Immune-related adverse events of anti-PD-1 immune checkpoint inhibitors: a single center experience.

Objectives: Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center. Patients and methods: Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors. Results: At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab. Conclusion: ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

HUNCHEST-II contributes to a shift to earlier-stage lung cancer detection: final results of a nationwide screening program.

OBJECTIVES: The introduction of low-dose CT (LDCT) altered the landscape of lung cancer (LC) screening and contributed to the reduction of mortality rates worldwide. Here we report the final results of HUNCHEST-II, the largest population-based LDCT screening program in Hungary, including the screening and diagnostic outcomes, and the characteristics of the LC cases. METHODS: A total of 4215 high-risk individuals aged between 50 and 75 years with a smoking history of at least 25 pack-years were assigned to undergo LDCT screening. Screening outcomes were determined based on the volume, growth, and volume doubling time of pulmonary nodules or masses. The clinical stage distribution of screen-detected cancers was compared with two independent practice-based databases consisting of unscreened LC patients. RESULTS: The percentage of negative and indeterminate tests at baseline were 74.2% and 21.7%, respectively, whereas the prevalence of positive LDCT results was 4.1%. Overall, 76 LC patients were diagnosed throughout the screening rounds (1.8% of total participants), out of which 62 (1.5%) patients were already identified in the first screening round. The overall positive predictive value of a positive test was 58%. Most screen-detected malignancies were stage I LCs (60.7%), and only 16.4% of all cases could be classified as stage IV disease. The percentage of early-stage malignancies was significantly higher among HUNCHEST-II screen-detected individuals than among the LC patients in the National Koranyi Institute of Pulmonology's archive or the Hungarian Cancer Registry (p < 0.001). CONCLUSIONS: HUNCHEST-II demonstrates that LDCT screening for LC facilitates early diagnosis, thus arguing in favor of introducing systematic LC screening in Hungary. CLINICAL RELEVANCE STATEMENT: HUNCHEST-II is the so-far largest population-based low-dose CT screening program in Hungary. A positive test's overall positive predictive value was 58%, and most screen-detected malignancies were early-stage lesions. These results pave the way for expansive systematic screening in the region. KEY POINTS: • Conducted in 18 medical facilities, HUNCHEST-II is the so far largest population-based low-dose CT screening program in Hungary. • The vast majority of screen-detected malignancies were early-stage lung cancers, and the overall positive predictive value of a positive test was 58%. • HUNCHEST-II facilitates early diagnosis, thus arguing in favor of introducing systematic lung cancer screening in Hungary.

Exhaled Biomarkers for Point-of-Care Diagnosis: Recent Advances and New Challenges in Breathomics.

Cancers, chronic diseases and respiratory infections are major causes of mortality and present diagnostic and therapeutic challenges for health care. There is an unmet medical need for non-invasive, easy-to-use biomarkers for the early diagnosis, phenotyping, predicting and monitoring of the therapeutic responses of these disorders. Exhaled breath sampling is an attractive choice that has gained attention in recent years. Exhaled nitric oxide measurement used as a predictive biomarker of the response to anti-eosinophil therapy in severe asthma has paved the way for other exhaled breath biomarkers. Advances in laser and nanosensor technologies and spectrometry together with widespread use of algorithms and artificial intelligence have facilitated research on volatile organic compounds and artificial olfaction systems to develop new exhaled biomarkers. We aim to provide an overview of the recent advances in and challenges of exhaled biomarker measurements with an emphasis on the applicability of their measurement as a non-invasive, point-of-care diagnostic and monitoring tool.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions.

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.

Assessment of Systemic and Cerebral Oxygen Saturation during Diagnostic Bronchoscopy: A Prospective, Randomized Study.

BACKGROUND: Arterial hypoxemia occurs in about 2.5-69% of cases during fiberoptic bronchoscopy and may necessitate administration of supplemental oxygen. Whether routine supplementary administration is indicated for all patients is a debated issue. In this prospective randomized study, we assessed the incidence of systemic desaturation (SpO2 <90% or a >4% decrease lasting for more than 60 s) and wanted to find out whether cerebral desaturation occurs in parallel with systemic changes. PATIENTS AND METHODS: 92 consecutive patients scheduled for diagnostic bronchoscopy were randomly assigned to the no oxygen (O2- group), 2 l/min supplemental O2, or 4 l/min supplemental O2 groups. Primary end points were systemic and cerebral desaturation rate during the procedure. Secondary end points were to delineate the main risk factors of systemic and cerebral desaturation. RESULTS: In the entire cohort, systemic desaturation occurred in 18.5% of patients (n = 17), corresponding to 5 patients (16%) in the O2 (-)group, 6 patients (19%) in the 2 l/min group, and 6 patients (20%) in 4 l/min group, respectively. In the O2 (-) group, the probability of desaturation was 41.7 times higher than that in the 2 l/min group (p=0.014 s), while there was no difference in the probabilities of desaturation between the 2 l/min and 4 l/min groups (p=0.22). Cerebral desaturation (more than 20% rSO2 decrease compared to baseline) did not occur in any patients in the three groups. Systemic desaturation developed earlier, and recovery after desaturation was longer in the O2 (-) group. Male gender, smoking, and systemic oxygen saturation at baseline and FEV1% were the most significant factors contributing to systemic desaturation during bronchoscopy. CONCLUSIONS: Administration of supplemental oxygen does not prevent systemic desaturation during flexible bronchoscopy, but may contribute to the shortening of desaturation episodes and faster normalization of oxygen saturation. According to our results, 2 l/min supplemental oxygen should routinely be administered to patients throughout the procedure. This trial is registered with NCT04002609.

[Reexpansion pulmonary edema]. / Reexpanziós tüdoödéma.

Reexpansion pulmonary edema (RPE) is a rare entity that develops after reexpansion in a chronically collapsed lung. There is a broad clinical spectrum of the disease ranging from asymptomatic appearance to lethal form that occurs in approximately 20% of the cases. The pathophysiological background is complex and not clarified in all details. RPE may be prevented by knowing and treating potential risk factors. This review summarizes the updated knowledge on the pathophysiological background, clinical picture and treatment modalities of RPE.

Lipid metabolite levels of prostaglandin D2 and eicosapentaenoic acid recovered from bronchoalveolar lavage fluid correlate with lung function of chronic obstructive pulmonary disease patients and controls.

One-step global profiling of analyte (mRNA, protein, metabolite) biomarkers may soon replace conventional blood and histological/biopsy diagnostics technologies. It is important to establish whether the numerous blood and other body fluid-derived potential novel diagnostics will be sufficiently efficacious and precise to replace, for example, imaging and functional diagnostic tests. Currently, imaging technologies and spirometry are indispensable for the diagnosis and management of chronic obstructive pulmonary disease (COPD). To validate the concept of using body fluid biomarkers in COPD and to address the question of whether biomarker levels correlate with lung function, we measured the level of a number of biologically relevant lipids and metabolites in the bronchoalveolar lavage (BAL) fluid of COPD and control subjects and examined whether these correlate with numeric parameters of lung function. Both the diagnosis and management of COPD rely on costly and labor intensive lung function tests. Thus, there is an imminent need to replace the current diagnostic approaches with simpler clinical assays. As a first step, we demonstrate proof of principle; the correlation of lipid biomarkers as measured by LC-MS with lung function. In the apparently BAL-accessible fluid compartment, the total recovered lipid metabolite amount, particularly prostaglandin D(2) and eicosapentaenoic acid show a remarkable linear correlation with lung function (R(2)>0.7). The study outcome is encouraging for the continuation of the work toward the measurement of lipid metabolite levels in more easily obtainable biological fluids such as sputum, exhaled air condensate, urine and plasma.

[Successful renal transplantation following lung transplantation: a survey of the first Hungarian case]. / Sikeres vesetranszplantáció tüdoátültetés után: az elso magyarországi eset ismertetése.

The authors review the case of their young patient, who underwent a lung transplantation in Vienna because of an end stage idiopathic pulmonary fibrosis. During the prolonged postoperative phase renal failure full of complications developed, which necessitated haemodialysis. As the pulmonological rehabilitation was complete, but the regular dialyses considerably raised the risk of opportunistic infections, and also significantly reduced the quality of life of the patient, renal transplantation was performed in Debrecen four years after the lung transplantation. This is the first lung transplanted patient in Hungary who also underwent renal transplantation. Now, more than two years after the renal transplantation the patient lives a compensated, rehabilitated life, the respiratory function values have improved and the renal function values are also acceptable. The number of transplanted patients has significantly increased in recent years worldwide, and also in Hungary. However, due to immunosuppressive medications, calcineurin inhibitors mainly, numerous complications must be reckoned with. An outstanding one among them is the secondary renal failure which may occur both in acute and chronic form and may even necessitate renal transplantation. Renal transplantation is an excellent treatment option for end stage renal failure patients, who had received another organ transplant earlier. Kidney transplantation improves quality of life and increases expected survival, too.

[The role of volume reduction surgery in the therapy of early stage chronic obstructive pulmonary disease]. / A volumenredukciós mutét, mint kezelési lehetoség a korai stádiumú krónikus obstruktív tüdobetegség terápiájában.

The role of volume reduction surgery in the therapy of early stage chronic obstructive pulmonary disease. COPD is a leading cause of morbidity and mortality worldwide. Assessment of COPD severity is based on the level of patient's symptoms, the severity of the spirometric abnormality and the presence of complications, such as respiratory failure, and right heart failure. Management of mild to moderate COPD is complex, involves the avoidance of risk factors to prevent disease progression, pharmacotherapy as needed to control symptoms, physiotherapy, and rehabilitation. The bases of pharmacotherapy are bronchodilators, which represent the first line symptom based pharmacologic intervention in COPD. Surgical treatment of emphysema was basically designed to improve subjective dyspnoea, respiratory function and quality of life in severely disabled patients. Three surgical options are currently employed, namely bullectomy, lung volume surgery and lung transplantation. During volume reduction surgery the hyperinflated areas are resected, so the functional residual volume is getting reduced, the respiratory muscle function is increased; the quality of life is improved. The authors are report a young early stage COPD patient who underwent a volume reduction surgery because of decline in physical condition, improving her disability. In conclusion in properly selected patients, lung volume surgery can offer prolonged functional benefit and satisfactory long term survival, even in early stage. The invasive options has a risk of both mortality and morbidity, they are directed only at patients who remain symptomatic despite optimal medical treatment.

[Adenomatoid malformation as peripheral round shadow in lung]. / A tüdoben perifériás kerek árnyék formájában jelentkezo cysticus adenomatoid malformatio.

The authors present a case report of a 17 years old female patient who had a peripheral round shadow on the chest X-ray. After the operation the histological examination verified cystic adenomatoid malformation. The cystic adenomatoid malformation is an abnormal growth of the terminal bronchiolar structures. It is a rare disease, but often associates with other developmental abnormalities. It is important in the differential diagnosis to separate this disease from other cystic pulmonary lesions or sequestration. It is usually recognized in antenatal period or early childhood, but rarely in adulthood. It is possible that there is a connection between the adenoid malformation and lung cancer.

[Therapy of patients with end-stage pulmonary disease. Review of lung transplantation based on four cases of our own]. / Végstádiumú tüdóbetegségben szenvedó betegek kezelése. Attekintés a tüdótranszplantációról négy eset kapcsán.

The pathogenesis of infiltrative pulmonary diseases is largely unknown, and their final outcome is variable. These inflammatory processes may involve the alveoli and the pulmonary interstices, and they may lead to pulmonary fibrosis. The development of end-stage pulmonary disease is irreversible. Patients with respiratory failure have a poor prognosis. For young patients at the end-stage of their pulmonary disease, lung transplantation is a promising therapeutic modality. The therapeutic protocols for unilateral or bilateral lung transplantation and heart-lung transplantation were established only in the last 10 years. In Hungary there is no center yet performing lung transplantation. This therapy is available only for those who could be effectively rehabilitated with this method. Four patients 27-35 years of age suffering pulmonary fibrosis, despite their young age developed honey-comb lungs with therapy resistant respiratory failure. No other organic symptoms were detected by detailed examination, so their predicted survival was dependent on their pulmonary status alone. Cases of four young patients, who were effectively treated with lung transplantation, are discussed from pre-operative preparations to post-operative follow-up, with the review of the literature.