Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

The immune-related adverse events paradox in locally advanced or metastatic urothelial cancer after atezolizumab immunotherapy: analysis of individual patient data from IMvigor210 and IMvigor211 trials.

OBJECTIVE: To investigate the association between immune-related adverse events (irAEs) and oncological outcomes in patients with advanced urothelial cancer receiving immune checkpoint inhibitors (ICIs), and whether the administration of systemic corticosteroids diminishes therapeutic impact. PATIENTS AND METHODS: The association between irAEs occurrence and clinical progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) was tested by means of multivariable Cox or competing-risks regression, when appropriate. Patients experiencing irAEs were further stratified based on systemic corticosteroids administration. A sensitivity analysis was conducted by repeating all the analyses with median time to irAE as landmark point. RESULTS: We relied on individual participant data from two prospective trials for advanced urothelial cancer: IMvigor210 and IMvigor211. A total of 896 patients who received atezolizumab for locally advanced or metastatic urothelial cancer were considered. Overall, irAEs were recorded in 195 patients and the median time to irAEs was 64 days. On multivariable analysis, irAEs were inversely associated with the risk of disease progression (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.40-0.61; P < 0.001), overall mortality (HR 0.51, 95% CI 0.41-0.64; P < 0.001), and cancer-specific mortality (subdistributional HR [sHR] 0.55, 95% CI 0.45-0.72; P < 0.001). Moreover, our results did not refute the supposition that the administration of systemic corticosteroids does not impact oncological outcomes (PFS: HR 0.92, 95% CI 0.62-1.34, P = 0.629; OS: HR 0.86, 95% CI 0.51-1.64, P = 0.613; CSS: sHR 0.90, 95% CI 0.60-1.36, P = 0.630). The sensitivity analysis confirmed our findings. CONCLUSIONS: The development of irAEs while receiving atezolizumab treatment was associated with improved oncological outcomes, namely overall and cancer-specific mortality, and PFS. These findings seem to not be substantially affected by administration of systemic corticosteroids.

Immunotherapy versus chemotherapy as first-line treatment for advanced urothelial cancer: A systematic review and meta-analysis.

BACKGROUND: Pembrolizumab and atezolizumab have recently been approved for the first-line treatment of patients with advanced urothelial carcinoma (aUC) who are not eligible for cisplatin-based chemotherapy and whose tumors have high PD-L1 expression; however, the use of these immunotherapeutic agents relative to standard of care chemotherapy has ongoing concerns. The aim of this present study is to compare the effectiveness of single-agent immune-oncology (IO) compounds versus platinum-based chemotherapy in the first-line setting of aUC. METHODS: A comprehensive search for phase III trials on IO versus chemotherapy was conducted in PubMed, EMBASE, Web of Science, and Scopus databases from 01/2016 to 05/2021. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct overall survival (OS) data. After demonstrating violation of the proportional hazard assumption, we used the difference in restricted mean survival time (ΔRMST) to compare OS. RESULTS: OS data from 2,068 individuals from 3 phase III trials investigating the role of IO vs chemotherapy were reconciled. Overall, patients receiving IO [n = 1,013 (49%)] or chemotherapy [n = 1,055 (51%)] had similar OS with a 24-month ΔRMST of -0.4 (95% CI: -1.1, 0.4; p = 0.2) months. In the cisplatin-ineligible population, patients receiving IO [n = 509 (49%)] or chemotherapy [n = 530 (51%)] had similar OS with a 24-month ΔRMST of 0.1 (95% CI: -0.9, 1.2; p = 0.7) months. In the cisplatin-ineligible population with PD-L1-high tumors, patients receiving IO [n = 226 (50%)] or chemotherapy [n = 226 (50%)] had similar OS with a 24-month ΔRMST of 1.1 (95% CI: -0.5, 2.7; p = 0.1) months. CONCLUSION: We found no OS benefit for patients treated with first-line immune checkpoint inhibition compared to chemotherapy among the overall population, cisplatin-ineligible patients, and PD-L1-high patients.

Oncologic Surveillance for Variant Histology Bladder Cancer after Radical Cystectomy.

PURPOSE: Presently, major guidelines do not provide specific recommendations on oncologic surveillance for patients who harbor variant histology (VH) bladder cancer (BCa) at radical cystectomy. We aimed to create a personalized followup scheme that dynamically weighs other cause mortality (OCM) vs the risk of recurrence for VH BCa, and to compare it with a similar one for pure urothelial carcinoma (pUC). MATERIALS AND METHODS: Within a multi-institutional registry, 528 and 1,894 patients with VH BCa and pUC, respectively, were identified. The Weibull regression was used to detect the time points after which the risk of OCM exceeded the risk of recurrence during followup. The risk of OCM over time was stratified based on age and comorbidities, and the risk of recurrence on pathological stage and recurrence site. RESULTS: Individuals with VH had a higher risk of recurrence (recurrence-free survival 30% vs 51% at 10 years, p <0.001) and shorter median time to recurrence (88 vs 123 months, p <0.01) relative to pUC. Among VH, micropapillary variant conferred the greatest risk of recurrence on the abdomen and lungs, and mixed variants carried the greatest risk of metastasizing to bones and other sites compared to pUC. Overall, surveillance should be continued for a longer time for individuals with VH BCa. Notably, patients younger than 60 years with VH and pT0/Ta/T1/N0 at radical cystectomy should continue oncologic surveillance after 10 years vs 6.5 years for pUC individuals. CONCLUSIONS: VH BCa is associated with greater recurrence risk than pUC. A followup scheme that is valid for pUC should not be applied to individuals with VH. Herein, we present a personalized approach for surveillance that may allow an improved shared decision.

Endovascular and Surgical Treatment Is Predictive of Readmission Risk After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a debilitating disease process accounting for 5% of strokes. Although improvements in care have reduced the case-fatality rates, patients have an increased risk of neurological and medical complications after discharge. Additionally, the readmission rates have been increasingly used as a metric for patient care quality. METHODS: In the present study, we reviewed the medical records of 206 patients who had been treated for aSAH at the University of Virginia from 2011 to 2018 to identify the causes and predictors of readmission. RESULTS: The all-cause readmission rate was 9.8%, 15.3%, and 21.3% within 30, 60, and 180 days, respectively. The readmission rate for neurologic causes was 7.7%, 12.6%, and 18.0% within 30, 60, and 180 days, respectively. The neurologic causes of readmission included aneurysm retreatment, cranioplasty, a fall, hydrocephalus, stroke symptoms, and syncope. Surgical treatment (odds ratio [OR], 4.11-6.30) and endovascular treatment (OR, 3.79-8.33) of vasospasm were associated with an increased risk of all-cause readmission. Endovascular aneurysm treatment (OR, 0.22) was associated with a decreased risk of all-cause readmission. The average interval to the first follow-up appointment at our institution was 55.3 ± 63.3 days. Of the patients who had been readmitted from the emergency room, 65% had not had follow-up contact with physicians at our institution until their readmission. CONCLUSIONS: To the best of our knowledge, the present study is the first to have examined the readmission rates for subarachnoid hemorrhage >90 days after treatment. Our results have suggested that the readmission rates >90 days after treatment could still be predicted by the hospital and treatment course during admission and that follow-up appointments with patients earlier in the clinic could identify those patients with a greater risk of readmission.