Medication-based Comorbidity Measures and Prostate Cancer Treatment Selection.

INTRODUCTION: We aimed to assess the association between comorbidities and prostate cancer management. PATIENTS AND METHODS: We studied 12,603 South Australian men diagnosed with prostate cancer between 2003 and 2019. Comorbidity was measured one year prior to prostate cancer diagnosis using a medication-based comorbidity index (Rx-Risk). Binomial logistic regression analyses were used to assess the association between comorbidities and primary treatment selection (active surveillance, radical prostatectomy (RP), external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT), brachytherapy, ADT alone, and watchful waiting (WW)). Certain common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and chronic pain) were also assessed. All models were adjusted for sociodemographic and tumor characteristics. RESULTS: Likelihood of receiving RP was lower among men with Rx-Risk score ≥3 (odds ratio (OR) 0.62, 95%CI:0.56-0.69) and Rx-Risk 2 (OR 0.80, 95%CI:0.70-0.92) compared with no comorbidity (Rx-Risk ≤0). Men with high comorbidity (Rx-Risk ≥3) were more likely to have received ADT alone (OR 1.76, 95%CI:1.40-2.21), EBRT (OR 1.30, 95%CI:1.17-1.45) or WW (OR 1.49, 95%CI:1.19-1.88) compared with Rx-Risk ≤0. Pre-existing cardiac and respiratory disorders, thrombosis, diabetes, depression and anxiety, and chronic pain were associated with lower likelihood of selecting RP and higher likelihood of EBRT (except chronic airway disease) or WW (except diabetes and depression and anxiety). Cardiac disorders and thrombosis were associated with higher likelihood of selecting ADT alone. Furthermore, age had greater effect on treatment choice than the level of comorbidity. CONCLUSION: High comorbidity burden was associated with primary treatment choice, with significantly less RP and more EBRT, WW and ADT alone among men with higher levels of comorbidity. Each of the individual comorbid conditions also influenced treatment selection.

Mitigating type 1 error inflation and power loss in GxE PRS: Genotype-environment interaction in polygenic risk score models.

The use of polygenic risk score (PRS) models has transformed the field of genetics by enabling the prediction of complex traits and diseases based on an individual's genetic profile. However, the impact of genotype-environment interaction (GxE) on the performance and applicability of PRS models remains a crucial aspect to be explored. Currently, existing genotype-environment interaction polygenic risk score (GxE PRS) models are often inappropriately used, which can result in inflated type 1 error rates and compromised results. In this study, we propose novel GxE PRS models that jointly incorporate additive and interaction genetic effects although also including an additional quadratic term for nongenetic covariates, enhancing their robustness against model misspecification. Through extensive simulations, we demonstrate that our proposed models outperform existing models in terms of controlling type 1 error rates and enhancing statistical power. Furthermore, we apply the proposed models to real data, and report significant GxE effects. Specifically, we highlight the impact of our models on both quantitative and binary traits. For quantitative traits, we uncover the GxE modulation of genetic effects on body mass index by alcohol intake frequency. In the case of binary traits, we identify the GxE modulation of genetic effects on hypertension by waist-to-hip ratio. These findings underscore the importance of employing a robust model that effectively controls type 1 error rates, thus preventing the occurrence of spurious GxE signals. To facilitate the implementation of our approach, we have developed an innovative R software package called GxEprs, specifically designed to detect and estimate GxE effects. Overall, our study highlights the importance of accurate GxE modeling and its implications for genetic risk prediction, although providing a practical tool to support further research in this area.

Clinical and functional outcomes for risk-appropriate treatments for prostate cancer.

Objectives: To describe real-world clinical and functional outcomes in an Australian cohort of men with localised prostate cancer according to treatment type and risk category. Subjects and methods: Men diagnosed from 2008 to 2018 who were enrolled in South Australian Prostate Cancer Clinical Outcomes Collaborative registry-a multi-institutional prospective clinical registry-were studied. The main outcome measures were overall survival, cancer-specific survival, decline in functional outcomes, biochemical recurrence and transition to active treatment following active surveillance. Multivariable adjusted models were applied to estimate outcomes. Results: Of the 8513 eligible men, majority of men (46%) underwent radical prostatectomy (RP) followed by external beam radiation therapy with or without androgen deprivation therapy (EBRT +/- ADT) in 22% of the cohort. Five-year overall survival was above 91%, and 5-year prostate cancer-specific survival was above 97% in the low- and intermediate-risk categories across all treatments. Five-year prostate cancer-specific survival in the active surveillance group was 100%. About 37% of men with high-risk disease treated with RP and 17% of men treated with EBRT +/- ADT experienced biochemical recurrence within 5 years of treatment. Of men on active surveillance, 15% of those with low risk and 20% with intermediate risk converted to active treatment within 2 years. The decline in urinary continence and sexual function 12 months after treatment was greatest among men who underwent RP while the decline in bowel function was greatest for men who received EBRT +/- ADT. Conclusion: This contemporary real-world evidence on risk-appropriate treatment outcomes helps inform treatment decision-making for clinicians and patients.

Utility of prescription-based comorbidity indices for predicting mortality among Australian men with prostate cancer.

BACKGROUND: Drug prescription registries has become an alternative data source to hospital admission databases for measuring comorbidities. However, the predictive validity of prescription-based comorbidity measures varies based on the population under investigation and outcome of interest. We aimed to determine which prescription-based index of comorbidity has most utility in Australian men with prostate cancer. METHODS: We studied 25,414 South Australian men diagnosed with prostate cancer between 2003 and 2019 from state-wide administrative linked datasets. The Rx-Risk index, Chronic Disease Score (CDS), Drug Comorbidity Index (DCI) and Pharmaceutical Prescribing Profile (P3) with one year lookback period from prostate cancer diagnosis were evaluated. The predictive ability of each index to determine all-cause deaths within two and five years of prostate cancer diagnosis was compared using the c-statistic from flexible parametric survival models, adjusting for age, socioeconomic status and year of prostate cancer diagnosis. RESULTS: The Rx-Risk index performed better in predicting two-year (c-statistic = 0.818) and five-year (c-statistic = 0.784) all-cause mortality than P3, CDS and DCI. Including comorbidity measures as continuous scores resulted in a better performance than including them as categories. Grouping scores into four categories (≤0, >0 - ≤1, >1 - ≤2, and >2) resulted in better performance and calibration than using fewer categories. CONCLUSION: Rx-Risk was validated in Australia and reflects Australian prescribing patterns. It showed better predictive performance for mortality in our study, with a modest improvement over P3, CDS and DCI. For research with prostate cancer populations, we recommend the use of drug-based comorbidity indices that have been validated in a similar population.

Clinical outcomes for men with positive surgical margins after radical prostatectomy-results from the South Australian Prostate Cancer Clinical Outcomes Collaborative community-based registry.

Objective: Positive surgical margins (PSMs) after radical prostatectomy (RP) indicate failure of surgery to completely clear cancer. PSMs confer an increased risk of biochemical recurrence (BCR), but how more robust outcomes are affected is unclear. This study investigated factors associated with PSMs following RP and determined their impact on clinical outcomes (BCR, second treatment [radiotherapy and/or androgen deprivation therapy], and prostate cancer-specific mortality [PCSM]). Methods: The study cohort included men diagnosed with prostate cancer (pT2-3b/N0/M0) between January 1998 and June 2016 who underwent RP from the South Australian Prostate Cancer Clinical Outcomes Collaborative database. Factors associated with risk of PSMs were identified using Poisson regression. The impact of PSMs on clinical outcomes (BCR, second treatment, and PCSM) was assessed using competing risk regression. Results: Of the 2827 eligible participants, 28% had PSMs-10% apical, 6% bladder neck, 17% posterolateral, and 5% at multiple locations. Median follow-up was 9.6 years with 81 deaths from prostate cancer recorded. Likelihood of PSM increased with higher pathological grade and pathological tumor stage, and greater tumour volume, but decreased with increasing surgeon volume (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.88-0.98, per 100 previous prostatectomies). PSMs were associated with increased risk of BCR (adjusted sub-distribution hazard ratio [sHR] 2.5; 95% CI 2.1-3.1) and second treatment (sHR 2.9; 95% CI 2.4-3.5). Risk of BCR was increased similarly for each PSM location, but was higher for multiple margin sites. We found no association between PSMs and PCSM. Conclusion: Our findings support previous research suggesting that PSMs are not independently associated with PCSM despite strong association with BCR. Reducing PSM rates remains an important objective, given the higher likelihood of secondary treatment with associated comorbidities.

Risk of secondary malignancy following radiation therapy for prostate cancer.

We investigated whether prostate cancer patients treated with external beam radiation therapy (EBRT) have a higher cumulative incidence of secondary cancer compared with patients treated with radical prostatectomy (RP). We used state-wide linked data from South Australia to follow men with prostate cancer diagnosed from 2002 to 2019. The cumulative incidence of overall and site-specific secondary cancers between 5 and 15 years after treatment was estimated. Fine-Gray competing risk analyses were performed with additional sensitivity analyses to test different scenarios. A total of 7625 patients were included (54% underwent RP and 46% EBRT). Characteristics of the two groups differed significantly, with the EBRT group being older (71 vs. 64 years), having higher comorbidity burden and being more likely to die during follow-up than the RP group. Fifteen-year cumulative incidence for all secondary cancers was 27.4% and 22.3% in EBRT and RP groups, respectively. In the adjusted models, patients in the EBRT group had a significantly higher risk of genitourinary (adjusted subhazard ratio (aSHR), 2.29; 95%CI 1.16-4.51) and lung (aSHR, 1.93; 95%CI 1.05-3.56) cancers compared with patients in the RP group. However, there was no statistically significant difference between the two groups for risk of any secondary cancer, gastro-intestinal, skin or haematologic cancers. No statistically significant differences in overall risk of secondary cancer were observed in any of the sensitivity analyses and patterns for risk at specific cancer sites were relatively consistent across different age restriction and latency/time-lag scenarios. In conclusion, the increased risk of genitourinary and lung cancers among men undergoing EBRT may relate partly to treatment effects and partly to unmeasured residual confounding.

Development of the consensus-based recommendations for Podiatry care of Neuropathy In Cancer Survivors (PodNICS): a Delphi consensus study of Australian podiatrists.

BACKGROUND: Chemotherapy Induced Peripheral Neuropathy (CIPN) is the most common presenting side effect of chemotherapy. As a sensory based neuropathy, this condition can persist for a long time after cessation of chemotherapy and impact the quality of life of cancer survivors. Podiatrists in Australia have been managing people with CIPN related lower limb complications, however guidelines on management of CIPN do not exist. The aim of this study was to achieve consensus and agreement of Australian podiatrists on strategies to best manage people presenting with symptoms of CIPN. METHODS: An online three-round modified Delphi survey of Australian podiatrists with expertise in CIPN was conducted in line with recommendations for conducting and reporting of Delphi studies (CREDES). Panellists responded to open-ended questions in Round 1, whereupon their responses were themed into statements and analysed for existing consensus. Statements not reaching consensus were returned during Round 2 to seek agreement from responders using a five-point Likert scale and to allow responders to make further comments. For a statement to reach consensus or agreement, 70% or more of panellists needed to make the same comment or agree or strongly agree with the same themed statement. Statements reaching 50 to 69% consensus or agreement were returned to panellists in Round 3 for them to consider their responses in the light of group outcomes. RESULTS: Round one resulted in 229 comments from 21 of 26 podiatrists who agreed to participate. These comments were themed into 53 statements with 11 consensus statements accepted. Round 2 resulted in 22 statements reaching agreement, and 15 new statements being generated from 18 comments made by 17 respondents. Round 3 resulted in 11 statements reaching agreement. Outcomes were developed into a set of clinical recommendations for diagnosis and management of people presenting with CIPN. These recommendations provide guidance on 1) identifying common signs and symptoms of CIPN including sensory, motor and autonomic symptoms; 2) diagnosis and assessment of CIPN including neurological, motor and dermatological assessment modalities; and 3) best clinical practice and management strategies for CIPN identified by podiatrists including both podiatry and non-podiatry specific care. CONCLUSIONS: This is the first study in podiatry literature to develop expert-informed consensus-based recommendations for clinical presentation, diagnosis and assessment and management of people with CIPN. These recommendations aim to help guide podiatrists in the consistent care of people with CIPN.

Factors impacting on sexual function among men on active surveillance for prostate cancer.

BACKGROUND: Active surveillance (AS) aims to reduce overtreatment and minimize the negative side effects of radical therapies (i.e., prostatectomy or radiotherapy) while preserving quality of life. However, a substantial proportion of men can experience a decline in sexual function during AS follow-up. The aim of this study was to identify predictors of declining sexual function among men on AS. METHODS: Men enrolled from 2008 to 2018 in the South Australian Prostate Cancer Clinical Outcomes Collaborative registry-a prospective clinical registry-were studied. Sexual function outcomes were measured using expanded prostate cancer index composite (EPIC-26) at baseline and 12-months postdiagnosis. Multivariable regression models adjusted for baseline score and other sociodemographic and clinical factors were applied to identify predictors of sexual function score at 12-months. RESULTS: A total of 554 men were included. Variables that showed significant association with decline in sexual function score at 12-months were: having two or more biopsies after diagnosis (mean change score (MCS): -16.3, p < 0.001) compared with no biopsy, higher number of positive biopsy cores (MCS: -1.6, p = 0.004), being in older age category (above 70 vs. below 60: MCS: -16.7, p < 0.001; 65-70 vs. below 60: MCS: -9.7, p = 0.024), having had depression (MCS: -9.0, p = 0.020), and impaired physical function (MCS: -10.0, p = 0.031). Greater socioeconomic advantage (highest vs. lowest quintile: MCS: 15.7, p = 0.022) and year of diagnosis (MCS: 2.6 for every year, p < 0.001) were positively associated with 12-months sexual function score. Neither biopsy type, biopsy timing nor PSA velocity were associated with declines in sexual function. CONCLUSIONS: Our findings suggest that multiple factors affected sexual function during AS. Interventions toward reducing the number of biopsies through less invasive monitory approaches, screening for physical and mental well-being, and targeted emotional support and counseling services may be helpful for men on AS.

Choice of imputation method for missing metastatic status affected estimates of metastatic prostate cancer incidence.

OBJECTIVES: To study how handling missing data on M stage in a clinical cancer register affects estimates of incidence of metastatic prostate cancer. STUDY DESIGN AND SETTING: Estimates of age-standardized incidence of metastatic prostate cancer were obtained by the use of data in a population-based clinical cancer register in Sweden and using four methods for imputation of missing M stage. Adjusted survival was used to compare men with known and imputed M stage. RESULTS: The proportion of men with missing M stage was high (66%) and varied according to the risk group and over calendar time. The estimated incidence of metastatic disease varied depending on imputation method, with all methods indicating a decreasing incidence over time. A combination of deterministic imputation (DI) and multiple imputation (MI) produced adjusted survival curves for men with imputed M stage that best resembled the survival for men with known M stage. CONCLUSIONS: Plausible estimates of incidence of metastatic prostate cancer in clinical cancer registers can be obtained by the use of a combination of DI of missing M stage and MI.

Developing a consensus statement for psychosocial support in active surveillance for prostate cancer.

Purpose: Our objective was to prioritise the psychosocial support needs of men on active surveillance for prostate cancer and to develop a consensus statement to provide guidance on best practice psychosocial support for men choosing active surveillance and their families. Subjects and methods: We undertook a patient and public involvement Delphi process over two rounds, informed by qualitative data and a comprehensive literature review, to prioritise the information and support needs of men on active surveillance for prostate cancer. Two panels were surveyed, a patient/carer panel (n = 55) and a health care provider panel (n = 114). Based on the findings of the Delphi surveys, an expert active surveillance discussion group developed a consensus statement to guide best practice. Results: Patients and health care professionals differed slightly in their ideas concerning priorities for active surveillance psychosocial support. Broadly, agreed priority areas included -patients being involved in decision-making, continuity of care, more streamlined access to health care teams, improved understanding of the risk of prostate cancer progression and information and support provided through both health care professionals and peers. Based on the identified priorities, the expert discussion group agreed on 22 consensus statements for best practice in psychosocial care for active surveillance in respect of (1) principles of an active surveillance programme; (2) structure of consultations; (3) content of information and support; and (4) delivery of information. Conclusion: This consensus statement provides a framework for patient-focused psychosocial support, which, if adopted, should increase uptake and adherence to active surveillance among men with prostate cancer.

Risk of progression following a negative biopsy in prostate cancer active surveillance.

BACKGROUND: Currently, follow-up protocols are applied equally to men on active surveillance (AS) for prostate cancer (PCa) regardless of findings at their initial follow-up biopsy. To determine whether less intensive follow-up is suitable following negative biopsy findings, we assessed the risk of converting to active treatment, any subsequent upgrading, volume progression (>33% positive cores), and serious upgrading (grade group >2) for negative compared with positive findings on initial follow-up biopsy. METHODS: 13,161 men from 24 centres participating in the Global Action Plan Active Surveillance Prostate Cancer [GAP3] consortium database, with baseline grade group ≤2, PSA ≤ 20 ng/mL, cT-stage 1-2, diagnosed after 1995, and ≥1 follow-up biopsy, were included in this study. Risk of converting to treatment was assessed using multivariable mixed-effects survival regression. Odds of volume progression, any upgrading and serious upgrading were assessed using mix-effects binary logistic regression for men with ≥2 surveillance biopsies. RESULTS: 27% of the cohort (n = 3590) had no evidence of PCa at their initial biopsy. Over 50% of subsequent biopsies in this group were also negative. A negative initial biopsy was associated with lower risk of conversion (adjusted hazard ratio: 0.45; 95% confidence interval [CI]: 0.42-0.49), subsequent upgrading (adjusted odds ratio [OR]: 0.52; 95%CI: 0.45-0.62) and serious upgrading (OR: 0.74; 95%CI: 0.59-92). Radiological progression was not assessed due to limited imaging data. CONCLUSION: Despite heterogeneity in follow-up schedules, findings from this global study indicated reduced risk of converting to treatment, volume progression, any upgrading and serious upgrading among men whose initial biopsy findings were negative compared with positive. Given the low risk of progression and high likelihood of further negative biopsy findings, consideration should be given to decreasing follow-up intensity for this group to reduce unnecessary invasive biopsies.

Patient-reported functional outcome measures and treatment choice for prostate cancer.

BACKGROUND: The aim of this study was to describe changes in patient-reported functional outcome measures (PROMs) comparing pre-treatment and 12 months after radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy and active surveillance (AS). METHODS: Men enrolled from 2010 to 2019 in the South Australian Prostate Cancer Clinical Outcomes Collaborative registry a prospective clinical registry were studied. Urinary, bowel, and sexual functions were measured using Expanded Prostate Cancer Index Composite (EPIC-26) at baseline and 12 months post-treatment. Higher scores on the EPIC-26 indicate better function. Multivariable regression models were applied to compare differences in function and extent of bother by treatment. RESULTS: Of the 4926 eligible men, 57.0% underwent RP, 20.5% EBRT, 7.0% brachytherapy and 15.5% AS. While baseline urinary and bowel function varied little across treatment groups, sexual function differed greatly (adjusted mean scores: RP = 56.3, EBRT = 45.8, brachytherapy = 61.4, AS = 52.8; p < 0.001). Post-treatment urinary continence and sexual function declined in all treatment groups, with the greatest decline for sexual function after RP (adjusted mean score change - 28.9). After adjustment for baseline differences, post-treatment sexual function scores after EBRT (6.4; 95%CI, 0.9-12.0) and brachytherapy (17.4; 95%CI, 9.4-25.5) were higher than after RP. Likewise, urinary continence after EBRT (13.6; 95%CI, 9.0-18.2), brachytherapy (10.6; 95%CI, 3.9-17.3) and AS (10.6; 95%CI, 5.9-15.3) were higher than after RP. Conversely, EBRT was associated with lower bowel function (- 7.9; 95%CI, - 12.4 to - 3.5) than RP. EBRT and AS were associated with lower odds of sexual bother (OR 0.51; 95%CI, 0.29-0.89 and OR 0.60; 95%CI, 0.38-0.96, respectively), and EBRT with higher odds of bowel bother (OR 2.01; 95%CI, 1.23-3.29) compared with RP. CONCLUSION: The four common treatment approaches for prostate cancer were associated with different patterns of patient-reported functional outcomes, both pre- and 12 months post-treatment. However, after adjustment, RP was associated with a greater decline in urinary continence and sexual function than other treatments. This study underscores the importance of collecting baseline PROMs to interpret post-treatment functional outcomes.

Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis.

OBJECTIVE: To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer. DESIGN: Prospectively registered systematic review and meta-analysis of literature. DATA SOURCES: Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors. ELIGIBILITY CRITERIA: Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but <2 mm), and negative margins (≥2 mm). RESULTS: 68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P<0.001) and local recurrence (1.98, 1.66 to 2.36, P<0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P<0.001) and local recurrence (2.09, 1.39 to 3.13, P<0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P<0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P<0.001) compared with negative margins. CONCLUSIONS: Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised. SYSTEMATIC REVIEW REGISTRATION: CRD42021232115.

Antibodies as biomarkers for cancer risk: a systematic review.

Increasing evidence has linked the humoral immune response with the development of various cancers. Therefore, there is growing interest in investigating the predictive value of antibodies to assess overall and tissue site-specific cancer risk. Given the large amount of antibody types and the broad scope of the search (i.e. cancer risk), the primary aim of this systematic review was to present an overview of the most researched antibodies (i.e. immunoglobulin (Ig) isotypes (IgG, IgM, IgA, and IgE), tumour and self-antigen-reactive antibodies, infection-related antibodies) in relation to overall and site-specific cancer risk. We identified various antibody types that have been associated with the risk of cancer. While no significant associations were found for IgM serum levels, studies found an inconsistent association among IgE, IgA, and IgG serum levels in relation to cancer risk. When evaluating antibodies against infectious agents, most studies reported a positive link with specific cancers known to be associated with the specific agent recognized by serum antibodies (i.e. helicobacter pylori and gastric cancer, hepatitis B virus and hepatocellular carcinoma, and human papillomavirus and cervical cancer). Several reports identified autoantibodies, as single biomarkers (e.g. anti-p53, anti-MUC1, and anti-CA125) but especially in panels of multiple autoantibodies, to have potential as diagnostic biomarkers for specific cancer types. Overall, there is emerging evidence associating certain antibodies to cancer risk, especially immunoglobulin isotypes, tumour-associated antigen-specific, and self-reactive antibodies. Further experimental studies are necessary to assess the efficacy of specific antibodies as markers for the early diagnosis of cancer.

Comparison of outcomes of different biopsy schedules among men on active surveillance for prostate cancer: An analysis of the G.A.P.3 global consortium database.

BACKGROUND: The optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database. MATERIALS AND METHODS: Intensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity. RESULTS: Out of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p < 0.001), while risk of upgrading did not differ (HR = 0.96; 95% CI = 0.84-1.10). CONCLUSION: Results suggest more frequent biopsy schedules may deter some men from continuing AS despite no evidence of grade progression.

Exercise prehabilitation during neoadjuvant chemotherapy may enhance tumour regression in oesophageal cancer: results from a prospective non-randomised trial.

BACKGROUND: There is increasing evidence for the use of exercise in cancer patients and data supporting enhanced tumour volume reduction following chemotherapy in animal models. To date, there is no reported histopathological evidence of a similar oncological benefit in oesophageal cancer. METHODS: A prospective non-randomised trial compared a structured prehabilitation exercise intervention during neoadjuvant chemotherapy and surgery versus conventional best-practice for oesophageal cancer patients. Biochemical and body composition analyses were performed at multiple time points. Outcome measures included radiological and pathological markers of disease regression. Logistic regression calculated ORs with 95% CI for the likelihood of pathological response adjusting for chemotherapy regimen and chemotherapy delivery. RESULTS: Comparison of the Intervention (n=21) and Control (n=19) groups indicated the Intervention group had higher rates of tumour regression (Mandard TRG 1-3 Intervention n=15/20 (75%) vs Control n=7/19 (36.8%) p=0.025) including adjusted analyses (OR 6.57; 95% CI 1.52 to 28.30). Combined tumour and node downstaging (Intervention n=9 (42.9%) vs Control n=3 (15.8%) p=0.089) and Fat Free Mass index were also improved (Intervention 17.8 vs 18.7 kg/m2; Control 16.3 vs 14.7 kg/m2, p=0.026). Differences in markers of immunity (CD-3 and CD-8) and inflammation (IL-6, VEGF, INF-y, TNFa, MCP-1 and EGF) were observed. CONCLUSION: The results suggest improved tumour regression and downstaging in the exercise intervention group and should prompt larger studies on this topic. TRIAL REGISTRATION NUMBER: NCT03626610.

Changes in five-year survival for people with acute leukaemia in South Australia, 1980-2016.

OBJECTIVES: To examine population changes in 5-year survival for people in South Australia diagnosed with acute leukaemia during 1980-2016, by socio-demographic characteristics. DESIGN, SETTING: Retrospective analysis of South Australian Cancer Registry data for the period 1980-2016. PARTICIPANTS: All South Australian residents diagnosed with primary acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) during 1980-2016. MAIN OUTCOME MEASURES: 5-year disease-specific survival and disease-specific mortality. RESULTS: Crude 5-year disease-specific survival was 58% (95% CI, 54-61%) for the 1035 people diagnosed with ALL during 1980-2016, and 18% (95% CI, 17-20%) for the 2814 people diagnosed with AML. Survival improved steadily across the study period: from 44% (95% CI, 35-52%) for people with ALL diagnosed during 1980-1984 to 69% (95% CI, 63-75%) for those diagnosed during 2010-2016; and from 9% (95% CI, 5-15%) to 23% (95% CI, 20-26%) for people diagnosed with AML. Disease-specific mortality increased with age, but was not influenced by socio-economic status or remoteness of residence. After adjusting for other factors, rates of change in risk of leukaemia-related death were greater for younger than older patients with ALL (for interaction: P = 0.004) or AML (P = 0.005), but were not significantly influenced by socio-economic status or remoteness. CONCLUSION: Five-year survival for people with acute leukaemia in South Australia continuously improved during 1980-2016, and socio-economic status and remoteness did not influence survival. It improved markedly for younger patients (under 50 years of age). However, survival is still relatively poor, especially for people over 50 years with AML.

Hormonal patterns in men with prediabetes and diabetes in NHANES III: possible links with prostate cancer.

PURPOSE: Pathways involving sex hormones and insulin-like growth factors (IGFs) have been proposed to explain, in part, the lower risk of prostate cancer among men with diabetes. To gain insights into potential biological mechanisms we explored differences in serum concentrations of sex hormones and IGFs across the trajectory from normoglycemia to prediabetes to poorly controlled diabetes. METHODS: Using cross-sectional data from the National Health and Nutrition Examination Survey III we examined differences in levels of circulating sex hormones, sex hormone-binding globulin (SHBG), IGF-1, and IFG-binding protein 3 (IGFBP-3), according to diabetes status: no diabetes [n = 648], prediabetes [n = 578], undiagnosed diabetes [n = 106], well-controlled diabetes [n = 42], and poorly controlled diabetes [n = 56]. Adjusted geometric mean concentrations were derived using multivariable linear regression, adjusted for age, race, and other lifestyle factors. RESULTS: Total testosterone concentrations were lower among prediabetics (4.89 ng/mL, 95% confidence interval (CI) 4.95-5.21) than men without prediabetes/diabetes (5.29 ng/mL, 95% CI 5.06-5.53) but did not reduce further across diabetes groups. Concentrations of estradiol, estimated free testosterone, SHGB, IGF-1, and IGFBP-3 did not differ. While the ratio of IGF-1 to IGFBP-3 was lower among men with prediabetics and undiagnosed diabetes than men without prediabetes/diabetes, there was no trend across groups. A positive trend for the ratio of estradiol-to-testosterone levels was observed across groups (p trend = 0.045). CONCLUSION: Our findings do not provide clear support for either an androgen driven or IGF-driven pathway for the inverse association between diabetes and prostate cancer risk.

Comparison of Characteristics, Follow-up and Outcomes of Active Surveillance for Prostate Cancer According to Ethnicity in the GAP3 Global Consortium Database.

BACKGROUND: Studies of active surveillance (AS) for prostate cancer (PCa) have focussed predominantly on Caucasian populations. Little is known about the experience of Asian men, while suitability for men of African descent has been questioned. OBJECTIVE: To compare baseline characteristics, follow-up, and outcomes for men on AS for PCa, according to ethnicity. DESIGN SETTING AND PARTICIPANTS: The study cohort included 13 centres from the GAP3 consortium that record ethnicity (categorised broadly as Caucasian/white, African/Afro-Caribbean/black, Asian, mixed/other, and unknown). Men with biopsy grade group >2, prostate-specific antigen (PSA) >20 ng/ml, T stage ≥cT3, or age >80 yr were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, follow-up schedules, outcome status, and reasons for discontinuation were compared across ethnic groups. Risk of upgrading, potential disease progression (grade group ≥3 or T stage ≥3), suspicious indications (any upgrading, number of positive cores >3, T stage ≥cT3, PSA >20 ng/ml, or PSA density >0.2 ng/ml/cc2), and conversion to treatment were assessed using mixed-effect regression models. RESULTS AND LIMITATIONS: The eligible cohort (n = 9158) comprised 83% Caucasian men, 6% men of African descent, 5% Asian men, 2% men of mixed/other ethnicity, and 4% men of unknown ethnicity. Risks of suspicious indicators (hazard ratio = 1.27; 95% confidence interval [CI] 1.12-1.45), upgrading (odds ratio [OR] = 1.40; 95% CI 1.14-1.71), and potential progression (OR = 1.46; 95% CI 1.06-2.01) were higher among African/black than among Caucasian/white men. Risk of transitioning to treatment did not differ by ethnicity. More Asian than Caucasian men converted without progression (42% vs 26%, p < 0.001). Heterogeneity in surveillance protocols and racial makeup limit interpretation. CONCLUSIONS: This multinational study found differences in the risk of disease progression and transitioning to treatment without signs of progression between ethnic groups. Further research is required to determine whether differences are due to biology, sociocultural factors, and/or clinical practice. PATIENT SUMMARY: This international study compared prostate cancer active surveillance outcomes by ethnicity. Risks of upgrading and disease progression were higher among African than among Caucasian men. Transitioning to treatment without progression was highest among Asian men. Understanding of these differences requires further investigation.