Martin Højgaard - Academia.edu (original) (raw)
Papers by Martin Højgaard
Cancer Research
Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations pr... more Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations predicted to exhibit synthetic lethality with ATRi (STEP2 genes). Biomarker analyses from TRESR (NCT04497116) identified predictors of sensitivity to RP-3500. Methods: Biomarker data were centrally assessed from: Tumor/normal sequencing including zygosity analysis (SNiPDx targeted NGS panel), ctDNA, and ATM IHC. Correlations with clinical outcomes: Overall Response (OR: RECIST 1.1 confirmed/unconfirmed CR/PR, PSA or CA125 response), PFS, and CBR (OR or therapy duration >16 weeks [w]) were assessed. Results: 120 pts (ovarian [n=22], prostate [n=22], breast [n=17], pancreatic [n=12], other [n=47]) with LOF alterations (ATM [n=44], BRCA1 [n=25], BRCA2 [n=15], CDK12 [n=9], RNASEH2 [n=5], PALB2 [n=5], SETD2 [n=5], other [n=12]) were enrolled based on local tumor NGS (n=71), germline testing (n=29), ctDNA (n=13), or IHC (n=7). Prior therapies included PARPi (39/120) and platinum (81/120). Loc...
Cancer Research
Purpose: The purpose of this study was to identify mechanisms of resistance to BRAF targeted ther... more Purpose: The purpose of this study was to identify mechanisms of resistance to BRAF targeted therapy using proteomics together with genomics and transcriptomics in patients with BRAFV600E mutated solid tumors. Experimental procedures: A total of nine patients with BRAFV600E mutated advanced solid tumors (5 with colorectal cancer, 2 with neuroendocrine carcinoma, 1 with cholangiocarcinoma and 1 with breast cancer) treated with BRAF targeted therapy (BRAF inhibitor in combination with either MEK inhibitor and/or EGRF antibody) as part of the Copenhagen Prospective Personalized Oncology study, were included in this study. Tumor biopsies at baseline and at disease progression were analyzed with whole exome/genome sequencing (WES/WGS), transcriptomics (RNA sequencing) and proteomics. Genomic variants were analyzed together with changes in protein expression. Three filtering steps were used to identify potential resistance mechanisms from the proteomics measurements. Proteins were filtere...
Journal of Clinical Oncology
3082 Background: RP-3500 is a selective and potent oral ATRi in development for advanced solid tu... more 3082 Background: RP-3500 is a selective and potent oral ATRi in development for advanced solid tumors harboring loss-of-function (LOF) alterations in genes associated with ATRi sensitivity. We determined whether ctDNA can facilitate enrollment/monitoring of pts treated with RP-3500. Methods: Serial plasma samples collected at baseline (BL, 99 pts) and early timepoints on therapy (89 pts, 3-9 weeks [wks]) were profiled for ctDNA (Tempus xF or Guardant360). Targeted next generation sequencing (NGS) (SNiPDx panel) was performed on matched peripheral blood mononuclear cells and tumor samples collected at BL. Molecular ctDNA response (MR) was defined as ≥50% reduction in mean variant allele frequency (VAF) from BL to any timepoint ≤9 wks on-therapy. Clonal hematopoiesis (CH) or germline alterations were excluded from the analysis. Efficacy was assessed in pts treated with > 100 mg RP-3500/day with ≥1 post-BL response assessment. Endpoints included progression-free survival (PFS) and c...
Neuro-Oncology, 2021
Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) ... more Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 1...
![Research paper thumbnail of [Trends in oncological phase I trials]](https://attachments.academia-assets.com/88901670/thumbnails/1.jpg)
](This review summarises the current knowledge of anticancer therapy. More than 1,100 cancer drugs ... more This review summarises the current knowledge of anticancer therapy. More than 1,100 cancer drugs are currently under development in the United States. The increasing biological insight and platforms for high throughput screening of drugs have changed the developmental landscape of anticancer therapies from classical cytotoxic agents to targeted agents and immunotherapy. There is an increasing number of targeted agents, which are only efficacious in tumours harbouring specific genomic alterations in early clinical development. Furthermore, the landscape of immunotherapy broadens, and personalised immunotherapy is in development. The integration of genomic testing into early clinical oncology trials is increasing.
Free Radical Biology and Medicine, 2015
precluding effect of silymarin on DEN initiated and Fe-NTA promoted renal tumorigenesis in Swiss ... more precluding effect of silymarin on DEN initiated and Fe-NTA promoted renal tumorigenesis in Swiss albino mice. PCNA immunohistochemistry revealed an elevation in renal cell proliferation in DEN/Fe-NTA tumorigenesis. 20 weeks of promotion with twice weekly administration of Fe-NTA (9 mg/kg bd wt, i.p.) to DEN initiated mice led to development of renal adenocarcinoma with acinar or papillary type of growth pattern with a significant leukocyte infiltration. Feeding of silymarin (0.5% silymarin diet) conferred a significant attenuation in PCNA staining and also protected against most pathological alterations. The molecular mechanisms implicated in antitumor promoting effect of silymarin were investigated. Single administration of Fe-NTA (9 mg/kg bd wt, i.p.) significantly induced COX-2 and iNOS expressions, augmented the serum IL-6 and TNF-levels and also led to a marked and a progressive increase in metallothionein (MT) expression. Pretreatment of mice with dietary silymarin not only reduced the COX-2 and iNOS expressions, but also significantly and dose dependently ameliorated the levels of the inflammatory cytokines. MT was found to be over-expressed in these animals. Fe-NTA also led to a concomitant augmentation in lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE) and protein oxidation such as 8hydroxy-20-deoxyguanosine (8-OHdG) and protein reactive carbonyl. Immunohistochemical studies of renal tissue revealed a significant and dose dependent decline in 4-HNE modified proteins, 8-OHdG and protein reactive carbonyl with prophylactic feeding of animals with 1.0% silymarin in diet for 4 weeks. Taken together, these results indicate silymarin to confer a potent protection against DEN/Fe-NTA renal carcinogenesis. Crucial target points at which silymarin exerts its effect probably include pro-inflammatory cytokines, MT protein and renal oxidative stress.
Basic & Clinical Pharmacology & Toxicology, 2014
Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alterna... more Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high-dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first-order elimination kinetics throughout the dosing range with supra-physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half-life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first-order elimination with half-life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.
Cancer Research
Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity... more Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification and characterization of germline variants in malignant mesothelioma is relevant for identifying potential actionable targets and genetic counseling of family members. Methods: Patients referred to the Phase I Unit at Rigshospitalet were prospectively enrolled into the Copenhagen Prospective Personalized Oncology trial and underwent whole exome sequencing for somatic and germline variants. Between January 2014 and September 2021, 45 patients with MM were identified and 40 patients underwent whole exome sequencing. Germline variants were selected according to association to inherited cancer using a 168-gene panel and variants were classified according to ACMG/AMP classification as pathological (class 5) or likely pathogenic (class 4). Results: 34 males (85%) and 6 females (15%) with a median age of 64 years (range: 43-77) were available for...
Oral Presentations - Proffered Abstracts
Translational Andrology and Urology
Background: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only b... more Background: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only be achieved through intravenous (IV) administration in humans. Treatment with intravenous AA is widely and increasingly used in complementary medicine despite a lack of clinical evidence for the efficacy of this treatment. Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g; week 2, 30 g; and weeks 3-12, 60 g) followed by efficacy evaluation at 12 weeks. The primary endpoint for efficacy was a 50% reduction in the prostate-specific antigen (PSA) level. The secondary endpoints included changes in health-related quality of life (HRQoL), biomarkers of bone metabolism, inflammation and bone scans. Clinicaltrials.gov identifier: NCT01080352. Results: Twenty-three patients were enrolled in this study, and 20 completed the efficacy evaluation at 12 weeks. The mean baseline PSA level was 43 µg/L. No patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 µg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did not result in disease remission. This study does not support the use of intravenous AA outside clinical trials.
Case Reports in Nephrology and Urology, 2012
This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCo... more This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online version of the article only. Distribution for non-commercial purposes only.
Advanced Healthcare Materials
Ugeskrift for laeger, Jan 17, 2014
Scandinavian Journal of Urology and Nephrology, 2010
Photoselective vaporization of the prostate is a relatively new surgical modality for male lower ... more Photoselective vaporization of the prostate is a relatively new surgical modality for male lower urinary tract symptoms. The method has a risk of tissue damage if laser pulses miss the prostatic adenoma and travel through the irrigation fluid in the bladder. Five cases of damage to the ureteral orifices are described, with hidden orifices, intravesical prostatic adenomas and prior prostatectomy as risk factors for laser-related injuries to ureteral orifices. A laser-coagulated ureteral orifice does not seem to regain patency spontaneously, so rapid nephrostomy and subsequent DJ stenting is recommended.
Experimental Physiology, 2006
We evaluated the effect of central blood volume on the MAP response to exercise by determining pl... more We evaluated the effect of central blood volume on the MAP response to exercise by determining plasma atrial natriuretic peptide (ANP) during moderate upright and supine A, L and combined arm and leg exercise (A + L) in 11 male subjects. In the upright position, MAP was higher during A than at rest (102 ± 6 versus 89 ± 6 mmHg; mean ± S.D.) and during L (95 ± 7 mmHg; P < 0.05), but similar to that during A + L (100 ± 6 mmHg). There was no significant change in plasma ANP during A, while plasma ANP was higher during L and A + L (42.7 ± 12.2 and 43.3 ± 17.1 pg ml −1 , respectively) than at rest (34.6 ± 14.3 pg ml −1 , P < 0.001). In the supine position, MAP was also higher during A than at rest (100 ± 7 versus 86 ± 5 mmHg) and during L (92 ± 5 mmHg; P < 0.01) but similar to that during A + L (102 ± 6 mmHg). During supine A, plasma ANP was higher than at rest and during L but lower than during A + L .0 pg ml −1 , respectively; P < 0.05). Thus, upright A was the exercise mode that did not enhance plasma ANP, suggesting that central blood volume did not increase. The results suggest that the similar blood pressure response to A and to A + L may relate to the enhanced central blood volume following the addition of leg to arm exercise.
Basic & Clinical Pharmacology & Toxicology, 2014
Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alterna... more Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high-dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first-order elimination kinetics throughout the dosing range with supra-physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half-life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first-order elimination with half-life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.
Cancer Research
Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations pr... more Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations predicted to exhibit synthetic lethality with ATRi (STEP2 genes). Biomarker analyses from TRESR (NCT04497116) identified predictors of sensitivity to RP-3500. Methods: Biomarker data were centrally assessed from: Tumor/normal sequencing including zygosity analysis (SNiPDx targeted NGS panel), ctDNA, and ATM IHC. Correlations with clinical outcomes: Overall Response (OR: RECIST 1.1 confirmed/unconfirmed CR/PR, PSA or CA125 response), PFS, and CBR (OR or therapy duration >16 weeks [w]) were assessed. Results: 120 pts (ovarian [n=22], prostate [n=22], breast [n=17], pancreatic [n=12], other [n=47]) with LOF alterations (ATM [n=44], BRCA1 [n=25], BRCA2 [n=15], CDK12 [n=9], RNASEH2 [n=5], PALB2 [n=5], SETD2 [n=5], other [n=12]) were enrolled based on local tumor NGS (n=71), germline testing (n=29), ctDNA (n=13), or IHC (n=7). Prior therapies included PARPi (39/120) and platinum (81/120). Loc...
Cancer Research
Purpose: The purpose of this study was to identify mechanisms of resistance to BRAF targeted ther... more Purpose: The purpose of this study was to identify mechanisms of resistance to BRAF targeted therapy using proteomics together with genomics and transcriptomics in patients with BRAFV600E mutated solid tumors. Experimental procedures: A total of nine patients with BRAFV600E mutated advanced solid tumors (5 with colorectal cancer, 2 with neuroendocrine carcinoma, 1 with cholangiocarcinoma and 1 with breast cancer) treated with BRAF targeted therapy (BRAF inhibitor in combination with either MEK inhibitor and/or EGRF antibody) as part of the Copenhagen Prospective Personalized Oncology study, were included in this study. Tumor biopsies at baseline and at disease progression were analyzed with whole exome/genome sequencing (WES/WGS), transcriptomics (RNA sequencing) and proteomics. Genomic variants were analyzed together with changes in protein expression. Three filtering steps were used to identify potential resistance mechanisms from the proteomics measurements. Proteins were filtere...
Journal of Clinical Oncology
3082 Background: RP-3500 is a selective and potent oral ATRi in development for advanced solid tu... more 3082 Background: RP-3500 is a selective and potent oral ATRi in development for advanced solid tumors harboring loss-of-function (LOF) alterations in genes associated with ATRi sensitivity. We determined whether ctDNA can facilitate enrollment/monitoring of pts treated with RP-3500. Methods: Serial plasma samples collected at baseline (BL, 99 pts) and early timepoints on therapy (89 pts, 3-9 weeks [wks]) were profiled for ctDNA (Tempus xF or Guardant360). Targeted next generation sequencing (NGS) (SNiPDx panel) was performed on matched peripheral blood mononuclear cells and tumor samples collected at BL. Molecular ctDNA response (MR) was defined as ≥50% reduction in mean variant allele frequency (VAF) from BL to any timepoint ≤9 wks on-therapy. Clonal hematopoiesis (CH) or germline alterations were excluded from the analysis. Efficacy was assessed in pts treated with > 100 mg RP-3500/day with ≥1 post-BL response assessment. Endpoints included progression-free survival (PFS) and c...
Neuro-Oncology, 2021
Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) ... more Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 1...
This review summarises the current knowledge of anticancer therapy. More than 1,100 cancer drugs ... more This review summarises the current knowledge of anticancer therapy. More than 1,100 cancer drugs are currently under development in the United States. The increasing biological insight and platforms for high throughput screening of drugs have changed the developmental landscape of anticancer therapies from classical cytotoxic agents to targeted agents and immunotherapy. There is an increasing number of targeted agents, which are only efficacious in tumours harbouring specific genomic alterations in early clinical development. Furthermore, the landscape of immunotherapy broadens, and personalised immunotherapy is in development. The integration of genomic testing into early clinical oncology trials is increasing.
Free Radical Biology and Medicine, 2015
precluding effect of silymarin on DEN initiated and Fe-NTA promoted renal tumorigenesis in Swiss ... more precluding effect of silymarin on DEN initiated and Fe-NTA promoted renal tumorigenesis in Swiss albino mice. PCNA immunohistochemistry revealed an elevation in renal cell proliferation in DEN/Fe-NTA tumorigenesis. 20 weeks of promotion with twice weekly administration of Fe-NTA (9 mg/kg bd wt, i.p.) to DEN initiated mice led to development of renal adenocarcinoma with acinar or papillary type of growth pattern with a significant leukocyte infiltration. Feeding of silymarin (0.5% silymarin diet) conferred a significant attenuation in PCNA staining and also protected against most pathological alterations. The molecular mechanisms implicated in antitumor promoting effect of silymarin were investigated. Single administration of Fe-NTA (9 mg/kg bd wt, i.p.) significantly induced COX-2 and iNOS expressions, augmented the serum IL-6 and TNF-levels and also led to a marked and a progressive increase in metallothionein (MT) expression. Pretreatment of mice with dietary silymarin not only reduced the COX-2 and iNOS expressions, but also significantly and dose dependently ameliorated the levels of the inflammatory cytokines. MT was found to be over-expressed in these animals. Fe-NTA also led to a concomitant augmentation in lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE) and protein oxidation such as 8hydroxy-20-deoxyguanosine (8-OHdG) and protein reactive carbonyl. Immunohistochemical studies of renal tissue revealed a significant and dose dependent decline in 4-HNE modified proteins, 8-OHdG and protein reactive carbonyl with prophylactic feeding of animals with 1.0% silymarin in diet for 4 weeks. Taken together, these results indicate silymarin to confer a potent protection against DEN/Fe-NTA renal carcinogenesis. Crucial target points at which silymarin exerts its effect probably include pro-inflammatory cytokines, MT protein and renal oxidative stress.
Basic & Clinical Pharmacology & Toxicology, 2014
Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alterna... more Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high-dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first-order elimination kinetics throughout the dosing range with supra-physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half-life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first-order elimination with half-life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.
Cancer Research
Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity... more Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification and characterization of germline variants in malignant mesothelioma is relevant for identifying potential actionable targets and genetic counseling of family members. Methods: Patients referred to the Phase I Unit at Rigshospitalet were prospectively enrolled into the Copenhagen Prospective Personalized Oncology trial and underwent whole exome sequencing for somatic and germline variants. Between January 2014 and September 2021, 45 patients with MM were identified and 40 patients underwent whole exome sequencing. Germline variants were selected according to association to inherited cancer using a 168-gene panel and variants were classified according to ACMG/AMP classification as pathological (class 5) or likely pathogenic (class 4). Results: 34 males (85%) and 6 females (15%) with a median age of 64 years (range: 43-77) were available for...
Oral Presentations - Proffered Abstracts
Translational Andrology and Urology
Background: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only b... more Background: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only be achieved through intravenous (IV) administration in humans. Treatment with intravenous AA is widely and increasingly used in complementary medicine despite a lack of clinical evidence for the efficacy of this treatment. Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g; week 2, 30 g; and weeks 3-12, 60 g) followed by efficacy evaluation at 12 weeks. The primary endpoint for efficacy was a 50% reduction in the prostate-specific antigen (PSA) level. The secondary endpoints included changes in health-related quality of life (HRQoL), biomarkers of bone metabolism, inflammation and bone scans. Clinicaltrials.gov identifier: NCT01080352. Results: Twenty-three patients were enrolled in this study, and 20 completed the efficacy evaluation at 12 weeks. The mean baseline PSA level was 43 µg/L. No patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 µg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did not result in disease remission. This study does not support the use of intravenous AA outside clinical trials.
Case Reports in Nephrology and Urology, 2012
This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCo... more This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online version of the article only. Distribution for non-commercial purposes only.
Advanced Healthcare Materials
Ugeskrift for laeger, Jan 17, 2014
Scandinavian Journal of Urology and Nephrology, 2010
Photoselective vaporization of the prostate is a relatively new surgical modality for male lower ... more Photoselective vaporization of the prostate is a relatively new surgical modality for male lower urinary tract symptoms. The method has a risk of tissue damage if laser pulses miss the prostatic adenoma and travel through the irrigation fluid in the bladder. Five cases of damage to the ureteral orifices are described, with hidden orifices, intravesical prostatic adenomas and prior prostatectomy as risk factors for laser-related injuries to ureteral orifices. A laser-coagulated ureteral orifice does not seem to regain patency spontaneously, so rapid nephrostomy and subsequent DJ stenting is recommended.
Experimental Physiology, 2006
We evaluated the effect of central blood volume on the MAP response to exercise by determining pl... more We evaluated the effect of central blood volume on the MAP response to exercise by determining plasma atrial natriuretic peptide (ANP) during moderate upright and supine A, L and combined arm and leg exercise (A + L) in 11 male subjects. In the upright position, MAP was higher during A than at rest (102 ± 6 versus 89 ± 6 mmHg; mean ± S.D.) and during L (95 ± 7 mmHg; P < 0.05), but similar to that during A + L (100 ± 6 mmHg). There was no significant change in plasma ANP during A, while plasma ANP was higher during L and A + L (42.7 ± 12.2 and 43.3 ± 17.1 pg ml −1 , respectively) than at rest (34.6 ± 14.3 pg ml −1 , P < 0.001). In the supine position, MAP was also higher during A than at rest (100 ± 7 versus 86 ± 5 mmHg) and during L (92 ± 5 mmHg; P < 0.01) but similar to that during A + L (102 ± 6 mmHg). During supine A, plasma ANP was higher than at rest and during L but lower than during A + L .0 pg ml −1 , respectively; P < 0.05). Thus, upright A was the exercise mode that did not enhance plasma ANP, suggesting that central blood volume did not increase. The results suggest that the similar blood pressure response to A and to A + L may relate to the enhanced central blood volume following the addition of leg to arm exercise.
Basic & Clinical Pharmacology & Toxicology, 2014
Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alterna... more Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high-dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first-order elimination kinetics throughout the dosing range with supra-physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half-life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first-order elimination with half-life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.