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RATIONALE: Autofluorescence bronchoscopy (AFB) is a valid strategy for detecting premalignant endobronchial lesions. However, no biomarker can reliably predict lung cancer risk of subjects with AFB-visualized premalignant lesions. OBJECTIVES: The present study set out to identify AFB-visualized squamous metaplastic (SqM) lesions with malignant potential by DNA copy number profiling. METHODS: Regular AFB examinations in 474 subjects at risk of lung cancer identified six subjects with SqM lesions at baseline, and carcinoma in situ or carcinoma (carcinoma in situ or greater) at the initial SqM site at follow-up bronchoscopy. These progressive SqM lesions were compared for immunostaining pattern and array comparative genomic hybridization-based chromosomal profiles with 23 SqM lesions of subjects who remained cancer-free. Specific DNA copy number alterations (CNAs) linked to cancer risk were identified and accuracy of CNAs to predict endobronchial cancer in this series was determined. MEASUREMENTS AND MAIN RESULTS: At baseline, p53, p63, and Ki-67 immunostaining were not predictive for a differential clinical outcome of SqM lesions. The mean number of CNAs in baseline SqM of cases was significantly higher compared with control subjects (P < 0.01). Chromosomal regions significantly more frequently altered in SqM of cases were 3p26.3-p11.1, 3q26.2-q29, 9p13.3-p13.2, and 17p13.3-p11.2 (family-wise error rate <0.10). CNAs were specifically detected at the site of future cancer. In cases, baseline-detected CNAs persisted in subsequent biopsies taken from the initial site, and levels increased toward cancer progression. In this series, a model based on CNAs at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3 predicted cancer with 97% accuracy. CONCLUSIONS: The data suggest that the presence of specific CNAs in SqM lesions predict endobronchial cancer. [ABSTRACT FROM AUTHOR]

Rationale: Some studies have shown a beneficial effect of corticosteroids in patients with community-acquired pneumonia (CAP), possibly by diminishing local and systemic antiinflammatory host response.Objectives: To assess the efficacy of adjunctive prednisolone treatment in patients hospitalized with CAP.Methods: Hospitalized patients, clinically and radiologically diagnosed with CAP using standard clinical and radiological criteria, were randomized to receive 40 mg prednisolone for 7 days or placebo, along with antibiotics. Primary outcome was clinical cure at Day 7. Secondary outcomes were clinical cure at Day 30, length of stay, time to clinical stability, defervescence, and C-reactive protein. Disease severity was scored using CURB-65 (a severity index for community-acquired pneumonia evaluating Confusion, blood Urea nitrogen, Respiratory rate, Blood pressure, and age 65 or older) and Pneumonia Severity Index.Measurements and Main Results: We enrolled 213 patients. Fifty-four (25.4%) patients had a CURB-65 score greater than 2, and 93 (43.7%) patients were in Pneumonia Severity Index class IV-V. Clinical cure at Days 7 and 30 was 84/104 (80.8%) and 69/104 (66.3%) in the prednisolone group and 93/109 (85.3%) and 84/109 (77.1%) in the placebo group (P = 0.38 and P = 0.08). Patients on prednisolone had faster defervescence and faster decline in serum C-reactive protein levels compared with placebo. Subanalysis of patients with severe pneumonia did not show differences in clinical outcome. Late failure (>72 h after admittance) was more common in the prednisolone group (20 patients, 19.2%) than in the placebo group (10 patients, 6.4%; P = 0.04). Adverse events were few and not different between the two groups.Conclusions: Prednisolone (at 40 mg) once daily for a week does not improve outcome in hospitalized patients with CAP. A benefit in more severely ill patients cannot be excluded. Because of its association with increased late failure and lack of efficacy prednisolone should not be recommended as routine adjunctive treatment in CAP. [ABSTRACT FROM AUTHOR]

RATIONALE: The role of antibiotics in acute exacerbations is controversial and their efficacy when added to systemic corticosteroids is unknown. OBJECTIVES: We conducted a randomized, placebo-controlled trial to determine the effects of doxycycline in addition to corticosteroids on clinical outcome, microbiological outcome, lung function, and systemic inflammation in patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease. METHODS: Of 223 patients, we enrolled 265 exacerbations defined on the basis of increased dyspnea and increased sputum volume with or without increased sputum purulence. Patients received 200 mg of oral doxycycline or matching placebo for 7 days in addition to systemic corticosteroids. Clinical and microbiological response, time to treatment failure, lung function, symptom scores, and serum C-reactive protein were assessed. MEASUREMENTS AND MAIN RESULTS: On Day 30, clinical success was similar in intention-to-treat patients (odds ratio, 1.3; 95% confidence interval, 0.8 to 2.0) and per-protocol patients. Doxycycline showed superiority over placebo in terms of clinical success on Day 10 in intention-to-treat patients (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.2), but not in per-protocol patients. Doxycycline was also superior in terms of clinical cure on Day 10, microbiological outcome, use of open label antibiotics, and symptoms. There was no interaction between the treatment effect and any of the subgroup variables (lung function, type of exacerbation, serum C-reactive protein, and bacterial presence). CONCLUSIONS: Although equivalent to placebo in terms of clinical success on Day 30, doxycycline showed superiority in terms of clinical success and clinical cure on Day 10, microbiological success, the use of open label antibiotics, and symptoms. Clinical trial registered with www.clinicaltrials.gov (NCT00170222). [ABSTRACT FROM AUTHOR]

Primary care physicians are often asked to provide sideline medical coverage at school athletic events. They may also be asked to cover organized adult recreational leagues and less formal events at community centers or neighborhood parks. Guidelines that describe the contents of sideline medical bags often focus on covering collegiate or professional contests. Having a well-thought-out plan of action and the necessary resources and equipment to deal with medical emergencies at less formal community venues is no less important. [ABSTRACT FROM AUTHOR]

Primary care physicians must be able to recognize wrist and hand injuries that require immediate attention. A complete history and physical examination, including assessment of distal limb function, are essential. Hemorrhage control is necessary in patients with vessel lacerations and amputations. Amputations require an understanding of the indications and contraindications in the management of the amputated limb. High-pressure injection injuries and compartment syndromes require a high index of suspicion for early recognition. Infectious entities include 'fight bite,' open fractures, purulent tenosynovitis, animal bites, and retained foreign bodies. Tendon disruptions should be recognized early to optimize management. [ABSTRACT FROM AUTHOR]

Diagnosis of upper extremity injuries depends on knowledge of basic anatomy and biomechanics of the hand and wrist. The wrist is composed of two rows of carpal bones. Flexor and extensor tendons cross the wrist to allow function of the hand and digits. The ulnar, median, and radial nerves provide innervation of the hand and wrist. A systematic primary and secondary examination of the hand and wrist includes assessment of active and passive range of motion of the wrist and digits, and dynamic stability testing. The most commonly fractured bone of the wrist is the scaphoid, and the most common ligamentous instability involves the scaphoid and lunate. [ABSTRACT FROM AUTHOR]

Rachida Rafiq,1 Hendrik J Prins,2 Wim G Boersma,2 Johannes MA Daniels,3 Martin den Heijer,1 Paul Lips,1 Renate T de Jongh1 1Department of Internal Medicine and Endocrinology, VU University Medical Center, Amsterdam, 2Department of Pulmonary Diseases, Northwest Hospital group, Alkmaar, 3Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands Background: Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function. In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections. As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients. Objective: To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients. Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life. Methods: We performed a randomized, double-blind, placebo-controlled pilot trial. Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months. Study visits were conducted at baseline, and at 3 and 6 months after randomization. During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed. In addition, participants kept a diary card in which they registered respiratory symptoms. Results: At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group. Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P

Musculoskeletal complaints are among the leading reasons for visits to physicians, and about one third of these patients meet diagnostic criteria for myofascial pain syndrome (MPS). Although MPS was identified more than a century ago, debate over its existence as a separate clinical entity continues. Physicians who learn to identify characteristic symptoms can differentiate MPS from fibromyalgia and provide effective treatment. Key to treatment is identification of trigger points that when stimulated produce patterns of pain throughout a limb or region. Treatment modalities for MPS include trigger point injection, shiatsu, and the spray and stretch technique. Prognosis for MPS is better than that for fibromyalgia, and treatment usually follows an individualized regimen. [ABSTRACT FROM AUTHOR]

Lumbosacral back pain is one of the most common reasons for patients with a work-related injury to present to a primary care physician. In most cases, low back pain has a good prognosis, but the condition is often the source of much frustration for clinicians, patients and employers. The family physician should be able to treat the patient's symptoms and address the psychosocial issues that frequently complicate recovery. Three decision points, based on the history and physical examination, allow the physician to determine the severity of illness and implement an appropriate treatment plan. These three points are as follows: Is it likely that systemic disease or bone pathology is the cause of pain? Has neurologic compromise occurred? Are social or psychologic stressors present that may prolong the clinical course? [ABSTRACT FROM AUTHOR]

Background: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB., Methods: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed., Findings: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy., Interpretation: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB., Funding: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers., Competing Interests: Declaration of interests All authors declare no competing interests. The workshop in Tübingen to assure harmonisation of the transbronchial cryobiopsy procedure was, in part, sponsored by Erbe Elektromedizin, Tübingen, Germany., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients., Objectives: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD., Methods: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life., Results: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes., Conclusions: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: In the context of an ongoing debate on the potential risks of hypoxemia and hyperoxemia, it seems prudent to maintain the partial arterial oxygen pressure (PaO2) in a physiological range during administration of supplemental oxygen. The PaO2 and peripheral oxygen saturation (SpO2) are closely related and both are used to monitor oxygenation status. However, SpO2 values cannot be used as an exact substitute for PaO2. The aim of this study in acutely ill and stable patients was to determine at which SpO2 level PaO2 is more or less certain to be in the physiological range., Methods: This is an observational study prospectively collecting data pairs of PaO2 and SpO2 values in patients admitted to the emergency room or intensive care unit (Prospective Inpatient Acutely ill cohort; PIA cohort). A second cohort of retrospective data of patients who underwent pulmonary function testing was also included (Retrospective Outpatient Pulmonary cohort; ROP cohort). Arterial hypoxemia was defined as PaO2 < 60 mmHg and hyperoxemia as PaO2 > 125 mmHg. The SpO2 cut-off values with the lowest risk of hypoxemia and hyperoxemia were determined as the 95th percentile of the observed SpO2 values corresponding with the observed hypoxemic and hyperoxemic PaO2 values., Results: 220 data pairs were collected in the PIA cohort. 95% of hypoxemic PaO2 measurements occurred in patients with an SpO2 below 94%, and 95% of hyperoxemic PaO2 measurements occurred in patients with an SpO2 above 96%. Additionally in the 1379 data pairs of the ROP cohort, 95% of hypoxemic PaO2 measurements occurred in patients with an SpO2 below 93%., Conclusion: The SpO2 level marking an increased risk of arterial hypoxemia is not substantially different in acutely ill versus stable patients. In acutely ill patients receiving supplemental oxygen an SpO2 target of 95% maximizes the likelihood of maintaining PaO2 in the physiological range., Competing Interests: The authors have declared that no competing interests exist.

Background: Accurate diagnosis and staging are crucial to ensure uniform allocation to the optimal treatment methods for non-small cell lung cancer (NSCLC) patients, but may differ among multidisciplinary tumor boards (MDTs). Discordance between clinical and pathologic TNM stage is particularly important for patients with locally advanced NSCLC (stage IIIA) because it may influence their chance of allocation to curative-intent treatment. We therefore aimed to study agreement on staging and treatment to gain insight into MDT decision-making., Research Question: What is the level of agreement on clinical staging and treatment recommendations among MDTs in stage IIIA NSCLC patients?, Study Design and Methods: Eleven MDTs each evaluated the same 10 pathologic stage IIIA NSCLC patients in their weekly meeting (n = 110). Patients were selected purposively for their challenging nature. All MDTs received exactly the same clinical information and images per patient. We tested agreement in cT stage, cN stage, cM stage (TNM 8th edition), and treatment proposal among MDTs using Randolph's free-marginal multirater kappa., Results: Considerable variation among the MDTs was seen in T staging (κ, 0.55 [95% CI, 0.34-0.75]), N staging (κ, 0.59 [95% CI, 0.35-0.83]), overall TNM staging (κ, 0.53 [95% CI, 0.35-0.72]), and treatment recommendations (κ, 0.44 [95% CI, 0.32-0.56]). Most variation in T stage was seen in patients with suspicion of invasion of surrounding structures, which influenced such treatment recommendations as induction therapy and type. For N stage, distinction between N1 and N2 disease was an important source of discordance among MDTs. Variation occurred between 2 patients even regarding M stage. A wide range of additional diagnostics was proposed by the MDTs., Interpretation: This study demonstrated high variation in staging and treatment of patients with stage IIIA NSCLC among MDTs in different hospitals. Although some variation may be unavoidable in these challenging patients, we should strive for more uniformity., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Resection is the standard treatment for stage I non-small cell lung cancer (NSCLC) in operable patients. Stereotactic body radiotherapy (SBRT) is recommended for inoperable patients. A shift from surgery to SBRT is expected in elderly patients due to increased frailty and competing risks. We assessed the current influence of age on treatment decision-making and overall survival (OS)., Materials and Methods: We performed a retrospective cohort study using data from patients with clinical stage I NSCLC diagnosed in 2012-2016 and treated with lobectomy, segmentectomy, wedge resection, or SBRT, retrieved from the Netherlands Cancer Registry. Patient characteristics and OS were compared between SBRT and (sub)lobar resection for patients aged 18-79 and ≥80 years., Results and Conclusion: 8764 patients treated with lobectomy (n = 4648), segmentectomy (n = 122), wedge resection (n = 272), or SBRT (n = 3722) were included. In 2012-2016, SBRT was increasingly used for octogenarians and younger patients from 75.3% to 83.7% and from 30.8% to 43.2%, respectively. Five-year OS in the whole population was 70% after surgery versus 39% after SBRT and 50% versus 27% in octogenarians. After correction for age, gender, year of diagnosis, and clinical T-stage, OS was equal after lobectomy and SBRT in the first 2 years after diagnosis. However, after >2 years, OS was better after lobectomy than after SBRT. SBRT is the prevailing treatment in octogenarians with stage I NSCLC. While surgery is associated with better OS than SBRT, factors other than treatment modality (e.g. comorbidity) may have had a significant impact on survival. The wider application of SBRT in octogenarians likely reflects the frailty of this group. Registries and trials are required to identify key determinants of frailty in this specific population to improve patient selection for surgery or SBRT., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

When searching for evidence-based answers about treating athletes with low back injury/pain, there are some difficulties. The first is defining who is an athlete. The second problem is that the lifetime prevalence of low back pain in the general population in our country approaches 100. Last, most studies published only deal with a narrow population of athletes, often performing very different types of physical activity. We searched the literature for studies that specifically evaluated athletes longitudinally. This article reviews the demographics, diagnostic challenges, history and physical examination, imaging choices, treatment, and controversies encountered when treating this population., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ventricular tachycardia (VT) storm, defined as recurrent VT requiring electrical cardioversion ≥3 times within 24 hours, is a rare presentation of long-QT syndrome. Pharmacologic autonomic modulation and/or left cardiac sympathetic denervation are established therapies in long-QT syndrome in adults but may not be effective or practical in the emergent treatment of VT storm. We present a novel case of a child with drug-refractory VT storm and prolonged QT requiring extracorporeal membrane oxygenation (ECMO) support. Continuous stellate ganglion blockade was remarkably effective in stabilizing his rhythm and should be considered in similar pediatric cases.

Objectives: Organization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging., Materials and Methods: General numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy., Results: In 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands., Conclusion: Surgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Optimal treatment selection for patients with non-small cell lung cancer (NSCLC) depends on the clinical stage of the disease. Particularly patients with mediastinal lymph node involvement (stage IIIA-N2) should be identified since they generally do not benefit from upfront surgery. Although the standardized preoperative use of PET-CT, EUS/EBUS and/or mediastinoscopy identifies most patients with mediastinal lymph node metastasis, a proportion of these patients is only diagnosed after surgery. The objective of this study was to identify all patients with unforeseen N2 disease after surgical resection for NSCLC in a large nationwide database and to evaluate the preoperative clinical staging process., Methods: Data was derived from the Dutch Lung Surgery Audit. Patients with pathological stage IIIA NSCLC after an anatomical resection between 2013 and 2015 were evaluated. Clinical and pathological TNM-stage were compared and an analysis was performed on the diagnostic work-up of patients with unforeseen N2 disease., Results: From 3585 patients undergoing surgery for NSCLC between 2013 and 2015, a total of 527 patients with pathological stage IIIA NSCLC were included. Of all 527 patients, 254 patients were upstaged from a clinical N0 (n = 186) or N1 (n = 68) disease to a pathological N2 disease (7.1% unforeseen N2). In these 254 patients, 18 endoscopic ultrasounds, 62 endobronchial ultrasounds and 67 mediastinoscopies were performed preoperatively., Conclusions: In real world clinical practice in The Netherlands, the percentage of unforeseen N2 disease in patients undergoing surgery for NSCLC is seven percent. To further reduce this percentage, optimization of the standardized preoperative workup is necessary., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Blood eosinophilia is frequently encountered in patients with AECOPD. However the impact of blood eosinophilia at admission in patients with AECOPD on outcome on the short and long term has not been extensively studied which was the objective of the present study., Methods: We used data of 207 exacerbations from a randomized clinical trial on antibiotic prescription based upon CRP-levels versus GOLD guided strategy and analyzed the impact of blood eosinophils (≥2% of total white cell count and eosinophil count ≥300 cell/microliter) on clinical outcome., Results: 207 patients were included of whom 39 (18·8%) had eosinophilia ≥2%, 23 patients (11.1%) had blood eosinophil ≥300 cell/microliter. Eosinophilia was associated with shorter median length of stay in the eosinophilic groups(≥2% and ≥300 cell/microliter) compared to the non-eosinophilic groups. Early treatment failure was reduced in the both the eosinophilic groups (≥2% and ≥300 cell/microliter). Late treatment failure (day 11-30) did not differ between the groups. Relapse, was more frequent the eosinophilic groups (≥2% and ≥300 cell/microliter), however in the latter group this did not reach statistical significance. Eosinophilia ≥2% was a risk factor for having relapse (eosinophilia ≥2%: HR = 2·351; 95%CI 1·335-4·139), whereas eosinophilia <2% was associated with a lower risk factor for having early treatment failure (HR = 0·339 95%CI 0·122-0·943)., Conclusion: We showed that blood eosinophilia at admission in patients with an AECOPD is associated with higher short-term treatment success rate. However, blood eosinophilia ≥2% predicts a less favorable outcome due to an increased risk of relapse., Clinical Trial Registration: NCT01232140., (Copyright © 2017. Published by Elsevier Ltd.)

Survival of all non-small cell lung cancer (NSCLC) patients is disappointing, with a 5-year survival of 18%. Staging NSCLC patients is crucial because it determines the choice of treatment and prognosis. Clinical staging is a complex process that comes with many challenges and with low accuracy between the clinical and pathological stage. Treatment modalities for stage I-III NSCLC consist of surgical resection, radiotherapy and chemotherapy. This review describes the current evidence on staging and the implications on adjuvant chemotherapy. For stage I disease, staging is most accurate. Primary treatment consists of surgery or stereotactic ablative radiotherapy. When a patient has stage II disease, staging is less accurate because more diagnostic modalities are necessary to stage the mediastinal lymph nodes. Surgery remains the primary treatment modality and platinum-based adjuvant chemotherapy gives a 4% 5-year survival benefit. Staging patients with stage III disease is difficult because of the heterogeneity of the patients. It should be decided if a patient has potentially resectable disease with or without risk of incomplete resection. Induction therapy with chemo(radio)therapy followed by surgical resection or definitive chemoradiotherapy are the treatments of choice. The 5-year survival can reach 44% in selected patients. Decisions in staging and treating patients with NSCLC should be made by a multidisciplinary team with sufficient expertise in all aspects of staging and treatment., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

The treatment of advanced nonsmall cell lung cancer (NSCLC) with PD-1/PD-L1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find better biomarkers than PD-L1 immunohistochemistry (IHC) that will identify patients likely to benefit from this therapy. In this exploratory study we assessed the differences in T-cell subsets and PD-1 expression levels on T-cells in tumour-draining lymph nodes (TDLNs) and peripheral blood mononuclear cells (PBMCs). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLNs of patients with NSCLC, and the results were compared to paired PBMC samples. For a select number of patients, we were also able to obtain cells from a non-TDLN (NTDLN) sample. Our data show that the frequency of PD-1 + CD4 + and CD8 + T-cells, as well as the PD-1 expression level on activated regulatory T (aT reg ) and CD4 + and CD8 + T-cells, are higher in TDLNs than in PBMCs and, in a small sub-analysis, NTDLNs. These elevated PD-1 expression levels in TDLNs may reflect tumour-specific T-cell priming and conditioning, and may serve as a predictive or early-response biomarker during PD-1 checkpoint blockade., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD).In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events.There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (-2.6 (-9.0-1.5)) and isotonic saline (-0.3 (-8.1-6.1)) in 22 patients (age range 22-73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild.12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials., (Copyright ©ERS 2017.)

Background: The clinical stage of non-small cell lung cancer (NSCLC) determines the initial treatment, whereas the pathologic stage best determines prognosis and the need for adjuvant treatment. In an era in which stereotactic ablative radiotherapy (SABR) has become an alternative modality to surgical intervention, clinical staging is even more important, because pathologic staging is omitted in the case of SABR. The objective of this study was to determine the concordance between clinical and pathologic stage in routine clinical practice for patients with early-stage NSCLC., Methods: Prospective data were derived from the Dutch Lung Surgery Audit (DLSA) in 2013 and 2014. Patients with clinical stage I NSCLC who underwent surgical resection and had a positron emission tomography-computed tomography (PET-CT) scan in their clinical workup were selected. Clinical and pathologic TNM (cTNM and pTNM) stages were compared., Results: From a total of 1,790 patients with clinical stage I, 1,555 (87%) patients were included in this analysis. Concordance between cTNM and pTNM was 59.9%. Of the patients with clinical stage I, 22.6% were upstaged to pathologic stage II or higher. In total, 14.9% of all patients with clinical stage I had nodal metastases, and 5.5% of all patients had unforeseen N2 disease. In patients with clinical stage T2a tumors, 21.3% had nodal metastases, 14.5% being N1 and 6.7% being N2 disease., Conclusions: Concordance between clinical and pathologic stage is 59.9%. In patients with clinical stage I NSCLC, 22.6% were upstaged to pathologic stage II or higher, which is an indication for adjuvant chemotherapy. Improvement in accuracy of staging is thus needed, particularly for these patients., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Clinical staging of non-small cell lung cancer (NSCLC) determines the initial treatment offered to a patient. The similarity between clinical and pathologic staging in some studies is as low as 50%, and others publish results as high as 91%. The Dutch Lung Surgery Audit is a clinical database that registers the clinical and pathologic TNM of almost all NSCLC patients who undergo operations in the Netherlands. The objective of this study was to determine the accuracy of clinical staging of NSCLC., Methods: Prospective data were derived from the Dutch Lung Surgery Audit in 2013 and 2014. Patients were included if they had undergone a surgical resection for stage IA to IIIB NSCLC without neoadjuvant treatment and had a positron emission tomography-computed tomography scan as part of the clinical workup. Clinical (c)TNM and pathologic (p)TNM were compared, and whether discrepancy was based on tumor or nodal staging was determined., Results: From 2,834 patients identified, 2,336 (82.4%) fulfilled the inclusion criteria and had complete data. Of these 2,336, 1,276 (54.6%) were staged accurately, 707 (30.3%) were clinically understaged, and 353 (15.1%) were clinically overstaged. In the understaged group, 346 patients had a higher pN stage (14.8%), of which 148 patients had unforeseen N2 disease (6.3%). In the overstaged group, 133 patients had a cN that was higher than the pN (5.7%)., Conclusions: Accuracy of NSCLC staging in the Netherlands is low (54.6%), even in the era of positron emission tomography-computed tomography. Especially accurate nodal staging remains challenging. Future efforts should include the identification of specific pitfalls in NSCLC staging., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Infectious complications occur following pulmonary resections preceded or not by induction chemoradiotherapy. We aimed to investigate whether bacterial colonization of the bronchial tree at the time of surgery was associated with postoperative complications., Patients and Methods: A retrospective analysis of all patients who underwent open anatomical pulmonary resections for malignancies at a single center was performed. Demographical data of the included patients, intraoperative data, and data on the postoperative course of patients were collected. Outcome of patients with a positive intraoperative bronchial culture was compared to patients with a negative bronchial culture. Relations between the presence of potential bacterial pathogens in the bronchial tree and other possible risk factors for the development of postoperative infectious and non-infectious complications, were analyzed using uni- and multivariate analysis., Results: Between January 2010 and January 2012, a total of 121 consecutive patients underwent open anatomical pulmonary resections for malignancy, of whom 45 were preceded by induction chemoradiotherapy and 5 by induction chemotherapy. Intraoperative bronchial cultures were taken from 58 patients (48 %). Patients with a positive bronchial culture developed significantly more infectious (88 % vs. 20 %, p < 0.001) and non-infectious complications (63 % vs. 12 %, p = 0.001). Positive intraoperative bronchial cultures showed the strongest association with the development of infectious and non-infectious postoperative complications (OR 24.8 and 12.2, respectively). After multivariate analysis, only BMI less than 20 kg/m(2) and the presence of a positive intraoperative bronchial culture were found to be independent risk factors for the development of infectious complications. Chemoradiotherapy was not associated with postoperative complications in the present study., Conclusions: Bacterial colonization of the bronchial tree assessed intraoperatively, appears to be associated with higher rates of infectious and non-infectious complications after pulmonary resection. Whether early starting of appropriate antibiotics based on intraoperative-taken culture findings will reduce the infectious complication rate in a subcategory of patients needs to be investigated.

Background: Infants with complex congenital heart disease are at high risk for developmental delays. Although the etiology of these delays is multifactorial, the physical environment may be a contributory factor. Extensive studies have been conducted in neonatal intensive care units measuring environmental influences on development, resulting in policy and practice changes. Cardiothoracic intensive care units and cardiac step-down units are new environments in which newborns with heart disease receive care. No environmental studies have been conducted in units caring for newborn infants recovering from cardiac surgery., Objective: The aim of this study is to examine the environmental experience of a newborn infant with heart disease after surgical intervention within the first month of life., Methods: Measurements of illumination, sound levels, and sleep were recorded on 1 infant for 2 consecutive postoperative days in the cardiothoracic intensive care unit and 2 consecutive days in the step-down unit., Results: Although average daily noise exposure remained below recommended guidelines on 3 of 4 days, the infant experienced intermittent periods of excessive noise (≥55 dBA) during 59 of 87 hours and 110 episodes of acute noise events greater than 70 dBA. Average daily light exposure was below the recommended guidelines. However, light levels were more than twice the recommended levels at multiple points daily. For each of the 4 observation days, the infant experienced 66 to 102 awakenings during sleep, and sleep durations were less than 30 minutes 90% of the time., Conclusions: This study provides the first report of potential environmental stressors in newborn infants cared for in cardiac specialty units. Excessive levels of light and noise as well as frequent interruptions for medical and nursing care may contribute to disorganized sleep and increased patient distress and may impact subsequent neurodevelopment. Studies are needed to identify potentially adverse aspects of the intensive caregiving environment for newborn infants who have undergone cardiac surgery.

We report Coulomb mediated hybridization of excitonic states in optically active InGaAs quantum dot molecules. By probing the optical response of an individual quantum dot molecule as a function of the static electric field applied along the molecular axis, we observe unexpected avoided level crossings that do not arise from the dominant single-particle tunnel coupling. We identify a new few-particle coupling mechanism stemming from Coulomb interactions between different neutral exciton states. Such Coulomb resonances hybridize the exciton wave function over four different electron and hole single-particle orbitals. Comparisons of experimental observations with microscopic eight-band k·p calculations taking into account a realistic quantum dot geometry show good agreement and reveal that the Coulomb resonances arise from broken symmetry in the artificial semiconductor molecule.

Unlabelled: Neutrophilic inflammation plays a causal role in Chronic Obstructive Pulmonary Disease (COPD). Neutrophil derived myeloperoxidase(MPO) matrix metalloproteinases(MMP's), and elastases are thought to contribute to the perpetuation of the disease. The tetracycline analogue doxycycline has been shown to inhibit neutrophil-mediated inflammation. It was thus reasoned that doxycycline may attenuate neutrophil-mediated inflammation in COPD., Methods: In this double blind randomized controlled trial the effect of a 3-week course of doxycycline on sputum and systemic inflammatory parameters was evaluated in stable COPD patients. In order to exclude inflammation by bacterial colonisation patients must have 2 negative sputum cultures in the previous year. The effect of doxycycline treatment on inflammatory markers (TNF-α, IL-1β and IL-6) and neutrophil specific markers in sputum (MPO, MMP's, and IL-8) and serum C-reactive protein was evaluated. Sputum was obtained by sputum induction with hypertonic saline., Results: A total of 41 patients were included. Ten patients were excluded as they were not able to produce sputum at the first or second visit. Baseline characteristics were similar in the two groups. In the remaining patients doxycycline did not influence sputum MPO concentrations. Also MMP-8 and 9, IL-6 and IL-8 concentrations as well as lung function parameters were not affected by doxycycline. Systemic inflammation by means of CRP was also not influenced by doxycycline., Conclusion: A three week course of doxycycline did not influence MPO sputum levels nor any of the other inflammatory sputum and systemic markers., Trial Registry: ClinicalTrials.gov; No.: NCT00857038 URL: clinicaltrials.gov., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear., Objectives: To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions., Methods: In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS)., Measurements and Main Results: During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05)., Conclusions: Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies.

Background: Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients., Methods/design: We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate., Discussion: This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined., Trial Registration: This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

A polarization sensitive endoscopic optical frequency domain imaging (PS-OFDI) system with a motorized distal scanning catheter is demonstrated. It employs a passive polarization delay unit to multiplex two orthogonal probing polarization states in depth, and a polarization diverse detection unit to detect interference signal in two orthogonal polarization channels. Per depth location four electro-magnetic field components are measured that can be represented in a complex 2x2 field matrix. A Jones matrix of the sample is derived and the sample birefringence is extracted by eigenvalue decomposition. The condition of balanced detection and the polarization mode dispersion are quantified. A complex field averaging method based on the alignment of randomly pointing field phasors is developed to reduce speckle noise. The variation of the polarization states incident on the tissue due to the circular scanning and catheter sheath birefringence is investigated. With this system we demonstrated imaging of ex vivo chicken muscle, in vivo pig lung and ex vivo human lung specimens.

Ischemia with subsequent necrosis of anastomoses, after central airway resection and reconstruction, remains a feared complication for thoracic surgeons and their patients. To date, there is no evidence to support the use of hyperbaric oxygen in the prevention of necrosis of airway reconstructions in humans. We present a patient who underwent central airway surgery with postoperative ischemia of an end-to-side anastomosis. Repeat visit to a hyperbaric oxygen chamber seemed to prevent the anastomosis from subsequent necrosis and dehiscence with complete healing as a result. In conclusion, hyperbaric oxygen treatment can be considered when ischemia or necrosis is observed in central airway anastomoses during postoperative bronchoscopic surveillance., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Unlabelled: A common feature of infection by positive-sense RNA virus is the modification of host cell cytoplasmic membranes that serve as sites of viral RNA synthesis. Coronaviruses induce double-membrane vesicles (DMVs), but the role of DMVs in replication and virus fitness remains unclear. Coronaviruses encode 16 nonstructural proteins (nsps), three of which, nsp3, nsp4, and nsp6, are necessary and sufficient for DMV formation. It has been shown previously that mutations in murine hepatitis virus (MHV) nsp4 loop 1 that alter nsp4 glycosylation are associated with disrupted DMV formation and result in changes in virus replication and RNA synthesis. However, it is not known whether DMV morphology or another function of nsp4 glycosylation is responsible for effects on virus replication. In this study, we tested whether mutations across nsp4, both alone and in combination with mutations that abolish nsp4 glycosylation, affected DMV formation, replication, and fitness. Residues in nsp4 distinct from glycosylation sites, particularly in the endoplasmic reticulum (ER) luminal loop 1, independently disrupted both the number and morphology of DMVs and exacerbated DMV changes associated with loss of glycosylation. Mutations that altered DMV morphology but not glycosylation did not affect virus fitness while viruses lacking nsp4 glycosylation exhibited a loss in fitness. The results support the hypothesis that DMV morphology and numbers are not key determinants of virus fitness. The results also suggest that nsp4 glycosylation serves roles in replication in addition to the organization and stability of MHV-induced double-membrane vesicles., Importance: All positive-sense RNA viruses modify host cytoplasmic membranes for viral replication complex formation. Thus, defining the mechanisms of virus-induced membrane modifications is essential for both understanding virus replication and development of novel approaches to virus inhibition. Coronavirus-induced membrane changes include double-membrane vesicles (DMVs) and convoluted membranes. Three viral nonstructural proteins (nsps), nsp3, nsp4, and nsp6, are known to be required for DMV formation. It is unknown how these proteins induce membrane modification or which regions of the proteins are involved in DMV formation and stability. In this study, we show that mutations across nsp4 delay virus replication and disrupt DMV formation and that loss of nsp4 glycosylation is associated with a substantial fitness cost. These results support a critical role for nsp4 in DMV formation and virus fitness., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder affecting motile cilia. This can lead to neonatal respiratory distress, early onset upper and lower airway infections, laterality abnormalities and sub- or infertility. Although disease progression shows large individual variability, all adult patients eventually develop extensive bronchiectasis. As in cystic fibrosis, early diagnosis and frequent follow-up with microbiological control is the best therapeutic strategy, as other treatment options are lacking. PCD is underdiagnosed and diagnosed late due to clinical unawareness, limited availability of diagnostic tests and difficult interpretation of test results. Diagnosis is currently based on a combination of assessment of ciliary motion and ultrastructure by high-speed video microscopy and electron microscopy, respectively. As nasal nitric oxide is low in almost all PCD patients, these measurements can be used for screening. Although there are 26 PCD genes known so far, the genetic basis of the disease has not been unraveled in an estimated 30-40% of patients. However, the rapid discovery of novel PCD genes in recent years is expected to enable accurate genetic characterization of most patients in the near future. Large-scale use of next-generation sequencing and the availability of large ciliary proteomic and transcriptomic databases accelerate the identification of novel PCD genes, especially those that play a key role in cytoplasmic assembly of ciliary ultrastructural components. These genetic advances are revolutionizing the process of obtaining a molecular diagnosis for PCD as we speak and may ultimately lead to an increased understanding of ciliogenesis and function, providing novel handles for therapeutic interventions in PCD patients.

We recently identified a DNA copy number aberration (CNA)-based classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia. The current study was set out to validate the prediction accuracy of this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions. The study included 36 high-risk subjects who had endobronchial lesions of various histological grades that were identified and biopsied by autofluorescence bronchoscopy and were subjected to arrayCGH in a nested case-control design. Of the 36 patients, 12 had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer free (78 months, range 21-142). The previously defined CNA-based classifier demonstrated 92% (95% CI 77% to 98%) accuracy for cancer (in situ) prediction. All nine subjects with CNA-based classifier-positive endobronchial lesions at baseline experienced cancer outcome, whereas all 24 controls and 3 cases were classified as being low risk. In conclusion, CNAs prove to be a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic intervention or surveillance.

Background: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis., Methods: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves., Results: CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%)., Conclusion: Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide. The majority of patents presenting with NSCLC have advanced disease, which precludes curative treatment. Early detection and treatment might result in the identification of more patients with early central lung cancer and improve survival. In addition, the study of early lung cancer improves understanding of lung carcinogenesis and might also reveal new treatment targets for advanced lung cancer. Bronchoscopic investigation of the central airways can reveal both early central lung cancer in situ (stage 0) and other preinvasive lesions such as dysplasia. In the current review we discuss the detection of early squamous lung cancer, the natural history of preinvasive lesions and whether biomarkers can be used to predict progression to cancer. Finally we will review the staging and management of preinvasive lung cancer lesions and the different therapeutic modalities that are available.

Introduction: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital, and oropharyngeal cancers. Since a causal contribution of hrHPV infection to lung cancer (LC) is still a matter of debate, a comprehensive study was performed to delineate hrHPV involvement in LC, using a Dutch study population., Methods: Archival tissue specimens from 223 patients (145 men, 78 women, median age 65 years, range 27-87 years), who presented with cancer in the lungs, were subjected to GP5+/6+ polymerase chain reaction and p16 immunohistochemistry. The series included primary lung carcinomas of patients without a history of cancer (n = 175), primary lung carcinomas of patients with an unrelated cancer in the past (n = 36), and carcinomas with primary presentation in the lungs of which the origin (i.e., primary or metastasis) was equivocal at the time of diagnosis (n = 12). GP5+/6+ polymerase chain reaction/p16 double-positive carcinomas were subjected to HPV genotyping, HPVE7 transcript analysis, loss of heterozygosity analysis, and array-comparative genomic hybridization., Results: Whereas all primary lung carcinomas were hrHPV-negative (211 of 211, 100%), three hrHPV-positive equivocal carcinomas (3 of 12, 25%) were identified. These patients (1 male, 2 females) had a history of hrHPV-associated disease; one tonsillar and two cervical carcinomas. A clonal relationship between individual tumor pairs was supported by identical hrHPV genotype, pattern of p16 expression, HPVE7 mRNA expression, and genomic aberrations., Conclusions: hrHPV presence in a tumor with primary presentation in the lungs signifies pulmonary metastasis from a primary hrHPV-positive cancer elsewhere in the body. No support was found for an attribution of hrHPV infection to the development of primary LC.

Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low-quality studies that use a surrogate end-point that relates to the clinical end-point in a partial manner at most. Such a medicine would surely not be recommended. The use of recombinant human erythropoietin (rHuEPO) to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to examine the evidence for the ergogenic properties of this drug, which is normally used to treat anaemia in chronic renal failure patients. The results of this literature search show that there is no scientific basis from which to conclude that rHuEPO has performance-enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying, at least. The use of rHuEPO in cycling is rife but scientifically unsupported by evidence, and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well-controlled trial in athletes in real-life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification to suggest that this would eradicate its use., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Increased concentrations of free-circulating plasma DNA (cpDNA) are observed in patients with invasive cancer, including lung cancer. Whether cpDNA levels are elevated in subjects with high-grade pre-invasive lesions of lung squamous cell carcinoma (SqCC) and whether its detection may be of value for identifying subjects at the highest risk of developing lung SqCC is currently unknown. The present study assessed cpDNA levels in subjects with high- and low-grade pre-invasive squamous endobronchial lesions relative to patients with clinically overt lung SqCC and healthy controls using real-time quantitative PCR methodology. The median cpDNA levels of the patients with invasive lung SqCC (n=16) were significantly higher compared with those of the healthy controls (n=16; P<0.01), whereas the cpDNA levels in the subjects with pre-invasive lesions (n=20) did not differ from those of the controls (P=0.29). The cpDNA levels in subjects with high-grade pre-invasive lesions were highly similar to those diagnosed with low-grade pre-invasive lesions (P=0.85). Our data suggest that cpDNA levels are not increased during the pre-invasive stages of lung squamous carcinogenesis.