Genotype and risk of tumour rupture in gastrointestinal stromal tumour.

BACKGROUND: Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype was associated with risk of rupture. METHODS: Rupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing. RESULTS: Two hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion-deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not. CONCLUSION: Gastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high-risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Effect of vitamin D supplementation and ultraviolet B exposure on serum 25-hydroxyvitamin D concentrations in healthy volunteers: a randomized, crossover clinical trial.

BACKGROUND: Solar ultraviolet (UV) radiation during the summer and vitamin D supplementation are two major sources of vitamin D for humans at northern latitudes. However, little is known about the relative efficiency of these two vitamin D sources. OBJECTIVES: The main goal was to compare the efficiency of high-dose oral vitamin D3 supplementation (2000 IU per day for 30 days) with a simulated summer UV exposure [10 sunbed sessions to a total dose of 23·8 standard erythema doses (SED)] to improve vitamin D status. METHODS: Healthy volunteers were randomized into two groups: group 1 received vitamin D supplementation followed by 10 whole-body sunbed exposures; group 2 started with 10 sunbed exposures followed by vitamin D supplementation. RESULTS: The oral supplementation with vitamin D3 resulted in a mean (SEM) serum 25-hydroxyvitamin D [25(OH)D] increase of 25·3 (5·4) nmol L(-1) . A similar increase, 19·8 (5·4) nmol L(-1) , was observed after simulated summer UV exposure. At the end of the study, serum 25(OH)D concentrations were similar in both groups. CONCLUSIONS: Twice-weekly whole-body sunbed exposure to a dose of 4·8 SED is equal to 2000 IU daily of oral vitamin D supplementation for 30 days and enough to achieve and maintain serum 25(OH)D concentrations > 75 nmol L(-1) in ~55% of cases. Based on our calculations, this dose corresponds to a cumulative weekly whole-body exposure of 3·4 SED (~ 40 min around midday during the summer at the latitude of Oslo).

Two cases with fatal outcome following total lung irradiation for metastatic bone sarcoma.

We report a single institution experience with total lung irradiation in 53 metastatic bone sarcoma patients in the context of two young female patients who died from treatment-induced pulmonary toxicity. A radiation dose of 19.5 Gy in 1.5 Gy daily fractions was given as two opposing fields with a conventional technique. Both patients succumbed within 3 months following radiotherapy. One patient had osteosarcoma whereas the other advanced Ewing's sarcoma; both with widespread metastases to the lungs at primary diagnosis. In retrospect, most likely high dose methotrexate lung toxicity observed in the osteosarcoma patient, and the GI-toxicity following pelvic radiotherapy in Ewing's case, both observed during the initial phase of their multimodal treatment, might indicate an increased individual radiosensitivity. In view of this, a review of our experience in 53 bone sarcoma patients (19 with Ewing's sarcoma and 34 with osteosarcoma) treated at our institution was conducted. We have not previously experienced significant toxicity following total lung irradiation. Among these, 42% (8/19) with Ewing's sarcoma and 9% (3/34) with osteosarcoma are long-term survivors and without clinically significant lung toxicity.

A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer.

PURPOSE: To investigate the dose-response relationship and pain-relieving effect of radium-223, a highly bone-targeted alpha-pharmaceutical. METHODS: One hundred patients with castration-resistant prostate cancer (CRPC) and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 k Bq/kg radium-223. The primary end-point was pain index (visual analogue scale [VAS] and analgesic use), also used to classify patients as responders or non-responders. RESULTS: A significant dose response for pain index was seen at week 2 (P = .035). At week 8 there were 40%, 63%, 56% and 71% pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 k Bq/kg groups, respectively. On the daily VAS, at week 8, pain decreased by a mean of -30, -31, -27 and -28 mm, respectively (P = .008, P = .0005, P = .002, and P < . 0001) in these responders (post-hoc analysis). There was also a significant improvement in the brief pain inventory functional index for all dose-groups (P = .04, .01, .002 and .02, Wilcoxon signed rank test). Furthermore, a decrease in bone alkaline phosphatase in the highest dose-group was demonstrated (P = .0067). All doses were safe and well tolerated. CONCLUSION: Pain response was seen in up to 71% of the patients with a dose response observed 2 weeks after administration. The highly tolerable side-effect profile of radium-223 previously reported was confirmed.

Definitive radiotherapy with adjuvant long-term antiandrogen treatment for locally advanced prostate cancer: health-related quality of life and hormonal changes.

We assessed self-reported health-related quality of life (HRQoL) and longitudinal changes in sex hormones among 86 prostate cancer (PCa) patients without distant metastases 5 years after radiotherapy (RT) combined with ongoing antiandrogen (AA) treatment. HRQoL outcomes were compared with scores from age-matched controls without a cancer diagnosis (NORM). Compared with NORM, patients scored statistically (P<0.05) and clinically (effect size >or=0.4) lower on sexual domains, and statistically (P<0.05) lower on physical function and vitality. Estimated free testosterone and measured serum estradiol had increased from baseline in most patients, but did not correlate with HRQoL outcomes 5 years after the start of treatment.

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts.

Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

Comparative analyses of the dynamic properties of the bladder wall studied by repetitive pelvic CT scans of patients and cryo-sections of cadavers.

In radiotherapy planning systems, delineation of hollow normal tissue organs, such as the bladder, is time-consuming. Automated delineation may presuppose two assumptions: (1) the bladder resembles a spherical shell and (2) the volume of bladder tissue is preserved regardless of the volume of urine (luminal volume) inside. The purpose of the present study was to test these assumptions. 22 CT scans from 7 patients were studied retrospectively. Transverse cross-sectional areas enclosed by the outer contour (A(out)) and inner contour of the bladder (A(in)) were recorded from the images. Hence, the transverse cross-sectional area of the wall, A(wall)=A(out)-A(in), and the volume of bladder tissue at various luminal volumes, could be calculated. To quantify the method uncertainty, the same procedure was applied on three spherical plastic phantoms. The results were also compared with data from the Visible Human Project's photographs of cadaver cryo-sections. Assumption no. 1 stated above, implies that A(wall) is constant regardless of the level of intersection of the sphere. The data from cryo-sections revealed a positive correlation for A(wall) and A(out), in contradiction to assumption no. 1 (p<0.001). The corresponding association derived from the repetitive CT scans of patients was also statistically significant (p<0.001) although linear regression revealed a less steep slope. A relationship was found between the volume of bladder tissue and luminal volume, hence contradicting assumption no. 2 (p<0.001). In conclusion the cross-sectional wall areas of the bladder, measured from patient CT scans, increase slightly with luminal cross-sectional areas in contradiction to expected values derived from a simplistic spherical shell model. In addition, the volume of bladder tissue is related to the luminal volume. Our results may be of practical value when developing automated delineation tools in radiotherapy planning systems.

Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.

Comparative analyses of the dynamic properties of the rectum studied by cryo-sections of human cadavers and pelvic CT scans of patients.

Optimization of radiotherapy treatment plans based on dose-volume histograms relies on accurate organ delineation. Hollow organs, such as the rectum, are difficult and time-consuming to delineate owing to unclear visualization of the border between wall tissue and filling. Automated hollow organ delineation would be a valuable tool, but its development depends upon improved understanding of the dynamics of the rectum in response to filling. Two reasonable assumptions proposed in the literature are that (1) the rectal wall tissue along a constant length of the rectal cylinder is preserved over time and (2) the rectal wall tissue is distributed homogeneously along the cylinder. Therefore, variations in wall thickness can be explained by variable rectal filling. To investigate these assumptions, transversal cross-sectional areas enclosed by the outer contour (A(out)) and inner contour (A(in)) of the rectum were recorded from digital photographs of cadaver cryo-sections from the U.S. National Library of Medicine's Visible Human Project. In addition, A(out) and A(in) were recorded from 19 CT scans of 5 of our own patients. The transversal cross-sectional area of the wall of the rectum, A(wall)=A(out)-A(in), was calculated. The data derived both from cryo-sections and repetitive CT scans of patients, revealed that there was a significant correlation between A(wall) and A(out), in contradiction to assumption (1) stated above (male cryo-sections: p<0.001, female cryo-sections: p=0.03, repetitive CT scans p<0.001). Moreover, the mean A(wall) calculated from one CT scan differed significantly from the mean A(wall) from other CT scans and was correlated with the mean A(out), i.e. rectal filling (p<0.001). This finding was confirmed by careful analysis of another study (p=0.001) and opposes assumption (2). Hence, the amount of wall tissue within a constant length of rectum is not preserved over time, but increases with increased filling. This implies that the longitudinal length of the rectum decreases in response to distension of the organ.

Radiation doses to non-Hodgkin's lymphoma cells and normal bone marrow exposed in vitro. Comparison of an alpha-emitting radioimmunoconjugate and external gamma-irradiation.

PURPOSES: The alpha-emitting radionuclide 211At conjugated to the CD20 targeting chimeric monoclonal antibody rituximab was studied to: (a) Estimate radiation dose components to lymphoma and bone marrow (BM) cells exposed in vitro. (b) Calculate the mean absorbed radiation doses in various normal tissues of mice following intravenous injection. MATERIALS AND METHODS: B-lymphoma cells (RAEL) and normal human BM cells were incubated with increasing concentrations of the radioimmunoconjugate. Based on binding kinetics and on measured cellular and nuclear diameters, the radiation doses were calculated using microdosimetric methods. RESULTS: Targeting of 211At-rituximab to RAEL cells was extensive and stable compared with the binding to BM cells. The absorbed radiation doses from cell-bound activity at an initial activity concentration of 10 kBq ml(-1) were 0.645 and 0.021 Gy to RAEL and BM cells, respectively. In comparison, the contribution from unbound conjugate in the medium during 1h exposure was 0.042 and 0.043 Gy. The D(0) value for RAEL cells was 0.55 Gy, but only 0.34 Gy for BM cells, whereas corresponding D(0) values were 0.72 and 1.21 Gy after a single exposure to external 60Co gamma-rays. Mean absorbed doses of 1.31, 0.48 and 0.36 Gy for blood, lungs and heart were calculated in mice injected with 5.4kBq g(-1) of 211At-rituximab. CONCLUSION: Despite the higher inherent sensitivity of the BM cells to the alpha-irradiation, there was, related to the radioactivity concentrations of 211At-rituximab, several logs greater cell kill in RAEL cells, illustrating the tumour-specific nature of the targeting.

Radionuclide therapy with bone-seeking compounds: Monte Carlo calculations of dose-volume histograms for bone marrow in trabecular bone.

The purpose of the present work was to investigate how haematopoietic stem cell survival is affected by the differences in the dose distribution that arise from different radionuclides contained in bone-seeking radiopharmaceuticals. This was carried out in three steps: (a) calculations of representative dose distributions in individual bone marrow cavities that are irradiated by sources of 89Sr, 186Re, 117mSn or 153Sm, uniformly distributed on the bone surfaces; (b) assessment of the corresponding haematopoietic stem cell survival and (c) a comparison of these results with results obtained using the assumption of a uniform dose distribution. Two different idealized models of the geometry of trabecular bone were formulated, each consisting of an infinite array of identical elements. Monte Carlo simulations were used to generate dose-volume histograms that were used to assess haematopoietic stem cell survival with two different assumptions about spatial cell distributions. Compared with a homogeneous dose distribution, the estimated cell survival was markedly higher for 117mSn and 153Sm, and only slightly different for 89Sr and 186Re. The quantitative results differed between the two geometric models and the assumptions about spatial cell distribution, but the trends were the same. The results imply that it is necessary to include dose distributions for individual bone marrow cavities in considerations concerning bone marrow toxicity.

Cytotoxicity of antiosteosarcoma recombinant immunotoxins composed of TP-3 Fv fragments and a truncated Pseudomonas exotoxin A.

Regrowth of drug-resistant tumor cells is responsible for approximately half of an unselected osteosarcoma population still dying of the disease despite aggressive combination therapy. Two monoclonal antibodies, TP-1 (immunoglobulin 2a) and TP-3 (immunoglobulin 2b) are available, which specifically recognize an antigen on osteosarcoma cells. In this work, we have fused the variable (V) genes of TP-3 to a truncated fragment of Pseudomonas exotoxin A, referred to as PE38. Two immunotoxins were made that differed in the Fv portion: TP-3(scFv)-PE38, which contains a peptide linker, and TP-3(dsFv)-PE38, which contains a disulfide bond for stabilization of the association between the V domains. Recombinant TP-3 immunotoxins were expressed in Escherichia coli and purified from inclusion bodies. We describe the design and expression of these immunotoxins, and their properties with regard to antigen binding, stability, and cytotoxicity. Toxicity studies were done in mice. We found that the immunotoxins exhibited very similar in vitro properties, whereas in vivo TP-3(dsFv)-PE38 was much better tolerated than TP-3(scFv)-PE38.

Interstitial fluid pressure in human osteosarcoma xenografts: significance of implantation site and the response to intratumoral injection of hyaluronidase.

Elevated interstitial fluid pressure (IFP) in solid tumors may reduce the effect of systemically administered anticancer drugs. Modulation of the tumor extracellular matrix might reduce the elevated IFP. To study the influence of the microenvironment, the IFP was measured in human osteosarcoma xenografts grown both subcutaneously and orthotopically. The IFP response was recorded in xenografts grown at both sites after direct intratumoral injection of bovine testicular hyaluronidase (500 or 1600 units in 50 microliters saline). Control tumors received 50 microliters saline alone or 10% bovine serum albumin in saline. IFP was measured centrally in the tumors using the wick-in-needle technique, and mean arterial blood pressure was monitored after carotid cannulation. Tumor tissue sections were stained with hyaluronectin and analyzed for hyaluronan content using confocal laser scanning fluorescence microscopy. The baseline IFP was significantly higher in orthotopic (30 +/- 9 mmHg, n = 30) compared with subcutaneous tumors (17 +/- 6 mmHg, n = 11) of comparable sizes (p < 0.001). Injection of hyaluronidase reduced the IFP in both tumor models to 61-81% compared with controls 1 h after injection (p < 0.05), without affecting the mean arterial blood pressure significantly. The hyaluronan staining intensity increased in subcutaneous tumor sections, but remained unchanged in orthotopic tumor sections 1 h after injection of 1600 units of hyaluronidase. The IFP was restored within 48 h after hyaluronidase injection. Interestingly, IFP increased with tumor volume in orthotopic tumors, but not in subcutaneous tumors. In conclusion, intratumoral hyaluronidase injection reduces the IFP transiently in solid osteosarcoma xenografts. Furthermore, this study emphasizes that physiological parameters might differ significantly between human osteosarcoma xenografts grown subcutaneously versus orthotopically in nude mice.

Hyaluronidase-induced periodic modulation of the interstitial fluid pressure increases selective antibody uptake in human osteosarcoma xenografts.

Periodic modulation of the elevated interstitial fluid pressure might improve filtration and uptake of tumor-targeting macromolecules (e.g. radioimmunoconjugates) in solid tumors. Cycling of the tumor interstitial fluid pressure was initiated by intratumoral injections of bovine testicular hyaluronidase (BTH, 1,600 U) in osteosarcoma-bearing nude mice. BTH injection was repeated at 3-day intervals up to 9 days, in conjunction with tail vein injections of 125I-labeled TP-3 monoclonal antibody against an osteosarcoma-associated antigen (n = 9) or non-specific 125I-labeled UPC-10 antibody (n = 9). Control mice received intratumoral injections of phosphate buffered saline (n = 18). The radioactivities of tumor and normal tissues (blood, liver, kidney and spleen) were measured and compared between the different groups. BTH injections increased the tumor uptake of specific 125I-labeled TP-3 significantly by approximately 70% in mice receiving 3 fractions compared to 1-2 fractions of the antibody (p < 0.05). The tumor/normal tissue ratio in mice receiving 3 fractions of 125I-labeled TP-3 (n = 5) was significantly higher for all tissues, compared with mice receiving 1-2 fractions (n = 4) (p < 0.05). Control injections did not affect the tumor/blood ratio, but increased the uptake of 125I-labeled TP-3 significantly in kidney and spleen (p < 0.05). Also, BTH reduced the uptake of 125I-labeled UPC-10 in tumor and liver by approximately 20% compared with controls (p < 0.05). The results indicate that periodic lowering of the tumor interstitial fluid pressure might increase the specificity of blood-borne monoclonal antibodies to solid tumors in vivo.

Oral presentations in science and medicine. An art in decline?

The presentation of understandable and stimulating lectures on difficult scientific and medical issues is in our opinion an art in decline. This disconcerting trend has, however, received little attention. In this essay, we expose the most common fallacies and pitfalls encountered in poor lectures, discuss the underlying reasons why they occur and consider some remedies to improve the situation. The status of oral communication should in our opinion be upgraded. To give a first rate, lucid lecture is an important service to the scientific community and should be recognised as such. When principal speakers at symposia are selected, and when researchers are considered for academic positions, documented proficiency in oral communication should be given more weight than is currently the case. This essay does not purport to be a treatise on rhetoric. We believe that a more efficient approach is to focus attention on the common blunders. This we have done in a provocative manner to invite comments and discussion.

Demonstration of highly specific toxicity of the alpha-emitting radioimmunoconjugate(211)At-rituximab against non-Hodgkin's lymphoma cells.

The ability of an alpha-emitter conjugated to a chimaeric anti-CD20 monoclonal antibody to kill selectively human B-lymphoma cells in vitro is reported. Two B-lymphoma cell lines RAEL and K422, and normal haematopoietic progenitor cells from human bone marrow aspirates were incubated with(211)At-rituximab (Rituxan(R) or MabTheratrade mark) and plated in clonogenic assays for survival analyses. Following 1 h incubation with(211)At-rituximab, in concentrations which gave an initial activity of 50 kBq ml(-1), a high tumour cell to normal bone marrow cell toxicity ratio was obtained; 4.1 to 1.0 log cell kill. Biodistribution studies of(211)At-rituximab in Balb/c mice showed similar stability as that of the iodinated analogue. The data indicate that testing of(211)At-rituximab in human patients is warranted.

Exposure of human osteosarcoma and bone marrow cells to tumour-targeted alpha-particles and gamma-irradiation: analysis of cell survival and microdosimetry.

PURPOSE: This study was designed to compare the cytotoxic effects of an alpha-emitting radioimmunoconjugate, which binds to osteosarcoma but not to bone marrow cells, with those of external gamma-irradiation. MATERIALS AND METHODS: The human osteosarcoma cell line, OHS-s1, and mononuclear cells from bone marrow (BM) harvested from healthy donors, were used for these experiments. Cells in suspension were added to various activity concentrations of the anti-osteosarcoma monoclonal antibody TP-3 radiolabelled with 211At. Following incubation for 1 h, unbound radioactivity was washed off and cell survival was determined from clonogenic assays. Microdosimetry was calculated based on binding and retention kinetics of 211At to the cells, as well as cellular and nuclear diameters. For comparison, cell suspensions were irradiated with a single dose of 60Co gamma-rays. RESULTS: 211At-labelled TP-3 showed heterogeneous binding to OHS-s1 cells, with a considerable variation among experiments. About 78% of the initially bound 211At decayed while associated with the OHS-s1 cells. D0 values estimated by microdosimetry were 0.33 (0.22-0.48, range) Gy and 1.18 (0.89-1.89) Gy for OHS-s1 and BM cells, respectively, whereas D0 values after external beam irradiation were 0.86+/-0.07Gy and 1.71+/-0.22Gy. The relative biological effectiveness (RBE) of 211At-labelled TP-3 at 37% survival was 3.43 for OHS-s1 and 1.55 for BM. CONCLUSIONS: High-LET targeted alpha-particle exposure killed osteosarcoma cells more effectively than bone marrow cells, although heterogeneous antigen expression among these tumour cells limited the magnitude of this effect.

[Radiotherapy of skeletal metastases]. / Strålebehandling av skjelettmetastaser.

INTRODUCTION: Patients with skeletal metastases represent a large cohort in clinical oncology, and the single most frequent indication for palliative radiotherapy. Patients with cancer of the breast, lung, prostate and those with myelomatosis, constitute approximately 80% of this group. MATERIAL AND METHODS: This paper summarizes data from relevant published clinical trials employing external irradiation for painful skeletal metastases. More recent randomised trials support the view that a single radiation dose of 8-10 Gy is equally efficient as ten treatments of 3 Gy delivered over two weeks. However, some still believe that fractioned regimes to a higher total dose provide better pain relief of a longer duration than a single fraction. RESULTS: We review the current diagnosis and treatment of patients with skeletal metastases and discuss some aspect of tumour biology. The etiology of pain and the pathogenesis of tumour cells affecting bone tissue, resulting in osteolysis and/or osteosclerosis, are discussed. Associated leukocyte-derived osteoclast-activating cytokines that stimulate pain receptors locally, can in part explain why radiotherapy gives such rapid pain relief. INTERPRETATION: The aims of radiotherapy must be assessed in relation to the life expectancy of the patient. Based on actual publications and own experiences, we suggest treatment with 8 Gy x 1 for the majority of patients, and reserve 3 Gy x 10 for patients with longer life expectancy. Both regimes allow retreatment, if and when pain eventually reoccur in previously irradiated areas.