Survivorship program including long-term toxicities and quality-of-life development over 10 years in a randomized trial in operable stage III non-small-cell lung cancer (ESPATUE).

Over 40% stage-III non-small-cell lung cancer (NSCLC) patients (pts) experience 5-year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality-of-life (QoL) in the further long-term follow-up. Therefore, we invited pts from our randomized phase-III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow-up imaging, laboratory parameters, cardio-pulmonary investigations, long-term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long-term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1-year follow-up. This is the first comprehensive SSP of very late survival follow-up reported in stage-III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.

Pulmonary Surfactant Proteins Are Inhibited by Immunoglobulin A Autoantibodies in Severe COVID-19.

Rationale: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. Objectives: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. Methods: We collected 147 blood, 9 lung tissue, and 36 BAL fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on BAL fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. Measurements and Main Results: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19 but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. Conclusions: Our data suggest that patients with severe COVID-19 harbor IgA autoantibodies against pulmonary surfactant proteins B and C and that these autoantibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation.

Is consolidative thoracic radiotherapy of extensive-stage small cell lung cancer still beneficial in the era of immunotherapy? A retrospective analysis.

PURPOSE: Extensive-stage small cell lung cancer (ES-SCLC) carries a dismal prognosis. The benefit of consolidative thoracic radiotherapy (TR) after first-line chemoimmunotherapy with PD-L1 inhibitors in this setting remains unclear. As TR can improve overall survival (OS) after conventional chemotherapy, we retrospectively analyzed OS of an inhouse cohort treated either with TR or with chemoimmunotherapy alone. METHODS: A total of 41 patients treated with chemoimmunotherapy with PD-L1 inhibitors (atezolizumab or durvalumab) for ES-SCLC at our hospital since 2019 were analyzed. TR was administered in 10 fractions of 3 Gy. Patient characteristics, number of immunotherapy cycles received, brain irradiation, and presence of hepatic and cerebral metastasis at diagnosis were assessed. Primary endpoint was OS after first diagnosis. RESULTS: Consolidative TR was associated with a significantly longer OS than systemic therapy alone (1-year OS 78.6% and 2­year OS 37.1% vs. 1­year OS 39.7% and 2 years not reached, p = 0.019). With regard to radiotherapy indication, survival at 1 year was 88.9% (log-rank p = 0.016) for patients receiving consolidative TR. For patients receiving TR in case of progression, 1­year survival was 66.7%. Hepatic and cerebral metastasis at first diagnosis had no significant effect on OS. CONCLUSION: TR was significantly associated with longer OS. The survival benefit of TR was most pronounced for consolidative radiotherapy after initial chemoimmunotherapy compared to TR in case of progression. Although retrospective findings need to be interpreted with caution, in the absence of prospective data, our findings provide a basis for offering consolidative TR in the era of chemoimmunotherapy.

Transbronchial cryobiopsy increases diagnostic confidence in interstitial lung disease: a prospective multicentre trial.

INTRODUCTION: The accurate diagnosis of individual interstitial lung diseases (ILD) is often challenging, but is a critical determinant of appropriate management. If a diagnosis cannot be made after multidisciplinary team discussion (MDTD), surgical lung biopsy is the current recommended tissue sampling technique according to the most recent guidelines. Transbronchial lung cryobiopsy (TBLC) has been proposed as an alternative to surgical lung biopsy. METHODS: This prospective, multicentre, international study analysed the impact of TBLC on the diagnostic assessment of 128 patients with suspected idiopathic interstitial pneumonia by a central MDTD board (two clinicians, two radiologists, two pathologists). The level of confidence for the first-choice diagnoses were evaluated in four steps, as follows: 1) clinicoradiological data alone; 2) addition of bronchoalveolar lavage (BAL) findings; 3) addition of TBLC interpretation; and 4) surgical lung biopsy findings (if available). We evaluated the contribution of TBLC to the formulation of a confident first-choice MDTD diagnosis. RESULTS: TBLC led to a significant increase in the percentage of cases with confident diagnoses or provisional diagnoses with high confidence (likelihood ≥70%) from 60.2% to 81.2%. In 32 out of 52 patients nondiagnostic after BAL, TBLC provided a diagnosis with a likelihood ≥70%. The percentage of confident diagnoses (likelihood ≥90%) increased from 22.7% after BAL to 53.9% after TBLC. Pneumothoraces occurred in 16.4% of patients, and moderate or severe bleeding in 15.7% of patients. No deaths were observed within 30 days. INTERPRETATION: TBLC increases diagnostic confidence in the majority of ILD patients with an uncertain noninvasive diagnosis, with manageable side-effects. These data support the integration of TBLC into the diagnostic algorithm for ILD.

Incidental lung volume reduction following fulminant pulmonary hemorrhage in a patient with severe emphysema.

Endoscopic lung volume reduction is an emerging technique meant to improve lung function parameters, quality of life, and exercise tolerance in patients with severe lung emphysema. This is the first report of lung volume reduction by autologous blood in a patient with non-bullous lung emphysema. A 74-year-old woman with heterogeneous lung emphysema developed accidentally diffuse lobar bleeding immediately after valve placement. Due to persistent hemorrhage, the valves had to be removed shortly thereafter. Despite extraction of the valves, respiratory function of the patient improved rapidly indicated also by a drop in the COPD assessment test questionnaire, 3 months later. This was consistent with both improvement of lung function tests and six-minute walking test.

Assessment of tumor vascularity in lung cancer using volume perfusion CT (VPCT) with histopathologic comparison: a further step toward an individualized tumor characterization.

OBJECTIVE: To measure perfusion in different lung cancer subtypes and compare results with histopathological/immunohistochemical results. METHODS: Seventy-two consecutive untreated patients with lung cancer (40 adenocarcinomas, 20 squamous cell, and 12 small cell lung cancers) were enrolled. A 40-second volume perfusion computed tomography of the tumor bulk was obtained. Blood flow (BF), blood volume (BV), and transit constant were determined. Tumor volume and tumor necrosis were determined on contrast-enhanced computed tomography. Pathologic specimens were assessed for microvessel density (MVD), hypoxia-induced transcription (hif-1/-2), and proliferation (Ki-67). RESULTS: Higher MVD is associated with higher BF and BV. Higher tumor grade leads to lower BF but increased necrosis and tumor volume. Markers of hypoxia were independent from perfusion parameters, extent of necrosis or MVD. Blood flow, BV, and MVD were not significantly different among lung cancer subtypes. Transit constant was significantly reduced in small cell lung cancer versus adenocarcinoma. CONCLUSIONS: Perfusion values are related to MVD and tumor grade but vary considerably among lung cancer subtypes.

Diagnostic Performance of Dynamic Whole-Body Patlak [18F]FDG-PET/CT in Patients with Indeterminate Lung Lesions and Lymph Nodes.

BACKGROUND: Static [18F]FDG-PET/CT is the imaging method of choice for the evaluation of indeterminate lung lesions and NSCLC staging; however, histological confirmation of PET-positive lesions is needed in most cases due to its limited specificity. Therefore, we aimed to evaluate the diagnostic performance of additional dynamic whole-body PET. METHODS: A total of 34 consecutive patients with indeterminate pulmonary lesions were enrolled in this prospective trial. All patients underwent static (60 min p.i.) and dynamic (0-60 min p.i.) whole-body [18F]FDG-PET/CT (300 MBq) using the multi-bed-multi-timepoint technique (Siemens mCT FlowMotion). Histology and follow-up served as ground truth. Kinetic modeling factors were calculated using a two-compartment linear Patlak model (FDG influx rate constant = Ki, metabolic rate = MR-FDG, distribution volume = DV-FDG) and compared to SUV using ROC analysis. RESULTS: MR-FDGmean provided the best discriminatory power between benign and malignant lung lesions with an AUC of 0.887. The AUC of DV-FDGmean (0.818) and SUVmean (0.827) was non-significantly lower. For LNM, the AUCs for MR-FDGmean (0.987) and SUVmean (0.993) were comparable. Moreover, the DV-FDGmean in liver metastases was three times higher than in bone or lung metastases. CONCLUSIONS: Metabolic rate quantification was shown to be a reliable method to detect malignant lung tumors, LNM, and distant metastases at least as accurately as the established SUV or dual-time-point PET scans.

Pulmonary lesion assessment: comparison of whole-body hybrid MR/PET and PET/CT imaging--pilot study.

PURPOSE: To compare the performance of magnetic resonance (MR)/positron emission tomography (PET) imaging in the staging of lung cancer with that of PET/computed tomography (CT) as the reference standard and to compare the quantification accuracy of a new whole-body MR/PET system with corresponding PET/CT data sets. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Ten patients in whom bronchial carcinoma was proven or clinically suspected underwent clinically indicated fluorine 18 fluorodeoxyglucose (FDG) PET/CT and, immediately thereafter, whole-body MR/PET imaging with a new hybrid whole-body system (3.0-T MR imager with integrated PET system). Attenuation correction of MR/PET images was segmentation based with fat-water separation. Tumor-to-liver ratios were calculated and compared between PET/CT and MR/PET imaging. Tumor staging on the basis of the PET/CT and MR/PET studies was performed by two readers. Spearman rank correlation was used for comparison of data. RESULTS: MR/PET imaging provided diagnostic image quality in all patients, with good tumor delineation. Most lesions (nine of 10) showed pronounced FDG uptake. One lesion was morphologically suspicious for malignancy at CT and MR imaging but showed no FDG uptake. MR/PET imaging had higher mean tumor-to-liver ratios than did PET/CT (4.4 ± 2.0 [standard deviation] for PET/CT vs 8.0 ± 3.9 for MR/PET imaging). Significant correlation regarding the tumor-to-liver ratio was found between both imaging units (ρ = 0.93; P < .001). Identical TNM scores based on MR/PET and PET/CT data were found in seven of 10 patients. Differences in T and/or N staging occurred mainly owing to modality-inherent differences in lesion size measurement. CONCLUSION: MR/PET imaging of the lung is feasible and provides diagnostic image quality in the assessment of pulmonary masses. Similar lesion characterization and tumor stage were found in comparing PET/CT and MR/PET images in most patients.

Influence of Pharyngeal Anaesthesia on Post-Bronchoscopic Coughing: A Prospective, Single Blinded, Multicentre Trial.

BACKGROUND: Local anaesthesia of the pharynx (LAP) was introduced in the era of rigid bronchoscopy (which was initially a conscious procedure under local anaesthetic), and continued into the era of flexible bronchoscopy (FB) in order to facilitate introduction of the FB. LAP reduces cough and gagging reflex, but its post-procedural effect is unclear. This prospective multicentre trial evaluated the effect of LAP on coughing intensity/time and patient comfort after FB, and the feasibility of FB under propofol sedation alone, without LAP. MATERIAL AND METHODS: FB was performed in 74 consecutive patients under sedation with propofol, either alone (35 patients, 47.3%) or with additional LAP (39 patients, 52.7%). A primary endpoint of post-procedural coughing duration in the first 10 min after awakening was evaluated. A secondary endpoint was the cough frequency, quality and development of coughing in the same period during the 10 min post-procedure. Finally, the ease of undertaking the FB and the patient's tolerance and safety were evaluated from the point of view of the investigator, the assistant technician and the patient. RESULTS: We observed a trend to a shorter cumulative coughing time of 48.6 s in the group without LAP compared to 82.8 s in the group receiving LAP within the first 10 min after the procedure, although this difference was not significant (p = 0.24). There was no significant difference in the cough frequency, quality, peri-procedural complication rate, nor patient tolerance or safety. FB, including any additional procedure, could be performed equally well with or without LAP in both groups. CONCLUSIONS: Our study suggests that undertaking FB under deep sedation without LAP does to affect post-procedural cough duration and frequency. However, further prospective randomised controlled trials are needed to further support this finding.

Diagnostic Yield of Transbronchial Lung Cryobiopsy Compared to Transbronchial Forceps Biopsy in Patients with Sarcoidosis in a Prospective, Randomized, Multicentre Cross-Over Trial.

BACKGROUND: Transbronchial lung forceps biopsy (TBLF) is of limited value for the diagnosis of interstitial lung disease (ILD). However, in cases with predominantly peribronchial pathology, such as sarcoidosis, TBLF is considered to be diagnostic in most cases. The present study examines whether transbronchial lung cryobiopsy (TBLC) is superior to TBLF in terms of diagnostic yield in cases of sarcoidosis. METHODS: In this post hoc analysis of a prospective, randomized, controlled, multicentre study, 359 patients with ILD requiring diagnostic bronchoscopic tissue sampling were included. TBLF and TBLC were both used for each patient in a randomized order. Histological assessment was undertaken on each biopsy and determined whether sarcoid was a consideration. RESULTS: A histological diagnosis of sarcoidosis was established in 17 of 272 cases for which histopathology was available. In 6 out of 17 patients, compatible findings were seen with both TBLC and TBLF. In 10 patients, where the diagnosis of sarcoidosis was confirmed by TBLC, TBLF did not provide a diagnosis. In one patient, TBLF but not TBLC confirmed the diagnosis of sarcoidosis. CONCLUSIONS: In this post hoc analysis, the histological diagnosis of sarcoidosis was made significantly more often by TBLC than by TBLF. As in other idiopathic interstitial pneumonias (IIPs), the use of TBLC should be considered when sarcoidosis is suspected.

Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer.

OBJECTIVES: Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques. MATERIALS AND METHODS: We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques. RESULTS AND CONCLUSION: Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6 %) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8 %) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6 % versus 6.5 %, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3 % versus 26.9 %). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.

Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer-The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient's progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival.

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

Efficacy and safety analysis of the German expanded access program of osimertinib in patients with advanced, T790M-positive non-small cell lung cancer.

PURPOSE: Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials. METHODS: We performed a retrospective data analysis on patients who were included into the German osimertinib EAP. RESULTS: Of 81 patients enrolled, 51 patients (62.9%) with sufficient case report form data were available for efficacy and safety analysis. Unconfirmed overall response rate was 80.0% with 2 patients (3.9%) achieving a complete remission and 37 patients (72.5%) having a partial remission. Disease control rate was 95.9% and only two patients showed refractory disease. Disease control rate did not correlate with clinical characteristics and was independent of number as well as type of the previous therapy line(s). Estimated progression-free survival was 10.1 months (95% CI 9.2-11.0 months). Osimertinib showed a favorable toxicity profile with no dose reductions in our observation period, even in patients with low performance status. Median survival from first diagnosis to data cut-off was 47.3 months (95% CI 43.3-51.9 months). Repeated tissue/liquid biopsy of three patients in our cohort who showed disease progression revealed an amplification of MET. CONCLUSIONS: We confirm safety and efficacy of osimertinib with high response rates among all subgroups, including patients with poor performance status and multiple prior therapy lines. Amplification of MET might mediate acquired resistance to osimertinib.

[An unexpected cause of pulmonary hypertension]. / Unklare pulmonale Hypertonie - Fall 6 / 2016.

HISTORY AND ADMISSION FINDINGS: We report on a 48-year-old man presenting with progressive hepatopathy and encephalopathy for two weeks based on a chronic hepatitis C. He takes ledipasvir and sofosbuvir (Harvoni) and ribavirin for almost 24 weeks. After admission to hospital his state deteriorated rapidly. He is directly transferred to the medical intensive care unit, where he died on day 3. INVESTIGATIONS: During the physical examination, a pronounced jaundice and significant peripheral edema were found. Laboratory tests showed anemia, an increased C-reactive proteine and bilirubin, a limited coagulation and renal insufficiency with elevated creatinine. Quantitative HCV-PCR was negative. Echocardiographically a severe tricuspid- and mitral-valve regurgitation was found in a massively increased pulmonary artery pressure and pulmonary heart disease. The gastroscopy revealed a Forrest IIb situation with corresponding clip supply. DIAGNOSIS, TREATMENT AND COURSE: In the autopsy we find signs of portal hypertension in presence of progressive liver cirrhosis. In addition, portopulmonary hypertension is diagnosed. The patient died on right ventricular failure resulting from a massively increased pulmonary pressure Conclusion: Advanced liver disease and an increased pulmonary pressure are often associated. Therefore, an early as possible diagnosis and classification are essential for adequate therapy in these patients.

Improved detection of bone metastases from lung cancer in the thoracic cage using 5- and 1-mm axial images versus a new CT software generating rib unfolding images: comparison with standard ¹8F-FDG-PET/CT.

RATIONALE AND OBJECTIVES: To evaluate the performance of a dedicated computed tomography (CT) software called "bone reading" generating rib unfolded images for improved detection of rib metastases in patients with lung cancer in comparison to readings of 5- and 1-mm axial CT images and (18)F-Fluordeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Ninety consecutive patients who underwent (18)F-FDG-PET/CT and chest CT scanning between 2012 and 2014 at our institution were analyzed retrospectively. Chest CT scans with 5- and 1-mm slice thickness were interpreted blindly and separately focused on the detection of rib metastases (location, number, cortical vs. medullary, and osteoblastic vs. sclerotic). Subsequent image analysis of unfolded 1 mm-based CT rib images was performed. For all three data sets the reading time was registered. Finally, results were compared to those of FDG-PET. Validation was based on FDG-PET positivity for osteolytic and mixed osteolytic/osteoblastic focal rib lesions and follow-up for sclerotic PET-negative lesions. RESULTS: A total of 47 metastatic rib lesions were found on FDG-PET/CT plus another 30 detected by CT bone reading and confirmed by follow-up CT. Twenty-nine lesions were osteolytic, 14 were mixed osteolytic/osteoblastic, and 34 were sclerotic. On a patient-based analysis, CT (5 mm), CT (1 mm), and CT (1-mm bone reading) yielded a sensitivity, specificity, and accuracy of 76.5/97.3/93, 81.3/97.3/94, and 88.2/95.9/92, respectively. On segment-based (unfolded rib) analysis, the sensitivity, specificity, and accuracy of the three evaluations were 47.7/95.7/67, 59.5/95.8/77, and 94.8/88.2/92, respectively. Reading time for 5 mm/1 mm axial images and unfolded images was 40.5/50.7/21.56 seconds, respectively. CONCLUSIONS: The use of unfolded rib images in patients with lung cancer improves sensitivity and specificity of rib metastasis detection in comparison to 5- and 1-mm CT slice reading. Moreover, it may reduce the reading time.

Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).

PURPOSE: Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction. PATIENTS AND METHODS: Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS). RESULTS: After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment. CONCLUSION: The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.

Does volume perfusion computed tomography enable differentiation of metastatic and non-metastatic mediastinal lymph nodes in lung cancer patients? A feasibility study.

OBJECTIVES: To compare the perfusion characteristics of mediastinal lymph node metastases with those of non-metastatic nodes in patients with newly diagnosed lung cancer using volume perfusion computed tomography (VPCT). MATERIALS AND METHODS: Between January 2010 and October 2011, 101 patients with histologically confirmed, untreated lung cancer received a 40-s VPCT of the tumor bulk; 32/101 patients had evident hilar/mediastinal metastatic disease and 17/101 patients had proven non-metastasized lymph nodes within the VPCT scan range. Validation or exclusion of metastatic node involvement was proven by mediastinoscopy, biopsy, positron emission tomography imaging and/or unequivocal volume dynamics on follow-up computed tomography. A total of 45 metastases and 23 non-metastatic lymph nodes were found within the scan range and subsequently evaluated. Blood flow (BF), blood volume (BV) and K(trans) were determined. Tumor volume was recorded as whole tumor volume. RESULTS: In a comparison between metastatic and non-metastatic lymph nodes, we controlled for age, lymph node volume, lung tumor volume, lung tumor location, and histologic type effects and found no significant differences with respect to BF, BV, K(trans) or heterogeneity in nodal perfusion (P > 0.05, respectively), even after adjusting lymph node perfusion values to the perfusion parameters of the primary tumor (P > 0.05, respectively). Metastatic lymph node volume had a significant increasing effect on perfusion heterogeneity (P < 0.05, respectively) and BV in the primary was a highly significant factor for BV in metastatic disease (P < 0.001). CONCLUSION: Perfusion characteristics of mediastinal metastatic and non-metastatic lymph nodes in untreated lung cancer show considerable overlap, so that a reliable differentiation via VPCT is not possible.

Pneumonectomy: calculable or non-tolerable risk factor in trimodal therapy for Stage III non-small-cell lung cancer?

OBJECTIVES: Lung cancer is the leading cause of death in cancer statistics throughout developed countries. While single surgical approach provides best results in early stages, multimodality approaches have been employed in advanced disease and demonstrated superior results in selected patients. With either full-dose chemotherapy and/or radiotherapy, patients usually have a poor general condition when entering surgical therapy and therefore neoadjuvant therapy can lead to a higher morbidity and mortality. Especially in the case of pneumonectomy as the completing procedure, mortality rate can exceed over 40%. Therefore, chest physicians often shy away from recommending pneumonectomy as final step in trimodal protocols. We analysed our experience with pneumonectomy after neoadjuvant chemoradiotherapy in advanced non-small-cell lung cancer (NSCLC) with a focus on feasibility, outcome and survival. METHODS: Retrospective, single-centre study of 146 patients with trimodal neoadjuvant therapy for NSCLC Stage III over 17 years time span. Follow-up was taken from our own outpatient files and with survival check of central registry office in Baden-Württemberg, Germany. RESULTS: A total of 118 men and 28 women received 62 lobectomies, 6 bi-lobectomies and 78 pneumonectomies after two different neoadjuvant protocols for Stage III NSCLC. Overall morbidity rate was 53 and 56% after pneumonectomy. Overall hospital mortality rate was 4.8 and 6.4% after pneumonectomy. Overall median survival rate was 31 months with a 5-year survival rate of 38% (Kaplan-Meier). Pneumonectomy, right-sited pneumonectomy and initial T- and N-stages were no risk factors for survival (log-rank test). Significant factors for survival were ypT-stage, ypN-stage, yUICC-stage in univariate testing (log-rank test) and ypUICC-stage in multivariate testing (Cox's regression). CONCLUSIONS: Pneumonectomy in neoadjuvant trimodal approach for Stage III NSCLC can be done safe with acceptable mortality rate. Patients should not withhold from operation because of necessitating pneumonectomy. Not the procedure but the selection, response rate and R0-resection are crucial for survival after trimodal therapy in experienced centres.