Charles Brenton Huggins: A historical review of the Nobel laureate's pioneering discoveries.

Androgen deprivation therapy for prostate cancer was pioneered by Charles Huggins, laureate of the Nobel Prize in Medicine in 1966. The authors tried to understand the scientific context and how previous findings paved Huggins way to his discoveries. With the help of summary or review articles on androgen deprivation therapy, the authors identified key publications and used his Nobel Prize speech as a basis to understand his discoveries. Furthermore, they used a recording of the laboratory-talk interview he gave about his findings to guide them to relevant publications. The authors found that the basis for Huggins' discoveries was the isolation of testosterone in 1935, not long before Huggins' 1941 hallmark publication. Huggins' work follows major experiments in the 19th century in orchiectomy done as a treatment for prostate hypertrophy. Researching the etiology of idiopathic hydrocele, Huggins analyzed the composition of prostate fluid. Further research led to the discovery of the influence of castration, testosterone, and estrogen on acid phosphatase. Recently developed methods facilitated the measurement of the phosphatases. He, therefore, had a biomarker for metastatic prostate cancer to measure treatment response. Very early on, he reported clinical improvements after castration in metastatic patients. Although the effect of orchiectomy on prostate hypertrophy was already known, Huggins was the first to show that testosterone stimulated and estrogen decreased the activity of prostate cancer. Huggins also established phosphatases as a tumor marker to measure disease response.

Friedrich Dessauer (1881-1963): the forgotten medical physicist, politician, and philosopher.

Today, the name Friedrich Dessauer is almost forgotten; however, his scientific, social, and political works should not be. Dessauer's professional career began at a young age as a professor of physics in Frankfurt am Main. It is said that he published 400 papers and 65 book chapters and pamphlets. He was a technical inventor who established laws that dealt with theories to explain the limited understanding of the effects of radiation on cells. He advocated for methods to improve the therapeutic ratio. As a devout Catholic politician, Dessauer was an early opponent of National Socialism. This led to him being thrown into prison for political reasons in 1933. He did not leave until 1934, and then for Istanbul, largely thanks to Turkish efforts and his appointment as director of a large new institution. While he was already a well-known physicist in Germany, he had to start from scratch in order to build a modern institute. A recent article in the journal Radiotherapy and Oncology celebrated his important contributions to radiology from Turkey. After his contract in Istanbul expired in 1937, he left for the small University of Fribourg in Switzerland, where he was unfortunately unable to continue his scientific productivity. Dessauer wrote textbooks as well as political and philosophical books, and attempted to bridge the gap between Catholicism and science. Additionally, after the war, he began to teach again in Frankfurt. In photos of Dessauer, radiation-induced skin changes on his face and hands were clearly visible. Towards the end of his life, he received many medals and honors for his achievements in Germany, some of them posthumously.

Tracing the Evolution of Prostate Brachytherapy in the 20th Century.

BACKGROUND: Prostate brachytherapy (BT) techniques have evolved over the past century. This paper aimed to preserve our collective memory of history and the early development of its technique. We searched articles in PubMed and Google Scholar using keywords referring to authors, dates, and BT technical details, including different radioactive sources and country-specific publications. We reviewed the work published by Holm and Aronowitz. The digital library Internet Archives was used to retrieve original journal articles, science newspaper printings, and government reports, which allowed us to situate the development of BT in its sociopolitical context in Europe and the USA. Our search was conducted in English, French, and German languages. SUMMARY: Early BT methods were developed by European physicians with early access to radium. Technical advancements were made by HH Young, who brought this practice to the USA, where Barringer pioneered the use of radon seeds and low-dose interstitial brachytherapy. While centralized radiotherapy centers, such as Memorial Hospital in New York, emerged for training and research, the high cost of radium and opposing interests made brachytherapy harder to implement in Germany. After World War II, the introduction of man-made radioisotopes allowed experiments with colloidal solutions and new seeds, including I-125. In the 1980s, transrectal ultrasound allowed for more accurate radioactive seed insertion and replaced the transrectal finger guidance.

Findings on Diagnostic Magnetic Resonance Imaging Before Radiotherapy for Prostate Cancer.

PURPOSE: Pre-treatment diagnostic magnetic resonance imaging (MRI) is used in prostate cancer detection and staging; however, little is known about its potential for radiotherapy treatment decision, or its prognostic value. We investigated the findings on pre-treatment MRI and its potential influence on treatment decisions, and its ability to predict biochemical recurrence in patients treated with radiotherapy. METHODS: Files of patients treated by radiotherapy from 2014 to 2022 were searched for if they had had an MRI within 12 months before radiotherapy. Prostate Imaging Reporting & Data System (PI-RADS) score, index lesion diameter and the presence of organ confined disease or extra-prostatic extension were correlated with their Cancer of the Prostate Risk Assessment (CAPRA) score. Distribution of radiological and clinical features between groups were estimated using a chi-squared test. RESULTS: Out of 1280 patients, 314 (24.5%) had an MRI. The distribution depended on the treatment received: 22.5% who received low-dose rate (LDR) brachytherapy as monotherapy, 24.0% treated with high-dose rate (HDR) boost and 32.0% treated with external-beam radiotherapy (EBRT) (P = .017). The CAPRA score significantly correlated with the PI-RADS score (r = .342, P < .01) and the diameter of the index lesion (r = .473, P < .01). A clinically significant number of 22% patients with CAPRA ≤ 3 disease presented with lesions ≥15 mm and were less likely to be treated with LDR monotherapy (P < .01). 39 patients had a recurrence, only 5 had an MRI: 4 had a lesion of ≥20 mm and 3 a seminal vesicle invasion. CONCLUSION: More than twenty percent of patients with CAPRA ≤3 presented on MRI a ≥15 mm lesion. An MRI could potentially affect treatment choice, and although exploratory our results suggest an important prognostic potential.

Low Serum Testosterone in Men with Newly Diagnosed Androgen-Deprivation Therapy-Naïve Prostate Cancer and Its Relationship to Cardiovascular Risk Factors: A RADICAL-PC Substudy.

PURPOSE: Cardiovascular disease is a common cause of death in prostate cancer patients. Low testosterone is associated with increased cardiovascular risk in the general male population. We investigated the relationship between serum testosterone, cardiovascular disease and risk factors in androgen-deprivation therapy-naïve prostate cancer patients. MATERIALS AND METHODS: We performed a cross-sectional analysis of a subgroup of 1,326 androgen-deprivation therapy-naïve men from RADICAL-PC (Role of Androgen-Deprivation Therapy In CArdiovascular Disease-A Longitudinal Prostate Cancer study) in whom serum testosterone was measured at baseline. RADICAL-PC is a prospective multicenter cohort study of men (2,565) enrolled within 1 year of prostate cancer diagnosis, or within 6 months of commencing androgen-deprivation therapy for the first time. Cardiovascular risk factors, cancer characteristics and total serum testosterone were collected at baseline. Low testosterone was defined as total serum testosterone <11 nmol/L (<320 ng/dL). A Framingham cardiovascular risk score ≥15 was considered high risk for future cardiovascular events. We performed logistic regression to calculate odds ratios for the association between testosterone and cardiovascular risk. RESULTS: Among 1,326 participants (median age 67 years, range 45-93), 553 (42%) had low testosterone. Low testosterone was associated with existing cardiovascular disease, diabetes, elevated hemoglobin A1c, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension and Framingham score >15. Among patients with low testosterone, the odds ratio for high cardiovascular risk was 1.33 (1.02-1.73) after adjusting for ethnicity, education, alcohol use, cancer characteristics, physical activity and body mass index. CONCLUSIONS: Among androgen-deprivation therapy-naïve prostate cancer patients, low testosterone is common and associated with increased cardiovascular risk factors.

Prevalence and Risk Factors of QTc Prolongation in Prostate Cancer Patients Undergoing Brachytherapy.

QTc prolongation is linked to Torsade de Pointes, sudden cardiac death, and overall cardiovascular mortality. 754 prostate cancer patients undergoing brachytherapy were analyzed, prolonged QTc was defined as ≥450ms. A prolonged QTc was more frequent (10.1 vs. 5.1%, p = 0.040) in patients with high-risk cancer than in low to intermediate risk patients. The absolute QTc-time was correlated with age (r = 0.125), neutrophil count (r = 0.130) and negatively correlated with the testosterone level (r=-0.205). Treating physicians should be aware of this and monitor the QTc during ADT to possibly decrease cardiac morbidity/mortality in these patients who are more likely to require ADT.

Biochemical failure-rate and preservation of erectile function after prostate seed brachytherapy in early-onset prostate cancer.

INTRODUCTION: To analyze biochemical failure-free survival and erectile dysfunction (ED) in younger men treated with prostate seed brachytherapy (PB). MATERIALS AND METHODS: Included were patients ≤ 55 years treated with PB. Erectile function at baseline and after treatment were assessed using the physician-reported CTCAE version 4.0. Biochemical failure (BF) was defined according to the Phoenix Consensus definition (PSA nadir + 2 ng/mL). The log-rank test (Kaplan-Meier method) and cox-regression analysis was used to calculate BF-free survival. RESULTS: Between July 2005 and November 2020, a total of 137 patients ≤ 55 years (range 44-55 years old) were treated with PB. Median follow up was 72 months. Twenty percent had Gleason 3+4 disease and 6% a PSA >10 ng/mL. Median prostate volume was 34 cc. Actuarial biochemical failure free survival at 5, 7, and 10 years, were 98%, 95% and 89%, respectively. Five patients received local salvage treatment. On multivariate analysis, CAPRA-score (HR 4.46, 95%CI 1.76-11.33, p = 0.002) and the dosimetric measure D90 > 130 Gy (p = 0.03) were predictive of BF. Five deaths occurred in our cohort, two due to cardiovascular reasons and three due to another malignancy. At baseline, all patients were able to have erections with or without medication. At 5 years and 7 years after PB, 80% and 64% of patients had little or no ED (erections without the need for medication) respectively. CONCLUSION: In young-onset patients treated with PB, failure rates are similar to their older counterparts. Sexual function decreases with time, even in patients with good sexual function.

Validation of the new STAR-CAP prognostic group staging system in prostate cancer patients treated with radiation therapy.

PURPOSE: To externally validate the STAR-CAP prognostic system for prostate cancer (PCa) and compare it to the CAPRA score to predict for biochemical recurrence (BCR) after radiation therapy (RTx). METHODS: We included patients treated with RTx between 2002 and 2021 for non-metastatic PCa at our institution. BCR was defined based on Phoenix criteria. The 5-year BCR-free survival was assessed by univariable Kaplan-Meier analyses and log-rank test. Multivariable Cox regression models tested the independent association of each model for BCR. Performance of both models to predict 5-year BCR-free survival was assessed using the area under the curve (AUC). RESULTS: The 2768 patients included were treated with high dose rate brachytherapy (13.3%) as a boost to external beam radiation therapy (EBRT), low dose rate seed brachytherapy (50.4%) or EBRT alone (35.9%). 14.4% of patients received concomitant androgen deprivation therapy (ADT). 222 patients experienced BCR (8%), with a median follow-up of 56 months. The 5-year BCR-free survival ranged from 88 (high risk) to 96% (low risk) in the STAR-CAP classification, and from 87 (high risk) to 97% (low risk) in the CAPRA system (p < 0.0001). Multivariate analyses, adjusted for ADT and type of treatment, confirmed the intrinsic ability of risk stratifications within each system to predict BCR (p < 0.001). Finally, AUC for the 5-year BCR prediction was 0.65 for STAR-CAP and 0.68 for CAPRA. CONCLUSION: Both CAPRA and STAR-CAP prognostic group staging systems provide sufficient stratification and their predictive ability for 5-year BCR-free survival is comparable, with a small advantage for CAPRA (3%).

The interaction between inflammation, urinary symptoms and erectile dysfunction in early-stage prostate cancer treated with brachytherapy.

Erectile function has been shown to decline as a function of increasing peripheral blood inflammatory markers, namely the neutrophil-to-lymphocyte ratio (NLR). We evaluated if the association between NLR and erectile dysfunction (ED) applies to patients with localised prostate cancer. We included 1,282 patients who underwent brachytherapy. ED was classified before treatment according to the Terminology Criteria for Adverse Event Scale version 3.0. ED was defined as the need for the use of oral pharmacologic or mechanical assistance to have satisfactory sexual function. We found that patients with ED were older (p < .001), more likely to have hypertension (p = .002), statin use (p = .002), diabetes (p < .001) or an IPSS ≥ 8 (p < .001). On univariable logistic regression analysis, an NLR of ≥3 was statistically significantly associated with ED (OR 1.32, p = .029). But on multivariable analysis, the association between elevated NLR and ED was not statistically significant (p = .17). Significant were age (OR 1.12, p < .001), IPSS ≥ 8 (OR 1.50, p = .008), the presence of hypertension, hyperlipidemia and diabetes (OR 2.27, p < .001), and prostate volume (OR 0.99, p = .041). The NLR does appear to be a surrogate marker of chronic inflammation that causes baseline ED in patients with localised prostate cancer.

The relationship between pre-radiation therapy testosterone levels and prostate cancer aggressiveness.

We investigated whether there is an association between testosterone levels and prostate cancer aggressiveness in patients treated with radiation therapy who underwent a prostatectomy or prostate radiotherapy (EBRT). A total of 380 patients who received primary or post-operative radiotherapy were identified. At the time of radiotherapy, baseline testosterone levels and body mass index (BMI) measurements were available. On multivariate analysis (MVA), higher prostate-specific antigen (PSA) levels were predictive of testosterone ≥10.4  (OR = 1.3, p = .04) and testosterone ≥12.0 nmol/L (OR = 1.3, p = .04). Patients with a Gleason score ≥8 were more likely to have testosterone <8 nmol/L than patients with a lower score (31% vs. 20%, p = .043). On univariate analysis, a Gleason score ≥8 was associated with a lower likelihood of having a normal (≥8 nmol/L) testosterone level (OR = 0.51, 95% CI: 0.3-0.9, p = .02), and on MVA adjusted for post-surgical versus primary EBRT and BMI (≥30 kg/m2 ), the Gleason score lost its statistical significance (p = .09). While higher PSA levels are associated with higher testosterone levels, the interaction between Gleason score and testosterone is unclear and merits further study.

Pre-radiotherapy PSA progression is a negative prognostic factor in prostate cancer patients using 5­alpha-reductase inhibitors.

OBJECTIVE: To investigate the impact of 5­alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer. PATIENTS AND METHODS: We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. RESULTS: At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1-28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2-7.0, p = 0.02) remained adverse risk factors. CONCLUSION: PSA progression experienced during 5­ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.

Impact of diabetes and metformin use on prostate cancer outcome of patients treated with radiation therapy: results from a large institutional database.

INTRODUCTION: Conflicting data exists on the influence of metformin on prostate cancer. We investigated the importance of metformin in patients treated with radiotherapy or brachytherapy. MATERIALS AND METHODS: All patients from a large institutionalized database, treated for primary localized prostate cancer with either brachytherapy or external-beam radiotherapy ± androgen deprivation therapy were identified. Groups were compared by Kaplan-Meier analyses and Cox regression models. Multivariate analysis was adjusted for CAPRA-Score, type of treatment and age. RESULTS: A total of 2441 patients with complete data was identified. Among the 382 patients (16% of total) were diabetic. Two-hundred and eighty-one of the 382 diabetics (74%) were treated with metformin and 101 were treated with other anti-diabetic medication. Median follow up was 48 months (interquartile range [IQR] 24-84). Two-hundred eighteen patients (9%) died and 150 (6%) experienced biochemical recurrence (BCR). On unadjusted univariate analysis for BCR-free survival, metformin users showed a 50% reduction in BCR compared to non-metformin users. The results remained significant on multivariate analysis comparing diabetic metformin users to non-metformin users (diabetics and non-diabetics combined) (hazard ratio [HR] 0.5-0.6, p = 0.03-0.04) but lost its significance when adjusting for cancer aggressiveness. On multivariate analysis, diabetics had worse overall survival (OS) than non-diabetics (HR 1.5, 95% confidence interval [CI] 1.08-2.06, p = 0.01), but diabetics on metformin fared better than diabetics not taking metformin (HR 0.5, 95% CI 0.26-0.86, p = 0.01). CONCLUSION: Metformin use in this analysis appears to be associated with better BCR and OS. Larger datasets and prospective trials are warranted to validate these results.

External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer.

BACKGROUND: Previous studies have examined testosterone levels after external beam radiation (EBRT) monotherapy, but since 2002 only sparse contemporary data have been reported. AIM: To examine testosterone kinetics in a large series of contemporary patients after EBRT. METHODS: The study was conducted in 425 patients who underwent definitive EBRT for localized prostate cancer from 2002 through 2014. Patients were enrolled in several phase II and III trials. Exclusion criteria were neoadjuvant or adjuvant androgen-deprivation therapy or missing data. Testosterone was recorded at baseline and then according to each study protocol (not mandatory in all protocols). Statistical analyses consisted of means and proportions, Kaplan-Meier plots, and logistic and Cox regression analyses. OUTCOMES: Testosterone kinetics after EBRT monotherapy and their influence on biochemical recurrence. RESULTS: Median follow-up of 248 assessable patients was 72 months. One hundred eighty-six patients (75.0%) showed a decrease in testosterone. Median time to first decrease was 6.4 months. Median percentage of decrease to the nadir was 30% and 112 (45.2%) developed biochemical hypogonadism (serum testosterone < 8 nmol/L). Of all patients with testosterone decrease, 117 (62.9%) recovered to at least 90% of baseline levels. Advanced age, increased body mass index, higher baseline testosterone level, and lower nadir level were associated with a lower chance of testosterone recovery. Subgroup analyses of 166 patients treated with intensity-modulated radiotherapy confirmed the results recorded for the entire cohort. In survival analyses, neither testosterone decrease nor recovery was predictive for biochemical recurrence. CLINICAL IMPLICATIONS: EBRT monotherapy influences testosterone kinetics, and although most patients will recover, approximately 45% will have biochemical hypogonadism. STRENGTHS AND LIMITATIONS: We report on the largest contemporary series of patients treated with EBRT monotherapy in whom testosterone kinetics were ascertained. Limitations are that testosterone follow-up was not uniform and the study lacked information on health-related quality-of-life data. CONCLUSION: Our findings indicate that up to 75% of patients will have a profound testosterone decrease, with up to a 40% increase in rates of biochemical hypogonadism, although the latter events will leave biochemical recurrence unaffected. Pompe RS, Karakrewicz PI, Zaffuto E, et al. External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer. J Sex Med 2017;14:876-882.

Comparison of external beam radiotherapy versus permanent seed brachytherapy as monotherapy for intermediate-risk prostate cancer - a single center Canadian experience.

INTRODUCTION: We tested different classification systems in order to separate intermediate-risk prostate cancers into prognostic groups. We then examined which groups were most suited for either prostate seed brachytherapy (PB) or external beam radiotherapy (EBRT). MATERIALS AND METHODS: We selected patients with D'Amico intermediate-risk prostate cancer who were treated exclusively with either PB or EBRT. Patients were excluded if they had received androgen deprivation therapy in combination with EBRT or a follow up of < 30 months without recurrence. The Kaplan-Meier method was used to compare groups. RESULTS: Our sample consisted of 475 patients treated from July 2002-September 2013. Median follow up for patients without biochemical failure (BF) was 56 months (interquartile range 44-78); 222 patients (47%) were treated with PB exclusively (D90 interquartile range 145-176 Gy) and 253 (53%) with EBRT exclusively (dose interquartile range 76-80 Gy). The rate of BF was significantly lower in patients treated with PB (5.4%) than in patients treated with EBRT (14.2%) (p = 0.036, log-rank test). Upon univariate analysis, significant predictors of BF included the number of unfavorable intermediate-risk factors (0, 1, 2, 3) (p = 0.024) as well as the Cancer of the Prostate Risk Assessment (CAPRA) score (p = 0.002). After adjusting for the type of treatment, only the CAPRA score remained predictive (p = 0.025). For patients with a CAPRA score of 0-2, those with PB fared better than those treated with EBRT (p = 0.042). This difference disappeared in patients with a CAPRA score of 3-5 (p = 0.5). CONCLUSIONS: Using our current selection criteria for monotherapy, we found that PB or EBRT as monotherapy are equally effective treatment options for intermediate-risk prostate cancer.

Seed loss in prostate brachytherapy : Operator dependency and impact on dosimetry.

INTRODUCTION: The aim of our study was to review seed loss and its impact on dosimetry as well as the influence of the treating physician on seed loss and dosimetry in patients treated with prostate brachytherapy using permanent loose (125)I implant. PATIENTS AND METHODS: We analyzed 1087 consecutive patients treated by two physicians between July 2005 and April 2015 at a single institution. Pelvic fluoroscopic imaging was done 30 days post implant and a chest X-ray when seed loss was observed. RESULTS: Seed loss occurred in 19.4 % of patients: in 20.0 % of implants done by the most experienced physician and in 17.2 % by the less experienced physician (p = 0.4) and migration to the thorax occurred in 5.9 % (6.9 vs. 2.2 %, p = 0.004). The mean seed loss rate was 0.57 % [standard deviation (SD) 1.39] and the mean rate of seeds in the thorax was 0.14 % (SD 0.65). The most experienced physician had a higher mean number of seeds lost: 0.36 versus 0.25 (p = 0.055), and a higher mean number of seed migration to the thorax: 0.1 versus 0.02 (p < 0.001). When at least one seed was lost, a decrease of 4.2 Gy (p < 0.001) in the D90 and a decrease of 3.5 % (p = 0.002) in the V150 was observed. CONCLUSION: We found a significant decrease in V150 and D90 with the occurrence of seed loss. Furthermore, we found a difference in seed migration among the physicians demonstrating that seed loss is operator dependant.

Neutrophil count is associated with survival in localized prostate cancer.

BACKGROUND: Increasing evidence suggests a close relationship between systemic inflammation and cancer development and progression. The neutrophil to lymphocyte ratio (NLR) has been shown to be an independent prognostic indicator in various advanced and localized cancers. We investigated the influence of markers of systemic inflammation such as leucocyte counts and metabolic co-morbidities on overall survival (OS) after radiotherapy for localized prostate cancer. METHODS: We conducted a retrospective study of patients with localized prostate cancer treated with definitive external beam radiotherapy or brachytherapy. Univariate and multivariate cox proportional hazards models were used to investigate the influence of the following factors on OS: age, neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), Cancer of the Prostate Risk Assessment (CAPRA) score as well as comorbidities associated with inflammation such as cardiac history, diabetes and use of a statin. A stepwise selection of variable based on the Akaike information criterion (AIC) was used for multivariate analysis. RESULTS: In total, 1772 pts were included; blood count data was available for 950 pts. Median age was 68 years (44-87). Actuarial 5 years OS and biochemical recurrence-free survival (BRFS) for the 1772 patients were 93% and 95%, respectively, with a median follow-up of 44 months (1-156). On univariate analysis, neutrophil count (p = 0.04), cardiac history (p = 0.008), age (p = 0.001) and CAPRA (p = 0.0002) were associated with OS. Lymphocytes, NLR and comorbidities other than cardiac history were not associated with mortality. On multivariate analysis, neutrophil count (HR = 1.18, 95 % CI: 1.017-1.37, p = 0.028), age (HR = 1.06, 95 % CI: 1.01-1.1, p = 0.008) and CAPRA (HR = 1.16, 95 % CI: 1.03-1.31, p = 0.015) were independent predictors of OS. CONCLUSION: Neutrophil count, as a possible marker of systemic inflammation, appear to be an independent prognostic factor for overall mortality in localized prostate cancer. A validation cohort is needed to corroborate these results.

The Cancer of the Prostate Risk Assessment (CAPRA) score predicts biochemical recurrence in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) dose escalation or low-dose rate (LDR) brachytherapy.

OBJECTIVE: To study the prognostic value of the University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score to predict biochemical failure (bF) after various doses of external beam radiotherapy (EBRT) and/or permanent seed low-dose rate (LDR) prostate brachytherapy (PB). PATIENTS AND METHODS: We retrospectively analysed 345 patients with intermediate-risk prostate cancer, with PSA levels of 10-20 ng/mL and/or Gleason 7 including 244 EBRT patients (70.2-79.2 Gy) and 101 patients treated with LDR PB. The minimum follow-up was 3 years. No patient received primary androgen-deprivation therapy. bF was defined according to the Phoenix definition. Cox regression analysis was used to estimate the differences between CAPRA groups. RESULTS: The overall bF rate was 13% (45/345). The CAPRA score, as a continuous variable, was statistically significant in multivariate analysis for predicting bF (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.10-1.72, P = 0.006). There was a trend for a lower bF rate in patients treated with LDR PB when compared with those treated by EBRT ≤ 74 Gy (HR 0.234, 95% CI 0.05-1.03, P = 0.055) in multivariate analysis. In the subgroup of patients with a CAPRA score of 3-5, CAPRA remained predictive of bF as a continuous variable (HR 1.51, 95% CI 1.01-2.27, P = 0.047) in multivariate analysis. CONCLUSION: The CAPRA score is useful for predicting biochemical recurrence in patients treated for intermediate-risk prostate cancer with EBRT or LDR PB. It could help in treatment decisions.

Risk factors for PSA bounce following radiotherapy: outcomes from a multi-modal therapy analysis.

INTRODUCTION: To identify risk factors for PSA bounce (PSAb) and compare characteristics of prostate cancer patients treated with brachytherapy and external beam radiotherapy (EBRT). MATERIALS AND METHODS: We identified 362 patients treated for low risk prostate adenocarcinoma (D'Amico criteria) with a follow up time of at least 36 months. Patients received either: 1) EBRT 76 Gy in 38 fractions (n = 58); 2) hypofractionated EBRT, 45 Gy in 9 once-weekly fractions (n = 74); 3) seed brachytherapy (n = 230). PSAb was defined as a rise >= 0.2 ng/mL with subsequent return to baseline within the first 3 years after treatment. Univariate and multivariate logistic regression models were estimated to assess the association between clinical factors and occurrence of PSAb. RESULTS: There was no significant difference between treatment groups (p = 0.349), with an overall PSAb rate of 28.5%. Upon univariate analysis, the following were predictive of a lower PSAb rate: older age (OR = 0.96), higher PSA at diagnosis (OR = 0.87), more positive biopsy cores (OR = 0.98), and a higher Cancer of the Prostate Risk Assessment (CAPRA) score (CAPRA of 3 versus 1: OR = 0.33). Multivariate analysis confirmed the significance of fewer positive biopsy cores (OR = 0.99) and a lower CAPRA score (CAPRA 3 versus 1: OR = 0.34). These factors also predicted a shorter time to first PSAb. CONCLUSIONS: We found comparable rates of PSAb after different regimens of radiotherapy. We hypothesize that it results from late damage to healthy prostatic tissue. This idea is supported by the fact that we found that clinical factors indicative of a lower tumor burden were predictive of a PSAb.

The Crosstalk between Nerves and Cancer-A Poorly Understood Phenomenon and New Possibilities.

INTRODUCTION: Crosstalk occurs between nerve and cancer cells. These interactions are important for cancer homeostasis and metabolism. Nerve cells influence the tumor microenvironment (TME) and participate in metastasis through neurogenesis, neural extension, and axonogenesis. We summarized the past and current literature on the interaction between nerves and cancer, with a special focus on pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa), and the role of the nerve growth factor (NGF) in cancer. MATERIALS/METHODS: We reviewed PubMed and Google Scholar for the relevant literature on the relationship between nerves, neurotrophins, and cancer in general and specifically for both PCa and PDAC. RESULTS: The NGF helped sustain cancer cell proliferation and evade immune defense. It is a neuropeptide involved in neurogenic inflammation through the activation of several cells of the immune system by several proinflammatory cytokines. Both PCa and PDAC employ different strategies to evade immune defense. The prostate is richly innervated by both the sympathetic and parasympathetic nerves, which helps in both growth control and homeostasis. Newly formed autonomic nerve fibers grow into cancer cells and contribute to cancer initiation and progression through the activation of ß-adrenergic and muscarinic cholinergic signaling. Surgical or chemical sympathectomy prevents the development of prostate cancer. Beta-blockers have a high therapeutic potential for cancer, although current clinical data have been contradictory. With a better understanding of the beta-receptors, one could identify specific receptors that could have an effect on prostate cancer development or act as therapeutic agents. CONCLUSION: The bidirectional crosstalk between the nervous system and cancer cells has emerged as a crucial regulator of cancer and its microenvironment. Denervation has been shown to be promising in vitro and in animal models. Additionally, there is a potential relationship between cancer and psychosocial biology through neurotransmitters and neurotrophins.