Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

Background: Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases. Methods: T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS, PTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test. Results: The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SIL-TAL1 was identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome, while the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p = 0.031) than point mutations. Conclusion: NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis. Nevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was validated as a negative prognostic marker in our series of T-ALL.

Follow-up care amongst long-term childhood cancer survivors: a report from the Swiss Childhood Cancer Survivor Study

In the Swiss Childhood Cancer Survivor Study, we aimed to assess the proportion of long-term survivors attending follow-up care, to characterise attendees and to describe the health professionals involved. We sent a questionnaire to 1252 patients, of whom 985 (79%) responded, aged in average 27 years (range 20-49). Overall, 183 (19%) reported regular, 405 (41%) irregular and 394 (40%) no follow-up. For 344, severity of late effects had been classified in a previous medical examination. Only 17% and 32% of survivors with moderate and severe late effects respectively had made regular visits a decade later. Female gender, after a shorter time since diagnosis, had radiotherapy, and having suffered a relapse predicted follow-up. In the past year, 8% had seen a general practitioner only, 10% a paediatric or adult oncologist and 16% other health specialists for a cancer related problem. These findings underline the necessity to implement tailored national follow-up programmes.

Daily Physical Activities and Sports in Adult Survivors of Childhood Cancer and Healthy Controls: A Population-Based Questionnaire Survey

Background Healthy lifestyle including sufficient physical activity may mitigate or prevent adverse long-term effects of childhood cancer. We described daily physical activities and sports in childhood cancer survivors and controls, and assessed determinants of both activity patterns. Methodology/Principal Findings The Swiss Childhood Cancer Survivor Study is a questionnaire survey including all children diagnosed with cancer 1976–2003 at age 0–15 years, registered in the Swiss Childhood Cancer Registry, who survived ≥5years and reached adulthood (≥20years). Controls came from the population-based Swiss Health Survey. We compared the two populations and determined risk factors for both outcomes in separate multivariable logistic regression models. The sample included 1058 survivors and 5593 controls (response rates 78% and 66%). Sufficient daily physical activities were reported by 52% (n = 521) of survivors and 37% (n = 2069) of controls (p<0.001). In contrast, 62% (n = 640) of survivors and 65% (n = 3635) of controls reported engaging in sports (p = 0.067). Risk factors for insufficient daily activities in both populations were: older age (OR for ≥35years: 1.5, 95CI 1.2–2.0), female gender (OR 1.6, 95CI 1.3–1.9), French/Italian Speaking (OR 1.4, 95CI 1.1–1.7), and higher education (OR for university education: 2.0, 95CI 1.5–2.6). Risk factors for no sports were: being a survivor (OR 1.3, 95CI 1.1–1.6), older age (OR for ≥35years: 1.4, 95CI 1.1–1.8), migration background (OR 1.5, 95CI 1.3–1.8), French/Italian speaking (OR 1.4, 95CI 1.2–1.7), lower education (OR for compulsory schooling only: 1.6, 95CI 1.2–2.2), being married (OR 1.7, 95CI 1.5–2.0), having children (OR 1.3, 95CI 1.4–1.9), obesity (OR 2.4, 95CI 1.7–3.3), and smoking (OR 1.7, 95CI 1.5–2.1). Type of diagnosis was only associated with sports. Conclusions/Significance Physical activity levels in survivors were lower than recommended, but comparable to controls and mainly determined by socio-demographic and cultural factors. Strategies to improve physical activity levels could be similar as for the general population.

Physical performance limitations in adolescent and adult survivors of childhood cancer and their siblings

Purpose This study investigates physical performance limitations for sports and daily activities in recently diagnosed childhood cancer survivors and siblings. Methods The Swiss Childhood Cancer Survivor Study sent a questionnaire to all survivors (≥16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976–2003 aged <16 years. Siblings received similar questionnaires. We assessed two types of physical performance limitations: 1) limitations in sports; 2) limitations in daily activities (using SF-36 physical function score). We compared results between survivors diagnosed before and after 1990 and determined predictors for both types of limitations by multivariable logistic regression. Results The sample included 1038 survivors and 534 siblings. Overall, 96 survivors (9.5%) and 7 siblings (1.1%) reported a limitation in sports (Odds ratio 5.5, 95%CI 2.9-10.4, p<0.001), mainly caused by musculoskeletal and neurological problems. Findings were even more pronounced for children diagnosed more recently (OR 4.8, CI 2.4–9.6 and 8.3, CI 3.7–18.8 for those diagnosed <1990 and ≥1990, respectively; p = 0.025). Mean physical function score for limitations in daily activities was 49.6 (CI 48.9–50.4) in survivors and 53.1 (CI 52.5–53.7) in siblings (p<0.001). Again, differences tended to be larger in children diagnosed more recently. Survivors of bone tumors, CNS tumors and retinoblastoma and children treated with radiotherapy were most strongly affected. Conclusion Survivors of childhood cancer, even those diagnosed recently and treated with modern protocols, remain at high risk for physical performance limitations. Treatment and follow-up care should include tailored interventions to mitigate these late effects in high-risk patients.

Clustering of health behaviours in adult survivors of childhood cancer and the general population

Little is known about engagement in multiple health behaviours in childhood cancer survivors.

The Swiss Childhood Cancer Registry: rationale, organisation and results for the years 2001-2005

QUESTIONS UNDER STUDY: Childhood cancer is a rare but severe disease. Therefore central registration of all cases is essential for surveillance and management. This paper describes the methodology and basic results of the Swiss Childhood Cancer Registry (SCCR). METHODS: The SCCR was established in 1976, originally as a national hospital-based registry of childhood malignancies. All 9 paediatric oncology-haematology clinics in Switzerland provide baseline and follow-up information on all children diagnosed with cancer. These data are registered centrally and diagnoses are coded according to the International Classification of Childhood Cancer. RESULTS: From 2001-2005, 887 cases of childhood cancer in Swiss residents under the age of 15 years were registered in the SCCR. Of these, 281 (31.7%) were leukaemias, 223 (24.0%) were CNS tumours, and 116 (13.1%) were lymphomas. The age-standardised annual incidence per 1 Million person-years (age below 15 years; world standardisation) was 154.0 (95% CI 143.7-164.3; N = 887). The incidence was higher for boys (170.2, 155.0-185.4; N = 501) than for girls (136.9, 123.0-150.8; N = 386). CONCLUSION: The close collaboration between all paediatric oncologists-haematologists in Switzerland and a university department allowed the creation of a national population-based cancer registry with detailed clinical information. The SCCR produces cancer type specific incidence and survival estimates and allows the development of nested research projects on childhood cancer aetiology, management and outcome, both on a national and on an international level.

Incidence of childhood cancer in Switzerland: the Swiss Childhood Cancer Registry

BACKGROUND: This report describes the incidence of childhood cancer in Switzerland, based on the data from the Swiss Childhood Cancer Registry (SCCR), a national hospital-based cancer registry with very high coverage, founded in 1976 by the Swiss Paediatric Oncology Group (SPOG). PROCEDURE: Malignancies were coded according to the International Classification of Childhood Cancer (ICCC-3). Incidence rates per 100,000 person-years were calculated for all malignancies and groups of malignancies in Swiss residents less than 15 years of age for the decade 1995-2004. RESULTS: The SCCR annually registered on average 174 new cases of cancer in Swiss residents aged <15 years, with a median age at diagnosis of 5.6 years. The crude incidence of childhood cancer in children aged <15 years was 13.5, higher for boys (15.0 per 100,000) than for girls (12.1 per 100,000), and was nearly twice as high in the first 5 years of life (19.3 per 100,000) than in the age group 5 to 14 years (10.8 per 100,000). CONCLUSION: Incidence of childhood cancers in the SCCR was similar to neighbouring countries and to data published by regional cancer registries in Switzerland for the same period, suggesting good completeness of registration. This makes the SCCR a valuable resource for national and international research on childhood cancer.

Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND Treatment of patients with paediatric acute lymphoblastic leukaemia has evolved such that the risk of late effects in survivors treated in accordance with contemporary protocols could be different from that noted in those treated decades ago. We aimed to estimate the risk of late effects in children with standard-risk acute lymphoblastic leukaemia treated with contemporary protocols. METHODS We used data from similarly treated members of the Childhood Cancer Survivor Study cohort. The Childhood Cancer Survivor Study is a multicentre, North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. We included cohort members if they were aged 1·0-9·9 years at the time of diagnosis of acute lymphoblastic leukaemia and had received treatment consistent with contemporary standard-risk protocols for acute lymphoblastic leukaemia. We calculated mortality rates and standardised mortality ratios, stratified by sex and survival time, after diagnosis of acute lymphoblastic leukaemia. We calculated standardised incidence ratios and absolute excess risk for subsequent neoplasms with age-specific, sex-specific, and calendar-year-specific rates from the Surveillance, Epidemiology and End Results Program. Outcomes were compared with a sibling cohort and the general US population. FINDINGS We included 556 (13%) of 4329 cohort members treated for acute lymphoblastic leukaemia. Median follow-up of the survivors from 5 years after diagnosis was 18·4 years (range 0·0-33·0). 28 (5%) of 556 participants had died (standardised mortality ratio 3·5, 95% CI 2·3-5·0). 16 (57%) deaths were due to causes other than recurrence of acute lymphoblastic leukaemia. Six (1%) survivors developed a subsequent malignant neoplasm (standardised incidence ratio 2·6, 95% CI 1·0-5·7). 107 participants (95% CI 81-193) in each group would need to be followed-up for 1 year to observe one extra chronic health disorder in the survivor group compared with the sibling group. 415 participants (376-939) in each group would need to be followed-up for 1 year to observe one extra severe, life-threatening, or fatal disorder in the group of survivors. Survivors did not differ from siblings in their educational attainment, rate of marriage, or independent living. INTERPRETATION The prevalence of adverse long-term outcomes in children treated for standard risk acute lymphoblastic leukaemia according to contemporary protocols is low, but regular care from a knowledgeable primary-care practitioner is warranted. FUNDING National Cancer Institute, American Lebanese-Syrian Associated Charities, Swiss Cancer Research.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012. OBJECTIVES To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo. AUTHORS' CONCLUSIONS In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Paediatric thyroid surgery is safe - experiences at a tertiary surgical centre.

PRINCIPLES Thyroidectomy in children is rare and mostly performed because of thyroid neoplasms. The aim of this study based on prospective data acquisition was to evaluate whether thyroid surgery in children can be performed as safely as in adults when undertaken by a team of adult endocrine surgeons and paediatric surgeons. METHODS Between 2002 and 2012, 36 patients younger than 18 years underwent surgery for thyroid gland pathologies. All surgical procedures were performed by an experienced endocrine surgeon and a paediatric surgeon. Baseline demographic data, surgical procedure, duration of operation, length of hospital stay, and postoperative morbidity and mortality were analysed. RESULTS The median age of all patients was 13 years (range 2-17 years), with predominantly female gender (n = 30, 83%). The majority of operations were performed because of benign thyroid disease (n = 27, 75%) and only a minority because of malignancy or genetic abnormality with predisposition for malignant transformation (MEN) (n = 9, 25%). Total thyroidectomy was performed in the majority of the patients (n = 24, 67%). The median duration of the surgical procedure was 153 minutes (range 90-310 minutes). The median hospital stay was 5 days (3-1 days). One patient developed persistent hypoparathyroidism after neck dissection due to cancer. One persistent and two temporary recurrent nerve palsies occurred. CONCLUSION This study demonstrated that paediatric thyroidectomy is safe as performed by this team of endocrine and paediatric surgeons, with acceptable morbidity even when total thyroidectomy was performed in the case of benign disease.

Paediatric palliative home care with Internet-based video-phones: lessons learnt

We have designed and tested an Internet-based video-phone suitable for use in the homes of families in need of paediatric palliative care services. The equipment uses an ordinary telephone line and includes a PC, Web camera and modem housed in a custom-made box. In initial field testing, six clinical consultations were conducted in a one-month trial of the videophone with a family in receipt of palliative care services who were living in the outer suburbs of Brisbane. Problems with variability in call quality-namely audio and video freezing, and audio break-up-prompted further laboratory testing. We completed a programme of over 250 test calls. Fixing modem connection parameters to use the V.34 modulation protocol at a set bandwidth of 24 kbit/s improved connection stability and the reliability of the video-phone. In subsequent field testing 47 of 50 calls (94%) connected without problems. The freezes that did occur were brief (with greatly reduced packet loss) and had little effect on the ability to communicate, unlike the problems arising in the home testing. The low-bandwidth Internet-based video-phone we have developed provides a feasible means of doing telemedicine in the home.

Caring for Children Dying from Cancer at Home: a Qualitative Study of the Experience of Primary Care Practitioners

Background. The rarity of childhood cancers makes providing palliative care in the community an unusual event for primary care practitioners. Providing this care requires effective interprofessional collaboration with the team that forms to provide the care often working together for the first and only time. Objective. To explore the experiences of primary care practitioners following their involvement in the palliative care of a child with cancer at home. Methods. The study design was a community-based qualitative study. The study location was the West Midlands region. Purposeful sample of GPs and community nurses involved in providing palliative care to 12 children. One-to-one in-depth interviews with 47 primary care professionals (10 GPs and 37 community nurses) and 5 facilitated case discussions were undertaken. Field notes were documented and grounded theory data analysis undertaken: chronological comparative data analysis identifying generated themes. Results. GPs had minimal input into the preceding care of children undergoing treatment for cancer but sought to re-establish their role at the child’s transition to palliative care. GPs felt they had a role to play and could add value to this phase of care, highlighted their continuing role with the child’s family and acknowledged that they had gained from the experience of contributing. However, lack of specialist knowledge and uncertainty about their role within the team made this more challenging. In contrast, community nurses were routinely involved in both active treatment and palliation care phases. There was little evidence of collaboration between the specialist and primary care professionals involved. There was considerable variation in out of hours provision across cases. Conclusions. Engaging primary care practitioners needs to be more actively anticipated and negotiated at the transition to palliation. Variation in out of hours care is another cause for concern. Enhancing inter-professional collaboration and planning during both active and palliative care phases may help. Keywords. Cancer, family medicine, palliative care, paediatric.

Using Social Worlds Theory to Explore Influences on Community Nurses’ Experiences of Providing Out of Hours Paediatric Palliative Care

Abstract Background: Paediatric oncology palliative care in the community is rare and nationally there is a lack of standardisation of out of hours nursing service provision. Objectives: This paper seeks to explore influences on the experiences of paediatric nurses providing out of hours palliative care within the family home to children with cancer. The study used social worlds theory to aid identification and demonstration of the findings. Methods: Twelve community-based palliative cases were purposively selected from children with cancer treated at one regional centre. Tape-recorded interviews were undertaken with 54 health professionals (general practitioners, community nurses and allied health professionals) involved in providing their palliative care and five facilitated case discussions completed. Data analysis followed a grounded theory approach; chronological comparative data analysis identifying generated themes. Social worlds theory was used as a framework to examine the data. Results: Nurses’ experiences are shaped by their social world and those of the nursing team,child and family and the inter-professional team providing the care. The lack of a formalised service, sub-optimal inter-professional working and impact of social worlds influence the experience of the nurse. Conclusions: Social worlds theory provided a new perspective in understanding these experiences based within a paediatric palliative care setting, knowledge that can be used to inform service provision.