alveolar-arterial oxygen gradient as rapid tools to diagnose and triage mildly symptomatic COVID-19 pneumonia patients.

BACKGROUND: In the coronavirus disease 2019 (COVID-19) pandemic, rapid clinical triage is crucial to determine which patients need hospitalisation. We hypothesised that chest computed tomography (CT) and alveolar-arterial oxygen tension ratio (A-a) gradient may be useful to triage these patients, since they reflect the severity of the pneumonia-associated ventilation/perfusion abnormalities. METHODS: A retrospective analysis was performed in 235 consecutive patients suspected for COVID-19. The diagnostic protocol included low-dose chest CT and arterial blood gas analysis. In patients with CT-based COVID-19 pneumonia, the association between "need for hospitalisation" and A-a gradient was investigated by a multivariable logistic regression model. The A-a gradient was tested as a predictor for need for hospitalisation using receiver operating characteristic curve analysis and a logistic regression model. RESULTS: 72 out of 235 patients (mean±sd age 55.5±14.6 years, 40% female) screened by chest CT showed evidence for COVID-19 pneumonia. In these patients, A-a gradient was shown to be a predictor of need for hospitalisation, with an optimal decision level (cut-off) of 36.4 mmHg (95% CI 0.70-0.91, p<0.001). The A-a gradient was shown to be independently associated with need for hospitalisation (OR 1.97 (95% CI 1.23-3.15), p=0.005; A-a gradient per 10 points) from CT severity score (OR 1.13 (95% CI 0.94-1.36), p=0.191), National Early Warning Score (OR 1.19 (95% CI 0.91-1.57), p=0.321) or peripheral oxygen saturation (OR 0.88 (95% CI 0.68-1.14), p=0.345). CONCLUSION: Low-dose chest CT and the A-a gradient may serve as rapid and accurate tools to diagnose COVID-19 pneumonia and to select mildly symptomatic patients in need for hospitalisation.

Synchronous peritoneal metastases from lung cancer: incidence, associated factors, treatment and survival: a Dutch population-based study.

Peritoneal metastases (PM) from lung cancer are rare and it is unknown how they affect the prognosis of patients with lung cancer. This population-based study aimed to assess the incidence, associated factors, treatment and prognosis of PM from lung cancer. Data from the Netherlands Cancer Registry were used. All patients diagnosed with lung cancer between 2008 and 2018 were included. Logistic regression analysis was performed to identify factors associated with the presence of PM. Cox regression analysis was performed to identify factors associated with the overall survival (OS) of patients with PM. Between 2008 and 2018, 129,651 patients were diagnosed with lung cancer, of whom 2533 (2.0%) patients were diagnosed with PM. The European Standardized Rate of PM increased significantly from 0.6 in 2008 to 1.4 in 2018 (p < 0.001). Age between 50 and 74 years, T3-4 tumour stage, N2-3 nodal stage, tumour morphology of a small cell lung cancer or adenocarcinoma, and the presence of systemic metastases were associated with the presence of PM. The median OS of patients with PM was 2.5 months. Older age, male sex, T3-4 tumour stage, N2-3 nodal stage, not receiving systemic treatment, and the presence of systemic metastases were associated with a worse OS. Synchronous PM were diagnosed in 2.0% of patients with lung cancer and resulted in a very poor survival.

Digital versus analogue chest drainage system in patients with primary spontaneous pneumothorax: a randomized controlled trial.

BACKGROUND: Patients with a primary spontaneous pneumothorax (PSP) who are treated with chest tube drainage are traditionally connected to an analogue chest drainage system, containing a water seal and using a visual method of monitoring air leakage. Electronic systems with continuous digital monitoring of air leakage provide better insight into actual air leakage and changes in leakage over time, which may lead to a shorter length of hospital stay. METHODS: We performed a randomized controlled trial comparing the digital with analogue system, with the aim of demonstrating that use of a digital drainage system in PSP leads to a shorter hospital stay. RESULTS: In 102 patients enrolled with PSP we found no differences in total duration of chest tube drainage and hospital stay between the groups. However, in a post-hoc analysis, excluding 19 patients needing surgery due to prolonged air leakage, hospital stay was significantly shorter in the digital group (median 1 days, IQR 1-5 days) compared to the analogue group (median 3 days, IQR 2-5 days) (p 0.014). Treatment failure occurred in 3 patients in both groups; the rate of recurrence within 12 weeks was not significantly different between groups (16% in the digital group versus 8% in the analogue group, p 0.339). CONCLUSION: Length of hospital stay was not shorter in patients with PSP when applying a digital drainage system compared to an analogue drainage system. However, in the large subgroup of uncomplicated PSP, a significant reduction in duration of drainage and hospital stay was demonstrated with digital drainage. These findings suggest that digital drainage may be a practical alternative to manual aspiration in the management of PSP. TRIAL REGISTRATION: Registered 22 September 2013 - Retrospectively registered, Trial NL4022 (NTR4195).

Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab.

BACKGROUND AND PURPOSE: Radiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy. MATERIALS AND METHODS: A 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24 × 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m(2)). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan-Meier survival curves and 1-, 2- and 5-year OS proportions were calculated. RESULTS: Between February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5 months (range 12.8-52.3), not significantly different between arms A and B; 33.0 (range 17.0-57.0) and 30.0 (11.0-52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS. DISCUSSION: In this phase II trial, the median OS for the entire group was remarkably high; 31.5 months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients.

Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating.

BACKGROUND: Modest benefits from concurrent chemoradiotherapy in patients with locally advanced NSCLC warrant further clinical investigations to identify more effective treatment regimens. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. We report on the safety and efficacy of the combination of daily dose Cisplatin and concurrent radiotherapy with or without weekly Cetuximab. PATIENTS AND METHODS: Patients received high dose accelerated radiotherapy (66 Gy in 24 fractions) and concurrent daily Cisplatin (6 mg/m(2)) without (Arm A) or with (Arm B) weekly Cetuximab (400 mg/m(2) loading dose one week prior to radiotherapy followed by weekly 250 mg/m(2)). The primary endpoint of the trial was objective local control rate (OLCR) determined at 6-8 weeks after treatment. Toxicity was reported as well. RESULTS: Between February 2009 and May 2011, 102 patients were randomized. Median follow up was 29 months. The OLCR was 84% in Arm A and 92% in Arm B (p=0.36). The one-year local progression free interval (LPFI) and overall survival (OS) were 69% and 82% for Arm A and 73% and 71% for Arm B, respectively (LPFI p=0.39; OS p=0.99). Toxicity compared equally between both groups. CONCLUSION: The addition of Cetuximab to radiotherapy and concurrent Cisplatin did not improve disease control in patients with locally advanced NSCLC but increased treatment related toxicity.

Glucocorticoid-induced changes in gene expression of airway smooth muscle in patients with asthma.

RATIONALE: Glucocorticoids are the mainstay of asthma therapy. However, it is unclear whether the benefits of glucocorticoids in asthma are merely based on antiinflammatory properties. Glucocorticoids may also alter gene expression of airway smooth muscle (ASM). We hypothesized that the gene expression profile of the ASM layer in endobronchial biopsies of patients with asthma is altered by oral glucocorticoid therapy as compared with placebo. OBJECTIVES: First, we investigated the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral glucocorticoid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and lung function. METHODS: Twelve steroid-free patients with atopic asthma were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolone (n = 6) or placebo (n = 6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using GS FLX+ (454/Roche). Gene networks were identified by Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. MEASUREMENTS AND MAIN RESULTS: Fifteen genes were significantly changed by 14 days of oral prednisolone. Two of these genes (FAM129A, SYNPO2) were associated with airway hyperresponsiveness (provocative concentration of methacholine causing a 20% drop in FEV1: r = -0.740, P < 0.01; r = -0.746, P < 0.01). Pathway analysis revealed three gene networks that were associated with cellular functions including cellular growth, proliferation, and development. CONCLUSIONS: Oral prednisolone changes the transcriptomic profile of the ASM layer in asthma. This indicates that in parallel to antiinflammatory properties, glucocorticoids also exert effects on gene expression of ASM, which is correlated with improved airway function.

Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthma versus controls.

The cellular and molecular pathways in asthma are highly complex. Increased understanding can be obtained by unbiased transcriptomic analysis (RNA-Seq). We hypothesised that the transcriptomic profile of whole human endobronchial biopsies differs between asthma patients and controls. First, we investigated the feasibility of obtaining RNA from whole endobronchial biopsies suitable for RNA-Seq. Secondly, we examined the difference in transcriptomic profiles between asthma and controls. This cross-sectional study compared four steroid-free atopic asthma patients and five healthy nonatopic controls. Total RNA from four biopsies per subject was prepared for RNA-Seq. Comparison of the numbers of reads per gene in asthma and controls was based on the Poisson distribution. 46 genes were differentially expressed between asthma and controls, including pendrin, periostin and BCL2. 10 gene networks were found to be involved in cellular morphology, movement and development. RNA isolated from whole human endobronchial biopsies is suitable for RNA-Seq, showing different transcriptomic profiles between asthma and controls. Novel and confirmative genes were found to be linked to asthma. These results indicate that biological processes in the airways of asthma patients are regulated differently when compared to controls, which may be relevant for the pathogenesis and treatment of the disease.

A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation.

PURPOSE: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. EXPERIMENTAL DESIGN: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. RESULTS: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). CONCLUSION: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.

Streptococcal lung abscesses from a dental focus following tocilizumab: a case report.

Patients suffering from dental infections and concurrently using immunosuppressive medication are at increased risk of developing systemic streptococcal infections. Tocilizumab is a novel therapeutic agent targeting interleukin-6. We describe a case of streptococcal lung abscesses from a dental focus after use of tocilizumab for treatment of Takayasu arteritis.

Prolonged sampling of spontaneous sputum improves sensitivity of hypermethylation analysis for lung cancer.

AIMS: The adequacy of lung cancer diagnosis with sputum cytology depends on duration of sputum sampling. The aim of this methodological study was to determine whether the hypermethylation detection rate of RASSF1A, adenomatous polyposis coli (APC) and cytoglobin (CYGB) is influenced by the duration of sputum collection. METHODS: Prospective sputum samples were collected from 53 lung cancer patients and 47 chronic obstructive pulmonary disease patients as controls. Subjects collected spontaneous sputum at home during nine consecutive days in three canisters I, II and III (ie, days 1-3, days 4-6, days 7-9, respectively). Quantitative methylation-specific PCR was performed to assess gene promoter methylation status of RASSF1A, APC and CYGB. RESULTS: Analysis of each canister separately showed hypermethylation of RASSF1A, APC and/or CYGB in samples I, II and III, in 43%, 40% and 47% of cases, respectively. In control samples, these numbers were 4%, 2% and 4%, respectively. Cumulative analysis for days 1-6 and days 1-9 revealed an increase in sensitivity to 53% and 64%, and specificity of 94% and 91%, respectively. CONCLUSION: Sputum collected over multiple successive days results in a gain in sensitivity for the detection of lung cancer, at the expense of a small loss in specificity. Condensed abstract Assessment of hypermethylation sensitivity of biomarkers in sputum collected over a prolonged period for the detection of lung cancer resulted in a promising gain in sensitivity, at the expense of a small loss in specificity.

In vivo imaging of the airway wall in asthma: fibered confocal fluorescence microscopy in relation to histology and lung function.

BACKGROUND: Airway remodelling is a feature of asthma including fragmentation of elastic fibres observed in the superficial elastin network of the airway wall. Fibered confocal fluorescence microscopy (FCFM) is a new and non-invasive imaging technique performed during bronchoscopy that may visualize elastic fibres, as shown by in vitro spectral analysis of elastin powder. We hypothesized that FCFM images capture in vivo elastic fibre patterns within the airway wall and that such patterns correspond with airway histology. We aimed to establish the concordance between the bronchial elastic fibre pattern in histology and FCFM. Second, we examined whether elastic fibre patterns in histology and FCFM were different between asthmatic subjects and healthy controls. Finally, the association between these patterns and lung function parameters was investigated. METHODS: In a cross-sectional study comprising 16 subjects (8 atopic asthmatic patients with controlled disease and 8 healthy controls) spirometry and bronchoscopy were performed, with recording of FCFM images followed by endobronchial biopsy at the airway main carina. Elastic fibre patterns in histological sections and FCFM images were scored semi-quantitatively. Agreement between histology and FCFM was analysed using linearly weighted kappa κw. RESULTS: The patterns observed in histological sections and FCFM images could be divided into 3 distinct groups. There was good agreement between elastic fibre patterns in histology and FCFM patterns (κw 0.744). The semi-quantitative pattern scores were not different between asthmatic patients and controls. Notably, there was a significant difference in post-bronchodilator FEV1 %predicted between the different patterns by histology (p = 0.001) and FCFM (p = 0.048), regardless of asthma or atopy. CONCLUSION: FCFM captures the elastic fibre pattern within the airway wall in humans in vivo. The association between post-bronchodilator FEV1 %predicted and both histological and FCFM elastic fibre patterns points towards a structure-function relationship between extracellular matrix in the airway wall and lung function. TRIAL REGISTRATION: Netherlands Trial Register NTR1306.