Merja Kallio

Factors Affecting Operative and Excess Long-term Mortality in 935 Patients with Intracranial Meningioma

Between 1953 and 1980, a total of 935 patients underwent surgery for intracranial meningioma in the Department of Neurosurgery of the Helsinki University Hospital. The patients were followed up until death or the end of the year 1987. The cumulative observed survival rate was 91% at 3 months, 89% at 1 year, and 63% at 15 years. The relative survival rate, that is, the ratio of the the observed and the expected rates, was 91% at 3 months, 89% at 1 year, and 78% at 15 years. Significant risk factors for operative mortality (7%) for the 652 patients operated on from 1966 to 1980 were poor preoperative clinical condition, absence of epilepsy, old age, incomplete tumor removal, pulmonary embolism, and an intracranial hematoma requiring evacuation. For those 828 patients who survived the first postoperative year, the factors predicting an excess risk of death for up to 15 years were incomplete tumor removal, poor pre- and postoperative clinical condition, anaplasia of the tumor, and hyperostosis. Patients whose tumors were not completely removed had a 4.2-fold relative excess risk of death as compared with patients whose tumors were completely removed, and patients who had malignant tumors had a 4.6-fold risk as compared with those who had benign tumors.

Boron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boronophenylalanine

SummaryTwo clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25–29 Gy (W), and the average whole brain dose 2–3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photo radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

Long-term survival of 1986 patients with intracranial meningioma diagnosed from 1953 to 1984 in Finland. Comparison of the observed and expected survival rates in a population-based series

Intracranial meningioma was diagnosed and histologically verified in 1986 patients, 597 men and 1389 women, between 1953 and 1984 in Finland. The closing date of this survival study was December 31, 1987, and the follow‐up was complete. Meningiomas, usually slowly growing and surgically curable benign tumors, caused considerable short‐term mortality, with a relative survival rate (RSR) of 83% at 1 year, and slight but continual long‐term mortality, with RSR of 71% at 15 years. From 1979 to 1984, when computed tomography (CT) was available, the mortality at 3 months for the patients who had surgical procedures was 2% in those younger than 45 years and 10% in those older than 64 years; patients who did not have operations had 1‐year mortality of 61%. The short‐term and long‐term excess mortalities are associated significantly with old age, no surgical procedure, and the period of diagnosis; the long‐term excess mortality also is associated with male gender.

A population‐based study on the incidence and survival rates of 3857 glioma patients diagnosed from 1953 to 1984

Intracranial glioma was diagnosed during the patients life and histologically verified in 3857 patients between 1953 and 1984 in Finland. Their survival up to the end of 1987 was analyzed, the follow‐up being complete. The treatment was by operation in 1193 cases, radiation in 459 cases, both operation and radiation in 1486 cases, and neither operation nor radiation in 719 cases. The 1‐year, 5‐year, 10‐year, and 15‐year cumulative relative survival rates were 0.53, 0.29, 0.20, and 0.18, respectively. The newborn to 14‐year‐olds lost 56% of their life expectancy; the 15‐year‐olds to 44‐year‐olds, 71%; the 45‐year‐olds to 64‐year‐olds, 88%; and the 65‐year‐olds to 99‐year‐olds, 91%. According to the model with the best fit in regression analysis the prognosis was significantly better among young, recently diagnosed patients who had undergone both operation and radiation.

Non-linear model for the kinetics of 10B in blood after BPA?fructose complex infusion

A numerical model with a memory effect was created to describe the kinetics of 10B in blood after a single 4-dihydroxyborylphenylalanine-fructose complex (BPA-F) infusion in boron neutron capture therapy (BNCT). The model formulation was based on the averaged data from 10 glioma patients from the Brookhaven National Laboratory (BNL) BNCT-trials. These patients received a 2 h i.v. infusion of a BPA-fructose complex that delivered 290 mg BPA/kg body weight. The model was validated by fitting the original BNL patient data and new patient data from the Finnish BNCT-trials. The new 3-parameter non-linear model provided mean absolute differences between the measured and estimated 10B concentrations in blood that were less than 3.9% when used to simulate actual patient irradiations that comprised two irradiation fields separated by a break to reposition the patient. The flexibility of the model was successfully tested with two different infusion protocols. The patient data were modelled with a two-compartment model and a bi-exponential fit for comparison. The 3-parameter model is better than previously described models in predicting the time course of blood 10B concentration after cessation of intravenous infusion of BPA-fructose.

Long-term results of the Ross procedure in a population-based follow-up

OBJECTIVES The purpose of this study was to evaluate the long-term outcomes of the Ross procedure in a nationwide follow-up. METHODS This retrospective study involved all children treated with the Ross procedure in Finland between 1994 and 2009. The clinical records were reviewed for demographic and anatomical characteristics, Ross operation data, surgical history and status at the latest follow-up. The median follow-up time was 11.5 (range 2.4-19.2) years. RESULTS Fifty-one patients underwent either the Ross (n = 37) or the Ross-Konno (n = 14) procedure at a median age of 4.8 (range 0.02-16.3) years, including 13 infants (<1 year of age). The indication for the Ross procedure was aortic valve stenosis, regurgitation or both, which was observed in 29, 24 and 47% of patients, respectively. The early mortality (before hospital discharge) rate was 10% (31% in infants) and the late mortality rate 6% (15% in infants). Higher mortality was discovered in patients treated with the Ross-Konno procedure (P = 0.001). The most common cause for reintervention was pulmonary homograft stenosis. The rate of freedom from right ventricular outflow tract reintervention was 98% at 5 years, 83% at 10 years and 59% at 15 years. The rate of freedom from autograft reintervention was 98% at 5 and 10 years, and 81% at 15 years. At the latest follow-up visit, mild-to-moderate aortic root dilatation was reported in 52% of patients, and 4 patients had undergone autograft-related reinterventions. Trivial autograft valve regurgitation was commonly seen, but only 1 patient developed severe autograft regurgitation requiring mechanical valve replacement 15.9 years after the Ross operation. CONCLUSIONS The most common reason for reintervention after the Ross procedure in children is homograft stenosis. Aortic root dilatation and autograft valve regurgitation are relatively common but rarely lead to reinterventions before adulthood. Intraoperative complications and complex cardiac anatomy are associated with high mortality in infants undergoing the Ross-Konno procedure. In our centre, the Ross procedure has provided good long-term results in this challenging group of paediatric patients.

Analysis of 10B by PIGE with factor analytical γ-ray peak identification

Abstract Studying the biodistribution of boronated compounds for B neutron capture therapy (BNCT) requires the accurate detection of low levels of boron (10B) in biological samples. Proton induced γ-ray emission analysis (PIGE) of 10B was found to be viable in a study of low density lipoprotein (LDL), in tissue and blood samples. However, the method is sensitive to Na present in the samples and can therefore not be used for accurate measurements of 10B concentrations below 5 ppm in samples containing Na. PIGE can be considered to be an appropriate reference method for chemical B analysis. The factor analytical method presented here is the most objective way to separate Na and B peaks from each other, and the factorizing method can be applied in different forms of spectral analysis.

Inborn Errors in Metabolism and 4-Boronophenylalanine–Fructose-Based Boron Neutron Capture Therapy

Abstract Laakso, J., Ruokonen, I., Lapatto, R. and Kallio, M. Inborn Errors in Metabolism and 4-Boronophenylalanine–Fructose-Based Boron Neutron Capture Therapy. Radiat. Res. 160, 606–609 (2003) Infusions of boronophenylalanine–fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

111In- and 99mTc-Labeled Low Density Lipoprotein Uptake by High-Grade Gliomas

The prerequisite for the boron neutron capture therapy (BNCT) of brain tumors is the specific and high accumulation of boron into the tumor. One of the suggested possible carriers of boron into the tumor is low density lipoprotein (LDL). The rationale for using LDL is that all growing tissues need cholesterol, likewise brain tumors, and LDL is the main carrier of cholesterol in the body.

At the Threshold of Clinical Trials

The aim of the Finnish BNCT-project is to start BNC-treatments of malignant brain tumors. The first clinical trial is planned to start in early 1999 at the treatment facility of the 250kW FiR 1 TRIGA research reactor. Excellent patient treatment facilities have been built at the reactor which is located only 5 km from the Helsinki University Central Hospital making the treatment facility very easy to reach.