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- Acquavella, J., et al.
(author)
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Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events
- 2016
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In: Clinical Epidemiology. - 1179-1349. ; 8, s. 267-272
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Journal article (peer-reviewed)abstract
- Objective: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. Methods: As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naive patients, zoledronic acid-naive patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA (R) clinical trials program. Conclusion: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies.
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- Ehrenstein, V., et al.
(author)
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Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator-mandated cohort postauthorization safety study in Denmark, Norway, and Sweden
- 2021
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In: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 127:21, s. 4050-4058
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Journal article (peer-reviewed)abstract
- BACKGROUND Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. METHODS This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)-death of a jawbone-is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid-treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.
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- Kjellman, M., et al.
(author)
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A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors
- 2021
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In: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 111:9, s. 840-849
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Journal article (peer-reviewed)abstract
- Background: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. Methods: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. Results: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. Conclusion: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.
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- Ljungberg, Börje, Professor, 1949-, et al.
(author)
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Survival advantage of upfront cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma compared with systemic and palliative treatments in a real-world setting
- 2020
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 54:6, s. 487-492
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Journal article (peer-reviewed)abstract
- Background Recently, the CARMENA and SURTIME studies, suggested that upfront cytoreductive nephrectomy (CN) should be abandoned for patients with intermediate and high-risk metastatic renal cell carcinoma (mRCC). However, CN remains an indication in low-risk and when immediate systemic treatment is not required. The aim was to evaluate the long-term overall survival (OS) in patients with primary mRCC, based on the first line treatment. Methods There were 1483 patients with primary mRCC in the National Kidney Cancer Registry from 2005 to 2013. Data on primary treatment, TNM stage, RCC type, tumor size, patient age and sex were extracted. Survival time was calculated from time of diagnosis to time of death or until July 2019. Mann-Whitney U and Chi-square tests, the Kaplan-Meyer method and Cox regression analyses were used. Results Patients primary treated with CN had a significantly longer OS (p < .001) than patients primary treated with systemic therapy or palliation. In a Cox regression multivariate analysis, the hazard ratio for CN compared with no CN was 1.600, 95%Ci (1.492 - 1.691),p < .001. Also occurrence of lymph node metastases, T-stage, patients age and year of diagnosis, remained as independent predictors of OS. Conclusion Patients primary treated with CN survived significantly longer than patients primary treated with systemic therapy or palliation, in all age groups. CN was an important first-line treatment option in mRCC patients.
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- Rosenblad, Andreas, Fil. dr, 1973-, et al.
(author)
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Surgical waiting times and all-cause mortality in patients with non-metastatic renal cell carcinoma
- 2022
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:5-6, s. 383-390
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Journal article (peer-reviewed)abstract
- Objective To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02-1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01-1.04; p < 0.001) and 1.05 (95% CI = 1.02-1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.
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| 26. |
- Siegenthaler, MP, et al.
(author)
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Mechanical reliability of the Jarvik 2000 Heart - Discussion
- 2006
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In: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 81:5, s. 1752-1759
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Journal article (peer-reviewed)abstract
- Background. Device failure is a limitation of permanent mechanical circulatory support. We studied the mechanical reliability of the Jarvik 2000 Heart, an axial flow pump with ceramic bearings designed to provide more than 10 years' durability. Methods. The Jarvik 2000 Heart was implanted in 102 patients between April 2000 and December 2004. Eighty-three pumps with an abdominal driveline were implanted as a bridge-to-transplantation, and 19 with post-auricular power supply as lifetime therapy. Eighteen pumps were recovered intact after clinical use and run continuously on the bench to further assess durability. Results. No implantable component failure occurred either in patients or during bench testing. The cumulative pump run-time was 110 years: 59 years overall in vivo and 51 years in vitro. The mean support time for bridge-to-transplant recipients was 159 days, and for discharged lifetime-therapy recipients 551 days. Six recipients were supported moer than 2 years, with the longest ongoing approaching 5 years. External cables caused three system failures, with a 95% freedom from system failure at 4 years. Device malfunctions, related to external cables ( 9) and lack of a backup battery ( 1), caused no adverse consequences. Before introduction of noncorrosive, gold-plated stainless steel connectors, corrosion was observed on three connectors to the retroauricular power supply. Conclusions. The Jarvik 2000 Heart has had no implantable component failure. Meaningful durability data and failure mode can only be established by real-time testing in patients. The reliability and dependability of this device, in addition to the exchangeability of external components, give promise for long-term circulatory support in critically ill heart failure patients.
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- Tandstad, T., et al.
(author)
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Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA)
- 2016
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:7, s. 1299-1304
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Journal article (peer-reviewed)abstract
- A total of 1118 patients with clinical stage I seminoma one course of adjuvant carboplatin or managed by surveillance were included. Stromal invasion of rete testis and tumor size > 4 cm are confirmed as risk factors predicting relapse. Relapse rates following one course of adjuvant carboplatin is high and there is need to explore more effective adjuvant treatment options in patients with seminoma.The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter > 4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. From 2007 to 2010, 897 patients were included in a prospective, population-based, risk-adapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (>n = 469) or surveillance (>n = 422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, >P = 0.011] and tumor diameter > 4 cm (HR 2.7, >P < 0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin < 7 x AUC compared with that in patients receiving a parts per thousand yen7 x AUC. Stromal invasion in the rete testis and tumor diameter > 4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin.
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| 30. |
- Tribukait, B, et al.
(author)
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Prediction of Overall Survival by Thymidine Kinase 1 Combined with Prostate-Specific Antigen in Men with Prostate Cancer
- 2023
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In: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 24:6
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Journal article (peer-reviewed)abstract
- Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988–1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.
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- Wolkerstorfer, A., et al.
(author)
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Natural course of sensitization to cow's milk and hen's egg in childhood atopic dermatitis : ETAC™ study group
- 2002
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In: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 32:1, s. 70-73
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Journal article (peer-reviewed)abstract
- Background: Sensitization to food allergens has been implicated in the pathogenesis of atopic diseases, in particular atopic dermatitis (AD). The aim of the present paper is to investigate the natural course of sensitization to egg and to cow's milk and its relationship with the severity of AD. Methods: The placebo intention-to-treat population of the ETAC™ (Early Treatment of the Atopic Child) study consisted of 397 children with AD aged 12-24 months (mean ± SD: 17.2 ± 4.1 months) who were followed for 18 months. All children were examined for objective SCORing Atopic Dermatitis (SCORAD) and specific IgE amongst other, to egg and to cow's milk at inclusion and after 3, 12 and 18 months. Fifteen patients were excluded from this analysis due to major protocol violations thus leaving 382 patients in the analysed population. Results: Sensitization to egg and to cow's milk was more common in atopic children with severe AD at all time-points. At inclusion, children sensitized to both egg and to cow's milk had the most severe AD (Kruskall-Wallis test P = 0.007). The degree of sensitization expressed in RAST classes was significantly related to the severity of AD. Furthermore, children sensitized to egg or to cow's milk at inclusion had a higher risk of persistence of AD (84% and 67%, respectively, vs. 57% in those not sensitized) and a higher objective SCORAD after 18 months follow-up. Conclusion: We found an association between severity of AD and sensitization to egg or to cow's milk. Moreover, sensitization to egg, and to a lesser extent cow's milk, indicates a worse outcome of AD in terms of persistence and severity of the disease.
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