Impaired insulin sensitivity is a key abnormality underlying the development of type 2 diabetes. Measuring insulin sensitivity is therefore of importance in identifying individuals at risk of ...developing diabetes and for the evaluation of diabetes-focused interventions. A number of measures have been proposed for this purpose. Among these the hyperinsulinemic euglycemic clamp (HEC) is considered the gold standard. However, as the HEC is a costly, time consuming and invasive method requiring trained staff, there is a need for simpler so called surrogate measures.
A frequently used approach to evaluate surrogate measures is through correlation with the HEC. We discuss limitations with this method. We suggest other aspects to take into consideration, such as repeatability, reproducibility, systematic biases and discrimination ability. In addition, we focus on three frequently used surrogate measures. We argue that they are one-to-one transformations of each other, and therefore question the benefits of further comparison between them. They give the same results in all rank-based methods, for instance Spearman correlations, Mann-Whitney tests and receiver operating characteristic (ROC) analysis.
We suggest investigating further aspects than correlation alone when evaluating a surrogate measure of insulin sensitivity. We recommend choosing one of the three surrogate measures HOMA-IR, QUICKI and FIRI for analysis of a clinical study.
Objectives
We aim to determine if robot‐assisted retroperitoneal lymph node dissection (R‐RPLND) can be performed as a safe option to open RPLND in selected patients with metastatic germ cell cancer.
...Patients and methods
This population‐based prospective study was performed at a one of two national referral centres for RPLND in Sweden. All patients referred during January 2017–March 2021 were screened for possible inclusion. R‐RPLND was performed using the Da Vinci Xi surgical system. Perioperative parameters, postoperative complications (Clavien–Dindo), final pathology, preservation of antegrade ejaculation and relapse rates were evaluated. Classifiers for selecting patients to open versus robotic RPLND were analysed by logistic regression modelling. The median follow‐up was 23 months.
Results
Of 87 patients referred, 29 were selected for R‐RPLND, 19 in a post‐chemotherapy setting. In median, retroperitoneal tumour diameter was 18 mm, BMI 24 kg/m2, operative time 433 min, estimated blood loss 50 ml and length of stay 3 days. One patient underwent open conversion due to failure to progress. Four patients had Clavien–Dindo grade 3 complications, of which three were chylous‐related. No in‐field recurrences occurred during follow‐up.
Conclusion
This population‐based study suggests that R‐RPLND can be safely performed in at least one third of patients referred for an RPLND. A relatively high rate of lymph‐leakage may represent a potential drawback. Tumour size may be the most important discriminator when deciding on robotic versus open RPLND. Further studies with longer follow‐up are needed to validate the results.
Background and Purpose
Melanin‐concentrating hormone (MCH) is an orexigen, and while rodents express one MCH receptor (MCH1 receptor), humans, non‐human primates and dogs express two MCH receptors ...(MCH1 and MCH2). MCH1 receptor antagonists have been developed for the treatment of obesity and lower body weight in rodents. However, the mechanisms for the body weight loss and whether MCH1 receptor antagonism can lower body weight in species expressing both MCH receptors are not fully understood.
Experimental Approach
A novel recently identified potent MCH1 receptor antagonist, AZD1979, was studied in wild type and Mchr1 knockout (KO) mice and by using pair‐feeding and indirect calorimetry in diet‐induced obese (DIO) mice. The effect of AZD1979 on body weight was also studied in beagle dogs.
Key Results
AZD1979 bound to MCH1 receptors in the CNS and dose‐dependently reduced body weight in DIO mice leading to improved homeostasis model assessment‐index of insulin sensitivity. AZD1979 did not affect food intake or body weight in Mchr1 KO mice demonstrating specificity for the MCH1 receptor mechanism. In DIO mice, initial AZD1979‐mediated body weight loss was driven by decreased food intake, but an additional component of preserved energy expenditure was apparent in pair‐feeding and indirect calorimetry studies. AZD1979 also dose‐dependently reduced body weight in dogs.
Conclusion and Implications
AZD1979 is a novel potent MCH1 receptor antagonist that affects both food intake and energy expenditure. That AZD1979 also lowers body weight in a species expressing both MCH receptors holds promise for the use of MCH1 receptor antagonists for the treatment of human obesity.
Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown.
We invited 37,887 men who were 50 to 60 years of ...age to undergo regular prostate-specific antigen (PSA) screening. Participants with a PSA level of 3 ng per milliliter or higher underwent magnetic resonance imaging (MRI) of the prostate; one third of the participants were randomly assigned to a reference group that underwent systematic biopsy as well as targeted biopsy of suspicious lesions shown on MRI. The remaining participants were assigned to the experimental group and underwent MRI-targeted biopsy only. The primary outcome was clinically insignificant prostate cancer, defined as a Gleason score of 3+3. The secondary outcome was clinically significant prostate cancer, defined as a Gleason score of at least 3+4. Safety was also assessed.
Of the men who were invited to undergo screening, 17,980 (47%) participated in the trial. A total of 66 of the 11,986 participants in the experimental group (0.6%) received a diagnosis of clinically insignificant prostate cancer, as compared with 72 of 5994 participants (1.2%) in the reference group, a difference of -0.7 percentage points (95% confidence interval CI, -1.0 to -0.4; relative risk, 0.46; 95% CI, 0.33 to 0.64; P<0.001). The relative risk of clinically significant prostate cancer in the experimental group as compared with the reference group was 0.81 (95% CI, 0.60 to 1.1). Clinically significant cancer that was detected only by systematic biopsy was diagnosed in 10 participants in the reference group; all cases were of intermediate risk and involved mainly low-volume disease that was managed with active surveillance. Serious adverse events were rare (<0.1%) in the two groups.
The avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduced the risk of overdiagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients. (Funded by Karin and Christer Johansson's Foundation and others; GÖTEBORG-2 ISRCTN Registry number, ISRCTN94604465.).
Reports on possible benefits for continence with nerve-sparing (NS) radical prostatectomy have expanded the indications beyond preservation of erectile function. It is unclear whether NS surgery ...affects oncological outcomes.
To determine whether the degree of NS during radical prostatectomy influences oncological outcomes.
Of 4003 patients enrolled in a prospective, controlled trial comparing open and robotic radical prostatectomy during 2008–2011, we evaluated 2401 patients who received robotic radical prostatectomy at seven Swedish centres. Patients were followed for 8 yr.
Data for recurrence and positive surgical margin status were assessed using validated patient questionnaires, patient interviews, and clinical record forms before and at 3, 12, and 24 mo and 6 and 8 yr after surgery. Cox and logistic regressions were used to model the effect on recurrence and positive surgical margins (PSM), respectively.
A total of 481 men had PSM and 467 experienced recurrence during follow-up. Median follow-up for men without recurrence was 6.6 yr. There were no statistically significant differences in recurrence rate between degrees of NS. The PSM rate was significantly higher with a higher degree of NS: interfascial NS, odds ratio (OR) 2.32 (95% confidence interval CI 1.69–3.16); intrafascial NS, OR 3.23 (95% CI 2.17–4.80). Recurrence rates were higher for patients with pT2 disease and PSM (hazard ratio HR 3.32, 95% CI 2.43–4.53) than for patients with pT3 disease without PSM (HR 2.08, 95% CI 1.66–2.62). The lack of central review of pathological specimens is a limitation.
A higher degree of NS significantly increased the risk of PSM but did not significantly increase the risk of cancer recurrence. Combined with the known functional benefits of NS surgery, these results underscore the need to identify an individualised balance.
In this report we looked at the effect of a nerve-sparing approach during removal of the prostate on cancer outcomes for patients having robot-assisted surgery at seven Swedish hospitals. We found that a high degree of nerve-sparing increased the rate of cancer positivity at the margins of surgical specimens and that positive surgical margins increased the risk of recurrence of prostate cancer.
Nerve-sparing radical prostatectomy increases the rate of positive surgical margins. Although no direct effect on recurrence is evident, this is important to address in mutual decision-making with the patient.
Higher age increased the risk of prostate cancer and the risk of higher Gleason score. These findings should be considered when counseling men for early diagnosis and treatment for prostate cancer.
...Studies have suggested associations between greater age, increased risk of prostate cancer (PC), and higher Gleason score.
The present study aimed at investigating these associations within the Göteborg-1 randomized, population-based PC screening trial.
The screening arm of the Göteborg-1 screening trial comprises 10000 randomly selected men (aged 50–64 yr at randomization) from the Göteborg region of Sweden. Between 1995 and 2014, they were biennially invited to prostate-specific antigen (PSA) testing to an upper age limit of 70 yr (range 67–71 yr). PSA ≥3 ng/ml triggered a prostate biopsy (sextant biopsy 1995–2009, thereafter a ten-core biopsy).
The impact of age on Gleason score, given a screen-detected PC, was investigated with multinomial logistic regression analyses adjusted for year of testing and screening round.
Overall, 7625 men had at least one PSA test and 1022 men were diagnosed with PC. For men with screen-detected PC, age was associated with the risk of clinically significant PC above and beyond screening round and year of testing (p < 0.001). For each 1-yr increase in age, the risk of being diagnosed with a Gleason score ≥3 + 4 cancer (vs <7) increased by 11% (95% confidence interval CI 4.7–17), whereas the risk of being diagnosed with a Gleason score ≥4 + 3 cancer (vs <7) increased by 8.5% (95% CI –1.6 to 20).
The increased risk of a higher Gleason score in older men should be considered when counseling men regarding early diagnosis and treatment for PC.
We found that older age increased both the risk of prostate cancer and the risk of more aggressive prostate cancer.
Our goal was to analyze results from 22 years of followup in the Göteborg randomized prostate cancer (PC) screening trial.
In December 1994, 20,000 men born 1930-1944 were randomly extracted from the ...Swedish population register and were randomized (1:1) into either a screening group (SG) or to a control group (CG). Men in the SG were repeatedly invited for biennial prostate specific antigen testing up to an average age of 69 years. Main endpoints were PC incidence and mortality (intention-to-screen principle).
After 22 years, 1,528 men in the SG and 1,124 men in the CG had been diagnosed with PC. In total, 112 PC deaths occurred in the SG and 158 in the CG. Compared with the CG, the SG showed a PC incidence rate ratio (RR) of 1.42 (95% CI, 1.31-1.53) and a PC mortality RR of 0.71 (95% CI, 0.55-0.91). The 22-year cumulative PC mortality rate was 1.55% (95% CI, 1.29-1.86) in the SG and 2.13% (95% CI, 1.83-2.49) in the CG. Correction for nonattendance (Cuzick method) yielded a RR of PC mortality of 0.59 (95% CI, 0.43-0.80). Number needed to invite and number needed to diagnose was estimated to 221 and 9, respectively. PC death risk was increased in the following groups: nontesting men, men entering the program after age 60 and men with >10 years of followup after screening termination.
Prostate specific antigen-based screening substantially decreases PC mortality. However, not attending, starting after age 60 and stopping at age 70 seem to be major pitfalls regarding PC death risk.
Our study results suggest that the effect of currently recommended prostate-specific antigen screening programs starting at age 50–55 yr might be underestimated, and that screening should start no ...later than age 55 yr.
The risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain.
To study the relationship between risk reduction for PC mortality and age at first PSA screening.
The randomized Göteborg-1 trial invited men for biennial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invitation but exposure to opportunistic PSA testing (control, n = 10 000).
Regular versus opportunistic PSA screening or no PSA.
We modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990–1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only).
Younger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the conventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration.
Given that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50–55 yr.
In this study from the Göteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men’s risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screening should start no later than at age 55 yr.
To describe the study design of the GÖTEBORG prostate cancer screening (PC) 2 (Göteborg-2), a prospective, randomised, population-based trial of PC screening. This trial evaluates whether ...prostate-specific antigen (PSA) testing followed by 3 Tesla prostate magnetic resonance imaging (MRI) and targeted biopsy can reduce overdiagnosis, while maintaining the detection of clinically significant cancer, compared to PSA-screening and systematic biopsy.
A random sample of men 50-60 years in the Göteborg area, Sweden, identified from the Total Population Register, were randomised to either a screening or control group (CG). Participants in the screening group (SG) were further randomised into one of three arms: (1) PSA-test; if PSA ≥ 3 ng/mL, then MRI and systematic biopsy, plus targeted biopsy to suspicious lesions as per Prostate Imaging - Reporting and Data System, version 2 (PI-RADSv2) 3-5; (2) PSA-test; if PSA ≥ 3 ng/mL, then MRI, and targeted biopsy only if PI-RADSv2 3-5; (3) identical to Arm 2, except lower PSA-cut-off ≥1.8 ng/mL. The primary outcome is the detection rate of clinically insignificant PC (defined as Gleason Score 3 + 3 Grade Group 1) comparing all men with PSA ≥ 3 ng/mL in Arm 1 vs. Arm 2 + 3.
Randomisation and enrolment started in September 2015. Accrual has hitherto resulted in 38,770 men randomised to the SG. The participation rate is 50%. Invitation to the first screening round was completed in June 2020.
The Göteborg-2 trial will provide new knowledge about the performance of prostate MRI in a screening setting.
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