Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases.

BACKGROUND: Brain metastases are associated with considerable negative effects on patients' outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases. MATERIALS AND METHODS: Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259. RESULTS: Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases. CONCLUSIONS: This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.

Clinical and prognostic implications of CD47 and PD-L1 expression in surgically resected small-cell lung cancer.

BACKGROUND: Pharmacological inhibition of the immune-checkpoint molecule CD47 has shown promising results in preclinical small-cell lung cancer (SCLC) models, whereas anti-programmed death-ligand 1 (PD-L1) inhibitors have been recently implemented in the standard of care of advanced-stage SCLC patients. Nevertheless, the expression pattern, clinical relevance and prognostic implication of both CD47 and PD-L1 are rather controversial in surgically treated SCLC patients. MATERIALS AND METHODS: In total, 104 Caucasian SCLC patients from two Central European thoracic centers were included in this study. CD47 and PD-L1 expression as well as the expression of the four major SCLC molecular subtype markers (ASCL1, NEUROD1, YAP1 and POU2F3) were measured by immunohistochemistry. Expression levels were independently evaluated and statistically correlated with clinicopathological data and survival. RESULTS: Positive CD47 and PD-L1 expressions were seen in 84.6% and 9.6% of the samples, respectively. Meanwhile, the tumor-associated stroma was positive for PD-L1 in 59.6% of the cases. Stromal PD-L1 expression correlated with longer overall survival (OS) (versus PD-L1-negative stroma; median OS was 42 versus 14 months, respectively, P = 0.003) and was confirmed as an independent predictor of favorable outcome upon multivariate analysis (hazard ratio 0.530, 95% confidence interval 0.298-0.943, P = 0.031). Notably, neither CD47 nor PD-L1 presence was related to a distinct molecular SCLC subtype. CONCLUSION: CD47 shows a remarkably high expression while tumoral PD-L1 expression is generally low in surgically treated SCLC. Importantly, stromal PD-L1 expression may indicate a favorable clinical outcome and serve as a novel prognostic factor in these patients. Additional studies are warranted to further investigate the clinical impact of CD47 and PD-L1 expression in SCLC.

Lung Transplantation in Hungary From Cardiac Surgeons' Perspective.

Thoracic organ transplantation made a fresh start in Hungary with the first double lung transplant in December 2015. This major leap in Hungarian transplantation was preceded by almost 10 years of preparation, new infrastructure development, and structural changes not only at the organizational level but in human resources as well. In the following years, until recently, altogether 47 lung transplants were performed on 24 men and 23 women. The underlying pathologies were as follows: chronic obstructive pulmonary disease, 25; cystic fibrosis, 11; idiopathic pulmonary fibrosis, 7; as well as other diseases, including bronchiectasis, eosinophilic granuloma, lymphangioleiomyomatosis, and primary pulmonary hypertension in 4 cases. The youngest recipient was 13 and the oldest was 65 years old. Overall survival rates at 30 days and at 1 year were 96% and 82%, respectively. No patients were lost in the cystic fibrosis and other diseases group, whereas the 1-year survival rates of the chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis groups were 73% and 71%, respectively. The results show the robustness and viability of the program, although there is still opportunity for further improvement. In this short paper, we summarize the fields of possible further cooperation of thoracic and cardiac teams as well as future challenges facing the new Hungarian lung transplant program.

Antibody-Mediated Rejection in a Multiple Lung Transplant Patient: A Case Report.

Lung transplant is an effective way to treat many end-stage lung diseases. However, one of the main barriers of allograft organ transplant is still the immunologic rejection of transplanted tissue, which is a response of the HLA molecules. Rejection is a complex process involving both T-cell-mediated delayed-type hypersensitivity reactions and antibody-mediated hypersensitivity reactions to histocompatibility molecules on foreign grafts. We report the case of a 25-year-old female patient with cystic fibrosis who underwent 2 lung transplants because of her initial diagnosis and appearance of bronchiolitis obliterans syndrome after the first transplant. Only 13 months after the second transplant, despite the therapies applied, a new rejection occurred associated with high mean fluorescent intensity donor-specific antibody levels, which resulted later in the death of the patient. The present case draws attention to the importance of matching HLA molecules between donor and recipient in addition to immunosuppressive therapy.

Breakthrough in the Transplantation of Thoracic Organs in Hungary.

In 2016 the focus was, by all means, on the transplantation on thoracic organs. More than 50 heart transplantations were performed in this year. With this achievement, the Hungarian Heart Transplantation Program became one of the leading programs in the world. In the Thoracic Surgery Unit of the National Institute of Oncology and the Thoracic Surgery Department of Semmelweis University the first successful lung transplantation was carried out on December 12, 2015 when the Hungarian Lung Transplantation Program was launched.

Launching the Hungarian Lung Transplantation Program.

The first successful lung transplantation was done in 1963 by James Hardy in the United States. The Vienna Lung Transplant program was launched in 1989 by Professor Walter Klepetko, and in 1996 lung transplantation became available in this center also for Hungarian patients. By 2013, conditions for full-scale Hungarian lung transplantation program were ripe. The Hungarian government invested 3 million Euros for infrastructural developments that made the operation and the perioperative care available. Besides funding, the professional training of medical personnel was also essential for this program to start. Hungarian specialists have had internship opportunities to study all aspects of lung transplantation at the Thoracic Surgery Department in Vienna. After successful preparations, the first lung transplantation in Hungary was performed on December 12, 2015.

Early Postoperative Problems After Lung Transplantation: First-Year Experiences in Light of the Newly Established National Hungarian Lung Transplantation Program.

Until December 2015, Hungarian patients' lung transplantations (LTXs) were done at the Medical University of Vienna. After several years of preparation, the National Hungarian Lung Transplantation Program was launched and the first milestone LTX was performed in Budapest on December 12, 2015. During the first 12 months, 18 lung transplantations took place in Hungary, including the first one. Data were retrospectively collected to analyze the early postoperative problems of the first 18 LTX patients of the newly launched Hungarian National Lung Transplantation Program. No patients with primary pulmonary hypertension and no children were transplanted during this period. We found that the postoperative problems of LTX differ from those of other huge thoracic surgeries both in a quantitative and a qualitative manner. We also reveal problems that are not present with other thoracic surgeries. The wide variety of problems during the early postoperative period after LTX can be managed by a highly organized and coordinated interdisciplinary teamwork.

Urgent Lung Transplantation in Severe Acute Respiratory Failure Based on Rapidly Progressive Interstitial Lung Disease: A Case Report.

Lung transplantation (LUTX) became a worldwide accepted standard therapy for certain well-defined chronic end-stage lung diseases. Until recently, patients on mechanical ventilation or extracorporeal life support techniques were hardly eligible for LUTX because of the inferior short-term results. However, a paradigm shift has occurred, and now these techniques represent bridging options to LUTX for listed patients. In the current practice, transplantation from the intensive care unit (ICU) is not extraordinary in patients on the waiting list. On the other hand, transplantation of an ICU patient who has previously been healthy without any chronic lung disease is still exceptional. Here we report a unique case of a 37-year-old woman without any relevant medical history who developed acute lung failure based on a cryptogenic organizing pneumonia. Her condition rapidly deteriorated and she required mechanical support, then she was bridged to transplantation on venovenous extracorporeal membrane oxygenation. She was listed for LUTX, and despite elevated panel-reactive antibody values, positive crossmatch LUTX was performed. Induction therapy, alemtuzumab, plasmapheresis, and intravenous immunoglobulin were administered. Her recovery was slow but finally she could be discharged from hospital in stable condition. After 2 months at home, she was readmitted to the hospital with respiratory failure from combined antibody-mediated rejection and infection. Before December 2015, the launch of Hungarian National Lung Transplantation Program, Hungarian patients were transplanted in Vienna. This case presents an exceptional example of national and international teamwork that aimed to save a young woman's life.

Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

Airway pathogens during the first year after lung transplantation: a single-center experience.

After lung transplantation, a high level of immunosuppression is needed to prevent rejection. This demand renders recipients more sensitive to infections. As pulmonary infections are a major clinical problem during the first postoperative year after lung transplantation, preventive treatment and regular surveillance examinations are needed for immediate, adequate therapy. We describe the airway pathogens registered during the first posttransplantation year among our 12 lung transplant recipients since December 2008. Samples were obtained for microbiologic analysis from the upper and lower respiratory tracts and from serum as part of routine care. During the first year after transplantation the most frequent pathogens were fungi (Candida albicans 82%; Aspergillus 50%), Pneumocystis (8%), gram-negative bacteria (Pseudomonas spp 60%; Klebsiella 25%, Acinetobacter 17%; Escherichia Coli 17%; and Enterococcus faecalis 25%), and Staphylococcus aureus (50%, including methicillin-resistant strains 25%). This pathogen spectrum in the first postoperative year after lung transplantation was similar to other centers. Colonization with Pseudomonas or fungi presented early and was prevalent among our patients.

Severe mixed sleep apnea after bilateral lung transplantation in a cystic fibrosis patient: a case report.

BACKGROUND: Lung transplantation is the only treatment for end-stage lung disease in selected patients. After lung transplantation, patient recovery is often slow owing to severe underlying diseases in the patient producing hypoxemia before, during, and after surgery, as well as infections and rejection episodes. Postoperative breathing and ventillatory disorders are also associated with diaphragmatic dysfunction and/or phrenic nerve damage. METHODS: Herein we have reported a case of a 35-year-old man undergoing bilateral lung transplantation owing to worsening of chronic respiratory failure from cystic fibrosis. After uncomplicated surgery, weaning was delayed due to nighttime dyspnea and hypoxemia attributed to diaphragm dysfunction. After improvement of diaphragm function, the symptoms persisted, requiring noninvasive nocturnal ventilatory support. Polysomnography confirmed severe mixed sleep apnea. RESULTS: Effective treatment with noninvasive bi-level positive airway pressure spontaneous/timed mode (BiPAP S/T) ventilation during the nights rendered the patient symptom free. Polysomnography confirmed successful treatment. CONCLUSION: Disordered breathing while sleeping is common after solid organ transplantation. BiPAP S/T ventilator therapy was effective to the treat dominantly central sleep apnea in our patient.

Granular cell tumour of the breast: case series and review of the literature.

Granular cell tumours (GCTs) are uncommon rare neoplasms that may occur in any part of the body. Approximately 5-8% of granular cell tumours occur within the breast. Although nearly always benign in behaviour, granular cell tumours of the breast can often mimic breast malignancies both clinically and on the basis of imaging techniques. This article reports five cases of benign granular cell tumours appearing in the breast, mimicking a malignant breast lesion. In addition to reporting the cases, the relevant literature was reviewed.

Congenital complete heart block associated with QT prolongation.

The coexistence of congenital complete heart block and QT prolongation represents a special type of arrhythmia. The electrophysiological and clinical characteristics of this syndrome were studied in eight patients suffering from congenital AV block and QT prolongation. Data from 22 patients suffering from congenital complete heart block only, served as a control. In the study group, the appearance of a torsade de pointes type of ventricular tachycardia could regularly be observed and the tachycardial attack could usually be provoked by ventricular extrastimuli. The corrected QT time was markedly prolonged; on ventricular stimulation, at higher pacing rates the QT interval shortened, but remained significantly higher than in the control group. Syncopal attacks--with the character of polymorphic tachycardia--appeared in each patient of the study group while occurring in only three patients from the control group. Patients were given pacemaker implants (using a higher pacing rate) and long-term administration of beta-receptor blockers. The outcome was favourable; no ventricular tachycardia or syncopal attack was observed in the follow-up period.

[Coronary surgery at the Cardiovascular Surgical Clinic (1976-1990)]. / Coronariasebészet az Er- és Szívsebészeti Klinikán (1976-1990).

In the Cardiovascular Surgical Clinic of the Semmelweis Medical University of Budapest the first coronary artery bypass grafting (CABG) procedure was performed in 1975. Since that time coronary artery surgery has become a routine everyday practice representing more than half of the total workload of adult cardiac surgery. The analysis of 1347 operations performed between 1976-1990 on patients with coronary heart disease showed the followings: the first few years--so called learning curve of CABG operations is characterised by high mortality. With passing time the number of cases performed each year increased rapidly and the surgical technique has improved too. At the same time the operative mortality figures showed decreasing tendency--it was 2.1% for the last 609 cases. All observed parameters showed some progress: in 1990 the average number of grafts per patient was 3.09, internal mammary artery usage 15 percent and the mean aortic cross clamp time per anastomosis 24.5 minutes. Complete myocardial revascularisation is the key point of coronary artery surgery. In order to achieve this target in all operated cases further technical improvement is necessary.

[Development and results of valve replacement surgery at the Városmajor Clinic 1976-1990 (retorospective clinical analysis)]. / A szívbillentyü-sebészet fejlödése és eredményei a Városmajori Klinikán 1976-1990 (retrospektív klinikai analízis).

In Hungary valve replacement is still a major indication for heart surgery in adults. In the Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest from 1976 to 1990 2435 patients were operated for valve disease. Majority of the cases had single (aortic n = 856, mitral n = 912) or double (aortic + mitral n = 513) valve replacement. Over this 15 years period there have been many alterations in patients characteristics and surgical technique as well. In spite of the increasing mean age of patients the operative mortality has decreased (in the last 5 years period it was 2.7%, 5.5% and 7.9% in the three groups respectively). At the same time the number of patients requiring valve re-replacement or combined valve + coronary procedure has increased. The use of bioprosthetic valves has fallen below 10 percent from the 60--80 percent observed between 1976--1980. The analysis showes excellent surgical results in the field of valve replacement in Hungary.

The association of carotid artery stenosis with carotid sinus hypersensitivity. Transitory cerebral ischaemic attack provoked by carotid sinus reflex.

The association of internal carotid stenosis with the carotid sinus syndrome represents a special clinical entity. Transitory cerebral ischaemic attack (TIA) will usually be manifested by activation of carotid sinus reflex. Eighteen patients were observed suffering from both carotid sinus hypersensitivity and TIA. The patients had had TIA's for many years. Unilateral internal carotid stenosis was detected in 15 cases, while 3 patients had bilateral carotid stenosis. On carotid sinus stimulation, syncope appeared and a TIA could be provoked. The mean duration of the syncopic attack was 5500 ms and was based on sinus arrest in 14 cases and on third degree AV block in 4 cases. In all patients carotid artery disobliteration was performed; in 14 patients pacemaker implantation was necessary, while 4 patients could be treated by atropine medication. The development of a TIA could be abolished in every patient and 14 patients remained totally symptom free.

Atrial standstill: an indication for rate responsive pacing.

Atrial standstill (atrial paralysis) is a rare reason for permanent bradycardia. A case of atrial standstill is presented. A 35-year-old man had suffered from bradycardia since his childhood. For 2 years he had complaints (diminishment of his working capacity, and dyspnea occurred with effort) as well. On admission, a slow (38/min) junctional escape rhythm could be detected. There were no signs of atrial mechanical activity (atrial contraction) according to chest x ray, echocardiography, and the atrial pressure curve. The electrophysiological study revealed that the atria could not be electrically stimulated, and no P wave (A wave) could be recorded on right atrial electrograms. The patient received a rate responsive pacemaker. After pacemaker implantation, he became symptom-free; his working capacity improved markedly and his heart size decreased. Owing to the permanent bradycardia and the lack of atrial stimulation, the atrial standstill represents an indication for ventricular rate responsive pacing. Atrial standstill, permanent bradycardia, and the inability to stimulate the atrium are indications for ventricular rate responsive pacing.

[Successful surgical management of rupture of the papillary muscle diagnosed by ultrasound]. / Ultrahanggal felismert papillaris izomruptura sikeres mütéti megoldása.

The rupture of the papillary muscle is an infrequent complication of myocardial infarction. Survival of the acute phase depends on the severity of the rupture and the remaining function of the left ventricle. Permanent survival may be ensured however only by surgical intervention. The authors present the case record of a patients whose disease in connection with a myocardial infarction was revealed by echocardiography and was operated on successfully. No such data were found in the Hungarian literature.

[New aspects of the Kearns-Sayre syndrome]. / A Kearns-Sayre syndroma néhány új vonatkozása.

The case report of the 23 years old female with Kearn-Sayre syndrome started about 15 years ago has some special cardiological aspects. By His band ECG the height of III. degree atrioventricular block was located in the atrioventricular node which is in sharp contrast with all former findings localizing the block into or distal to His band. In the pathogenesis of the unexpected block localisation--besides the muscular degeneration accepted generally in KSS--the recent myocardial infarction of the patient could have a causal role. Electronmicroscopical investigation carried out on the biopsy specimen from the right ventricle revealed both the characteristic hallmarks of "generalized mitochondriopathy" and the pathological glycogen accumulation having been published in skeletal muscles before. The mitral valve prolaps diagnosed in the patient has never been mentioned in KSS. Trauma suffered in early childhood might have a pathogenetic role. In discordance with literature steroid treatment of the diabetic patient with KSS didn't result in lactacidosis.

Pacemaker twiddler's syndrome (rotation of the pacemaker around the electrode cable, a rare complication of pacemaker therapy).

Rotation of the pacemaker generator around the electrode cable (i.e. twiddler's syndrome) was observed by the authors in six cases during the implantation of 4250 pacemakers. Twiddler's syndrome developed in three cases following implantation and in three cases after the replacement of the pacemaker. As a result of the rotation of the device, displacement of the electrode occurred in all cases. The factors predisposing to rotation of the device were as follows: (i) a loose, dilated pocket in 5 cases; (ii) seroma formation around the device in 2 cases; (iii) manipulation with the pacemaker in one case. For treating twiddler's syndrome, reimplantation was performed, fashioning a small and tight pocket for the device and fixing it by transfixing sutures. After reimplantation, the patients became complaint free, no recurrences occurred.