Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

Inhibitor development in previously untreated patients with severe haemophilia A: a nationwide multicentre study in Finland.

INTRODUCTION: Currently the most serious treatment complication of haemophilia is the inhibitor development (ID), i.e. neutralizing antibody development. AIM: This nationwide multicentre study in Finland evaluated the incidence and risk factors of ID in previously untreated patients (PUPs) with severe haemophilia A (FVIII:C < 0.01 IU mL(-1) ). METHODS: We enrolled all PUPs (N = 62) born between June 1994 and May 2013 with at least 75 exposure days (EDs) to screen ID during follow-up extending to September 2013. RESULTS: Thirteen ID (21% of 62) occurred; 10 (16% of 62) with high titre. Fifty-one patients (82%) were on primary prophylaxis (regular prophylaxis before the age of 2 and before the first joint bleed) from the median age of 11.4 months, 90% via a central venous access device. The initial product was rFVIII in 63% and pd-FVIII in 37%, moreover in 24% pd-FVIII was switched to rFVIII concentrate during the 75 EDs. Non-transient inhibitors developed in 9/51 (17.6%; 13.7% high titre) children with primary and in 4/11 (36.4%; 27.3% high titre) patients with secondary prophylaxis (P = 0.24). Overall, 74% had a high-risk genotype similarly distributed among the prophylaxis groups. The history of a major bleed enhanced ID (aHR, 4.0; 95% CI, 1.2-13.7), whereas FVIII treatment intensity or source and early implantation of ports did not increase ID risk. CONCLUSION: The cumulative incidence of ID was low notwithstanding prevalent high-risk mutations. Despite patient-related risk factors, our management involving early intensive primary prophylaxis via ports helps to prevent bleeds and lower the incidence of inhibitors.

Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland.

Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long-term access but associates with infectious and non-infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD-related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children.

A retrospective nationwide case study on the use of a new antifungal agent: patients treated with caspofungin during 2001-2004 in Finland.

The aim of this study was to evaluate the efficacy and safety of caspofungin in patients treated in Finland during the period 2001-2004. The medical records of 78 adult patients treated with caspofungin in five major hospitals were reviewed retrospectively. Fifty-nine (76%) patients had proven invasive fungal infection, of whom 22 (28%) had aspergillosis and 37 (47%) had candidiasis. Nineteen (24%) patients were treated empirically; only 13 (17%) patients received caspofungin as primary therapy. A favourable response was achieved in 52 (67%) patients. The response rate was 78% in patients with candidiasis, and 50% in patients with aspergillosis. At the end of the study period, 40 (51%) patients remained alive; of the 38 deaths, nine (24%) were caused by fungal infection. The response rates were lower, although not significantly, for patients with high (>20) vs. low (< or =20) Acute Physiology and Chronic Health Evaluation (APACHE II) scores (response rate 50% vs. 68%, p 0.48, respectively), and were also lower in patients with long-term (>20 days) vs. shorter duration (< or =20 days) neutropenia (55% vs. 73%, p 0.32, respectively), and in those with an underlying haematological malignancy vs. patients with other diseases (59% vs. 73%, p 0.2, respectively). In five (6%) patients, caspofungin therapy was discontinued prematurely because of adverse drug reactions (ADRs) (elevated liver enzyme values in three patients, neuropathic pain in one, and skin rash in one). Serious ADRs occurred in two (3%) patients (severe hepatic insufficiency with consequent death, and eosinophilia with elevated alkaline phosphatase levels), and laboratory abnormalities, mostly mild and reversible, in 24 (31%) patients. In this unselected patient population, caspofungin was safe, well-tolerated, and had an efficacy comparable to that in previous reports from prospective trials.

Surgically treated patients with axial and peripheral Ewing's sarcoma family of tumours: A population based study in Finland during 1990-2009.

BACKGROUND: The surgical treatment of Ewing's sarcoma family tumours (ESFTs) is challenging especially with axial tumours. The aim of the study was to analyse surgical treatment and outcome in a nationwide, population-based material consisting of surgically treated axial and peripheral ESFTs of bone and soft tissue. METHODS: The data were collected from the Finnish National Cancer Registry and the medical records of patients diagnosed during 1990-2009. Fifty-seven patients with surgically treated ESFTs were included, 22 with an axial and 35 with a peripheral primary tumours. The surgical treatment, its complications, survival and prognostic factors were analysed. RESULTS: Fifty-four patients underwent surgery with a curative intent and three underwent de-bulking operations. Bone reconstruction was performed in six patients with an axial and 15 with a peripheral tumour. Positive resection margins were associated with a worse five-year local relapse-free survival (33% vs. 84% for those with resection margins free of tumour cells, p = 0.003). The five-year sarcoma-specific survival was affected only by an axial location of the primary (61% vs. 89% for those with a peripheral tumour, p = 0.031). The late complications were mainly associated with bone reconstruction and more frequent among patients with a peripheral compared to an axial tumour (p = 0.031). CONCLUSIONS: In the treatment of ESFTs, achieving adequate resection margins is crucial to avoid local relapses. Surgical complications are common particularly with bone reconstruction.

Impaired development of bone mineral density during chemotherapy: a prospective analysis of 46 children newly diagnosed with cancer.

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2-L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual-energy X-ray absorptiometry in 46 children (age 2.9-16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy-terminal propeptide (PICP), and type I collagen carboxy-terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6-month follow-up. A significant decrease in lumbar BMDvol (-2.1%, p < 0.05), and in femoral BMDareal (-9.9%, p = 0.0001) and BMDvol (-8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow-up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.

Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.

In the present study, longitudinal changes in bone mineral density, bone turnover, and bone hormonal metabolism were evaluated in newly diagnosed children with cancer. Lumbar spine (L2-L4) and femoral neck bone mineral densities (grams per cm2) were measured by dual energy x-ray absorptiometry in 28 children (age, 2.9-16.0 yr; median, 8.0 yr; 10 acute lymphoblastic leukemias, 18 solid tumors) at diagnosis and after a 1-yr follow-up. Apparent volumetric density (grams per cm3) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxyl-terminal propeptide (PICP), and type I collagen carboxyl-terminal telopeptide were measured serially during the study. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, insulin-like growth factor I (IGF-I), and IGF-binding protein-3 were analyzed at diagnosis and at 1-yr follow-up. A significant decrease in femoral bone mineral density and apparent volumetric density was observed during the year after diagnosis [(mean (SD), -10.1% (8.8%) and -11.3% (8.1%) respectively; P < 0.01], whereas age- and sex-matched controls showed annual increments of +5.4% (7.7%; P < 0.01) and +0.7% (5.7%; P = NS) respectively. The markers of bone formation (PICP and OC) were significantly decreased at diagnosis. By the end of the follow-up, PICP and OC were normalized, whereas the marker of bone resorption (type I collagen carboxyl-terminal telopeptide) was significantly increased. Reduced levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and IGF-binding protein-3 were observed during the study. To conclude, increased bone resorption and impaired development of femoral bone density were observed in children with cancer during chemotherapy. Deficient accumulation of bone mass may lead to impaired development of peak bone mass and predispose children with cancer to increased risk of osteoporosis and diminished skeletal resistance to fractures later in life.

Imipenem compared with ceftazidime plus vancomycin as initial therapy for fever in neutropenic children with cancer.

Two antibiotic regimens were assessed, imipenem as monotherapy and ceftazidime plus vancomycin as combination therapy, for initial empiric therapy in febrile neutropenic children with cancer. In a prospective randomized trial of 89 evaluable consecutive episodes, 45 were treated with imipenem and 44 with ceftazidime-vancomycin. In 87% of the episodes the neutropenia was severe. Of the 89 episodes 20% were bacteremias, 10% were clinically defined focal infections and 70% were considered fevers of unknown origin. The initial treatment was successful in 82% of the imipenem group and 59% of the ceftazidime plus vancomycin group. Both regimens were well-tolerated. There was no mortality, probably owing to the prompt admission and institution of antimicrobial therapy. All of the patients were treated until neutrophil recovery; no recurrent infections were seen. In conclusion imipenem monotherapy was well-tolerated and effective as initial therapy for fever in neutropenia in children.

Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children.

In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P < 0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia.

High-dose thiotepa with autologous bone marrow rescue in pediatric solid tumors.

High-dose thiotepa was given as a single agent at a total dose of 1125 mg/m2 with autologous bone marrow rescue to nine patients with recurrent/refractory/poor risk pediatric malignancies (primitive neuroepithelial tumor (PNET), two; neuroblastoma, one; Wilms' tumor, one; osteosarcoma, one; Ewing's sarcoma one, Hodgkin's disease one, high-grade glioma, two). The response rate in these heavily pretreated patients was 71% (five out of seven evaluable patients) including two complete responses (Wilms', glioma), three partial responses (osteosarcoma, Ewing's sarcoma, Hodgkin's disease), and two with stable disease (PNET, glioma). The median duration of response was 2.5 months. The extramedullary toxicity was acceptable with symptoms mainly of skin and gastrointestinal tract. The data indicate that high-dose thiotepa is effective in several types of recurrent pediatric solid tumors, and merits further evaluation in combination regimens.

Amino-terminal sequence analysis of four plasmid-encoded virulence-associated proteins of Salmonella typhimurium.

We have expressed four virulence-associated proteins encoded by the Salmonella typhimurium plasmid pEX102 in Escherichia coli. The genes coding for the proteins MkaA, MkaB, MkaC and MkaD subcloned in the vectors pUC19 or Bluescript KS+ directed substantial production of these proteins in E. coli. The same host harbouring pEX102 did not produce these proteins in detectable amounts. The proteins were exclusively found in the particulate fraction. The amino-terminal sequence analysis showed that the N-termini of these proteins corresponded to the ones predicted from the open reading frames found previously in the DNA sequence of the virulence determinant and that no N-terminal signal sequence processing of the proteins occurred.

Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants.

OBJECTIVE: To study prospectively the effects of prematurity and perinatal events on the coagulation status of premature infants. PATIENTS AND MAIN OUTCOME MEASURES: Blood samples from premature infants born before 37 gestational weeks were taken for analysis of coagulation factors II, V, VII, and X and platelet count. RESULTS: A total of 125 premature infants, 71 boys, were studied at the median postnatal age of 40 minutes (range 12-100). The lowest median activities of coagulation factors II, V, VII, and X and the platelet count were observed, as expected, in infants (n = 21) born at 24-27 weeks gestation. Twin B (n = 14) had lower median activities of coagulation factors II, V, VII, and X than twin A. Infants with evidence of mild asphyxia (Apgar score at 5 minutes < 7 or cord pH < 7.26) had significantly (p < 0.05) lower levels of coagulation factors II, V, VII, and X and platelet counts than infants without asphyxia. Infants who were small for gestational age (SGA) had significantly (p < 0.05) lower levels of coagulation factors V and VII and platelet counts than infants of appropriate size for gestational age. Other prenatal and perinatal variables examined (sex, maternal hypertension and/or pre-eclampsia, antenatal steroid use, mode of delivery, Apgar scores) did not show any significant associations with coagulation status, which may be explained by the small number of infants studied. CONCLUSIONS: The data strongly suggest that there are distinct differences in specific coagulation tests in different patient populations, which could assist in the identification of extremely preterm, SGA, or asphyxiated preterm infants who may be susceptible to haemorrhagic problems perinatally.

Insulin-like growth factor-I in cerebrospinal fluid and serum in Rett syndrome.

Rett syndrome is a neurodevelopmental disease characterized by failure of somatic and brain growth. The insulin-like growth factor system mediates most actions of growth hormone. Evidence that it plays an important role in early development of the brain is increasing. The aim of the study reported was to assess the role of the insulin-like growth factor system in the pathogenesis of Rett syndrome. We measured insulin-like growth factor-I levels in serum (8 patients, mean age 9.1 years) and cerebrospinal fluid (13 patients, mean age 7 years) using a sensitive radioimmunoassay method and compared them with those in age-matched controls (13 and 26 patients, respectively). Neither serum nor cerebrospinal fluid insulin-like growth factor-I levels differed from those in controls. We also measured insulin-like growth factor binding protein-3 levels in serum (in 9 patients and 8 controls) and in cerebrospinal fluid (in 12 patients and 11 controls) and serum growth hormone levels (in 8 patients and 11 controls); the levels in patients did not differ from those in controls. We found no significant correlation between serum and cerebrospinal fluid insulin-like growth factor-I in Rett syndrome. This may indicate an independent role of insulin-like growth factor system in the central nervous system, making serum insulin-like growth factor-I measurement unreliable as an indicator of disturbed function in the central nervous system. Our results did not support the notion that a defective insulin-like growth factor-I system explains the lack of somatic and brain growth in Rett syndrome.

Recombinant human granulocyte-macrophage colony-stimulating factor in combination with antibiotics in the treatment of febrile neutropenia in children.

Fever and neutropenia are life-threatening complications of chemotherapy in children with cancer. Prompt initiation of empiric broad-coverage antimicrobial therapy at the first signs of fever has reduced the mortality rates to about 2-5%. However, myelosuppression with febrile neutropenia is the major dose-limiting side effect of anticancer chemotherapy, results in prolonged hospitalization, and frequently delays the scheduled cycles of chemotherapy. Prophylactic use of hematopoietic growth factors has been shown to reduce the incidence of fever and infectious complications in children with cancer and neutropenia. Therapeutic use of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in combination with antibiotics in children with febrile neutropenia has also shown a clear beneficial effect. The number of hospital days due to treatment of febrile neutropenia, the number of days on broad-spectrum antibiotics and the duration of neutropenia were significantly reduced with the use of rHuGM-CSF. Importantly, rHuGM-CSF did not prolong the days with fever in children admitted with febrile neutropenia. In the treatment of documented fungal superinfection, it may be beneficial if rHuGM-CSF and an antifungal drug are used as combination therapy. rHuGM-CSF is non-toxic and well tolerated in children with cancer.

MUTbase: maintenance and analysis of distributed mutation databases.

MOTIVATION: To develop tools for the submission of mutations to databases and maintenance of locus-specific mutation databases. Advanced, integrated computer systems are needed to store and organize the increasing mutation information. RESULTS: The MUTbase program suite provides an easy, interactive and quality-controlled submission of information to mutation databases. For further study of the databases on the World Wide Web, a number of tools are provided. The program package also writes and updates a large number of Web pages, e.g. about the distribution and statistics of disease-causing mutations, and changes in restriction patterns.