Pharmaceutical Prevention and Management of Cardiotoxicity in Hematological Malignancies.

Modern treatment modalities in hematology have improved clinical outcomes of patients with hematological malignancies. Nevertheless, many new or conventional anticancer drugs affect the cardiovascular system, resulting in various cardiac disorders, including left ventricular dysfunction, heart failure, arterial hypertension, myocardial ischemia, cardiac rhythm disturbances, and QTc prolongation on electrocardiograms. As these complications may jeopardize the significantly improved outcome of modern anticancer therapies, it is crucial to become familiar with all aspects of cardiotoxicity and provide appropriate care promptly to these patients. In addition, established and new drugs contribute to primary and secondary cardiovascular diseases prevention. This review focuses on the clinical manifestations, preventive strategies, and pharmaceutical management of cardiotoxicity in patients with hematologic malignancies undergoing anticancer drug therapy or hematopoietic stem cell transplantation.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

Thrombocytopenia in COVID­19 and vaccine­induced thrombotic thrombocytopenia.

The highly heterogeneous symptomatology and unpredictable progress of COVID­19 triggered unprecedented intensive biomedical research and a number of clinical research projects. Although the pathophysiology of the disease is being progressively clarified, its complexity remains vast. Moreover, some extremely infrequent cases of thrombotic thrombocytopenia following vaccination against SARS­CoV­2 infection have been observed. The present study aimed to map the signaling pathways of thrombocytopenia implicated in COVID­19, as well as in vaccine­induced thrombotic thrombocytopenia (VITT). The biomedical literature database, MEDLINE/PubMed, was thoroughly searched using artificial intelligence techniques for the semantic relations among the top 50 similar words (>0.9) implicated in COVID­19­mediated human infection or VITT. Additionally, STRING, a database of primary and predicted associations among genes and proteins (collected from diverse resources, such as documented pathway knowledge, high­throughput experimental studies, cross­species extrapolated information, automated text mining results, computationally predicted interactions, etc.), was employed, with the confidence threshold set at 0.7. In addition, two interactomes were constructed: i) A network including 119 and 56 nodes relevant to COVID­19 and thrombocytopenia, respectively; and ii) a second network containing 60 nodes relevant to VITT. Although thrombocytopenia is a dominant morbidity in both entities, three nodes were observed that corresponded to genes (AURKA, CD46 and CD19) expressed only in VITT, whilst ADAM10, CDC20, SHC1 and STXBP2 are silenced in VITT, but are commonly expressed in both COVID­19 and thrombocytopenia. The calculated average node degree was immense (11.9 in COVID­19 and 6.43 in VITT), illustrating the complexity of COVID­19 and VITT pathologies and confirming the importance of cytokines, as well as of pathways activated following hypoxic events. In addition, PYCARD, NLP3 and P2RX7 are key potential therapeutic targets for all three morbid entities, meriting further research. This interactome was based on wild­type genes, revealing the predisposition of the body to hypoxia­induced thrombosis, leading to the acute COVID­19 phenotype, the 'long­COVID syndrome', and/or VITT. Thus, common nodes appear to be key players in illness prevention, progression and treatment.

Fish evaluation of additional cytogenetic aberrations and hyperdiploidy in childhood Burkitt lymphoma.

Beyond MYC rearrangement, Burkitt lymphoma (BL) often presents with additional aberrations. Biopsy touch imprints from 72 children with BL were tested with interphase fluorescence in-situ hybridization (i-FISH) for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements and copy-number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Diploid status deviations were investigated with chromosome enumeration probes. MYC rearrangement was demonstrated in all cases. Additional aberrations included +1q (21/72:29.2%), +7q (14/72:19.4%), 13q- (14/72:19.4%), 9p-(6/72:8.3%) and hyperdiploidy (6/72:8.3%). Advanced clinical stage IV, +7q and 9p- were associated with shorter overall survival, with stage IV and +7q retaining prognostic significance on multivariate analysis. No relapse or death was reported among the hyperdiploid cases. This i-FISH investigation provides information on the genetic profile of BL and may prove valuable for patients with no karyotype analysis. Demonstration of hyperdiploidy could evolve research on clonal evolution pathways and probably identify a subgroup of children with favorable prognosis.

The Diagnostic, Prognostic and Therapeutic Role of miRNAs in Adrenocortical Carcinoma: A Systematic Review.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological tools is difficult. Thus, new biomarkers have been tested. We conducted a review of the recent literature on the advances of the diagnostic, prognostic and therapeutic role of miRNAs on ACC patients. More than 10 miRNAs validated by multiple studies were found to present a diagnostic and prognostic role for ACC patients, from which miR-483-5p and miR-195 were the most frequently met biomarkers. In particular, upregulation of miR-483-5p and downregulation of miR-195 were the most commonly validated molecular alterations. Unfortunately, data on the therapeutic role of miRNA are still scarce and limited mainly at the experimental level. Thus, the role of miRNA regulation in ACC remains an area of active research.

Survivin and caspases serum protein levels and survivin variants mRNA expression in sepsis.

Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases' responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n = 107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n = 75) and to healthy controls (n = 89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ΔEx3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -ΔΕx3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p < 0.05). Survivin correlated with IL-8 and caspase-9 (p < 0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.

Antihypertensive Drugs and Risk of Cancer: Between Scylla and Charybdis.

Antihypertensive drugs namely angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, and diuretics are among the most clearly documented regimens worldwide with an overall cardioprotective benefit. Given that malignancy is the second leading cause of mortality, numerous observational studies aimed to investigate the carcinogenic potential of these agents with conflicting results. The purpose of this review was to summarize current data in an effort to explore rare side effects and new mechanisms linking antihypertensive drugs with the risk of developing cancer.

A life-threatening drug-drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer.

In the current report we present the case of a patient experiencing a life-threatening drug-drug interaction involving the concurrent administration of capecitabine and brivudine. A 65- year-old female with metastatic breast cancer was commenced on brivudine for Herpes Zoster, while on capecitabine treatment, by a physician unfamiliar with the potential repercussions of this drug-drug interaction. As a result, she developed skin rash, severe oral mucositis, and severe and prolonged pancytopenia. These side effects were attributed to a serious interaction of capecitabine with brivudine, resulting in inhibition of dihydropyrimidine dehydrogenase. The patient was admitted for supportive care including intravenous hydration, parenteral nutrition, mouth care solutions, fluconazole, antimicrobial therapy, filgrastim, red blood cell and platelet transfusions. She successfully recovered and was discharged on the 26th day after her admission. Drug-drug interactions can be serious, even life-threatening; thus the physicians should be cautious when prescribing new drugs.

Labile hypertension: a new disease or a variability phenomenon?

Blood pressure (BP) is a physiological parameter with short- and long-term variability caused by complex interactions between intrinsic cardiovascular (CV) mechanisms and extrinsic environmental and behavioral factors. Available evidence suggests that not only mean BP values are important, but also BP variability (BPV) might contribute to CV events. Labile hypertension (HTN) is referred to sudden rises in BP and it seems to be linked with unfavorable outcomes. The aim of this article was to review and summarize recent evidence on BPV phenomenon, unraveling the labile HTN concept along with the prognostic value of these conditions.

Detection of CALR Mutations Using High Resolution Melting Curve Analysis (HRM-A); Application on a Large Cohort of Greek ET and MF Patients.

BACKGROUND AND OBJECTIVES: Somatic mutations in the calreticulin gene (CALR) are detected in approximately 70% of patients with essential thrombocythemia (ET) and primary or secondary myelofibrosis (MF), lacking the JAK2 and MPL mutations. To determine the prevalence of CALR frameshift mutations in a population of MPN patients of Greek origin, we developed a rapid low-budget PCR-based assay and screened samples from 5 tertiary Haematology units. This is a first of its kind report of the Greek patient population that also disclosed novel CALR mutants. METHODS: MPN patient samples were collected from different clinical units and screened for JAK2 and MPL mutations after informed consent was obtained. Negative samples were analyzed for the presence of CALR mutations. To this end, we developed a modified post Real Time PCR High-Resolution Melting Curve analysis (HRM-A) protocol. Samples were subsequently confirmed by Sanger sequencing. RESULTS: Using this protocol we screened 173 MPN, JAK2 and MPL mutation negative, patients of Greek origin, of whom 117 (67.63%) displayed a CALR exon nine mutation. More specifically, mutations were detected in 90 out of 130 (69.23%) essential thrombocythaemia cases (ET), in 18 out of 33 (54.55%) primary myelofibrosis patients (pMF) and in 9 out of 10 (90%) cases of myelofibrosis secondary to ET (post-ET sMF). False positive results were not detected. The limit of detection (LoD) of our protocol was 2%. Furthermore, our study revealed six rare novel mutations which are to be added in the COSMIC database. CONCLUSIONS: Overall, our method could rapidly and cost-effectively detect the mutation status in a representative cohort of Greek patients; the mutation make-up in our group was not different from what has been published for other national groups.

The impact of apelin and relaxin plasma levels in masked hypertension and white coat hypertension.

Masked hypertension (HTN) and white coat hypertension represent two reverse forms of clinical HTN with questionable prognostic significance. Recent evidence supports that low apelin and relaxin plasma levels contribute to vascular damage accelerating atherogenesis and predisposing to HTN and cardiovascular (CV) events. The aim of this study was to compare apelin and relaxin plasma levels between patients with masked hypertension (MH) and those with white coat HTN (WCH). Overall, 130 patients not receiving antihypertensive therapy were studied. All patients underwent 24-hour ambulatory BP monitoring (ABPM) and office BP measurements. Plasma apelin and relaxin levels were measured by ELISA method. According to BP recordings, 24 subjects had MH (group A) and 32 had WCH (group B). Apelin (200 ± 111 pg/mL vs 305 ± 127 pg/mL, P < 0.01) and relaxin (35.2 ± 6.7 pg/mL vs 46.8 ± 23.6 pg/mL, P < 0.01) plasma levels were significantly lower in patients with MH compared to those with WCH, respectively. In conclusion, our findings showed that patients with MH had significantly lower apelin and relaxin levels compared to those with WCH. This observation implies an additional prognostic role for adipokines supporting the concept that MH is closer to essential HTN whereas WCH is a more benign condition.

A delayed diagnosis: recurrent fever and beta thalassaemia.

Familial Mediterranean fever and beta-thalassaemia are two genetic disorders, with a largely common geographical distribution. However, they have not much else in common, as the first is an autoinflammatory disorder, while the other is a haemoglobinopathy. We describe a patient with known beta-thalassaemia intermedia who presented with recurrent fevers and he was diagnosed with familial Mediterranean fever 2 years later. We discuss whether there is an association between the two disorders and the cognitive biases that lead to the delay in the diagnosis of familial Mediterranean fever.

Colistin resistance in carbapenemase-producing Klebsiella pneumoniae bloodstream isolates: Evolution over 15 years and temporal association with colistin use by time series analysis.

Colistin is often the only available treatment option against infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp). In this study, the evolution of colistin resistance among CP-Kp and its relationship with colistin use in a tertiary-care hospital in Athens, Greece, was investigated. All CP-Kp blood isolates recovered between January 2002 and June 2016 were tested for susceptibility to colistin by agar dilution and broth microdilution methods. Data on colistin use were collected from the pharmacy database. Time series of colistin use and resistance were analysed using the Box and Jenkins method. A transfer function model was built to quantify the dynamic relationship between colistin use and resistance. Overall, 313 CP-Kp isolates were identified. The percentage colistin resistance increased from 0% in 2002 to 26.9% in 2016 (R2 = 0.5, P < 0.01). A temporal association between colistin use and resistance was observed; an increase in colistin use by 1 DDD/100 patient-days led to a 0.05 increase in the incidence rate of colistin resistance. The time lag between the effect of colistin use on subsequent variations in colistin resistance was 3 months. Colistin use and prior levels of colistin resistance could explain 69% of colistin resistance; in the remaining 31%, other factors might have played a role. The results presented here demonstrate a significant temporal association between colistin use and colistin resistance. These findings have important implications in implementing strategies to contain colistin resistance.

The Role of Angiogenesis Inhibitors in Hypertension: Following "Ariadne's Thread".

Arterial hypertension (HT) is one of the most frequently recorded comorbidities among patients under antiangiogenic therapy. Inhibitors of vascular endothelial growth factor and vascular endothelial growth factor receptors are most commonly involved in new onset or exacerbation of pre-existing controlled HT. From the pathophysiology point of view, data support that reduced nitric oxide release and sodium and fluid retention, microvascular rarefaction, elevated vasoconstrictor levels, and globular injury might contribute to HT. The purpose of this review was to present recent evidence regarding the incidence of HT induced by antiangiogenic agents, to analyze the pathophysiological mechanisms, and to summarize current recommendations for the management of elevated blood pressure in this field.

Significance of survivin mRNA blood levels in patients with melanoma.

PURPOSE: Survivin represents a key anti-apoptotic molecule that is highly expressed in the vast majority of tumors. The aim of the study was to examine the significance of survivin mRNA blood levels in melanoma patients. METHODS: In this prospective translational research study, survivin mRNA blood levels were measured in melanoma patients treated with adjuvant interferon or systemic treatment for advanced disease. RESULTS: Sixty-four patients with melanoma and 40 healthy controls were included. The majority of them had tumor stages III and IV. The upper 95% confidence interval (95%CI) of survivin levels in controls was set as normal cut-off. Fifty-two (81.3%) patients had survivin levels above normal cut-off. Melanoma patients had higher survivin levels than controls (p<0.0001). Survivin levels were non-significantly higher in stage III compared to stage IV patients. Patients with survivin levels above vs. below median had median progression-free survival (PFS) 19.5 months vs. 7.4 months (p=0.045), but median overall survival (OS) not reached vs. 18.4 months (p=0.091). Cox proportional hazard models showed that only tumor stage was associated with PFS and OS. There was no statistically significant change in survivin levels between baseline and during treatment (p=0.845) or during follow-up (p=0.101). CONCLUSION: Although melanoma patients had significantly higher survivin levels than controls, the study showed that survivin mRNA blood levels did not represent an independent prognostic factor for patients with melanoma. The role of circulating survivin should be further examined in larger studies.

Serum S100B levels correlate with stage, N status, mitotic rate and disease outcome in melanoma patients independent to LDH.

PURPOSE: S100B protein is currently used as an immunohistochemistry marker to confirm melanoma diagnosis in biopsy specimens. Moreover, accumulating evidence supports its potential use as a tumor biomarker in blood. This study aimed to explore the potential uses of serum S100B protein as a biomarker in melanoma patients. METHODS: From 2012 to 2015, 107 sequential patients were diagnosed and treated for melanoma. All patients were tested for serum S100B and lactate dehydrogenase (LDH) at diagnosis and during their regular follow-up. Potential correlations between S100B serum levels and baseline characteristics and its impact on survival were assessed. RESULTS: S100B serum levels were within normal limits in patients with stages I and II, elevated in stage III, and very high in stage IV. In bivariate analysis, serum S100B levels >0.11µg/l and stage IV were the only independent prognostic factors associated with poor survival. Furthermore, S100B >0.5µg/l was associated with stage IV and poor survival. However, there was no significant association with LDH. S100B serum levels were positively correlated with mitotic rate (p=0.003), but only in stage IV patients (p=0.015). In stage III, a statistically significant difference in S100B serum levels were observed between N3, N2 and N1 stages, with higher levels for N2 (p=0.012) and N3 (p=0.009) compared to N1, and no difference between stages N2 and N3 (p=1.000). Also, no correlation was found between the number of primary melanoma lesions and S100B. CONCLUSIONS: S100B serum levels reflect tumor load, correlate with response to treatment, might identify patients who are at increased risk of disease relapse, may predict prognosis independent to LDH, and could be used as early biomarkers of tumor recurrence.

Tumor Protein 53 Gene Mutations Without 17p13 Deletion Have No Significant Clinical Implications in Chronic Lymphocytic Leukemia. Detection of a New Mutation.

BACKGROUND: The tumor protein p53 (TP53) gene may be inactivated through 17p13 deletion, somatic mutations, or both. In chronic lymphocytic leukemia (CLL) although 17p13 deletion is correlated with poor prognosis, the role of sole TP53 mutations remains controversial. MATERIALS AND METHODS: We carried out a mutation analysis of TP53 gene in 72 patients with CLL. RESULTS: Seventy-one (98.6%) patients carried the polymorphic site c.215C>G, p.Pro72Arg, but its presence was not correlated with overall survival (OS). Moreover, 19 (26.4%) patients carried a mutation of TP53. Among the eight detected mutations, to our knowledge, one (c.587G>A) has never been reported in the past. There was a correlation of the mutation burden with the stage of the disease (p=0.022), but not with OS. None of the detected mutations was individually correlated with OS. CONCLUSION: The clinical significance of TP53 mutations is still a matter of debate and larger studies and meta-analyses are required to reach an unequivocal conclusion.