Mervi Taskinen

Risk group assignment differs for children and adults 1–45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL‐2008 protocol

The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.

Testicular tumors in children and adolescents

OBJECTIVE To analyze the spectrum of testicular tumors in children in an unselected population-based series, as well as the results of testis-preserving surgery. PATIENTS AND METHODS Our hospital database was analyzed for operations for testicular tumors from 1981 to 2006. The clinical data and findings during follow up (4.7 years) were recorded. RESULTS Thirty-four patients were operated on because of testicular tumors. In 23 (68%) the tumor was benign: benign teratoma (16), Leydig-cell tumor (2), epidermoid cyst (2), Sertoli-cell tumor (1), cystic dysplasia (1), intratesticular focal fibrosis (1). Eleven patients (32%) had a malignant tumor: yolk-sac tumor (6), embryonal carcinoma (5). Twenty out of the 26 (77%) prepubertal boys had a benign tumor in contrast to only three of the eight (38%) adolescent males (P=0.079). Testis-preserving surgery was performed in 10 patients. In eight, the tumor was curatively excised and remaining testis preserved. Two patients with benign teratoma had a recurrence due to incomplete primary resection. In one patient who underwent orchiectomy for benign teratoma, two metachronous teratomas were detected in the contralateral testis 6 years after primary surgery. CONCLUSIONS In children, most testicular tumors are benign, especially before puberty. If testis-preserving surgery is contemplated, complete excision of the tumor should be ascertained. The possibility of metachronous bilateral tumors should be considered in the follow up of testicular teratomas.

Extended follow‐up of the Finnish cartilage‐hair hypoplasia cohort confirms high incidence of non‐Hodgkin lymphoma and basal cell carcinoma

Cartilage‐hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia with short stature, sparse hair and defective cell‐mediated immunity. It is caused by mutations in the RMRP (ribonuclease mitochondrial RNA processing) gene, encoding the RNA component of the ribonuclease complex RNase MRP. The aim of this study was to further elucidate the risk and spectrum of cancer in CHH. A cohort of 123 Finnish patients with CHH (51 males) was followed for malignancy through the Finnish Cancer Registry. The number of identified cancers was compared with expected numbers of cancer using population‐based data to obtain standardized incidence ratios (SIR). Hospital records were reviewed for clinical data related to the malignancies. During the follow‐up (2,365 person‐years; mean 19.2 years), 14 cases of cancer were diagnosed in the CHH cohort (expected number 2.0; SIR 7.0, CI 3.8–12). Non‐Hodgkin lymphoma was the most frequent cancer type (n = 9; SIR 90.2, CI 39.0–180) followed by squamous cell carcinoma (3), leukemia (1) and Hodgkin lymphoma (1). One tumor was not histologically classified. Nine of the 14 cancers were diagnosed in patients less than 45 years of age. In addition, ten patients had basal cell carcinoma of the skin (expected number 0.3; SIR 33.2, CI 16–61). Patients with CHH have significantly increased risk for developing non‐Hodgkin lymphoma or basal cell carcinoma at early age; the overall prognosis is poor. The underlying pathogenetic mechanisms remain to be elucidated in future studies. Careful follow‐up, extending beyond pediatric age, is warranted for early diagnosis of malignancies.

Insufficient growth hormone secretion is associated with metabolic syndrome after allogeneic stem cell transplantation in childhood.

The aim was to evaluate whether the metabolic syndrome associates with other endocrinopathies observed after allogeneic stem cell transplantation (SCT) in childhood. Thirty-one SCT long-term survivors, transplanted for leukemia (n=26) or nonmalignant hematologic diseases (n=5) were evaluated by oral glucose tolerance test and assessment of serum lipids at a median age of 15 (range 7 to 34) years. Hyperinsulinemia, hypertriglyceridemia, and abdominal obesity were required for the diagnosis of metabolic syndrome. Growth hormone (GH) secretion was evaluated either with GH releasing hormone and arginine (n=14), clonidine (n=15), or insulin-tolerance (n=2) test. A GH peak level of <20 mU/L was considered insufficient. The thyroid and gonadal functions were assessed. Twelve patients (39%) had metabolic syndrome. Nine out of 12 (75%) patients with metabolic syndrome had insufficient GH response in provocative testing as opposed to 6/19 (31%) of those without it (P=0.02). No difference was observed in thyroid or gonadal function between patients with versus without metabolic syndrome. In conclusion, metabolic syndrome is frequently associated with insufficient GH secretion in the SCT long-term survivors. This should implicate a close follow-up of the metabolic parameters in SCT patients with either frank GH insufficiency or signs of inadequate GH response in provocative testing.

Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol.

L‐asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re‐exposure to L‐asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase‐intensive protocol has been poorly reported. Children (1–17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase‐associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L‐asparginase (PEG‐asparaginase) 1000 iu/m2/dose at 2–6 weeks intervals, with a total of 30 weeks of exposure to PEG‐asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1–13), and 11 d (median) from the latest administration of PEG‐Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re‐exposed to L‐asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re‐exposure to PEG‐asparaginase in ALL patients with mild AAP seems safe.

Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy

PURPOSE We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. RESULTS Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). CONCLUSION CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols.

Infant milk feeding influences adult bone health: A prospective study from birth to 32 years

Background Peak bone mass, attained by early adulthood, is influenced by genetic and life-style factors. Early infant feeding and duration of breastfeeding in particular, associate with several health-related parameters in childhood. The aim of this study was to examine whether the effects of early infant feeding extend to peak bone mass and other bone health characteristics at adult age. Methods and Findings A cohort of 158 adults (76 males) born in Helsinki, Finland, 1975, prospectively followed up from birth, underwent physical examination and bone densitometry to study bone area, bone mineral content (BMC), and bone mineral density (BMD) at 32 years of age. Life-style factors relevant for bone health were recorded. For data analysis the cohort was divided into three equal-size groups according to the total duration of breastfeeding (BF): Short (≤3 months), Intermediate and Prolonged (≥7 months) BF groups. In males short BF is associated with higher bone area, BMC, and BMD compared to longer BF. Males in the Short BF group had on average 4.7% higher whole body BMD than males in the Prolonged BF group. In multivariate analysis, after controlling for multiple confounding factors, the influence of BF duration on adult bone characteristics persisted in males. Differences between the three feeding groups were observed in lumbar spine bone area and BMC, and whole body BMD (MANCOVA; p = 0.025, p = 0.013, and p = 0.048, respectively), favoring the Short BF group. In women no differences were observed. Conclusions In men, early infant milk feeding may have a significant impact on adult bone health. A potential explanation is that the calcium and phosphate contents were strikingly higher in formula milk and commercial cow milk/cow milk dilutions as opposed to human milk. Our novel finding merits further studies to determine means to ensure optimal bone mass development in infants with prolonged breastfeeding.

Testicular torsion: Orchiectomy or orchiopexy?

OBJECTIVE To evaluate the impact on testicular function of the surgical approach used to treat testicular torsion. PATIENTS AND METHODS Seventeen males operated on for testicular torsion at a median age of 14 years were investigated. Serum follicle-stimulating hormone (FSH), testosterone and inhibin B as well as testicular volume were measured early (median 36 days) and/or late (median 1.1 years) after operation. RESULTS Orchiectomy was performed in six, and testicular detorsion and orchiopexy in 11 patients. The duration of the preoperative symptoms in the detorsion group was 15 h (range 6-168) and in the orchiectomy group 42 h (range 24-96) (P=0.03). Preoperative colour Doppler ultrasonography showed some circulation in 40% of the patients. At 1 month the median serum inhibin B level was significantly higher after preserving surgery (P=0.01). At 1 year postoperatively, the median serum FSH level tended to be lower after testicular preservation (P=0.09). Abnormal inhibin B or FSH values were observed in 35% of the patients. CONCLUSIONS Testicular function is often compromised in patients with testicular torsion. Testis-preserving surgery yields better testicular function than orchiectomy in the short term if the testis is not obviously necrotic. Testicular torsion does not necessarily cause the circulation to cease completely, and preserving surgery can also sometimes be attempted after delayed diagnosis.

Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly.

The oculoauriculovertebral anomaly (OAV) or Goldenhar syndrome is a malformation complex that has been described in several chromosomal rearrangements. Among them a deletion of the terminal 5p has recurred in seven previous patients. We wish to report on an additional such patient in order to reinforce the significance of this genomic region in the cause of at least a subgroup of OAV cases. Future studies, particularly in the OAV patients with a lateral facial cleft, might define one genetic background of the disorder. Our patient had a complex translocation chromosome 45,XX, inv(2) (q32q37)mat, dic(5;21) (p15.3;q22.3)dn, resulting in a terminal 5p deletion, a terminal deletion of 21q demonstrated by FISH studies, and a duplication of 21q22.11–q22.12 documented by molecular karyotyping. In addition to OAV she developed myelodysplasia treated with bone marrow transplantation. We discuss her clinical findings with reference to her karyotype findings and review the patients with OAV and a terminal deletion of 5p.

Incidence, epidemiology and treatment results of osteosarcoma in Finland - a nationwide population-based study

Abstract Background. Patients diagnosed with osteosarcoma in Finland during 1991–2005 were retrospectively analyzed in a nationwide, population-based study. We focused on the incidence, treatment and outcome of osteosarcoma patients. We also evaluated the value of known prognostic parameters. Material and methods. Osteosarcomas were retrieved from the files of the national Finnish Cancer Registry. Only patients with histologically confirmed osteosarcoma were included in the analysis. Histological review was performed. Results. The study consists of 144 osteosarcoma patients with a mean follow-up of 9.8 years for survivors. Mean annual incidence of histologically confirmed osteosarcoma was 1.8 new osteosarcomas per million. The 10-year sarcoma-specific survival for the whole population was 63% and 73% for patients with local disease at presentation. Overall limb-salvage rate was 73% and local control was 84% for patients with a peripheral tumor. Development of local recurrence and major deviation from the chemotherapy protocol were significant adverse factors for sarcoma-specific survival in multivariate analysis. Conclusion. The present nationwide and population-based study is our second report of treatment and prognosis of osteosarcoma in Finland. With modern chemotherapy the prognosis of local osteosarcoma has improved in Finland from 47% during 1971–1980 and 65% during 1981–1990 at five years to the present 73% during 1991–2005 at 10 years. The 10-year sarcoma-specific survival of 73% is excellent and comparable to results reported with contemporary treatment protocols in high-volume centers. However, improvement in limb-salvage rate and local control probably requires centralization of treatment of this rare disease.