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Response to androgen receptor signaling inhibitors (ARSI) varies widely in metastatic castration resistant prostate cancer (mCRPC). To improve treatment guidance, biomarkers are needed. We use whole-genomics (WGS; n  = 155) with matching whole-transcriptomics (WTS; n  = 113) from biopsies of ARSI-treated mCRPC patients for unbiased discovery of biomarkers and development of machine learning-based prediction models. Tumor mutational burden ( q  < 0.001), structural variants ( q  < 0.05), tandem duplications ( q  < 0.05) and deletions ( q  < 0.05) are enriched in poor responders, coupled with distinct transcriptomic expression profiles. Validating various classification models predicting treatment duration with ARSI on our internal and external mCRPC cohort reveals two best-performing models, based on the combination of prior treatment information with either the four combined enriched genomic markers or with overall transcriptomic profiles. In conclusion, predictive models combining genomic, transcriptomic, and clinical data can predict response to ARSI in mCRPC patients and, with additional optimization and prospective validation, could improve treatment guidance. Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.

Cell‐free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration‐resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test‐sequencing system (mFast‐SeqS), a quick, tumor‐agnostic and affordable ctDNA assay that requires a small input of DNA, to generate a genome‐wide aneuploidy (GWA) score in mCRPC patients, and correlated this to matched metastatic tumor biopsies. In this prospective multicenter study, GWA scores were evaluated from blood samples of 196 mCRPC patients prior to treatment (baseline) with taxanes (docetaxel and cabazitaxel) and androgen receptor signaling inhibitors (ARSI; abiraterone and enzalutamide), and from 74 mCRPC patients at an early timepoint during treatment (early timepoint; median 21 days). Z‐scores per chromosome arm were tested for their association with tumor tissue genomic alterations. We found that a high tumor load in blood (GWAhigh) at baseline was associated with poor response to ARSI [HR: 2.63 (95% CI: 1.86–3.72) P < 0.001] but not to taxanes. Interestingly, GWAhigh score at the early timepoint was associated with poor response to both ARSIs [HR: 6.73 (95% CI: 2.60–17.42) P < 0.001] and taxanes [2.79 (95% CI: 1.34–5.78) P = 0.006]. A significant interaction in Cox proportional hazards analyses was seen when combining GWA status and type of treatment (at baseline P = 0.008; early timepoint P = 0.018). In summary, detection of ctDNA in blood by mFast‐SeqS is cheap, fast and feasible, and could be used at different timepoints as a potential predictor for outcome to ARSI and taxane treatment in mCRPC. mFast‐SeqS‐based genome‐wide aneuploidy scores are concordant with aneuploidy scores obtained by whole genome sequencing from tumor tissue and can predict response to ARSI treatment at baseline and, at an early time point, to ARSI and taxanes. This assay can be easily performed at low cost and requires little input of cfDNA.

Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons. These SVs could be quantified in ctDNA samples of patients with metastatic prostate cancer using a digital PCR assay. The results suggest that SV dynamics correlate with and may improve existing treatment-response biomarkers such as PSA. https://github.com/UMCUGenetics/SHARC .

Circulating tumor cell (CTC)- and/or tumor-derived extracellular vesicle (tdEV) loads in the blood of metastatic castration-resistant prostate cancer (CRPC) patients are associated with worse overall survival and can be used as predictive markers of treatment response. In this study, we investigated the quantity/quality of CTCs and tdEVs in metastatic castration-naive prostate cancer (CNPC) and CRPC patients, and whether androgen deprivation therapy (ADT) affects CTCs and tdEVs. We included 104 CNPC patients before ADT initiation and 66 CRPC patients. Blood samples from 31/104 CNPC patients were obtained 6 months after ADT. CTCs and tdEVs were identified using ACCEPT software. Based on the morphology, CTCs of metastatic CNPC and CRPC patients were subdivided by manual reviewing into six subclasses. The numbers of CTCs and tdEVs were correlated in both CNPC and CRPC patients, and both CTCs (p = 0.013) and tdEVs (p = 0.005) were significantly lower in CNPC compared to CRPC patients. Qualitative differences in CTCs were observed: CTC clusters (p = 0.006) and heterogeneously CK expressing CTCs (p = 0.041) were significantly lower in CNPC patients. CTC/tdEV numbers declined 6 months after ADT. Our study showed that next to CTC-load, qualitative CTC analysis and tdEV-load may be useful in CNPC patients.

Objectives A previously developed decision model to prioritize surgical procedures in times of scarce surgical capacity used quality of life (QoL) primarily derived from experts in one center. These estimates are key input of the model, and might be more context-dependent than the other input parameters (age, survival). The aim of this study was to validate our model by replicating these QoL estimates. Methods The original study estimated QoL of patients in need of commonly performed procedures in live expert-panel meetings. This study replicated this procedure using a web-based Delphi approach in a different hospital. The new QoL scores were compared with the original scores using mixed effects linear regression. The ranking of surgical procedures based on combined QoL values from the validation and original study was compared to the ranking based solely on the original QoL values. Results The overall mean difference in QoL estimates between the validation study and the original study was − 0.11 (95% CI:  -0.12 - -0.10). The model output (DALY/month delay) based on QoL data from both studies was similar to the model output based on the original data only: The Spearman’s correlation coefficient between the ranking of all procedures before and after including the new QoL estimates was 0.988. Discussion Even though the new QoL estimates were systematically lower than the values from the original study, the ranking for urgency based on health loss per unit of time delay of procedures was consistent. This underscores the robustness and generalizability of the decision model for prioritization of surgical procedures.

Patients with an indication for an implantable cardioverter–defibrillator but no indication for pacing were randomly assigned to a subcutaneous or a transvenous ICD. At 49 months, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks.

There is increasing data that show a persistently impaired pulmonary function upon recovery after severe infection. Little is known however about the extent, recovery and determinants of pulmonary impairment across the full spectrum of COVID-19 severity over time. In a well characterized, prospective cohort of both hospitalised and non-hospitalised individuals with SARS-CoV-2 infection, the RECoVERED study, pulmonary function (diffusing capacity for carbon monoxide (DLCO)) and spirometry) was measured until one year after disease onset. Additionally, data on sociodemographics, clinical characteristics, symptoms, and health-related quality of life (HRQL) were collected. Pulmonary function and these determinants were modelled over time using mixed-effect linear regression. Determinants of pulmonary function impairment at 12 months after disease onset were identified using logistic regression. Between May 2020 and December 2021, 301 of 349 participants underwent at least one pulmonary function test. After one year of follow-up, 25% of the participants had an impaired pulmonary function which translates in 11%, 22%, and 48% of the participants with mild, moderate and severe/critical COVID-19. Improvement in DLCO among the participants continued over the period across one, six and twelve months. Being older, having more than three comorbidities (p<0·001) and initial severe/critical disease (p<0·001) were associated with slower improvement of pulmonary function over time, adjusted for age and sex. HRQL improved over time and at 12 months was comparable to individuals without impaired pulmonary function.

Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited. To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance. Nationwide retrospective cohort study. Tertiary referral centers in the Netherlands (multicenter). Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied. SDHA mutation detection yield, clinical manifestations, and SDHA-related disease penetrance. Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%]), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%]). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers. Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed.

BackgroundIt remains unclear if the increased colorectal neoplasia detection rate in inflammatory bowel disease (IBD) by high-definition (HD) dye-based chromoendoscopy compared with HD white-light endoscopy is due to enhanced contrast or increased inspection times. Longer withdrawal times may yield similar neoplasia detection rates as found by HD chromoendoscopy.ObjectiveTo compare colorectal neoplasia detection rates for HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy, using single-pass HD white-light endoscopy as an additional control group.DesignIn a multicentre, randomised controlled trial, IBD patients aged ≥18 years without active disease and scheduled for endoscopic surveillance were included. Patients were 2:2:1 randomised to HD white-light endoscopy with segmental re-inspection of each colonic segment (double pass), HD chromoendoscopy or single-pass HD white-light endoscopy. The primary outcome was colorectal neoplasia detection rate. Assuming equal colorectal neoplasia rates (non-inferiority margin of 10%) between segmental re-inspection and chromoendoscopy and superiority of segmental re-inspection vs single-pass HD white-light endoscopy, a sample size of 566 patients was required.ResultsIn total, 563 patients were analysed per-protocol. Colorectal neoplasia detection rates were 10.3% (n=24/234) for HD white-light endoscopy with segmental re-inspection and 13.1% (n=28/214) for HD chromoendoscopy. This confirmed non-inferiority to HD chromoendoscopy (Δ−2.8%, lower limit 95% CI −7.8, p<0.01). In addition, the number of detected colorectal neoplasia per 10 min of withdrawal time was similar between HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy (0.062 vs 0.058, p=0.83). Single-pass HD white-light endoscopy yielded a lower colorectal neoplasia rate (6.1%; n=7/115) than segmental re-inspection but this was not statistically significant (Δ4.1%, 95% CI −2.2:9.6%, p=0.19).ConclusionsHD white-light endoscopy with segmental re-inspection was non-inferior to HD chromoendoscopy for colorectal neoplasia detection in IBD patients. It can therefore be assumed that the benefit of HD chromoendoscopy may be explained by the longer withdrawal time and not necessarily the enhanced contrast. However, re-inspection per se did not lead to a significantly higher colorectal neoplasia rate than single-pass HD white-light endoscopy alone.

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an immune inhibitory receptor expressed on human myeloid cells. We previously showed that dendritic cell (DC)-driven Th17 cell differentiation of human naive CD4 + T cells requires presence of neutrophils, which is inhibited by SIRL-1 ligation. VSTM1-v2 is a soluble isoform of SIRL-1, which was previously proposed to function as a Th17 polarizing cytokine. Here, we investigated the effect of VSTM1-v2 on DC-driven Th17 cell development. Neutrophils induced DC-driven Th17 cell differentiation, which was not enhanced by VSTM1-v2. Similarly, we found no effect of VSTM1-v2 on cytokine-driven Th17 cell development. Thus, our results do not support a role for VSTM1-v2 in Th17 cell differentiation.