A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors

BackgroundWhile immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).ObjectiveWe aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.Design, setting, and participantsPatients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.Outcome measurements and statistical analysisWe used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.Results and limitationsAmong 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.ConclusionsWe developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.Patient summaryWith multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE  HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Tocilizumab in the treatment of rheumatoid arthritis: a cost-effectiveness analysis in the UK.

Since receiving a positive recommendation in England, Wales and Scotland, tocilizumab (TCZ) is one of the options available to clinicians for the treatment of rheumatoid arthritis (RA) patients in the UK

D-DEMOS: A Distributed, End-to-end Verifiable, Internet Voting system

E-voting systems have emerged as a powerful technology for improving democracy by reducing election cost, increasing voter participation, and even allowing voters to directly verify the entire election procedure. Prior internet voting systems have single points of failure, which may result in the compromise of availability, voter secrecy, or integrity of the election results. In this paper, we present the design, implementation, security analysis, and evaluation of D-DEMOS, a complete e-voting system that is distributed, privacy-preserving and end-to-end verifiable. Our system includes a fully asynchronous vote collection subsystem that provides immediate assurance to the voter her vote was recorded as cast, without requiring cryptographic operations on behalf of the voter. We also include a distributed, replicated and fault-tolerant Bulletin Board component, that stores all necessary election-related information, and allows any party to read and verify the complete election process. Finally, we also incorporate trustees, i.e., individuals who control election result production while guaranteeing privacy and end-to-end-verifiability as long as their strong majority is honest. Our system is the first e-voting system whose voting operation is human verifiable, i.e., a voter can vote over the web, even when her web client stack is potentially unsafe, without sacrificing her privacy, and still be assured her vote was recorded as cast. Additionally, a voter can outsource election auditing to third parties, still without sacrificing privacy. Finally, as the number of auditors increases, the probability of election fraud going undetected is diminished exponentially. We provide a model and security analysis of the system. We implement a prototype of the complete system, we measure its performance experimentally, and we demonstrate its ability to handle large-scale elections

Cost-effectiveness of an insertable cardiac monitor to detect atrial fibrillation in patients with cryptogenic stroke

Background and aims Documentation of atrial fibrillation is required to initiate oral anticoagulation therapy for recurrent stroke prevention. Atrial fibrillation often goes undetected with traditional electrocardiogram monitoring techniques. We evaluated whether atrial fibrillation detection using continuous long-term monitoring with an insertable cardiac monitor is cost-effective for preventing recurrent stroke in patients with cryptogenic stroke, in comparison to the standard of care. Methods A lifetime Markov model was developed to estimate the cost-effectiveness of insertable cardiac monitors from a UK National Health Service perspective using data from the randomized CRYSTAL-AF trial and other published literature. We also conducted scenario analyses (CHADS2 score) and probabilistic sensitivity analyses. All costs and benefits were discounted at 3.5%. Results Monitoring cryptogenic stroke patients with an insertable cardiac monitor was associated with fewer recurrent strokes and increased quality-adjusted life years compared to the standard of care (7.37 vs 7.22). Stroke-related costs were reduced in insertable cardiac monitor patients, but overall costs remained higher than the standard of care (£19,631 vs £17,045). The incremental cost-effectiveness ratio was £17,175 per quality-adjusted life years gained, compared to standard of care in the base-case scenario, which is below established quality-adjusted life years willingness-to-pay thresholds. When warfarin replaced non-vitamin-K oral anticoagulants as the main anticoagulation therapy, the incremental cost-effectiveness ratio was £13,296 per quality-adjusted life years gained. Conclusion Insertable cardiac monitors are a cost-effective diagnostic tool for the prevention of recurrent stroke in patients with cryptogenic stroke. The cost-effectiveness results have relevance for the UK and across value-based healthcare systems that assess costs relative to outcomes. </jats:sec