Defining the challenges and opportunities for using patient-derived models in prostate cancer research.

BACKGROUND: There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants. METHODS: In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research. RESULTS: An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups. CONCLUSIONS: There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future.

Decade-long trends in prostate cancer biopsy grade groups and treatment within a population-based registry.

OBJECTIVE: To assess changes in diagnosis prostate cancer (PCa) grade, biopsy and treatment approach over a decade (2011-2020) at a population level within a clinical quality cancer registry. PATIENTS AND METHODS: Patients diagnosed by prostate biopsy between 2011 and 2020 were retrieved from the Victorian Prostate Cancer Outcomes Registry, a prospective, state-wide clinical quality registry in Australia. Distributions of each grade group (GG) proportion over time were modelled with restricted cubic splines, separately by biopsy technique, age group and subsequent treatment method. RESULTS: From 2011 to 2020, 24 308 men were diagnosed with PCa in the registry. The proportion of GG 1 disease declined from 36-23%, with commensurate rises in GG 2 (31-36%), GG 3 (14-17%) and GG 5 (9.3-14%) disease. This pattern was similar for men diagnosed by transrectal ultrasonography or transperineal biopsy. Patients aged <55 years had the largest absolute reduction in GG 1 PCa, from 56-35%, compared to patients aged 55-64 (41-31%), 65-74 (31-21%), and ≥75 years (12-10%). The proportion of prostatectomies performed for patients with GG 1 disease fell from 28% to 7.1% and, for primary radiation therapy, the proportion fell from 22% to 3.5%. CONCLUSION: From 2011 to 2020, there has been a substantial decrease in the proportion of GG 1 PCa diagnosed, particularly in younger men. The percentage of interventional management performed in GG 1 disease has fallen to very low levels. These results reflect the implementation of major changes to diagnostic and treatment guidelines and inform the future allocation of treatment methods.

Can 68 Ga-PSMA positron emission tomography and multiparametric MRI guide treatment for biochemical recurrence after radical prostatectomy?

OBJECTIVE: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) and Gallium-68 (68 Ga)-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in guiding salvage therapy for patients with biochemical recurrence (BCR) post-radical prostatectomy. PATIENTS AND METHODS: Patients were evaluated with paired mpMRI and 68 Ga-PSMA PET/CT scans for BCR (prostate-specific antigen [PSA] >0.2 ng/mL). Patient, tumour, PSA and imaging characteristics were analysed with descriptive statistics. RESULTS: A total of 117 patients underwent paired scans to investigate BCR, of whom 53.0% (62/117) had detectable lesions on initial scans and 47.0% (55/117) did not. Of those without detectable lesions, 8/55 patients proceeded to immediate salvage radiotherapy (sRT) and 47/55 were observed. Of patients with negative imaging who were initially observed, 46.8% (22/47) did not reach threshold for repeat imaging, while 53.2% were rescanned due to rising PSA levels. Of these rescanned patients, 31.9% (15/47) were spared sRT due to proven distant disease, or due to absence of disease on repeat imaging. Of the original 117 patients, 53 (45.3%) were spared early sRT due to absence of disease on imaging or presence of distant disease, while those undergoing delayed sRT still maintained good PSA responses. Of note, patients with high-risk features who underwent sRT despite negative imaging demonstrated satisfactory PSA responses to sRT. Study limitations include the observational design and absence of cause-specific or overall survival data. CONCLUSION: Our findings support the use of mpMRI and 68 Ga-PSMA PET/CT in guiding timing and necessity of salvage therapy tailored to detected lesions, with potential to reduce unnecessary sRT-related morbidity. Larger or randomized trials are warranted to validate this.

Defining Diagnostic Criteria for Prostatic Ductal Adenocarcinoma at Multiparametric MRI.

Background Prostatic ductal adenocarcinoma (DAC) is an aggressive histologic variant of prostate cancer that often warrants multimodal therapy and poses a significant diagnostic challenge clinically and at imaging. Purpose To develop multiparametric MRI criteria to define DAC and to assess their diagnostic performance in differentiating DAC from prostatic acinar adenocarcinoma (PAC). Materials and Methods Men with histologically proven DAC who had multiparametric MRI before radical prostatectomy were retrospectively identified from January 2011 through November 2018. MRI features were predefined using a subset of nine DACs and then compared for men with peripheral-zone DACs 1 cm or greater in size and men with matched biopsy-confirmed International Society of Urological Pathology grade group 4-5 PAC, by four independent radiologists blinded to the pathologic diagnosis. Diagnostic performance was determined by consensus read. Patient and tumor characteristics were compared by using the Fisher test, t-tests, and Mann-Whitney U test. Agreement (Cohen κ) and sensitivity analyses were also performed. Results There were 59 men with DAC (median age, 63 years [interquartile range, 56, 67 years]) and 59 men with PAC (median age, 64 years [interquartile range, 59, 69 years]). Predefined MRI features, including intermediate T2 signal, well-defined margin, lobulation, and hypointense rim, were detected in a higher proportion of DACs than PACs (76% [45 of 59] vs 5% [three of 59]; P < .001). On consensus reading, the presence of three or more features demonstrated 76% sensitivity, 94% specificity, 94% positive predictive value [PPV], and 80% negative predictive value [NPV] for all DACs and 100% sensitivity, 95% specificity, 81% PPV, and 100% NPV for pure DACs. The DACs and PACs showed no difference in contrast enhancement (100% vs 100%; P >.99, median T2 signal intensity (254 vs 230; P = .99), or apparent diffusion coefficient (median, 677 10-6 mm2/sec vs 685 10-6 mm2/sec; P = .73). Conclusion The presence of intermediate T2 signal, well-defined margin, lobulation, and/or hypointense rim, together with restricted diffusion and contrast enhancement at multiparametric MRI of the prostate, suggests prostatic ductal adenocarcinoma rather than prostatic acinar adenocarcinoma. © RSNA, 2022 Online supplemental material is available for this article.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Cancer in Lockdown: Impact of the COVID-19 Pandemic on Patients with Cancer.

The lockdown measures of the ongoing COVID-19 pandemic have disengaged patients with cancer from formal health care settings, leading to an increased use of social media platforms to address unmet needs and expectations. Although remote health technologies have addressed some of the medical needs, the emotional and mental well-being of these patients remain underexplored and underreported. We used a validated artificial intelligence framework to conduct a comprehensive real-time analysis of two data sets of 2,469,822 tweets and 21,800 discussions by patients with cancer during this pandemic. Lung and breast cancer are most prominently discussed, and the most concerns were expressed regarding delayed diagnosis, cancellations, missed treatments, and weakened immunity. All patients expressed significant negative sentiment, with fear being the predominant emotion. Even as some lockdown measures ease, it is crucial that patients with cancer are engaged using social media platforms for real-time identification of issues and the provision of informational and emotional support.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

Patterns of metastases of prostatic ductal adenocarcinoma.

BACKGROUND: The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy. METHODS: All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected. RESULTS: A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P < .05). Approximately 87% of men with de novo metastases progressed despite multiple systemic therapies, 37.6% required intervention for the palliation of symptoms, and 10.1% responded to systemic therapy and underwent treatment of the primary tumor. Men with de novo metastatic DAC and those who developed metastases after treatment had multiple metastatic sites (including bone and viscera), with higher rates of lung metastases noted in the posttreatment group (23.2% vs 44.2%; P = .01). A total of 45 patients who were treated with curative intent developed metastases at a median of 22 months (range, 0.9-74.8 months) after treatment, at low prostate-specific antigen levels (median, 4.4 ng/mL [interquartile range, 1.7-11.1 ng/mL]). CONCLUSIONS: The current study described the metastatic patterns of DAC in both patients with de novo metastatic disease and those who later progress to metastases. Men receiving treatment for DAC with curative intent require stringent long-term follow-up with imaging modalities, including chest imaging given the predilection toward lung metastases noted among these patients.

Downgrading from Biopsy Grade Group 4 Prostate Cancer in Patients Undergoing Radical Prostatectomy for High or Very High Risk Prostate Cancer.

PURPOSE: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy. MATERIALS AND METHODS: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy. RESULTS: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01). CONCLUSIONS: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

The cytoreductive prostatectomy in metastatic prostate cancer: what the individual trials are hoping to answer.

OBJECTIVE: To review the ongoing randomised trials of cytoreductive prostatectomy (CRP) in de novo hormone-sensitive metastatic prostate cancer (HSPC) in order to identify their goals and assess their strengths and weaknesses. METHODS: PubMed, MEDLINE and clinical trials websites searches were performed to identify currently ongoing trials of CRP in de novo HSPC. RESULTS: Nine randomised clinical trials in CRP were identified and included: Southwest Oncology Group (SWOG) 1802, Surgery in Metastatic Carcinoma of Prostate (SIMCAP), Adjuvant Treatments to the Local Tumour for Metastatic Prostate Cancer: Assessment of Novel Treatment Algorithms (IP2-ATLANTA), Testing Radical prostatectomy in men with prostate cancer and oligoMetastases to the bone (TRoMbone), Impact of Radical Prostatectomy as Primary Treatment in Patients with Prostate Cancer with Limited Bone Metastases (g-RAMPP), Cytoreductive Prostatectomy vs Cytoreductive Prostate Irradiation as a Local Treatment Option for Metastatic Prostate Cancer: a Multicentric Feasibility Trial (LoMP II), Androgen-Deprivation Therapy or Androgen-Deprivation Therapy Plus Definitive Treatment (Radiation or Surgery) (FUSCC-OMPCa), and the Testing Radical Prostatectomy in Chinese Men with Prostate Cancer and oligoMetastases to the Bone study. Each study was different; assessing various primary outcome measures including overall survival (OS), progression-free survival and feasibility to randomise between standard therapy and CRP or between radiation therapy and CRP in the metastatic setting. In the oligometastatic setting, the trials assess OS, feasibility to randomise and time to castration resistance. Similarly, a number of secondary endpoints ranging from cancer-specific outcomes to quality-of-life outcomes are being investigated. The inclusion criteria in these trials also varied in terms of volume of metastatic disease (oligometastatic to high-volume metastatic disease), diagnosis of metastases (imaging based vs biopsy confirmed), imaging modalities used (conventional to newer modalities), as well as outcomes and follow-up regimes. CONCLUSION: While there are differences in each protocol, each trial aims to address different aspects of CRP in de novo HSPC. Therefore, the specific goals of each study and the limitations have to be taken into consideration when interpreting the results of these trials.

Systematic review: bacterial colonisation of conduits and neobladders-when to test, watch, and treat.

BACKGROUND: Urinary diversion procedures frequently result in bacterial colonisation. There is an increased incidence of developing urinary tract infections (UTIs) in this patient population. Current guidelines, however, recommend against treating this colonisation. This systematic review aimed to determine when and how to test, monitor, and treat bacteriuria in patients with urinary diversion. METHODS: A systematic search strategy was conducted based on keywords "urinary diversion" and "bacteriuria", on MEDLINE, Embase, and Google Scholar. Articles were screened and included only if they reported on (i) testing methods for bacteriuria, (ii) surveillance of bacteriuria over time, or (iii) when and how to treat bacteriuria. Results were summarised and reported using a narrative synthesis. RESULTS: Altogether, 26 studies were included in this review. Inconsistencies were noted in the definitions of bacteriuria, with most studies reporting bacteriuria as > 104 cfu/mL (8/17 studies). Bacteriuria prevalence varied greatly (range 9.1-100%). Monitoring bacteriuria over time may help detect a reduction in bacteriuria, as demonstrated in three studies (follow-up range 5-18 months; sample size 18-56). The link between preceding bacteriuria and subsequent UTIs has not been fully explored yet. Short-term antimicrobial therapy may be useful in the immediate post-operative setting; however, long-term prophylactic treatment is ineffective in preventing bacteriuria. CONCLUSIONS: We recommend consistent reporting of bacteriuria definitions, the benefits of monitoring bacteriuria over time, and use of short-term antimicrobial therapy; bacteriuria should not be treated with long-term therapy.

Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer.

OBJECTIVES: To assess whether metformin reduces radio-resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1-α (HIF1α). PATIENTS AND METHODS: All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa-specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H2 O2 -induced oxidative stress. RESULTS: A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow-up of 95.7 months. There were no differences in age, initial prostate-specific antigen level, Gleason score, T-stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5-fold increase in PCa-specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high-dose metformin (>1 g/d) with those on low-dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 µM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H2 O2 ). CONCLUSIONS: No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin-HIF1α pathway in this patient group.

Risk stratification and avoiding overtreatment in localized prostate cancer.

PURPOSE OF REVIEW: Significant morbidity is associated with overtreatment of clinically localized prostate cancer (PCa). Risk stratification tools such as novel biomarkers, MRI and risk calculators are useful in predicting which patients would benefit from active surveillance. This review examines current risk stratification tools in localized PCa and the safety of active surveillance in these patients. RECENT FINDINGS: Very low risk, low-risk and favourable intermediate-risk PCa variants may benefit from treatment with active surveillance. These disease categories have been shown (with up to 10-year follow-up) to have survival and cancer-specific complication rates similar to immediate definitive treatment. Novel biomarkers sensitively predict upstaging, recurrence and metastatic progression while multiparametric MRI reliably detects clinically significant PCa and is valuable in the biopsy naïve patient considering active surveillance. Lastly, risk calculators and nomograms are being developed to combine clinical data and provide optimal individualized treatment while minimizing overtreatment in clinically localized disease. SUMMARY: Although large randomized trials are needed to validate treatment pathways, current data supports active surveillance in certain clinically localized PCa. Many tools exist to define and support active surveillance in this group.

The Patient-Reported Information Multidimensional Exploration (PRIME) Framework for Investigating Emotions and Other Factors of Prostate Cancer Patients with Low Intermediate Risk Based on Online Cancer Support Group Discussions.

BACKGROUND: This study aimed to use the Patient Reported Information Multidimensional Exploration (PRIME) framework, a novel ensemble of machine-learning and deep-learning algorithms, to extract, analyze, and correlate self-reported information from Online Cancer Support Groups (OCSG) by patients (and partners of patients) with low intermediate-risk prostate cancer (PCa) undergoing radical prostatectomy (RP), external beam radiotherapy (EBRT), and active surveillance (AS), and to investigate its efficacy in quality-of-life (QoL) and emotion measures. METHODS: From patient-reported information on 10 OCSG, the PRIME framework automatically filtered and extracted conversations on low intermediate-risk PCa with active user participation. Side effects as well as emotional and QoL outcomes for 6084 patients were analyzed. RESULTS: Side-effect profiles differed between the methods analyzed, with men after RP having more urinary and sexual side effects and men after EBRT having more bowel symptoms. Key findings from the analysis of emotional expressions showed that PCa patients younger than 40 years expressed significantly high positive and negative emotions compared with other age groups, that partners of patients expressed more negative emotions than the patients, and that selected cohorts (< 40 years, > 70 years, partners of patients) have frequently used the same terms to express their emotions, which is indicative of QoL issues specific to those cohorts. CONCLUSION: Despite recent advances in patient-centerd care, patient emotions are largely overlooked, especially in younger men with a diagnosis of PCa and their partners. The authors present a novel approach, the PRIME framework, to extract, analyze, and correlate key patient factors. This framework improves understanding of QoL and identifies low intermediate-risk PCa patients who require additional support.

Trends in incidence and survival for upper tract urothelial cancer (UTUC) in the state of Victoria--Australia.

OBJECTIVE: To investigate the incidence and mortality trends of upper tract urothelial cancers (UTUC) in Victoria over the last decade. PATIENTS AND METHODS: Age-adjusted incidence and mortality rates were calculated for UTUC. These were identified using data from the Victorian Cancer Registry from 2001 until 2011 based on histological diagnoses. Age at diagnosis, sex and demographical location were compared. RESULTS: The age-standardised incidence of UTUC remained stable from 2001 to 2011. There were 278 deaths from UTUC over this period with an overall 5-year survival rate of 32%. There was no significant difference in survival between 2001-06 and 2007-11 (30% vs 36%, respectively). Lower age at diagnosis was associated with a significant improvement in survival (P = 0.01). Sex and geographical location appeared to have no effect on survival. CONCLUSION: The 5-year survival rates for UTUC in Victoria are poor, particularly in comparison to worldwide data. In contrast to worldwide trends, the incidence of UTUC appears to be stable. No significant improvement in 5-year survival rates over the short study period was identified. These findings highlight the difficulties in managing this rare yet deadly malignancy.

HIF1α expression under normoxia in prostate cancer--which pathways to target?

PURPOSE: HIF1α over expression correlates with poor prognosis in a number of cancers. Although it is widely accepted that hypoxia induces HIF1α expression up-regulation by a reduction in oxygen dependent degradation, HIF1α up-regulation under normoxic conditions is noted with increasing frequency in many cancers. We reviewed the current knowledge of mechanisms of normoxic and hypoxic HIF1α up-regulation, and its therapeutic implications with a particular focus on its role as a potential biomarker in prostate cancer. MATERIALS AND METHODS: Although the literature on the role of HIFs in cancer development and progression has been reviewed extensively, few publications have specifically considered the role of HIFs in prostate cancer. Therefore, we searched PubMed® and Google® with the key words prostate cancer, castration resistance, metastasis, hypoxia, HIF1α, HIF2α and regulation. Relevant articles, including original research studies and reviews, were selected based on contents and a synopsis was generated. RESULTS: Normoxic expression of HIF1α has an important role in the development of prostate cancer chemoresistance, radioresistance and castrate resistance. Thus, HIF1α could serve as a potential biomarker. Furthermore, agents that target HIF1α could be used as adjuvant therapy to decrease resistance to conventional treatment modalities. HIF1α over expression in prostate cancer can be regulated at 3 levels, including transcription, translation and protein stability, by a number of mechanisms such as gene amplification, single nucleotide polymorphism, increased transcription of HIF1α mRNA, expression of truncated isoforms of HIF1α and stabilization of HIF1α. However, there is no definitive consensus and the intriguing question of how HIF1α is up-regulated in prostate cancer is still unanswered. CONCLUSIONS: HIF1α over expression under normoxia could serve as a biomarker for chemoresistance, radioresistance and castrate resistance in prostate cancer. There is an urgent need to identify the cause of HIF1α over expression in castrate resistant prostate cancer cells and tumors to guide the choice of HIF inhibitors (transcription or translation based) that are best suited for treating castrate resistant prostate cancer.

Waiting for definitive care: An analysis of elapsed time from decision to surgery or transfer in a rural centre.

OBJECTIVE: To examine the timing of operative management and interhospital transfer of emergency general surgical patients in a regional setting. DESIGN: Retrospective cohort study. SETTING: The surgical unit at a major rural referral centre for North-Eastern Victoria servicing a population of 90 000. PARTICIPANTS: General surgical patients (n = 649) admitted via the emergency department at Northeast Health Wangaratta between January 2011 and March 2013 undergoing operative management (n = 608) or transfer to a tertiary centre (n = 44). MAIN OUTCOME MEASURES: Timing of operative management, using appendicectomy as a benchmark operation, was measured as time from presentation to decision to operate, time from decision to surgery, percentage after-hours operating and length of stay (LOS). Time to interhospital transfer was calculated and reasons for delay were sought. RESULTS: Two hundred forty-six appendicectomies were performed. Median time from decision to operate to theatre was 3 hours (interquartile range (IQR) 2-8), and total LOS was 43 hours (IQR: 28-56). Two hundred seventy-two procedures (43%) were performed out-of-hours, including 48% of appendicectomies. Median time from decision making to transfer was 10.3 hours (IQR: 4.7-25). Transfer was less likely to be delayed in trauma patients when compared with urgent non-trauma patients (5.3 versus 10.6 hours; P = 0.04). CONCLUSION: Even in the absence of a strict four-hour rule program and a dedicated emergency surgical unit, main outcome measures appear to be comparatively efficient. However, the duration for transfer of patients is suboptimal because of the lack of established pathways for urgent non-trauma transfer from rural centres and bed availability in tertiary hospitals.

Population-based analysis of prostate-specific antigen (PSA) screening in younger men (<55 years) in Australia.

OBJECTIVE: To analyse the trends in opportunistic PSA screening in Australia, focusing on younger men (<55 years of age), to examine the effects of this screening on transrectal ultrasonography (TRUS)-guided biopsy rates and to determine the nature of prostate cancers (PCas) being detected. SUBJECTS AND METHODS: All men who received an opportunistic screening PSA test and TRUS-guided biopsy between 2001 and 2008 in Australia were analysed using data from the Australian Cancer registry (Australian Institute of Health and Welfare) and Medicare databases. The Victorian cancer registry was used to obtain Gleason scores. Age-standardized and age-specific rates were calculated, along with the incidence of PCa, and correlated with Gleason scores. RESULTS: A total 5 174 031 PSA tests detected 128 167 PCas in the period 2001-2008. During this period, PSA testing increased by 146% (a mean of 4629 tests per 100 000 men annually), with 80 and 59% increases in the rates of TRUS-guided biopsy and incidence of PCa, respectively. The highest increases in PSA screening occurred in men <55 years old and up to 1101 men had to be screened to detect one incident case of PCa (0.01%). Screening resulted in two thirds of men aged <55 years receiving a negative TRUS biopsy. There was no correlation with Gleason >7 tumours in patients aged <55 years. CONCLUSION: Despite the ongoing controversy about the merits of PCa screening, there was an increase in PSA testing, especially in men <55 years old, leading to a modestly higher incidence of PCa in Australia. Overall, PSA screening was associated with high rates of negative TRUS-biopsy and the detection of low/intermediate grade PCa among younger patients.

Bladder carcinoma in situ (CIS) in Australia: a rising incidence for an under-reported malignancy.

OBJECTIVES: To investigate the incidence of carcinoma in situ (CIS) in Australia and examine implications for its diagnosis and management, as CIS of the urinary bladder is a non-reportable disease in Australia. METHODS: Analysis of annual hospitalisation data using Australian Institute of Health and Welfare (AIHW) datasets showed an increase in CIS from 2001 onwards. To determine whether the increase seen with AIHW data represented a true increase in the rates offices, patient level data was examined using the Centre for Health record linkage (CHeReL) datasets. RESULTS: CHeReL linked data of 13,790 males and 5902 females, calculated the average incidence of CIS to be 20.9 per 100,000 and 6.5 per 100,000 respectively in those aged > 50 years, showing a rapid increase in the rates of CIS from 2001. There was an 11% (P = 0.04) and 14% (P = 0.02) annual increase in incidence of CIS in men and women and these rates increased with age. CONCLUSIONS: National data (AIHW) substantially underestimate the incidence of CIS in the Australian population. Patient level data suggest CIS rates are rapidly increasing in Australia despite high treatment rates. Closer surveillance and awareness of these high rates warrants further study and we recommend that CIS be considered a reportable disease.