Prognostic impact of the IASLC grading system of lung adenocarcinoma: a systematic review and meta-analysis.

AIMS: Tumour grading is an essential part of the pathologic assessment that promotes patient management. The International Association for the Study of Lung Cancer (IASLC) proposed a grading system for non-mucinous lung adenocarcinoma in 2020. We aimed to validate the prognostic impact of this novel grading system on overall survival (OS) and recurrence-free survival (RFS) based on literature data. METHODS AND RESULTS: The review protocol was registered in PROSPERO (CRD42023396059). We aimed to identify randomized or non-randomized controlled trials published after 2020 comparing different IASLC grade categories in Medline, Embase, and CENTRAL. Hazard ratios (HRs) with 95% confidence intervals (CIs) of OS and RFS were pooled and the Quality In Prognosis Studies (QUIPS) tool was used to assess the risk of bias in the included studies. Ten articles were eligible for this review. Regarding OS estimates, grade 1 lung adenocarcinomas were better than grade 3 both in univariate and multivariate analyses (HROSuni = 0.19, 95% CI: 0.05-0.66, p = 0.009; HROSmulti = 0.21, 95% CI: 0.12-0.38, p < 0.001). Regarding RFS estimates, grade 3 adenocarcinomas had a worse prognosis than grade 1 in multivariate analysis (HRRFSmulti : 0.22, 95% CI: 0.14-0.35, p < 0.001). CONCLUSION: The literature data and the result of our meta-analysis demonstrate the prognostic relevance of the IASLC grading system. This supports the inclusion of this prognostic parameter in daily routine worldwide.

Proposal of a grading system for squamous cell carcinoma of the lung - the prognostic importance of tumour budding, single cell invasion, and nuclear diameter.

The prognostic markers of lung squamous cell carcinoma (LSCC) are less investigated. The aim of our study was to evaluate tumour budding (TB), minimal cell nest size, nuclear diameter (ND), and spread through air spaces (STAS) among patients with resected LSCC, semi-quantitatively. Furthermore, we aimed to identify a grading system for the best prognostic stratification of LSCC. Patients who underwent surgical resection at the Department of Surgery, University of Szeged between 2010 and 2016 were included. Follow-up data were collected from medical charts. Morphological characteristics were recorded from histologic revision of slides. Kaplan-Meier analysis, log rank test and Cox proportional-hazards model, ROC curve analysis, and intraclass correlation were utilised. Altogether 220 patients were included. In univariate analysis, higher degree of TB, infiltrative tumour border, larger ND, the presence of single cell invasion (SCI) and STAS were associated with adverse prognosis. Based on our results, we proposed an easily applicable grading scheme focusing on TB, ND, and SCI. In multivariate analysis, the proposed grading system (pOS < 0.001, pRFS < 0.001) and STAS (pOS = 0.008, pRFS < 0.001) were independent prognosticators. Compared to the previously introduced grading systems, ROC curve analysis revealed that the proposed grade had the highest AUC values (AUCOS: 0.83, AUCRFS: 0.78). Each category of the proposed grading system has good (ICC: 0.79-0.88) reproducibility. We validated the prognostic impact of TB, SCI, ND, and STAS in LSCC. We recommend a reproducible grading system combining TB, SCI, and ND for proper prognostic stratification of LSCC patients. Further research is required for validation of this grading scheme.

Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise.

The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp, and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42), and increased the short-term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hr to 29.7±20.3/hr) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.

The More Extensive the Spread through Air Spaces, the Worse the Prognosis Is: Semi-Quantitative Evaluation of Spread through Air Spaces in Pulmonary Adenocarcinomas.

INTRODUCTION: The extent of spread through air spaces (STAS) is less investigated among patients with lung adenocarcinoma who underwent sublobar resection. Therefore, we aimed to evaluate the extent of STAS semi-quantitatively, to assess its prognostic impact on overall survival (OS) and recurrence-free survival (RFS), and to investigate the reproducibility of this assessment. METHODS: The number of tumour cell clusters and single tumour cells within air spaces was recorded in three different most prominent areas (200x field of view). The extent of STAS was categorized into three groups, and the presence of free tumour cluster (FTC) was recorded. RESULTS: Sixty-one patients were included. Recurrence was more frequent with higher grade (p = 0.003), presence of lymphovascular invasion (p = 0.027), and presence of STAS of any extent (p = 0.007). In multivariate analysis, presence of FTC (HR: 5.89; 95% CI: 1.63-21.26; p = 0.005) and more pronounced STAS (HR: 7.46; 95% CI: 1.60-34.6; p = 0.01) had adverse impact on OS and RFS, respectively. Concerning reproducibility, excellent agreement was found among STAS parameters (ICC range: 0.92-0.94). DISCUSSION: More extensive STAS is an unfavourable prognostic factor in adenocarcinomas treated with sublobar resection. As the evaluation of extent of STAS is reproducible, further investigation is required to gather more evidence.

[Changes of the T cell composition in the thymus during the COVID-19 pandemic]. / A csecsemomirigy T-sejtjeinek összetételében létrejövo változások a COVID­19-pandémia alatt.

INTRODUCTION: In our study, we aimed to investigate whether the COVID-19 infection itself or the vaccination against it affect the differentiation of T cells in the thymus, and whether the reduction in T cell counts observed in the blood of COVID-19-infected individuals is also observed at the tissue level in the thymus. METHOD: Data from a total of 55 thymectomy patients were processed to create three groups: 1) the pre-COVID-19 (PC) group included 22 patients, 12 women and 10 men, who underwent thymectomy between 2008 and 2013; 2) in the no-COVID-19 (NC) group (patients without verified infection or vaccination), 20 patients, 11 women and 9 men, underwent thymectomy in 2020-2021; 3) the vaccinated or infected COVID-19 (VIC) group included 13 patients, 4 women and 9 men, who underwent thymectomy also in 2020-2021. The pathological samples were immunohistochemically tested for CD4, CD8, CD25 and FOXP3 to verify the helper, cytotoxic and regulatory T cells. RESULTS: The VIC group had significantly lower values for CD4, compared to the PC and NC groups. The FOXP3 value was significantly lower in the VIC and NC groups compared to the PC group. No significant differences were found for CD8 and CD25 between the groups studied. DISCUSSION: The COVID-19 infection or vaccination affects the T cell composition of the thymus. Decreased expression of CD4 has been demonstrated in the VIC group, which confirms a decrease in the T cell counts that also occurs in the thymus. The low FOXP3 levels observed in the NC group during the COVID-19 era, compared to the PC group, may be indicative of a high rate of asymptomatic coronavirus infections and a worsening of immunetolerance. CONCLUSION: First in the world, we have verified that the helper T cell composition of the thymus in COVID-19 infection era is reduced, and in the asymptomatic patients the immune function is decreased as well. Orv Hetil. 2022; 163(52): 2062-2066.

Adjuvant chemotherapy could improve the survival of pulmonary sarcomatoid carcinoma: A systematic review and meta-analysis.

BACKGROUND: Complete surgical removal is currently considered to be the best treatment option for pulmonary sarcomatoid carcinoma (PSC) especially in early stage operable disease; however, the reported recurrence-free survival is low. Benefits of adjuvant chemotherapy in PSC patients are still controversial, and there is no obvious agreement on the optimal treatment modalities of this disease. Therefore, we aimed to investigate the prognosis in terms of overall survival (OS) in patients with PSC who received adjuvant chemotherapy. METHODS: The review protocol was registered in PROSPERO (CRD42022306084). Patients with PSC who underwent surgical therapy with or without adjuvant chemotherapy were included into the meta-analysis. Hazard ratios (HR) with 95% confidence intervals (CIs) for OS were pooled and ROBINS-I tool was used to assess risk of bias of the included studies. RESULTS: We identified four retrospective cohort studies with 6768 records from MEDLINE, Embase, and CENTRAL databases up to 9th September 2021, and altogether 1835 patients were included to the analysis. The present meta-analysis shows that patients receiving adjuvant chemotherapy had a significantly longer OS than patients who underwent surgical treatment alone (HR = 0.5657, 95%CI: 0.4391-0.7290, p < 0.0001). CONCLUSIONS: Despite the limited information on the chemotherapy regimens in the included studies, patients with PSC may benefit from adjuvant chemotherapy. More publications are required to evaluate and compare efficient adjuvant chemotherapy protocols in PSC cases.

Perioperative Systemic Inflammation in Lung Cancer Surgery.

Systemic inflammation (SI) is a response of the immune system to infectious or non-infectious injuries that defends the body homeostasis. Every surgical intervention triggers SI, the level of which depends on the extent of damage caused by the surgery. During the first few hours after the damage, the innate or natural immunity, involving neutrophils, macrophages, and natural killer cells, plays a main role in the defense mechanism, but thereafter the adaptive immune response ensues. The number of leukocytes is elevated, the levels of lymphocytes and natural killer cells are reduced, and the cytokines released after surgery correlate with surgical damage. Minimally invasive thoracic surgery procedures induce less inflammatory response and reduce the immune defense in patients to a more moderate level compared with the open surgery procedures; this immunosuppression can be further diminished in spontaneous ventilation cases. The normal functioning of the immune defense is important in controlling the perioperative circulatory tumor cells. Moreover, elevated levels of inflammatory cytokines before immune therapy have a negative impact on the response, and significantly shorten the progression-free survival. Clinically, the lower are the levels of cytokines released during lung surgery, the lesser is the postoperative morbidity, especially pneumonia and wound infection. The return to normal levels of lymphocytes and cytokines occurs faster after spontaneous ventilation surgery. The use of locoregional anesthesia can also reduce SI. Herein, we review the current knowledge on the effects of different operative factors on postoperative SI and defense mechanism in lung cancer surgery.

Pulmonary necrotizing sarcoid granulomatosis / A tüdo nekrotizáló sarcoid granulomatosisa.

Összefoglaló. A nekrotizáló sarcoid granulomatosis a granulomatosus pulmonalis angitisek közé tartozó, ritka kórkép. Egyesek a sarcoidosis variánsának, mások primer pulmonalis vasculitisnek tartják. A kórkép klinikai és patológiai jellegzetességeit két eset bemutatásával ismertetjük. A 20 éves nobeteg sürgosséggel került pulmonológiai osztályra száraz köhögés, jobb oldali, mély belégzéssel összefüggo mellkasi fájdalom és láz miatt, a 63 éves férfi beteget pedig pneumoniát követo kontroll-mellkasröntgenfelvételen látott elváltozás kivizsgálása során észlelték. Az autoimmun panel vizsgálata, a mikrobiológiai tesztek mindkét betegnél negatívnak bizonyultak, a légzésfunkciós vizsgálat és a bronchoszkópos vizsgálat nem talált eltérést. A mellkas-CT-felvételen lágyrész-denzitású nodulusok látszottak egyoldali dominanciával, a folyamatot nem kísérte a hilusi nyirokcsomók szimmetrikus megnagyobbodása. A nodulusok szövettani vizsgálata vált indokolttá, melyet videoasszisztált torakoszkópos tüdoreszekciós mintavétellel biztosítottak. Mikroszkóposan a tüdoparenchymában gócos nekrózisokat, a környezetükben el nem sajtosodó epitheloid sejtes granulomatosus gócokat, az átfutó artériákban pedig granulomatosus arteritist láttak; a klinikai adatok figyelembevételével a tüdo nekrotizáló sarcoid granulomatosisa diagnózisát állították fel. A tüdobetegség mindkét betegnél egy év alatt spontán regrediált. Az irodalom adatait és az eseteket összegezve, a tüdo nekrotizáló sarcoid granulomatosisában mikrobiológiai vizsgálatokkal nem igazolható tüdofertozés, és az immunológiai kivizsgálás sem tár fel szisztémás autoimmun betegséget; a diagnózis a klinikai kép és a képalkotó vizsgálatok alapján indikált szövettani vizsgálattal állítható fel. A betegség szteroidkezelésre jól reagál, de elofordul spontán regresszió is, az utóbbira láttunk példát. Bár az entitás átmenetet képez a nekrotizáló vasculitisek és a sarcoidosis között, egyre több érv szól amellett, hogy a sarcoidosis spektrumába tartozik. Orv Hetil. 2021; 162(38): 1541-1547. Summary. Necrotizing sarcoid granulomatosis is a rare entity currently classified as a subtype of granulomatous pulmonary angiitis. It is considered to be either a variant of sarcoidosis or a primary pulmonary angiitis. Two cases are demonstrated to present its clinical and pathological features. A 20-year-old female patient was admitted to the department of pulmonology with dry cough, right-sided chest pain during hyperventilation and fever. A 63-year-old male patient was observed with a right-sided lesion on chest X-ray after pneumonia. In both cases, autoimmune panel examination, microbiology tests, spirometry function test and bronchoscopy were unremarkable. Chest CT scans have revealed nodules with soft-tissue density without bilateral hilar lymphadenopathy. In order to clarify the diagnosis, video-assisted thoracoscopic resection (biopsy) was performed. Microscopically, parenchymal focal necrosis with adjacent to non-caseating granulomas and granulomatous angiitis were detected. In both cases, spontaneous remission occurred within a year. Histological examination - integrated with clinical data and radiological tests' results - is the gold standard form of evaluation to confirm necrotizing sarcoid granulomatosis; furthermore, exclusion of pneumonia and autoimmune diseases are also required. The disease responds well to corticosteroids; moreover, spontaneous remission is often reported, as it happened in both cases. Necrotizing sarcoid granulomatosis is a transition between necrotizing vasculitides and sarcoidosis; although more and more evidence appears supporting the fact that necrotizing sarcoid granulomatosis may belong to the spectrum of sarcoidosis. Orv Hetil. 2021; 162(38): 1541-1547.