Ingela Franck Lissbrant

Vascular density is a predictor of cancer‐specific survival in prostatic carcinoma

Microvessel density has been shown to give prognostic information in a variety of solid tumors, but its role in prostatic carcinoma needs further elucidation.

TESTOSTERONE INDUCES VASCULAR ENDOTHELIAL GROWTH FACTOR SYNTHESIS IN THE VENTRAL PROSTATE IN CASTRATED RATS

PURPOSE Recent studies suggest that the vasculature is important for the control of prostate growth. Castration induces an involution of the prostate gland and its vasculature. Replacement of testosterone stimulates endothelial cell proliferation and normalizes vascular volumes and blood flow several days before organ regrowth. Antiangiogenesis treatment inhibits the growth of prostate tumors. Understanding the regulation of the prostate vasculature may therefore provide important knowledge of the mechanisms responsible for the growth of non-malignant and malignant prostate tissue. Castration induced regression and testosterone stimulated regrowth of the prostatic vasculature have here been used to study the involvement of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptors flt-1 and flk-1/KDR in the regulation of the prostatic vasculature. MATERIALS AND METHODS VEGF, flt-1, and flk-1/KDR levels were quantified in the rat ventral prostate following castration and testosterone replacement. Methods used were competitive RT-PCR, Western blot and immunohistochemistry. RESULTS VEGF mRNA and protein levels were significantly decreased by castration and testosterone treatment induced VEGF synthesis in the rat ventral prostate epithelium. Flt-1 and flk-1/KDR receptor levels were unaffected by castration and testosterone treatment. CONCLUSIONS Castration down regulates VEGF and testosterone induces VEGF synthesis in epithelial cells in the rat ventral prostate.

Blood Vessels are Regulators of Growth, Diagnostic Markers and Therapeutic Targets in Prostate Cancer

The vasculature plays an important role in the normal and malignant prostate. Under basal conditions both glandular epithelial and stromal prostate cells produce an abundance of blood flow and angiogenesis regulating substances and the expression of these is generally increased in prostate tumors. The proportion of proliferating endothelial cells is high in the normal prostate compared to other tissues in the body. After castration effects on the vasculature, such as decreased blood flow and vascular regression, precede effects on the glandular compartment. Correspondingly, hormone induced prostate growth is characterized by early effects on the vasculature such as increased blood flow and endothelial cell proliferation, thus indicating that the vasculature may be involved in the androgenic regulation of the prostate. Prostatic intraepithelial neoplasia (PIN) and prostate cancer are associated with increased vascular density and in experimental models prostate cancer growth is apparently angiogenesis-dependent since tumor growth and progression can be inhibited by antiangiogenic treatment. Moreover, vascular density has been related to prognosis in prostate cancer patients. A better understanding of the pathways regulating angiogenesis in the normal prostate and how these pathways change during malignant transformation can hopefully lead to better prognostic markers and therapies for the large group of patients with prostate cancer. The purpose of this review is therefore to summarize the current knowledge on the role and regulation of the vasculature in the prostate and its potential clinical applications.The vasculature plays an important role in the normal and malignant prostate. Under basal conditions both glandular epithelial and stromal prostate cells produce an abundance of blood flow and angiogenesis regulating substances and the expression of these is generally increased in prostate tumors. The proportion of proliferating endothelial cells is high in the normal prostate compared to other tissues in the body. After castration effects on the vasculature, such as decreased blood flow and vascular regression, precede effects on the glandular compartment. Correspondingly, hormone induced prostate growth is characterized by early effects on the vasculature such as increased blood flow and endothelial cell proliferation, thus indicating that the vasculature may be involved in the androgenic regulation of the prostate. Prostatic intraepithelial neoplasia (PIN) and prostate cancer are associated with increased vascular density and in experimental models prostate cancer growth is apparently angiogenesis-dependent since tumor growth and progression can be inhibited by antiangiogenic treatment. Moreover, vascular density has been related to prognosis in prostate cancer patients. A better understanding of the pathways regulating angiogenesis in the normal prostate and how these pathways change during malignant transformation can hopefully lead to better prognostic markers and therapies for the large group of patients with prostate cancer. The purpose of this review is therefore to summarize the current knowledge on the role and regulation of the vasculature in the prostate and its potential clinical applications.

Evaluation of the 2015 Gleason Grade Groups in a Nationwide Population-based Cohort

BACKGROUND New five-tiered Gleason grade groups (GGGs) were recently proposed, in which Gleason 6 is GGG 1, Gleason 3+4 is GGG 2, Gleason 4+3 is GGG 3, Gleason 8 is GGG 4, and Gleason 9-10 is GGG 5. OBJECTIVE To examine the performance of the new GGGs in men with prostate cancer from a nationwide population-based cohort. DESIGN, SETTING, AND PARTICIPANTS From the National Prostate Cancer Register of Sweden, we identified 5880 men diagnosed with prostate cancer from 2005 to 2007, including 4325 who had radical prostatectomy and 1555 treated with radiation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Kaplan-Meier survival analysis, Cox proportional hazards models, and concordance indices were used to examine the relationship between the GGGs and biochemical recurrence after radical prostatectomy and radiation therapy. RESULTS AND LIMITATIONS Among men treated with surgery, the 4-yr biochemical recurrence-free survival rates were 89%, 82%, 74%, 77%, and 49% for GGG 1-5 on biopsy, and 92%, 85%, 73%, 63%, and 51% based on prostatectomy GGG, respectively. For men treated by radiation therapy, men with biopsy GGG of 1-5 had 4-yr biochemical recurrence-free survival rates of 95%, 91%, 85%, 78%, and 70%. Adjusting for preoperative serum prostate-specific antigen and clinical stage, biopsy GGGs were significant independent predictors of biochemical recurrence after radical prostatectomy and radiation therapy. The new 5-tier system resulted in virtually no change in predictive accuracy compared with the current 3- and 4-tier classifications. Limitations include a median follow-up of 4.6 yr, precluding the ability to examine long-term oncologic outcomes. CONCLUSIONS The newly proposed GGGs offer a simplified, user-friendly nomenclature to aid in patient counseling, with similar predictive accuracy in a population-based setting to previous classifications. PATIENT SUMMARY The new Gleason grade groups, ranging from 1-5, provide a simplified, user-friendly classification system to predict the risk of recurrence after prostatectomy and radiation therapy.

Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors

Abstract Endothelial cells in the intact adult are, apart from those in the female reproductive organs, believed to be quiescent. Systematic examination of endothelial cell proliferation in male reproductive organs has not been performed and was therefore the aim of the present study. Intact adult rats were either pulse labeled or long-term labeled with bromodeoxyuridine to label proliferating cells. The roles of Leydig cells and testosterone were examined after castration or treatment with the Leydig cell toxin ethane dimethane sulfonate (EDS) and testosterone substitution. After perfusion fixation, all blood vessels remained open and were easily identified. In all male reproductive organs studied, particularly in the testis and epididymis, endothelial cell proliferation was considerably higher than in other tissues such as the liver, brain, and muscle. Proliferating endothelial cells were observed in all types of blood vessels in male reproductive organs, but other characteristics of new blood vessel formation were not seen. High endothelial cell proliferation may reflect a continuous high turnover of endothelial cells rather than classical angiogenesis. In the epididymis, the ventral and dorsolateral prostate lobes, and the seminal vesicles, endothelial cell proliferation decreased after testosterone withdrawal and increased following testosterone treatment. In the testis, endothelial cell proliferation was decreased after Leydig cell depletion but remained low after testosterone substitution. High, hormonally regulated endothelial cell proliferation is not unique to the female but is also seen in the male reproductive organs.

Localized Expression of Angiopoietin 1 and 2 May Explain Unique Characteristics of the Rat Testicular Microvasculature

Abstract The testicular vasculature is unique in several ways. The unfenestrated endothelial cells constitute one part of the blood-testis barrier, and testicular microvessels are normally resistant to inflammation mediators. At the same time that angiogenic factors and inflammation mediators are constitutively produced, the proportion of proliferating endothelial cells is considerably higher than in other organs, but new blood vessels are not formed. Hormonal stimulation of the testis with hCG increase endothelial cell proliferation, vascular permeability, and sensitivity to locally injected inflammation mediators. In the present study, we examined whether local expression of angiopoietin (ang) 1, an inhibitor of vascular leakage and sprouting angiogenesis, and its antagonist, ang 2, could be involved in establishing this vascular phenotype. Using reverse transcription-polymerase chain reaction and immunohistochemistry, we demonstrate that testicular vascular endothelial growth factor-A (VEGF-A), ang 1, ang 2, and the ang-receptor tie 2 are expressed in the testis and that hormonal stimulation with hCG is accompanied by increased expression of VEGF-A and ang 2. The ang 1 protein is expressed in testicular microvessels under basal conditions, and it is largely unaffected after hCG stimulation. Expression of ang 2 in microvessels, in contrast, is low under basal conditions and is up-regulated by hCG. Intratesticular injection of human recombinant ang 1 protein inhibits hCG-induced increase in vascular permeability. Injection of ang 2 in the testis increases endothelial cell proliferation and the volume of the interstitial space. We therefore suggest that ang 1 stabilizes testicular microvessels under basal conditions and that a shift in this balance caused by increased ang 2, together with increased VEGF-A, allows vascular leakage, high endothelial cell proliferation, and presumably, vascular growth after hormonal stimulation.

Population‐based study of long‐term functional outcomes after prostate cancer treatment

To evaluate long‐term urinary, sexual and bowel functional outcomes after prostate cancer treatment at a median (interquartile range) follow‐up of 12 (11–13) years.

Population-based study on use of chemotherapy in men with castration resistant prostate cancer

Abstract Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that men who died of prostate cancer (PCa) underwent a period of CRPC before they died. Results. Among the 2677 men who died from PCa during the study inclusion period, 556 (21%) had received chemotherapy (intravenous or per oral) detectable within the observation period in SALT database. Specifically, 239 (61%) of men < 70 years had received chemotherapy, 246 (30%) of men between 70 and 79 years and 71 (5%) men older than 80 years. The majority of men 465/556 (84%) had received a docetaxel-containing regimen. Among chemotherapy treated men, 283/556 (51%) received their last dose of chemotherapy during the last six months prior to death. Treatment with chemotherapy was more common among men with little comorbidity and high educational level, as well as in men who had received curatively intended primary treatment. Conclusion. A majority of men younger than 70 years with CRPC were treated with chemotherapy in contrast to men between 70 and 79 years of whom half as many received chemotherapy. Chemotherapy treatment was often administered shortly prior to death. The low uptake of chemotherapy in older men with CRPC may be caused by concerns about tolerability of treatment, as well as treatment decisions based on chronological age rather than global health status.

Association of Radical Local Treatment with Mortality in Men with Very High-risk Prostate Cancer: A Semiecologic, Nationwide, Population-based Study

BACKGROUND Current guidelines recommend androgen deprivation therapy only for men with very high-risk prostate cancer (PCa), but there is little evidence to support this stance. OBJECTIVE To investigate the association between radical local treatment and mortality in men with very high-risk PCa. DESIGN, SETTING, AND PARTICIPANTS Semiecologic study of men aged <80 yr within the Prostate Cancer data Base Sweden, diagnosed in 1998-2012 with very high-risk PCa (local clinical stage T4 and/or prostate-specific antigen [PSA] level 50-200ng/ml, any N, and M0). Men with locally advanced PCa (local clinical stage T3 and PSA level <50ng/ml, any N, and M0) were used as positive controls. INTERVENTION Proportion of men who received prostatectomy or full-dose radiotherapy in 640 experimental units defined by county, diagnostic period, and age at diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCa and all-cause mortality rate ratios (MRRs). RESULTS AND LIMITATIONS Both PCa and all-cause mortality were half as high in units in the highest tertile of exposure to radical local treatment compared with units in the lowest tertile (PCa MRR: 0.51; 95% confidence interval [CI], 0.28-0.95; and all-cause MRR: 0.56; 95% CI, 0.33-0.92). The results observed for locally advanced PCa for highest versus lowest tertile of exposure were in agreement with results from randomized trials (PCa MRR: 0.75; 95% CI, 0.60-0.94; and all-cause MRR: 0.85; 95% CI, 0.72-1.00). Although the semiecologic design minimized selection bias on an individual level, the effect of high therapeutic activity could not be separated from that of high diagnostic activity. CONCLUSIONS The substantially lower mortality in units with the highest exposure to radical local treatment suggests that radical treatment decreases mortality even in men with very high-risk PCa for whom such treatment has been considered ineffective. PATIENT SUMMARY Men with very high-risk prostate cancer diagnosed and treated in units with the highest exposure to surgery or radiotherapy had a substantially lower mortality.

Dashboard report on performance on select quality indicators to cancer care providers

Abstract Objective: Cancer quality registers are attracting increasing attention as important, but still underutilized sources of clinical data. To optimize the use of registers in quality assurance and improvement, data have to be rapidly collected, collated and presented as actionable, at-a-glance information to the reporting departments. This article presents a dashboard performance report on select quality indicators to cancer care providers. Materials and methods: Ten quality indicators registered on an individual patient level in the National Prostate Cancer Register of Sweden and recommended by the National Prostate Cancer Guidelines were selected. Data reported to the National Prostate Cancer Register are uploaded within 24 h to the Information Network for Cancer Care platform. Launched in 2014, “What’’s Going On, Prostate Cancer” provides rapid, at-a-glance performance feedback to care providers. Results: The indicators include time to report to the National Prostate Cancer Register, waiting times, designated clinical nurse specialist, multidisciplinary conference, adherence to guidelines for diagnostic work-up and treatment, and documentation and outcome of treatment. For each indicator, three performance levels were defined. Conclusion: What’s Going On, a dashboard performance report on 10 selected quality indicators to cancer care providers, provides an example of how data in cancer quality registers can be transformed into condensed, at-a-glance information to be used as actionable metrics for quality assurance and improvement.