Publications by authors named "Oyvind S Bruland"

96 Publications

Radon-220 diffusion from 224Ra-labeled calcium carbonate microparticles: Some implications for radiotherapeutic use.

PLoS One 2021 4;16(3):e0248133. Epub 2021 Mar 4.

Oncoinvent AS, Oslo, Norway.

Alpha-particle emitting radionuclides continue to be the subject of medical research because of their high energy and short range of action that facilitate effective cancer therapies. Radium-224 (224Ra) is one such candidate that has been considered for use in combating micrometastatic disease. In our prior studies, a suspension of 224Ra-labeled calcium carbonate (CaCO3) microparticles was designed as a local therapy for disseminated cancers in the peritoneal cavity. The progenies of 224Ra, of which radon-220 (220Rn) is the first, together contribute three of the four alpha particles in the decay chain. The proximity of the progenies to the delivery site at the time of decay of the 224Ra-CaCO3 microparticles can impact its therapeutic efficacy. In this study, we show that the diffusion of 220Rn was reduced in labeled CaCO3 suspensions as compared with cationic 224Ra solutions, both in air and liquid volumes. Furthermore, free-floating lead-212 (212Pb), which is generated from released 220Rn, had the potential to be re-adsorbed onto CaCO3 microparticles. Under conditions mimicking an in vivo environment, more than 70% of the 212Pb was adsorbed onto the CaCO3 at microparticle concentrations above 1 mg/mL. Further, the diffusion of 220Rn seemed to occur whether the microparticles were labeled by the surface adsorption of 224Ra or if the 224Ra was incorporated into the bulk of the microparticles. The therapeutic benefit of differently labeled 224Ra-CaCO3 microparticles after intraperitoneal administration was similar when examined in mice bearing intraperitoneal ovarian cancer xenografts. In conclusion, both the release of 220Rn and re-adsorption of 212Pb are features that have implications for the radiotherapeutic use of 224Ra-labeled CaCO3 microparticles. The release of 220Rn through diffusion may extend the effective range of alpha-particle dose deposition, and the re-adsorption of the longer lived 212Pb onto the CaCO3 microparticles may enhance the retention of this nuclide in the peritoneal cavity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932545PMC
March 2021

Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study.

Clin Sarcoma Res 2020 Nov 17;10(1):22. Epub 2020 Nov 17.

Department of Oncology, Skåne University Hospital, and Lund University, Lund, Sweden.

Background: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B.

Methods: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m) and ifosfamide (6 g/m), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented.

Results: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3-10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7-77.4). The median follow-up time was 5.4 years (range 0.3-10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8-89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3).

Conclusions: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39.
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http://dx.doi.org/10.1186/s13569-020-00145-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672981PMC
November 2020

Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcoma: A Nonrandomized Controlled Trial.

JAMA Oncol 2021 Jan 21;7(1):e205865. Epub 2021 Jan 21.

Sarcoma Unit, Department of Radiotherapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Importance: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity.

Objective: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity.

Design, Setting, And Participants: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020.

Interventions: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks.

Main Outcomes And Measures: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects.

Results: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%.

Conclusions And Relevance: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers.

Trial Registration: ClinicalTrials.gov Identifier: NCT02106312.
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http://dx.doi.org/10.1001/jamaoncol.2020.5865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662477PMC
January 2021

Calibration of sodium iodide detectors and reentrant ionization chambers for Pb activity in different geometries by HPGe activity determined samples.

Appl Radiat Isot 2020 Dec 7;166:109362. Epub 2020 Aug 7.

Nucligen AS, Oslo, Norway.

Lead-212 is a promising radionuclide for cancer therapy, but no primary Pb activity standardization has been published. A need therefore exists for accurate estimation of injected doses of Pb activity in equilibrium with progeny, when it comes to preclinical and clinical trials. In this study, Pb activity was determined using a high purity germanium (HPGe) detector, which allowed the determination of geometry-specific calibration factors for commercially available reentrant ionization chambers (ICs) and sodium iodide (NaI) detectors.
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http://dx.doi.org/10.1016/j.apradiso.2020.109362DOI Listing
December 2020

In situ Generated 212Pb-PSMA Ligand in a 224Ra-Solution for Dual Targeting of Prostate Cancer Sclerotic Stroma and PSMA-positive Cells.

Curr Radiopharm 2020 ;13(2):130-141

Nucligen AS, Oslo, Norway

Background: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy.

Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour cells are obtained.

Methods: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with 212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2 human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts).

Results: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15 μg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb- NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA- 617. Radium-224 was not chelated and, hence, showed high uptake in bones.

Conclusion: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted.
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http://dx.doi.org/10.2174/1874471013666200511000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527546PMC
January 2020

Use of a simple form to facilitate communication on long-term consequences of treatment in sarcoma survivors.

Clin Sarcoma Res 2020 16;10. Epub 2020 Jan 16.

1Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, P.O. Box 4953, Oslo, 0424 Norway.

Background: To report on our experience using a simple optional form to facilitate communication on late effects between the patients and the oncologists during outpatient follow-up and to detail on the spectrum of challenges reported by sarcoma survivors.

Methods: The form was presented for the patients to complete before their consultation and covered topics related to late effects and unmet needs that the patient wished to discuss with the medical personnel. Logistic regression analysis examined how the distribution of the topics varied with age, gender, diagnosis and type of treatment received.

Results: The form was manageable in a busy outpatient clinic. Of the 265 patients that received the form, 236 (89%) returned it. Patients in a palliative setting and those with other diagnosis than bone sarcoma (BS) and soft-tissue sarcoma (STS) were excluded for subsequent analyses. The final study-cohort comprised 160 patients, 54 (34%) with BS and 106 (66%) with STS. Among these, 140 (88%) had late-effect topics they wanted to discuss with their oncologist. Fatigue was raised by 39% of the patients, pain by 29% and impaired mobility by 23%. BS patients raised fatigue more often (< 0.005) than those with STS. Patients who had undergone multimodal treatment with chemotherapy raised fatigue more frequently ( < 0.001) than those who had only undergone surgery, radiotherapy or both.

Conclusions: A simple form on the long-term consequences of sarcoma treatment achieved a high response rate, was feasible to use in an outpatient clinic and facilitated communication on these issues. Fatigue was the most frequent topic raised and it was raised significantly more often in patients who had undergone chemotherapy.
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http://dx.doi.org/10.1186/s13569-019-0124-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964017PMC
January 2020

Prognostic Impact of Proximal Distal Localization in Extremity Long Bone Osteosarcomas.

Anticancer Res 2019 May;39(5):2459-2466

Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.

Background/aim: This study aimed to identify the prognostic factors and outcomes of osteosarcoma (OS) located in proximal versus distal extremity long bones.

Patients And Methods: A nationwide cohort comprising all Norwegian high-grade OSs in extremity long bones between 1982 and 2009 was investigated.

Results: The univariate analysis results identified no significant differences in survival between patients with OS in proximal long bones (101 cases) as a group in comparison to patients with OS in the distal part of these bones (120 cases). However, proximal femur and primary metastasis were both independent adverse prognostic factors for sarcoma-specific survival in multivariate analyses, while elevated LDH and secondary OS were inferior prognostic factors for event-free survival. Adequate surgery and chemotherapy had a positive impact on survival.

Conclusion: OS of the proximal femur had an unfavorable outcome in comparison to OS in other anatomical locations in extremity long bones.
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http://dx.doi.org/10.21873/anticanres.13365DOI Listing
May 2019

Perspectives on treatment side effects in patients with metastatic gastrointestinal stromal tumour: a qualitative study.

Clin Sarcoma Res 2019 30;9. Epub 2019 Apr 30.

1Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 5960, Nydalen, 0424 Oslo, Norway.

Background: This study aims to explore how patients with metastatic gastrointestinal stromal tumour (GIST) experience the adverse effects of treatment, as expressed by the individuals themselves.

Methods: A qualitative, phenomenological and hermeneutic design was applied. Twenty patients with metastatic GIST participated in the study. In-depth and semi-structured interviews were conducted and then analysed by means of an inductive thematic analysis.

Results: The majority of participants reported experiencing a changed life after being diagnosed with metastatic GIST and commencing systemic medical treatment. More than half of them described partially debilitating self-reported side effects and complaints that had a detrimental impact on their lives. The life-prolonging tyrosine kinase inhibitor treatment prompted the participants to adapt to 'a new normal'. Several participants also emphasised having an ambivalent relationship with the pill, although most looked upon it as 'a friend' because it kept them alive. Paradoxically, while the participants struggled with the side effects of treatment as well as the consequences of living with a chronic cancer, half of them considered themselves to be healthy and, thus, to not actually be cancer patients.

Conclusions: We observed a gap between the biomedical perspective on disease that health professionals typically adopt and the individual experiences of patients living with metastatic GIST. For those patients who are living in limbo between having metastatic cancer and offered an effective treatment, a holistic view of health on the part of their healthcare providers seems crucial. A vital goal should hence be to improve communication between healthcare professionals and GIST patients so as to secure an individualised follow-up with guidance on coping with, and adapting to, their new normal. The study was approved by the data protection officer of the Oslo University Hospital (Approval Number 2016/15358).
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http://dx.doi.org/10.1186/s13569-019-0116-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492319PMC
April 2019

Ewing Sarcoma in Nepal Treated With Combined Chemotherapy and Definitive Radiotherapy.

J Glob Oncol 2019 03;5:1-10

Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Purpose: To our knowledge, we conducted the first prospective oncologic clinical trial in Nepal aimed at providing state-of-the-art chemotherapy to patients with Ewing sarcoma. The efficacy of external-beam radiotherapy (RT) as the sole local treatment modality was explored and deemed justified as a result of the lack of available advanced tumor-orthopedic services in Nepal.

Patients And Methods: Twenty patients, 11 female and 9 male patients between the ages of 6 and 37 years, with newly diagnosed Ewing sarcoma were enrolled. Neoadjuvant combination chemotherapy, comprising well-established drug combinations, was administered in five courses before external-beam RT, during which one course of etoposide and ifosfamide was given. After RT, six additional chemotherapy courses were scheduled.

Results: RT was tolerated well, providing rapid symptom relief and local tumor control, with no pathologic fractures observed among the 15 patients who received such treatment. Eleven patients completed the entire treatment protocol; seven patients were under continued follow-up, with no evidence of disease in six patients at a median follow-up time of 2.3 years (range, 1.3 to 3.1 years) and one patient alive but with a regional recurrence. Four patients experienced metastatic relapse and died as a result of their disease. Three treatment-related deaths linked to toxicity from chemotherapy occurred. Four of the six patients who refused to complete the treatment protocol and were lost to follow-up experienced progressive disease and were assumed dead.

Conclusion: This study was feasible with RT as the sole local treatment modality in combination with chemotherapy. As a result of the high number of patients lost to follow-up, no firm conclusions can be drawn, but the majority of the patients who completed treatment obtained durable long-term remissions.
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http://dx.doi.org/10.1200/JGO.19.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449078PMC
March 2019

Clinical epidemiology and treatment outcomes of spindle cell non-osteogenic bone sarcomas - A nationwide population-based study.

J Bone Oncol 2019 Feb 20;14:002-2. Epub 2018 Nov 20.

Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, P.O. Box 4953, Nydalen, N-0424 Oslo, Norway.

Purpose: To describe epidemiological and clinical characteristics, as well as long-term treatment outcomes of spindle cell non-osteogenic bone sarcomas (SCS), comprising leiomyosarcoma, fibrosarcoma and undifferentiated pleomorphic sarcoma in bone.

Method: We have analysed a nationwide cohort of 104 patients with histologically verified SCS diagnosed between 1975 and 2009, based on registry sources supplemented with clinical records from Norwegian hospitals involved in sarcoma management.

Results: In this unselected cohort, a stable annual incidence for SCS patients of slightly below 0.6 per million was observed, with a dominant peak among elderly patients. SCS is mostly a high-grade malignancy (92%) with a male to female ratio of 1.6 for all patients. The axial to appendicular ratio was 0.7, seemingly independent of age. More than one fourth of the patients (29%) had primary metastatic disease. Another 32 patients (46%) developed metastases during follow-up and 12 (17%) experienced local relapses. The five-year sarcoma-specific survival rate was 37%, with no documented improvement over time. Primary metastatic disease was an adverse prognostic factor for survival. Predisposing factors were documented in 19 patients (18%). Negative prognostic factors for overall survival were tumour size >9 cm, age > 40 years, axial tumour localization, FS as subtype and pathologic fracture at time of diagnoses. As expected, patients who received both surgery and chemotherapy as their primary treatment for high-grade SCS (25%) significantly had best sarcoma specific five years survival (62%).

Conclusion: We confirm SCS as a rare high-grade bone sarcoma entity, mostly among elderly patients and with a poor overall outcome. The combined treatment of surgery and chemotherapy is essential to achieve optimal long-term survival of SCS.
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http://dx.doi.org/10.1016/j.jbo.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290118PMC
February 2019

Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).

Eur J Cancer 2018 08 19;99:78-85. Epub 2018 Jun 19.

Department of Oncology, Skåne University Hospital and Lund University, Lund, Sweden. Electronic address:

Purpose: To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy.

Methods: High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m) and ifosfamide (6 g/m) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4.

Results: For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death.

Conclusions: A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2018.05.011DOI Listing
August 2018

Osteonecrosis of the Jaw in a Patient With Bone Metastatic Prostate Cancer After Long-term Bisphosphonate Treatment With Severe Deterioration Following Radium-223.

Clin Genitourin Cancer 2018 10 16;16(5):328-331. Epub 2018 May 16.

Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2018.05.003DOI Listing
October 2018

Therapeutic Effect of α-Emitting Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer.

Transl Oncol 2018 Apr 28;11(2):259-267. Epub 2018 Jan 28.

Oncoinvent AS, Oslo, Norway.

Background: Ovarian cancer patients with chemotherapy-resistant residual microscopic disease in the peritoneal cavity have a considerable need for new treatment options. Alpha-emitting radionuclides injected intraperitoneally may be an attractive therapeutic option in this situation as they are highly cytotoxic, while their short range in tissues can spare surrounding radiosensitive organs in the abdomen. Herein we evaluate the therapeutic efficacy of a novel α-emitting compound specifically designed for intracavitary radiation therapy.

Methods: The α-emitter Ra was absorbed on calcium carbonate microparticles. Immunodeficient, athymic nude mice with human ovarian cancer cells growing intraperitoneally were treated with different activity levels of Ra-microparticles. Tumor growth, survival, and tolerance of the treatment were assessed. Two tumor models based on the cell lines, ES-2 and SKOV3-luc, with different growth patterns were studied.

Results: In both models, intraperitoneal treatment with Ra-microparticles gave significant antitumor effect with either considerably reduced tumor volume or a survival benefit. An advantageous discovery was that only a few kilobecquerels per mouse were needed to yield therapeutic effects. The treatment was well tolerated up to a dose of 1000 kBq/kg with no signs of acute or subacute toxicity observed.

Conclusions: Intraperitoneal α-therapy with Ra-microparticles demonstrated a significant potential for treatment of peritoneal micrometastases in ovarian carcinoma.
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http://dx.doi.org/10.1016/j.tranon.2017.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789152PMC
April 2018

Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice.

J Labelled Comp Radiopharm 2018 05 12;61(6):472-486. Epub 2018 Mar 12.

Oncoinvent AS, Oslo, Norway.

Internal therapy with α-emitters should be well suited for micrometastatic disease. Radium-224 emits multiple α-particles through its decay and has a convenient 3.6 days of half-life. Despite its attractive properties, the use of Ra has been limited to bone-seeking applications because it cannot be stably bound to a targeting molecule. Alternative delivery systems for Ra are therefore of considerable interest. In this study, calcium carbonate microparticles are proposed as carriers for Ra, designed for local therapy of disseminated cancers in cavitary regions, such as peritoneal carcinomatosis. Calcium carbonate microparticles were radiolabeled by precipitation of Ra on the particle surface, resulting in high labeling efficiencies for both Ra and daughter Pb and retention of more than 95% of these nuclides for up to 1 week in vitro. The biodistribution after intraperitoneal administration of the Ra-labeled CaCO microparticles in immunodeficient mice revealed that the radioactivity mainly remained in the peritoneal cavity. In addition, the systemic distribution of Ra was found to be strongly dependent on the amount of administered microparticles, with a reduced skeletal uptake of Ra with increasing dose. The results altogether suggest that the Ra-labeled CaCO microparticles have promising properties for use as a localized internal α-therapy of cavitary cancers.
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http://dx.doi.org/10.1002/jlcr.3610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001669PMC
May 2018

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial.

Eur Urol 2018 Mar 11;73(3):427-435. Epub 2017 Jul 11.

Karolinska University Hospital, Stockholm, Sweden.

Background: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment.

Objective: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection.

Design, Setting, And Participants: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr.

Outcome Measurements And Statistical Analysis: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics.

Results And Limitations: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up.

Conclusions: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns.

Patient Summary: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.
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http://dx.doi.org/10.1016/j.eururo.2017.06.021DOI Listing
March 2018

Multimodal treatment of craniofacial osteosarcoma with high-grade histology. A single-center experience over 35 years.

Neurosurg Rev 2017 Jul 17;40(3):449-460. Epub 2016 Nov 17.

Department of Neurosurgery, Oslo University Hospital - Rikshospitalet, 4950 Nydalen, Oslo, 0424, Norway.

High-grade craniofacial osteosarcoma (CFOS) is an aggressive malignancy with a poor prognosis. Our goals were to evaluate treatment outcomes in those treated at a single referral institution over 35 years and to compare our results to the available literature. A retrospective analysis of all 42 patients treated between 1980 and 2015 at Oslo University Hospital, Norway, identified in a prospectively collected database, was conducted. Mean follow-up was 79.6 months. Overall survival at 2 and 5 years was 70.5 and 44.7%, respectively. The corresponding disease-specific survival rates were 73.0 and 49.8%. Treatment was surgery only in eight cases. Additional therapy was administered in 34 patients: chemotherapy in nine, radiotherapy in seven, and a combination of these in 18 cases. Stratified analysis by resection margins demonstrated significantly better survival at 2 and 5 years after radical surgical treatment. Neoadjuvant chemotherapy and subsequent adequate surgery resulted in better survival than surgery alone. Half of the patients either had a primary or familial cancer predisposition. This is the largest single-center study conducted on high-grade CFOS to date. Our experience indicates that neoadjuvant chemotherapy with complete surgical resection significantly improved survival, compared to surgery alone.
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http://dx.doi.org/10.1007/s10143-016-0802-zDOI Listing
July 2017

Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma.

PLoS One 2016 24;11(10):e0165382. Epub 2016 Oct 24.

Sciencons AS, Oslo, Norway.

Background: Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo.

Methods And Results: A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of 125I-labeled OI-3 antibody variants was compared with 125I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, 177Lu, and their biodistributions were studied in the nude mouse model. The 177Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant.

Conclusion: Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077112PMC
June 2017

Genome Analysis of Osteosarcoma Progression Samples Identifies FGFR1 Overexpression as a Potential Treatment Target and CHM as a Candidate Tumor Suppressor Gene.

PLoS One 2016;11(9):e0163859. Epub 2016 Sep 29.

Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.

Osteosarcoma (OS) is the most common primary malignant tumor of bone, showing complex chromosomal rearrangements but with few known consistent changes. Deeper biological understanding is crucial to find new therapies to improve patient survival. We have sequenced the whole exome of two primary tumors (before and after chemotherapy), one metastatic tumor and a matched normal sample from two OS patients, to identify mutations involved in cancer biology. The metastatic samples were also RNA sequenced. By RNA sequencing we identified dysregulated expression levels of drug resistance- and apoptosis-related genes. Two fusion transcripts were identified in one patient (OS111); the first resulted in p53 inactivation by fusing the first exon of TP53 to the fifth exon of FAM45A. The second fusion joined the two first exons of FGFR1 to the second exon of ZNF343. Furthermore, FGFR1 was amplified and highly expressed, representing a potential treatment target in this patient. Whole exome sequencing revealed large intertumor heterogeneity, with surprisingly few shared mutations. Careful evaluation and validation of the data sets revealed a number of artefacts, but one recurrent mutation was validated, a nonsense mutation in CHM (patient OS106), which also was the mutation with the highest expression frequency (53%). The second patient (OS111) had wild-type CHM, but a downregulated expression level. In a panel of 71 clinical samples, we confirmed significant low expression of CHM compared to the controls (p = 0.003). Furthermore, by analyzing public datasets, we identified a significant association between low expression and poor survival in two other cancer types. Together, these results suggest CHM as a candidate tumor suppressor gene that warrants further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042545PMC
September 2016

Negative and Positive Consequences of Cancer Treatment Experienced by Long-term Osteosarcoma Survivors: A Qualitative Study.

Anticancer Res 2015 Nov;35(11):6081-90

School of Medicine, University of St. Andrews, Fife, Scotland, U.K.

Background: Our study aimed to explore how survivors of osteosarcoma of the lower extremity experience physical and psychosocial late effects several years after undergoing arduous treatment. A qualitative, phenomenological and hermeneutic approach was applied.

Materials And Methods: Osteosarcoma survivors (n=8) previously treated at the Norwegian Radium Hospital, Oslo University Hospital, participated in the study. In-depth and semi-structured interviews were conducted. The interviews were analyzed using inductive thematic analysis.

Results: Three to ten years after diagnosis, the majority of participants had experienced both negative and positive consequences following treatment. Changes in activity and exclusion from participation in different areas were the most challenging consequences. Several of their experiences are similar to those described by people with disabilities.

Conclusion: It is important to understand osteosarcoma survivors' own experiences in order to assist those who struggle to reorient in life and to construct a new identity for themselves.
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November 2015

Can Imatinib Be Safely Withdrawn in Patients with Surgically Resected Metastatic GIST?

Anticancer Res 2015 Nov;35(11):5759-65

Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Patients with advanced gastrointestinal stromal tumors (GIST) are currently recommended for treatment with tyrosine kinase inhibitors (TKI) in a life-long sequence. The standard first-line treatment is imatinib mesylate (IM), which is switched to other drugs at progression or if the patient does not tolerate IM. This strategy has served many patients well as patients with advanced GIST now live for a median of approximately 5 years, compared to 18 months prior the TKI era. The prevailing hypothesis is that IM and other TKIs fail to completely eradicate metastatic GIST and that progression is inevitable if IM treatment is discontinued. Following a response to IM and surgery of metastatic lesions harbouring foci responsible for drug resistance and subsequent clinical relapse, we hypothesize that this may lead to a cure and the justification to stop IM in selected patients. We suggest that this novel strategy, a priori, warrants further investigation. We reviewed the available literature, present three clinical cases and put forward for discussion a treatment algorithm that needs confirmation within the context of a prospective clinical study.
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November 2015

Clinical Epidemiology of Low-Grade and Dedifferentiated Osteosarcoma in Norway during 1975 and 2009.

Sarcoma 2015 30;2015:917679. Epub 2015 Aug 30.

Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, 0424 Oslo, Norway ; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.

Purpose. To describe epidemiological, clinical characteristics and treatment outcomes of low-grade osteosarcoma (LGOS), including dedifferentiated osteosarcoma (DLGOS). Method. We analysed a nationwide cohort comprised of patients with histologically verified LGOS and DLGOS between 1975 and 2009, based on registry sources supplemented with clinical records from hospitals involved in sarcoma management. Results. Fifty-four patients were identified, 12 of whom had DLGOS. The annual incidence for all patients was 0.3 per million, with the peak incidence in the third decade of the life. Fifteen patients experienced local relapses during follow-up and ten developed metastatic diseases, including three at primary diagnosis. Patients with DLGOS dominated the metastatic relapse group. The five-year sarcoma-specific survival rate was 91%, with no documented improvement over time. Free margin following surgical resection of the primary tumour had a positive impact on survival. As expected, both local relapse and metastasis during follow-up were associated with an unfavourable outcome. Radiotherapy predicted poor survival due to the selection of high-risk patients in need of such treatment. Neither higher age nor axial tumour localisation was adverse prognostic factors. Conclusion. LGOS has an excellent prognosis when surgically resected with a free margin; however, LGOS has the potential to dedifferentiate and metastasize with a poor outcome.
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http://dx.doi.org/10.1155/2015/917679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568035PMC
September 2015

Cured of primary bone cancer, but at what cost: a qualitative study of functional impairment and lost opportunities.

Sarcoma 2015 9;2015:484196. Epub 2015 Apr 9.

Institute of Health and Society, Department of Health Sciences, University of Oslo, P.O. Box 1089, Blindern, 0317 Oslo, Norway.

Purpose. Our study aims to explore how former cancer patients experience physical and psychosocial late effects 3-7 years after they underwent treatment for primary bone sarcoma in the hip/pelvic region. A qualitative, phenomenological, and hermeneutic design was applied. Methods. Sarcoma survivors (n = 10) previously treated at Oslo University Hospital, Norwegian Radium Hospital were selected to participate. In-depth and semistructured interviews were conducted. The interviews were analysed using inductive thematic analysis. Results. The participants reported that the late effects had three core spheres of impact: "their current daily life," "their future opportunities," and "their identity." They expressed negative changes in activity, increased dependence on others, and exclusion from participation in different areas. Their daily life, work, sports activities, and social life were all affected. Several of their experiences are similar to those described by people with functional impairment or disability. Conclusion. Patients cured of bone cancer in the hip/pelvic region pay a significant price in terms of functional impairment, practical challenges, exclusion from important aspects of life, and loss of previous identity. It is important to appreciate this in order to help bone cancer survivors who struggle to reorient their life and build a secure new identity.
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http://dx.doi.org/10.1155/2015/484196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407620PMC
May 2015

Extraskeletal osteosarcoma in Norway, between 1975 and 2009, and a brief review of the literature.

Anticancer Res 2015 Apr;35(4):2129-40

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Aim: To evaluate the clinicopathological features of extraskeletal osteosarcoma (ESOS) and its response to multimodal therapy.

Patients And Methods: A nationwide cohort comprising all Norwegian histologically verified ESOS patients between 1975 and 2009 supplemented with clinical reports from all hospitals involved in sarcoma management.

Results: Thirty-seven patients were classified as ESOS, mostly elderly people. Seventy-six % had an axial tumour, including nine patients with radiation-induced ESOS. The gender balance was equal. The 5-year sarcoma-specific survival (SSS) was 16 %. Adequate surgical remission had a positive impact on SSS, in contrast to chemotherapy and radiotherapy. Primary metastatic disease, elevated tumour size and elevated serum alkaline phosphatase, serum lactate dehydrogenase and Ki67, respectively, all predicted poor outcome.

Conclusion: The relatively poor prognosis of ESOS may relate to both primary chemotherapy resistance and different biologic characteristics of these tumours as compared to conventional osteosarcoma. Hence, new predictive molecular markers and therapeutic approaches for treatment of ESOS are needed.
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April 2015

Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.

Int J Radiat Oncol Biol Phys 2015 Apr;91(5):898-906

Department of Radiation Oncology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio. Electronic address:

The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2014.12.061DOI Listing
April 2015

Prognostic factors and treatment results of high-grade osteosarcoma in norway: a scope beyond the "classical" patient.

Sarcoma 2015 17;2015:516843. Epub 2015 Feb 17.

Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, 0424 Oslo, Norway ; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.

Purpose. A retrospective study of prognostic factors and treatment outcome of osteosarcoma (OS) during modern chemotherapy era with focus on patients with primary metastatic disease, nonextremity localisation, or age >40 years (nonclassical OS). Methods. A nationwide cohort, comprising 424 high-grade Norwegian bone OS patients, was based on registry sources supplemented with clinical records from hospitals involved in sarcoma management between 1975 and 2009. Results. Only 48% were younger patients with tumour in the extremities and without metastasis at diagnosis (classical OS). A considerable discrepancy in survival between classical and nonclassical OS was observed: 61% versus 26% 10-year sarcoma specific survival. Twice as many of the former received both adequate surgery and chemotherapy compared to the latter. This could only partly explain the differences in survival due to inherent chemoresistance in primary metastatic disease and a higher rate of local relapse among patients with axial tumours. Metastasis at diagnosis, increased lactate dehydrogenase, age > 40 years, and tumour size above median value were all adverse prognostic factors for overall survival. Conclusion. We confirm a dramatic difference in outcome between classical and nonclassical high-grade OS patients, but treatment variables could only partly explain the dismal outcome of the latter.
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http://dx.doi.org/10.1155/2015/516843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346701PMC
March 2015

Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females.

Scand J Public Health 2015 May 4;43(3):324-30. Epub 2015 Mar 4.

Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway Institute of Physics, University of Oslo, Oslo, Norway.

Aims: Ultraviolet (UV) radiation is a major source for vitamin D production. Furthermore, UV destroys cobalamins (also called vitamin B12) in solution. However, data from humans are scarce. The aim of the present study was to clarify if UV exposure has any effect on serum cobalamins, as compared to vitamin D levels, in healthy volunteers.

Methods: This single-center, open observational study was conducted in a research institute: 23 non-pregnant, non-lactating, healthy, fair-skinned female subjects had their serum cobalamin and 25-hydroxyvitamin D (25(OH)D, the marker for vitamin D status) levels measured before and after exposure to UV.

Results: UV exposure increased serum 25(OH)D levels from 61.6 nmol/L to 88.5 nmol/L (44%; p < 0.001). A statistically insignificant decay in serum cobalamin levels from 300 pmol/L to 260 pmol/L (13%; p = 0.142) was observed in the volunteers after the first UV exposure; however, no additional decline of statistical significance was seen after subsequent exposures.

Conclusions: Multiple exposure to UV radiation give a significant increase in 25(OH)D levels, but has no detrimental effect on cobalamin concentrations.
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http://dx.doi.org/10.1177/1403494815572206DOI Listing
May 2015

Primary bone cancer in Leonbergers may be associated with a higher bodyweight during adolescence.

Prev Vet Med 2015 Apr 14;119(1-2):48-53. Epub 2015 Feb 14.

Norwegian University of Life Sciences (NMBU), Faculty of Veterinary Medicine and Biosciences, NMBU School of Veterinary Science, Department of Companion Animal Clinical Sciences, Small Animal Section, Box 8146 Dep., N-0033 Oslo, Norway. Electronic address:

Weight-bearing stress may be a risk factor for both human and canine primary bone cancer. A cohort of Leonbergers (LB) was followed from birth to death and the cause of death recorded. We hypothesised that dogs dying due to primary bone cancer would be larger; measured by bodyweight (BW) and the circumference of the distal radius and ulna (CDRU) than those of the same breed that died of other causes. Information obtained from breeders, owners and veterinary surgeons were questionnaire-based. The dogs were examined by a veterinary surgeon at pre-specified "observational ages" (3, 4, 6, 12, 18, and 24 m). Data were recorded, including BW and CDRU. The study population consisted of 196 LB, 9 of which died due to primary bone cancer (6 males, 3 females). Individual growth curves, showing BW and CDRU during the first 2 years of life, were made for these 9 dogs and compared to gender-specific mean values for LB that died from other causes. These curves showed that LB succumbing to primary bone cancer generally had a higher BW during the growth period than the remaining dogs, and that this difference appeared to be largest in the male LB. Male LB that developed primary bone cancer later in life also had a larger CDRU during most part of this period, as compared to those that did not develop this disease. Logistic regression showed a statistically significant effect of BW on the odds ratio of developing primary bone cancer at 12 m and 18 m and of CDRU at 18 m, and a Poisson regression verified consistency of these results. At these ages, an increase in BW of 1 kg yielded a nearly 20% higher risk of developing primary bone cancer, while a 1 cm larger CDRU was associated with a nearly 70% increased risk. These findings support that weight-bearing stress during the period of high proliferative activity in the long bones associated with growth may increase the risk of canine primary bone cancer.
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http://dx.doi.org/10.1016/j.prevetmed.2015.02.003DOI Listing
April 2015

177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

PLoS One 2014 28;9(7):e103070. Epub 2014 Jul 28.

Nordic Nanovector AS, Oslo, Norway.

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.

Methodology/principal Findings: Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.

Conclusions/significance: 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113375PMC
November 2015