High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: Biopsy analysis of 70 cases from the Slovak Lymphoma Registry.

We performed a twelve-year retrospective analysis of diffuse large B-cell lymphoma (DLBCL) patients' biopsies with rearrangements of genes MYC, BCL2, and/or BCL6, commonly referred to as double-hit and triple-hit high-grade B-cell lymphomas (DH/TH HGBL). Our aim was to present complex characteristics of the DH/TH HGBL group of patients diagnosed in the Slovak National Lymphoma Register together with the evaluation of the relationship between immunohistochemical (IHC) protein expressions of c-myc, bcl2, bcl6, and cyclin D1 in tissue specimens and the presence of rearrangements of their protein-coding genes by FISH analysis in order to find a clinically relevant diagnostic algorithm that would be the most time- and cost-efficient. For this study, a standard panel of histomorphological, IHC, and FISH methods was used to analyze the characteristics of 70 DH/TH HGBL patients' biopsies. Our study showed a predominance of the immunohistochemical GCB subtype over the non-GCB subtype (59:10 cases) in DH/TH lymphomas. The centroblastic morphology was the most commonly observed (30/70 cases; 43%). Furthermore, our study showed a high predominance of DH lymphoma cases with simultaneous MYC and BCL2 genes rearrangements (40/70; 57%), followed by an almost equal incidence of DH lymphomas with rearrangements of MYC and BCL6 genes (16/70; 23%) and of TH lymphomas (14/70; 20%). 15 of 16 FISH-examined DLBCL cases were negative for CCND1 rearrangement. A great majority of DH/TH cases showed also immunohistochemical overexpression of corresponding proteins (62/70; 89%), mostly in a form of triple expressor of c-myc/bcl2/bcl6 proteins (36/70; 51%), followed by c-myc/bcl2 and c-myc/bcl6 double expressor proteins positivity (20/70 and 6/70, respectively). Comparing preferential FISH testing of DE/TE and GCB DLBCL cases for genetic rearrangements we would be able to detect 89% and 84% of our HGBL-DH, TH group of patients, respectively. None of the examined methods for economically rational FISH testing showed enough concordance with IHC analysis results. We might, therefore, advocate the complex testing of all DLBCL patients' biopsies including FISH analyses.

Colposcopic scoring indexes in the evaluation of cervical lesions with the cytological result of atypical squamous cells, cannot exclude high-grade lesion.

AIM: Colposcopic indexes including Reid index and Swede score were developed to make the colposcopy more objective. The aim of our study was to evaluate the significance of colposcopic indexes in the evaluation of ASC-H cervical lesions. METHODS: We carried out a cross-sectional study in the Clinic of Obstetrics and Gynecology between January 2013 and December 2018. The study included 535 women, from which 66 women had a cytological result ASC-H. Scoring of all colposcopic findings was assessed according to Reid modified index and Swede score and a composite score was determined. Frequency distributions were compared using χ2 /Fisher exact test. Spearman rank correlation coefficient was computed between RCI and Swede score. RESULTS: Sensitivity, specificity, positive and negative predictive value and positive likelihood ratio of modified Reid colposcopic index at a cutoff of ≥4 for the detection of HSIL+ lesions were: 86.11% (95% CI: 70.5-95.3), 83.33% (95% CI: 65.3-94.4), 86.11% (95% CI: 69.7-94.8), 83.33% (95% CI: 64.5-93.7) and 5.17 (95% CI: 2.3-11.6). Swede score with the cutoff value ≥5 showed comparable results to modified Reid index with the increased sensitivity: 94.44% (95% CI: 81.3-99.3). CONCLUSION: ASC-H category represents the trickiest cytological diagnosis as it is underlined with the high risk of severe cervical dysplasia. Evaluating the cervical lesion by the use of colposcopic indices helps the gynecologist to objectively evaluate all the pathologies of uterine cervix. Swede score with the cutoff value 8 also enables a 'see and treat' option in management of atypical squamous cells, cannot exclude high-grade lesions.

Mullerian adenosarcomas of the uterine cervix with sarcomatous overgrowth.

Mullerian adenosarcoma with sarcomatous overgrowth (MASO) of the uterine cervix is an extremely rare variant of adenosarcoma of the genital tract associated with aggressive clinical course. We searched the PubMed and Medline databases for MASO of the cervix and we identified and reviewed eleven cases published between years 2004 and 2017. The most common clinical picture includes abnormal vaginal bleeding, postcoital bleeding, pelvic pain and foul-smelling vaginal discharge. Therapeutic options for MASO are still undefined. Radical hysterectomy with sufficient tumour-free margins combined with adjuvant chemotherapy and radiotherapy should serve as an effective treatment tool with favourable outcome.

Different amplification patterns of 3q26 and 5p15 regions in cervical intraepithelial neoplasia and cervical cancer.

PURPOSE: The aim of this study was to evaluate and correlate the amplification of chromosomal regions 3q26 and 5p15 in different cytological and histological subgroups of patients and to compare the sensitivity and specificity of amplification tests with cytology, colposcopy and HPV status. METHODS: The work was conducted at the Department of Obstetrics and Gynaecology in cooperation with the Institute of Pathological Anatomy, JFM CU in Martin and UNM during years 2013-2016. Prospective longitudinal study included 131 patients. We focused on the FISH diagnosis of the amplification of regions encoding the components of telomerase enzyme (3q26, 5p15) in cytology specimens. We manually evaluated 100 atypical cells per slide and analysed the amplification patterns. Correlations between cytological, histological, HPV DNA results and amplification patterns of chromosomal regions 3q26 and 5p15 were analysed by chi-squared test and non-parametric Man - Whitney U test. RESULTS: The results showed that the amplification of chromosomal regions increases with the degree of dysplasia toward the invasive disease (p < 0.001). Whereas the increase in the amplification of 3q26 is noticeable already at CIN 2 + lesions (p < 0.01), 5p15 amplification is shifted up toward CIN 3/CIS (p < 0.001) and cervical cancer. Amplification of selected regions correlated with each other and also with hrHPV-positive status (p < 0.01). CONCLUSION: The analysis of the amplification of 3q26 and 5p15 regions may serve in the future for the differential diagnosis of cervical lesions and to determine their malignant potential. High specificity of these tests can improve the excellent sensitivity of HPV DNA test.

Differential mRNA expression of the main apoptotic proteins in normal and malignant cells and its relation to in vitro resistance.

BACKGROUND: Apoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer. Now it is clear that some oncogenic mutations disrupt apoptosis, leading to tumour initiation, progression or metastasis. Here, expression of apoptotic genes in context of drug resistance was investigated. METHODS: We examined total of 102 samples from leukemic patients (n = 60) and patients with solid tumours (n = 42). We used RT-PCR to determine the levels of mRNA expression and the in vitro chemoresistance of leukemic cells was evaluated using the MTT assay. RESULTS: We found statistically significant increase in mRNA expression of all investigated proteins (p53, BAX, Bcl-2 and Bcl-XL) between the leukemia samples and leukocytes from healthy volunteers. We did not find any significant difference in mRNA levels among the solid tumour samples. Notably, we showed a significant positive correlation in both leukemic and solid tumour patient groups between p53 and BAX mRNA. We found that the highest values for the Bcl-2/BAX ratio were in solid tumours in comparison to leukemic cells or normal leukocytes. Moreover, we assessed the impact of p53 and BAX mRNA levels on the sensitivity of the leukemic cells to selected cytostatics. CONCLUSIONS: Elevated levels of p53 and BAX mRNA may indicate cellular response to possible changes in genomic DNA integrity associated with malignant transformation. We suggest that the BAX gene is regulated by the p53 protein but the initiation of apoptosis through the transcription activation of BAX is blocked by the high levels of Bcl-2. Given that the apoptosis resistance mechanisms are different among oncological patients as well as stages of identical malignancy cases, personalized and specific combination therapy is proposed to be more effective in clinical application.

[Changes of the WHO classification of myeloid neoplasms in the context of the 2016 revision]. / Zmeny WHO klasifikácie myeloidných neoplázií v kontexte revízie z roku 2016.

Continual progress of knowleges in hematopathology and genetics of hematologic tumors requires actualisation of widely accepted and presently used WHO classification of myeloid neoplasms published 8 years ago. However, the basic principles of this classification remain unchanged, therefore the authors of new WHO classification mention the "revision" of previous and not the introduction o new classification. The aim of this paper is to outline the most important changes of myeloid neoplasm diagnostics to pathologists, hematologists and other clinicians in Czech Republic and Slovakia. This review is based on several papers recently published by opinionleaders in this field.

[Changes of the WHO classification of lymphoid neoplasms in the context of the 2016 revision]. / Zmeny WHO klasifikácie lymfoidných neoplázií v kontexte revízie z roku 2016.

As a result of increasing knowledge, the validity of any tumour classification could not be unlimited. The aim of this article is to review the most important changes in the WHO classification of lymphoid neoplasms of a non-Hodgkin type that have been announced and published in relation to its revision in 2016. These changes are based on better understanding of pathogenesis and genetics of diseases, refine diagnostic criteria, reflect existence of rare forms and introduce new provisional categories of lymphoid neoplasms. WHO classification becomes more complex and the number of disease entities is increasing. However, until the the monography will be published, all changes are preliminary and incomplete, requiring work with available lymphoma literature.

Rituximab-associated progressive multifocal leukoencephalopathy.

The definition "Progressive Multifocal Leukoencephalopathy" (PML) was first used in 1958 to describe a fatal demyelinating central nervous system (CNS) disease in patients with lymphoproliferative disorders. In 1971, the virus responsible for the disease was isolated and named John Cunningham virus (JCV). We present a rare case of a 62-year-old male with chronic lymphocytic leukemia and PML. In our work, we discuss the diagnostic and therapeutic challenges and offer suggestions for preventing PML development. The main learning points are: 1. Regularly check the level of immunoglobulins and the CD4+ : CD8+ T-cell ratio, intravenous administration of immunoglobulins should be considered when recording their reduction. 2. In checking the CD4+ : CD8+ T-cell ratio and verifying the impossibility of raising the level of immunoglobulins, we must weigh the possible benefits of continuing treatment with monoclonal antibody against the risks. 3. Physicians should maintain a high index of suspicion for the development of PML in patients under treatment with monoclonal antibodies, especially when there is a new development of neurological signs or symptoms.Key words: JC virus - progressive multifocal leukoencephalopathy - recommendation - rituximab.

DNA methylation as mechanism of apoptotic resistance development in endometrial cancer patients.

DNA methylation is a significant epigenetic modification which plays a key role in regulation of gene expression and influences functional changes in endometrial tissue. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients. The aim of our study was to examine the promoter DNA methylation changes in 22 apoptosis-associated genes in endometrioid endometrial cancer patients, precancerous lesions and healthy tissue from various normal menstrual cycle phases using a unique pre-designed methylation platform. We observed as the first a significant difference in promoter DNA methylation status in genes: BCL2L11 (p < 0.001), CIDEB (p < 0.03) and GADD45A (p < 0.05) during endometrial carcinogenesis and BIK gene (p < 0.03) in different phases of normal menstrual cycle. The results of our study indicate that deregulation of mitochondrial apoptotic pathway can considerably contributes to the apoptosis resistance development and may be helpful in identifying of new potent biomarkers in endometrial cancer.

[Clinically relevant possibilities and limits of differential diagnosis of megaloblastic anemia and myelodysplastic syndrome - refractory anemia type in bone marrow biopsies]. / Klinicky relevantné moznosti a limity diferenciálnej diagnostiky megaloblastovej anémie a myelodysplastického syndrómu typu refraktérnej anémie v trepanobioptických vzorkách kostnej drene.

INTRODUCTION: Megaloblastic anemia (MA) represents a subtype of macrocytic anemia caused by impaired DNA synthesis, mostly due to folate and vitamin B12 deficiency. Its mildest forms lead to macrocytosis without concomitant anemia, but more severe forms to thrombocytopenia and/or leucopenia as well. In majority of the cases, the diagnosis of MA dose not represent a serious clinical problem, however, other causes of macrocytosis including myelodysplastic syndrome (MDS) must be excluded. MATERIAL AND METHODS: In the period 2004-2015 we identified in our registry 126 consecutive bone marrow (BM) biopsies of patients with cytopenia/s in peripheral blood and suspicion either on MA or MDS of refractory anemia (RA) type. We performed a retrospective analysis of BM biopsies focused on evaluation of parameters useful for the differential diagnosis, as represented by (a) cellularity and proportions of BM precursors, (b) and their topography, (c) presence of maturation defects and dysplastic changes, (d) grade and extent of myelofibrosis, (e) iron deposits and (f) presence of "inflammatory" response in BM. Histological analyses were supported by immunohistochemical examinations. RESULTS: The series consisted of biopsies of 126 patients (61 men and 65 women) with average age 63 (14-88 years) - almost all patients (121/126) presented with anemia. Based on the findings we distinguished three diagnostic groups - MA (31 patients), MDS-RA (39) and bioptically unclasifiable case ("DIF DG" - 56 patients). Abnormalities of the BM cellularity were observed in 81 % and of topography in 73 % of all cases respectively. Megalobastic differentiation of erythropoesis was detected in 79 % and diagnostic dysplastic changes in 25 % of all biopsy cases. In 29 % of all biopsies ring sideroblasts were present, megakaryocytic nuclear lobulisation defects density changes were found in 61 % of all patients. In 14 % of all biopsies the BM myelofibrosis was absent, in contrast 5 % of the biopsies showed severe diffuse fibrosis. "Inflammatory" response was developed in 44 % of all biopsies. Iron deposits were absent in 26 %, decreased in 35 % and increased in 33 % of all the cases. CONCLUSIONS: From the point of view of histopathologist it seems to be difficult to distinguish BM hematopoietic changes in patients with MA and MDS-RA respectivelly, as histological examinations allowed determination of a definitive and correct diagnosis in about 55% of the cases. The crucial problem represents a decision whether the observed changes really result from the development of a clonal disease.Key words: megaloblastic anemia - megaloblastic differentiation - refractory anemia.

DNA Methylation Machinery in the Endometrium and Endometrial Cancer.

During the normal menstrual cycle, endometrial tissue undergoes many biochemical and morphological changes which are under the control of steroid hormone levels. DNA methylation plays a key role in gene expression regulation and influences functional changes in endometrial tissue. Eliminating senescent cells from the functional layer of the endometrium is mediated by apoptotic cell death, which helps maintain cellular homeostasis. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and thus apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients with advanced disease. Despite intensive study of the cancer epigenome, there is missing information about disrupted apoptotic gene regulation in DNA methylation levels. Therefore, it is necessary to spread our knowledge in the field of epigenetics to help us differentiate normal and cancer tissues and detect the early stages of cancer disease.

[Lungs "Hassalloid´s-like" bodies in children with epidermolysis bullosa junctionalis and bart´s syndrome]. / "Hassalloidné" telieska v plúcach u dietata s epidermolysis bullosa junctionalis a s Bartovým syndrómom.

Epidermolysis bullosa and Bart´s syndrome are fairly accurately documented diseases by histopathology. In the article the authors describe interesting and hitherto undescribed phenomenon in the lungs male infant with epidermolysis bullosa junctionalis and Barts syndrome, who died 17 days after birth and 13 days after surgery for pyloric atresia, on multiorgan failure within basic congenital diseases.Histologically in lung alveoli was found to the massive presence of foamy macrophages and numerous globoid formations resembling morphological and immunohistochemical "Hassall´s" bodies in a thymus of the newborn. It was a acidophillic spherical bodies concentric tracks in the connective tissue with focal presence of fibrin, as a unique proof CKAE1/AE3 and CKHMW positive epithelial cells and CD68-positive histiocytic elements. An interesting finding was the follicular skin structure in the center "hassalloid´s-like" body, which suggests an aspiration components of the skin during intrauterine life.Normal Apgar score at birth of the child (10/10/10 s.) and severe histological features on the death of the child testify for the first pathogenetic formation "hassalloid´s-like" bodies in the lungs during the 17-day life of a disabled child.

[Follicular and mantle cell lymphoma diagnosed in biopsies of gastroenterocolic region]. / Folikulový lymfóm a lymfóm z plástových buniek v biopsiách orgánov zalúdocno-crevnej oblasti.

The authors present a retrospective analysis of follicular lymphomas (FL) and mantle cell lymphomas (MCL) diagnosed according to the WHO classification (2008) in consecutive biopsies of GI organs in a period of 11 years. The series includes 18 patients with FL verified in 22 biopsies and 44 patients with MCL diagnosed in 54 biopsies. FL represented always a solitary tumor, most often - up to ¾ of all the cases - of a small intestine, more often in its jejunoileal than duodenal parts. The biopsies were obtained almost equally by endoscopical approach, they were usually mucosal and rarely polypectomic, as well as by surgical resections (54,5 % and 45,5 % of the cases respectively). FL of grade 3 was identified in approximately 11 % of the cases, while majority of the patients showed FL of grade 1 or 2. Only 2 patients with duodenal FL relapsed and bioptically verified recidives did not show signs of a high grade transformation. Although it was difficult to identify a nodular growth pattern in more common small biopsies, a typical histomorphology and phenotype mostly allowed the FL diagnosis in the majority of the cases. The FL diagnosis had to be supported by detection of BCL2 translocation only in one case. MCL appeared most often in the stomach and large intestine, the small intestinal cases represented less than 23 %. In » of the patients the lymphoma was multifocal and manifested as lymphomatoid polyposis affecting most often both large and small intestine. In a majority of the MCL patients, the diagnosis was done in mucosal and polypectomic endoscopic biopsies, surgical intervention and resection was recorded in less than 10 % of the cases. Most of the patients showed conventional "centrocytic" MCL morphology and approximately » of the cases showed blastoid MCL. The rebiopsies of 9 patients revealed a relaps of the disease which was locoidentical in 5 of them; in other 4 patients the biopsies documented a dissemination to other GI organs. The blastic transformation was recognized only in one of the relapsing patients. In contrast to FL, in 18 % of the biopsies the MCL diagnosis required a CCND1 gene rearrangement detection by FISH. In summary both of the studied GI lymphomas showed different and heterogenous incidence, clinical manifestation and necessity to support the biopsy diagnosis also by FISH examination. The correct FL and MCL diagnosis represents a conditio sine qua non for an indication of different therapeutical modalities as well as for the prognostic stratification of the patients.

Amplification of TERT and TERC genes in cervical intraepithelial neoplasia and cervical cancer.

OBJECTIVES: Telomerase is activated in various stages of oncogenesis. For cervical cancer, telomerase is already active in precancerous lesions. In our study we focused on the analysis of the amplification patterns of telomerase genes TERT and TERC. DESIGN AND SETTING: We included 39 patients in our study between January 2012 and April 2013. Each patient underwent a classical gynaecological examination and a colposcopy. During the colposcopic examination we collected material for a Pap smear, HPV DNA test (HC2) and LBC (LiquiPrep™), and performed punch biopsies for histopathological evaluation. Residual cytologic sample was hybridized with the FISH probe and telomerase genes were analysed. RESULTS: The amplification of the TERT gene showed us a very similar amplification pattern as TERC and gradually corresponded with both histolopathological (p<0.001) and cytopathological findings (p<0.001). The specificity and sensitivity of TERC gene amplification for the detection of CIN2+ lesions (cut off value 2.3) was 88.2% and 95.5% respectively (PPV 91.3%, NPV 93.8%). CONCLUSIONS: We identified increasing amplification pattern of telomerase genes in cervical lesions. According to our results telomerase genes could help in the future to determine the malignant potential of cervical lesions and could be tested together with cytology and HPV DNA in order to obtain the highest combined sensitivity and specificity for CIN2+ lesion detection.

[Bart´s syndrome associated with epidermolysis bullosa junctionalis and with pyloric atresia. An autopsy case report]. / Bartov syndróm asociovaný s epidermolysis bullosa junctionalis a s atréziou pyloru. Nekroptická kazuistika.

Barts syndrome, in literature also known under the name CLAS (Congenital Localised Absence of Skin), first described by Bart in 1966 as congenital localized absence of skin, epidermolysis bullosa congenita and nail abnormalities. The authors present a macroscopic and histological findings of a newborn with Barts syndrome, with epidermolysis bullosa junctionalis and atresia pylori, who died 17 days after birth and 13 days after surgery for pyloric stenosis.

Amplification of 3q26 and 5p15 regions in cervical intraepithelial neoplasia.

OBJECTIVE: To analyze different amplification patterns of 3q26 and 5p15 regions in low-grade and high-grade cervical intraepithelial neoplasia. DESIGN: Experimental research. SETTING: Department of Obstetrics and Gynecology at a medical faculty in Slovakia. POPULATION: A group of 83 patients referred for colposcopic examination. METHODS: Amplification of 3q26 and 5p15 regions was analyzed on the 100 most atypical cells from a cervical cytology slide by fluorescent in situ hybridization using a multicolor hybridization probe. Chi-squared and Man-Whitney U-tests were used for statistical analysis. MAIN OUTCOME MEASURES: Liquid-based cytology samples and biopsy samples obtained during colposcopic examination correlated with high-risk human papillomavirus status and with amplification patterns of selected regions analyzed by fluorescent in situ hybridization. RESULTS: The number of cells with 3q26 and 5p15 gain rises with the severity of the lesion p < 0.01. The sensitivity of 3q26 amplification for CIN2+ lesions was 72.1% (95% confidence interval 56.3-84.7) and specificity was 90.0% (95% confidence interval 76.3-97.1). The sensitivity of 5p15 amplification for CIN2+ lesions was 69.8% (95% confidence interval 53.9-82.8) and specificity was 85.0% (95% confidence interval 70.2-94.3). CONCLUSION: Evaluation of telomerase components can help in differential diagnosis of low-grade and high-grade cervical lesions and in individualized management of these patients.

A novel JAK2 exon 12 mutation identified in the retrospective analysis of paraffin-embedded tissues of polycythemia vera patients.

The aim of the study was to screen formalin-fixed, paraffin-embedded tissues of polycythemia vera patients for the presence of JAK2(V617F) and JAK2 exon 12 mutations. Of 64 cases, 60 were positive for JAK2(V617F) mutation using allele-specific polymerase chain reaction (PCR). Using modified allele-specific PCR, samples of 4 JAK2(V617F)-negative patients were analyzed for the presence of JAK2 exon 12 mutations. In one case, we found a PCR product matching with allele-specific primer, which was designed to detect the N542-E543del mutation. Surprisingly, in the result sequence we have detected another recently described mutation, R541-E543delinsK. In the other 3 JAK2(V617F)-negative patients, allele-specific PCR for the detection of JAK2 exon 12 mutations did not yield any product. However, in 1 case, the sequencing of JAK2 exon 12 PCR product revealed a novel mutation, H538-K539delinsF. We confirmed that paraffin-embedded tissues represent a valuable source of DNA, which can be used in diagnostics of both JAK2 exon 12 and exon 14 mutations and we described 1 novel JAK2 exon 12 mutation.

On- and off-responses of heart rate to exercise - relations to heart rate variability.

During physical exercise, heart rate (HR) increases by parasympathetic withdrawal and increase of sympathetic activity to the heart. HR variability (HRV) in time and frequency domains provides information about autonomic control of the cardiovascular system. Non-linear analysis using the Poincaré plot method is able to reveal supplementary information about cardiac autonomic control. The aim of this study was to determine the association between HRV parameters, the initial increase of HR at the onset of exercise (on-response) and HR decrease in the recovery phase after acute exercise (off-response). HR was continuously monitored in 17 healthy male subjects (mean age: 20.3 +/- 0.2 (SEM) years) at rest (25 min supine; 5 min standing), during exercise (8 min of step test at 70% of maximal power output) and in the recovery phase (30 min supine). HRV analysis in time and frequency domains and evaluation of the Poincaré plot measures (length, widths) were performed on selected segments of HR time series. HR on- and off-responses were quantified using an exponential curve fitting technique. The time constants T(on) and T(off), representing the rate of on- and off-responses to exercise, were computed. Postexercise HRV indices and time constant of on-response - T(on) - to exercise were negatively correlated. From preexercise HRV indices, only Poincaré plot parameters were correlated with T(on). No correlation between HRV indices and parameters of off-response was found. In conclusion, preexercise HRV parameters are not closely correlated with the rate of cardioacceleration at the onset of exercise and cannot predict the rate of HR recovery. On the other hand, postexercise HRV parameters are related to the rate of initial adjustment of HR to exercise referring to the importance of rapid HR on-response for a faster recovery after exercise.