High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

BACKGROUND: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. METHODS: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. RESULTS: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). CONCLUSIONS: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Body composition, pulmonary function tests, exercise capacity, and quality of life in chronic obstructive pulmonary disease patients with obesity.

PURPOSE OF THE STUDY: Larger proportions of chronic obstructive pulmonary disease (COPD) patients are currently overweight or with obesity than underweight, and the combination of COPD and obesity is increasing. The purpose of this study was to investigate differences in the body composition, pulmonary function tests, exercise capacity, and health-related quality of life among normal weight, overweight, and obese patients with COPD. STUDY DESIGN: A total of 514 patients with COPD were included in the study. According to the World Health Organization criteria for body mass index, the patients were classified as normal weight, overweight, and obese. Evaluations included fat-free mass, fat-free mass index, phase angle, pulmonary function tests, and 6-minute walk test. Dyspnea was assessed using the modified Medical Research Council dyspnea scale, and the health-related quality of life was evaluated using COPD Assessment Test and St. George's Respiratory Questionnaire. Values were compared among the three groups. RESULTS: There were 315 male and 199 female patients, with a mean age of 66.7 ± 8.4 years. Fat-free mass, fat-free mass index, and phase angle values were significantly higher in COPD patients with obesity than in other patients (P < .001, P < .001, P < .001). Forced expiratory volume in 1 s, forced expiratory volume in 1 s/forced vital capacity, and diffusing capacity of lung for carbon monoxide value in pulmonary function tests were significantly higher in COPD patients with obesity than in other patients (P = .046, P < .001, P < .001), while the forced vital capacity values were similar in all groups. Exercise capacity (6-min walk test distance), dyspnea symptoms (modified Medical Research Council scale), and health-related quality of life (COPD Assessment Test and St. George's Respiratory Questionnaire) did not differ significantly between groups. CONCLUSIONS: According to our study, obesity has no negative effect on pulmonary function tests, dyspnea perception, exercise capacity, and health-related quality of life.

Differences in nutritional status of patients with chronic obstructive pulmonary disease between Mediterranean and non-Mediterranean regions in Croatia.

The nutritional status of patients with chronic obstructive pulmonary disease (COPD) is a significant factor that influences the prognosis of the disease. This observational study aimed to analyse the nutritional status of COPD patients and assess the associations between nutritional status, disease severity, and exercise capacity in four different regions of Croatia. In this multicentre study, 534 COPD patients were recruited and evaluated concerning fat-free mass (FFM), fat-free mass index (FFMI), skeletal muscle mass index (SMMI), phase angle (PhA), pulmonary function tests, and the 6-minute walk test (6MWT). There were 325 (60.9%) male and 209 (39.1%) female patients with a mean age of 66.7±8.4 years. Most patients (73.2%) exhibited a moderate to severely abnormal obstructive pattern and had a reduced 6MWT distance (396.5±110.8 m). Among the participants, 32.8% were overweight and 22.3% were obese, and they had satisfactory values for nutritional status variables (FFM, FFMI, SMMI, PhA). There were no statistical differences between the centres in terms of nutritional status variables. There was a significantly positive correlation of FEV1 with BMI (r=0.148, p=0.001), PhA (r=0.256, p=0.00), FFM (r=0.365, p=0.00), and SMMI (r=0.238, p=0.00). However, there was no significant correlation of the 6MWT with BMI (r=-0.049, p=0.254), FFM (r=0.065, p=0.133), and SMMI (r=-0.007, p=0.867). The data analysis demonstrated that our patients were not underweight and that there was no significant difference between the centres in terms of BMI, FFM, FFMI, SMMI, and PhA. This lack of significant difference was observed even though one of the regions studied was Mediterranean.

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project.

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

Risk factors and severity of functional impairment in long COVID: a single-center experience in Croatia.

AIM: To determine the frequency of common symptoms in long COVID and their effect on the quality of life, and to determine the factors contributing to a more severe long COVID. METHODS: The study enrolled 266 patients who were either referred to long-COVID outpatient clinic or were inpatients undergoing rehabilitation. The data were collected between December 2020 and May 2021. We evaluated the symptoms experienced during acute and long COVID and comorbidities. Functional status was assessed with Post Covid Functional Status (PCFS). RESULTS: The final sample consisted of 261 patients. After acute COVID-19 period (>4 weeks), almost 80% of patients had impaired functional status. Only 21.5% reported no functional impairment (0 on PCFS scale). A higher PCFS score was associated with female sex (P<0.001) and oxygen therapy requirement during acute disease (P=0.001). However, it was not associated with having a pre-existing lung disease (P=0.749). Disease severity did not pose a risk for developing a more severe long COVID. CONCLUSION: Women were at greater risk for developing greater functional impairment in long COVID, although we have no explanation why. Malignant disease and hypertension also presented a risk factor for greater functional impairment. More studies are warranted to determine if patients with certain lung disease are more susceptible to long COVID.

The Interplay of Lung Cancer, COVID-19, and Vaccines.

Patients with cancer are more susceptible to a higher risk of coronavirus infection and its severe complications than the general population. In addition, these patients were not included in the pivotal clinical trials for COVID-19 vaccines. Therefore, considerable uncertainty remains regarding the management of cancer patients during the COVID-19 pandemic and the safety of COVID-19 vaccinations in cancer patients. In this review, we summarize the current knowledge generated from the beginning of the COVID-19 pandemic on the vulnerability of cancer patients to the coronavirus disease, as well as the effectiveness of COVID-19 vaccines in this population. We also discuss the available data on the effects of anticancer treatment with immune checkpoint inhibitors on the immune responses to SARS-CoV-2 in cancer patients. Special attention in this review will be given to patients with lung cancer, as such patients are at an increased risk for severe effects from COVID-19.

Lipid profile and atherogenic indices in patients with stable chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Limited number of studies investigated lipid profile in chronic obstructive pulmonary disease (COPD) with inconsistent results. This study aimed to investigate lipid parameters in sera of patients with stable COPD and their associations with disease severity, smoking, comorbidities and therapy. METHODS AND RESULTS: The study included 137 COPD patients and 95 controls. Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assessed. Non-HDL-C (NHC), atherogenic coefficient (AC), TG/HDL-C, atherogenic index of plasma (AIP), Castelli's risk index I and II (CRI-I, CRI-II), and monocyte to HDL ratio (MHR) were calculated. HDL-C and MHR were increased, while other lipid parameters and indices were decreased in COPD patients compared to healthy individuals. Smoking did not influence lipid parameters. However, lipid profile was altered only in more severe disease stages. AC, CRI-I and CRI-II showed positive association with lung function parameters in COPD patients, and negative with COPD multicomponent indices (ADO, BODCAT, BODEx, CODEx and DOSE). Combined model that included CRI-II, C-reactive protein, fibrinogen and white blood cells showed great diagnostic performances, and correctly classified 72% of study participants with an AUC of 0.800 (0.742-0.849), P < 0.001. Bronchodilator monotherapy and statins have opposite impact on TC, LDL-C and NHC, while TG, TG/HDL-C and AIP were increased in COPD patients with cardiovascular diseases. CONCLUSION: Lipid disbalance is present in COPD, and it seems to occur later as the disease progresses. Further studies are needed to illuminate the underlying mechanism of dyslipidaemia.

Diagnostic accuracy, sensitivity, and specificity of CT pulmonary artery to aorta diameter ratio in screening for pulmonary hypertension in end-stage COPD patients.

AIM: To determine the diagnostic accuracy of pulmonary artery to aorta ratio in screening for pulmonary hypertension in advanced chronic obstructive pulmonary disease (COPD) patients. METHODS: A prospective, diagnostic study was conducted in University Hospital Center Zagreb between January 2015 and March 2018. The study enrolled 100 patients who consecutively underwent chest computed tomography (CT), echocardiographic exam, and right heart catheterization. Two independent observers measured pulmonary artery and ascending aorta diameters. The correlation between the ratio and mean pulmonary artery pressure, measured invasively, was assessed. Patients with echocardiographic signs of moderate systolic or diastolic left ventricular dysfunction were excluded (n=44). RESULTS: Sixty-six patients (55.5% men), with a median age of 61, were identified. Median forced expiratory volume during the first second (FEV1) was 34±12, FEV1/forced vital capacity <0.70. Patients with and without pulmonary hypertension had pulmonary artery diameter of 36±7 mm and 27±4.6 mm, respectively (P<0.001). Median pulmonary artery/aorta (PA/A) ratios for patients with and without pulmonary hypertension were 1.05 and 0.81, respectively (P<0.001). PA/A ratio above 0.95 was an independent predictor of pulmonary hypertension with a specificity of 100% and a sensitivity of 74.51% (area under the curve=0.882; standard error=0.041; P<0.001). CONCLUSION: PA/A ratio as measured on chest CT images can be used as a screening tool instead of echocardiography.

Comorbidities and Syndemics in the COVID-19 Age: Challenges and Opportunities for Bringing Separated Branches of Medicine Closer to Each Other.

The Corona Virus Disease 2019 (COVID-19) as a unique disaster has stressed the extreme importance of the three issues for medicine, society and humanity in general: comorbidity, pandemic and syndemic. There are many reasons why the study of comorbidities and syndemics of COVID-19 is of great importance for researchers, clinicians and health policy makers who are responsible for health care organization and funding in a bid to develop more effective and efficient prevention and treatment. Thinking about COVID-19 through a syndemics concept and taking biological, psychological, social and spiritual dimensions into account, physicians could be more effective in clinical practice and community-based interventions. The outcome of SARS-CoV-2 infection is determined by the virus-host interaction, with pathogenicity of SARS-CoV-2 being related to the presence of comorbid diseases. The risk for severe COVID-19 clinical manifestations and death increases with age of patients and comorbidity. General mechanisms of multi-system dysfunction and multi-organ damage reported in COVID-19 are probably related to ubiquitous expression of ACE2 in many tissues and its important role in the renin-angiotensin-aldosterone system (RAAS) functioning. Physicians all over the world should be aware of COVID-19 related comorbidities, multisystem disorders and syndemics, as well as treatment and preventive strategies. COVID-19 age is a right time to reconsider the state of science and practice in comorbidity medicine field from the both epistemological and treatment perspective. Comorbidities and multimorbidities are indifferent to medical specializations, so the integrative and complementary medicine is an imperative in the both education and practice. Shifting the paradigm from vertical and mono-morbid interventions to comorbidity, multimorbidity and multi-system disease approaches enhances effectiveness and efficiency of human resources utilization. The aim of this review is to summarize the theoretical concepts and clinical experience and research regarding comorbidity in general, and specifically related to the COVID-19 pandemic, syndemics and infodemic.