Neoadjuvant therapy with immune checkpoint inhibitors in operable nonsmall cell lung cancer.

PURPOSE OF REVIEW: In localized nonsmall cell lung cancer (NSCLC) systemic recurrences after surgery are common. Therefore, adjuvant or neoadjuvant chemotherapy is used. With the advent of immune checkpoint inhibitors (ICIs) in metastatic disease the question is whether ICIs can further improve the outcome. RECENT FINDINGS: In several phase I/II trials, major pathological response (MPR) rates with several ICIs between 7% and 50% were seen. No major additional side effects occurred. In combination with chemotherapy CheckMate-816 randomized additional neoadjuvant nivolumab and achieved a high pathological complete response (pCR) rate and a better event-free survival (EFS) - without negatively influencing surgery. More randomized trials are performed with neoadjuvant immunochemotherapy and adjuvant treatment after surgery. In Keynote-671, pembrolizumab is used pre and postoperatively with a significantly higher EFS rate at 2 years (62.4% vs. 40.6%). Similar preliminary results are reported in the AEGEAN (durvalumab) and Neotorch (toripalimab) trials. Higher tumour stage and MPR, partly programmed cell death 1 ligand 1 (PD-L1) expression, tumour mutational burden (TMB) and circulating tumour DNA (ctDNA) are correlated with efficacy. SUMMARY: Neoadjuvant immunochemotherapy improves MPR and EFS rates, especially in more advanced tumours and tumours expressing PD-L1 - without relevantly increasing toxicities. But further and longer evaluation is needed.

[Early detection of lung cancer - current status and implementation scenarios]. / Lungenkrebsfrüherkennung ­ derzeitiger Stand und Implementationsszenarien.

The prognosis of conventionally diagnosed lung cancer patients is still rather poor. Two large, randomized trials using screening by low dose CT could demonstrate that early detection in persons with smoking as risk factor can improve this prognosis. Early detection of lung cancer can be achieved by structured screening programs using low dose CT for persons at increased risk, but in addition also by consequent management of incidental pulmonary nodules, which are seen on imaging for other reasons. Integral part of these programs should be prevention measures, especially a consequent, repeated, low-threshold offer of a service for smoking cessation. Programs for lung cancer screening for persons at increased risk are only beneficial for the screenees and cost-effective, if the various parts of the program are optimally integrated and coordinated and all necessary disciplines (especially respiratory medicine, radiology, pathology, thoracic surgery, radiotherapy) are included in a multidisciplinary manner. For Germany the certified lung cancer centres in structured cooperation with physicians in private practice (respiratory physicians, radiologists, general practitioners) would be a good option. It is essential that there is a good perception for the need of early detection of lung cancer in politics and the public and that the persons at risk are reached, contacted and motivated by various methods.

[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation.

Relationship of spirometric, body plethysmographic, and diffusing capacity parameters to emphysema scores derived from CT scans.

Phenotyping of chronic obstructive pulmonary disease (COPD) with computed tomography (CT) is used to distinguish between emphysema- and airway-dominated type. The phenotype is reflected in correlations with lung function measures. Among these, the relative value of body plethysmography has not been quantified. We addressed this question using CT scans retrospectively collected from clinical routine in a large COPD cohort. Three hundred and thirty five patients with baseline data of the German COPD cohort COPD and Systemic Consequences-Comorbidities Network were included. CT scans were primarily evaluated using a qualitative binary emphysema score. The binary score was positive for emphysema in 52.5% of patients, and there were significant differences between the positive/negative groups regarding forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), intrathoracic gas volume (ITGV), residual volume (RV), specific airway resistance (sRaw), transfer coefficient (KCO), transfer factor for carbon monoxide (TLCO), age, pack-years, and body mass index (BMI). Stepwise discriminant analyses revealed the combination of FEV1/FVC, RV, sRaw, and KCO to be significantly related to the binary emphysema score. The additional positive predictive value of body plethysmography, however, was only slightly higher than that of the conventional combination of spirometry and diffusing capacity, which if taken alone also achieved high predictive values, in contrast to body plethysmography. The additional information on the presence of CT-diagnosed emphysema as conferred by body plethysmography appeared to be minor compared to the well-known combination of spirometry and CO diffusing capacity.

Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach.

BACKGROUND: Recent investigations showed single associations between uric acid levels, functional parameters, exacerbations and mortality in COPD patients. The aim of this study was to describe the role of uric acid within the network of multiple relationships between function, exacerbation and comorbidities. METHODS: We used baseline data from the German COPD cohort COSYCONET which were evaluated by standard multiple regression analyses as well as path analysis to quantify the network of relations between parameters, particularly uric acid. RESULTS: Data from 1966 patients were analyzed. Uric acid was significantly associated with reduced FEV1, reduced 6-MWD, higher burden of exacerbations (GOLD criteria) and cardiovascular comorbidities, in addition to risk factors such as BMI and packyears. These associations remained significant after taking into account their multiple interdependences. Compared to uric acid levels the diagnosis of hyperuricemia and its medication played a minor role. CONCLUSION: Within the limits of a cross-sectional approach, our results strongly suggest that uric acid is a biomarker of high impact in COPD and plays a genuine role for relevant outcomes such as physical capacity and exacerbations. These findings suggest that more attention should be paid to uric acid in the evaluation of COPD disease status.

Heterogeneous pattern of differences in respiratory parameters between elderly with either good or poor FEV1.

BACKGROUND: The relationship of spirometric values to other respiratory and functional parameters in advanced age is not well studied. We assessed this relationship in elderly subjects with either good or poor spirometric parameters to reveal whether different domains of lung function show comparable differences between the two groups. METHODS: Among subjects of the population-based KORA-Age cohort (n = 935, 65-90y; 51% male) two groups were selected from either the lower (LED; n = 51) or the upper (UED; n = 72) end of the FEV1 distribution. All subjects did not have a history of lung disease and were non-smokers at the time of the study. Measurements included spirometry, body plethysmography, diffusing capacity for NO and CO, respiratory pump function and exhaled NO (FeNO). In addition, 6-min walking distance as a functional overall measure, as well as telomere length of blood leukocytes and serum 8-hydroxydeoxyguanosine (8-OHdG) as potential markers of overall biological ageing and stress were determined. RESULTS: In the majority of parameters, LED subjects showed significantly impaired values compared to UED subjects. Differences in spirometric parameters, airway resistance and respiratory pump function ranged between 10% and more than 90% in terms of predicted values. In contrast, volume-related CO and NO diffusing capacity showed differences between groups of lower than 5%, while telomere length, 8-OHdG and FeNO were similar. This was reflected in the differences in "functional age" as derived from prediction equations. CONCLUSIONS: In elderly subjects without a history of lung disease differences in spirometric parameters were associated with differences in other lung-mechanical parameters including body plethysmography but not with differences in volume-corrected gas exchange measures. Thus, the concept of a general "lung age" as suggested by the widespread use of this term in connection with spirometry should be considered with caution.

Less radiation, same quality: contrast-enhanced multi-detector computed tomography investigation of thoracic lymph nodes with one milli-sievert.

PURPOSE: Mediastinal, hilar, and peripheral pulmonary lymphadenopathy is a hallmark sign of different benign and malignant diseases of the chest. Contrast-enhanced (CE) chest CT is a test frequently applied to examine thoracic lymph node zones. We attempted to find out whether mediastinal, hilar, and peripheral lymph nodes delineate equally in CE chest CT with reduced dose (CE-LDCT, about 1 mSv) when compared with accepted standard CE chest CT (CE-SDCT). MATERIALS AND METHODS: In this ethics committee-approved, mono-institutional, retrospective (20 months) matched case-control study, two independent, blinded observers compared measurable lymph node delineation (yes-no) in six different International Association for the Study of Lung Cancer (IASLC) zones (upper mediastinal, aortopulmonary, subcarinal, lower mediastinal, hilar, peripheral) between 62 CE-LDCT cases and 124 CE-SDCT controls (respective tube charge, 100, 120 KVp, computed tomography dose index, 1.66 ± 0.51, 5.36 ± 2.24 mGy, automatic exposure control-modulated 64-row multi-detector chest CT with iterative image reconstruction). Individual matching for gender (53% female), age (53 ± 19 years), body height, weight, anterior-posterior and transverse diameters of chest and lung ruled out pre-test confounders. Lymph node size (cut-off value, 1 cm) was a potential post-test confounder. Two-tailed T test and Chi-square test were significant for p < 0.05. RESULTS: Measurable lymph nodes delineated equally in cases (261/372 IASLC zones, 70%; 280/372, 75%) and controls (528/744, 71%; 519/744, 70%; no significant differences, power 90%). One observer delineated significantly more peripheral zone lymph nodes in cases (35/62) than in controls (43/124); there were no significant differences otherwise. Lymph node size did not differ significantly; effective dose was 1.0 ± 0.3 mSv in cases and 3.4 ± 1.5 mSv in controls. CONCLUSION: CE-LDCT with about 1 mSv demonstrated equal delineation of thoracic lymph nodes when compared with accepted standard CE-SDCT.

Transfer factor for carbon monoxide in patients with COPD and diabetes: results from the German COSYCONET cohort.

BACKGROUND: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes. METHODS: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO%pred) and the transfer coefficient (KCO%pred). RESULTS: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO%pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV%pred, TLC%pred, ITGV%pred, FEV1%pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes. CONCLUSION: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.

GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin. METHODS: Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS). RESULTS: A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively. DISCUSSION: Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.

Thoracic lymph node delineation at dose-reduced (1 mSv) dose-modulated contrast enhanced MDCT: a retrospective pilot study.

PURPOSE: To compare contrast-enhanced low-dose multidetector-row computed tomography (CE-LDCT) of the chest with unenhanced (UN-) LDCT and contrast-enhanced standard-dose CT (CE-SDCT) in regard to the delineation of intrathoracic lymph nodes. MATERIALS AND METHODS: Based on the international association for the study of lung cancer (IASLC) grouping of thoracic lymph nodes, two independent radiologists retrospectively assessed lymph node delineation in 9 CE-LDCTs (64 rows, 120 KV, p < 30 mAs/slice) and in 2 control groups of 36 UN-LDCTs and 36 CE-SDCTs, each matched for gender, age, chest/lung diameters, and clinical history. At a significance level of p < 0.025 (Bonferroni-correction for two control groups), two-tailed Chi-square and Fisher's exact tests were applied. For the evaluation of the inter-observer agreement, Cohen's kappa statistics were used. RESULTS: CE-LDCT delineated lymph node groups significantly more often than UN-LDCT, in general (p < 0.001) and individually in the subcarinal (p < 0.025), the hilar (p < 0.001), and the peripheral lung (p < 0.001) zones. There were no significant differences in lymph node delineation between CE-LDCT and CE-SDCT. Inter-observer agreement was substantial to perfect for all lymph node zones (κ 0.64-1.0). Measurable lymph nodes did not significantly differ in size between cases and controls. CONCLUSION: At CE-LDCT of the chest, delineation of mediastinal and hilar lymph node groups was superior to UN-LDCT and similar to CE-SDCT. CE-LDCT may be a promising alternative for patients with non-malignant lung disease, unclear chest X-ray findings, or the need for follow-up.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.

Telomere length in circulating leukocytes is associated with lung function and disease.

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (ß= -0.0452, p=0.024) as well as COPD (ß= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Resectable non-stage IV nonsmall cell lung cancer: the surgical perspective.

Surgery remains an essential element of the multimodality radical treatment of patients with early-stage nonsmall cell lung cancer. In addition, thoracic surgery is one of the key specialties involved in the lung cancer tumour board. The importance of the surgeon in the setting of a multidisciplinary panel is ever-increasing in light of the crucial concept of resectability, which is at the base of patient selection for neoadjuvant/adjuvant treatments within trials and in real-world practice. This review covers some of the topics which are relevant in the daily practice of a thoracic oncological surgeon and should also be known by the nonsurgical members of the tumour board. It covers the following topics: the pre-operative selection of the surgical candidate in terms of fitness in light of the ever-improving nonsurgical treatment alternatives unfit patients may benefit from; the definition of resectability, which is so important to include patients into trials and to select the most appropriate radical treatment; the impact of surgical access and surgical extension with the evolving role of minimally invasive surgery, sublobar resections and parenchymal-sparing sleeve resections to avoid pneumonectomy.

Current status of and future strategies for multimodality treatment of unresectable stage III nonsmall cell lung cancer.

Stage III nonsmall cell lung cancer (NSCLC) encompasses a heterogeneous group of patients, some of whom may be candidates for potentially curative surgery, although for the majority surgery is not an option. Recommended therapy for patients with unresectable stage III disease is concurrent treatment with chemotherapy and thoracic radiotherapy, although even with this dual modality therapy survival remains disappointing. Novel classes of agents including targeted therapies have been shown to improve survival in advanced stage NSCLC, raising the possibility that these agents may have benefits in multimodal therapy when combined with chemoradiotherapy. Here we consider the rationale for combining new agents with chemoradiotherapy and the evidence from clinical studies assessing multimodal strategies for the management of patients with unresectable stage III NSCLC.

Spirometric reference values for advanced age from a South german population.

BACKGROUND: The diagnostic use of lung function using spirometry depends on the validity of reference equations. A multitude of spirometric prediction values have been published, but in most of these studies older age groups are underrepresented. OBJECTIVES: The aim of the present study was to establish new spirometric reference values for advanced age and to compare these to recent prediction equations from population-based studies. METHODS: In the present study spirometry was performed in a population-based sample from the KORA-F4 and KORA-Age cohorts (2006-2009, Augsburg, Germany) comprising 592 never-smoking subjects aged 42-89 years and with no history of respiratory disease. Using quantile regression analysis, equations for the median and lower limit of normal were derived for indices characterizing the expiratory flow-volume curve: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF), and forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF25, FEF50 and FEF75). RESULTS: FEV1 and FVC were slightly higher, and PEF was lower compared to recently published equations. Importantly, forced expiratory flow rates at middle and low lung volume, as putative indicators of small airway disease, were in good agreement with recent data, especially for older age. CONCLUSION: Our study provides up-to-date reference equations for all major indices of flow-volume curves in middle and advanced age in a South German population. The small deviations from published equations indicate that there might be some regional differences of lung function within the Caucasian population of advanced age in Europe.

Guideline adherence of tumor board recommendations in lung cancer and transfer into clinical practice.

PURPOSE: Evaluating patients and treatment decisions in a multidisciplinary tumor board has led to better quality of care and longer survival in cancer patients. The aim of this study was to evaluate tumor board recommendations for thoracic oncology patients regarding guideline adherence and transferal of recommendations into clinical practice. METHODS: We evaluated tumor board recommendations of the thoracic oncology tumor board at Ludwig-Maximilians University (LMU) Hospital Munich between 2014 and 2016. We compared patient characteristics between guideline-adherent and non-guideline-adherent recommendations, as well as between transferred and non-transferred recommendations. We used multivariate logistic regression models to evaluate factors associated with guideline adherence. RESULTS: Over 90% of recommendations by the tumor board were either adherent to the guidelines (75.5%) or over fulfilling guidelines (15.6%). Almost 90% of recommendations were transferred to clinical practice. If a recommendation was not according to the guidelines, the reason was mostly associated with the general condition (age, Charlson comorbidity index, ECOG) of the patient or due to the patients' request. Surprisingly, sex also had a significant influence on the guideline adherence of recommendations, with females being more likely to get recommendations not according to the guidelines. CONCLUSION: In conclusion, the results of this study are promising, as the guideline adherence of recommendations as well as the transferal of recommendations into clinical practice were high. In the future, a special focus should be put on fragile patients as well as female patients.

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome.

BACKGROUND: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. CASE REPORT: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. CONCLUSION: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases.

Influence of air pressure, humidity, solar radiation, temperature, and wind speed on ambulatory visits due to chronic obstructive pulmonary disease in Bavaria, Germany.

Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality in the world. The disease is often aggravated by periods of increased symptoms requiring medical attention. Among the possible triggers for these exacerbations, meteorological factors are under consideration. The objective of this study was to assess the influence of various meteorological factors on the health status of patients with COPD. For this purpose, the daily number of ambulatory care visits due to COPD was analysed in Bavaria, Germany, for the years 2006 and 2007. The meteorological factors were provided by the model at the European Centre for Medium Range Weather Forecast (ECMWF). For the multivariate analysis, a generalised linear model was used. In Bavaria, an increase of 1% of daily consultations (about 103 visits per day) was found to be associated with a change of 0.72 K temperature, 209.55 of log air surface pressure in Pa, and a decrease of 1% of daily consultations with 1,453,763 Ws m(2) of solar radiation. There also seem to be regional differences between north and south Bavaria; for instance, the effect of wind speed and specific humidity with a lag of 1 day were only significant in the north. This study could contribute to a tool for the prevention of exacerbations. It also serves as a model for the further evaluation of the impact of meteorological factors on health, and could easily be applied to other diseases or other regions.

Screening for Lung Cancer in Individuals Who Never Smoked: An International Association for the Study of Lung Cancer Early Detection and Screening Committee Report.

Screening with low-dose computed tomography of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss more than 50% of lung cancers, and in some geographic areas, such as East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials revealed the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals who never smoked are uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, and intrinsic factors, such as age, are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never smokers. It is worth considering if and how never smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries owing to multiple factors and the epidemiologic differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never smokers. This report aims to outline current knowledge on risk factors for lung cancer in never smokers to propose research strategies for this topic and initiate a broader discussion on lung cancer screening of never smokers. Similar considerations can be made in current and ex-smokers, which do not fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.