Tomáš Kepák

Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study.

To outline an outpatient-based treatment for children with relapsed solid tumors, who already have been extensively pretreated, we defined a 4-drug protocol named COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy). Using this protocol, we performed a pilot study to determine its feasibility in children with relapsed and/or high-risk pediatric solid tumors. Patients and Methods: 22 children received the COMBAT protocol. Treatment consisted of daily celecoxib administration along with daily 13-cisretinoic acid (2 weeks on / 2 weeks off) and cycles of metronomic temozolomide (90 mg/m2 for 42 days) and low-dose etoposide (21 days). The treatment was scheduled for a period of 1 year. Results: 9 of the 14 patients assessable for response demonstrated evidence of treatment benefit manifested as prolonged disease stabilization or response. The protocol medication was well tolerated with very good compliance. Only minimal side effects where observed which responded to dose modification or local therapy. Conclusions: The COMBAT regimen is well tolerated by patients with intensive prior therapy including myeloablative regimens. Favorable responses observed in this cohort of patients support the further exploration of this and/or similar strategies in the treatment of pediatric solid tumors.

Efficacy of pregabalin in neuropathic pain in paediatric oncological patients

OBJECTIVE To evaluate the safety and efficacy of pregabalin in the management of chemotherapy-induced neuropathic pain in patients with childhood solid tumors and leukaemia. MATERIALS AND METHODS In an open-label study, 30 children (11 boys and 19 girls; mean age 13.5 years) who were treated for solid tumors and leukaemia, and developed a painful peripheral neuropathy, were medicated with pregabalin in the daily dose of 150-300 mg for 8 weeks. RESULTS Twenty-eight patients completed the 8-week follow-up. A significant and long-lasting pain relief was noted in 86% of these patients. Median VAS score decreased by 59% at the 8th week from baseline. Adverse effects were infrequent and transient. CONCLUSION The treatment with pregabalin resulted in a significant improvement in pain symptoms. The use of pregabalin in children is off-label so far. However, this drug seems to be a safe and effective remedy, which could significantly broaden the therapeutic spectrum in paediatric oncological patients suffering from neuropathic pain.

World disparities in risk definition and management of retinoblastoma: a report from the International Retinoblastoma Staging Working Group.

Following from the publication of the International Retinoblastoma Staging System, an open internet discussion group was created at the www.cure4kids.org resource. The results of a survey distributed among participants are discussed. Although most patients with retinoblastoma were treated under prospective protocols, there was a wide variation in the definition of risk criteria and in the criteria for giving adjuvant chemotherapy following enucleation. Definition of high‐risk histological features and the criteria for use of adjuvant therapy will be standardized in future studies. Internet meetings are a valuable mechanism for enabling participation from under‐resourced countries in the development of cooperative studies. Pediatr Blood Cancer 2008;50:692–694.

Survivorship after childhood cancer: PanCare: A European Network to promote optimal long-term care.

Survival after childhood cancer has improved substantially over recent decades. Although cancer in childhood is rare increasingly effective treatments have led to a growing number of long-term survivors. It is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe. Such good survival prospects raise important questions relating to late effects of treatment for cancer. Research has shown that the majority will suffer adverse health outcomes and premature mortality compared with the general population. While chronic health conditions are common among childhood cancer survivors, each specific type of late effect is very rare. Long-term effects must be considered particularly when addressing complex multimodality treatments, and taking into account the interaction between aspects of treatment and genotype. The PanCare Network was set up across Europe in order to effectively answer many of these questions and thereby improve the care and quality of life of survivors. The need for a structured long-term follow-up system after childhood cancer has been recognised for some time and strategies for implementation have been developed, first nationally and then trans-nationally, across Europe. Since its first meeting in Lund in 2008, the goal of the PanCare Network has been to coordinate and implement these strategies to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. This paper will outline the structure and work of the PanCare Network, including the results of several European surveys, the start of two EU-funded projects and interactions with relevant stakeholders and related projects.

Metronomic Chemotherapy with the COMBAT Regimen in Advanced Pediatric Malignancies: A Multicenter Experience

Background: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. Methods: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. Results: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3–69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. Conclusion: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.

Chronic Inflammation in Immune Aging: Role of Pattern Recognition Receptor Crosstalk with the Telomere Complex?

Age-related decline in immunity is characterized by stem cell exhaustion, telomere shortening, and disruption of cell-to-cell communication, leading to increased patient risk of disease. Recent data have demonstrated that chronic inflammation exerts a strong influence on immune aging and is closely correlated with telomere length in a range of major pathologies. The current review discusses the impact of inflammation on immune aging, the likely molecular mediators of this process, and the various disease states that have been linked with immunosenescence. Emerging findings implicate NF-κB, the major driver of inflammatory signaling, in several processes that regulate telomere maintenance and/or telomerase activity. While prolonged triggering of pattern recognition receptors is now known to promote immunosenescence, it remains unclear how this process is linked with the telomere complex or telomerase activity. Indeed, enzymatic control of telomere length has been studied for many decades, but alternative roles of telomerase and potential influences on inflammatory responses are only now beginning to emerge. Crosstalk between these pathways may prove to be a key molecular mechanism of immunosenescence. Understanding how components of immune aging interact and modify host protection against pathogens and tumors will be essential for the design of new vaccines and therapies for a wide range of clinical scenarios.

Predictors of Posstraumatic Stress and Posttraumatic Growth in Childhood Cancer Survivors

This longitudinal study aims to analyze predictors of posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) among gender, age, objective factors of the disease and its treatment, family environment factors and negative emotionality. The sample consisted of 97 childhood cancer survivors (50 girls and 47 boys) aged 11–25 years who were in remission 1.7 to seven years at T1 and four to 12.5 years at T2. Survivors completed a set of questionnaires including the Benefit Finding Scale for Children and the University of California at Los Angeles Posttraumatic Stress Disorder Index. Regression and correlation analyses were performed. The relation between PTSS and PTG was not proven. A higher level of PTSS (T2) was associated with higher levels of negative emotionality (T1). A higher level of PTG (T2) was connected to a higher level of warmth in parenting (T1), female gender and older age at assessment. Medical variables such as the severity of late effects and the time from treatment completion did not play a significant role in the prediction of PTSS and PTG. PTG and PTSS are more influenced by factors of parenting and emotional well-being of childhood cancer survivors than by objective medical data.

Fertility Among Female Survivors of Childhood, Adolescent, and Young Adult Cancer: Protocol for Two Pan-European Studies (PanCareLIFE)

Background Despite a significant number of studies on female fertility following childhood, adolescent, and young adult (CAYA) cancer, studies establishing precise (dose-related) estimates of treatment-related risks are still scarce. Previous studies have been underpowered, did not include detailed treatment information, or were based on self-report only without any hormonal assessments. More precise assessments of who is at risk for sub- or infertility are needed. Objective The objective of our study is to describe the design and methods of 2 studies on female fertility (a cohort study and a nested case-control study) among female survivors of CAYA cancer performed within the European PanCareLIFE project. Methods For the cohort study, which aims to evaluate the overall risk of fertility impairment, as well as the risk for specific subgroups of female CAYA cancer survivors, 13 institutions from 9 countries provide data on fertility impairment. Survivors are defined as being fertility impaired if they meet at least one of 8 different criteria based on self-reported and hormonal data. For the nested case-control study, which aims to identify specific treatment-related risk factors associated with fertility impairment in addition to possible dose-response relationships, cases (fertility impaired survivors) are selected from the cohort study and matched to controls (survivors without fertility impairment) on a 1:2 basis. Results Of the 10,964 survivors invited for the cohort study, data are available from 6619 survivors, either questionnaire-based only (n=4979), hormonal-based only (n=72), or both (n=1568). For the nested case-control study, a total of 450 cases and 882 controls are identified. Conclusions Results of both PanCareLIFE fertility studies will provide detailed insight into the risk of fertility impairment following CAYA cancer and diagnostic- or treatment-related factors associated with an increased risk. This will help clinicians to adequately counsel both girls and young women, who are about to start anticancer treatment, as well as adult female CAYA cancer survivors, concerning future parenthood and to timely refer them for fertility preservation. Ultimately, we aim to empower patients and survivors and improve their quality of life. Registered Report Identifier RR1-10.2196/10824

The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy

Telomeropathies are rare disorders associated with impaired telomere length control mechanisms that frequently result from genetic mutations in the telomerase complex. Dyskeratosis congenita is a congenital progressive telomeropathy in which mutation in the telomerase RNA component (TERC) impairs telomere maintenance leading to accelerated cellular senescence and clinical outcomes resembling premature aging. The most severe clinical feature is perturbed hematopoiesis and bone-marrow failure, but the underlying mechanisms are not fully understood. Here, we developed a model of telomerase function imbalance using shRNA to knockdown TERC expression in human induced pluripotent stem cells (iPSCs). We then promoted in vitro hematopoiesis in these cells to analyze the effects of TERC impairment. Reduced TERC expression impaired hematopoietic stem-cell (HSC) differentiation and increased the expression of cellular senescence markers and production of reactive oxygen species. Interestingly, telomere length was unaffected in shTERC knockdown iPSCs, leading to conclusion that the phenotype is controlled by non-telomeric functions of telomerase. We then assessed the effects of TERC-depletion in THP-1 myeloid cells and again observed reduced hematopoietic and myelopoietic differentiative potential. However, these cells exhibited impaired telomerase activity as verified by accelerated telomere shortening. shTERC-depleted iPSC-derived and THP-1-derived myeloid precursors had lower phagocytic capacity and increased ROS production, indicative of senescence. These findings were confirmed using a BIBR1532 TERT inhibitor, suggesting that these phenotypes are dependent on telomerase function but not directly linked to telomere length. These data provide a better understanding of the molecular processes driving the clinical signs of telomeropathies and identify novel roles of the telomerase complex other than regulating telomere length.

The Influence of Developmental Stage on the Relationship Between Severity of Late Effects of Anticancer Therapy and Perceived Quality of Life of Childhood Cancer Survivors

The present study aims to investigate the relationship between severity of late effects and subjective quality of life of childhood cancer survivors in different age brackets. The sample consisted of 147 cancer survivors (70 boys and 77 girls) aged 8 to 18 who were in remission 2 to 5 years. The analyses were carried out separately for younger (8-12 years) and older (13-19 years) age groups. Cancer survivors were asked to complete Minnesota–Minneapolis Quality of Life Instrument (MMQL) as well as other methods of measuring involvement in everyday life activities and parent–child interactions Social And Health Assessment (SAHA) were used. Severity of late effects was assessed on a 4-point scale in accordance with Common Terminology Criteria for Adverse Events v3.0. While severity of late effects correlated positively only with parental warmth in younger age bracket, there were many relationships between severity of late effects and quality of life in older age bracket. The difference between the two age brackets is explained by the fact that adolescents are able to assess the impact of the disease.