Burnout, staff support, and coping in Pediatric Oncology.

GOALS OF WORK: The goals of the study were the following: (1) to study the rate of burnout of the staff in Pediatric Oncology and compare it with that of a group of staff in other pediatric specialties, (2) to find out if job satisfaction, role clarity, staff support, and ways of coping are related to the burnout of these two groups, and (3) as a secondary aim, to identify other parameters, i.e., profession, experience, having children, etc., which might affect burnout, staff support, and ways of coping. MATERIALS AND METHODS: The study group (n = 58) consisted of the staff of two Pediatric Oncology units and a Bone Marrow Transplantation unit, and the control group (n = 55) consisted of the staff of two Pediatric departments and one Pediatric Orthopedics department. The Maslach Burnout Inventory, the Staff Support Questionnaire, the Shortened Ways of Coping Questionnaire-Revised, and the Social Readjustment Scale were used. MAIN RESULTS: No differences were found in burnout between Pediatric Oncology staff and that of other specialties, the existing staff support, and the ways of coping. Decreased role clarity and wishful thinking, as a way of coping, were positively correlated to emotional exhaustion, whereas a negative correlation of the lack of role clarity existed with personal accomplishment. Not having children and less experience increased burnout in both groups studied. CONCLUSIONS: The hospital management and the heads of departments should be knowledgeable of ways to prevent burnout in their staff. Strategies targeting role clarity and wishful thinking are useful toward this goal.

Clinical and morphological features of paediatric myelodysplastic syndromes: a review of 34 cases.

BACKGROUND: The clinical and morphological spectrum of myelodysplastic syndromes (MDS) during childhood has not yet been completely documented. We herein present the clinical features and morphological data from peripheral blood (PB), bone marrow aspirates (BMA) and bone marrow biopsies (BMB) of a series of paediatric MDS patients, with particular emphasis on their specific morphological characteristics and their diverse underlying genetic background. PATIENTS AND METHODS: Thirty-four patients with MDS (median age 8.45 y) were consecutively diagnosed and treated during a period of 15 y (1988-2002). Diagnosis was based on clinical manifestations, morphology of PB, BMA and BMB, and cytogenetic analysis of BM cells. Clonogenic methylcellulose cell cultures were performed in 23/34 patients. Patients were categorized into group A [26 primary/de novo MDS, i.e. refractory anaemia (RA) 18, RA with excess of blasts (RAEB) 2, RAEB in transformation (RAEB-t) 6] and group B (8 secondary MDS, i.e. RA 4, RAEB 1, RAEB-t 3). Treatment options varied according to protocols active during the period of the study and the availability of a suitable BM donor. Survival probabilities were estimated using the Kaplan-Meier method. RESULTS: Dysplastic features of the erythroid, myeloid and megakaryocytic lineage were detected at BMA in 85%, 50% and 90% of the patients, respectively, while decreased cellularity was found at BMB in 21/34 patients (60%). RA patients of group A presented at BMB significant hypocellularity (14/18) as a prominent finding due to decrease of the myeloid (13/18 patients) and/or the megakaryocytic (14/18 patients) lineage. Hypocellularity in RA was accompanied by dysplasia of the erythroid (17/18 patients) and megakaryocytic (16/18 patients) lineage, the presence of abnormal localization of immature precursors (ALIP, 8/18 patients), fibrosis (5/18) and stromal changes (11/18). Chromosomal aberrations were revealed in 17/34 patients, of which monosomy 7 was present in seven. Cell cultures demonstrated abnormal myeloid and/or erythroid in vitro clonal growth pattern in all the examined patients. An associated disorder or inherited disease, was identified in 14/26 patients (54%) with primary MDS. Cumulative survival of group A patients was 44.2% (RA 66.6%, RAEB/RAEBt 14.6%; p = 0.001), and of the whole group 42.4%, at 14 y. CONCLUSIONS: Hypocellularity of significant degree is a constant and prominent feature among paediatric MDS, especially those with RA. A large variety of associated disorders underlies the clinical appearance of paediatric MDS, reflecting their marked heterogeneity. RA represents the prominent subtype during childhood (69% in this study), and it appears to have the best prognosis, while prognosis of RAEB/RAEBt remains extremely poor.

Cerebellar granulocytic sarcoma in an infant with CD56+ acute monoblastic leukemia.

Granulocytic sarcoma (GS) is a form of extramedullary leukaemia (EML). The presence of the neural cell adhesion molecule (NCAM) on the surface of the blasts, which is recognized by the CD56 monoclonal antibody, enhances their propensity for tissue penetration. GS within the central nervous system (CNS), in particular within the cerebellum, is extremely uncommon. We review the literature and describe an infant with isolated cerebellar GS relapse, which antedated a CD56+ acute monoblastic leukaemia bone marrow (BM) relapse.

Chromosome fragility and predisposition to childhood malignancies.

In order to clarify the possible connection between autosomal folate sensitive Fragile Sites (FS) and genetic susceptibility to haemopoetic disease in children we investigated the frequency and distribution of FS in the Peripheral Blood Lymphocytes (PBL) of 56 children with newly diagnosed and untreated haematologic malignancies and their parents. The incidence was compared with that of 146 normal controls (children and adults). In all patients the Bone Marrow (BM) karyotype was also determined. Heritable FS were detected in 49 patients (87.5%). 20 children had more than one FS and in all cases it was inherited from one of their parents, although there was a significant excess of transmitting mothers. 19 different FS were identified: 14 common, 4 rare and one, 22q11, which has not been previously reported, but it is considered as important as it coincides with the cancer breakpoint resulting in the formation of the Philadelphia (Ph) chromosome. The frequency of FS in the PBL of the patients was significantly higher than in the controls and this increase was independent of any abnormality detected in the malignant cells of the BM. However, patients with an abnormal BM karyotype displayed increased frequency of FS induction as compared to patients with a normal karyotype. In three cases the heritable FS was found to be at or near the breakpoints of the chromosomal rearrangements detected in the malignant cells. The findings are discussed with regard to cancer specific breakpoints, oncogene loci and sites where viral DNA can be inserted to the genome. The results of this study suggest that autosomal folate sensitive FS may increase the risk for haematologic malignancies through a complex mechanism which remains to be clarified.

Aggregation of childhood leukemia in geographic areas of Greece.

A total of 872 children aged up to 14 years, who were diagnosed with leukemia in Greece during the decade 1980-89, were allocated by place of residence to the 601 administrative districts of the country. Evaluation of spatial clustering was done using the Potthoff-Whittinghill method, which validly assesses heterogeneity of leukemia risk among districts with variable expected numbers of cases. There was highly significant evidence for spatial clustering occurring particularly among children living in urban and, to a lesser extent, semi-urban areas. The evidence was stronger for children younger than 10 years old, applied also to children in different five-year age groups, and persisted when cases of acute lymphoblastic leukemia were analyzed separately. These findings provide support to the hypothesis that localized environmental exposures could contribute to the etiology of childhood leukemia, but they cannot distinguish between exposures of physical or chemical nature, nor can they exclude socially conditioned patterns of exposure to infectious agents.

Immune response of immunocompromised children with malignancies to a recombinant hepatitis B vaccine.

The aim of this study was to interpret the antibody response to hepatitis B vaccination following an intensified four-dose schedule in 140 cancer patients who presented at our clinic between January 1, 1993 and December 31, 1994. According to therapy status, the patients were divided into two groups: group A consisted of 76 patients undergoing chemotherapy and group B of 64 patients in complete remission and off treatment. The eligibility requirements were negative hepatitis B virus (HBV), HCV, and human immunodeficiency virus serologic markers. A total of four dose (20 micrograms per dose) of recombinant HB vaccine was administered intramuscularly in the deltoid region at 0, 1, 2, and 6 months. Blood from the vaccinated subjects was obtained at months 1, 2, 3, and 7 in order to measure anti-HBs titer levels. Protective anti-HBs titers were considered to be those > or = 10 mIU/mL. The overall seroconversion rate 1 month after the fourth dose was 57% (80/140 patients), and the seroconversion rates for groups A and B were 31.5% (24/76 patients) and 87.5% (56/64 patients), respectively. Our results indicated that immunocompromised children undergoing chemotherapy (although less responsive than children in complete remission and off treatment) still preserved their potential to produce protective titers of anti-HBs. On this basis we recommend (1) HB vaccination after diagnosis of malignancy in pediatric patients whenever a high prevalence of HB infection exists and (2) vaccination of patients of therapy and in complete remission.

Infant leukaemia after in utero exposure to radiation from Chernobyl.

There has been no documented increase in childhood leukaemia following the Chernobyl accident. However, different forms of childhood leukaemia may not be equally susceptible to radiation carcinogenesis. Infant leukaemia is a distinct form associated with a specific genetic abnormality. Outside the former Soviet Union, contamination resulting from the Chernobyl accident has been highest in Greece and Austria and high also in the Scandinavian countries. All childhood leukaemia cases diagnosed throughout Greece since 1 January 1980 have been recorded. Here we report that infants exposed in utero to ionizing radiation from the Chernobyl accident had 2.6 times the incidence of leukaemia compared to unexposed children (95% confidence interval, 1.4 to 5.1; P approximately 0.003), and those born to mothers residing in regions with high radioactive fallout were at higher risk of developing infant leukaemia. No significant difference in leukaemia incidence was found among children aged 12 to 47 months. Preconceptional irradiation had no demonstrable effect on leukaemia risk at any of the studied age groups.

Secondary malignancies in a child with Hodgkin's disease: T-cell lymphoma and myelodysplastic syndrome evolving into acute nonlymphoblastic leukaemia.

Hodgkin's disease (HD) has been linked to an increase risk of second malignant neoplasms (SMN), especially non-Hodgkin's lymphoma (NHL) and acute nonlymphoblastic leukaemia (ANLL). The mutagenic property of cytotoxic therapy as well as defective immunity have been implicated as playing a major role in the development of SMN in patients previously treated for HD. We report a case of a 14-year-old girl with HD who developed two different second malignancies within a latent period of 28 months following HD diagnosis. The patient presented initially with bilateral cervical and supraclavicular as well as mediastinal and paraaortic lymphadenopathy. She was staged as IIIA, nodular sclerosing type HD, and was given eight alternative cycles of MOPP-ABVD followed by "mantle" field radiotherapy to a total dose of 3.3 Gy plus 0.4 Gy to the upper mediastinum. Within 8 months following the completion of therapy, a period of myelodysplasia and progressive severe immune deficiency, considered as a result of initial treatment, occurred. Eighteen months after HD diagnosis while the patient was continuously neutropenic and heavily immunocompromised, a peripheral T-cell lymphoma of the angiocentric immunoproliferative lesion type (AIL) Grade III, appeared in both lungs within and beyond the radiation field, with no evidence of HD in biopsy specimens. After institution of a new chemotherapy regimen (L17M), a satisfactory response regarding NHL lesions was noted. However, 10 months later the myelodysplastic syndrome (MDS) accompanied by complex chromosomal abnormalities evoluted to frank ANLL with a rapid fatal course. This case supports the hypothesis that combined modality treatment accompanied by severe immunodeficiency may result in the development of multiple second malignancies even within a very short latent period, especially in a subgroup of HD patients who may be particularly increased risk of second cancers.

Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology.

The method introduced by Knox for evaluation of space-time clustering has been applied to 872 cases of childhood (0-14 year old) leukaemia diagnosed in Greece over the 10 year period 1980-89. Greek towns are characterised by substantial population mixing due to internal migration, whereas there is relative isolation in mountainous rural areas. Predetermined space (5 km) and time (1 year) limits were used on the basis of previous reports in order to define the clustering cell. There is highly significant evidence for clustering of childhood leukaemia in Greece as a whole, the observed number of pairs that are close in both spaces and time exceeding the expected number by 5.2% (P = 0.004). The excess is particularly evident for leukaemia cases in 0 to 4-year-old children, among whom the observed number of pairs that are close in both space and time exceeded the expected number by 9.4% (P = 0.004). There is no evidence of space-time clustering for leukaemia cases older than 5 years. The overall pattern is descriptively similar in urban and semiurban areas and is especially marked for acute lymphoblastic leukaemia at the childhood peak ages (2-4 years) with an excess of 19% (P = 0.0006). In the rural population there is evidence for clustering of cases belonging to older and broader age groups, a phenomenon compatible with a delay in the development of herd immunity against putative infectious aetiological agents. The findings of the present study provide support for the hypothesis that a substantial proportion of cases of childhood leukaemia may arise as a rare sequel to exposure to an agent or agents, most probably viral in nature.

Seventeen years of experience with chronic idiopathic thrombocytopenic purpura in childhood. Is therapy always better?

Between 1975 and 1992 450 children with idiopathic thrombocytopenic purpura (ITP) were diagnosed, and of those 100 (22%) developed the chronic form of the disease. Approximately half the patients with chronic ITP presented with mild to moderate hemorrhagic manifestations at the onset of purpura (30 cases) and/or later during the course of the disease (25 cases). The incidence of intracranial hemorrhage was 1%, and the mortality rate due to overwhelming septicemia after splenectomy was also 1%. Overall one-third of the patients received no therapy; two-thirds of them went into spontaneous remission within 8 months to 8 years from the onset of ITP. Steroids given in conventional or high doses (51 cases) achieved a transient (if any) rise in platelet count, but in no case were steroids curative. Remission related to intravenous immune globulin (IVIG) therapy was noticed in 38.5% of the children (10 of 26) after variable courses. The response rate to splenectomy was 95.0%. Ultimately the long-term outcome in children with chronic ITP was as follows: remission, 58 cases (spontaneous, 30; after IVIG therapy, 10; after splenectomy, 18); hemostatic platelet values, 22 cases (spontaneous, 16; after IVIG, 5; after splenectomy, 1). Thirteen children were lost in follow-up, and 7 remain thrombocytopenic but asymptomatic. These data indicate that chronic ITP in childhood runs a benign course in most cases and may remit with or without therapy even several years from onset. Therefore, therapeutic intervention has to be individualized, and splenectomy, which is not always safe, should be reserved for problematic cases that fail to respond to conventional therapeutic modalities.

Survival from childhood leukemia depending on socioeconomic status in Athens.

One hundred and twenty children first diagnosed as having acute leukemia between 1988 and 1992 in Athens, Greece, were followed until May 15, 1993. The socioeconomic status of the children's families was assessed by means of paternal occupation, paternal schooling, maternal schooling, ownership of a car, ability to choose a private medical facility and freedom in the choice of the attending physician. The analysis was done by proportional-hazards modelling, controlling for age and gender. All six socioeconomic indicators, alternatively evaluated, showed that fatality rates were higher in the lower socioeconomic groups, although nominal statistical significance was reached for only one of them. With respect to family ownership of a private car, the fatality rate ratio between children of families who own a car and children of families who do not was 0.29 with a 95% confidence interval of 0.13-0.62 (p = 0.002). These results suggest that in Greece, socially disadvantaged children have a less favorable survival from childhood leukemia.

Trends and geographical distribution of childhood leukemia in Greece in relation to the Chernobyl accident.

Parts of Greece have been exposed to fallout radiation from the Chernobyl accident as much as any of the countries boardering with the former Soviet Union, because of the direction of the prevailing winds after the accident. Although fallout radiation did not reach levels expected to be associated with measurable effects, there is widespread concern in Greece that the incidence of childhood leukemia may be rising in the more heavily affected parts of Greece. Patient discharge data from all Greek hospitals treating childhood leukemia were used to calculate the annual incidence of the disease from January 1980 to June 1986 (preaccident period), from July 1986 to June 1988 (immediate postaccident period) and from July 1988 to June 1991 ("relevant" post-accident period, that accommodates the presumed latent period of the disease). Fallout radiation measurements (in Bq/kg Cs-137) were used to create 17 regions of similar (within regions) but highly variable (between regions) levels of fallout deposition. Background radiation (in Bq/kg Ra-226) and annual incidence of childhood leukemia by region were also estimated. There was no evidence of increased incidence of childhood leukemia during the immediate or the "relevant" post-Chernobyl period in any part of the country. Furthermore, regression analyses did not show any significant or suggestive association of childhood leukemia by region with either background or fallout radiation. These results indicate that the Chernobyl accident did not affect noticeably the incidence of childhood leukemia in Greece during the five-year post accident period.

Age of exposure to infections and risk of childhood leukaemia.

PIP: Between January and August 1992 in Greece, researchers conducted telephone interviews with parents of children with leukemia (136 cases, most in Attica [Athens and its environs] and the others on the island of Crete) and with parents of children not afflicted with leukemia (187 controls) to determine whether childhood leukemia may be a result of a subclinical infection at an earlier age. They controlled for place of residence when they conducted the multiple logistic regression analyses. They used attendance at a day care facility as a proxy for earlier infection because children come in close contact with each other at day cares, thereby exposing them to many infectious agents. Children who attended a day care had a lower relative risk of developing leukemia than those who did not attend day care (.67), but attendance did not have a significant protective effect. It did appear to have a significant protective effect for children who attended day care during infancy (for at least 3 months during the first 2 years of life), however, (relative risk = .28; p = .03). Significance remained even when the researchers considered different operational definitions of early attendance. Exposure to magnetic fields appeared to have a protective effect also against the development of childhood leukemia, but this effect did not reach significance (p = .07). The relative risk for 100 m from an electricity substation was 0.35. There was a slight, but insignificant increase in the relative risk for children living close to power lines, however (1.19 for 5 m; p = .63). Significant risk factors included young age at diagnosis and mothers with less than high school education.^ieng

Auxologic data and hormonal profile in long-term survivors of childhood acute lymphoid leukemia.

PURPOSE: Eighty patients, 50 girls and 30 boys 13.5 +/- 4.09 years of age, on continuous first remission, were evaluated 7.9 +/- 3.2 years after the diagnosis of acute lymphoid leukemia (ALL). PATIENTS, METHODS AND RESULTS: All patients were treated according to current protocols. Cranial irradiation dose was 1,800 rad in 10 fractions for 50 patients, and 2,400 rad in 18 fractions for the remaining 30. The mean percentile and SDS for height were 42.5 +/- 26 and -0.3 +/- 1.1 for boys, and 37.8 +/- 15.3 and -0.54 +/- 0.9 for girls, respectively. The final height and the corresponding SDS was 171 +/- 5.75 cm and -0.35 +/- 0.8 for boys, and 158 +/- 7.1 cm and -0.89 +/- 1.1 for girls, respectively. Using skin fold thickness, obesity was observed in a high percentage of patients. The head circumference (HC) percentile was 36.8 +/- 24 for boys and 40.9 +/- 29 for girls, and was even lower (30.96 +/- 25.5) for those who received a radiation dose of 2,400 rad. Menarche was earlier in girls with ALL than in normal girls (11.6 +/- 1.5 vs. 12.4 +/- 1.02 years). Testicular size was within normal limits, except in three boys whose size was at or below the third percentile. In two of them, testes had been irradiated. The mean thyroxin, thyroid-stimulating hormone, and prolactin values were within normal limits (8.6 +/- 2 micrograms/dl, 2.6 +/- 1.1 microU/dl, and 5.9 +/- 4.8 ng/ml, respectively). The somatomedin-C values for patients in the prepubertal stage were 1.49 +/- 0.85 versus 0.96 +/- 0.6 in the controls (p < 0.05), whereas for patients in the pubertal stage they were 1.92 +/- 1 versus 1.88 +/- 1 in the controls. The sex steroid and dehydroepiandrosterone sulfate values were within normal limits. In a high percentage of children, follicle-stimulating hormone and luteinizing hormone values were above the normal range for their age, sex, and pubertal stage. The mean glycosylated hemoglobin values were normal. CONCLUSIONS: 1. Linear growth, although impaired in the group as a whole, is within the normal range for the majority of children with ALL. A small percentage of children have significantly impaired growth, and must be identified early and receive appropriate therapy. 2. Obesity is more frequently present in patients with ALL. 3. HC is lower than expected, indicating impaired brain growth, which is worse in children irradiated with 2,400 rad. 4. Menarche is earlier and the gonadotrophin level is higher than normal, suggestive of either hypothalamic dysfunction, subtle ovarian failure, or both.

Diabetes mellitus and exocrine pancreatic insufficiency in a girl with auto-immune haemolysis.

A 7-year-old girl developed diabetes mellitus and exocrine pancreatic insufficiency after 3.5 years of almost continuous treatment with azathioprine and/or prednisone for idiopathic auto-immune haemolytic anaemia. Although both drugs have been reported to preserve endogenous insulin secretion and to interrupt the diabetogenic process they may be responsible for diabetes and exocrine pancreatic insufficiency in our patient.

Abnormal glucose tolerance in children with acute leukemia. Effect of induction chemotherapy including L-asparaginase.

The glycemic and insulin response to an oral glucose load was studied in 17 children with acute lymphoblastic leukemia (ALL) and 13 normal controls. The patients were randomly assigned to either group A, receiving prednisone and vincristine, or group B, receiving these agents and, in addition, L-asparaginase from days 9-19 of the study. The glucose load was performed prior to (phase I), and on days 8 (phase II), and 19 (phase III) of chemotherapy. The mean glycemic response in both groups of patients was significantly higher than in controls at diagnosis and prior to any treatment, while mean insulin levels were not significantly different from controls. One week after initiation of treatment, the mean glycemic response improved, and was associated with hyperinsulinism. After the second week of treatment, the mean glucose and insulin response curves in group A were similar to controls. In group B, while insulin values returned to normal, blood glucose levels remained higher than in controls, but not significantly so. These findings suggest that: 1) The leukemic process itself, through mechanisms as yet undetermined, causes impairment of glucose tolerance, and 2) the diabetogenic effect of L-asparaginase is not manifested in all patients.

Electrolyte abnormalities in lymphosarcoma after chemotherapy.

A 12-year-old female with lymphosarcoma responding to treatment including vincristine and cyclophosphamide developed clinical and laboratory findings compatible with the syndrome of inappropriate secretion of antidiuretic hormone. Some additional findings were observed, i.e. uremia, hypopotassemia and alkalosis, that have not so far been recorded in that syndrome. All abnormalities were corrected upon water restriction. A similar episode occurred after a 2nd drug course. It too was corrected upon water restriction. The patient was clinically free from her malignancy in both episodes. It is suggested that our child had probably an expanded form of the syndrome of inappropriate secretion of antidiuretic hormone.