Hemostatic System in Malignancy: Providing the “Soil” in Metastatic Niche Formation

Malignancy arises and progresses in tight association with changes in the tumor microenvironment and deregulation of hemostatic system. Cancer induces hemostatic imbalance through production and secretion of procoagulant substances, suppression of anticoagulant mechanisms, endothelial activation, and angiogenic switch. Cancer cells are equipped with certain coagulation signaling receptors such as tissue factor (TF) and urokinase plasminogen activator receptor (uPAR). Tissue factor: as major initiator of coagulation, TF is considered the main cause for hypercoagulability in cancer. Constitutive TF expression by cancer cells is a hallmark of malignancy rendering tumors proangiogenic and prometastatic. TF fosters metastasis through coagulation-dependent pathways leading to fibrin deposition in the evolving premetastatic niche. TF has been identified as an independent predictor for metastatic development and adverse prognosis. uPAR: Tissue overexpression of uPAR is demonstrated in almost all human cancers and is associated with advanced disease. Increased uPAR expression is driven by molecular events involving K-ras and SRC oncogenes. Transactivation of these receptors, mediated by binding to hemostatic proteins, activates intracellular signaling pathways, modulates gene expression and facilitates processes of tumor initiation, epithelial-to-mesenchymal transition, anoikis, and metastasis. By manipulating hemostatic processes, tumor induces tolerant host environment necessary for evasion of defense attacks, survival, and progression

Assessment of clinical utility and predictive potential of pre-chemotherapy soluble urokinase plasminogen activator receptor: Observational single center study

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 – 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 – 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): And randomised, phase 3, open-label, multicentre study

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary

Acute Poisoning with Dapsone and Olanzapine: Severe Methemoglobinemia and Coma with a Favourable Outcome / Острое Отравление Медикаментами Dapsone И Olanzapine: Тяжёлая Метгемоглобинемия И Кома С Благоприятным Исходом

Дапсон является лекарством, которое обычно применяется для лечения проказы (лепры). В Европе его предписывают в редких случаях, прежде всего для лечения некоторых кожных заболеваний, напр. dermatitis herpetiformis. Отравления Дапсоном тоже исключительно редки, поэтому информация о них представляет интерес для токсикологической практики. Здесь мы описываем случай острого отравления Даксоном, единственный в серии из 21 000 случаев острых отравлений, лечение которых проводилось в клинике клинической токсикологии Университетской больницы „Св. Георги” ЕАД, Пловдив, Болгария в течение периода 1999 - 2013 г

Liquid biopsy: an innovative and reliable method for detecting not only somatic, but also germline mutations in patients with colorectal and non-small cell lung carcinoma

AbstractLiquid biopsy is a non-invasive method of detecting cancer-related mutations from circulating cell-free DNA (cfDNA) and has emerged as a promising alternative to traditional tissue biopsies. However, its utility has so far been limited to the detection of somatic mutations in cancer cells. Our study examined germline mutations that are associated with pharmacogenetics in 19 patients diagnosed with colorectal cancer and 12 patients with non-small cell lung carcinoma, utilizing the highly advanced and non-invasive technique of liquid biopsy, followed by subsequent next-generation sequencing for comprehensive analysis. Despite the relatively modest sample size of patients under consideration, our results indicated a noteworthy correlation between the presence of adverse effects and the identified germline mutations. We have identified the following mutations with significant implications for pharmacogenetics: MTHFR c.1286A > C, MTHFR c.665C > T, DPYD c.2194G > A, DPYD c.85C > T, XPC c.2815C > A, UMPS c.638G > C, SLC22A2 c.808T > G, EGFR c.1562G > A, ABCB1 2677 T > G, GSTP1 c.313A > G, ERCC2 c.2251A > C, and SLC19A1 c.80A > G. In addition, we observed various adverse drug reactions in our patient cohort, encompassing myelosuppression, hepatotoxicity, neurotoxicity and gastrointestinal toxicity. Liquid biopsy has the potential to revolutionize cancer diagnosis and treatment by detecting both somatic and germline mutations. The preliminary results of studies on germline mutations are promising, but further research is needed to address the remaining challenges and to establish the utility of liquid biopsy as a reliable diagnostic tool for germline mutations

Analysis of the pharmacotherapeutic effectiveness of the tyrosine kinase inhibitors therapy in patients with Chronic Myeloid Leukemia in a single hematology center in Plovdiv, Bulgaria

Aim. The aim of this study is to evaluate treatment retrospectively, response to the therapy and outcomes in patients with chronic myeloid leukemia (CML) and to what extent the European recommendations of LeukemiaNET (ELN) are followed at the Hematology Clinic, University Hospital “St. Georgi”, MU Plovdiv. Methods. All patients with Ph+, BCR-ABL1+ CML who were treated and observed between 01.01.2018 and 12.31.2022 at the clinic were included in the study and were analyzed retrospectively. Results. One hundred and eighty-eight patients with a mean age of 61.26 (21–91) years were analyzed. 151 (80.3%) were in chronic phase (CP), 27 (14.4%) in accelerating one and 10 (5.3%) in blast crisis. The actual overall survival rate was 79.26%, while for CP it is very high – 86.75%, and the mortality rate is 20.74%. All patients received some form of tyrosine kinase inhibitors therapy (TKIs-therapy). The first line TKI was imatinib in 120 patients (64%), and 68 (36%) received a second-generation TKI. Treatment response was monitored with TKIs by RT-qPCR. Conclusion. CML patients treated in the hematology clinic receive standard care in accordance with ELN and BMSH recommendations. Overall survival (OS) in routine care is comparable to published data from international studies. Molecular monitoring provides a good basis for disease control in CP. There are unmet needs in the treatment of patients in advanced stages

Autoimmune Phenomena in Patients with Solid Tumors

Introduction: Autoimmune disorders have been documented in solid tumors and malignant hematological disorders. They are very common and well studied in lymphomas which are associated with immune imbalance. They are less common in solid tumors and are categorized as paraneoplastic syndromes with unclear pathogenesis

YKL-40 – A NEW DIAGNOSTIC BIOMARCER FOR BENIGN BREAST DISEASES AND BREAST CANCER

Benign breast diseases encompass a wide spectrum of lesions, which raise a lot of questions about their classification, diagnosis, prognosis and surgical treatment. The aim of this study is to measure the serum level of YKL-40 in cases of different groups of benign breast diseases, to compare it to the level of healthy women as well as to those with breast cancer and to examine its tissue expression after surgical treatment. We use it as a diagnostic marker and as a criterion for differential diagnosis.Forty nine (49) patients with benign breast diseases and twenty (20) patients with breast cancer were examined. All of them had their serum level of YKL-40 measured preoperatively and its tissue expression examined immunohystochemically after the surgical intervention. There were significant differences in both concentration and tissue expression of this marker in patients with different groups of benign breast diseases and breast cancer. YKL-40 can be an important biomarker in the diagnosis and differential diagnosis of breast diseases