Cytogenetyczne i molekularne uwarunkowania agresywnej postaci przewlekłej białaczki limfocytowej

Chronic lymphocytic leukemia (CLL) mainly affects people older than 60 years. Accumulation of morphologically mature but dysfunctional B-lymphocytes in the bone marrow, lymph nodes and peripheral blood is a characteristic feature of this disease. Chromosomal aberrations are observed in lymphocytes of most CLL patients. Typical alterations include deletions of 13q14 and 11q, trisomy 12, and deletions of 17p. Altered expression of the genes located within involved regions, i.e. microRNA15/16 (13q14.3), ATM (11q22-q23) or TP53 (17p13) may be associated with the development and progression of the disease. Cryptic mutations may also contribute to leukemogenesis. Among others, they affect TP53, NOTCH1, SF3B1 and BIRC genes.CLL is a disease with heterogeneous course. There are two clinical forms – indolent and aggressive. The former is characterized by long time to first treatment and demise usually occurs because of coexisting diseases or is associated with leukemia-dependent immunodeficiency. Rapid clinical course and short overall survival, sometimes in spite of appropriate treatment implementation, is typical for aggressive form of CLL. For patients with this form, the moment of treatment initiation and the choice of first-line therapy are especially important, and depend inter alia on prognostic and predictive factors.Established poor prognostic factors in CLL include chromosomal aberrations, i.e., deletion of 17p or 11q, high ZAP-70 kinase expression, mutations/deletions of TP53, and lack of mutation of immunoglobulin heavy chain variable region genes (IgVH).In this paper we tried to point out the importance of some of the prognostic and predictive factors used routinely in the diagnostic management of CLL. Prognostic and predictive potential of microRNA expression level and recently described cryptic changes in the TP53, NOTCH1, SF3B1 and BIRC3 have also been presented

MicroRNA molecules as a significant constituent in gene regulation mechanisms related to cancer

W niniejszej pracy przedstawiono zależności pomiędzy zmianami w ekspresji poszczególnych mikroRNA a powsta­waniem i rozwojem wybranych nowotworów. Dokonano przeglądu doniesień na temat użyteczności badań nad ekspresją mikroRNA, które w przyszłości mogą być wartościowymi i pożądanymi przez diagnostów i lekarzy wskaź­nikami prognostycznymi i predykcyjnymi. Mogą się one stać podwaliną do opracowania nowych metod leczniczych z wykorzystaniem antysensownych miRNA (antagomiry) czy leków mających na celu kompensację ilości cząsteczek w przypadku delecji lub uszkodzeń genów dla konkretnych mikroRNA. Dałoby to potencjalną możliwość regulacji ekspresji genów o znaczeniu strategicznym w procesach związanych z powstawaniem i rozwojem nowotworów.This paper presents the relationship between changes in the expression of specific microRNAs and the formation and development of selected cancers. An overview of reports is provided on the usefulness of research on microRNA expression, which in the future may become valuable and desirable prognostic and prediction factors for diagnosticians and clinicians. miRNA will presumably become the cornerstone for the development of new therapeutic approaches using antisense miRNAs (antagomirs) or drugs aimed at miRNA offsetting in the case of deletion or damage to their genes. It would offer the potential possibility of the regulation of gene expression which is of great significance for the origin and development of cancers

Circulating microRNAs as a potential diagnostic marker in chronic pancreatitis, pancreatic cancer and colorectal cancer

Introduction. We evaluated the expression of selected circulating microRNAs (miRNAs) in chronic pancreatitis (CP), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) patients and healthy volunteers to test for differences in their levels and potential use as biomarkers.  Material and methods. A study of plasma miRNAs expression was performed in 88 patients: 40 (45%) CP patients, 20 (23%) PDAC patients, and 28 (32%) CRC patients. Expression of miRNA-17-5p, miRNA-93-5p, miRNA-320a-5p, miRNA-519d-3p, miRNA-526b-3p, and miRNA-5590-3p was assessed by the qRT-PCR method.  Results. Higher expression of miRNA-93-5p was observed in patients with PDAC (p = 0.02) and CRC (p = 0.005) compared to healthy individuals. Lower expression of miRNA-519d-3p was found in PC (p = 0.01) and PDAC (p = 0.02) compared to healthy volunteers. Higher expression of miRNA-93-5p was observed in patients with CP who had a higher concentration of CA-19-9 compared to patients with a low level or unknown status of this marker (p = 0.03). Examination of miRNA-519-3p expression distinguished patients with CP from healthy volunteers with sensitivity and specificity of 60% and 80%, respectively. Testing miRNA-93-5p and miRNA-519 expression distinguished PDAC patients and healthy participants with sensitivity and specificity of 60% and 77% (for miRNA-93-5p examination), as well as 59% and 79% (for miRNA-519-3p examination). Examination of miRNA-17 and miRNA-93-5p distinguished CRC patients and healthy donors. Sensitivity and specificity of this test were 78% and 50% for miRNA-17 examination, as well as 78% and 80% for miRNA-93-5p examination.  Conclusions. Our data indicate that miRNA-93, miRNA-17, and miRNA-519 demonstrate potential as biomarker molecules in the diagnosis of CP, PDAC, and CRC.

Immunotherapy with pembrolizumab in a patient with advanced non-small-cell lung cancer with high PD-L1 expression and MET exon 14 splice site mutation: a case report

Lung cancer is one of the major oncological problems in Poland. Pembrolizumab monotherapy can be applied as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC) with the expression of programmed death ligand 1 (PD-L1) in ≥ 50% of tumor cells. The article presents a case report of a female patient with advanced lung adenocarcinoma and high PD-L1 expression and an additional MET exon 14 skipping mutation. Despite the advanced stage of the disease, the patient benefited spectacularly from pembrolizumab administered following stereotactic radiotherapy for central nervous system (CNS) metastases. Partial remission followed by long-term stabilization of the disease was achieved. Unfortunately, the therapy was discontinued due to grade-3 pulmonary toxicity observed after 3 years of treatment. Despite the discontinuation of the pembrolizumab therapy, the disease has currently been stabilized and inflammatory changes have slowly resolved upon administration of corticosteroid

Optimizing treatment strategies for a MET exon 14 skipping mutation in non-small-cell lung cancer: a case report of sequential immunotherapy and targeted therapy and literature review

The MET exon 14 skipping mutation is found in approximately 3–4% of non-small cell lung cancers (NSCLC). In 2020, the American Food and Drug Administration approved the first drug targeting this mutation. Capmatinib is a selective MET tyrosine kinase inhibitor. In the European Union, capmatinib is used when the patient needs further treatment after receiving immunotherapy or platinum-based chemotherapy, or both. In the described case, due to disease progression during treatment with pembrolizumab and then with platinum-based chemotherapy, next-generation sequencing was performed, which allowed for detection of the MET gene exon 14 skipping mutation. Targeted therapy with capmatinib was the only method of treatment resulting in a partial response to the disease and improvement of the patient’s quality of life. This case indicates the importance of detailed molecular diagnosis and selection of the optimal method of treatment to prolong survival of the patient with advanced NSCLC. Due to promising results of research conducted so far, in the future, selective MET tyrosine kinase inhibitors — capmatinib and tepotinib — may become the new standard of first-line treatment in NSCLC patients with the MET exon 14 skipping mutation

Tumor heterogeneity and its impact on sotorasib response in a patient with non-small cell lung cancer

Mutations in the Kirsten rat sarcoma virus (KRAS) gene are the most common mutations in NSCLC, and they occur in 25–40% of patients with lung adenocarcinoma. Sotorasib, a selective KRAS inhibitor, is an anticancer drug used in NSCLC patients with a G12C mutation in the KRAS gene. In previously treated patients, this therapy was safer and more effective than docetaxel chemotherapy. Heterogeneity refers to differences between tumor cells within a single tumor as well as in primary and metastatic lesions. It may influence the response to targeted therapies and the development of acquired resistance to these therapies. It is assumed that sotorasib efficacy is lower in patients with known tumor molecular heterogeneity, which may be common in patients exposed to tobacco smoke.  This case report presents a 63-year-old woman with advanced NSCLC and a confirmed G12C mutation in the KRAS gene detected with the real-time PCR technique. A later next-generation sequencing (NGS) examination did not show the presence of this mutation. However, the NGS study was performed on material from a different metastatic lesion. The negative NGS result from this material was confirmed by the real-time PCR technique. The patient had a short-term benefit from first-line chemotherapy and second-line nivolumab immunotherapy (disease stabilization). Due to progression (progression of measurable lesions and new metastases to the CNS), the patient received brain radiotherapy and then sotorasib in the third line of treatment. However, the effectiveness of KRAS inhibition was limited. Regression of the lesion with a detected mutation in the KRAS gene and progression of lesions without this mutation were observed. Sotorasib therapy was terminated. The woman died two years after diagnosis, not benefiting from subsequent lines of therapy.  NSCLC heterogeneity (presence of mutations in only some clones of cancer cells) may be responsible for primary and acquired resistance to molecularly targeted therapies, including KRAS inhibitors.

Anxiety in children and adolescents with chronic kidney disease - multicenter national study results

Background/Aims: Chronic medical illness is a significant risk factor for the development of psychiatric disorders. The aims of the study were: to investigate the level of anxiety in children with chronic kidney disease (CKD) and to identify factors associated with the presence of that emotional problem. Methods: CKD children on hemodialysis (HD, n=22), peritoneal dialysis (PD, n=20,) and on conservative treatment (CT, n=95) were enrolled in the study. We used State-Trait Anxiety Inventory (STAI) for adolescents and STAI-C for children. Socio-demographic and physical factors were assessed. Results: There was a significantly higher level of anxiety-state among HD children (8-12 years) compared with other groups of participants of the same age and Polish population norms. The level of anxiety among adolescents (13-18 years), both anxiety-state and anxiety-trait, was significantly higher in the HD group compared with other groups, which did not differ among themselves. In the HD adolescents, there was a correlation between the anxiety-state and the duration of the disease as well as with the number of hospitalizations. PD adolescents in the mainstream education had higher levels of anxiety-state and anxiety-trait compared with home schooled patients. Conclusions: Even though children and adolescents with CKD are at risk of developing a variety of emotional disorders, the level of anxiety among the researched group, with the exception of HD patients, was not significantly different than the level of anxiety among healthy subjects. Adolescents on HD who present a high level of anxiety should undergo long-term psychological treatment

Different MET gene alterations in lung adenocarcinoma patients

Introduction. In this study, we attempted to detect selected abnormalities in the MET gene using various molecular techniques.  Material and methods. Twenty-six lung adenocarcinoma patients had a diagnosis of abnormalities in the genes: EGFR, ALK, ROS1, MET, and RET. They were diagnosed using various techniques and assessment of PD-L1 expression using immunohistochemistry. Copy number variation of MET gene was assessed by qPCR and FISH techniques, MET exon 14 mutation by RT-PCR method, and MET mRNA expression by the RT-qPCR technique. Statistical analyses were performed using Statistica v. 13.1 and MedCalc 15.8.  Results. Most patients (57.7%) had a high MET gene copy number in the qPCR method, which was not confirmed by the FISH method. A significant positive correlation (R = +0.573, p = 0.0022) between the MET gene copy number assessed with the qPCR method and the relative MET mRNA expression was found.  Conclusions. The positive correlation between the MET mRNA expression and the MET gene copy number in the qPCR test indicates that these methods could complement each other. The performance of these two tests simultaneously increases the reliability of the MET gene assessmen

Disease-related social situation in family of children with chronic kidney disease - parents' assessment : a multicentre study

Introduction and Objective. Chronic kidney disease (CKD) in children burdens life of patients and their families. Little is known about parents` assessment of families’ social situation. However, the knowledge of the details of a patient’s and his family’s life standards might influence modification and optimization of applied therapy. Therefore, the main goal of the present study was to explore the selected elements of life situation of patients suffering with CKD as well as their parents, depending on the CKD stage and appropriate treatment. Materials and Methods. Cross-sectional national study was conducted. A total of 203 children with CKD and 388 their parent-proxies (196 women and 192 men) were enrolled into this study. Patient data and questionnaires filled by both parents, concerning social-demographic parameters and assessment of changes in families after CKD diagnosis in the child, were analysed. Results. CKD children are being brought up in proper families whose financial situation is not good. Children need help in process of education. Perception of current situation differed between both parents in the change of the income source, taking care of CKD child, change in social relations and evaluating relations with medical staff. Parents do not obtain proper support from social workers. Conclusion. Families of CKD children require support in area of financial and educational help for school children. The discrepancies in evaluation of family situation between mothers and fathers of ill children might be the source of conflicts possibly resulting in worsening the outcome for CKD children

Perception of health-related quality of life in children with chronic kidney disease by the patients and their caregivers : multicentre national study results

Objective The aim of the study was to analyse the healthrelated quality of life (HRQoL) in Polish children with chronic kidney disease (CKD) dependant on the CKD stage, treatment modality and selected social life elements in families of the patients. Furthermore, potential differences between self-report and parent/proxy reports and the factors influencing them were assessed. Methods A total of 203 CKD children (on haemodialysis (HD), peritoneal dialysis (PD) and conservative treatment (CT)) and their 388 parent/proxies were enrolled into a cross-sectional national study. The demographic and social data were evaluated. We used the Paediatric Quality of Life Inventory 4.0 Generic Core Scales to assess the HRQoL in children. Results Health-related quality of life scores for all CKD groups were significantly lower in all domains compared with population norms, the lowest one being in the HD group. In CT children, HRQoL did not depend on the CKD stage. Both parents assessed the HRQoL of their children differently depending on their involvement in the care. There are differences between the HRQoL scores of the children and their parents