A Combined Cyto- and Histopathological Diagnostic Approach Reduces Time to Diagnosis and Time to Therapy in First Manifestation of Metastatic Spinal Disease: A Cohort Study.

Malignant spinal lesions (MSLs) are frequently the first manifestation of malignant disease. Spinal care, diagnostic evaluation, and the initiation of systemic therapy are crucial for outcomes in patients (pts) with advanced cancer. However, histopathology (HP) may be time consuming. The additional evaluation of spinal lesions using cytopathology (CP) has the potential to reduce the time to diagnosis (TTD) and time to therapy (TTT). CP and HP specimens from spinal lesions were evaluated in parallel in 61 pts (CP/HP group). Furthermore, 139 pts in whom only HP was performed were analyzed (HP group). We analyzed the TTD of CP and HP within the CP/HP group. Furthermore, we compared the TTD and TTT between the groups. The mean TTD in CP was 1.7 ± 1.7 days (d) and 8.4 ± 3.6 d in HP (p < 0.001). In 13 pts in the CP/HP group (24.1%), specific therapy was initiated based on the CP findings in combination with imaging and biomarker results before completion of HP. The mean TTT in the CP/HP group was 21.0 ± 15.8 d and was significantly shorter compared to the HP group (28.6 ± 23.3 d) (p = 0.034). Concurrent CP for MSLs significantly reduces the TTD and TTT. As a result, incorporating concurrent CP for analyzing spinal lesions suspected of malignancy might have the potential to enhance pts' quality of life and prognosis in advanced cancer. Therefore, we recommend implementing CP as a standard procedure for the evaluation of MSLs.

[Interdisciplinary diagnostics and therapy of malignant mesothelioma]. / Interdisziplinäre Diagnostik und Therapie von malignen Mesotheliomen.

The asbestos-related malignant mesothelioma (MM) is one of the common occupational cancers in Germany with approximately 1000 new cases per year. Provided that the appropriate diagnostic criteria are fulfilled, MM can be diagnosed with high specificity from both histological and cytological specimens. However, many MM are detected cyto-/histologically only at advanced stages. Clinical/radiological aspects complement each other and enable interdisciplinary assessment of tumor stage and individualized decisions on the best possible therapeutic options. Diagnostically, video-assisted thoracoscopy (VATS) has the highest priority. Therapy planning is based on the MM subtype, tumor spread and stage, and the patient's clinical condition. MM has generally a very unfavorable prognosis. Accordingly, the standard therapy aims at a macroscopic radical tumor resection in terms of cytoreduction within the framework of a suitable multimodal therapy concept (chemotherapy, radiotherapy, psychooncology). The aim of palliative measures should be primarily symptom control. Overall, interdisciplinary diagnosis and therapy of MM is crucial for the best possible care of MM patients.

Rapid Remote Online Evaluation in Endoscopic Diagnostics: An Analysis of Biopsy-Proven Respiratory Cytopathology.

BACKGROUND: This prospective study assesses the use of rapid remote online cytological evaluation for diagnosing endoscopical achieved biopsies. It focuses on its effectiveness in identifying benign and malignant conditions using digital image processing. METHODS: The study was conducted between April 2021 and September 2022 and involved analyses of 314 Rapid Remote Online Cytological Evaluations in total (154 imprint cytologies, 143 fine needle aspirations and 17 brush cytologies) performed on 239 patients at the LungenClinic Grosshansdorf. During on-site evaluation via telecytology, the time requirement was recorded and the findings were compared with the cyto-/histological and final diagnoses. RESULTS: By means of rapid remote online evaluation, findings of 86 cytological benign, 190 malignant and 38 unclear diagnoses were recorded (Ø assessment time, 100 s; range, 11-370 s). In 27 of the 37 specimens with unclear diagnoses, the final findings were malignant tumours and only 6 were benign changes. The diagnosis of another 4 of these 37 findings remained unclear. Excluding these 37 specimens, rapid remote online evaluation achieved a sensitivity of 90.5% with a specificity of 98.5% and a correct classification rate of 92.4% with regard to the final diagnosis of all cases. As expected, an increase in the sensitivity rate for the cytological detection of malignant tumours (76.1% vs. 92.5%) was found especially in fine-needle aspirations. CONCLUSIONS: Rapid remote online analysis allows the fast quantitative and qualitative evaluation of clinically obtained cytological specimens. With a correct classification rate of more than 93%, sampling deficiencies can be corrected promptly and diagnostic and therapeutic approaches can be derived.

Comparative evaluation of PD-L1 expression in cytology imprints, circulating tumour cells and tumour tissue in non-small cell lung cancer patients.

Alternative sources of tumour information need to be explored in patients with non-small cell lung cancer (NSCLC). Here, we compared programmed cell death ligand 1 (PD-L1) expression on cytology imprints and circulating tumour cells (CTCs) with PD-L1 tumour proportion score (TPS) from immunohistochemistry staining of tumour tissue from patients with NSCLC. We evaluated PD-L1 expression using a PD-L1 antibody (28-8) in representative cytology imprints, and tissue samples from the same tumour. We report good agreement rates on PD-L1 positivity (TPS ≥ 1%) and high PD-L1 expression (TPS ≥ 50%). Considering high PD-L1 expression, cytology imprints showed a PPV of 64% and a NPV of 85%. CTCs were detected in 40% of the patients and 80% of them were PD-L1+ . Seven patients with PD-L1 expression of < 1% in tissue samples or cytology imprints had PD-L1+ CTCs. The addition of PD-L1 expression in CTCs to cytology imprints markedly improved the prediction capacity for PD-L1 positivity. A combined analysis of cytological imprints and CTCs provides information on the tumoural PD-L1 status in NSCLC patients, which might be used when no tumor tissue is available.

Inter-species cell detection - datasets on pulmonary hemosiderophages in equine, human and feline specimens.

Pulmonary hemorrhage (P-Hem) occurs among multiple species and can have various causes. Cytology of bronchoalveolar lavage fluid (BALF) using a 5-tier scoring system of alveolar macrophages based on their hemosiderin content is considered the most sensitive diagnostic method. We introduce a novel, fully annotated multi-species P-Hem dataset, which consists of 74 cytology whole slide images (WSIs) with equine, feline and human samples. To create this high-quality and high-quantity dataset, we developed an annotation pipeline combining human expertise with deep learning and data visualisation techniques. We applied a deep learning-based object detection approach trained on 17 expertly annotated equine WSIs, to the remaining 39 equine, 12 human and 7 feline WSIs. The resulting annotations were semi-automatically screened for errors on multiple types of specialised annotation maps and finally reviewed by a trained pathologist. Our dataset contains a total of 297,383 hemosiderophages classified into five grades. It is one of the largest publicly available WSIs datasets with respect to the number of annotations, the scanned area and the number of species covered.

Combination of Biochemical and Cytological Findings for Better Diagnosis in Pleural Effusions.

Serous pleural effusions result from increased permeability and changed hydrostatic or colloid osmotic pressure. Laboratory biochemical findings provide conclusions about the effusion compositions. Together with the anamnesis and clinical assessment, they enable the evaluation of the effusion nature. The present study retrospectively analyzed combined biochemical and morphological findings in 2307 effusions of patients from two clinical centers: LungenClinic Grosshansdorf in Germany and Duzce University in Turkey. The effusion cytology results of 1771 and 536 patients from the respective centers were combined with clinical/radiological/biochemical findings and counter compared with the final diagnoses. Cytology verified 738 malignant tumors (643 and 95, respectively). Most effusions were benign (n = 1569; 77%) and 367 of them were paramalignant (293 and 74, respectively) and 594 were inflammatory (465 and 129, respectively). There was a distinctly lower number of malignant tumors in transudates than exudates (87 vs. 725; p < 0.0001). Squamous cell carcinoma was more frequent in paramalignant pleura effusions (122 cases out of the 367 effusions) than pleural carcinomatosis (32 cases out of the 780 malignant tumors; p < 0.0001). The cell formula was a suitable marker for malignant mesothelioma, predominantly mesothelial, or neutrophilic characterized by elevated LDH (>500 U/L) in the early stage of empyema or its late manifestation. In conclusion, most effusions are benign. Cytologists, assisted by clinical and biochemical data and microscopic findings, can make significant differential diagnostic contributions beyond the sole detection of malignancy.

Surgical Site Cytology to Diagnose Spinal Lesions.

Patients with new-onset malignant spinal lesions often have an urgent need for local spine intervention and systemic therapy. For optimal management, it is crucial to diagnose the underlying disease as quickly and reliably as possible. The aim of our current study was to determine the feasibility, sensitivity, specificity, and diagnostic certainty of complementary cytological evaluation of spinal lesions suspected of malignancy. In 44 patients, we performed histopathological biopsies and in parallel cytologic preparations from the malignant site. Cytological smears were prepared and stained for May-Grunwald and Giemsa. Bone biopsies were histopathologically analyzed according to the existing standard-of-care practices. In 42 of 44 cases (95%), a cytological sample was successfully obtained. In 40 cases (95.2%, Cohen's kappa: 0.77), the cytological diagnosis agreed with the histological diagnosis regarding the identification of a malignant lesion. This resulted in a sensitivity of 97% and a specificity of 80% as well as a diagnostic safety of 95%. Cytological analysis in the context of spinal surgery proved sufficient to establish a diagnosis of malignancy or its exclusion, expanding the existing diagnostic spectrum. Furthermore, implementation of this process as a routine clinical diagnostic might shorten the time to diagnosis and improve the treatment of this vulnerable patient group.

Recommendations for immunocytochemistry in lung cancer typing: An update on a resource-efficient approach with large-scale comparative Bayesian analysis.

OBJECTIVES: The majority of lung cancer cases are of advanced stage and diagnosis is usually made using minimally invasive small biopsies and cytological specimens. The WHO 2015 classification recommends limiting immunocytochemistry (ICC) to lung cancer typing and molecular testing drives for personalised therapies. An algorithm using Bayes' theorem could be useful for defining antibody profiles. This study aims to assess the impact of different antibody profiles for cytological samples on the accuracy of lung cancer typing with a large-scale Bayesian analysis. METHODS: A retrospective examination of 3419 consecutive smears and/or cytospins diagnosed over 2011-2016 found 1960 primary lung cancer tumours: 972 adenocarcinomas (ADC), 256 squamous carcinomas (SQC), 268 neuroendocrine tumours (NET), and 464 non-small cell cancer-not otherwise specified (NSCC-NOS). The a priori and a posteriori probabilities, before and after ICC using antibodies singly or in combination, were calculated for different lung cancer types. RESULTS: TTF-1 or CK7 alone improved the a posteriori probabilities of correct cytological typing for ADC to 86.5% and 95.8%, respectively. For SQC, using p40 (∆Np63) or CK5/6 together with CK5/14 led to comparable results (78.3% and 90.3%). With synaptophysin or CD56 alone, improvements in a posteriori probabilities to 87.5 and 90.3% for the correct recognition of NET could be achieved. CONCLUSIONS: Based on morphological and clinical data, the use of two antibodies appears sufficient for reliable detection of the different lung cancer types. This applies to diagnoses that were finalised following ICC both on a clinical or cytological basis and on a histological basis.

Cytological Diagnostic Procedures in Malignant Mesothelioma.

Malignant mesotheliomas (MM) are rare tumors with high mortality rates, whose incidence varies regionally and nationally, and the diagnosis is difficult. Histology-based diagnosis is considered the gold standard despite its low sensitivity of 57-84%. However, recent advances in cytological analysis offer promise for diagnostic advancements. In this study, we reappraised the current cytological guidelines for the MM diagnosis and concluded on their practicability and reliability. The study included 5731 consecutive specimens of pleural effusions from 4552 patients (3026 males of the average age of 67.5 years and 1526 females of the average age of 65.4 years) between December 2017 and January 2000. Out of these patients, 444 (9.8%) were diagnosed with MM. The effusions were examined by immunocytochemistry using routine Giemsa staining. Additionally, hyaluronic acid (HA) was assessed. Cytological findings confirmed 223 out of the 444 MM. The additional 88 cases with negative cytology were corroborated by supplemental assessments of HA above 30 mg/L. Cytological evaluation accomplished the sensitivity of 0.50, specificity of 0.99, and a positive predictive value (PPV) of 0.97 for MM diagnosis. The use of HA determination raised the sensitivity to 0.70 without affecting the specificity or PPV. We conclude that cytological evaluation of effusions aided by the assessment of HA demonstrates the diagnostic sensitivity and specificity for MM no less than the hitherto standard histological evaluation. The cytology-based MM diagnosis may thus be routinely considered when MM is suspected and may offer confirmatory advantages in difficult or doubtful diagnostic cases.

Frozen Section or Intraoperative Cytology: Are We Ready for a Paradigm Shift in Thoracic Surgery?

Intraoperative frozen sections of specimens taken during thoracic surgery are widely seen as the gold standard. However, the accuracy of intraoperative cytology remains contentious. The study aims to estimate the value of intraoperative cytology by analyzing feasibility, accuracy, time requirements, and possible limitations when compared to standard frozen sections. To this end, we examined a total of 532 intraoperatively harvested specimens out of the 518 resected thoracic tumors from 360 patients between August 2016 and August 2017. The specimens were subject to intraoperative rapid cytology that was later counter compared to the final histology results. The mean time between the intraoperative harvesting and arrival at the laboratory was 2.23 min, and it took a further 3.5 min until the results were communicated to the surgeon. Cytologically, 218 cases (41%) were classified as malignant, 291 (55%) as benign, and 23 (4%) remained unclear. In 55 malignant cases, we observed additional benign formations. The final histological examination performed later yielded 267 malignant and 265 benign cases. Therefore, the sensitivity and specificity of rapid intraoperative cytology were 82% and 99%, respectively, with a negative/positive predictive value of 86%/99%. We conclude that the intraoperative rapid cytology is a fast, accurate, sensitive, and specific procedure for intraoperative decision making and is a distinctly helpful alternative or adjunct for the thoracic surgeon, providing that one is aware of the plausible limitations of this technique.

Surgical Strategy and Clinical Outcome in Patients with Bronchial Carcinoids.

Carcinoids are malignant neuroendocrine neoplasms showing good long-term survival after oncologic therapy. The study evaluated the influence of operative strategies and individual decision-making on the outcome and long-term survival in 222 patients with bronchial carcinoids. The patients underwent preoperative pulmonary function tests and bronchoscopy to facilitate surgical decision-making. A hundred and twelve tumors were detected endoscopically, including 32 in the main and lobar bronchi. We performed 5 isolated bronchus resections, 4 segmentectomies, 15 wedge resections, 10 pneumonectomies, 19 sleeve resections, 26 bilobectomies, 138 lobectomies, and 2 chest wall resections. Three patients were technically inoperable. Systematic mediastinal lymphadenectomy was routinely performed although most patients' computer tomography scans showed N0. A hundred and sixty-two patients had typical (155 N0, 7 N+) and 60 patients had atypical carcinoids (39 N0, 21 N+). There was no intraoperative mortality. The hospital mortality was below 2%. Overall, 1-, 5-, and 10-year survival rates were 99%, 94%, and 89%, respectively, in typical carcinoids. Atypical carcinoids show similar 1- and 5-year survival rates, but the 10-year survival rate was below 70%, decreasing in higher N-stages. The N-stage was the most important survival factor. In conclusion, bronchial carcinoids should be surgically treated the way lung cancer is. Anatomic resection and systematic lymphadenectomy are the treatments of choice. The availability of bronchoplastic techniques and preoperative assessment is essential for individual decision-making, focusing predominantly on postoperative quality of life.

Microbiological and Clinical Outcomes of Treating Non-Mycobacterium Avium Complex Nontuberculous Mycobacterial Pulmonary Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary disease caused by nontuberculous mycobacteria (NTM) is steadily increasing worldwide. METHODS: A systematic review of non-Mycobacterium avium complex studies published prior to October 2016 was conducted with respect to microbiological and clinical outcomes of current treatment regimens. RESULTS: We retrieved 352 citations, which yielded 24 studies eligible for evaluation. Sixteen studies were retrospective chart reviews, three studies were prospective, and only five studies were randomized. The weighted average proportion of sputum culture conversion (SCC) after subtracting posttreatment relapses for patients with M abscessus was 41.2% (95% CI, 28.6%-54.5%) but was 69.8% (95% CI, 41.0%-91.9%) with subspecies M massiliense in macrolide-containing regimens, 80.2% (95% CI, 58.4%-95.2%) in patients with M kansasii, 32.0% (95% CI, 16.5%-49.8%) for M xenopi (MX) and 54.4% (95% CI, 34.7%-73.4%) for M malmoense. SCCs in the total of 55 patients who underwent lung resection and had MX or M abscessus was high at 75.9%. The risk of bias was low in four of five randomized studies. However, heterogeneous use of outcome parameters (eight definitions of "relapse," eight of "treatment success," and four of "cure") hampered comparison of nonrandomized studies as well as producing possible bias by a posteriori exclusion (13.3%) and uncompleted treatment of participants (25.3%). CONCLUSIONS: As a sustained microbiological response without surgery is unsatisfactory in treating M abscessus, MX, and M malmoense, functional and quality of life aspects should be given more emphasis in the individual evaluation of treatment outcome. Further, properly planned studies with sufficient power are needed, as are new drugs or better-tolerated application of current antibiotics, or both.

Intraoperative fine needle aspirations - diagnosis and typing of lung cancer in small biopsies: challenges and limitations.

BACKGROUND: Due to therapeutic implications with regard to both efficiency and safety of chemotherapy agents it is important to differentiate between subtypes of NSCLC. Up to today we experience a continuous reservation regarding the use of fine needle aspiration cytology. The aim of the present study is to estimate the value of cytologic criteria for lung cancer typing on small biopsies independent from all possible technique failures. METHODS: Between January 1997 and December 2008 760 intraoperative FNAC- (fine needle aspiration cytology) specimens from 702 patients have been examined. Cytologic evaluation and immediate communication of results to the surgeons followed. Afterwards, intraoperative cytologic findings were compared with final histologic diagnoses of the resected specimens. RESULTS: Intraoperative cytologic analysis yielded a sensitivity of 94.8 %, a specificity of 98.8 %. An overall positive predictive value of 99.8 % with respect to final histologic analysis of primary lung cancer was achieved. The highest value could be reached for adenocarcinomas, followed by carcinoids and squamous cell carcinomas. CONCLUSIONS: Lung cancer typing according to cytologic criteria is feasible and accurate as well as comparable with results of histologic analysis on small specimens. Herewith, clinicians can come up to the increasing demands on minimally invasive harvested specimens with regard to therapeutic implications.

Prognostic value of bronchial provocation and FENO measurement for asthma diagnosis--results of a delayed type of diagnostic study.

OBJECTIVES: To compare the prognostic value of FENO with bronchoprovocation testing when the clinical course within the first year after assessment was taken into account; to compare the prognostic values with respect to eosinophilic versus non-eosinophilic inflammatory pattern. METHODS: Cross-sectional diagnostic study with a delayed-type reference standard in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease. INDEX TEST: FENO measurement. Reference standard: ratio FEV1/VC or airway resistance assessed by body plethysmography, with additional bronchoprovocation or bronchodilator testing, as well as spontaneous sputum (smear slides). This was combined with a follow-up evaluation by a structured interview after 12 months. RESULTS: 302 (76.8%) patients were reached for follow-up. Regarding asthma diagnosis, the area under the curve (AUC) for FENO was 0.603 (95%CI 0.528-0.677) for the whole group. With eosinophilic asthma as target, AUC increased (0.819 (95%CI 0.703-0.934)) and exceeded that of bronchoprovocation (0.711 (95%CI 0.584-0.874)). FENO showed no diagnostic value in non-eosinophilic asthma. In patients reporting wheezing and allergic rhinitis at the initial assessment, its positive predictive value was 90.9% (95%CI 62.3%-98.4) at a cut-off of 45 ppb, and 100% (95%CI 56.6-100%) at 81 ppb. CONCLUSIONS: FENO bears limited information when measured non-specifically in primary care, but is useful for diagnosing eosinophilic asthma. If sputum is not available, information on wheezing and rhinitis can narrow down the range of patients in whom FENO is informative. Moreover, the evaluation of the clinical value of FENO benefits from taking into account follow-up data to confirm the diagnosis.

Low-dose endotoxin inhalation in healthy volunteers--a challenge model for early clinical drug development.

BACKGROUND: Inhalation of endotoxin (LPS) induces a predominantly neutrophilic airway inflammation and has been used as model to test the anti-inflammatory activity of novel drugs. In the past, a dose exceeding 15-50 µg was generally needed to induce a sufficient inflammatory response. For human studies, regulatory authorities in some countries now request the use of GMP-grade LPS, which is of limited availability. It was therefore the aim of this study to test the effect and reproducibility of a low-dose LPS challenge (20,000 E.U.; 2 µg) using a flow- and volume-controlled inhalation technique to increase LPS deposition. METHODS: Two to four weeks after a baseline sputum induction, 12 non-smoking healthy volunteers inhaled LPS on three occasions, separated by at least 4 weeks. To modulate the inflammatory effect of LPS, a 5-day PDE4 inhibitor (Roflumilast) treatment preceded the last challenge. Six hours after each LPS inhalation, sputum induction was performed. RESULTS: The low-dose LPS inhalation was well tolerated and increased the mean percentage of sputum neutrophils from 25% to 72%. After the second LPS challenge, 62% neutrophils and an increased percentage of monocytes were observed. The LPS induced influx of neutrophils and the cumulative inflammatory response compared with baseline were reproducible. Treatment with Roflumilast for 5 days did not have a significant effect on sputum composition. CONCLUSION: The controlled inhalation of 2 µg GMP-grade LPS is sufficient to induce a significant neutrophilic airway inflammation in healthy volunteers. Repeated low-dose LPS challenges potentially result in a small shift of the neutrophil/monocyte ratio; however, the cumulative response is reproducible, enabling the use of this model for "proof-of-concept" studies for anti-inflammatory compounds during early drug development.

FENO measurement and sputum analysis for diagnosing asthma in clinical practice.

OBJECTIVES: To determine the diagnostic accuracy of fractional exhaled nitric oxide (FENO) measurement in pneumologists routine diagnostic work-up; and to determine the impact of the inflammatory pattern on diagnostic accuracy. METHODS: Prospective diagnostic study in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease (OAD). Index test was FENO measurement. Reference standard was the Tiffeneau ratio (FEV(1)/VC) or airway resistance as assessed by whole body plethysmography, with additional bronchoprovocation or bronchodilator testing. Morning sputum was analysed with smear slides which were prepared and stained by Giemsa. RESULTS: 154 patients were diagnosed as having asthma (145 diagnoses based on bronchial provocation, 9 based on bronchodilator results), 5 had COPD. For the whole group, asthma could be ruled in at FENO > 71 ppb (PPV 80%; 95% CI 63-90%) and ruled out at FENO ≤ 9 ppb (NPV 82%; 95% CI 67-91%) (area under the curve (AUC) = 0.656; 95% CI 0.600-0.712; p < 0.001). 128 patients delivered sputum. FENO was 44.3 ppb (sd 48.9) in patients with predominant eosinophilic inflammation, 18.5 ppb with neutrophilic inflammation, and 23.1 ppb in others (p = 0.003). Diagnostic accuracy of FENO increased when patients with neutrophilic inflammation were omitted from analysis (AUC = 0.745; 95% CI 0.651-0.838; p < 0.001). Then asthma could be ruled in at FENO > 31 ppb (PPV 82%; 95% CI 63-92%) and ruled out at FENO ≤ 12 ppb (NPV 81%; 95% CI 62-91%). CONCLUSIONS: FENO measurement can be useful as an additional diagnostic tool in pneumologists' practice. The diagnostic value of FENO could be improved when inflammatory patterns are taken into account.

Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms.

RATIONALE: Fibroblasts are believed to be the major cells responsible for the production and maintenance of extracellular matrix. Alterations in fibroblast functional capacity, therefore, could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate maintenance of tissue structure. OBJECTIVES: To evaluate the hypothesis that deficient fibroblast repair characterizes cells obtained from individuals with chronic obstructive pulmonary disease (COPD) compared with control subjects. METHODS: Fibroblasts were cultured from lung tissue obtained from individuals undergoing thoracotomy and were characterized in vitro. MEASUREMENTS AND MAIN RESULTS: Fibroblasts from individuals with COPD, defined by reduced FEV(1), manifested reduced chemotaxis toward fibronectin and reduced contraction of three-dimensional collagen gels, two bioassays associated with fibroblast repair function. At least two mechanisms appear to account for these differences. Prostaglandin E (PGE), a known inhibitor of fibroblast repair functions, was produced in increased amount by fibroblasts from subjects with COPD, which also expressed increased amounts of the receptors EP2 and EP4, both of which signal through cyclic AMP. Incubation of fibroblasts with indomethacin or with the PKA inhibitor KT-5720 partially restored COPD subject fibroblast function. In addition, fibroblasts from subjects with COPD produced more transforming growth factor (TGF)-beta1, but manifested reduced response to TGF-beta1. The functional alterations in fibroblasts correlated with both lung function assessed by FEV(1) and, for the data available, with severity of emphysema assessed by Dl(CO). CONCLUSIONS: Fibroblasts from individuals with COPD have reduced capability to sustain tissue repair, which suggests that this may be one mechanism that contributes to the development of emphysema.

Assessing airway inflammation in clinical practice - experience with spontaneous sputum analysis.

BACKGROUND: The assessment of airway inflammation for the diagnosis of asthma or COPD is still uncommon in pneumology-specialized general practices. In this respect, the measurement of exhaled nitric oxide (NO), as a fast and simple methodology, is increasingly used. The indirect assessment of airway inflammation, however, does have its limits and therefore there will always be a need for methods enabling a direct evaluation of airway inflammatory cell composition. Sampling of spontaneous sputum is a well-known, simple, economic and non-invasive method to derive a qualitative cytology of airway cells and here we aimed to assess today's value of spontaneous sputum cytology in clinical practice. METHODS: Three pneumologists provided final diagnoses in 481 patients having sputum cytology and we retrospectively determined posterior versus prior probabilities of inflammatory airway disorders. Moreover, in a prospective part comprising 108 patients, pneumologists rated their confidence in a given diagnosis before and after knowing sputum cytology and rated its impact on the diagnostic process on an analogue scale. RESULTS: Among the 481 patients, 45% were diagnosed as having asthma and/or airway hyperresponsiveness. If patients showed sputum eosinophilia, the prevalence of this diagnosis was elevated to 73% (n = 109, p < 0.001). The diagnosis of COPD increased from 40 to 66% in patients with neutrophilia (n = 29, p < 0.01).Thirty-three of the 108 patients were excluded from the prospective part (26 insufficient samples, 7 incomplete questionnaires). In 48/75 cases the confidence into a diagnosis was raised after knowing sputum cytology, and in 15/75 cases the diagnosis was changed as cytology provided new clues. CONCLUSION: Our data suggest that spontaneous sputum cytology is capable of assisting in the diagnosis of inflammatory airway diseases in the outpatient setting. Despite the limitations by the semiquantitative assessment and lower sputum quality, the supportive power and the low economic effort needed can justify the use of this method, particularly if the diagnosis in question is thought to have an allergic background.

In contrast to lung fibroblasts--no signs of senescence in skin fibroblasts of patients with emphysema.

Smoking is known to be linked to skin ageing and there is evidence for premature senescence of parenchymal lung fibroblasts in emphysema. To reveal whether the emphysema-related changes in cellular phenotype extend beyond the lung, we compared the proliferation characteristics of lung and skin fibroblasts between patients with and without emphysema. Parenchymal lung fibroblasts and skin fibroblasts from the upper torso (thus limiting sun exposure bias) were obtained from patients without, or with mild, or with moderate to severe emphysema undergoing lung surgery. We analysed proliferation rate, population doublings (PD), staining for senescence-associated beta-galactosidase (beta-gal) and gene expression of IGFBP-3 and IGFBP-rP1. Population doubling time of lung fibroblasts differed between control, mild, and moderate to severe emphysema (median (IQR) 29.7(10.0), 33.4(6.1), 44.4(21.2) h; p=0.012) and staining for beta-gal was elevated in moderate to severe emphysema. Compared to control subjects, skin fibroblasts from patients with emphysema did not differ with respect to proliferation rate, PD and beta-gal staining, and showed a lower abundance of mRNA for IGFBP-3 and -rP1 (p<0.05, each). These results suggest that the induction of a senescent fibroblast phenotype by cigarette smoke, as observed in emphysema, primarily occurs in the lung.