Cardiovascular complications among hematopoietic cell transplantation survivors - the role of cardiomarkers.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and nonmalignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. HSCT can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was to assess the prognostic value of high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing and early identification of patients at high risk of a cardiac event after allogeneic HSCT. PATIENTS AND METHODS: Sixty-three patients with the median age of 37 years at the time of allogeneic HSCT for hematologic diseases were studied. Cardiac bio-markers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before the conditioning regimen and 1 month after HSCT by echocardiography. RESULTS: The differences in plasma NT-proBNP and hs-cTnT concentrations during the 30 days following HSCT were statistically significant (P < 0.001 vs. P = 0.02). Seven of 63 patients (11.1 %) developed a cardiac event defined as cardiovascular dys-rhythmias, pericarditis with cardiac tamponade and heart failure. By multivariate analysis, the strongest prognostic factor of cardiac event was an increased level of hs-cTnT and NT-proBNP persisted for a period of 14 days after HSCT (P < 0.0001). The area under the curve from hs-cTnT testing plus NT-proBNP testing together (AUC = 0.95) was superior to each dia-gnostic modality alone. CONCLUSION: Measurements of plasma NT-proBNP and hs-cTnT concentrations might be a useful tool for identification of high-risk patients requiring further cardiological follow up. Measurement of hs-cTnT plus NT-proBNP together was superior to hs-cTnT and NT-proBNP measurements alone.

Fatal myocarditis after the first dose of nivolumab.

BACKGROUND: Thymic carcinoma (TC) is a rare subtype of thymic epithelial malignancy. Surgical resection is a mainstay in the treatment of TC, while radiotherapy and chemotherapy are modalities used in adjuvant or palliative setting. Immune checkpoint inhibitors (ICI) including anti-PD-1 (programmed cell death 1) antibodies represent an emerging treatment modality in TC; however, their administration could be associated with life-threatening toxicity. CASE: We present a case of a 59-year-old female with grade III TC, who had received neoadjuvant chemotherapy followed by surgery and subsequent adjuvant radio-immunotherapy with an ICI, nivolumab. We provide our experience with the toxicity of an administered treatment. RESULTS: Fourteen days after the first dose of nivolumab and on 21st day after starting of radiotherapy (total dose of 40 Gy), the patient developed fulminant myocarditis with subsequent heart failure. Despite immunosuppressive therapy with high-dose glucocorticoids and mycophenolate mofetil and intensive support, the patient died within 6 days after the onset of first symptoms. CONCLUSION: Physicians should be aware of these extremely rare, but potentially fatal complications of immunotherapy.

Metabolic syndrome in long-term survivors after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and non-malignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. Hematopoietic stem cell transplantation can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was the evaluation of the prevalence of metabolic syndrome (MS) among survivors of allogeneic HSCT. PATIENTS AND METHODS: We analyzed 74 patients with a median age at transplant of 35 years, who had been followed for a median of 5 years (2-23 years) after allogeneic HSCT. MS was defined according to the National Cholesterol Education Programs Adult Treatment Panel III (NCEP ATP III) criteria and by the International Diabetes Federation (IDF) definition. RESULTS: The prevalence of MS among HSCT recipients was 40.5% applying the NCEP ATP III definition and 39.2% the IDF, a 2.02-fold increase compared to the general Slovak population. MS was more common in men. The most common MS features were abdominal obesity, hypertriglyceridemia and hypertension. The lowest prevalence of MS was in the age group of 20-29 years; and the highest prevalence in the age group of 60-69 years. The 10-year cumulative incidence of MS was 32.5%. The most significant risk factor for MS was total body irradiation, positive family history and age > 40 years at HSCT. Seven patients (9.45%) developed cardiovascular complications. The median 10-year general cardiovascular risk scores for males and females were found to be 13.3% and 6.68%, respectively. CONCLUSIONS: Detected increased prevalence of metabolic syndrome after allogeneic HSCT in patients surviving more than 2 years after this procedure may provide next stimulus to promote longer follow-up studies and to design of interventions to prevent late effects among survivors of serious hematologic diseases.

Cardiovascular events and atherogenic lipid profile in chronic myeloid leukemia patients treated with nilotinib versus imatinib.

OBJECTIVES: The aim of this study was to assess cardiotoxicity and potential adverse effects related to lipid metabolism during treatment with tyrosine kinase inhibitors (TKIs) imatinib and nilotinib in patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Eighty-two consecutive patients with CML, who received nilotinib and/or imatinib in a single haemato-oncological Slovak center between years 2002-2018 were evaluated in a retrospective study. The mean age was 55.8 years (range 22-77 years). Median of follow-up was 61.3 months. RESULTS: A significantly higher incidence of dyslipidemia, significantly higher levels of potential risk markers of cardiovascular disease small dense LDL cholesterol (sdLDL-CH) and a significant increase in total cholesterol were found in the patients during treatment with nilotinib in comparison to imatinib. Dyslipidemia led to drug therapy in 22 % of the patients in the nilotinib group. Fourteen percent of the patients in the nilotinib group had one or more cardiovascular events, including peripheral artery disease (10 %), myocardial infarction (4 %) and stroke (4 %). CONCLUSION: A higher risk of cardiovascular events and atherogenic dyslipidemia were associated with nilotinib therapy. Patients treated with TKI, especially nilotinib, require an early modification of cardiovascular risk factors and a careful cardiologic surveillance so that antileukemic therapy with this highly effective agent could continue (Tab. 4, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: tyrosine kinase inhibitors, cardiovascular events, dyslipidemia, small dense LDL-cholesterol, nilotinib, imatinib.

Long-term sexual functioning in germ-cell tumor survivors.

BACKGROUND: Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. METHODS: GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). RESULTS: In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). CONCLUSIONS: This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.

Atherosclerosis in cancer patients.

Cancer-related mortality have been declining in the last decades. Approximately half of adults and more than two thirds of children oncological patients live longer than 5 years after diagnosis. However, this optimistic scenario has been counterbalanced by an increasing cardiovascular risk in cancer patients. Atherosclerotic damage has been underestimated in oncology practice for a long time, but recently a significant number of cancer patients with cardiovascular risk factors and serious artery disease during and after anticancer therapy has been reported. Complexity of atherosclerosis in cancer patients is challenging. Herein, we describe cardiovascular risk factors and pathophysiological mechanisms of atherosclerosis induced by selected classic chemotherapeutics, targeted cancer therapies, hormonal agents and radiotherapy and new clinical data regarding atherosclerosis, which received a particular attention in recent years (Tab. 1, Ref. 26). Keywords: cardiovascular disease, atherosclerosis, cardiotoxicity, risk factors, hypertension, hyperlipidemia.

The effect of GnRH agonists on angiogenesis and its implications for the myocardium in patients with cardiac risk.

Gonadotropin-releasing hormone agonists were described as anti-angiogenic factors in tumors. Simultaneously they were associated with increased cardiovascular risk in patients treated for prostate cancer, especially in those with preexisting cardiac disease. Studies aiming to elucidate the mechanisms by which androgen deprivation therapy causes cardiovascular effects are rare. We believe that gonadotropin-releasing hormone agonists can impair myocardial angiogenesis. That, in patients with myocardial disease can deepen hypoxia, significantly worsen the condition of the myocardium, and therefore increase the risk of cardiac failure. Careful assessment of the myocardial status and consequent timing and typing of therapy can minimalize the adverse effects. Ideally through close cooperation between cardiologists and oncologists (Fig. 1, Ref. 25). Keywords: angiogenesis, cardiovascular risk, follicle stimulating hormone, GnRH agonist, testosterone.

New principles of cancer therapy give new hope for oncological patients.

The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins, 1988), and bone marrow transplantation for leukemia (Thomas, 1990). Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. T-cells were shown to have receptors that bind to structures recognized as non-self and such interactions trigger the immune system to engage in defense. However, additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T-cells, inhibiting immune activation. This intricate balance between the accelerators and inhibitors is essential for a tight control. New strategy was developed into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma. In several patients, signs of remaining cancer disappeared. The results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable. Such remarkable results had never been seen in this patient group before (Fig. 2, Ref. 12). Keywords: Nobel Prize, physiology, medicine, immune system, inhibition, cancer therapy.

Are GnRH and FSH potentially damaging factors in the cardiovascular system?

In the physiological view the human cardiomyocytes express receptors of gonadotropin-releasing hormone and follicle-stimulating hormone. The local effects of these hormones in the heart are related also to some interstitial cells, such as endothelial cells with follicle-stimulating hormone receptors and immune cells with gonadotropin-releasing hormone receptors. The administration of androgen deprivation therapy in patients with prostate cancer is associated with increased incidence of cardiovascular complications. It is suggested that negative action of this therapy on cardiovascular system is due to the loss of testosterone but also levels of gonadotropin-releasing hormone and follicle-stimulating hormone are changed by therapy. In this article we review the literature to date with an emphasis on recent investigation focused on potential role of abnormal gonadotropin-releasing hormone and follicle-stimulating hormone levels induced by gonadotropin-releasing hormone agonists on the cardiovascular risk. These facts exacerbate the complexity of specific hormone and cell relationships within heart and vessels. Androgen deprivation therapy reveals the physiological relationships between hormones and specific tissues that are not part of the endocrine system.

Infectious complications in chronic lymphocytic leukemia- a retrospective analysis: single institution experience.

The aim of this study was to evaluate the incidence of a variety of infectious complications in patients with CLL regarding the duration of CLL and the type of treatment. We present the retrospective analysis of patients with CLL treated at our institution in years 2004-2016. We collected data about the type of infection, pathogenes, treatment and severity of infections surpassed in connection with administration treatment. In the study one hundred and ten patients were evaluated. The average age of patients was 61.7 years (range 34.5-91.9 years). Fludarabine was the most widely used regimen, followed by bendamustine and alemtuzumab. We recorded 393 episodes of infections, of which 114 (29%) were severe and life threatening of degree 3-5, and 279 (71%) of degree 2. The most common infections were the upper respiratory tract infections together with sinusitis (45.03%), pneumonia (26.20%), CMV reactivation occured in 8.14%, infections of the skin was in 7.6 %. Most infections have occurred with the administration of monoclonal antibody alemtuzumab, these patients were at significantly higher risk of infection [RR 2.59 (1.30 to 5.17)] than patients receiving obinutuzumab [RR 0.63 (0.48 to 0.82)] (p = 0.0001). On the contrary, the safety profile of BCR signaling pathway inhibitors was very acceptable [RR 1.17 (0.70 - 1.96)]. The number of infections have decreased during the first 12 months of treatment with ibrutinib. In the study group we recorded 19 deaths, 8 (7.27%) of them were of infectious etiology. The risk of infectious complications is lifelong in patients with CLL, it can be minimized by early detection and aggressive management. Novel targeted agents used in therapy of CLL have a good safety profile, even the risk of infection is decreased during administration.

Androgen deprivation therapy and cardiovascular complications.

Cardiovascular complications associated with the use of antiandrogens have already been known for some time. Based on the results of the latest meta-analyses and clinical studies published in the last few years, the attention of the scientific community is focused on the deleterious cardiovascular effects of gonadotropine-releasing hormon agonists in context of the androgen deprivating therapy. The cardiac toxicity is a problem especially in patients with preexisting cardiovascular comorbidities. Increased arterial wall thickening along with endothelial dysfunction has been observed in patients with descreased androgens levels in the peripheral blood. The treatment with gonadotropine-releasing hormon agonists may disrupt the intracellular concentration of calcium ions and the contractile process and potentially result in pathological remodelling of heart. Here, we give several possible mechanisms of action of gonadotropine-releasing hormon agonists on the cardiovascular system that may be a potential explanation of the clinical observations (Ref. 44).

Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.

With the increasing number of paediatric cancer patients and with their prolonged survival, the evidence of a number of serious complications induced by anticancer therapy is rising. Osteonecrosis (ON) of bone is one of these treatment-related effects with a multifactorial pathogenesis. In the past few years, several polymorphisms of candidate genes with possible role in development of this disorder were studied.We summarized potential risk factors leading to increased susceptibility to osteonecrosis of bone development in cancer patients during childhood and to present current knowledge in the field of genetic aspects of this condition (Ref. 86).

[Dental abnormalities after treatment for childhood cancer]. / Dentálne abnormality po protinádorovej liecbe v detskom veku.

Childhood cancer therapy often increases the risk of dental complications, such as tooth and roots agenesis, microdontia, abnormal development of tooth enamel, increased risk of cavity and other abnormalities. In a comparison with other late adverse effects of chemotherapy, radiotherapy and hematopoietic stem cell transplantion, a relative small number of clinical stud-ies observing patients for more than two years after completion of anticancer treatment was published. In this article, we review the incidence of dental abnormalities caused by commonly used anticancer treatment modalities as well as discuss their risk factors. Early identification of high-risk patients, early detection and management of dental abnormalities and better education of patients or their guardians, may have an impact on quality of life of cancer survivors.

[Role of cardiac bio-markers in monitoring of cardiotoxicity after hematopoietic stem cell transplantation]. / Úloha kardiálnych bio-markerov v monitorovaní kardiotoxicity po transplantácii kmenových krvotvorných buniek.

Advances in hematopoietic stem cell transplantation (HSCT) have increased survival in hematologic diseases. However, HSCT survivors are at risk of developing acute and longterm complications. Cardiac events, such as heart failure, myocardial ischemia and arrhythmias may represent potentially life  threatening conditions. Acute cardiotoxicity can occur during the first 100 days after HSCT. Conditioning regimens, including total body irradiation and high dose chemotherapy, previous chemoradiotherapy, including anthracyclines and chest irradiation, are known to be associated with an increased risk of cardiac complications after HSCT. Infectious complications resulting in sepsis due to posttransplant granulocytopenia may also impair myocardial function. Therefore the main strategy for minimizing cardiotoxicity is early detection of high risk patients and prompt prophylactic treatment. Measurement of cardio specific bio-markers can be a valid diagnostic tool for early identification, assessment, and monitoring of cardiotoxicity. In the present article, we review the usefulness of cardiac troponins and natriuretic peptides, the most commonly used bio-markers of myocardial ischemia and ventricular dysfunction, to detect and to predict the development of cardiotoxicity after HSCT.

Abnormal cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Clinical cardiac complications in oncologic patients may develop from subclinical myocardial damage. Biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T (cTnT) have been hypothesized to reflect preclinical cardiotoxicity earlier than echocardiography. The aim of this study was to assess prospectively the serial values of these cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS: Twenty-one patients who were treated with allogeneic HSCT for acute leukemia at mean age of 32.8 years (range: 19-58) were studied. The conditioning regimen included high-dose cyclophosphamide in combination with total body irradiation (TBI) or busulphan. All patients were treated with anthracyclines earlier (median cumulative dose 250 mg/m, range: 150-580). METHODS: Cardiomarkers were measured before the preparative regimen (PR) and on days 1, 14 and 30 after HSCT. Their cardiac systolic function was assessed before PR, and 1-2 months after HSCT by echocardiography. RESULTS AND CONCLUSION: The differences in NT-proBNP before PR and after HSCT were statistically significant (p<0.001). The values of cTnT before and after HSCT were also significantly different (p=0.005). Persistent abnormalities (30 days after HSCT) of NT-proBNP levels were found in 19/21 patients (90.5 %) and of cTnT levels in 10/21 patients (47.6 %). The median cTnT concentrations were higher in patients treated with TBI than in patients without TBI (p=0.013). The median NT-proBNP values were higher in patients pretreated with higher cumulative doses of anthracyclines (>250 mg/m vs ≤250 mg/m) Cardiac symptoms developed in 3/21 (14.3 %) patients (Tab. 1, Fig. 3, Ref. 36).

[Coronary heart disease and hypertension as late effects of testicular cancer treatment--a minireview]. / Ischemická choroba srdca a hypertenzia ako neskoré následky liecby nádorov testis-- prehl'ad.

The modern treatment of testicular cancer has led to notable improvement in the prognosis of these patients. A significant number of testicular cancer survivors suffer from late effects of their treatment that can occur several years after the treatment. Cardiovascular late effects represent one of the most serious effects with respect to their life-threatening potential. Considering the higher risk of coronary heart disease, numerous studies have investigated the prevalence of cardiovascular risk factors in patients treated for testicular cancer. Higher prevalence of hypertension in patients after treatment for testicular cancer may be one of the reasons for their serious cardiovascular morbidity and mortality.The aim of this is to summarize the current knowledge on the impact of review treatment modalities used in testicular cancer therapy on prevalence of hypertension and its pathogenetic context. Both chemotherapy and radiotherapy are associated with increased prevalence of hypertension several years after completing the treatment. In patients treated with chemotherapy, hypertension is associated with administration of cisplatin. Cisplatin remains in organism for up to 20 years after administration and may lead to endothelial dysfunction. Regular and long-term monitoring of cardiovascular risk should be introduced to ensure better quality of life in these patients.

Clinical relevance of thiopurine S-methyltransferase gene polymorphisms.

The therapeutic response to thiopurines may result in either severe toxic or inadequate effect based on the interindividual genetic variability. Same drug doses of various anticancer drugs cause considerable interindividual differences in the therapeutic response. Genetic factors have a major impact on effectiveness of several anticancer drugs such as mercaptopurine, 5-fluorouracil, platinum agents, and cyclophosphamide. Heredity related differences in interindividual response to thiopurine therapy represent perhaps the most compelling evidence of pharmacogenomics' usefulness in identification of patients in risk for adverse drug reactions. A number of variations in the gene for thiopurine methyltransferase (TPMT) have been associated with the low activity of this enzyme. Patients with intermediate and low activity of TPMT have a greater incidence of thiopurine toxicity. This minireview summarizes results of studies assessing the role of genetic polymorphisms in the gene encoding TPMT and their relationship to the toxicity of thiopurines.

Secondary malignancies after hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) offers patients with malignant and nonmalignant diseases the oportunity to pursue life-prolonging therapy. The number of survivors after successful HSCT is continually increasing. However, HSCT can induce tissue and organ damage that occurs not only "on treatment" , but long after completing therapy. Secondary malignancies belong to serious late complications after HSCT. A significant association of certain risk factors with increased likelihood of secondary malignancies after HSCT has been published over the last ten years. Better knowledge of pathogenesis of these complications, their early identification and treatment may contribute to better health outcomes of allogeneic and autologous hematopoietic stem cell transplantation recipients. We review here the incidence and risk factors of secondary malignancies after hematopoietic stem cell transplantation.

[The late effects in patients treated with allogeneic hematopoietic stem cell transplantation]. / Neskoré následky u pacientov liecených alogénnou transplantáciou kmenových krvotvorných buniek.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (HSCT) has become a curative treatment option for a variety of malignant and non-malignant hematological disorders. The number of long-term survivors after HSCT is continuously increasing and quality of their life represents a multidisciplinary concern. The aim of this study was to evaluate the prevalence of the late effects in long-term allogeneic HSCT survivors. PATIENTS AND METHODS: The study included 45 patients aged 12-63 years who survived at least two years after allogeneic HSCT for a hematological disorder. Twelve (26.7%) patients received an irradiation-based conditioning regimen. Median follow-up was 6 years (range 2-18 years). RESULTS: Toxicity varied from subclinical to life-threatening. The prevalence of at least one late toxic effect was 88.9%. Endocrine and metabolic complications included thyroid abnormalities in 12 (26.7%) patients, bone and joints complications in 13 (28.8%) and metabolic syndrome in 13 (28.8%). Ocular complications were diagnosed in 20 (44.4%), cardiovascular abnormalities in 15 (33.3%), pulmonary dysfunction in 6 (13.3%) and secondary malignancies in 3 (6.67%) survivors. The number of complications per patient increased with time from HSCT. Chronic graft-versus-host disease was the most significant risk factor associated with ocular, pulmonary and osteoarticular complications. CONCLUSION: Late toxicity of allogeneic HSCT in patients surviving for more than 2 years after this procedure may facilitate conduct of longer follow-up studies and an implementation of interventions to prevent late effects among survivors of serious hematological diseases