The risk factors for developing primarily detected pulmonary tuberculosis requiring hospitalization

Department of Pneumophthisiology, State University of Medicine and Pharmacy "Nicolae Testemitanu", Chișinău, Republic of Moldova, Congresul consacrat aniversării a 75-a de la fondarea Universității de Stat de Medicină și Farmacie „Nicolae Testemițanu” din Republica Moldova, Ziua internațională a științei pentru pace și dezvoltarePurpose: studying the impact of risk factors and the effectiveness of treatment in patients with pulmonary tuberculosis, primarily screened, treated inpatient and outpatient. Conclusions: 1. Most inpatient cases included men of working age, detected by the passive method, 1/3 of which having a contact with a TB-infected person, 1/4 being migrants, and every tenth was homeless or freed from the jail. The outpatient clinic revealed a predominant number of women and people detected by the active method 2. The social factors were more highlighted in the patients treated in the inpatient departments, such as unfavorable living conditions, lack of employment, low level of education, and vicious skills. 3. Hospitalized patients had 2-3 comorbidities, often in a decompensation stage that required permanent and thorough medical monitoring, whereas most patients in outpatient conditions did not present or had only one associated disease. 4. According to the ranking of risk factors it was established that patients who are exposed to socio-economic factors (smoking, unsatisfactory living conditions, unemployment, low level of education) and medico-biological (association of two chronic pathologies), are more likely to develop tuberculosis that requires hospitalization. 5. A multitude of risk factors present in inpatients, compared to outpatients, lead to the development of TB processes with more serious evolution, and efficient sorting of patients according to hospitalization criteria has contributed to achieving a high success rate of treatment

Factorii de risc în dezvoltarea tuberculozei pulmonare primar depistată care necesită spitalizare

Background. The elucidation and updating of risk factors allows the establishment of an efficient and targeted policy in the fight against tuberculosis, allowing the much more efficient management of the limited resources available to the Republic of Moldova. Objective of the study. The aim of the paper is to study the impact of risk factors in patients with pulmonary tuberculosis treated inpatient and outpatient, and the effectiveness of treatment. Material and Methods. A case-control analytical, crosssectional, retrospective study was performed. A total of 243 cases of pulmonary tuberculosis were included - new cases, with negative and positive microbiological results sensitive to treatment. They were divided into two groups: the study group (190), the inpatients and the control group (53) were those treated in the outpatient setting. Results. Risk factors in the development of TB that require hospitalization are: demographics: men (OR = 3.29, CI 95% 1.75-6.17), passive detection (OR = 3.25, CI 95% 1.72-6.11 ) epidemiological - contact (OR = 3.66, 95% 1.63-8.21); socio-economic: unfavorable living conditions (OR = 7.4, 95% CI 3.63-15.09), unemployed (OR = 4.77, 95% CI 2.27-10.06), primary education (OR = 4, 59, 95% 1.05-19.91), secondary education (OR = 5.02, 95% 1.49-16.89), smoking (OR = 13.86, 95% 1.86-103.4 ), alcohol and smoking (OR = 3.47, 95% CI 1.18-10.18); medicobilogical: two chronic pathologies (OR = 13.86, 95% CI 1.86-103.41), hepatopathies (OR = 3.06, 95% CI 1.04- 9.01). Conclusion. Inpatients have more risk factors than outpatients, which leads to the development of TB processes with more serious evolution, and efficient sorting of patients according to hospitalization criteria has contributed to a high success rate of treatment. Introducere. Elucidarea și actualizarea factorilor de risc, permite stabilirea unei politici eficiente și țintite în lupta cu tuberculoza, permițând gestionarea mult mai eficientă a resurselor limitate de care dispune Republica Moldova. Scopul lucrării. Studierea impactului factorilor de risc la bolnavii de tuberculoză pulmonară tratați în staționar, în ambulatoriu și eficacitatea tratamentului. Material și Metode. A fost efectuat un studiu analitic, transversal, retrospectiv de tip caz-control. În total au fost incluse 243 de cazuri de tuberculoză pulmonară - cazuri noi, cu rezultate microbiologice negative și pozitiv sensibile la tratament. Aceștia au fost repartizați în două loturi: lotul de studiu (190), au constituit bolnavii tratați în staționar și lotul control (53), cei tratați în ambulatoriu. Rezultate. Factori de risc în dezvoltarea TB, care necesită spitalizare sunt: demografici: bărbații (OR=3,29, IÎ95% 1,75-6,17), depistarea pasivă (OR=3,25, IÎ95% 1,72-6,11); epidemiologici - contactul (OR=3,66, IÎ95% 1,63-8,21); socioeconomici: condițiile nefavorabile de trai (OR=7,4, IÎ95% 3,63-15,09), neangajații (OR=4,77, IÎ95% 2,27-10,06), studiile primare (OR=4,59, IÎ95% 1,05-19,91), studiile gimnaziale (OR=5,02, IÎ95% 1,49-16,89), fumatul (OR=13,86, IÎ95% 1,86-103,4), alcoolul și fumatyl (OR=3,47, IÎ95% 1,18-10,18); medicobilogici: două patologii cronice (OR=13,86, IÎ95% 1,86-103,41), hepatopatiile (OR=3,06, IÎ95% 1,04-9,01). Concluzii. Bolnavii din staționar au mai mulți factori de risc, decât cei din ambulatoriu, ceea ce duce la dezvoltarea proceselor TB cu evoluţie mai gravă, iar trierea eficientă a bolnavilor conform criteriilor de spitalizare a contribuit la obținerea unei rate înalte de succes al tratamentului

Performance of international prognostic indices in plasmablastic lymphoma: a comparative evaluation

Purpose!#!Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell malignancy with a heterogenous clinical and prognostic spectrum, determined by multiple factors, including age, HIV- and MYC-status. While there exist several validated scoring systems for diffuse large B-cell lymphoma, which incorporate basic clinical features (age, lactate dehydrogenase, sites of (extranodal) involvement, stage and performance), none of these have been systematically assessed in PBL.!##!Methods!#!We determined the (age-adjusted; aa)-International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI) in a comprehensive multi-center cohort (n = 78) of PBL patients. Further, all indices were comparatively investigated for model quality and concordance.!##!Results!#!Univariate analysis revealed significant prognostic capabilities for all indices, all of which identified a subgroup with favorable outcome. Discriminatory power between patients with less benign prognosis and especially refractory disease exhibited significant variability. Subsequently, stratified models for each risk score were compared employing corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index). Here, the NCCN-IPI outperformed both IPI and R-IPI regarding c-index with ambiguous cAIC results, underlining its clinical utility and suggesting it for preferential use in clinical practice.!##!Conclusion!#!Our current observations support the use of the IPI and its enhanced derivatives in PBL patients. There is, however, a distinct requirement for novel prognostic tools to better delineate subgroups at risk for early relapse or refractory disease as well as late relapse. A comprehensive molecular characterization of a clinically annotated cohort of PBL patients is therefore urgently warranted

The Glasgow prognostic score at diagnosis Is a predictor of clinical outcome in patients with multiple myeloma undergoing autologous haematopoietic stem cell transplantation

ackground: Immunity and inflammatory response affect the tumour microenvironment and the progression of malignancies. Metabolic and inflammatory parameters and ratios of the peripheral blood correlate with outcome in cancer patients. There exist several established and validated inflammation-based scores of prognostic significances including the Glasgow Prognostic Score (GPS). Methods: In this retrospective, multicentre study, we investigated the prognostic capabilities of baseline GPS in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation as a complementary resource for risk stratification. For GPS calculation, a C-reactive-protein (CRP) value of >10 mg/dL counts as one point and an albumin value of <35 g/L connotes another point, resulting in three different subgroups (group I: 0 points; group II: 1 point; and group III: 2 points). Patients with MM admitted to the participating institutions between January 2010 and July 2018 were screened, and established prognostic scores and ratios were assessed. Characteristics significantly associated with overall survival (OS) or progression-free survival (PFS), upon univariate analysis, were included in a Cox proportional hazards model. Results: Following initial assessment, we identified 224 fully evaluable patients who underwent autologous haematopoietic stem cell transplantation for multiple myeloma. A centralised review of pathology and cytogenetic reports was conducted, and a central hematopathology assessment was performed in 175 of 224 cases (78.1%). Proceeding to high-dose chemotherapy and subsequent autologous stem cell transplantation was the main inclusion criterion for all transplant-eligible patients in the study. The median age at diagnosis was 59 years (range: 35–76 years) with a median follow-up of 76 months. Multivariate analysis revealed neutrophil–platelet score (NPS) (HR = 0.528, 95% CI = 0.284–0.984) and B symptoms at primary diagnosis (HR = 1.838, 95% CI = 1.232–2.740) to be independent predictors of PFS while high-risk cytogenetic changes (HR = 2.358, 95% CI = 1.413–3.934, p = 0.001) could be identified as an independent predictor of OS, and GPS to be the only independent predictor of both OS and PFS (OS: HR = 2.127, 95% CI = 1.431–3.162, p < 0.0001 and PFS: HR = 1.405; 95% CI = 1.058–1.867, p = 0.019). Conclusions: Our data show that baseline GPS correlates with rates of relapse and refractory disease in MM patients undergoing autologous transplantation. In a multivariate analysis, these effects were proven to hold prognostic capabilities beyond and independent from established prognosticators. These results require further validation in a prospective setting

Systemic Inflammation and Tumour-Infiltrating T-Cell Receptor Repertoire Diversity Are Predictive of Clinical Outcome in High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements

Simple Summary The current version of the World-Health-Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues acknowledges the provisional entity of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) which is associated with dire prognosis compared to triple-negative diffuse-large-B-cell-lymphoma (tnDLBCL). There is growing evidence for the essential prognostic role of the tumor-microenvironment (TME) and especially the extent of tumor-infiltration by the adaptive immune-system through tumor-infiltrating-lymphocytes (TIL) across a variety of cancers. More precisely, the clonal-architecture of the tumor-infiltrating T-cell-receptor (TCR)-repertoire has recently emerged as a key determinant of risk-stratification in patients with hematological malignancies. Moreover, inflammation-based prognostic-scores, such as the Glasgow-prognostic-score (GPS) were shown to reflect the TME. We therefore performed a large scale next-generation-sequencing (NGS) and clinicopathological study of the TCR-beta-chain-repertoire in HGBL-DH/TH revealing several entity-exclusive clonotypes distinct from tnDLBCL, suggestive of tumor-neoantigen-selection and correlate our findings with the GPS in context of clinical outcome in HGBL-DH/TH. High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (double/triple-hit high grade B-cell lymphoma, HGBL-DH/TH) constitutes a provisional entity among B-cell malignancies with an aggressive behavior and dire prognosis. While evidence for the essential prognostic role of the composition of the tumor-microenvironment (TME) in hematologic malignancies is growing, its prognostic impact in HGBL-DH/TH remains unknown. In this study, we outline the adaptive immune response in a cohort of 47 HGBL-DH/TH and 27 triple-negative diffuse large B-cell lymphoma (tnDLBCL) patients in a large-scale, next-generation sequencing (NGS) investigation of the T-cell receptor (TCR) beta-chain repertoire and supplement our findings with data on the Glasgow-Prognostic Score (GPS) at diagnosis, as a score-derived measure of systemic inflammation. We supplement these studies with an immunophenotypic investigation of the TME. Our findings demonstrate that the clonal architecture of the TCR repertoire of HGBL-DH/TH differs significantly from tnDLBCL. Moreover, several entity-exclusive clonotypes, suggestive of tumor-neoantigen selection are identified. Additionally, both productive clonality and percentage of maximum frequency clone as measures of TCR repertoire diversity and tumor-directed activity of the adaptive immune system had significant impact on overall survival (OS; productive clonality: p = 0.0273; HR: 2.839; CI: 1.124-7.169; maximum productive frequency: p = 0.0307; HR: 2.167; CI: 1.074-4.370) but not PFS (productive clonality: p = 0.4459; maximum productive frequency: p = 0.5567) in HGBL-DH/TH patients, while GPS was a significant predictor of both OS and PFS (OS: p < 0.0001; PFS: p = 0.0002). Subsequent multivariate analysis revealed GPS and the revised international prognostic index (R-IPI) to be the only prognosticators holding significant impact for OS (GPS: p = 0.038; R-IPI: p = 0.006) and PFS (GPS: p = 0.029; R-IPI: p = 0.006) in HGBL-DH/TH. Through the identification of expanded, recurrent and entity-exclusive TCR-clonotypes we provide indications for a distinct subset of tumor-neoantigenic elements exclusively shared among HGBL-DH/TH. Further, we demonstrate an adverse prognostic role for both systemic inflammation and uniform adaptive immune response

Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBLDH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBLDH/TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NF.B signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6rearranged HGBL

Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing

Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor kappa B (NF kappa B) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies