The paradigm of hematological malignant versus non-malignant manifestations, driven by primary immunodeficiencies: a complex interplay.

Hematological malignancies (HM) developed on underlying primary immunodeficiencies (PID) are rare and of unusual features. Differentiating between malignant and non-malignant lymphoproliferation in cases of pediatric hematology and oncology and revealing their molecular predisposition demonstrate the complex interplay between PID and HM. We retrospectively studied a case series of seven pediatric patients, all with PID with manifestations raising suspicion for HM or hypereosinophilic syndrome (HES) or confirmed HM of lymphoid origin. Combined immunodeficiency (CID) without detection of a known mutated gene or with ataxia-telangiectasia (AT), STAT3 gain of function (GOF), DOCK8 deficiency, and CTLA4 deficiency were diagnosed in three, one, one, one, and one patient, respectively. Acute lymphoblastic leukemia and Hodgkin lymphoma followed by second primary Burkitt lymphoma were diagnosed in one patient with CID each, while lymphomatoid granulomatosis in one patient with AT. Lymphoproliferative disease occurred in STAT3 GOF, CTLA4 deficiency and CID, one patient each, and idiopathic HES in DOCK8 deficiency (median age at presentation of PID or any hematological manifestation: four years). Four patients underwent hematopoietic cell transplantation (HCT) for STAT3 GOF, DOCK8 deficiency and CID in one, one, and two cases, respectively (median age: 10 years). At the last follow-up, all transplanted patients were alive. Reporting on patients' phenotype, genotype and course of disease shed light on the prevalence, characteristics, and pathophysiology of HM complicating PID. Discriminating the non-yet malignant lymphoproliferation from its malignant equivalent on the same pathophysiology background proved of additional value. Outcomes of PID after HCT, herein reported, are favorable.

Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients.

Pediatric refractory or relapsed acute lymphoblastic leukemia (ALL) poses unique therapeutic challenges, with novel immunotherapy approaches offering potential cure opportunities. In this frame, the use of Blinatumomab may induce durable remissions, serving as a successful bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we retrospectively summarize the Greek experience on pediatric relapsed/refractory B-cell precursor ALL patients that were treated with Blinatumomab in a compassionate, off-label setting as an effort to achieve disease clearance and proceed to allo-HSCT. In our cohort of 9 patients, 6/9 (66.7%) responded to Blinatumomab, achieving complete morphological remission (CR) after the 1st cycle, while minimal/measurable residual disease (MRD)-negativity (<10-4) after the 1st cycle was achieved in 2/2 patients (100.0%) with prior CR. A successful bridge to HSCT was feasible in 5/9 patients (55.6%). Median relapse-free survival (RFS) was 3.0 months (range 0.5-21.4 months) and median overall survival (OS) was 8.7 months (range 1.4-47.1 months) for the whole pediatric cohort. There was a trend of prolonged survival among patients who achieved MRD response after the 1st Blinatumomab administration. MRD response (defined as the >=2-log reduction of MRD value before and after Blinatumomab administration), was associated with a median RFS/OS of 7.4/7.6 months, while lack of MRD response was associated with a median RFS/OS of 0.5/3.0 months, respectively. Novel therapeutic maneuvers, in order to overcome disease resistance, i.e. increased usage of Blinatumomab dose (45 µg/m2/day), combination with donor lymphocyte infusions (DLIs), use of other immunotherapy salvage approaches (inotuzumabozogamicin), are herein discussed. Additionally, the optimal number of Blinatumomab cycles, the CD19-negative relapses and lineage switch, are also addressed. Our data although referred to a limited, however refractory or relapsed and heavily pretreated number of patients, strongly suggest that Blinatumomab may well induce sustained remissions and serve as an effective bridge to HSCT. Whether immunotherapy combined with chemotherapy can outweigh the need for subsequent allo-HSCT, if incorporated into frontline high-risk ALL therapy, remains an optimistic issue to be verified in future randomized clinical trials.

ETV6/RUNX1-positive childhood acute lymphoblastic leukemia (ALL): The spectrum of clonal heterogeneity and its impact on prognosis.

The prognostic significance of the ETV6/RUNX1-fusion and of the accompanying aberrations is disputable; whether co-existing sub-clones are responsible for delayed MRD-clearance and thus, moderate outcome, remains to be clarified. We studied, in a paediatric cohort of 119 B-ALLs, the relation between the ETV6/RUNX1 aberration and the co-existing subclones with (a) presenting clinical/biological features, (b) early response to treatment(MRD) and (c) long-term outcome over a 12-year period. Patients were homogeneously treated according to BFM-based-protocols. 27/119 patients (22.7%) were ETV6/RUNX1-positive; 19/27 (70.4%) harbored additional genetic abnormalities while 9/19 (33.3%) presented with clonal heterogeneity. The most common abnormalities were del12p13 (37%), 3-6×21q22 (22.2%), del9p21 (18.5%) and 2-3xETV6/RUNX1 (18.5%). MRDd15-positivity (≥10-3) was detected in 44% of the cohort; the corresponding MRD among patients carrying subclones rises to 88.9%. Common features of all relapses were sub-clonal diversity, FCM-MRDd15-positivity and additional del(9p21) while there were no censored relapses among ETV6/RUNX1-positive patients with sole translocation and absence of additional aberrations, within a median follow-up time of 90 months. In our study, the presence of clonal heterogeneity and impaired FCM-MRD clearance among ETV6/RUNX1-positive patients, ultimately influenced prognosis. Longer follow-up is needed in order to further validate these initial results.

Cognitive and socio-emotional development and manifestation of learning disabilities of 8- to 10-year-old children born after intracytoplasmatic sperm injection compared to naturally conceived children.

OBJECTIVE: The purpose of the present study was to investigate the cognitive and socio-emotional development, as well as the mani- festation of learning disabilities of eight- to ten-year-old children born after intracytoplasmatic sperm injection (ICSI). MATERIALS AND METHODS: Developmental outcomes of 40 children born after ICSI were compared with those of 40 children born after spontaneous conception (SC). Outcome measures included the Raven's Progressive Matrices Test, Child Behavior Checklist (CBCL), and Athina Test of Learning Difficulties. RESULTS: Regarding cognitive development, ICSI children tend to obtain a similar intelligence score with SC children on Raven's Test. No significant differences were noted on CBCL's syndrome and abilities' profiles, and on Athina Test. CONCLUSIONS: ICSI and SC children show a comparable cognitive and socio-emotional development and have the same chances of manifesting learning disabilities. None of the demographic factors taken into consideration (age, sex of the child, and educational level of the parents) nor the mode of conception seem to affect their well-being.

History of Maternal Fetal Loss and Childhood Leukaemia Risk in Subsequent Offspring: Differentials by Miscarriage or Stillbirth History and Disease Subtype.

BACKGROUND: Despite the putative intrauterine origins of childhood (0-14 years) leukaemia, it is complex to assess the impact of perinatal factors on disease onset. Results on the association of maternal history of fetal loss (miscarriage/stillbirth) with specific disease subtypes in the subsequent offspring are in conflict. We sought to investigate whether miscarriage and stillbirth may have different impacts on the risk of acute lymphoblastic leukaemia (ALL) and of its main immunophenotypes (B-cell and T-cell ALL), as contrasted to acute myeloid leukaemia (AML). METHODS: One thousand ninety-nine ALL incidents (957 B-ALL) and 131 AML cases along with 1:1 age and gender-matched controls derived from the Nationwide Registry for Childhood Hematological Malignancies and Brain Tumors (1996-2013) were studied. Multivariable regression models were used to assess the roles of previous miscarriage(s) and stillbirth(s) on ALL (overall, B-, T-ALL) and AML, controlling for potential confounders. RESULTS: Statistically significant exposure and disease subtype-specific associations of previous miscarriage(s) exclusively with AML [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.00, 2.81] and stillbirth(s) with ALL [OR 4.82, 95% CI 1.63, 14.24] and B-ALL particularly, emerged. CONCLUSION: Differential pathophysiological pathways pertaining to genetic polymorphisms or cytogenetic aberrations are likely to create hostile environments leading either to fetal loss or the development of specific leukaemia subtypes in subsequent offspring, notably distinct associations of maternal miscarriage history confined to AML and stillbirth history confined to ALL (specifically B-ALL). If confirmed and further supported by studies revealing underlying mechanisms, these results may shed light on the divergent leukemogenesis processes.

Socioeconomic disparities in survival from childhood leukemia in the United States and globally: a meta-analysis.

BACKGROUND: Despite advancements in the treatment of childhood leukemia, socioeconomic status (SES) may potentially affect disease prognosis. This study aims to evaluate whether SES is associated with survival from childhood leukemia. METHODS: The US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) 1973-2010 data were analyzed; thereafter, results were meta-analyzed along with those from survival (cohort) studies examining the association between SES indices and survival from childhood leukemia (end-of-search date: 31 March 2014). Random-effects models were used to calculate pooled effect estimates (relative risks, RRs); meta-regression was also used. RESULTS: We included 29 studies yielding 28 804 acute lymphoblastic leukemia (ALL), 3208 acute myeloblastic leukemia (AML) and 27 650 'any' leukemia (denoting joint reporting of all subtypes) cases. According to individual-level composite SES indices, children from low SES suffered from nearly twofold higher death rates from ALL (pooled RR: 1.83, 95% confidence interval 1.00-3.34, based on four study arms); likewise, death RRs derived from an array of lower area-level SES indices ranged between 1.17 and 1.33 (based on 11 study arms). Importantly, the survival gap between higher and lower SES seemed wider in the United States, with considerably (by 20%-82%) increased RRs for death from ALL in lower SES. Regarding AML, poorer survival was evident only when area-level SES indices were used. Lastly, remoteness indices were not associated with survival from childhood leukemia. CONCLUSION: Children with lower SES suffering childhood leukemia do not seem to equally enjoy the impressive recent survival gains. Special health policy strategies and increased awareness of health providers might minimize the effects of socioeconomic disparities.

Blood stream infections throught the entire course of acute lymphoblastic leukemia treatment.

The incidence, type and mortality of bacteremias were evaluated in a pediatric patient cohort, during the entire course of treatment for acute lymphoblastic leukemia (ALL). Eighty-six patients with newly diagnosed ALL were studied. A bacteremic episode was defined as blood isolation of a pathogen in the presence of clinical symptomatology of septicaemia. Bacteremias were analyzed according to the treatment element being delivered and the degree of neutropenia. A central venous catheter (CVC) was inserted at diagnosis in all patients. Fifty-two episodes of bacteremias were encountered in 38/86 (44%) patients, while 48/86 patients had no positive blood culture. Three out of the 38 patients had bacteremia and CVC area infection, simultaneously. Most blood stream infections (29/52, 56%) were documented during the induction phase. Isolated Gram-positive organisms were 48%, Gram-negative 50% and 2% of the positive blood cultures represented fungaemias. The most common Gram-positive isolates were Staphylococcus species (N=22) and the commonest Gram-negative isolated pathogens were Escherichia coli and Pseudomonas aeruginosa. The majority of bacteremias (75%) occurred during neutropenia. The initial antibiotic treatment was ceftazidime or piperacillin/tazobactam and amikacin or tobramycin. CVC was not removed in the majority of bacteremias (94%). No infection related fatality was recorded. Bacteremias constituted a severe and common complication in our patient cohort. However, infection-related fatality rate was negligible, most probably due to the prompt initiation of broad coverage antimicrobial therapy.

Maternal smoking during pregnancy and childhood lymphoma: a meta-analysis.

Results from epidemiological studies exploring the association between childhood lymphoma and maternal smoking during pregnancy have been contradictory. This meta-analysis included all published cohort (n = 2) and case-control (n = 10) articles; among the latter, the data of the Greek Nationwide Registry for Childhood Hematological Malignancies study were updated to include all recently available cases (-2008). Odds ratios (ORs), relative risks and hazard ratios were appropriately pooled in three separate analyses concerning non-Hodgkin lymphoma (NHL, n = 1,072 cases), Hodgkin lymphoma (HL, n = 538 cases) and any lymphoma (n = 1,591 cases), according to data availability in the included studies. An additional metaregression analysis was conducted to explore dose-response relationships. A statistically significant association between maternal smoking (any vs. no) during pregnancy and risk for childhood NHL was observed (OR = 1.22, 95% confidence interval, CI: 1.03-1.45, fixed effects model), whereas the risk for childhood HL was not statistically significant (OR = 0.90, 95% CI: 0.66-1.21, fixed effects model). The analysis on any lymphoma did not reach statistical significance (OR = 1.10, 95% CI = 0.96-1.27, fixed effects model), possibly because of the case-mix of NHL to HL. No dose-response association was revealed in the metaregression analysis. In conclusion, this meta-analysis points to a modest increase in the risk for childhood NHL, but not HL, among children born by mothers smoking during pregnancy. Further investigation of dose-response phenomena in the NHL association, however, warrants accumulation of additional data.

Delayed exposure to infections and childhood lymphomas: a case-control study.

OBJECTIVES: Delayed exposure to common infections during childhood, have been implied to cause strong immunological response to a single infectious agent that eventually triggers leukemogenesis. The aim of the present study was to investigate whether decreased exposure to infections, as reflected in a more seronegative spectrum to several common infectious agents, is associated with increased risk for the development of childhood lymphomas. METHODS: All 125 children (up to 14 years old), with Hodgkin (HL, n = 52) and non-Hodgkin lymphomas (NHL, n = 73) diagnosed through the national network of childhood Hematology-Oncology units during an 8-year period were enrolled in the study along with 125 age- and gender-matched controls. Past exposure to nine common infections [respiratory syncytial virus (RSV), influenza A and B, parainfluenza type 1, adenovirus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV6), Bartonella henselae] was assessed using serological markers. RESULTS: After controlling for possible confounding factors, the overall seronegativity status upon diagnosis was statistically significantly associated with NHL [odds ratio; 95% CI: 1.45 (1.10-1.93), p = 0.01] and less so with HL risk [odds ratio; 95% CI: 1.30 (0.83-2.05), p = 0.25]. A statistically significant association of seronegativity with the development of NHL was evident for RSV [odds ratio; 95% CI: 7.27 (1.59-33.28), p = 0.01], EBV [odds ratio; 95% CI: 6.73 (1.45-31.20), p = 0.01] and suggestive association for influenza B [odds ratio; 95% CI: 2.60 (0.90-7.55), p = 0.08] and influenza A [odds ratio; 95% CI: 2.35 (0.81-6.80), p = 0.11]. In contrast, there was no evidence for association of HL with negative serology for any of the infectious agents tested. CONCLUSIONS: The risk of lymphomas, especially NHL, might be higher when, due to lower exposure to several infectious agents, the relatively unmodulated immune system of a child is challenged by environmental stimuli that can trigger development of lymphomas. The results, however, need further confirmation, through more pertinent methodological designs.

Childhood leukaemias and lymphomas in Greece (1996-2006): a nationwide registration study.

BACKGROUND: Monitoring time trends in the incidence of childhood leukaemias and lymphomas requires efficient and continuous data collecting systems. In countries without official cancer registries, such as Greece, ad hoc nationwide registration of incident childhood leukaemias and lymphomas could help elucidate the underlying aetiology and monitor socioeconomic differentials in health care delivery. METHODS: We registered all cases and produced age, gender, type and immunophenotype specific figures and overall crude and age adjusted annual incidence rates and secular trends for 863 leukaemia and 311 lymphoma incident cases diagnosed in children <15 years of age across Greece during 1996-2006, namely the first 11 years of the Nationwide Registry for Childhood Hematological Malignancies. RESULTS: The epidemiological profiles of leukaemias/lymphomas in Greece are similar to those in industrialised countries. No secular trends are observed for either malignancy during the studied period. However, the calculated incidence for leukaemia (46.60 cases per 1 million children annually) is among the highest in the EU-27 (19% higher than average; p<0.001), whereas that for lymphoma (16.8 cases per 1 million children annually) is around the EU-27 average. CONCLUSIONS: Minimal secular changes in childhood leukaemias/lymphomas have been noted recently in the EU-27, which cannot be easily explained in countries with small populations. Therefore, centralised EU databases such as the Automated Childhood Cancer Information System (ACCIS) should be enlarged to generate sufficient statistical power for monitoring time trends. It would be interesting to explore whether different lifestyle patterns across the EU might be responsible for the observed excess leukaemia incidence in countries such as Greece.

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.

p16 inactivation associated with aggressive clinical course and fatal outcome in TEL/AML1-positive acute lymphoblastic leukemia.

The authors describe a 7-year-old boy with TEL/AML1-positive pre-B acute lymphoblastic leukemia, with hemizygous 9p21 deletion at presentation and no p16(INK4A) protein expression. Despite an initial response to a standard chemotherapy regimen, the patient suffered two hematologic relapses and died 34 months after diagnosis. The authors discuss the possibility that complete p16(INK4A) gene inactivation may adversely modify the prognostic significance of TEL/AML1 fusion in childhood acute lymphoblastic leukemia, and present evidence from clinical and in vitro observations in favor of this assumption.

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.

An integrated evaluation of socioeconomic and clinical factors in the survival from childhood acute lymphoblastic leukaemia: a study in Greece.

An evaluation of the role of socioeconomic factors in the survival of children with leukaemia, controlling for major clinical prognostic indicators, has been attempted in very few studies and the role of these factors may be different in various cultural settings. Our investigation aims to study the independent role of socioeconomic factors on the prognosis of childhood acute lymphoblastic leukaemia (ALL) in Greece. During a 7-year period (1996-2002) 293 cases of incident ALL were diagnosed and followed up in four Childhood Haematology-Oncology Units, which covered over half of all childhood ALL cases nationwide. At the time of diagnosis, information concerning age, gender, maternal schooling, maternal marital status, sibship size, distance of residence from the treating centre, attendance of day care centre and clinical information was recorded. The influence of these factors on survival was studied by modelling the data through Cox's proportional-hazards regression. After adjustment for clinical prognostic factors, children of mothers who were not currently married, were of low educational level or were living far from the treating centre tended to have lower survival (P-values 0.02, 0.14 and 0.08, respectively). There was also evidence that two factors that are predictive of disease occurrence, that is sibship size and attendance of day care centre, may also predict survival (P-values 0.04 and 0.26, respectively). In conclusion, socioeconomic factors are likely to influence survival from ALL at least in some sociocultural contexts. Moreover, there is evidence that factors that could affect incidence of ALL through modulation of herd immunity may also have prognostic implications for this disease.

Conventional cytogenetics and fluorescence in situ hybridization in persistent cytopenias and myelodysplastic syndromes in childhood.

Accurate detection of the abnormal clone in children with persistent cytopenia (PC) may confirm the diagnosis of myelodysplastic syndrome (MDS) and determine prognosis and evolution of the disease. Bone marrow (BM) samples were obtained from 65 children, 11 of which were finally diagnosed as primary or secondary MDS. Ten to 20 G-banded metaphases were analyzed and FISH was performed using a-satellite probes for chromosomes 7 and 8. Conventional cytogenetic analysis (CCA) was successful in 40/65 samples, revealing clonal aberrations in 3 patients with MDS. FISH was successful in all cases, detecting monosomy 7 and trisomy 8 abnormal clones in 5 patients. Abnormalities were identified in 3/6 children with primary MDS and 3/5 with secondary MDS. None of the patients with PC of etiology other than MDS had a clonal abnormality in the BM. The results confirm the high incidence of chromosome abnormalities in childhood MDS and the sensitivity of FISH in detecting minor abnormal clones.

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.

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.

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.