Sacubitril/valsartan for cardioprotection in breast cancer (MAINSTREAM): design and rationale of the randomized trial.

AIMS: In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial. METHODS AND RESULTS: MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. CONCLUSIONS: The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).

Expression of CTLA-4 and CD86 Antigens and Epstein-Barr Virus Reactivation in Chronic Lymphocytic Leukemia-Any Link with Known Prognostic Factors?

Infection with Epstein-Barr virus (EBV) worsens the prognosis in chronic lymphocytic leukemia (CLL), but the underlying mechanisms are not yet established. We intended to assess whether EBV affects the course of CLL by the deregulation of the CTLA-4/CD86 signaling pathway. We used polymerase chain reaction to measure the load of EBV DNA in the blood of 110 newly diagnosed patients with CLL. The expression of CTLA-4 and CD86 antigen on lymphocytes was assessed with flow cytometry. Additionally, CTLA-4 and CD86 serum concentrations were measured through enzyme-linked immunosorbent assays. Fifty-four percent of the patients had detectable EBV DNA [EBV(+)]. In EBV(+) patients the CTLA-4 and CD86 serum concentrations and their expressions on investigated cell populations were significantly higher than in EBV(-) patients. EBV load correlated positively with unfavorable prognostic markers of CLL and the expression of CTLA-4 on CD3+ lymphocytes (r = 0.5339; p = 0.027) and CD86 on CD19+ cells (r = 0.6950; p < 0.001). During a median follow-up period of 32 months EBV(+) patients were more likely to require treatment or have lymphocyte doubling (p < 0.001). Among EBV(+) but not EBV(-) patients, increased expressions of CTLA-4 lymphocytes were associated with elevated risks of progression. We propose that EBV coinfection may worsen prognosis in CLL patients, partly due to EBV-induced up-regulation of CTLA-4 expression.

Toll-like Receptor 2 as a Marker Molecule of Advanced Ovarian Cancer.

Ovarian cancer is a global problem that affects women of all ages. Due to the lack of effective screening tests and the usually asymptomatic course of the disease in the early stages, the diagnosis is too late, with the result that less than half of the patients diagnosed with ovarian cancer (OC) survive more than five years after their diagnosis. In this study, we examined the expression of TLR2 in the peripheral blood of 50 previously untreated patients with newly diagnosed OC at various stages of the disease using flow cytometry. The studies aimed at demonstrating the usefulness of TLR2 as a biomarker in the advanced stage of ovarian cancer. In this study, we showed that TLR2 expression levels were significantly higher in women with more advanced OC than in women in the control group. Our research sheds light on the prognostic potential of TLR2 in developing new diagnostic approaches and thus in increasing survival in patients with confirmed ovarian cancer.

Immunological Prognostic Factors in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the treatment of MM focus on developing new diagnostic techniques; however, the search for prognostic markers is also crucial. This enables the classification of patients into risk groups and, thus, the selection of the most optimal treatment method. Particular attention should be paid to the possible use of immune factors, as the immune system plays a key role in the formation and course of MM. In this review, we focus on characterizing the components of the immune system that are of prognostic value in MM patients, in order to facilitate the development of new diagnostic and therapeutic directions.

Chronic Lymphocytic Leukemia-Induced Humoral Immunosuppression: A Systematic Review.

Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact of humoral immunity deficiency on the clinical and therapeutic approach. A systematic literature review was carried out by two independent authors who searched PubMed databases for studies published up to January 2020. Additionally, Google Scholar was used to evaluate search results and support manual research. The search resulted in 240 articles eligible for analysis. After all criteria and filters were applied, 22 studies were finally applied to the analysis. The data analysis showed that the clinical heterogeneity of CLL patients correlates with the diversity of molecular abnormalities determining the clinical picture of the disease, the analysis of which enables setting therapeutic targets. Additionally, in improving the therapeutic method, it is worth introducing supportive therapies with the use of vaccines, antibiotics and/or immunoglobins. Moreover, humoral immunodeficiency in CLL has a strong influence on the risk of infection in patients for whom infections are a major cause of morbidity and mortality.

Predictors of new-onset heart failure and overall survival in metastatic breast cancer patients treated with liposomal doxorubicin.

Cardiovascular diseases (CVDs) are the major cause of morbidity/mortality among breast cancer (BC) patients. Observation of the daily practice in eight experienced Polish oncology centers was conducted to find all possible predictors of new cases of heart failure (HF) and overall survival (OS) of metastatic BC patients treated with liposomal doxorubicin, taking into account the impact of pre-existing CVDs. HF was the cause of premature discontinuation of liposomal doxorubicin therapy in 13 (3.2%) of 402 patients. The probability of developing HF was higher in women with pre-existing CVDs (HR 4.61; 95%CI 1.38-15.38). Independent of CVDs history, a lower risk of HF was observed in those treated with a cumulative dose of liposomal doxorubicin > 300 mg/m2 (HR 0.14; 95% CI 0.04-0.54) and taxane-naive (HR 0.26; 95% CI 0.07-0.96). Multivariate analysis including the presence of pre-existing CVDs and occurrence of new HF, revealed a liposomal doxorubicin in cumulative doses of > 300 mg/m2 as a beneficial predictor for OS (HR 0.61; 95% CI 0.47-0.78) independently of subsequent chemotherapy (HR 0.72; 95% CI 0.57-0.92) or endocrine therapy (HR 0.65; 95% CI 0.49-0.87). Higher doses of liposomal doxorubicin can decrease mortality in metastatic BC without increasing the risk of HF. The clinical benefit is achieved regardless of pre-existing CVDs and subsequent anticancer therapy.

CAR-T Cell Therapy-An Overview of Targets in Gastric Cancer.

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.

Changes in survival of colorectal cancer patients in Swietokrzyskie Province (Southern Poland) from the second half of the 1990s to the early 21st century - a population-based study.

INTRODUCTION AND OBJECTIVES: For years, the increase in cancer incidence and deaths has constituted a significant health and social problem. Variation in the burden in cancers in different regions of the world requires constant monitoring of the epidemiological situation in this regard. Assessing survival in cancer patients is a valuable source of information for patients and physicians alike, as well as for politicians who have a direct impact on the shaping of health policy and health systems. The aim of the present study was to assess the changes in the 5-year relative survival of colorectal cancer patients during 1995-2014. MATERIAL AND METHODS: The data of 8,970 patients with colorectal cancer in the years 1995-2014, 5,033 males and 3,937 females aged 67.5 ± 11.7 from Swietokrzyskie Cancer Registry were used. Cases were classified according to the topographical codes ICD-O-3: C18.0-C18.9, C19.9, C20.9, C21.0-C21.2, C21.8. The end of follow-up was fixed at 31 December 2014. Four five-year calendar periods were defined. In each calendar period, relative survival rates using the Ederer II method were estimated separately for males and females. RESULTS: In 2010-2014 (against 1995-1999), the absolute increase in the 5-year relative survival in males and females with colon cancer was the highest and reached 9.8 percentage point (p.p.) and 9.6 p.p., respectively. Patterns of survival for both colon and rectal cancer patients according to gender and age were very similar. CONCLUSIONS: In 1995-2014, an increase in the value of relative survival rates of males and females with colorectal cancer was observed. Systematic increase in funding in health care was a chance for reducing the burden of colorectal cancer by more widespread and equal access of effective early detection and cancer treatment.

Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy.

Despite the significant progress of modern anticancer therapies, multiple myeloma (MM) is still incurable for the majority of patients. Following almost three decades of development, chimeric antigen receptor (CAR) T-cell therapy now has the opportunity to revolutionize the treatment landscape and meet the unmet clinical need. However, there are still several major hurdles to overcome. Here we discuss the recent advances of CAR T-cell therapy for MM with an emphasis on future directions and possible risks. Currently, CAR T-cell therapy for MM is at the first stage of clinical studies, and most studies have focused on CAR T cells targeting B cell maturation antigen (BCMA), but other antigens such as cluster of differentiation 138 (CD138, syndecan-1) are also being evaluated. Although this therapy is associated with side effects, such as cytokine release syndrome and neurotoxicity, and relapses have been observed, the benefit-risk balance and huge potential drive the ongoing clinical progress. To fulfill the promise of recent clinical trial success and maximize the potential of CAR T, future efforts should focus on the reduction of side effects, novel targeted antigens, combinatorial uses of different types of CAR T, and development of CAR T cells targeting more than one antigen.

Immunogenicity And Safety Of The 13-Valent Pneumococcal Conjugate Vaccine In Patients With Monoclonal Gammopathy Of Undetermined Significance - Relationship With Selected Immune And Clinical Parameters.

PURPOSE: Patients with monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of developing infections. Streptococcus pneumoniae vaccinations are recommended for immunocompromised patients, including patients with lymphoproliferative disorders such as MGUS. The objective of the study was to assess the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in treatment-naive MGUS patients versus healthy subjects. All study groups were evaluated for the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses, and selected peripheral blood lymphocyte subpopulations, including the proportion of plasmablasts before and after immunization. PATIENTS AND METHODS: A total of 22 previously untreated patients with MGUS and 15 healthy age- and sex-matched volunteers were included in the study. All participants were immunized with PCV13 Prevenar13 (Pfizer). The following parameters were assessed: 1) serum-specific pneumococcal antibody titers before and 30 days after vaccination, 2) percentage of plasmablasts, defined as CD19+/IgD-/CD27++, before and 7 days after vaccination, 3) serum total IgG and IgG1, IgG2, IgG3, IgG4 levels before and 30 days after vaccination. RESULTS AND CONCLUSION: PCV13 vaccination in MGUS patients is safe and effectively protects against S. pneumoniae infection. In unvaccinated individuals, vaccination should be carried out as soon as possible after diagnosis. It can protect patients against serious infectious complications, which can contribute to extending the time to progression and transformation into more aggressive diseases. PCV13 vaccination is more effective in MGUS patients with a lower concentration of M protein. Serum M protein concentration in patients diagnosed with MGUS may be a useful predictor of the effectiveness of vaccination.

Programmed cell death 1 expression and Epstein-Barr virus infection in chronic lymphocytic leukaemia: a prospective cohort study.

PURPOSE: Infection with Epstein-Bar virus (EBV) is associated with an unfavourable prognosis in chronic lymphocytic leukaemia (CLL), but the underlying mechanisms remain unknown. We aimed to establish whether EBV worsens the course of CLL by up-regulating the programmed cell death 1 expression. PATIENTS AND METHODS: Using polymerase chain reaction, we measured EBV DNA in the blood of 110 newly diagnosed, treatment-naïve patients with CLL. We used flow cytometry to measure the expression of programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1) on CD4+, CD8+, and CD19+ cells. Additionally, PD-1 and PD-L1 serum concentrations were measured using enzyme-linked immunosorbent assays. We related the expressions of PD-1 and PD-L1 to EBV DNA load and clinical outcomes. RESULTS: Fifty-nine (54%) patients had detectable EBV DNA [EBV(+)], and these patients had more advanced disease at baseline than the rest. PD-1 and PD-L1 serum concentrations and their expressions on all cell populations were higher in EBV(+) than EBV(-) patients. EBV load correlated positively with unfavourable clinical markers of CLL and the expression of PD-1 and PD-L1 on CD4+ and CD8+ cells (rho =0.42-0.75; p<0.001). EBV(+) patients had increased risks of treatment initiation and lymphocyte doubling during a median follow-up period of 32 months (p<0.001). Among EBV(+), but not EBV(-), patients, higher expressions of PD-1 and PD-L1 on CD4+ and CD8+ cells were associated with higher risks of treatment initiation and lymphocyte doubling (p≤0.020). CONCLUSION: EBV-induced up-regulation of PD-1-PD-L1 expression is associated with worse outcomes in CLL.

Acute decompensated heart failure as a reason of premature chemotherapy discontinuation may be independent of a lifetime doxorubicin dose in lymphoma patients with cardiovascular disorders.

BACKGROUND: Algorithm of anthracycline-based chemotherapy with favourable cardio-oncological outcome should be clearly re-defined for lymphoma patients with significant pre-existing cardiovascular diseases. A clinical benefit of liposomal forms of anthracycline is still debatable. METHODS: Polish registry included observations of 138 lymphoma patients with concomitant cardiovascular disorders who received liposomal doxorubicin as cardioprotective alternative of conventional form. It was created to analyse the importance of a strategy of administration of conventional/liposomal doxorubicin and a lifetime doxorubicin dose for development of acute decompensated heart failure (ADHF) as a reason of premature chemotherapy discontinuation. RESULTS: ADHF was the cause of premature termination of chemotherapy only in 11 patients (7.97%). The five new episodes of ADHF related to liposomal doxorubicin were recorded in subgroup of 70 patients with pre-existing heart failure (7.14%). There was the similar incidence of ADHF when liposomal doxorubicin was applied after conventional form in dose 200mg/m2 or if earlier signs of iatrogenic myocardial damage was recognised: 5 cases in subgroup of 51 patients with baseline cardiovascular risk factors (9.8%). ADHF was observed in one of 17 patients (5.88%) receiving liposomal doxorubicin as second line chemotherapy after first line with conventional doxorubicin. Consequently throughout the study group ADHF didn't depend on the total cumulative dose of all types of doxorubicin: OR=0.85; 95%CI: 0.66-1.10; p=0.22 for each 50mg/m2. CONCLUSION: The schedule of administration of conventional/liposomal doxorubicin can decide that lifetime combined doses of anthracyclines become insignificant for ADHF occurrence and premature discontinuation of chemotherapy in lymphoma patients with pre-existing cardiovascular disturbances.

Sudden cardiac arrest in takotsubo cardiomyopathy - a case study.

We present a 59-year-old woman who was admitted to hospital after sudden cardiac arrest due to ventricular fibrillation. Finally takotsubo syndrome was diagnosed. In the acute phase of takotsubo syndrome life-threatening ventricular arrhythmias and significant hemodynamic disorders may occur due to strong adrenergic stimulation and myocardial ischemia. It has been proved that the occurrence of torsade de pointes tachycardia in the acute phase of takotsubo cardiomyopathy is associated with QT prolongation. There are no clear guidelines on pharmacological treatment and implantable cardioverter defibrillator implantation after a past takotsubo episode. Takotsubo cardiomyopathy has not been entirely explained as an etiological disease.

Population of Polish patients participating in the Heart Failure Pilot Survey (ESC-HF Pilot).

BACKGROUND: Heart failure (HF) is currently one of the main causes of cardiovascular mortality. In order to collect current epidemiological data on patients with HF, the Heart Failure Pilot Survey (ESC-HF Pilot) registry was initiated. AIM: Primary objective of the study was to compare clinical epidemiology of outpatients and inpatients with HF and investigate currently used diagnostic and therapeutic modalities in Poland and 11 other European countries. METHODS: The ESC-HF Pilot Survey study was a prospective multicentre observational registry conducted in 2009-2011 in 136 cardiology centres in 12 European countries selected to represent different health systems and care attitudes across Europe. All outpatients with HF and patients admitted due to acute decompensated HF were included into the registry during the enrolment period (1 day per week for 8 consecutive months). Researchers completed detailed medical data questionnaires for all HF patients recruited to the study. RESULTS: In all participating centres across Europe, 6108 patients were recruited, including 1159 patients from Poland (19% of the survey population). The majority of Polish participants were admitted due to acute HF (73%), while ambulatory chronic HF patients predominated in the remaining European centres (69%). Polish patients develop HF at a younger age compared to other European countries (proportion of patients above 65 years: 54 vs. 65%, respectively) and they are more severely ill (NYHA class III: 44 vs. 34%, respectively; NYHA class IV: 18 vs. 11%; mean BNP level 910 vs. 773 pg/mL). Angiographically documented coronary artery disease was the major aetiology of HF in Poland (39 vs. 33%) which explains a higher rate of invasive revascularisation procedures in the Polish population (13 vs. 7%). In Poland, therapy with implantable cardioverter- -defibrillators was used more frequently during the initial hospitalisation (7 vs. 4%), but the rate of cardiac resynchronisation therapy device implantation was smaller than in other European countries (4 vs. 7%). Drug therapy used in our country was comparable to the rest of Europe, except for more frequent use of aldosterone antagonists. Despite significant differences in the clinical characteristics seen between Polish and other European patients participating in the ESC-HF Pilot study, mortality at 3 months did not differ between Polish and other European centres (2.5 vs. 3%). CONCLUSIONS: The ESC-HF Pilot Survey findings indicate a very high standard of inpatient HF treatment but at the same time unsatisfactory current ambulatory HF therapy in Poland.

Myocarditis - clinical course and 2-year outcome in 32 patients.

BACKGROUND: Acute myocarditis is one of the most challenging diagnoses in cardiology. It is a disease with variable clinical presentation, progression and outcome. AIM: To assess clinical characteristics and outcome of patients hospitalised with diagnosis of acute myocarditis from year 2006 to 2008. METHODS: We analysed hospital files of consecutive 32 patients admitted to our hospital due to myocarditis. All demographic, clinical and laboratory data were analysed and compared between patients with acute or subacute myocarditis. After discharge the patients were followed for 8-24 months. RESULTS: The majority of patients were males (84%) in a mean age of 33 years. Clinical and echocardiographic parameters improved in 25 (78%) of patients during hospital stay. During follow-up decreased left ventricular ejection fraction (LVEF) was observed more often in patients with subacute than acute myocarditis (mean LVEF values of 49 vs. 61%, respectively). Patients with a subacute form of the disease more frequently required chronic pharmacological therapy and more often retired from occupational activities. CONCLUSIONS: Diagnosis of myocarditis is still challenging. Careful history taking, serial laboratory, ECG and echocardiographic examinations are helpful in therapeutic decisions making and assessing prognosis. Patient with subacute myocarditis are more symptomatic than patients with acute myocarditis.

[A large thrombus in the right atrium and in the inferior vena cava associated with a portal vein thrombosis in a patient with hepatic cirrhosis - a case report]. / Masywna skrzeplina prawego przedsionka i zyly glównej dolnej towarzyszaca zakrzepicy zyly wrotnej u chorej z marskoscia watroby.

A case of a 54-year-old female with hepatic cirrhosis, who developed a large thrombus in the inferior vena cava that extended up to the right atrium and was associated with a portal vein thrombosis. She was admitted to our hospital because of symptoms of overt heart failure. A two-dimensional echocardiogram demonstrated a large mass in the right atrium originated from the inferior vena cava system. Computed tomography scans revealed tumor of the liver and a portal vein thrombosis. The patient was discharged on oral anticoagulation. Her remaining 1-year course has been uncomplicated.

[Prinzmetal's angina: clinical manifestation in a 79-year-old man with atherosclerotic coronary artery disease]. / Dlawica naczynioskurczowa - manifestacja kliniczna u 79-letniego chorego z miazdzyca tetnic wiencowych.

A case of a 79-year-old man with risk factors of ischaemic heart disease is presented. He was admitted to the Cardiology Ward because of recurrent angina pectoris with ST-segment elevation in the anterior electrocardiographic leads. Coronary arteriography revealed 90% stenosis of the marginal branch of the left coronary artery, which was supplied by coronary angioplasty. During hospitalisation recurrent episodes of angina pectoris were noted, only in night hours, with ST-segment elevations in anterior electrocardiographic leads. Pharmacotherapy with calcium blockers and nitrates eliminated the episodes of chest pain in a ten-month follow-up.