| 1. |
- Anand, Aseem, et al.
(författare)
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Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients
- 2020
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X .- 1535-5667. ; 61:5, s. 671-675
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Tidskriftsartikel (refereegranskat)abstract
- For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.
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| 2. |
- Ronquist, Karl Göran, et al.
(författare)
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Energy-requiring uptake of prostasomes and PC3 cell-derived exosomes into non-malignant and malignant cells
- 2016
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial cells lining the prostate acini release, in a regulated manner (exocytosis), nanosized vesicles called prostasomes that belong to the exosome family. Prostate cancer cells have preserved this ability to generate and export exosomes to the extracellular space. We previously demonstrated that human prostasomes have an ATP-forming capacity. In this study, we compared the capacity of extracellular vesicles (EVs) to generate ATP between normal seminal prostasomes and exosomes secreted by PC3 cells (PC3 exosomes), a prostate cancer cell line. Proteomic analyses identified enzymes of the glycolytic chain in both prostasomes and PC3 exosomes, and we found that both of them were capable of generating ATP when supplied with substrates. Notably, the net production of extracellular ATP was low for prostasomes due to a high ATPase activity contrary to an elevated net ATP level for PC3 exosomes because of their low ATPase activity. The uptake of the 2 types of EVs by normal prostate epithelial cells (CRL2221) and prostate cancer cells (PC3) was visualized and measured, demonstrating differential kinetics. Interestingly, this uptake was dependent upon an ongoing glycolytic flux involving extracellular ATP formation by EVs and/or intracellular ATP produced from the recipient cells. We conclude that the internalization of EVs into recipient cells is an energy-requiring process also demanding an active V-ATPase and the capacity of EVs to generate extracellular ATP may play a role in this process.
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| 3. |
- Stattin, Pär, et al.
(författare)
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Real World Outcomes in Patients With Metastatic, Castration-Resistant Prostate Cancer Treated With Radium-223 in Routine Clinical Practice in Sweden
- 2023
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Ingår i: Clinical Genitourinary Cancer. - : Elsevier. - 1558-7673 .- 1938-0682. ; 21:1, s. 107.e1-107.e9
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Estimate the effect of Radium-223 (Ra-223) on the incidence of bone fractures, prostate cancer death, and all-cause death compared with other standard treatments for metastatic, castration-resistant prostate cancer (mCRPC).METHODS: Using a cohort design, we estimated the effect of Ra-223 on the risk of bone fractures, all-cause and prostate cancer-specific mortality across different lines of treatment for mCRPC using Prostate Cancer data Base Sweden (2013-2018). The comparator group comprised other standard treatments for mCRPC. We used 36-month risk differences and hazard ratios (HRs) as effect estimates.RESULTS: The number of eligible individuals was 635, 453, 262, and 84 for the first-, second-, third-, and fourth-line cohorts, respectively. When compared Ra-223 to other standard treatments, the difference in the 36-month risk of fracture was 6% (95% confidence interval [CI], -7% to 18%) in the first-line cohort (n = 635) and 8% (95% CI, -7% to 18%) in the second-line cohort (n = 453). The number of fractures in the third-/fourth-line cohorts was too small for an adjusted comparison. The difference in 36-month mortality was higher in the first-line cohort 13% (95% CI, -3% to 31%), but lower in the second- and third-/fourth-line cohorts-8% (95% CI, -23% to 7%) and -14% (95% CI, -21% to 16%) respectively. Most deaths were due to prostate cancer.CONCLUSION: Results suggest that the difference in the risk of fractures is small, if any. A difference in the risk of mortality may be present in first-line treatment, but a decreased risk of mortality was observed in second and later lines of treatment. The results on mortality need to be considered in the context of potential unmeasured or residual confounding.
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| 4. |
- Thellenberg-Karlsson, Camilla, 1972-, et al.
(författare)
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A randomised, double-blind, dose-finding, phase II multicentre study of ODX in the treatment of patients with castration-resistant prostate cancer and skeletal metastases
- 2023
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 181, s. 198-207
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Tidskriftsartikel (refereegranskat)abstract
- Aims: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease.Methods: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period.Results: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety.Conclusions: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).
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| 5. |
- Holmberg, Lars, et al.
(författare)
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Cumulative incidence of and risk factors for BCG infection after adjuvant BCG instillations
- 2024
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Ingår i: BJU INTERNATIONAL. - : Blackwell Publishing. - 1464-4096 .- 1464-410X. ; 134:2, s. 229-238
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTo investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guerin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC).Patients and MethodsWe analysed the timing and occurrence of BCG infections and absolute and relative risk in relation to patient characteristics available in the Swedish nationwide database 'BladderBaSe 2.0'. The cumulative incidence proportion of a BCG infection was indicated by a reported diagnosis of tuberculosis (TB) in the patient registry or filing a prescription for tuberculostatic drugs.ResultsThe cumulative incidence proportion was 1.1% at the 5-year follow-up in 5033 patients exposed to adjuvant BCG instillations. The incidence rate was highest during the first 2 years after start of BCG instillations. Women had a lower risk than men (hazard ratio 0.23, 95% confidence interval 0.07-0.74). Age and calendar time at diagnosis, comorbidity, tumour risk group, previous medication with corticosteroids, immunosuppressive drugs, or time between transurethral resection of the bladder tumour and commencing the adjuvant BCG instillation were not associated with risk.ConclusionsThese data further supports that the overall risk of a BCG infection after BCG-instillation treatment for NMIBC is low. The great majority of infections occur in the first 2 years, calling for an awareness of the diverse symptoms of BCG infection during this period. We provide evidence for male sex as a risk factor; however, the statistical precision is low and with a risk of selection bias, making it difficult to rule out the other suggested risk factors without further studies with different approaches.
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| 6. |
- Robba, Chiara, et al.
(författare)
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Oxygen targets and 6-month outcome after out of hospital cardiac arrest : a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial
- 2022
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535 .- 1466-609X. ; 26, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients’ outcome. Methods: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. Results: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003). Conclusions: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration: clinicaltrials.gov NCT02908308, Registered September 20, 2016.
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| 7. |
- Blennow Nordström, Erik, et al.
(författare)
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Neuropsychological outcome after cardiac arrest : A prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2)
- 2020
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study is designed to provide detailed knowledge on cognitive impairment after out-of-hospital cardiac arrest (OHCA) and its relation to associated factors, and to validate the neurocognitive screening of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial), assessing effectiveness of targeted temperature management after OHCA. Methods: This longitudinal multi-center clinical study is a sub-study of the TTM2-trial, in which a comprehensive neuropsychological examination is performed in addition to the main TTM2-trial neurocognitive screening. Approximately 7 and 24 months after OHCA, survivors at selected study sites are invited to a standardized assessment, including performance-based tests of cognition and questionnaires of emotional problems, fatigue, executive function and insomnia. At 1:1 ratio, a matched control group from a cohort of acute myocardial infarction (MI) patients is recruited to perform the same assessment. We aim to include 100 patients per group. Potential differences between the OHCA patients and the MI controls at 7 and 24 months will be analyzed with a linear regression, using composite z-scores per cognitive domain (verbal, visual/constructive, working memory, episodic memory, processing speed, executive functions) as primary outcome measures. Results from OHCA survivors on the main TTM2-trial neurocognitive screening battery will be compared with neuropsychological test results at 7 months, using sensitivity and specificity analyses. Discussion: In this study we collect detailed information on cognitive impairment after OHCA and compare this to a control group of patients with acute MI. The validation of the TTM2 neurocognitive screening battery could justify its inclusion in routine follow-up. Our results may have a potential to impact on the design of future follow-up strategies and interventions after OHCA. Trial registration: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018
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| 8. |
- Jahnson, Staffan, et al.
(författare)
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Thromboembolism in Muscle-Invasive Bladder Cancer : A Population-based Nationwide Study
- 2021
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Ingår i: Bladder Cancer. - : IOS Press. - 2352-3727 .- 2352-3735. ; 7:2, s. 161-171
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Routine VTE prophylaxis within 30 days of radical cystectomy (RC) for urinary bladder cancer (UBC) is used to protect from venous thromboembolism (VTE). However, randomized studies and nationwide population-based studies are lacking.OBJECTIVE: To study VTE and risk factors for VTE in muscle-invasive UBC in a nationwide population-based series, with a focus on the association with RC with and without chemotherapy.MATERIALS AND METHODS: We studied all patients with clinical stage T2-T4 UBC diagnosed 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe). Previous VTE events and risk factors for VTE were registered from 1987. Cox regression analyses and Kaplan-Meier curves were performed to study risk factors for VTE and cumulative incidence of VTE.RESULTS: In 9720 patients (71% males) with a median age of 74 years 546 (5.6%) had VTE after diagnosis. In Cox analyses controlling for patient's and tumour characteristics, and risk factors for VTE, VTE after diagnosis and first treatment date were associated with chemotherapy with or without RC. Cumulative incidence of VTE increased during 24 months after diagnosis and first treatment date. VTE were less common in patients with previous cardiovascular disease.CONCLUSION: VTE was commonly observed after 30 days from diagnosis and from first treatment date in patients with T2-T4 UBC, particularly after chemotherapy. The findings suggest that long-term intervention studies of benefit and possible harms of VTE prophylaxis after UBC should be undertaken.
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| 9. |
- Jerlström, Tomas, 1969-, et al.
(författare)
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No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy : a nation-wide register-based study
- 2020
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Ingår i: World journal of urology. - : Springer. - 0724-4983 .- 1433-8726. ; 38:2, s. 381-388
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking.METHODS: We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not.RESULTS: Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82-1.39) or mortality (OR 0.75 95% CI 0.36-1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30-0.81).CONCLUSION: This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.
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| 10. |
- Moseby-Knappe, Marion, et al.
(författare)
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Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators
- 2022
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Ingår i: Resuscitation Plus. - : Elsevier. - 2666-5204. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys (R) electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.
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