Main topics related to the disease, death, and dying in communication between parents and their adolescent children with incurable cancer.

OBJECTIVES: The article focuses on main topics related to disease, death, and dying in communication between parents and their adolescent children with this diagnosis. METHODS: We conducted qualitative research comprising 13 interviews with parents who lost their adolescent child to cancer. We used a semi-structured interview and interpretative phenomenological analysis. RESULTS: Results introduced 6 basic topics: mutual protection, openness in the communication about cancer and death, making treatment decisions together, talks at the time of passing, hope, and spiritual experience. CONCLUSION: Adolescents appreciate age-appropriate, open communication about their disease. Talking about the disease and its prognosis appears to be the way from mutual protection to open truthfulness. Openness also includes the participation of adolescents in further treatment. For some parents, it makes sense to constantly protect the child from the fact of death. Caregivers should support discussions about death between parents and their terminally ill adolescent children and accept individual decisions to talk about death (Tab. 1, Ref. 25).

Clinical impact of genomic analysis in children with B-acute lymphoblastic leukemia: A pilot study in Slovakia.

Acute lymphoblastic leukemia (ALL) belongs to a genetically heterogeneous disease associated with a wide range of chromosomal and molecular changes. Determining these changes at the time of diagnosis can help the therapeutic decision, and contributes to the prediction of patients' clinical outcomes. A part of B-ALL (B-other) lacks cytogenetic abnormalities with clinical relevance for prognosis. Our first goal was to retrospectively review genetic results of patients from 2013-2017 and identify number of B-other patients in Slovak population. The second goal was to implement single nucleotide polymorphism (SNP) array analysis to improve the diagnosis and risk stratification. In this study we reviewed 133 B-ALL patients. We found that nearly 40% of them (52 cases) belonged to the B-other ALL group. Eighteen B-other ALL patients were subjected to the analysis using SNP-array. Overall, we identified 126 cytogenomic changes and in 4 patients the SNP array revealed clinically relevant markers of adverse prognosis and high relapse risk. Integrating identified genetic changes into clinical practice can bring improvement of prognosis assessment for children with ALL in Slovakia.

Diagnosis and treatment of juvenile myelomonocytic leukemia in Slovak Republic: novel approaches.

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive clonal myeloproliferative disorder of infancy and early childhood caused by oncogenic mutations in genes involved in the Ras pathway. Long-term survival has only been achieved with hematopoietic stem cell transplantation (HSCT), being able to cure more than 50% patients. To manage the disease before HSCT remains an important issue with constant searching for optimal treatment modalities. According to several retrospective analyses, azacitidine (AZA) induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant, suggesting its use as a promising "bridging" therapy before HSCT. In this paper we report our first consecutive cohort of patients with JMML treated at our institution as well as our experience with the diagnosis, novel treatment and management of these patients before the HSCT. We present 6 patients with JMML, harboring different somatic mutations (PTPN11 and NRAS), with distinct clinical features; 3 of them had been treated with AZA 75 mg/m2 i.v. on days 1 to 7 of a 28-day cycle before the HSCT. Response to therapy was evaluated after each cycle in accordance with the International response criteria. One patient had a progression of splenomegaly during the treatment and after three cycles he was urgently transplanted. At the present, he is remaining in complete remission 3 years after HSCT. Two patients showed impressive response following the first cycle of the therapy with a regression of splenomegaly and monocyte count, normalized leukocytes, platelets and absent blasts in peripheral blood. The treatment was well tolerated with no adverse effect recorded. The clinical activity and favorable toxicity of AZA in JMML provide a rationale for its use as a "bridging" therapy before HSCT. Prospective trials with accompanying translational studies are required to provide further information regarding individual factors that may direct the most appropriate choice of pretransplantation therapy.

[Treatment Refusal in Pediatric Oncology]. / Odmietnutie liecby v detskej onkológii.

BACKGROUND: Pediatric oncologists are often faced with situations in which parents or guardians refuse recommended treatment for curable childhood cancer. Deciding how to proceed in such situations is an ethical dilemma. The aim of this article is to consider optimal approaches when parents are strongly against oncological treatment, potentially compromising their childrens rights for health care and to the chance for cure. CASES: In this paper, we report two cases of treatment refusal from our department and the impact of such decisions on the children themselves. Case no. 1 describes a child with retinoblastoma whose parents refused standard treatment in order to seek alternative treatment abroad. Case no. 2 describes a patient with a primary lymphoma of bone who received treatment by a court order after parental refusal. CONCLUSION: When parents refuse a treatment for potentially curable cancer, the medical team often focuses on the certainty of death without treatment. In the background, there is a smaller but still significant risk that - even if the treatment is eventually accepted or compelled - the child will still die from treatment-related complications or refractory disease, possibly with considerable suffering. The reasons for refusing a treatment vary. The entire medical team is tasked with trying to respectfully understand the reasoning behind the parents unwillingness to accept the treatment, in order to address all possible misunderstandings and to propose solutions that could be acceptable for the parents. In some situations however, it is necessary to resolve the dilemma by legal means in order to protect the life of the child.Key words: oncology - ethics - decision making - treatment refusal - legal guardians The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 8. 2017Accepted: 7. 9. 2017.

The role of CRP, PCT, IL-6 and presepsin in early diagnosis of bacterial infectious complications in paediatric haemato-oncological patients.

Bacterial infection is the most common complication in paediatric oncological patients during cancer treatment. A suitable tool for early prediction of unfavourable course of infection is still needed. We performed a prospective longitudinal observational study to evaluate of the role of serum biomarkers (C-reactive protein, procalcitonin, interleukin-6, presepsin) in the early diagnosis of bacteraemia (gram-negative versus gram-positive) in patients with haematological malignancies. We observed 69 febrile episodes in 33 patients (17 male, 16 female; 1.5-18.9 years, mean 7.31 years, median 5 years). Within this sample, there were 22 cases of positive blood cultures, 16 cases of sepsis, 38 cases of fever with no signs or symptoms of sepsis, and two deaths from infectious complications. All markers tested had good negative predictive value (73% - 93%). CRP was characterized by good specificity for registration bacteraemia (96%, 95% CI: 85% - 99%), but other results were inconclusive. We identified comparably balanced sensitivity (64% - 81%) and specificity (61% - 88%) for interleukin-6 and procalcitonin, and we proved their quality to predict positive blood culture and clinical signs of sepsis as well. Patients with gram-negative bacteraemia had significantly elevated levels of PCT and IL-6 in comparison with a group of patients with gram-positive bacteraemia (p = 0.04 for PCT and p = 0.005 for IL-6). Presepsin was characterized by poor specificity (27%, 95% CI: 15% - 43%) and positive predictive value (24%, 95% CI: 12 - 39%) for predicting bacteraemia, and by better sensitivity (84%, 95% CI: 55% - 98%) and specificity (58%, 95% CI: 42% - 73%) for predicting clinical signs of sepsis.

Improved outcome for children and adolescent with acute lymphoblastic leukemia in the first decade of the 21st century: A report from the Slovak Republic.

Our aim was to analyze event-free (EFS) and overall survival (OS) among children and adolescents with acute lymphoblastic leukemia (ALL) treated with International BFM Intercontinental trial (ALL IC 2002) therapy in the Slovak Republic. In total, 280 children and adolescent age 1 to 18 years were treated with ALL IC BFM 2002 based therapy from 2002 to 2012, which was divided into two periods. During 2002-2007, when patients were actively enrolled in the ALL IC-BFM 2002 trial, and during 2008-2012 when the trial was closed and patients were treated with the same therapy without randomization. Five-year EFS and OS rates were 79% (+/- 2.6%) and 86% (+/- 2.1%), respectively, similar to results obtained in the ALL-BFM 95 trial, which was the basis for ALL IC BFM 2002 therapy. The EFS (p<0.012) and OS (p<0.003) were significantly better than the prior Slovak experience in 1997-2001. Survival is improved in standard and intermediate risk groups, including those age 1 to 6 years, and older; with B-cell or T-cell immunophenotype, and is also excellent for those with good early response. The rate of death in induction, cumulative incidence of death in complete remission and of relapse decreased. However, outcome was suboptimal for patients in the high risk group. Current EFS and OS rates for children and adolescents with ALL in the Slovak Republic resembled those obtained in Western Europe as a result of clinical trial participation, and clinical experience acquired with intensive BFM type treatment.

Constitutive 53BP1/γH2AX foci are increased in cells of ALL patients dependent on BCR-ABL and TEL-AML1 preleukemic gene fusions.

Childhood leukemia arises from hematopoietic stem cells by induction of mutations. Quite often chromosomal translocations arise prenatally as first key event in multistage process of leukemogenesis. These translocations result in so called preleukemic gene fusions (PGFs), such as BCR-ABL and TEL-AML1, which generate hybrid proteins with altered properties. Critical DNA damage resulting in translocations are DNA double-strand breaks (DSBs). BCR-ABL and TEL-AML1 were shown to be associated with increased constitutive DSBs in various model systems. We analyzed cells from peripheral blood and CD34-/CD34+ cells from bone marrow of pediatric acute lymphoblastic leukemia (ALL) patients harboring BCR-ABL or TEL-AML1. We used sensitive technique that is based on automated enumeration of DSB co-localizing proteins γH2AX and 53BP1, which form so called DNA repair foci. We found that level of constitutive γH2AX/53BP1 foci is significantly higher in cells of ALL pediatric patients than in healthy subjects. There was also significant increased level of constitutive γH2AX/53BP1 foci in cells from ALL patients harboring BCR-ABL or TEL-AML1 compared to patients without PGFs. The same increase was observed regardless cell type for both PGFs. Our data on increased DSB levels in the BCR-ABL/TEL-AML1 patient's cells support a model where BCR-ABL/TEL-AML1 induces DNA instability through facilitating mutagenesis and appearance of additional genetic alterations driving leukemogenesis.

Combined multiplex and monoplex RT-PCR as a reliable and cost-effective method for molecular diagnostics of pediatric acute lymphoblastic leukemia.

The precise diagnosis of acute lymphoblastic leukemia is essential for correct prognosis assessment and therapy regimen selection. At present, immunophenotyping, cytogenetics and molecular screening are major and complementary methods utilized in a routine leukemia diagnostics. The aim of this study was to validate the application of multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay for molecular diagnosis of the most common pediatric acute lymphoblastic leukemia-associated fusion transcripts. Our data show that screening of bone marrow and/or peripheral blood by RT-PCR, consisting of multiplex and monoplex PCR, confirmed results of real-time quantitative PCR (RT qPCR). This screening may provide a reliable, specific and sensitive method amenable to standard laboratory practice and a cost-effective alternative to more complex and expensive RT qPCR techniques.

The MLL recombinome of acute leukemias in 2013.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Uncommon leukemic case of anaplastic large cell lymphoma diagnosed through a typical chromosomal abnormality t(2;5) with a null phenotype and aberrant expression of NG2 and CD13.

Anaplastic large cell lymphoma represents approximately 10-15 % of pediatric non-Hodgkin lymphomas. Leukemic presentation is very rare, and in particular, the null phenotype ALCL without typical anaplastic morphology together with aberrant expression of CD13 and/or CD11b represents a diagnostic challenge. We report a case of a 9 year-old boy with leukemic presentation of ALCL with the typical translocation t(2;5)(p23;q35); in this patient, the only positive antigens identified by immunophenotyping were CD13, NG2 HLA-DR, and CD38. To our knowledge, aberrant expression of NG2 has never been reported in ALCL cases (Tab. 1, Fig. 6, Ref. 20).

[GATA1-mutation associated leukemia in children with trisomy 21 mosaic]. / GATA1-Mutations-assoziierte Leukämien bei Kindern mit Trisomie 21-Mosaik.

Mutations of the hematopoietic transcription factor GATA1 (GATA1s) are pathognomonic in newborn with transient leukemia and children with Down syndrome and myeloid leukemia (ML-DS). Both TL and ML-DS can also occur in children with trisomy 21 mosaic.Between 2002 and 2011, 15 newborns and infants were diagnosed with DS mosaic. 9 of them presented with TL and 8 children suffered from ML-DS; 2 of them with a history of TL. In children without stigmata the special morphology and immunophenotype of blasts triggered the screening for GATA1 mutation and trisomy 21 mosaic.All newborns with TL achieved complete remission (CR). Due to clinical symptoms caused by the leukemic blasts, in 3 children low-dose cytarabine was applied. 1 patient died due to cardiac defect. In all patients GATA 1 s was confirmed. 6 children with ML-DS were initially treated according the AML-BFM protocol. After ML-DS was confirmed, therapy was continued with the intensity reduced schedule according to the ML-DS 2006 protocol. All children are still in CR (follow-up 1.8-7 years, median 2.7 yrs). 2 children with unknown trisomy 21 mosaic were diagnosed as acute megakaryoblastic leukemia (AMKL) and treated according the high risk arm of the AML-BFM 2004 including allogeneic stem cell transplantation in one child). GATA1 mutation was identified retrospectively. Both children are alive in CR.GATA1s associated leukemia has to be excluded in all young children with AMKL (<5 years old) to prevent overtreatment. Treatment with reduced intensity seems sufficient in children trisomy 21 mosaic and ML-DS.

Minimal residual disease detection using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: Slovak experience.

Acute lymphoblastic leukemia is the most common form of cancer in children. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher. The main cause of treatment failure is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy. An intense effort has been made to develop methods to determine the degree of minimal residual leukemia cells present in patients considered to be in morphological remission. Because of the strong correlation between minimal residual disease (MRD) levels and risk of relapse, monitoring of MRD provides unique information regarding treatment response. The MRD monitoring based on real-time quantitative PCR detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements is currently considered to be the most reliable tool for MRD-based diagnosis in ALL. Because the significance of MRD monitoring has been strongly supported by several studies and because it has been implemented in the latest protocols, there has been a significant effort to develop MRD monitoring in the Slovak Republic since 2005. Between October 2006 and December 2009, 50 children with ALL who were treated at three Slovak centers were included in the RQ PCR MRD pilot project. A total of 40 patients with BCP-ALL ( B cell precursor ALL) and 4 patients with T ALL were analyzed for Ig/TCR rearrangement. We identified 106 different rearrangements in the 44 ALL patients analyzed. Based on MRD stratification, we identified 26 patients who were stratified into the HRG ( high risk group) (n = 3; 11.5%), IRG ( intermediate risk group) (n = 14; 54%) and SRG ) standard risk group) (n = 9; 34.5%). Morphology-based risk stratification allows the identification of most HRG patients identified also by MRD-based stratification, but fails to discriminate the IRG assigned to therapy reduction. Patients in the SRG and the IRG could profit from MRD-based risk assignment

Systemic malignancies presenting as primary osteolytic lesion.

The tumor formation may be the earliest manifestation preceeding other symptoms, signs and bone marrow evidence of systemic malignancy - leukemia/lymphoma. Here we present three cases of systemic malignancy in which bone lesions were the first manifested signs of the disease. All three cases were thought to be orthopedic cases and had been treated as so without genuing improvement. We would like to draw an attention to children who present with multifocal musculoskeletal pain and the importance of whole-body scaning. We describe interesting cases of diffuse large cell lymphoma and leukemia that initially presented as primary osteolytic bone lesion and discuss the differential diagnosis, literature review of non-Hodgkin's lymphoma arising in bone as the primary site (Tab. 1, Fig. 3, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Predictors of inferior outcome in community acquired bacterial meningitis.

The aim of this study was to assess mortality and sequellae within cases from Nationwide survey of community acquired meningitis and identify risk factors for inferior outcome. Risk factors such as underlying disease (diabetes mellitus, cancer, trauma, neonatal age, splenectomy, alcoholism, sepsis, other infections), etiology, clinical symptoms and outcome (death, improvement and cured after modifications of ATB therapy, cured without change of therapy, cured with neurologic sequellae) were recorded and analysed with univariate analysis (chi2 or t test for trends, CDC Atlanta 2004). Analysing risk factors for inferior outcome (death or cured with neurologic sequellae), we compared patients who died or survived with neurologic sequellae to all patients with community acquired bacterial meningitis. Univariate analysis showed that trauma (p<0.05), alcohol abuse (p<0.05), diabetes, S. aureus (p<0.05) and gram-negative etiology (A. baumannii, Ps. aeruginosa or Enterobacteriaceae) (36% vs. 11,9%, p<0.05) were predicting inferior outcome. Analysing risk factors for treatment failure (death or failed but cured after change of antibiotic treatment) prior sepsis (34.1% vs. 13.9%, p<0.01) and gram-negative etiology (25% vs. 11.9%, p<0.02) were statistically significant predictors of treatment failure. Neisseria meningitis had less failures (p<0.05). Concerning infection associated mortality again diabetes mellitus (p<0.05), alcoholism (p<0.05) staphylococcal and gram-negative etiology (p<0.05) were significant predictors of death. N. meningitis had surprisingly less treatment failures (appropriate and rapid initial therapy). Neurologic sequellae were more common in patients with alcohol abuse (p<0.05), craniocerbral trauma (p<0.05) and less common in meningitis with pneumococcal etiology (p<0.05).

Comparison of postsurgical and community acquired bacterial meningitis--analysis of 372 cases within a nationwide survey.

The aim of this study was to assess if differences in etiology and risk factors among 372 cases of bacterial meningitis acquired after surgery (PM) or in community (CBM) have impact on outcome of infected patients. Among 372 cases of bacterial meningitis within last 17 years from 10 major Slovak hospitals, 171 were PM and 201 CBM. Etiology, risk factors such as underlying disease, cancer, diabetes alcoholism, surgery, VLBW, ENT infections, trauma, sepsis were recorded and mortality, survival with sequellae, therapy failure were compared in both groups. Significant differences in etiology and risk factors between both groups were reported. Those after neurosurgery had more frequently Coagulase negative staphylococci (p<0.001), Enterobacteriaceae (p=0.01) and Acinetobacter baumannii (p=0.0008) isolated from CSF and vice versa Streptococcus pneumoniae (p<0.001), Neisseria meningitis (p<0.001) and Haemophillus influenza (p=0.0009) were more commonly isolated from CSF in CBM. Neurosurgery (p<0.001), sepsis (p=0.006), VLBW neonates (p=0.00002) and cancer (p=0.0007) were more common in PM and alcohol abuse (p<0.001) as well as otitis/sinusitis (p<0.001) and Roma ethnic group (p=0.001) in CAM. Initial treatment success was significantly more frequently observed among CAM (p<0.001) but cure after modification was more common in PM (p=0.002). Therefore outcome in both groups was similar (14.6% vs. 12.4%, p=NS).

Bacterial meningitis after craniocerebral trauma in the community.

Craniocerebral trauma is one of major risk factors for development of meningitis. We reviewed 30 cases of bacterial meningitis occurring in community after craniocerebral trauma. Alcohol abuse was significant risk factor occurring in trauma patients with meningitis present in 50% in our cohort (p=0.0001). The most common pathogen in posttraumatic meningitis was Str. pneumoniae (90% vs. 33.8%, p=0.0001). However mortality was very low, only 5% probably because of early diagnosis and treatment of patients at risk for bacterial meningitis but neurologic sequellea were significantly more common (p=0.00001) in patients after craniocerebral trauma.

Bacterial meningitis after sinusitis and otitis media: ear, nose, throat infections are still the commonest risk factors for the community acquired meningitis.

We investigated how many cases of bacterial meningitis in our national survey were associated with sinusitis or otitis media. Among 372 cases of bacterial meningitis within our nationwide 17 years survey, 201 cases were community acquired (CBM) and in 40 (20%) otitis media or sinusitis acuta/chronica were reported 1-5 weeks before onset of CBM. Diabetes mellitus (20% vs. 7.5%, p=0.01), alcohol abuse (35% vs. 15.4%, p=0.003) and trauma (30% vs. 14.9%, p=0.02) were significantly associated with CBM after ENT infections. Concerning etiology, CBM after sinusitis/otitis was insignificantly associated with pneumococcal etiology (50% vs. 33.8 %, NS) and significantly associated with other (L. monocytogenes, Str. agalactiae) bacterial agents (9.9 % vs. 25 %, p=0.008) . However those significant differences for new ENT related CBM had no impact on mortality (12.4 % vs. 5%, NS), failure after initial antibiotics (10 % vs. 9.5%, NS) and neurologic sequellae (12.5 % vs. 15.4 %, NS).

Meningococcal meningitis is still the commonest neuroinfection in the community in tropics: overview of 62 cases.

Within last 17 years we went through all charts of bacterial meningitis within our nationwide survey and among 372 cases we found 62 cases of MM, in 12 cases with meningococcal disease (with shock, petechial effusions or disseminated intravascular coagulation or digital gangrenes). MM was usually observed in young adults without any of investigated risk factors like neoplasia, ENT (ear, nose, throat) focuses, elderly age, sepsis, diabetes, alcoholism, trauma, neonatal VLBW etc. Trauma, diabetes mellitus, alcohol abuse and chronic sinusitis/otitis were significantly less frequently found as a risk factor for MM. Mortality was very low, only 4.8% and was lower than overall mortality in CBM (12.4%, NS). Also the proportion of neurologic sequellae (9.7%) and initial treatment failure (8.1%) were comparable or even lower. This positive outcome results are probably because all N. meningitis strains were susceptible to penicillin, chloramphenicol, cefotaxim, cotrimoxazol or ciprofloxacin. Other reason for low mortality was that most cases received oral antibiotic immediately, even before admission (50 of 62). 95.2% of cases survived, 90.3% without any transient neurological residual symptoms.

Meningitis in diabetic patients.

Community acquired bacterial (CBM) meningitis in diabetic patients was analyzed for risk factors and outcome in a cohort of 201 cases of meningitis within last 17 years: 15 patients with diabetes mellitus and meningitis were identified and compared for etiology and mortality as well as for neurologic sequellae with all CBM cases.

Etiology and resistance patterns of respiratory isolates in Kenyan adults with AIDS from slum population.

We investigated regularly swabs of adults dispenzarised at Mary Immaculate Clinic of Trnava University in Nairobi providing free health care for about 50 000 population of Mukuru Slums. 20 patients who were treated for AIDS by our clinic (those who started HAART before Free National AIDS Cooperation Programme - NASCOP) were assessed after 1, 2 and 3 years (18 of 20 completed the survey, other 2 loss of follow up, probably died. Exposure to other molecules can select resistant mutants. Previous exposure to TMP/SMX was similar in both groups and therefore was not responsible for the difference between resistance patterns.