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End of life for children with cancer refers to the closeness of death, and consequently, care at the end of life entails the anticipation of death. Clear medical decisions and best possible symptom control should be in place. Furthermore, clinicians should be prepared to provide anticipatory guidance and to respond to questions that parents may ask including “When will my child die?”; “Will he suffer?”; “What will it be like?”; “What does she need?”; and “How can we be of help?” To assure that a child can die in the family’s preferred location, careful arrangements may need to be made. This chapter will address these end-of-life considerations for children with cancer and their families.

Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.

BACKGROUND Uncertainty about cure puts childhood cancer survivors at risk of mental distress. We asked survivors if they had been told they had been cured and investigated associated factors. PROCEDURE We used nationwide registry data and a questionnaire survey for ≥five-year survivors of childhood cancer (n = 301), followed by online focus groups with a purposive sample of Swiss pediatric oncologists (n = 17). Discussions were coded by investigators using thematic analysis. RESULTS Overall, 235 among 301 survivors (78%; 95% confidence interval, 73%-83%) reported having been told they were cured. The proportion was 89% (81%-97%) among lymphoma and 84% (77%-91%) among leukemia survivors, but only 49% (33%-65%) among central nervous system tumor survivors. Pediatric oncologists acknowledged that telling survivors they are cured may reassure them that their cancer lies behind them. However, many refrained from telling all patients. Reasons included the possibility of late effects (cure disrupted by a continued need for follow-up care) or late relapse (uncertainty of biological cure), case-by-case strategies (use of "cure" according to individual factors), and reluctance (substitution of noncommittal terms for "cure"; waiting for the patient to raise the topic). CONCLUSIONS Not all physicians tell survivors they have been cured; their choices depend on the cancer type and risk of late effects.

BACKGROUND The extent to which physical performance limitations affect the ability of childhood cancer survivors to reach healthy activity levels is unknown. Therefore this study aims to describe the effect of different types of limitations on activity levels in survivors. PROCEDURE Within the Swiss Childhood Cancer Survivor Study we sent a questionnaire to all survivors (≥16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976-2005 aged

OBJECTIVES: We aimed to (i) evaluate psychological distress in adolescent survivors of childhood cancer and compare them to siblings and a norm population; (ii) compare the severity of distress of distressed survivors and siblings with that of psychotherapy patients; and (iii) determine risk factors for psychological distress in survivors. METHODS: We sent a questionnaire to all childhood cancer survivors aged

Objective: This study is the ! rst to assess posttraumatic stress disorder (PTSD) in young children with cancer and to examine individual, medical, and parent-related determinants. Methods: Forty-eight patients with cancer, ages 8‐48 months, were assessed in an average of 15 months after their diagnosis, using mothers as informants to complete the Posttraumatic Stress Disorder Semi-Structured Interview and Observational Record for Infants and Young Children. Additionally, mothers and the attending pediatric oncologist completed questionnaires on various determinants of child PTSD. Results: Nine children (18.8%) met the age-appropriate criteria for full PTSD proposed by Scheeringa et al., and 20 children (41.7%) met criteria for partial PTSD. Multivariate logistic regression analysis revealed that higher child age at diagnosis (odds ratio=1.11) and maternal PTSD severity (odds ratio=1.14) increased the risk of full or partial PTSD in children. Conclusions: This study provides evidence for a substantial prevalence of PTSD in young children with cancer and identi! es important risk factors. Copyright © 2012 John Wiley & Sons, Ltd.

Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations.

BACKGROUND: The objective of this study was to describe educational achievements of childhood cancer survivors in Switzerland compared with the general population. In particular, the authors investigated educational problems during childhood, final educational achievement in adulthood, and its predictors. METHODS: Childhood cancer survivors who were aged

Purpose To evaluate the degree of psychological distress in adult childhood cancer survivors in Switzerland and to characterize survivors with significant distress. Methods Childhood cancer survivors who were age younger than 16 years when diagnosed between 1976 and 2003, had survived more than 5 years, and were currently age 20 years or older received a postal questionnaire. Psychological distress was assessed using the Brief Symptom Inventory (BSI). Raw scores were transformed into T scores according to the German norm sample, and the proportion of participants being at increased risk for psychological distress was calculated (case rule: T ≥ 63). t tests and univariable and multivariable logistic regressions were used for statistical analyses. Results One thousand seventy-six survivors (63.% of eligible survivors, 71.9% of contacted survivors) returned the questionnaire, 987 with complete data on BSI. Comparison with the norm populations showed lower T scores (T < 50) in the Global Severity Index (GSI; T = 46.2), somatization (T = 47.6), obsessive-compulsive tendencies (T = 46.9), and anxiety (T = 48.4). However, more childhood cancer survivors (especially women) had increased distress for GSI (14.4%), interpersonal sensitivity (16.5%), depression (13.4%), aggression (16.9%), and psychotic tendencies (15.6%) than the expected 10% from the norm population. Caseness was associated with female sex, being a single child, older age at study, and self-reported late effects, especially psychological problems. Conclusion Results show that childhood cancer survivors, on average, have less psychological distress than a norm population but that the proportion of survivors at risk for high psychological distress is disproportionally large. Monitoring psychological distress in childhood cancer survivors may be desirable during routine follow-up, and psychological support should be offered as needed.

Udgivelsesdato: 2009-Aug-27 Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples. Thirteen of these mutations alter codon Y371. In this report, we also demonstrate that CBL and RAS/PTPN11 mutations were mutually exclusive in these patients. Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML.

Atypical Spitz tumors can hardly be differentiated from spitzoid melanoma. CGH might help in the differential diagnosis. An 8 year old child with an atypical Spitz tumor (with a CGH pattern compatible with melanoma) of 8.0 mm Breslow thickness and micrometastases in two lymph node regions was seen at our department. The management and prognosis of atypical Spitz tumors is controversial, and aggressive procedural steps similar to melanoma are usually not recommended. Even performing sentinel lymph node biopsy has been questioned. After extensive interdisciplinary consultations, we did not recommend resection of both lymph node regions and chose instead to follow-up with regular whole-body MRI and adjuvant treatment with pegylated interferon. Treatment decisions for atypical Spitz tumors are a major medical and ethical challenge due to the limited available data.

To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome.

The management of acute appendicitis in the febrile neutropenic patient after intensive chemotherapy is controversial. We report our single-center-experience of 5 children diagnosed with appendicitis during febrile neutropenia after chemotherapy for acute leukemia or lymphoma. All patients presented with an isolated appendicitis without signs of overt mucositis or more diffuse enterocolitis. The clinical diagnosis was confirmed by ultrasonography. Perforation with retrocecal abscess was present in 1 patient. Administration of combination antimicrobial regimens including meropenem resulted in complete resolution in all patients. Our observations indicate that acute appendicitis in clinically stable neutropenic cancer patients can be managed conservatively without surgery.

Background Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disease of infancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment modality, while the role of anti-leukemic therapy prior to HSCT is uncertain. A comparative evaluation of the efficacy of different clinical protocols and great variety of anti-neoplastic drugs applied pre-HSCT is hampered by the lack of uniform criteria of response. Classification schemas applied in other forms of leukemia are of little value, because in JMML therapy may result in divergent responses in solid organs compared to peripheral blood (PB). Procedure We therefore defined separate response criteria for white blood count (WBC), platelet count, liver size, and spleen size. We then retrospectively evaluated the efficacy of 129 treatment courses other than HSCT administered to 63 children with JMML. Treatment consisted of intensive therapy according to AML-type chemotherapy, maintenance-type combination therapy, and single agent therapy. To account for the variability observed in the natural course of disease, we also evaluated 32 episodes of “no therapy.” Results Best responses within 3 months of initiation of therapy were highly variable for the four response criteria. In contrast to platelet count and liver size, there was a significant correlation between WBC or spleen size and therapy. Response rates for WBC and spleen size were best for purine analogs, etoposide, and cytarabine as single agents or for maintenance-type combination therapy. Conclusion To rigorously test future therapeutic strategies in this rare disease an international consensus on the definition of response criteria will be helpful. Pediatr Blood Cancer 2007;49:629–633. © 2006 Wiley-Liss, Inc.

Disclosure: No relevant conflicts of interest to declare. To study the clinical significance of recurrent chromosome aberrations in childhood MDS, cytogenetic data of 394 consecutive children with refractory cytopenia (RC) (N=215), RAEB (N=141) and RAEB-T (N=38) analyzed in the regional cytogenetic reference centers and registered in the prospective study EWOG-MDS 98 between 1998 and 2005 were evaluated. At diagnosis, a karyotype could be defined in 279/394 patients (pts) (71%). No karyotype was obtained in 16% of pts with RC compared to 8% pts with RAEB and RAEB-t (p

RC is one of the most common variants of childhood MDS, characterized by clonal ineffective hematopoiesis and sustained peripheral cytopenia. Allogeneic HSCT represents a widely employed, curative treatment for children with RC. We analyzed the outcome of 48 children (33 males, 15 females; median age at transplantation 11 years, range 2.9–19) affected by RC, given allogeneic HSCT after a myeloablative preparative regimen and reported to the European Working Group on Childhood MDS (EWOG-MDS). Karyotype analysis was available in all patients, but 4. Clonal abnormalities were detected in 17 patients, involving chromosome 7 in 13 children. Bone marrow cellularity was reduced in 34, normal in 8 and increased in the remaining 6 patients. Nineteen patients were transplanted from an HLA-identical sibling, while the remaining 29 were given HSCT from an unrelated donor (UD). Bone marrow, cord blood and peripheral blood stem cells were employed in 38, 1 and 9 patients, respectively. Busulfan (BU) and cyclophosphamide (CY) were used as preparation to the allograft in 12 patients, while 36 children were given a regimen including BU, CY and melphalan (L-PAM). Cyclosporine-A (Cs-A) alone was mainly used as graft-versus-host disease (GvHD) prophylaxis in children transplanted from a relative, while the majority of patients transplanted from an UD were given the combination of Cs-A, short-term methotrexate and anti-thymocyte globulin. All patients engrafted, the median time to neutrophil and platelet recovery being 16 days (range, 9–79) and 26 days (range, 10–170), respectively. Two patients had secondary graft failure at 74 and 93 days after HSCT, respectively; one of them was successfully re-transplanted. The cumulative probability of developing grade II-IV acute GVHD was 37% (95% CI, 26–54%). Thirteen out of the 41 patients at risk developed chronic GVHD, which was limited in 8 patients and extensive in 5. The cumulative incidence of chronic GVHD was 35% (95% CI, 23–55%). With a median follow-up of 3.5 years (range 4 months-7.8 years), 39 patients are alive with sustained donor engraftment (1 after a second transplant), 9 patients having died for either transplant-related complications (8 patients) or disease recurrence (1 child). The 5-year probability of disease-free survival (DFS) is 77% (95% CI, 65–89%). In patients transplanted from an HLA-identical sibling and from an UD the DFS probability at 5 years is 78% (95% CI, 59–97%), and 76% (95% CI, 60–91%), respectively (P=n.s). The 5-year probability of DFS was 61% (95% CI, 38–83%) and 86% (95% CI, 74–99%) for children who did or did not experience grade II-IV acute GvHD (P=0.04). The outcome of patients prepared with either BU/CY or BU/CY/L-PAM was 92% (95% CI, 76–100%) and 71% (95% CI, 56–86%), respectively (P=n.s). These data indicate that a myeloablative allogeneic HSCT is able to cure a large proportion of children with RC, especially if GvHD is successfully prevented. Transplantation-related mortality represents the main cause of treatment failure, while relapse is rarely observed. The addition of L-PAM does not offer any advantage in comparison to BU/CY. Outcome of children with RC given allogeneic HSCT from either a relative or an UD is similar.

Sodium valproat (VPA) is a commonly used antiepileptic drug in children. It is known to cause a variety of different haematological side effects, including thrombocytopenia, a decrease in plasma fibrinogen, von Willebrand factor (VWF)- and factor XIII, impaired platelet aggregation with ADP and Collagen and prolonged PFA-100 closure times. The mechanisms responsible for such a variety of haematological abnormalities are still poorly understood and controversy exists about their clinical relevance and the risk for significant bleeding. We report on 4 children with severe bleeding complications during VPA treatment that had been followed at our institution. A first child with a cerebral malformation and no history of bleeding developed a subdural haematoma during VPA treatment without trauma. Additional studies revealed decreased von Willebrand factor levels that persisted with episodes of severe epistaxis also after VPA was stopped. A second infant suffered from herpes encephalitis with generalised seizures and died from an intracranial bleeding a day after a VPA loading dose was administred. Laboratory studies revealed prolonged PFA100 closure times. A third child with a therapeutic VPA serum-levels developed asymptomatic mild thrombocytopenia (around 100 G/l); unexpectedly in this child a tonsillectomy was complicated with sever diffuse haemorrhage that required red cell transfusion and intensive care treatment. Finally, a forth child who had been on VPA therapy for years causing prolonged PFA100 closure times, developed a large spinal epidural haematoma during epidural anaesthesia three days after urological surgery. This child had received VWF containing factor concentrate preoperatively only. For the bleeding additional VWF containing factor concentrate was given, the catheter was removed and the child recovered completely. Paediatricians, neurologists and anesthesists should be aware of the haemostatic side effects of VPA that can lead to significant bleeding. Before starting VPA therapy, patients should be evaluated for the presence of a congenital bleeding disorder. Preoperatively for any surgical intervention and in case of the occurrence of bleeding symptoms the patients have to be further evaluated for a VPA-induced disorder of the plasmatic haemostasis or an impaired platelet function. Haemostatic side effects of VPA can occur at therapeutic VPA serum levels and are found at any time during the course of VPA treatment. VPA has to be used cautiously in severely ill children and in intensive care patients and the risk of bleeding of any surgical or anesthesiological procedure has to be evaluated. Treatment options for VPA induced haemostatic abnormalities include plasma derived factor concentrates that contain VWF and the use of antifibrinolytic agents. Further studies have to assess the feasibility of standard treatment with the vasopressin analog DDAVP for this group of patients taking into account their high risk for seizures.

MDS in children is a rare disorder characterized by dysplasia and defined genetic abnormalities. In most patients (pts) MDS arises without known predisposing conditions (primary MDS). Here, we report the results of 55 males and 30 females with advanced primary MDS enrolled in the prospective EWOG-MDS trial 97. Data were analysed according to the most advanced FAB-type prior to SCT: 32 pts were classified as RAEB, 40 as RAEB-t and 13 as myelodysplasia-related AML (MDR-AML). Median age at diagnosis was 9.5 yrs (0.1–17.6) and median time from diagnosis of advanced MDS to SCT 4 mo (0.5–31). Cytogenetics revealed monosomy 7 in 32 pts, trisomy 8 in 7, a complex karyotype in 9 and other abnormalities in 9; karyotype was normal in 26 pts and unknown in 2. 31 pts had received AML-like therapy prior to SCT. All pts were given an unmanipulated graft after condititioning with busulfan 16 mg/kg, cyclophosphamide 120 mg/kg and melphalan 140 mg/m. Source of stem cells was bone marrow in 56 pts, peripheral blood in 25, cord blood in 2 and unknown in 2. 36 pts were transplanted from an HLA-identical relative (MFD), 49 pts from an HLA-identical or 1-antigen disparate unrelated donor (UD). GVHD prophylaxis consisted of CSA alone for MFD, whereas recipients of a UD graft generally received CSA, methotrexate and anti-lymphocyte globulin. Two pts suffered graft failure. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was 40% (SE 5%) and 25% (SE 5%), respectively. 18 pts suffered transplant-related mortality (TRM), the cumulative incidence of TRM in pts grafted from a MFD or UD being 14 and 25%, respectively (p=n.s.). Presence of acute GVHD II-IV (p

Myelodysplastic syndrome (MDS) represents a heterogeneous group of hematopoietic stem cell disorders. Although the precise pathogenesis of MDS remains to be clarified, cytogenetic abnormalities appear to be involved in the disease mechanism and are considered an important factor in predicting clinical outcome. Here, we report the outcome of conventional cytogenetic analysis performed at diagnosis in 300 children with MDS who were enrolled in the prospective study EWOG-MDS 98. The patients were divided into 3 clinical groups: primary refractory cytopenia (RC) (n=142), primary advanced MDS (aMDS) (n=94), and MDS secondary to chemo- or radiation therapy, bone marrow failure disorders or familial disease (sMDS) (n=64). A full cytogenetic result was obtained in 263 cases (87.7%) including 116 (44.1%) with an abnormal clone. Comparing the 3 diagnostic subgroups, there was a statistically significant difference in the frequency of abnormalities observed. In RC, only 25 of 116 patients with successful analysis had a detectable clone that showed monosomy 7 as sole aberration in the majority of cases (52%). In addition, this subgroup also showed the greatest rate of failure to obtain a karyotypic result. In contrast, 42 (65.6%) of the sMDS cases were cytogenetically abnormal with a broad spectrum of aberrations including 16 patients (25%) with a complex karyotype (≥4 abr.). The presence of karyotypic evolution was also more frequently observed in this group. The overall karyotypic results showed monosomy 7 to be present in 50% of all abnormal cases, a figure that greatly exceeded the prevalence of the other frequent non-random aberrations of −5/del(5q), +8, del(7q), and +21, each of which occurred in 5–10% of abnormal cases. Despite the small numbers of these latter cases, clear trends of karyotypic events occurring in a particular clinical subgroup were demonstrated in the form of +8 with aMDS and −5/del(5q) with sMDS. The clinical and cytogenetic subgroups were further analyzed for correlations with gender and age. Whereas no clinical group showed any correlation between gender and karyotype, in RC and aMDS it was shown that patients with monosomy 7 were significantly younger than those with another karyotypic result (median 3.2 vs. 10.4 yrs and 5.2 vs. 11.0 yrs, respectively). The results demonstrate that while a general karyotypic picture can be defined in childhood MDS, future studies need to clearly differentiate between individual clinical subgroups.

Treatment-related myelodysplastic syndrome (tMDS) is a serious complication of therapy of childhood cancer. Here we report on 59 patients (pts) (35 males, 24 females) with tMDS enrolled in the prospective study EWOG-MDS 98. Prior malignancy was ALL in 21 pts, AML in 5, lymphoma in 6, CNS tumors in 12, and other solid tumors in 15. Median age at diagnosis of tMDS was 11.2 yrs (range 1.2 – 23.2), and median time between first malignancy and tMDS 3.3 yrs (range 0.5 – 11.1). Disease was classified as refractory cytopenia in 15 pts, RAEB in 30 and RAEB-T in 14. Of the 47 pts with cytogenetic analysis at diagnosis, 77% had an abnormal karyotype, including 38% that were complex. Monosomy 7 with or without other abnormalities was detected in 38%. Progression of disease was noted in 26 of 52 evaluable pts at a median time of 2.5 mo (range 0.3 – 16) from diagnosis; the cumulative incidence of progression being 74%. After a median follow-up time of 20 mo (range 3–69) 28 pts are alive with an estimated 5-year overall survival of 32% (95% CI 20 – 51). No child survived beyond 15 mo from diagnosis without receiving allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was performed in 45 pts. Source of stem cells was bone marrow in 24 pts, peripheral blood in 20 and cord blood in 1. The donor was an HLA-identical relative (MFD) in 18 cases, while 26 pts were transplanted from an HLA-matched or 1-antigen/allele disparate unrelated donor (UD) and 1 pt from a 2-antigen disparate parent. Preparative regimen included busulfan 16 mg/kg, cyclophosphamide 120 mg/kg and melphalan 140 mg/m2 in 32 pts. Prophylaxis of GVHD generally consisted of cyclosporine-A for MFD, combined with methotrexate and ALG for UD. Two patients had graft failure. The cumulative incidence of grade II–IV acute GVHD and chronic GVHD were 32% (95% CI 28 – 37) and 24% (95% CI 19 – 28), respectively. Twelve pts suffered transplant-related mortality (TRM), the cumulative incidence of TRM in pts transplanted from a MFD or UD being 12% and 39%, respectively (P=0.058). Prior therapy with platinum compounds was an independent predictor of an increased risk of TRM. Fifteen pts relapsed at a median time of 9 mo (range 2 – 29) after HSCT, the 5-year cumulative incidence of relapse being 44% (95% CI 21 – 66). A WBC > 4 G/L at diagnosis predicted a higher risk of relapse. Twenty-one of the 45 pts transplanted are alive and 19 are disease-free. The estimated 5-year EFS after HSCT was 27% (95% CI 15 – 47). Prior therapy with platinum compounds, a WBC > 4 G/L at diagnosis, and a female donor predicted inferior EFS, while HSCT from an UD versus MFD resulted in similar outcome (5-year EFS, 21% and 39%, respectively). AML-type therapy prior to HSCT did not improve survival. Innovative stragegies for improving the outcome of these patients are warranted.