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Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGFß and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGFß or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

Objective: There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. Methods: This is part 1 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. It covers the early detection, diagnostics, staging, patient support and management of the non-metastatic disease. Part 2 covers recurrence after local treatment and management of the metastatic disease. Results: The 2022 Swedish guidelines include several new recommendations: rectal iodine-povidone to reduce post-biopsy infections, external beam radiation with focal boost to the tumour, use of a pre-rectal spacer to reduce rectal side effects after external beam radiotherapy in some expert centres, 6 months’ concomitant and adjuvant rather than neoadjuvant and concomitant hormonal treatment together with radiotherapy for unfavourable intermediate and high-risk disease, and adjuvant abiraterone plus prednisolone together with a GnRH agonist for a subgroup of men with very high-risk disease. The Swedish guidelines differ from the European by having more restrictive recommendations regarding genetic testing and pelvic lymph node dissection, the risk group classification, recommending ultra-hypofractionated (7 fractions) external radiotherapy for intermediate and selected high-risk cancers, by not recommending any hormonal treatment together with radiotherapy for favourable intermediate-risk disease, and by recommending bicalutamide monotherapy instead of a GnRH agonist for some patient groups. Conclusions: The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

Objective: There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. Methods: This is part 2 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. This part covers recurrence after local treatment and management of metastatic and castration resistant disease. Part 1 covers early detection, diagnostics, staging, patient support and management of non-metastatic disease. Results: The 2022 Swedish guidelines include several new recommendations. Among these is a recommendation of a period of observation with repeated PSA tests for patients with approximately 10 years’ life expectancy who experience a BCR more than 2–5 years after radical prostatectomy, to allow for estimating the PSA doubling time before deciding whether to give salvage radiotherapy or not. Recent results from the PEACE-1 trial led to the recommendation of triple-treatment with a GnRH agonist, abiraterone plus prednisolone and 6 cycles of docetaxel for patients with high-volume metastatic disease who are fit for chemotherapy. The Swedish guidelines differ from the European ones by having more restrictive recommendations about genetic testing of and high-dose zoledronic acid or denosumab treatment for men with metastatic prostate cancer, and by recommending considering bicalutamide monotherapy for selected patients with low-volume metastatic disease. Conclusions: The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

Background: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. Methods: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c–T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10–20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0–2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. Findings: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25–72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p

Purpose To quantify the relationship between the rectal dose distribution and the prevalence of self-reported rectal bleeding among men treated with salvage radiotherapy (ST) delivered by three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. To use this relationship to estimate the risk of rectal bleeding for a contemporary cohort of patients treated with volumetric modulated arc therapy (VMAT) ST. Methods and patients Rectal bleeding of any grade was reported by 56 (22%) of 255 men in a PROM-survey at a median follow-up of 6.7 years after 3DCRT ST. Treatment plan data were extracted and dose–response relationships for the rectal volumes receiving at least 35 Gy (V35Gy) or 63 Gy (V63Gy) were calculated with logistic regression. These relationships were used to estimate the risk of rectal bleeding for a cohort of 253 patients treated with VMAT ST. Results In the dose–response analysis of patients in the 3DCRT ST cohort, both rectal V35Gy and V63Gy were statistically significant parameters in univariable analysis (p = 0.005 and 0.003, respectively). For the dose–response models using either rectal V35Gy or V63Gy, the average calculated risk of rectal bleeding was 14% among men treated with VMAT ST compared to a reported prevalence of 22% for men treated with 3DCRT ST. Conclusions We identified dose–response relationships between the rectal dose distribution and the risk of self-reported rectal bleeding of any grade in a long-term perspective for men treated with 3DCRT ST. Furthermore, VMAT ST may have the potential to decrease the prevalence of late rectal bleeding.

To estimate the long-term risks of severe late toxicities for radiation therapy (RT) following radical prostatectomy (RP) in an unselected nationwide cohort, as severe side-effects are rare but may occur years later.The study population comprised all men undergoing RP between 1997 and 2016 in the Prostate Cancer database Sweden (PCBaSe) (n = 40 962). By (1:2) matching, two cohorts were created: 2789 men exposed to postoperative RT and 5578 unexposed men with comparable age, comorbidities, and year of surgery. Cumulative incidences and rate ratios were calculated for the following outcomes: symptoms and interventions of the urinary or intestinal tract demanding inpatient care, secondary malignancies, and non-prostate cancer mortality.The largest differences were seen for late toxicities affecting the urinary tract. The 10-year cumulative incidences among those exposed to postoperative RT vs the RP-only group were: 17.8% vs 10.5% for procedures of the urinary tract (difference 7.3%, 95% confidence interval [CI] 4.4 to 10.3; relative risk [RR] 1.74, 95% CI 1.47 to 2.05); 6.0% vs 1.2% for haematuria (difference 4.8%, 95% CI 3.1 to 6.5; RR 6.50, 95% CI 4.31 to 10.10); and 2.4% vs 1.1% for bladder cancer (difference 1.4%, 95% CI 0.4 to 2.3; RR 2.71, 95% CI 1.72 to 4.33). The groups were similar regarding intestinal toxicity, other secondary malignancies, and non-prostate cancer mortality. Adjustments for preoperative tumour risk factors did not importantly affect the rate ratios.Severe late toxicity after postoperative RT following RP predominately affects the bladder and can appear many years after RT.

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.

The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq ) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920–3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands.

Simple Summary A tremendous effort and rapid development of the prostate-specific membrane antigen (PSMA)-targeting radio ligands for radionuclide therapy has resulted in encouraging response rates for advanced prostate cancer. Different radionuclides have been utilized or suggested as suitable candidates. In this study, a dynamic model of metastatic progress was developed and utilized to estimate a radiopharmaceutical’s potential of obtaining metastatic control of advanced prostate cancer. The simulations performed demonstrated the advantage of utilizing radionuclides with short-range particle emission, i.e., alpha-emitters and low-energy electrons. The recently-proposed beta-emitting radionuclide terbium-161 demonstrates great potential of being a future candidate towards targeted radionuclide therapy of advanced prostate cancer. This is in line with recent encouraging preclinical results and development of upscaling the product quality. Recently, the first in-human application with a [161Tb]Tb-DOTATOC also demonstrated good SPECT image quality, which can enable dosimetry calculations for new 161Tb-based radiopharmaceuticals. Abstract The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920–3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands.

The extent of late side-effects in prostate cancer patients, after radical prostatectomy (RP = reference group) and salvage radiation therapy (SRT) in a self-reporting perspective (PROM) is still under-reported. We aimed to investigate the rate and severity of side-effects and quality-of-life (QoL) according to PROM.A PROM survey was administered to a cohort of SRT patients matched to a reference group with median follow-up 10 years after surgery. In total, 740 patients were analyzed. To investigate the association between SRT versus reference group regarding side-effects and QoL, a Poisson regression analysis was conducted and presented as relative risk estimates (RR) together with 95% confidence intervals regarding questions related to urinary, rectal, sexual symptoms and QoL.RRs ranged from of 1.7-6.5 on rectal symptoms and 1.2-1.4 for urinary symptoms. In general health, QoL and sexual function all RRs were below 1.1. With increasing age, higher RRs were seen for urinary leakage and lowered sexual function whereas longer time following irradiation showed higher RRs for rectal symptoms and rectal leakage. Limitations of this study include the cross-sectional design and lack of baseline assessment.Adding SRT to RP does not seem to result in other than acceptable side-effects in the majority of men receiving SRT when taking a long follow-up time (median 10 years after surgery) into account. However, a subset of men develop severe side-effects where rectal bleeding dominates.

This study compares two different strategies for maintaining a constant bladder volume during a course of postoperative radiotherapy in prostate cancer. In addition, we studied how changes in bladder filling affect the clinical target volume (CTV) and the coverage hereof.Twenty-nine patients with PSA-relapse after radical prostatectomy were divided into two groups: voiding and drinking 300 ml 1 hour before treatment (Group 1); and maintained a comfortably filled bladder (Group 2). The bladder volumes were calculated based on the planning CT (pCT) and a weekly Cone Beam CT (CBCT) during the treatment period. Furthermore, the variability of bladder extension was analyzed and correlated to the volume of the bladder covered with the 95% of the dose (VThe estimated median bladder volumes were 120 ml (95% CI: (93, 154)) and 123 ml (95% CI: (98, 155)) in groups 1 and 2, respectively. The intra-individual variation in bladder volume, assessed as the standard deviation, was 64 ml (95% CI: (46, 105)) in Group 1 and 61 (95% CI: (45, 94)) ml in Group 2. Increasing the bladder volume extended the bladder cranially while the caudal extension was almost constant. The correlation between bladder volume and VThe intention to maintain a constant volume for the bladder is not fulfilled with either of the protocols in this study, and changes in bladder volumes does not seem to affect the position, or the coverage of the CTV.

Purpose Three aspects of the RayPilot real-time tracking system were investigated: (1) feasibility of the transmitter with respect to implantation and explantation procedures, (2) user and patients’ experiences and (3) quantification of the transmitter positional stability in relation to fiducial markers. Methods and materials Ten prostate cancer patients scheduled for radiotherapy received transmitter implantation in the prostate, concomitantly with fiducial markers. Transmitter and marker positions were assessed in 3D by orthogonal kV-imaging at daily treatment setup in eight patients. Results The transmitter was successfully implanted in all patients. Patients reported mild to moderate discomfort and impact on daily activities due to the implant but overall subjective tolerability was good. One patient had spontaneous explantation of the transmitter after four fractions. One patient had transmitter 3D shifts >9 mm, but also inter-marker shifts >6 mm. The mean inter-marker shift in the remaining patients was 2 mm). In three patients, mean transmitter 3D shifts were Conclusions Implantation and explantation of the transmitter is generally feasible and safe. Patient tolerability is good overall. However, due to interfractional transmitter positional instability in this cohort, use of the system for real-time tracking should be combined with other daily setup techniques.

TPS192 Background: Radiotherapy of the primary tumor in metastatic prostate cancer is life-prolonging in patients with limited disease spread. Several different fractionation schedules have been used, most widely used is a four-week schedule of 2.75-3 Gy in 19-20 fractions. More data is emerging around hypo-fractionated radiotherapy in the curative setting. We hypothesize that a modified version of the Scandinavian Hypo-trial fractionation 6.1Gy per fraction x 6 fractions over a span of 2½ week will be non-inferior in side-effects as a 4-week schedule but more convenient for patients and caregivers. Methods: The Hypo-M1 trial is a randomized, stratified, multi-center, phase 3 clinical trial recruiting 420 patients in 9 Swedish centers. Key eligibility criteria include histological confirmed prostate cancer, indication for radiotherapy of low burden metastatic prostate cancer, defined as a max of 4 skeletal metastases at any site or lymph node metastases outside the pelvis and no other diseases or treatments interfering with radiotherapy or a score > 20 on the International prostate symptom score (IPSS) scale. Patients will be randomized to either 3 Gy x 19 or 6.1Gy x 6. Stratification factors are T1-T3 vs T4 and randomizing centre. Type of staging procedures performed, CT and whole-body bone scan is recommended, PSMA-PET allowed and further treatment beyond ADT is recorded but not stratification variables. Standard treatment may include docetaxel, apalutamide, abiraterone and enzalutamide at the treating physician’s discretion. Toxicity will be measured before, at the end of radiotherapy and at 1, 3, 6, 12 months and at 3 years. Measures used are the CTCAE v 5.0 and RTOG scales and QoL life will be measured at the same time points with the Prostate Cancer Symptom Scale (PCSS), a validated QoL instrument focusing on prostate cancer radiotherapy. The primary endpoint is QoL at 3 months and key secondary is acute toxicity at 3 months, late toxicity and QoL at 12 months, failure free survival and cause specific survival. The sample size is calculated for a continuous outcome non-inferiority trial with a one-sided alpha-value of 2.5 % and a beta-value of 80 %. The non-inferiority limit is set to 7.5 % This will require 175 patients with complete follow up in each treatment arm. Expecting a response rate of 80 % for the PCSS at the main time end point the total number of patients in each arm will be 210. The National Prostate Cancer Registry, covering 98% of all prostate cancer cases in Sweden, will be used as CRF including also a randomization module, making this a truly population based clinical trial. As of October 12, 2021, accrual is set to begin in December. The Hypo-M1 trial is an investigator-led, academic trial sponsored by the Swedish Society of Urological Oncology with study coordination provided by Cancer Center of Umeå University Hospital, Umeå, Sweden. Clinical trial information: NCT04612907.

Summary Background Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation. Methods In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321. Findings Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1–7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80–87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758–1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity. Interpretation Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer. Funding The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

For effective clinical management of patients being treated with (223)Ra, 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 (223)Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with (223)Ra 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 (223)Ra.

Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided. The article reports on discussions held by a panel of experts attending a meeting that took place in September 2016 in Oslo, Norway, sponsored by Bayer Healthcare. Dr Paul Hoban of Cancer Communications and Consultancy Ltd, Knutsford, UK provided medical writing assistance, which was funded by Bayer Healthcare. Sí

Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330.more » The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2} approaches normal tissue levels, the therapeutic effect is improved so that the normal tissue absorbed doses can be decreased by more than 95%, while retaining TCP, in the most favorable scenario and by up to about 80% with oxygen levels previously achieved in vivo, when the least favourable oxygenation case is used as starting point. The major difference occurs in poorly oxygenated cells. This is also where the pO{sub 2}-dependence of the oxygen enhancement ratio is maximal. Conclusions: Improved tumor oxygenation together with increased radionuclide uptake show great potential for optimising treatment strategies, leaving room for successive treatments, or lowering absorbed dose to normal tissues, due to increased tumor response. Further studies of the concomitant use of antiangiogenic drugs and radionuclide therapy therefore appear merited.« less

Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26–99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.

Ultrahypofractionation for prostate cancer : Outcome from the Scandinavian phase 3 HYPO-RT-PC trial

Background and purpose The Micropos 4DRT system is being developed to provide accurate, precise, objective, and continuous target localization during radiotherapy. This study involves the first in vivo use of the system, aiming to evaluate the localization accuracy of this electromagnetic positioning technique compared with radiographic localization and to assess its real-time tracking ability. Material and methods An active positioning marker was inserted in the prostatic urethra of 10 patients scheduled to receive radiotherapy for localized prostate cancer. A receiving sensor plate (antennae system) was placed at a known position in the treatment tabletop. Initial in vivo system calibrations were performed in three subjects. Ten additional patients were then enrolled in a study arm that compared radiographic transponder location to radiotransponder location simultaneously acquired by the Micropos 4DRT system. Frontal and side radiographs were taken with the radiopaque transponder located at three different positions within the prostatic urethra. Results The transponder insertions were all successful and without complications. Comparison of the transponder location as per the Micropos 4DRT system with the radiographic transponder localization showed an average (±SD) absolute and relative 3D difference of 2.7 ± 1.2 and 1.7 ± 1.0 mm, respectively. Continuous transponder tracking capability was also demonstrated. Conclusions Electromagnetic positioning using the Micropos transponder system is feasible in vivo. Evaluation of this novel non-ionizing localization system, in this study using a transponder positioned in the prostatic urethra, indicates transponder localization accuracy to isocenter comparable with X-ray localization of a radiopaque marker.

Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liver-specific inactivation of IGF1 (LI-IGF1−/− mice) displayed an ∼80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe −19%, PPPAr) mRNA and protein levels were observed in the VP lobe (−34% and −30% respectively, both P−/− mice than in ORX controls (−40%, P

Adiponectin is a hormone secreted from adipose tissue, and serum levels are decreased with obesity and insulin resistance. Because prolactin (PRL) and growth hormone (GH) can affect insulin sensitivity, we investigated the effects of these hormones on the regulation of adiponectin in human adipose tissue in vitro and in rodents in vivo. Adiponectin secretion was significantly suppressed by PRL and GH in in vitro cultured human adipose tissue. Furthermore, PRL increased adiponectin receptor 1 (AdipoR1) mRNA expression and GH decreased AdipoR2 expression in the cultured human adipose tissue. In transgenic mice expressing GH, and female mice expressing PRL, serum levels of adiponectin were decreased. In contrast, GH receptor deficient mice had elevated adiponectin levels, while PRL receptor deficient mice were unaffected. In conclusion, we demonstrate gene expression of AdipoR1 and AdipoR2 in human adipose tissue for the first time, and show that these are differentially regulated by PRL and GH. Both PRL and GH reduced adiponectin secretion in human adipose tissue in vitro and in mice in vivo. Decreased serum adiponectin levels have been associated with insulin resistance, and our data in human tissue and in transgenic mice suggest a role for adiponectin in PRL and GH induced insulin resistance.

Extreme Hypofractionation versus Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate Cancer : Early Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-RT-PC"

The probasin (Pb)-PRL transgenic mice that overexpress the rat PRL gene specifically in the prostate develop a dramatic enlargement of the prostate gland. The objective of this study was to characterize the molecular mechanisms involved in the prostate hyperplasia seen in the Pb-PRL transgenic mice. cDNA microarray analysis was used to identify differentially expressed transcripts in the hyperplastic prostates of 6-month-old transgenic mice compared with age-matched controls. We report the identification of 266 genes (175 upregulated and 91 down-regulated) that were differentially expressed in the enlarged transgenic prostates compared with controls. Subsequential real-time RT-PCR was used to verify a set of differentially regulated transcripts. The hyperplastic prostates of Pb-PRL transgenic mice demonstrate a molecular pattern supporting the importance of reduced degree of apoptosis for the development of the phenotype. Immunohistochemical analysis of apoptotic activity using two different markers of apoptosis (single-stranded DNA and activated caspase-3) were performed, and the results showed diminished apoptosis activity in the prostate of Pb-PRL transgenic mice compared with control prostates. The increased stromal/ epithelial ratio of the Pb-PRL transgenic prostate together with up-regulation of a significant fraction of genes involved in tissue remodeling activity, including the synthesis and degradation of the extracellular matrix and changes in protease activity, suggest that activation of the stroma is involved in the development of prostate hyperplasia. Overall, the differentially expressed transcripts identified in this study show many molecular similarities between the prostate hyperplasia of PRL-transgenic mice and human prostate pathology, including both benign prostatic hyperplasia and prostate cancer. (Endocrinology 144: 4955– 4966, 2003)

BACKGROUND Transgenic mice overexpressing the rat prolactin (PRL) gene under control of the metallothionein-1 promoter (Mt-1) develop a dramatic prostatic enlargement. These animals also display significantly elevated testosterone serum levels. In this study, we aim to clarify the role of circulating androgen levels in the promotion of abnormal prostate growth in the adult PRL transgenic mouse prostate. METHODS Prostate morphology and androgen-receptor distribution patterns were analyzed in castrated and testosterone substituted adult PRL transgenic and in wild-type males. RESULTS Progressive prostatic hyperplasia in adult PRL transgenic males was not affected by substitution to serum testosterone levels corresponding to wild-type. Furthermore, prolonged testosterone treatment in adult wild-type males did not produce any significant changes in prostate growth or morphology compared with wild-type controls. Immunohistochemical studies revealed a significantly increased proportion of androgen receptor positive epithelial cells in all lobes of the PRL transgenic prostate versus wild-type. CONCLUSION The present study demonstrates that progressive prostate hyperplasia in adult PRL transgenic mice is not dependent on elevated serum androgen levels. Furthermore, prolonged androgen treatment in adult wild-type male mice appears to have no significant effect on prostate growth. In addition, our results suggest that prolonged hyperprolactinemia results in changes in prostate epithelial and stromal cell androgen receptor distribution. Prostate 53: 24–33, 2002. © 2002 Wiley-Liss, Inc.

BACKGROUND Transgenic mice overexpressing the rat prolactin (PRL) gene develop a dramatic enlargement of the prostate gland. The objective of this study was to characterize the molecular mechanisms in the prostate of importance for the prostate hyperplasia seen in these transgenic mice. METHODS cDNA representational difference analysis (cDNA RDA) was used to isolate differentially expressed transcripts in the prostate hyperplasia of the transgenic mice compared with wildtype littermates. Furthermore, cDNA microarray analysis was used to verify the RDA output. RESULTS Here we report 10 transcripts, some of them described to be involved in proliferation and apoptosis, which are differentially expressed in the enlarged transgenic prostates compared with controls. CONCLUSION The identified differentially expressed transcripts presented herein supports molecular similarities between the prostate hyperplasia of PRL-transgenic mice and human BPH that may contribute to explain the molecular basis of prostate hyperplasia. Prostate 52:139–149, 2002. © 2002 Wiley-Liss, Inc.

To construct a Monte Carlo (MC)-based simulation model for analyzing the dependence of tumor oxygen distribution on different variables related to tumor vasculature [blood velocity, vessel-to-vessel proximity (vessel proximity), and inflowing oxygen partial pressure (pO2)].A voxel-based tissue model containing parallel capillaries with square cross-sections (sides of 10 μm) was constructed. Green's function was used for diffusion calculations and Michaelis-Menten's kinetics to manage oxygen consumption. The model was tuned to approximately reproduce the oxygenational status of a renal carcinoma; the depth oxygenation curves (DOC) were fitted with an analytical expression to facilitate rapid MC simulations of tumor oxygen distribution. DOCs were simulated with three variables at three settings each (blood velocity, vessel proximity, and inflowing pO2), which resulted in 27 combinations of conditions. To create a model that simulated variable oxygen distributions, the oxygen tension at a specific point was randomly sampled with trilinear interpolation in the dataset from the first simulation. Six correlations between blood velocity, vessel proximity, and inflowing pO2 were hypothesized. Variable models with correlated parameters were compared to each other and to a nonvariable, DOC-based model to evaluate the differences in simulated oxygen distributions and tumor radiosensitivities for different tumor sizes.For tumors with radii ranging from 5 to 30 mm, the nonvariable DOC model tended to generate normal or log-normal oxygen distributions, with a cut-off at zero. The pO2 distributions simulated with the six-variable DOC models were quite different from the distributions generated with the nonvariable DOC model; in the former case the variable models simulated oxygen distributions that were more similar to in vivo results found in the literature. For larger tumors, the oxygen distributions became truncated in the lower end, due to anoxia, but smaller tumors showed undisturbed oxygen distributions. The six different models with correlated parameters generated three classes of oxygen distributions. The first was a hypothetical, negative covariance between vessel proximity and pO2 (VPO-C scenario); the second was a hypothetical positive covariance between vessel proximity and pO2 (VPO+C scenario); and the third was the hypothesis of no correlation between vessel proximity and pO2 (UP scenario). The VPO-C scenario produced a distinctly different oxygen distribution than the two other scenarios. The shape of the VPO-C scenario was similar to that of the nonvariable DOC model, and the larger the tumor, the greater the similarity between the two models. For all simulations, the mean oxygen tension decreased and the hypoxic fraction increased with tumor size. The absorbed dose required for definitive tumor control was highest for the VPO+C scenario, followed by the UP and VPO-C scenarios.A novel MC algorithm was presented which simulated oxygen distributions and radiation response for various biological parameter values. The analysis showed that the VPO-C scenario generated a clearly different oxygen distribution from the VPO+C scenario; the former exhibited a lower hypoxic fraction and higher radiosensitivity. In future studies, this modeling approach might be valuable for qualitative analyses of factors that affect oxygen distribution as well as analyses of specific experimental and clinical situations.

An altered endocrine status of elderly men has been hypothesized to be important for development of prostate hyperplasia. The present study addresses the question whether increased PRL expression is of importance for development of prostate hyperplasia in mice. Three lines of PRL transgenic mice were generated having serum levels of PRL of approximately 15 ng/ml, 100 ng/ml, and 250 ng/ml, respectively. These mice developed dramatic enlargement of the prostate gland, approximately 20 times the normal prostate weight and they had a 4- to 5-fold increased DNA content. Histologically, the prostate glands in the transgenic mice were distended from secretion, and the amount of interstitial tissue was increased. The levels oftestosterone and IGF-I were increased in the PRL transgenic animals. In mice overexpressing the bovine GH gene, displaying elevated IGF-I levels, the prostate gland was slightly larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through elevated plasma IGF-I levels. The present study suggests that PRL is an important factor in the development of prostate hyperplasia acting directly on the prostate gland or via increased plasma levels of testosterone.

Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, led to the reduction of prostate size, which could be used in future therapy.

Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation.The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model).Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations.Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution.

Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO2) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO2 and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO2-distribution due to antiangiogenic treatment in combination with radionuclide therapy.Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10(10) tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were 90Y, 131I, 177Lu, and 211At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO2-distributions: micro1 = 2.483, sigma1 = 0.711; micro2 = 2.946, sigma2 = 0.689; micro3 = 3.689, and sigma3 = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern.As tumor pO2 approaches normal tissue levels, the therapeutic effect is improved so that the normal tissue absorbed doses can be decreased by more than 95%, while retaining TCP, in the most favorable scenario and by up to about 80% with oxygen levels previously achieved in vivo, when the least favourable oxygenation case is used as starting point. The major difference occurs in poorly oxygenated cells. This is also where the pO2-dependence of the oxygen enhancement ratio is maximal.Improved tumor oxygenation together with increased radionuclide uptake show great potential for optimising treatment strategies, leaving room for successive treatments, or lowering absorbed dose to normal tissues, due to increased tumor response. Further studies of the concomitant use of antiangiogenic drugs and radionuclide therapy therefore appear merited.

Benign prostatic hyperplasia (BPH) and prostate cancer are age-related diseases, affecting a majority of elderly men in the western world, and are known to be influenced by several different hormones, including sex hormones. Although the hormone prolactin (PRL) is well known to exert trophic effects on prostate cells, its involvement in pathophysiological conditions is still poorly characterized. In order to evaluate the potential role of PRL in promoting prostate growth, we have used a recently developed transgenic mouse model that overexpresses the PRL gene specifically in the prostate (Pb-PRL transgenic mice). The PRL transgenic mice develop a significant prostate hyperplasia which increases with age. The prostates of the Pb-PRL transgenic mice display a prominent stromal hyperplasia with mild epithelial dysplastic features, leading to an increased stromal/epithelial ratio. Accumulation of secretory material is also a major characteristic. By using cDNA microarray analysis we have obtained interesting insights into the molecular mechanisms involved in the prostate hyperplasia. Of particular interest is the significance of reduced apoptosis for the development/progression of the prostate phenotype. This finding was further confirmed by immunohistochemical analysis using two different apoptosis markers. Moreover, in line with the prominent expansion of the stromal compartment were the identified changes in gene expression seen in the PRL transgenic prostate, suggesting that activation of the stroma is important for the development of the prostate hyperplasia.

Hyperprolactinemia results in prostatic hypertrophy and hyperplasia, but it is not known whether prolactin plays an essential role in these processes in the prostate. To address this question, we investigated prostate development, gene expression, and simian virus 40 (SV40)T-induced prostate carcinogenesis in prolactin receptor knockout mice. These animals showed a small increase in dorsolateral and ventral prostate weight but no change in the weight of the anterior prostate. The dorsal but not ventral or lateral lobes showed a 12% loss of epithelial cells; all other morphological parameters were normal. The area of SV40T-induced prostate intraepithelial neoplasia was reduced by 28% in the ventral lobe but not the dorsal lobe, and no tumors were seen in 20 prolactin receptor knockout animals, compared with 1 of 11 detected in wild-type and 4 of 21 found in heterozygous animals. Oligonucleotide microarrays were used to identify essential transcriptional roles of prolactin and revealed a small set of genes with decreased expression involved in sperm/oocyte interaction and copulatory plug formation. Infertility or reduced fertility was apparent in these animals. These findings establish essential though subtle roles for prolactin in the regulation of prostate morphology, gene expression, SV40T-induced neoplasia, and reproductive function.

Prolactin (PRL) is one of several polypeptide factors known to exert trophic effects on the prostate. We have previously reported a dramatic prostate enlargement with concurrent chronic hyperprolactinemia and elevated serum androgen levels in a PRL transgenic mouse (Mt-PRL) with ubiquitous expression of the transgene. To address the role of local PRL action in the prostate, a new transgenic mouse model (Pb-PRL) was generated using the prostate-specific rat probasin (Pb) minimal promoter to drive expression of the rat PRL gene. Pb-PRL transgenic males developed a significant enlargement of both the dorsolateral and ventral prostate lobes evident from 10 wk of age and increasing with age. Expression of the transgene was restricted to the prostate and detected from 4 wk of age. Low levels of transgenic rat PRL were detectable in the serum of adult Pb-PRL animals. Serum androgen levels were normal. The Pb-PRL prostate displayed significant stromal hyperplasia, ductal dilation, and focal areas of epithelial dysplasia. Quantitative analysis of prostatic tissue cellularity demonstrated a marked increase in the stromal to epithelial ratio in all lobes of Mt-PRL and Pb-PRL transgenic prostates compared with controls. Microdissections demonstrated an increased ductal morphogenesis in dorsolateral and ventral prostate lobes of Mt-PRL prostate vs. Pb-PRL and controls. In conclusion, this study indicates the ability of PRL to promote, directly or indirectly, ductal morphogenesis in the developing prostate and further to induce abnormal growth primarily of the stroma in the adult gland in a setting of normal androgen levels.

The study of normal prostate development and prostate pathobiology has historically been mainly focused on actions of androgens. Androgens regulate proliferation and differentiation of prostatic cells. Although indispensable, androgens alone are not sufficient for the normal development and function of the prostate gland (1). The physiological importance of non-androgenic hormones and growth factors is well established. Prolactin (PRL) is one factor with the potential to act on normal prostate, alone or synergistically, with androgens (2). The possibility of PRL involvement in the progression of prostate cancer was first indicated in clinical studies more than 25 years ago. Additional clinical observations are presented along with findings in experimental work, providing possible explanations for PRL action in normal and pathophysiological conditions of the prostate gland.

Purpose: Oxygen distribution models have been used to analyze the influences of oxygen tensions on tissue response after radiotherapy. These distributions are often generated assuming constant oxygen tension in the blood vessels. However, as red blood cells progress through the vessels, oxygen is continuously released into the plasma and the surrounding tissue, resulting in longitudinally varying oxygen levels in the blood vessels. In the present study, the authors investigated whether a tumor oxygenation model that incorporated longitudinally varying oxygen levels would provide different predictions of necrotic fractions and radiosensitivity compared to commonly used models with a constant oxygen pressure. Methods: Our models simulated oxygen diffusion based on a Green's function approach and oxygen consumption according to the Michaelis-Menten equation. The authors constructed tumor models with different vascular fractions (VFs), from which they generated depth oxygenation curves and a look-up table of oxygen pressure gradients. The authors evaluated models of spherical tumors of various sizes, from 1 to 10{sup 4} mg. The authors compared the results from a model with constant vessel oxygen (CVO) pressure to those from models with longitudinal variations in oxygen saturation and either a constant VF (CVF) or variable VF (VVF) within the tumor tissue. The authorsmore » monitored the necrotic fractions, defined as tumor regions with an oxygen pressure below 1 mmHg. Tumor radiation sensitivity was expressed as D{sub 99,} the homogeneous radiation dose required for a tumor control probability of 0.99. Results: In the CVO saturation model, no necrosis was observed, and decreasing the VF could only decrease the D{sub 99} by up to 10%. Furthermore, the D{sub 99} vs VF dependence was similar for different tumor masses. Compared to the CVO model, the extended CVF and VVF models provided clearly different results, including pronounced effects of VF and tumor size on the necrotic fraction and D{sub 99}, necrotic fractions ranging from 0% to 97%, and a maximal D{sub 99} increment of 57%. Only minor differences were observed between different vessel architectures, i.e., CVF vs VVF. In the smallest tumor with a low necrotic fraction, the D{sub 99} strictly decreased with increasing blood velocity. Increasing blood velocity also decreased the necrotic fraction in all tumor sizes. VF had the most profound influence on both the necrotic fraction and on D{sub 99}. Conclusions: Our present analysis of necrotic formation and the impact of tumor oxygenation on D{sub 99} demonstrated the importance of including longitudinal variations in vessel oxygen content in tumor models. For small tumors, radiosensitivity was particularly dependent on VF and slightly dependent on the blood velocity and vessel arrangement. These dependences decreased with increasing tumor size, because the necrotic fraction also increased, thereby decreasing the number of viable tumor cells that required sterilization. The authors anticipate that the present model will be useful for estimating tumor oxygenation and radiation response in future detailed studies.« less

PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation.METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model).RESULTS: Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations.CONCLUSIONS: Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution. (Less)

An altered endocrine status of elderly men has been hypothesized to be important for development of prostate hyperplasia. The present study addresses the question whether increased PRL expression is of importance for development of prostate hyperplasia in mice. Three lines of PRL transgenic mice were generated having serum levels of PRL of approximately 15 ng/ml, 100 ng/ml, and 250 ng/ml, respectively. These mice developed dramatic enlargement of the prostate gland, approximately 20 times the normal prostate weight and they had a 4- to 5-fold increased DNA content. Histologically, the prostate glands in the transgenic mice were distended from secretion, and the amount of interstitial tissue was increased. The levels oftestosterone and IGF-I were increased in the PRL transgenic animals. In mice overexpressing the bovine GH gene, displaying elevated IGF-I levels, the prostate gland was slightly larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through elevated plasma IGF-I levels. The present study suggests that PRL is an important factor in the development of prostate hyperplasia acting directly on the prostate gland or via increased plasma levels of testosterone.

The aim of this study was to investigate the regulation of resistin, a recently identified adipocyte-secreted peptide, in the adipose tissue of prolactin (PRL)-transgenic (tg) mice using ribonuclease protection assay. The level of resistin mRNA increased 3.5-fold in the adipose tissue of untreated male PRL-tg mice compared to controls. However, there was no difference in resistin expression in the adipose tissue of female PRL-tg mice compared to control mice. PRL-tg male mice have elevated serum testosterone levels and we therefore analyzed the effects of testosterone alone on resistin mRNA expression. Furthermore, the effects of elevated androgen levels on PRL receptor (PRLR) mRNA expression in the adipose tissue were investigated. Resistin mRNA increased 2.6-fold in the adipose tissue of control male mice with elevated serum androgen levels. In addition, PRLR mRNA expression was increased in the adipose tissue of male mice with elevated testosterone. These results suggest testosterone to be a regulator of resistin and PRLR mRNA expression in the adipose tissue of male mice.