A case of bilateral pneumothorax following computer-tomography guided transthoracic biopsy in a woman with suspected pulmonary cancer.

Computer-tomography-guided needle biopsies are useful for diagnosing, staging, and classification of peripheral pulmonary nodules. However, the procedure carries a risk of iatrogenic pneumothorax. This report describes a patient-case where a woman had undergone a computer-tomography guided biopsy. Approximately 4 hours following discharge the patient was admitted to the emergency ward with severe chest pain and dyspnea. Chest x-ray revealed bilateral pneumothorax and subcutaneous emphysema at the biopsy site. Pleural drainage was administered on the patient's right side. Another chest x-ray following drainage showed regression of pneumothorax on both sides thus indicating communicating pleural cavities. Medical history revealed that the patient had been thymectomized 2 years earlier and a computer tomography visualized that the patient lacked mediastinal separation of the two pleural cavities. It is possible that patients with a history of mediastinal or thoracic surgery should be observed longer following procedures carrying risk of iatrogenic pneumothorax.

Correction: Christensen et al. Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer. Diagnostics 2021, 11, 279.

In the original publication [...].

Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer.

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01-1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

18F-FLT PET/CT Adds Value to 18F-FDG PET/CT for Diagnosing Relapse After Definitive Radiotherapy in Patients with Lung Cancer: Results of a Prospective Clinical Trial.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has previously demonstrated higher specificity for malignancy than 18F-FDG PET. We investigated the value of 18F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18F-FLT PET/CT was higher than that of 18F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [P = 0.0020]). The difference in specificity between 18F-FLT PET/CT and 18F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18F-FLT PET/CT was lower than that of 18F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [P = 0.0078]). Adding 18F-FLT PET/CT when 18F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion:18F-FLT PET/CT adds diagnostic value to 18F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18F-FLT PET/CT was highest after cRT. We suggest adding 18F-FLT PET/CT when 18F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained.

Early initiated postoperative rehabilitation enhances quality of life in patients with operable lung cancer: Secondary outcomes from a randomized trial.

INTRODUCTION: Patients with lung cancer report a lower degree of Health Related Quality of Life (HRQoL) compared with other cancer patients. HRQoL reflects how patients experience the impact of their disease and its treatment on their quality of daily living. A widely used questionnaire in lung cancer patients is the Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire. Here we report the secondary outcomes on FACT-L data from the Postoperative Rehabilitation in Operation for Lung CAncer (PROLUCA) study, which describes the effect of early (14 days) versus late initiated (14 weeks) postoperative rehabilitation. MATERIALS AND METHODS: The PROLUCA study was designed as a two-armed randomized controlled trial with an early rehabilitation group (14 days after surgery (ERG)) or a control arm with a late rehabilitation group (14 weeks after surgery (LRG)). The results for seven domain scores obtained using the FACT-L at the following time-points: baseline, 14 weeks, 26 weeks and 52 weeks after surgery are presented here. RESULTS: 119 patients were randomized to the ERG and 116 to the LRG. In the ERG, HRQoL measured by both FACT-L and FACT-G (general core instrument) showed a continuous improvement up to 26 weeks after which HRQoL decreased after further 26 weeks without structured intervention. In the LRG a non-significant deterioration was detected over the first 14 weeks after surgery. After participation in the 12 weeks rehabilitation program, an increase in HRQoL was seen, without reaching the same level as the early group. CONCLUSION: Analyses of the seven domain scores obtained using FACT-L and FACT-G reflect the importance of starting exercise early after surgery since the ERG avoid a temporary decrease in HRQoL. It is therefore recommended to start up a structured rehabilitation program 14 days after surgery, containing high intensity interval training and strength exercise twice a week for 12 weeks.

Early initiated postoperative rehabilitation reduces fatigue in patients with operable lung cancer: A randomized trial.

INTRODUCTION: Little is known about the optimal amount and timing of exercise strain in concern of the operation wound and with regard improvement of physical function and quality of life (QOL) after surgery for lung cancer. On this background, we decided to investigate the effect of early vs. late initiated postoperative rehabilitation in patients with operable lung cancer on exercise capacity, functional capacity, muscle strength, and QOL. METHODS: The study was designed as a two-armed randomized controlled trial with randomization to either early initiated postoperative rehabilitation (14 days after surgery (ERG)) or a control arm with late initiated postoperative rehabilitation (14 weeks after surgery (LRG)). The primary endpoint was a change in maximum oxygen consumption (VO2peak) from baseline to post intervention 26 weeks following lung resection. Fatigue was measured with EORTC QLQ C30 LC13. RESULTS: From April 2013 to June 2016, 582 patients with operable NSCLC were screened for eligibility. With 119 patients randomized in the early rehabilitation group (ERG) and 116 randomized to late rehabilitation group (LRG). There was no significant difference from baseline to 26 weeks between ERG and LRG (p = 0.926). There was a significant difference from baseline to 14 weeks between groups (p = 0.0018). There was a significant difference from 14 weeks to 26 weeks between the two groups (p < 0.001). We found no significant differences in QOL but we found a significant difference between ERG and LRG from baseline to 14 weeks in fatigue level in favour of ERG. CONCLUSION: This is the first randomized controlled trial to investigate the effects of early vs. late initiated postoperative rehabilitation in patients with lung cancer. There is no difference in the commencement (early vs. late) of a postoperative exercise program for patients with lung cancer on exercise capacity. But to reduce fatigue patients should be recommended to initiate early exercise programs.

Long term safety and visibility of a novel liquid fiducial marker for use in image guided radiotherapy of non-small cell lung cancer.

Safety and clinical feasibility of injecting a novel liquid fiducial marker for use in image guided radiotherapy in 15 patients with non-small cell lung cancer are reported. No major safety or toxicity issues were encountered. Markers present at start of radiotherapy remained visible in cone beam computed tomography and fluoroscopy images throughout the treatment course and on computed tomography images during follow-up (0-38 months). Marker volume reduction was seen until 9 months after treatment, after which no further marker breakdown was found. No post-treatment migration or marker related complications were found.

Target position uncertainty during visually guided deep-inspiration breath-hold radiotherapy in locally advanced lung cancer.

PURPOSE: The purpose of this study was to estimate the uncertainty in voluntary deep-inspiration breath-hold (DIBH) radiotherapy for locally advanced non-small cell lung cancer (NSCLC) patients. METHODS: Perpendicular fluoroscopic movies were acquired in free breathing (FB) and DIBH during a course of visually guided DIBH radiotherapy of nine patients with NSCLC. Patients had liquid markers injected in mediastinal lymph nodes and primary tumours. Excursion, systematic- and random errors, and inter-breath-hold position uncertainty were investigated using an image based tracking algorithm. RESULTS: A mean reduction of 2-6mm in marker excursion in DIBH versus FB was seen in the anterior-posterior (AP), left-right (LR) and cranio-caudal (CC) directions. Lymph node motion during DIBH originated from cardiac motion. The systematic- (standard deviation (SD) of all the mean marker positions) and random errors (root-mean-square of the intra-BH SD) during DIBH were 0.5 and 0.3mm (AP), 0.5 and 0.3mm (LR), 0.8 and 0.4mm (CC), respectively. The mean inter-breath-hold shifts were -0.3mm (AP), -0.2mm (LR), and -0.2mm (CC). CONCLUSION: Intra- and inter-breath-hold uncertainty of tumours and lymph nodes were small in visually guided breath-hold radiotherapy of NSCLC. Target motion could be substantially reduced, but not eliminated, using visually guided DIBH.

Liquid fiducial marker applicability in proton therapy of locally advanced lung cancer.

BACKGROUND AND PURPOSE: We investigated the clinical applicability of a novel liquid fiducial marker (LFM) for image-guided pencil beam scanned (PBS) proton therapy (PBSPT) of locally advanced lung cancer (LALC). MATERIALS AND METHODS: The relative proton stopping power (RSP) of the LFM was calculated and measured. Dose perturbations of the LFM and three solid markers, in a phantom, were measured. PBSPT treatment planning on computer tomography scans of five patients with LALC with the LFM implanted was performed with 1-3 fields. RESULTS: The RSP was experimentally determined to be 1.164 for the LFM. Phantom measurements revealed a maximum relative deviation in dose of 4.8% for the LFM in the spread-out Bragg Peak, compared to 12-67% for the solid markers. Using the experimentally determined RSP, the maximum proton range error introduced by the LFM is about 1mm. If the marker was displaced at PBSPT, the maximum dosimetric error was limited to 2 percentage points for 3-field plans. CONCLUSION: The dose perturbations introduced by the LFM were considerably smaller than the solid markers investigated. The RSP of the fiducial marker should be corrected in the treatment planning system to avoid errors. The investigated LFM introduced clinically acceptable dose perturbations for image-guided PBSPT of LALC.

Liquid fiducial marker performance during radiotherapy of locally advanced non small cell lung cancer.

BACKGROUND AND PURPOSE: We analysed the positional and structural stability of a long-term biodegradable liquid fiducial marker (BioXmark) for radiotherapy in patients with locally advanced lung cancer. MATERIAL AND METHODS: Markers were injected via endoscopic- or endobronchial ultrasound in lymph nodes and reachable primary tumours. Marker volume and Hounsfield Units (HU) changing rates were estimated using breath-hold CBCT. Inter-fraction variation in marker position relative to gross tumour volume (GTV) position was established, as well as the inter-fraction variation in mediastinal marker registration relative to a carina registration through the treatment. RESULTS: Fifteen patients were included and 29 markers analysed. All markers that were in situ at planning were visible through the treatment. Mean HU was 902±165HU for lymph node and 991±219HU for tumour markers. Volume degradation rates were -5% in lymph nodes and -23% in primary tumours. Three-dimensional inter-fraction variation for marker position relative to the GTV position was -0.1±0.7mm in lymph nodes and -1.5±2.3mm in primary tumours. Inter-fraction variations in marker registration relative to carina registration were -0.4±1.2mm in left-right, 0.2±2.0mm in anterior-posterior and -0.5±2.0mm in cranio-caudal directions. CONCLUSIONS: The liquid fiducial markers were visible and stable in size and position throughout the treatment course.

Simulator training for endobronchial ultrasound: a randomised controlled trial.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is very operator dependent and has a long learning curve. Simulation-based training might shorten the learning curve, and an assessment tool with solid validity evidence could ensure basic competency before unsupervised performance.A total of 16 respiratory physicians, without EBUS experience, were randomised to either virtual-reality simulator training or traditional apprenticeship training on patients, and then each physician performed EBUS-TBNA procedures on three patients. Three blinded, independent assessor assessed the video recordings of the procedures using a newly developed EBUS assessment tool (EBUSAT).The internal consistency was high (Cronbach's α=0.95); the generalisability coefficient was good (0.86), and the tool had discriminatory ability (p<0.001). Procedures performed by simulator-trained novices were rated higher than procedures performed by apprenticeship-trained novices: mean±sd are 24.2±7.9 points and 20.2±9.4 points, respectively; p=0.006. A pass/fail standard of 28.9 points was established using the contrasting groups method, resulting in 16 (67%) and 20 (83%) procedures performed by simulator-trained novices and apprenticeship-trained novices failing the test, respectively; p<0.001.The endobronchial ultrasound assessment tool could be used to provide reliable and valid assessment of competence in EBUS-TBNA, and act as an aid in certification. Virtual-reality simulator training was shown to be more effective than traditional apprenticeship training.

The prevalence of EGFR mutations in non-small cell lung cancer in an unselected Caucasian population.

EGFR mutation frequencies in unselected Caucasian populations are unknown. This study assesses the prevalence of EGFR mutations in an unselected population-based cohort, and the correlation between mutation and gender, age, ethnicity, smoking habits, and pathological data. NSCLC patients diagnosed in a well-defined Danish population were included. The type of the diagnostic material, and data on smoking were registered. The mutation analyses were investigated by Therascreen EGFR RGQ-PCR Kit or Sanger sequencing. A total of 658 men and 598 women were included. 6.2% were never smokers, 38.9% were ex-smokers, and 54.9% were current smokers. One thousand one hundred and sixty-one (92.4%) patients had sufficient material for mutation analysis. Cytological material was used for 38% of the mutation analyses. 5.4% had mutation in the EGFR gene (4.3% men/6.7% women). 87% were activating mutations. 8.0% of adenocarcinomas, and 1.9% of squamous cell carcinomas were mutated. 29.4%, 4.4% and 2.9% of never, ex- and current smokers were mutated (p < 0.001). No difference in mutation rate was observed between patients with cytology only, histology only or both cytology and histology available. 5.4% of the patients had EGFR mutation. Adenocarcinomas were mutated more often (8.0%) than squamous cell carcinomas (1.9%). Mutations were found in never smokers as well as in former and current smokers. No difference in gender and age regarding mutation status was observed. EGFR mutations analysis was possible in almost all patients with no difference between cytology and histology specimens.

[Lung cancer screening with low dose CT requires careful consideration].

Results from the American National Lung Screening Trial (NLST) show a significant reduction in lung cancer and all-cause mortality in a high risk population screened with annual low-dose CT. Handling of pulmonary nodules, false positive tests, overdiagnosis, psychosocial consequences and cost-efficiency etc. are all aspects that require careful consideration. This paper gives an overview of the current knowledge on these issues. Before a recommendation can be made, we need an overall evaluation of both the benefits and harms in CT screening for lung cancer.

[Lung cancer screening with low-dose CT - Danish and international results].

Lung cancer is the cancer type that causes the largest number of deaths in Denmark. With advances in medical imaging and widespread use of computed tomography (CT), it is possible to detect even small abnormalities in lung tissue. This has led to a great interest in lung cancer screening with low-dose CT and launching of randomised screening trials worldwide. This paper gives an overview of the current lung cancer screening trials in Denmark and internationally and focuses on main lung cancer findings and mortality results.

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT.

BACKGROUND: The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. METHODS: 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. RESULTS: Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs. 24, p<0.001), and more were low stage (48 vs 21 stage I-IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA-IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). CONCLUSION: CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

Establishing pass/fail criteria for bronchoscopy performance.

BACKGROUND: Several tools have been created to assess competence in bronchoscopy. However, educational guidelines still use an arbitrary number of performed procedures to decide when basic competency is acquired. OBJECTIVES: The purpose of this study was to define pass/fail scores for two bronchoscopy assessment tools, and investigate how these scores relate to physicians' experience regarding the number of bronchoscopy procedures performed. METHODS: We studied two assessment tools and used two standard setting methods to create cut scores: the contrasting-groups method and the extended Angoff method. In the first we compared bronchoscopy performance scores of 14 novices with the scores of 14 experienced consultants to find the score that best discriminated between the two groups. In the second we asked an expert group of 7 experienced bronchoscopists to judge how a borderline trainee would perform on each item of the test. RESULTS: Using the contrasting-groups method we found a standard that would fail all novices and pass all consultants. A clear pass related to prior experience of 75 procedures. The consequences of using the extended Angoff method were also acceptable: all trainees who had performed less than 50 bronchoscopies failed the test and all consultants passed. A clear pass related to 80 procedures. CONCLUSIONS: Our proposed pass/fail scores for these two methods seem appropriate in terms of consequences. Prior experience with the performance of 75 and 80 bronchoscopies, respectively, seemed to ensure basic competency. In the future objective assessment tools could become an important aid in the certification of physicians performing bronchoscopies.

Reliable and valid assessment of clinical bronchoscopy performance.

BACKGROUND: There have been several attempts to systematically assess performance in bronchoscopy. Earlier validation studies have used bronchoscopy simulators, not real-life performance in patients. OBJECTIVES: The aim of this study was to explore the reliability and validity of an assessment tool aimed for the use in a clinical setting. METHODS: Five junior residents, 5 senior residents and 9 consultants performed 3 bronchoscopies each. All 57 bronchoscopies were video-recorded and assessed blindly and independently by two bronchoscopy experts using the new assessment tool. RESULTS: The interrater reliability was high, with Cronbach's α = 0.86. Assessment of 3 bronchoscopies by a single rater had a generalizability coefficient of 0.84. The correlation between experience and performance was good (Pearson correlation = 0.76). There were significant differences between the groups for all aspects of the assessment, but post hoc tests showed different discriminative abilities. CONCLUSIONS: This new tool for assessing clinical bronchoscopy performance has a high interrater reliability. One rater assessing performance of 3 bronchoscopies ensures sufficient reliability. The assessment tool demonstrated sufficient construct validity.

A prospective study evaluating the presence of Rickettsia in Danish patients with sarcoidosis.

Rickettsia helvetica has previously been proposed as an aetiological agent in sarcoidosis. The purpose of the present study was to detect possible signs of Rickettsia infection in a Danish population of patients with sarcoidosis. Twenty-six patients with newly diagnosed sarcoidosis were prospectively enrolled in the study. The diagnosis was confirmed by biopsy in 18 and by clinical characteristics in 8 patients; 11 patients with different non-sarcoid lung diseases were recruited as controls. We obtained information regarding tick exposure and sarcoid disease manifestations by a structured interview. Evidence of rickettsial infection was assessed by an immunofluorescence assay testing for antibodies towards Rickettsia as well as specific real-time polymerase chain reaction (PCR) on lung biopsy specimens. We performed fluorescent in situ hybridization (FISH) on the biopsies to detect rickettsial and eubacterial rRNA. One sarcoidosis patient had serum rickettsial IgG antibodies above the chosen cut-off level. We found no positive rickettsial PCR or FISH analyses in any of the biopsy specimens. One sarcoid patient sample and 1 control sample contained unidentified bacteria. There was no difference in the reported frequency of tick bite between patients and controls. In conclusion, we found no evidence of Rickettsia being involved in the pathogenesis of sarcoidosis in Denmark.