Combined morphologic-metabolic biomarkers from [18F]FDG-PET/CT stratify prognostic groups in low-risk NSCLC.

AIM: The aim of this study was to derive prognostic parameters from 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG-PET/CT) in patients with low-risk NSCLC and determine their prognostic value. METHODS: 81 (21 female, mean age 66 a) therapy-naive patients that underwent [18F]FDG-PET/CT before histologic confirmation of NSCLC with stadium I and II between 2008-2016 were included. A mean follow-up time of 58 months (13-176), overall and progression free survival (OS, PFS) were registered. A volume of interest for the primary tumor was defined on PET and CT images. Parameters SUVmax, PET-solidity, PET-circularity, and CT-volume were analyzed. To evaluate the prognostic value of each parameter for OS, a minimum p-value approach was used to define cutoff values, survival analysis, and log-rank tests were performed, including subgroup analysis for combinations of parameters. RESULTS: Mean OS was 58±28 months. Poor OS was associated with a tumor CT-volume >14.3 cm3 (p=0.02, HR=7.0, CI 2.7-17.7), higher SUVmax values >12.2 (p=0.003; HR=3.0, CI 1.3-6.7) and PET-solidity >0.919 (p=0.004; HR=3.0, CI 1.0-8.9). Combined parameter analysis revealed worse prognosis in larger volume/high SUVmax tumors compared to larger volume/lower SUVmax (p=0.028; HR=2.5, CI 1.1-5.5), high PET-solidity/low volume (p=0.01; HR=2.4, CI 0.8-6.6) and low SUVmax/high PET-solidity (p=0.02, HR=4.0, CI 0.8-19.0). CONCLUSION: Even in this group of low-risk NSCLC patients, we identified a subgroup with a significantly worse prognosis by combining morphologic-metabolic biomarkers from [18F]FDG-PET/CT. The combination of SUVmax and CT-volume performed best. Based on these preliminary data, future prospective studies to validate this combined morphologic-metabolic imaging biomarker for potential therapeutic decisions seem promising.

Immune checkpoint inhibitors in non-small cell lung cancer - When should we dare to stop treatment?

Over the last years, the emergence of immune checkpoint inhibitors (ICI) has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients in a palliative setting with previously very poor prognosis may now show remarkable responses over years. Yet, ICI therapy is very cost-intensive and involves frequent contacts with healthcare resources. Some of the early trial protocols restricted ICI treatment duration to two years. Now follow-up data of these studies is available and reveal the possibility of a persistent response after two or more years without further treatment for patients having successfully completed two years of therapy. May we now dare to think (and speak) of cure in the palliative setting? Does it mean we can stop ICI therapy after an initial two-year treatment? In this review, we try to improve confidence in clinical decision-making for this patient group. To this end, trials with a restricted treatment duration of two years and other data considering potential ICI discontinuation in responding patients were evaluated. Up to 25% of patients successfully complete an initial two-year course of ICI. Within this group about 40-46% of patients are alive at five years without further treatment with five-year survival rates of up to 83%. Data on ICI rechallenge are scarce, yet it does not seem to provide the same level of efficacy as at first exposure. At present there are no established biomarkers to help with decision-making. Possible future (bio-)markers, such as PD-L1, mutations, circulating tumor DNA (ctDNA) or Positron emission tomography (PET) need to be evaluated further in a prospective setting. In conclusion, we propose that the concept of discontinuing ICI therapy in patients with tumor response has to be seriously taken into consideration as it may be of benefit to our patients and health care systems.

Importance of interdisciplinarity in modern oncology: results of a national intergroup survey of the Young Oncologists United (YOU).

PURPOSE: Modern, personalized treatment concepts in oncology require an interdisciplinary and multiprofessional collaboration. In addition to its relevance in patient care, interdisciplinary collaboration is also becoming increasingly important in clinical research as well as medical education and resident training in oncology. METHODS: Between November 2021 and March 2022, an online survey was conducted among German early career research groups, represented by Young Oncologists United (YOU). The aim was to identify the status and need for interdisciplinarity at clinic, educational, and research levels. RESULTS: A total of 294 participants completed the questionnaire in full. 90.7% of the respondents fully or predominantly agreed with the statement that interdisciplinary work plays a major role in their daily clinical work. 78.9% wished for more interdisciplinary collaboration. Of the 49.7% of participants who have never participated in an interdisciplinary research project, 80.1% said they would like to participate in such a study project in the future. Lack of time resources, too much organizational effort, and possible political conflicts between institutions were identified as factors that make practical implementation difficult. 74.1% declared their willingness to become active in an oncology early career research group. CONCLUSION: Interdisciplinary collaboration has become increasingly important in oncology. Networks that span different disciplines could help to promote interdisciplinary research projects among young scientists and improve exchange in professional practice and education with the implication of improved patient care.

Long COVID: Distinction between Organ Damage and Deconditioning.

(1) Background: Long COVID syndrome refers to long-term sequelae of the novel viral disease, which occur even in patients with initially mild disease courses. However, there is still little evidence of the actual organic consequences and their frequency, and there is no standardized workup to diagnose long COVID syndrome yet. In this study, we aim to determine the efficiency of a stepwise diagnostic approach for reconvalescent COVID-19 patients with cardiopulmonary symptoms. (2) Methods: The diagnostic workup for long COVID syndrome included three steps. In the first step, the focus was on broad applicability (e.g., blood tests and body plethysmography). In the second step, cardiopulmonary exercise testing (CPET) and cardiac MRI (CMR) were used. The third step was tailored to the individual needs of each patient. The observation period lasted from 22 February to 14 May 2021. (3) Results: We examined 231 patients in our long COVID unit (mean [SD] age, 47.8 [14.9], 132 [57.1%] women). Acute illness occurred a mean (SD) of 121 (77) days previously. Suspicious findings in the first visit were seen in 80 (34.6%) patients, prompting further diagnostics. Thirty-six patients were further examined with CPET and CMR. Of those, 16 (44.4%) had pathological findings. The rest had functional complaints without organ damage ("functional long COVID"). Cardiopulmonary sequelae were found in asymptomatic as well as severe courses of the initial COVID-19 disease. (4) Conclusions: A structured diagnostic pathway for the diagnosis of long COVID syndrome is practicable and rational in terms of resource allocation. With this approach, manifest organ damage can be accurately and comprehensively diagnosed and distinguished from functional complaints.

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.

INTRODUCTION: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. OBJECTIVE: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. METHODS AND RESULTS: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. CONCLUSIONS: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.

Apnea and heart rate detection from tracheal body sounds for the diagnosis of sleep-related breathing disorders.

Sleep apnea is one of the most common sleep disorders. Here, patients suffer from multiple breathing pauses longer than 10 s during the night which are referred to as apneas. The standard method for the diagnosis of sleep apnea is the attended cardiorespiratory polysomnography (PSG). However, this method is expensive and the extensive recording equipment can have a significant impact on sleep quality falsifying the results. To overcome these problems, a comfortable and novel system for sleep monitoring based on the recording of tracheal sounds and movement data is developed. For apnea detection, a unique signal processing method utilizing both signals is introduced. Additionally, an algorithm for extracting the heart rate from body sounds is developed. For validation, ten subjects underwent a full-night PSG testing, using the developed sleep monitor in concurrence. Considering polysomnography as gold standard the developed instrumentation reached a sensitivity of 92.8% and a specificity of 99.7% for apnea detection. Heart rate measured with the proposed method was strongly correlated with heart rate derived from conventional ECG (r 2 = 0.8164). No significant signal losses are reported during the study. In conclusion, we demonstrate a novel approach to reliably and noninvasively detect both apneas and heart rate during sleep.

Validation of a New System Using Tracheal Body Sound and Movement Data for Automated Apnea-Hypopnea Index Estimation.

STUDY OBJECTIVES: The current gold standard for assessment of obstructive sleep apnea is the in-laboratory polysomnography. This approach has high costs and inconveniences the patient, whereas alternative ambulatory systems are limited by reduced diagnostic abilities (type 4 monitors, 1 or 2 channels) or extensive setup (type 3 monitors, at least 4 channels). The current study therefore aims to validate a simplified automated type 4 monitoring system using tracheal body sound and movement data. METHODS: Data from 60 subjects were recorded at the University Hospital Ulm. All subjects have been regular patients referred to the sleep center with suspicion of sleep-related breathing disorders. Four recordings were excluded because of faulty data. The study was of prospective design. Subjects underwent a full-night screening using diagnostic in-laboratory polysomnography and the new monitoring system concurrently. The apnea-hypopnea index (AHI) was scored blindly by a medical technician using in-laboratory polysomnography (AHIPSG). A unique algorithm was developed to estimate the apneahypopnea index (AHIest) using the new sleep monitor. RESULTS: AHIest strongly correlates with AHIPSG (r2 = .9871). A mean ± 1.96 standard deviation difference between AHIest and AHIPSG of 1.2 ± 5.14 was achieved. In terms of classifying subjects into groups of mild, moderate, and severe sleep apnea, the evaluated new sleep monitor shows a strong correlation with the results obtained by polysomnography (Cohen kappa > 0.81). These results outperform previously introduced similar approaches. CONCLUSIONS: The proposed sleep monitor accurately estimates AHI and diagnoses sleep apnea and its severity. This minimalistic approach may address the need for a simple yet reliable diagnosis of sleep apnea in an ambulatory setting. CLINICAL TRIAL REGISTRATION: Trial name: Validation of a new method for ambulant diagnosis of sleep related breathing disorders using body sound; URL: https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011195; Identifier: DRKS00011195.

Necitumumab plus Gemcitabine and Cisplatin as First-Line Therapy in Patients with Stage IV EGFR- Expressing Squamous Non-Small-Cell Lung Cancer: German Subgroup Data from an Open-Label, Randomized Controlled Phase 3 Study (SQUIRE).

BACKGROUND: In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody necitumumab to first-line gemcitabine and cisplatin (GC + N) in advanced squamous non-small-cell lung cancer (sqNSCLC) significantly improved overall survival (OS); the safety profile was acceptable. We explored data for the German subpopulation (N = 96) of SQUIRE patients with EGFR-expressing tumors. PATIENT AND METHODS: Patients with stage IV sqNSCLC were randomized 1:1 to up to 6 cycles of open-label GC + N or GC alone. GC + N patients with no progression continued on necitumumab monotherapy until disease progression or intolerable toxicity. The primary endpoint was OS; the secondary endpoints included progression-free survival (PFS), safety and health-related quality of life (EQ-5D, Lung Cancer Symptom Scale (LCSS)). RESULTS: The 96 German SQUIRE patients with EGFR-expressing tumors (GC + N 42, GC 54) received a median of 4 GC cycles; the GC + N patients received 5 cycles of necitumumab. Adding necitumumab was associated with 41% risk reduction of death (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.94, p = 0.026) and 44% risk reduction of progression (HR 0.56, 95% CI 0.33-0.95, p = 0.029). Adverse events typically associated with EGFR antibody treatment (including rash, hypomagnesemia) were more common with GC + N. The time to deterioration of the EQ-5D and LCSS scores showed no notable differences between the treatment arms, except for appetite loss (delayed for GC + N). CONCLUSION: The survival benefit from adding necitumumab to first-line GC was more pronounced in the German SQUIRE subpopulation with EGFR-expressing tumors than in the overall (intention-to-treat) population; toxicity was manageable and consistent with the overall population.

Blood pressure monitoring during exercise: Comparison of pulse transit time and volume clamp methods.

During physical exercise, pulse transit time (PTT), expressed as the interval between ventricular electrical activity and peripheral pulse wave, may provide a surrogate estimate for blood pressure by the use of specific calibration procedures. The objective of this study was to determine systolic blood pressure (SBP) values derived from the PTT method and from an established method of non-invasive continuous blood pressure measurement based on the volume clamp technique, and to compare their agreement with sphygmomanometry during exercise tests. In 18 subjects, electrocardiogram (ECG) and finger-photoplethysmography were continuously recorded during maximal cycle exercise tests. Intermittent and continuous blood pressure measurements were simultaneously taken using automated sphygmomanometry and a Portapres Model-2 device, respectively. PTT was calculated for each ECG R-wave and the corresponding steepest upstroke slope in the photoplethysmogram, and was transformed to a continuous blood pressure estimate using multipoint nonlinear regression calibration based on the individual subject's sphygmomanometer readings. Bland-Altman limits of agreement between PTT-derived SBP estimates and sphygmomanometer values were -24.7 to 24.1 mmHg, and between Portapres and sphygmomanometer SBP values were -42.0 to 70.1 mmHg. For beat-to-beat SBP estimation during exercise, PTT measurement combined with multipoint nonlinear regression calibration based on intermittent sphygmomanometry may be an alternative to volume clamp devices.

Blood pressure monitoring during exercise: comparison of pulse transit time and volume clamp methods.

During physical exercise, pulse transit time (PTT), expressed as the interval between ventricular electrical activity and peripheral pulse wave, may provide a surrogate estimate for blood pressure by the use of specific calibration procedures. The objective of this study was to determine systolic blood pressure (SBP) values derived from the PTT method and from an established method of non-invasive continuous blood pressure measurement based on the volume clamp technique, and to compare their agreement with sphygmomanometry during exercise tests. In 18 subjects, electrocardiogram (ECG) and finger-photoplethysmography were continuously recorded during maximal cycle exercise tests. Intermittent and continuous blood pressure measurements were simultaneously taken using automated sphygmomanometry and a Portapres Model-2 device, respectively. PTT was calculated for each ECG R-wave and the corresponding steepest upstroke slope in the photoplethysmogram, and was transformed to a continuous blood pressure estimate using multipoint nonlinear regression calibration based on the individual subject's sphygmomanometer readings. Bland-Altman limits of agreement between PTT-derived SBP estimates and sphygmomanometer values were -24.7 to 24.1 mmHg, and between Portapres and sphygmomanometer SBP values were -42.0 to 70.1 mmHg. For beat-to-beat SBP estimation during exercise, PTT measurement combined with multipoint nonlinear regression calibration based on intermittent sphygmomanometry may be an alternative to volume clamp devices.

ROS1 rearrangements in lung adenocarcinoma: prognostic impact, therapeutic options and genetic variability.

BACKGROUND: While recent data show that crizotinib is highly effective in patients with ROS1 rearrangement, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1-positive patients. PATIENTS AND METHODS: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome of these patients were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1-negative patients. RESULTS: 19 patients of 1035 evaluable (1.8%) had ROS1-rearrangement. The median OS has not been reached. Stage IV patients with ROS1-rearrangement had the best OS of all subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response to chemotherapy. Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years. Ten patients with ROS1-rearrangement (52.6%) harbored additional aberrations. CONCLUSION: ROS1-rearangement is not only a predictive marker for response to crizotinib, but also seems to be the one of the best prognostic molecular markers in NSCLC reported so far. In stage IV patients, response to chemotherapy was remarkable high and overall survival was significantly better compared to other subgroups including EGFR-mutated and ALK-fusion-positive NSCLC.

Relation of exercise capacity with lung volumes before and after 6-minute walk test in subjects with COPD.

INTRODUCTION: There is growing evidence that exercise-induced variation in lung volumes is an important source of ventilatory limitation and is linked to exercise intolerance in COPD. The aim of this study was to compare the correlations of walk distance and lung volumes measured before and after a 6-min walk test (6MWT) in subjects with COPD. METHODS: Forty-five subjects with stable COPD (mean pre-bronchodilator FEV1: 47 ± 18% predicted) underwent a 6MWT. Body plethysmography was performed immediately pre- and post-6MWT. RESULTS: Correlations were generally stronger between 6-min walk distance and post-6MWT lung volumes than between 6-min walk distance and pre-6MWT lung volumes, except for FEV1. These differences in Pearson correlation coefficients were significant for residual volume expressed as percent of total lung capacity (-0.67 vs -0.58, P = .043), percent of predicted residual volume expressed as percent of total lung capacity (-0.68 vs -0.59, P = .026), inspiratory vital capacity (0.65 vs 0.54, P = .019), percent of predicted inspiratory vital capacity (0.49 vs 0.38, P = .037), and percent of predicted functional residual capacity (-0.62 vs -0.47, P = .023). CONCLUSIONS: In subjects with stable COPD, lung volumes measured immediately after 6MWT are more closely related to exercise limitation than baseline lung volumes measured before 6MWT, except for FEV1. Therefore, pulmonary function testing immediately after exercise should be included in future studies on COPD for the assessment of exercise-induced ventilatory constraints to physical performance that cannot be adequately assessed from baseline pulmonary function testing at rest.

Effects of nasal positive expiratory pressure on dynamic hyperinflation and 6-minute walk test in patients with COPD.

INTRODUCTION: Dynamic hyperinflation is an important target in the treatment of COPD. There is increasing evidence that positive expiratory pressure (PEP) could reduce dynamic hyperinflation during exercise. PEP application through a nasal mask and a flow resistance device might have the potential to be used during daily physical activities as an auxiliary strategy of ventilatory assistance. The aim of this study was to determine the effects of nasal PEP on lung volumes during physical exercise in patients with COPD. METHODS: Twenty subjects (mean ± SD age 69.4 ± 6.4 years) with stable mild-to-severe COPD were randomized to undergo physical exercise with nasal PEP breathing, followed by physical exercise with habitual breathing, or vice versa. Physical exercise was induced by a standard 6-min walk test (6 MWT) protocol. PEP was applied by means of a silicone nasal mask loaded with a fixed-orifice flow resistor. Body plethysmography was performed immediately pre-exercise and post-exercise. RESULTS: Differences in mean pre- to post-exercise changes in total lung capacity (-0.63 ± 0.80 L, P = .002), functional residual capacity (-0.48 ± 0.86 L, P = .021), residual volume (-0.56 ± 0.75 L, P = .004), S(pO2) (-1.7 ± 3.4%, P = .041), and 6 MWT distance (-30.8 ± 30.0 m, P = .001) were statistically significant between the experimental and the control interventions. CONCLUSIONS: The use of flow-dependent expiratory pressure, applied with a nasal mask and a PEP device, might promote significant reduction of dynamic hyperinflation during walking exercise. Further studies are warranted addressing improvements in endurance performance under regular application of nasal PEP during physical activities.

Histology as a potential clinical predictor of outcome in advanced non-small-cell lung cancer treated with vinorelbine and mitomycin combination chemotherapy.

BACKGROUND: The importance of clinical predictors in the treatment of non-small-cell lung cancer (NSCLC) has increased during the last decade. This retrospective study analyzed the combined patient-level data from two phase II trials that investigated the efficacy and safety of combination chemotherapy with vinorelbine and mitomycin in patients with locally advanced or metastatic NSCLC. The aim of this analysis was to determine if patients' baseline and disease characteristics, including histology, gender, smoking history, and expression of TTF-1, might be potential predictors of outcome. METHODS: Response rates, unadjusted survival times, and Cox covariate-adjusted hazard ratios (HRs) were calculated. Results were reported separately for each subgroup in each individual trial and in the pooled data set. RESULTS: A total of 175 patients were included in this analysis. Adjusted HRs for both overall survival (OS) and progression free survival (PFS) favored the nonadenocarcinoma histology subgroup, achieving a statistical significance for OS in the pooled data (n = 175; HR 0.68; 95 % CI 0.49-0.94; p = 0.019). TTF-1-negative immunohistochemistry was associated with a significantly higher response rate (25 vs. 0 %; p = 0.04) and with a nonsignificant advantage in OS (n = 33; HR 1.23; 95 % CI 0.56-2.73; p = 0.608). Gender and smoking history were not strongly related to outcome. CONCLUSIONS: The results of this analysis indicate that patients with nonadenocarcinoma histology might get superior benefit from combination chemotherapy with vinorelbine and mitomycin. These results should be confirmed in a prospective study.

Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case.

IgG4-related lung disease is commonly associated with autoimmune pancreatitis. Recently, isolated IgG4-related interstitial lung disease (ILD) without other organ involvement has newly been reported in two cases with clinical features of nonspecific interstitial pneumonitis (NSIP).We report the first case of an isolated IgG4-related ILD in a 78-year-old man with dry cough and dyspnea, whose clinical findings proved to be different from NSIP. Serum IgG4 levels were increased. Chest CT scan revealed bilateral consolidations especially in the lower lobes, enlarged mediastinal and hilar lymph nodes and pleural effusions. Video-assisted thoracoscopic (VATS) lung biopsy revealed a pattern similar to usual interstitial pneumonia (UIP) and an abundant IgG4-positive plasma cell infiltration. He was effectively treated by steroid therapy.Increasing recognition of IgG4 related diseases has led to a growing number of new entities. The novel concept of isolated IgG4-related ILD as a pulmonary manifestation of a systemic IgG4-related disorder should be taken into account as a possible differential diagnosis of ILD and mass-forming lesions, even when no other organ manifestation is clinically apparent at the time of diagnosis. Lung specific diagnostic criteria and algorithms are required to enhance diagnostic accuracy in cases of possible IgG4-related ILD.