Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial.

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.

Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation.

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.

Prostate cancer staging with extracapsular extension risk scoring using multiparametric MRI: a correlation with histopathology.

OBJECTIVES: To evaluate the diagnostic performance of preoperative multiparametric MRI with extracapsular extension (ECE) risk-scoring in the assessment of prostate cancer tumour stage (T-stage) and prediction of ECE at final pathology. MATERIALS AND METHODS: Eighty-seven patients with clinically localised prostate cancer scheduled for radical prostatectomy were prospectively enrolled. Multiparametric MRI was performed prior to prostatectomy, and evaluated according to the ESUR MR prostate guidelines by two different readers. An MRI clinical T-stage (cTMRI), an ECE risk score, and suspicion of ECE based on tumour characteristics and personal opinion were assigned. Histopathological prostatectomy results were standard reference. RESULTS: Histopathology and cTMRI showed a spearman rho correlation of 0.658 (p < 0.001) and a weighted kappa = 0.585 [CI 0.44;0.73](reader A). ECE was present in 31/87 (36 %) patients. ECE risk-scoring showed an AUC of 0.65-0.86 on ROC-curve for both readers, with sensitivity and specificity of 81 % and 78 % at best cutoff level (reader A), respectively. When tumour characteristics were influenced by personal opinion, the sensitivity and specificity for prediction of ECE changed to 61 %-74 % and 77 %-88 % for the readers, respectively. CONCLUSIONS: Multiparametric MRI with ECE risk-scoring is an accurate diagnostic technique in determining prostate cancer clinical tumour stage and ECE at final pathology. KEY POINTS: • Multiparametric MRI is an accurate diagnostic technique for preoperative prostate cancer staging • ECE risk scoring predicts extracapsular tumour extension at final pathology • ECE risk scoring shows an AUC of 0.86 on the ROC-curve • ECE risk scoring shows a moderate inter-reader agreement (K = 0.45) • Multiparametric MRI provides essential knowledge for optimal clinical management.

Early experience with multiparametric magnetic resonance imaging-targeted biopsies under visual transrectal ultrasound guidance in patients suspicious for prostate cancer undergoing repeated biopsy.

OBJECTIVES: The purpose of this study was to investigate the detection rate of prostate cancer (PCa) by multiparametric magnetic resonance imaging-targeted biopsies (mp-MRI-bx) in patients with prior negative transrectal ultrasound biopsy (TRUS-bx) sessions without previous experience of this. MATERIAL AND METHODS: Eighty-three patients with prior negative TRUS-bx scheduled for repeated biopsies due to persistent suspicion of PCa were prospectively enrolled. mp-MRI was performed before biopsy and all lesions were scored according to the Prostate Imaging Reporting and Data System (PI-RADS) and Likert classification. All underwent repeated TRUS-bx (10 cores) and mp-MRI-bx under visual TRUS guidance of any mp-MRI-suspicious lesion not targeted by systematic TRUS-bx. RESULTS: PCa was found in 39 out of 83 patients (47%) and mp-MRI identified at least one lesion with some degree of suspicion in all 39 patients. Both PI-RADS and Likert scoring showed a high correlation between suspicion of malignancy and biopsy results (p < 0.0001). Five patients (13%) had cancer detected only on mp-MRI-bx outside the TRUS-bx areas (p = 0.025) and another seven patients (21%) had an overall Gleason score upgrade of at least one grade based on the mp-MRI-bx. Secondary PCa lesions not visible on mp-MRI were detected by TRUS-bx in six out of 39 PCa patients. The secondary foci were all Gleason 6 (3 + 3) in 5-10% of the biopsy core. According to the Epstein criteria, 37 out of 39 cancer patients were classified as clinically significant. CONCLUSION: Using mp-MRI, even without previous experience, can improve the detection rate of significant PCa at repeated biopsy and allows more accurate Gleason grading.

Inoculation of Sphingobacterium multivorum in the prostate by prostate biopsy.

This report describes three cases of infection with Sphingobacterium multivorum after transrectal ultrasound-guided prostate biopsy. The pathogen is ubiquitous in water and soil but has been described fewer than 10 times causing infections in humans. An infection hygiene evaluation identified and changed a step in the biopsy process in order to reduce the risk of inoculating the patient with environmental microorganisms.

[The seven CanMEDS roles in postgraduate medical education should be revised]. / De syv lægeroller i den postgraduate uddannelse bør revideres.

The seven CanMEDS roles were adopted by the Danish reform in postgraduate medical education in 2004. The roles have become a natural part of defining specialist competence. However, the definition of the seven roles from 2000 might not be aligned with the perception of good medical practice anno 2013. It is recommended to redefine the seven roles to reach agreement with contemporary demands for specialist competence.

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy.

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group × time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity.

Adipose tissue exerts important endocrine and metabolic functions in health and disease. Yet the bioenergetics of this tissue is not characterized in humans and possible regional differences are not elucidated. Using high resolution respirometry, mitochondrial respiration was quantified in human abdominal subcutaneous and intra-abdominal visceral (omentum majus) adipose tissue from biopsies obtained in 20 obese patients undergoing bariatric surgery. Mitochondrial DNA (mtDNA) and genomic DNA (gDNA) were determined by the PCR technique for estimation of mitochondrial density. Adipose tissue samples were permeabilized and respirometric measurements were performed in duplicate at 37 degrees C. Substrates (glutamate (G) + malate (M) + octanoyl carnitine (O) + succinate (S)) were added sequentially to provide electrons to complex I + II. ADP ((D)) for state 3 respiration was added after GM. Uncoupled respiration was measured after addition of FCCP. Visceral fat contained more mitochondria per milligram of tissue than subcutaneous fat, but the cells were smaller. Robust, stable oxygen fluxes were found in both tissues, and coupled state 3 (GMOS(D)) and uncoupled respiration were significantly (P < 0.05) higher in visceral (0.95 +/- 0.05 and 1.15 +/- 0.06 pmol O(2) s(1) mg(1), respectively) compared with subcutaneous (0.76 +/- 0.04 and 0.98 +/- 0.05 pmol O(2) s(1) mg(1), respectively) adipose tissue. Expressed per mtDNA, visceral adipose tissue had significantly (P < 0.05) lower mitochondrial respiration. Substrate control ratios were higher and uncoupling control ratio lower (P < 0.05) in visceral compared with subcutaneous adipose tissue. We conclude that visceral fat is bioenergetically more active and more sensitive to mitochondrial substrate supply than subcutaneous fat. Oxidative phosphorylation has a higher relative activity in visceral compared with subcutaneous adipose tissue.

[Microsurgical varicocele operation: a retrospective statement of Danish results]. / Mikrokirurgisk varicoceleoperation: en retrospektiv opgørelse af danske resultater.

INTRODUCTION: Varicoceles are present in about 15% of the male population. The treatment is surgical and internationally there has been an increase in the use of a subinguinal microsurgical approach in which the veins of the spermatic cord are ligated. The purpose of this paper is to evaluate the results of the first microsurgical varicocelectomies performed in Denmark. MATERIAL AND METHODS: The medical records of boys and men who underwent microsurgical varicocelectomy between 1 February 1999 and 1 June 2007 at Rigshospitalet, Gentofte Hospital and Herlev Hospital, were reviewed. RESULTS: A total of 132 patients were included in the study. Ten recurrences (8%) and ten complications (8%) were found (one lesion of the vas deferens, six haematomas, two hydroceles and one patient with haematoma/infection). Following surgery, two patients underwent orchiectomy due to a lack of blood flow and sustained pain from the scrotum one year after the operation, respectively. When pain was the indication for surgery, resolution of this symptom was seen in 69 of 77 patients (90%). In one patient, the pain increased. After the implementation of a structured surgery schedule and after assigning the procedure to a single surgeon only, the number of recurrences and complications for the last 47 operated patients decreased to 0% and 4%, respectively. CONCLUSION: In trained hands microsurgical varicocelectomy was an effective method with few complications and recurrences.

[Recurrence of varicocele caused by renal tumour]. / Recidiv af varicocele forårsaget af renal tumor.

A 31-year-old man referred with six to seven years' history of a left-side WHO grade III varicocele and normal palpatory abdominal findings underwent microsurgical subinguinal varicocelectomy. At 3-month follow-up there was complete remission. The varicocele recurred after one year and abdominal ultrasound demonstrated a solid mass in the left kidney. A radical nephrectomy was performed and histology demonstrated renal cell carcinoma pT2. We recommend performing an abdominal ultrasound in adults if recurrence of a varicocele is detected following microsurgical subinguinal varicocelectomy.

[Treatment of localised prostate cancer]. / Behandling af lokaliseret prostatacancer.

The incidence of prostate cancer is increasing sharply in Denmark and an increasing proportion of patients have clinically localised disease at diagnosis. The therapeutic strategy encompasses intended curative therapy: radical prostatectomy with complete removal of the prostate gland and seminal vesicles performed as an open procedure or laparoscopically, external beam radiation therapy, or implantation of radioactive seeds into the prostate (brachytherapy). In older patients with good prognostic factors, active surveillance should be considered. The various therapeutic modalities are reviewed.

[Occupationally conditioned bladder cancer--are the patients identified?]. / Arbejdsbetinget blaerecancer--bliver patienterne fundet?

INTRODUCTION: A minor percentage of bladder cancer cases in Denmark are caused by occupational exposure to carcinogens. The disease is therefore also present on the National Board of Industrial Injuries' list of occupational diseases, and reporting of these is compulsory for Danish physicians. In spite of this, only very few cases are reported annually. The aim of this study was to examine whether sufficiently detailed information on occupational exposure was obtained from the patient at the time of diagnosis, and if this presumed lack of information could be the reason for the possible low number of reporting. MATERIAL AND METHODS: We have examined 82 medical records from bladder cancer patients admitted or treated at Herlev University Hospital in the period from 01.01 2002 to 06.16 2004. General information, including information on occupation, was noted and examined. RESULTS: 48 charts lacked occupational history or had an insufficient degree of information so that a possible occupational disease could not be excluded. In the remaining 34 medical records, there were four patients with a positive exposure history which should, therefore, have been reported. There was no information in the medical records as to whether this had been done. CONCLUSION: Medical records of many bladder cancer patients lack sufficient information on occupational exposure. The four cases that should have been reported furthermore suggest that the physicians need to be educated on the known exposures and on how to report a patient with a positive exposure history. This could be a considerable reason for the few annually reported cases.

[HCG in the treatment of cryptorchidism. The effect of age and position of the testis]. / Humant choriongonadotropin-behandling af kryptorkisme. Effekt af alder og testisplacering.

In a recent study, the effect of human chorionic gonadotropin (HCG) in the treatment of children with cryptorchidism aged less than four years was questioned. The purpose of the present study was to determine, on the basis of a retrospective examination of patients' records, the effect of HCG treatment, whether outcomes are age-dependent and whether the effects of treatment are related to the position of the testis. Patients diagnosed with undescended testis who had been treated at the Department of Urology at Gentofte Hospital (Copenhagen) in the period from 1 November 1998 to 31 May 2003 were identified. Patients who had been treated with HCG were included in the sample. Boys who at an earlier stage had been operated on in the inguinal or scrotal region, or who had suffered from inguinal hernia, were excluded, and clinical retractile testes were separated from true undescended testes. The criterion of success for efficient treatment was complete descent to the bottom of the scrotum. In the 306 records examined, 121 patients met the inclusion criteria. In total, there were 170 undescended testes. The patients' median age at time of treatment was 3.6 years. The overall success rate was 34.7%. The success rates in the individual age categories were: 1-2 years, 36.7%; 3-4 years, 33.4%; and 5-13 years, 35%. The position of the testis at the beginning of treatment showed that the lower the pretreatment position, the better the success rate. The overall success of HCG treatment of cryptorchidism was 34.7%. No age dependency of HCG effects was found, but the position of the testis before treatment influenced the success rate.

Physical training may enhance beta-cell function in type 2 diabetes.

In healthy young subjects, training increases insulin sensitivity but decreases the capacity to secrete insulin. We studied whether training changes beta-cell function in type 2 diabetic patients. Patients, stratified into "moderate" and "low" secretors according to individual C-peptide responses to an intravenous glucagon test, were randomly assigned to a training program [ergometer cycling 30-40 min/day, including at least 20 min at 75% maximum oxygen consumption (Vo(2 max)), 5 days/wk for 3 mo] or a sedentary schedule. Before and after the intervention (16 h after last training bout), a sequential hyperglycemic (90 min at 11, 18, and 25 mM) clamp was performed. An intravenous bolus of 5 g of arginine was given at the end. Training increased Vo(2 max) 17 +/- 13% and decreased heart rate during submaximal exercise (P < 0.05). During the 3 mo of sedentary lifestyle, insulin and C-peptide responses to the clamp procedures were unchanged in both moderate and low secretors. Likewise, no change in beta-cell response was seen after training in the low secretors (n = 5). In contrast, moderate secretors (n = 9) showed significant increases in beta-cell responses to 18 and 25 mM hyperglycemia and to arginine stimulation. Glucagon responses to arginine as well as measures of insulin sensitivity and Hb A(1c) levels were not altered by training. In conclusion, in type 2 diabetic patients, training may enhance beta-cell function if the remaining secretory capacity is moderate but not if it is low. The improved beta-cell function does not require changes in insulin sensitivity and Hb A(1c) concentration.