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No meta-analysis is yet available for the risk of metabolic syndrome (MetS) following androgen deprivation therapy (ADT) for men with prostate cancer. To summarize the evidence for the link between ADT and MetS or its components quantitatively with a meta-analysis including all studies published to date. PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on the association between metabolic syndrome, hyperglycemia, diabetes, hypertension, dyslipidemia or obesity and androgen deprivation therapy in patients with prostate cancer. Random effects methods were used to estimate pooled relative risks (RRs) and 95% confidence intervals (CI). A total of nine studies was included. There was a positive association between ADT and risk of MetS (RR: 1.75 (95% CI: 1.27-2.41)). Diabetes was the only MetS component present in more than 3 studies, and also showed an increased risk following ADT (RR: 1.36 (95% CI: 1.17-1.58)). This is the first quantitative summary addressing the potential risk of MetS following ADT in men with PCa. The positive RRs indicate that there is a need to further elucidate how type and duration of ADT affect these increased risks of MetS and diabetes as the number of men with PCa treated with ADT is increasing.

Background Prostate cancer (PCa) and type 2 diabetes mellitus (T2DM) are prevalent conditions that often occur concomitantly. However, many aspects of the impact of T2DM, particularly the duration of T2DM and antidiabetic medications, on PCa risk are poorly understood. Methods To assess the association of duration of T2DM and antidiabetic medication with PCa risk, we designed a matched case-control study, including 31,415 men with PCa and 154,812 PCa-free men in Prostate Cancer data Base Sweden (PCBaSe) 4.1. Results Overall, a decreased risk of PCa was observed for men with T2DM (odds ratio (OR): 0.81, 95% confidence interval (CI): 0.78–0.84), as compared to men without T2DM. The decreased risk of PCa was consistently showed across duration of T2DM. With respect to use of antidiabetic drugs, this inverse association with duration was also found for all medications types, as compared to men without T2DM, including insulin, metformin and sulphonylurea (SU) (e.g. 3- < 5 yr insulin OR:0.69, 95%CI:0.60–0.80; 3- < 5 yr metformin OR: 0.82, 95%CI: 0.74–0.91; 3- < 5 yr SU OR: 0.72, 95%CI: 0.62–0.83). When stratifying by PCa risk categories, this decreased risk was most evident for diagnosis of low and intermediate-risk PCa (low-risk OR: 0.65, 95%CI: 0.66–0.70, intermediate-risk OR: 0.80, 95%CI: 0.75–0.85). Conclusions The study showed an inverse association between pre-existing T2DM and PCa across different durations of T2DM and all types of T2DM medication received. This inverse association was most evident for low- and intermediate-risk PCa, suggesting that whilst T2DM and its medication may protect some men from developing PCa, the relationship warrants further study.

Background Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link. Methods Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR). Results Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 – 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1. Conclusion A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality.

Background Gonadotropin Releasing Hormones agonists (GnRH), which are first line treatment for metastatic prostate cancer (PCa), increase risk of type 2 diabetes mellitus (T2DM). This study aims to quantify the association of use of GnRH with diabetes control in PCa men with T2DM. Methods Nationwide population-based cohort study in the Swedish National Diabetes Register and Prostate Cancer data Base Sweden 4.1, on the association between GnRH and diabetes control in T2DM men with PCa by comparing T2DM men with PCa vs. without PCa, as well as comparing T2DM men with PCa on or not on GnRH. The primary exposure was use of GnRH. Worsening diabetes control was the primary outcome, defined as: 1) HbA1c rose to 58 mmol/mol or higher; 2) HbA1c increase by 10 mmol/mol or more; 3) Start of antidiabetic drugs or switch to insulin. We also combined all above definitions. Cox proportional hazards regression was used to analyze the association. Results There were 5714 T2DM men with PCa of whom 692 were on GnRH and 28,445 PCa-free men with T2DM with similar baseline characteristics. Diabetes control was worse in men with GnRH vs. PCa-free men (HR: 1.24, 95% CI: 1.13–1.34) as well as compared with PCa men without GnRH (HR:1.58, 95% CI: 1.39–1.80), when we defined the worsening control of diabetes by combining all definitions above. Conclusion Use of GnRH in T2DM men with PCa was associated with worse glycemic control. The findings highlight the need to closely monitor diabetes control in men with T2DM and PCa starting GnRH.

Background Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor − 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. Methods METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/− 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy’s and St Thomas’ Hospital and the Royal Marsden Hospital, London. Discussion This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. Trial registration EudraCT number 2014–005193-11 . Registered on September 09, 2015.

Purpose To determine new-onset or worsening T2DM risk in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate (AA) vs. enzalutamide (ENZA) in England. Methods Records of patients on AA and/or ENZA (2015−2021) were analysed retrospectively from UK- or England-wide databases and data sets. The primary endpoint was new-onset or worsening T2DM, analysed using a Cox model. Results Of 1382 patients, 84 (6.1%) met the primary endpoint; 42 of 826 patients (5.1%) received ENZA and 42 of 556 patients (7.6%) received AA. Among patients without baseline T2DM ( n  = 1049), 50 developed new-onset T2DM: 24 (3.9%) on ENZA and 26 (5.9%) on AA. Among patients with baseline T2DM ( n  = 333), 34 (10.2%) had worsening T2DM: 18 (8.3%) on ENZA and 16 (13.8%) on AA. Patients on ENZA had longer median follow-up (445 vs. 408 days) and treatment duration (164 vs. 139 days) than those on AA, who were also more likely to have new-onset or worsening T2DM than those on ENZA (HR: 1.8; 95% CI: 1.4–2.7; P  = 0.0101). The number needed to harm for an additional patient to experience new-onset or worsening T2DM when receiving AA instead of ENZA was 40 overall, 50 in patients without baseline T2DM, and 18 in patients with baseline T2DM. Conclusion Patients with mCRPC receiving AA were more likely to experience new-onset or worsening T2DM than those on ENZA, despite having a shorter treatment duration. Further research is required to substantiate these findings in earlier disease settings with longer treatment duration.

We report the first case of TB associated with triplet therapy (chemotherapy and immunotherapy concurrently) for lung cancer, developing just 44 days after treatment initiation. We feel that several important learning points arise from the discussion that are likely to be very relevant to the broad readership of Thorax, and have important clinical and scientific implications. In the three discussion paragraphs, we highlight that: 1) Triplet therapy is now standard first-line treatment for inoperable lung cancer. 2) TB reactivation is increasingly recognised as an adverse effect of immune checkpoint inhibition, but sending diagnostic samples is critical to avoid a missed diagnosis. 3) These insights from novel cancer immunotherapies are challenging the traditional views of the host-pathogen interaction in TB, with wide implications for future control strategies. We propose that the cases reported in the literature are likely to be the tip of the iceberg as most people with lung cancer managed with antiprogrammed death-1 agents who develop new lung lesions will be treated with standard antibiotics and then palliated when they do not respond.

BackgroundGonadotropin-releasing hormone agonists (GnRH) used in prostate cancer (PCa) are associated with atherogenic dyslipidaemia. It can be assumed that GnRH need to be used with greater caution in men with type 2 diabetes mellitus (T2DM). This study investigated association of GnRH with atherogenic lipids (AL) in PCa men with T2DM.MethodsTwo cohorts including 38,311 men with 11 years follow-up based on Swedish national registers were defined (PCa-Exposure cohort and GnRH-Exposure cohort). Based on European guidelines on cardiovascular diseases (CVD), primary outcomes were defined as: 1.0 mmol/L increase in AL and lipid-lowering therapy (LLT) intensification. We used Cox proportional-hazards models and Kaplan–Meier curves to assess the association.ResultsThere was an association between GnRH and increased AL (i.e., triglyceride, PCa-Exposure cohort: HR 1.77, 95% CI 1.48–2.10; GnRH-Exposure cohort: HR 1.88, 95% CI 1.38–2.57). There was also an association between PCa diagnosis and increased AL. In contrast, no association between LLT intensification and GnRH was found.ConclusionIn this large population-based study, men with T2DM on GnRH for PCa had an increased risk of increased atherogenic lipids. These results highlight the need to closely monitor lipids and to be ready to intensify lipid-lowering therapy in men with T2DM on GnRH for PCa.

Background Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death. Methods Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy’s Cancer Centre and King’s College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality. Results Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15–3.38)], Asian ethnicity [3.42 (1. 59–7.35)], haematological cancer [2.03 (1.16–3.56)] and a cancer diagnosis for >2–5 years [2.81 (1.41–5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis). Conclusions Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients.

PurposePathways 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.MethodsUsing 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.ResultsTotal 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).ConclusionOur 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.