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- De Laere, B, et al.
(författare)
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Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC (n = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan–Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02–2.84), p = 0.04, and OS HR (95%CI): 2.5 (1.06–5.71), p = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.
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- Karpouzas, George A., et al.
(författare)
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Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors : a post hoc analysis of ORAL Surveillance
- 2023
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Ingår i: Therapeutic Advances in Musculoskeletal Disease. - : Sage Publications. - 1759-7218 .- 1759-720X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs).Objectives: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi).Design: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi.Methods: In ORAL Surveillance, 4362 patients aged >= 50 years with active RA despite methotrexate, and >= 1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death.Results: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05.Conclusion: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi.
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- Martini, A., et al.
(författare)
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The natural history of untreated muscle-invasive bladder cancer
- 2020
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Ingår i: Bju International. - : Wiley. - 1464-4096 .- 1464-410X. ; 125:2, s. 270-275
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Tidskriftsartikel (refereegranskat)abstract
- Objective To describe the natural history of untreated muscle-invasive bladder cancer (MIBC) and compare the oncological outcomes of treated and untreated patients. Patients and Methods We utilised a database encompassing all patients with newly diagnosed bladder cancer in Stockholm, Sweden between 1995 and 1996. The median follow-up for survivors was 14.4 years. Overall, 538 patients were diagnosed with bladder cancer of whom 126 had clinically localised MIBC. Patients were divided into two groups: those who received radical cystectomy or radiation therapy, and those who did not receive any form of treatment. Multivariable Cox or competing-risks regressions were adopted to predict metastasis, overall survival (OS), and cancer-specific mortality (CSM), when appropriate. Analyses were adjusted for age at diagnosis, sex, tumour stage, clinical N stage, and treatment. Results In all, 64 (51%) patients did not receive any definitive local treatment. In the untreated group, the median (interquartile range) age at diagnosis was 79 (63-83) vs 69 (63-74) years in the treated group (P < 0.001). Overall, 109 patients died during follow-up. At 6 months after diagnosis, 38% of the untreated patients had developed metastatic disease and 41% had CSM. The 5-year OS rate for untreated and treated patients was 5% (95% confidence interval [CI] 1, 12%) vs 48% (95% CI 36, 60%), respectively. Patients not receiving any treatment had a 5-year cumulative incidence of CSM of 86% (95% CI 75, 94%) vs 48% (95% CI 36, 60%) for treated patients. Untreated patients had a higher risk of progression to metastatic disease (hazard ratio [HR] 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and CSM (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004). Conclusions Untreated patients with MIBC are at very high risk of near-term CSM. These findings may help balance the risks vs benefits of integrating curative intent therapy particularly in older patients with MIBC.
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