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Background Collider bias is often considered a potential explanation when the association between obesity and disease diagnosis differs from that with disease outcome, as seen in the “obesity paradox.” For prostate cancer (PCa), in particular localized PCa, an “inverse” obesity paradox has been observed, where body mass index (BMI) is negatively associated with diagnosis (hazard ratio [HR] ~0.9 per 5‐kg/m2 increase), but positively associated with PCa‐specific death (HR ~ 1.2). However, collider bias in this context remains unexplored. Methods We simulated binary disease diagnosis and outcome data, including the typically unmeasured/unknown background variable (U) that could introduce collider bias. We calculated U‐unadjusted (biased) and U‐adjusted (true) marginal odds ratios (OR) from a case‐only analysis, and determined the bias percentage using ORBiased−ORTrue/ORTrue×100 $$ \\left({\\mathrm{OR}}_{\\mathrm{Biased}}-{\\mathrm{OR}}_{\\mathrm{True}}\\right)/{\\mathrm{OR}}_{\\mathrm{True}}\\times 100 $$ . Similar simulations were performed for classical confounding. Results Across a broad range of plausible parameter values for the PCa context, collider bias did not distort the OR of BMI on PCa death by more than 4%, equivalent to a ± 0.04 distortion in the OR estimate for continuous BMI. In comparison, classical confounding showed a higher potential for distorting BMI and PCa death associations than collider bias. Conclusions Collider bias alone is unlikely to explain the inverse obesity paradox in (localized) PCa, reinforcing some mechanistic evidence that the observed positive relationship between BMI and PCa death is real, and not a statistical artifact. This finding emphasizes the importance of exploring alternative mechanisms beyond collider bias to better understand the underlying factors driving this paradox.

Nivolumab belongs to the standard therapy in the second‐line setting of metastatic renal cell carcinoma (mRCC). Although deep and long‐lasting responses are seen in some patients, the majority of patients will further progress. PD‐L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO‐1, a negative immune‐regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO‐1 and other immune inhibitory molecules (PD‐L1, PD‐L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin‐fixed, paraffin‐embedded sections of RCC specimens by immunohistochemistry. IDO‐1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO‐1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non‐responders (33.3%, n = 3/9; P = .028), resulting in a better progression‐free survival during immunotherapy (IDO‐1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log‐rank test). In addition, IDO‐1 was positively correlated with CD8+ T cell expression (rs = .691, P = .006). PD‐L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non‐responders: 83.3% vs 88.9%). No differences were noticed in the PD‐L1 expression on tumor‐infiltrating immune cells (PD‐L1 < 1% in 66.7% of both responders and non‐responders). In contrast to PD‐L1, these results suggest that IDO‐1 may be a more promising predictive biomarker for response to immune‐based cancer therapy in mRCC. In this retrospective study, we analyzed the predictive value ot the expression of IDO1 on tumor tissue of renal cell carcinoma patients undergoing checkpoint inhibition. A signifcanty correlation between the overexpression of IDO1 in tumor endothelial cells and response to nivolumab therapy could be found for the first time.

Prostate cancer (PCa) incidence has steadily increased in Sweden, more steeply in the mid-1990s caused by increased opportunistic prostate-specific antigen (PSA) testing. Tallness, normal weight, and non-smoking are associated with more PSA testing, which increases detection of low-risk and localised PCa. We investigated time trends of height, body mass index (BMI), and smoking with PCa risk in 171,889 men in Sweden aged 50–64 years at baseline, who were linked to nationwide cancer registers during follow-up. Cox regression determined the association of these factors assessed before 1980, 1980–1994, and 1995–2004 with PCa risk. During 15 follow-up years, 8,049 men were diagnosed with PCa. The association of height with PCa was weakly positive across all calendar periods. For obesity (BMI ≥30 kg/m 2 ) vs. normal weight (BMI 18.5–24.9 kg/m 2 ) and current vs. never smoking, the associations changed from null before 1980 (HR 1.03, 95% CI 0.86–1.23, and 1.11, 95% CI 0.97–1.27) to negative in 1995–2004 (HR 0.83, 95% CI 0.74–0.93, and 0.86, 95% CI 0.79–0.93; p interaction between periods = 0.05 and 0.001). In men with clinical characteristics available, height was positively associated with both aggressive and non-aggressive PCa whilst obesity and smoking showed negative associations only with non-aggressive PCa. These findings likely reflect differences in PSA testing by BMI and smoking habits and contribute important knowledge for etiological studies of PCa.

The γ‐interferon‐induced enzymes indoleamine 2,3‐dioxygenase and GTP‐cyclohydrolase are key players in tumor immune escape mechanisms. We quantified serum levels of neopterin and tryptophan breakdown (tryptophan, kynurenine, and kynurenine‐to‐tryptophan ratio) in addition to prostate‐specific antigen (PSA) in newly diagnosed prostate cancer (PCa) patients (n = 100) before radical prostatectomy (RP) as well as at time of biochemical recurrence (BCR) after RP (n = 50) in comparison to healthy men (n = 49). Effects of biomarkers on the risk of PCa diagnosis on transrectal biopsy, worse histopathological characteristics of the RP specimens, and cancer‐specific survival (CSS) after BCR were investigated. Neopterin (hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.08–5.61; P = 0.032) and kynurenine (HR, 2.93; 95% CI, 1.26–6.79; P = 0.012) levels were univariately associated with CSS. When adjusted for other biomarkers, only neopterin remained an independent predictor of CSS (HR, 2.56; 95% CI, 1.07–6.12; P = 0.035). Only PSA was associated with an increased risk of PCa diagnosis on biopsy, univariately (odds ratio, 3.14; 95% CI, 1.68–5.88; P < 0.001) as well when adjusted for other biomarkers (odds ratio, 3.29; 95% CI, 1.70–6.35; P < 0.001). Moreover, only preoperative PSA was able to predict positive surgical margin (area under the receiver operating characteristic curve [AUC] = 0.71; 95% CI, 0.59–0.82; P = 0.001), higher Gleason score (AUC = 0.75; 95% CI, 0.66–0.85; P < 0.001) and extraprostatic involvement (AUC = 0.79; 95% CI, 0.69–0.88; P < 0.001) at RP specimens, respectively. Although serum neopterin and tryptophan breakdown cannot be considered as biomarkers in detecting PCa or in predicting worse final pathological findings, neopterin levels are useful for stratifying patients into different prognostic groups after BCR. Accelerated neopterin and tryptophan breakdown seems to play an important role regarding prostate carcinogenesis, with the highest levels in patients with biochemical recurrence after radical prostatectomy. Neopterin was the only independent prognostic factor for cancer‐specific survival after biochemical recurrence. These data may support the recommendation of neopterin measurement in making decision for further oncologic treatment strategies and in monitoring patients during therapy following biochemical recurrence.

Background Insulin resistance has been shown to be related to a higher risk of several cancers, but the association with prostate cancer (PCa) has been inconsistent. Methods We investigated prediagnostic markers of insulin resistance in men in four cohorts in Sweden, in relation to PCa risk (total, non‐aggressive and aggressive) and PCa death using multivariable‐adjusted Cox regression. The number of men, PCa cases and PCa deaths was up to 66,668, 3940 and 473 for plasma glucose and the triglyceride‐glucose (TyG) index, and up to 3898, 586 and 102 for plasma insulin, glycated haemoglobin (HbA1c) and leptin. Results Higher HbA1c was related to a lower risk of non‐aggressive PCa but no significant associations were found for insulin resistance markers with the risk of aggressive or total PCa. In PCa cases, higher glucose and TyG index were related to a higher risk of PCa death (hazard ratio [HR] per higher standard deviation, 1.22, 95% CI 1.00–1.49 and 1.24, 95% CI 1.00–1.55), which further increased when restricting the analyses to glucose and TyG index measures taken <10 years before the PCa diagnosis (HR, 1.70, 95% CI 1.09–2.70 and 1.66, 95% CI 1.12–2.51). No associations were observed for other markers in relation to PCa death. Conclusions The results of this study showed no associations of insulin resistance markers with the risk of clinically relevant PCa, but higher glucose and TyG index were associated with poorer survival from PCa. The lack of association for other insulin resistance markers may be due to their smaller sample size.

Obesity is suggested to underlie development of other metabolic aberrations, but longitudinal relationships between metabolic factors at various ages has not been studied in detail. Data from 27,379 men and 32,275 women with in total 122,940 health examinations in the Västerbotten Intervention Project, Sweden and the Vorarlberg Health Monitoring and Prevention Programme, Austria were used to investigate body mass index (BMI), mid-blood pressure, and fasting levels of glucose, triglycerides, and total cholesterol at baseline in relation to 10-year changes of these factors and weight. We included paired examinations performed 10±2 years apart and used them for longitudinal analysis with linear regression of changes between the ages 30 and 40, 40 and 50, or 50 and 60 years. Higher levels of BMI were associated with increases in glucose and mid-blood pressure as well as triglycerides levels, and, to a lesser extent, decreases in cholesterol levels. For instance, per 5 kg/m2 higher BMI at age 40, glucose at age 50 increased by 0.24 mmol/l (95%CI: 0.22-0.26) and mid-blood pressure increased by 1.54 mm Hg (95%CI: 1.35-1.74). The strongest association observed was between BMI at age 30 and mid-blood pressure, which was 2.12 mm Hg (95% CI: 1.79-2.45) increase over ten years per 5 kg/m2 higher BMI level. This association was observed at an age when blood pressure levels on average remained stable. Other associations than those with BMI at baseline were much weaker. However, triglyceride levels were associated with future glucose changes among individuals with elevated BMI, particularly in the two older age groups. BMI was most indicative of long-term changes in metabolic factors, and the strongest impact was observed for increases in blood pressure between 30 and 40 years of age. Our study supports that lifestyle interventions preventing metabolic aberrations should focus on avoiding weight increases.

BackgroundImmune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE).MethodsTTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes.ResultsAmong 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59–1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69–1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72–1.44) for PFS, and 0.90 (95% CI, 0.62–1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26–4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68–2.36) and TTE (HR = 1.43, 95% CI 0.89–2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival.ConclusionUsing TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.

To reduce the number of unnecessary biopsies in patients with benign prostatic disease, however, without missing significant PCa the present study re-evaluates the age-dependent PSA cut-offs in the Tyrol Prostate Cancer (PCa) early detection program. The study population included 2225 patients who underwent prostate biopsy due to elevated PSA levels at our department. We divided our patient collective into four age groups: ≤49 years (n = 178), 50-59 years (n = 597), 60-69 years (n = 962) and ≥70 years (n = 488). We simulated different scenarios for PSA cut-off values between 1.25 and 6 ng/mL and fPSA% between 15 and 21% for all four age groups and calculated sensitivity, specificity, confidence intervals and predictive values. PCa was detected in 1218 men (54.7%). We found that in combination with free PSA ≤21% the following PSA cut-offs had the best cancer specificity: 1.75 ng/ml for men ≤49 years and 50-59 years, 2.25 ng/ml for men aged 60-69 years and 3.25 ng/ml for men ≥70 years. Using these adjusted PSA cut-off values all significant tumors are recognized in all age groups, yet the number of biopsies is reduced. Overall, one biopsy is avoided in 13 to 14 men (number needed to screen = 13.3, reduction of biopsies = 7.5%) when decision regarding biopsy is done according to the \"new\" cut-off values instead of the \"old\" ones. For the different age groups the number needed to screen to avoid one biopsy varied between 9.2 (≤49 years) and 17.4 (50-59 years). With \"new\", fine-tuned PSA cut-offs we detect all relevant PCa with a significant reduction of biopsies compared to the \"old\" cut-off values. Optimization of age-specific PSA cut-offs is one step towards a smarter strategy in the Tyrol PCa Early Detection Program.

PurposeThe Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality.ParticipantsODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17–103 years in 1963–2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019–2021, varying between the registers.Findings to dateAmong all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977–1994) in men and 2001 (1991–2010) in women, age 19 (18–40) years in men and 30 (26–36) years in women and BMI 22.9 (20.9–25.4) kg/m2 in men and 23.2 (21.2–26.1) kg/m2 in women. Normal weight (BMI 18.5–24.9 kg/m2) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m2) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8–40.8) years in men and 19.6 (9.3–29.0) years in women. During follow-up, 283 244 men and 123 457 women died.Future plansThe large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes.

Background Current guidelines recommend repeat computed tomography (CT) imaging in high-grade blunt renal injury within 48–96 h, yet diagnostic value and clinical significance remain controversial. The aim of this work was to determine the possible gain of CT re-imaging in uncomplicated patients with blunt renal trauma at 48 h after injury, presenting one of the largest case series. Methods A retrospective database of patients admitted to our centre with isolated blunt renal trauma due to sporting injuries was analysed for a period of 20 years (2000–2020). We included only patients who underwent repeat imaging at 48 h after trauma irrespective of AAST renal injury grading (grade 1–5) and initial management. The primary outcome was intervention rates after CT imaging at 48 h in uncomplicated patients versus CT scan at the time of clinical symptoms. Results A total of 280 patients (mean age: 37.8 years; 244 (87.1%) male) with repeat CT after 48 h were included. 150 (53.6%) patients were classified as low-grade (grade 1–3) and 130 (46.4%) as high-grade (grade 4–5) trauma. Immediate intervention at trauma was necessary in 59 (21.1%) patients with high-grade injuries: minimally invasive therapy in 48 (81.4%) and open surgery in 11 (18.6%) patients, respectively. In only 16 (5.7%) cases, intervention was performed based on CT re-imaging at 48 h (low-grade vs. high-grade: 3.3% vs. 8.5%; p  = 0.075). On the contrary, intervention rate due to clinical symptoms was 12.5% (n = 35). Onset of clinical progress was on average (range) 5.3 (1–17) days post trauma. High-grade trauma (odds ratio [OR] grade 4 vs. grade 3 , 14.62;  p  < 0.001; OR grade 5 vs. grade 3 , 22.88, p  = 0.004) and intervention performed at the day of trauma (OR 3.22;  p  = 0.014) were powerful predictors of occurrence of clinical progress. Conclusion Our data suggest that routine CT imaging 48 h post trauma can be safely omitted for patients with low- and high-grade blunt renal injury as long as they remain clinically stable. Patients with high-grade renal injury have the highest risk for clinical progress; thus, close surveillance should be considered especially in this group.