A generalized calibrated Bayesian hierarchical modeling approach to basket trials with multiple endpoints.

A basket trial simultaneously evaluates a treatment in multiple cancer subtypes, offering an effective way to accelerate drug development in multiple indications. Many basket trials are designed and monitored based on a single efficacy endpoint, primarily the tumor response. For molecular targeted or immunotherapy agents, however, a single efficacy endpoint cannot adequately characterize the treatment effect. It is increasingly important to use more complex endpoints to comprehensively assess the risk-benefit profile of such targeted therapies. We extend the calibrated Bayesian hierarchical modeling approach to monitor phase II basket trials with multiple endpoints. We propose two generalizations, one based on the latent variable approach and the other based on the multinomial-normal hierarchical model, to accommodate different types of endpoints and dependence assumptions regarding information sharing. We introduce shrinkage parameters as functions of statistics measuring homogeneity among subgroups and propose a general calibration approach to determine the functional forms. Theoretical properties of the generalized hierarchical models are investigated. Simulation studies demonstrate that the monitoring procedure based on the generalized approach yields desirable operating characteristics.

Susceptibility to preoperative seizures in glioma patients with elevated homocysteine levels.

OBJECTIVE: Seizures are a common clinical presentation in patients with glioma and substantially impact patients' quality of life. Hyperhomocysteinemia is defined as abnormally high serum levels of homocysteine (Hcy) and is reportedly linked to susceptibility to various nervous system diseases. However, it remains unclear whether and how hyperhomocysteinemia and its associated genetic polymorphisms promote seizures in glioma patients. METHODS: We retrospectively reviewed all medical data from 127 patients with malignant gliomas, who underwent initial tumor resection by our team between July 2019 and June 2021 and had preoperative measurements of serum Hcy levels. According to whether they had at least one seizure before surgery, they were divided into the seizure and nonseizure groups. We also detected polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and measured intratumoral Hcy levels in these patients. RESULTS: Hyperhomocysteinemia was a susceptibility factor for preoperative seizures in glioma patients according to both univariate analyses (P < 0.001) and multivariate logistic regression analyses (OR 1.239, 95% CI 1.062-1.445, P = 0.007). Patients with the MTHFR C677T variant exhibited elevated serum Hcy levels (P = 0.027) and an increased prevalence of preoperative seizures (P = 0.019). Intratumoral Hcy levels were positively correlated with serum Hcy levels (R = 0.231, P = 0.046) and were elevated in patients with hyperhomocysteinemia (P = 0.031), the MTHFR C677T variant (P = 0.002) and preoperative seizures (P = 0.003). High intratumoral Hcy levels, rather than hyperhomocysteinemia or the MTHFR C677T variant, emerged as an independent risk factor for preoperative seizures (OR 1.303, 95% CI 1.015-1.673, P = 0.038). Furthermore, the effects of hyperhomocysteinemia on epileptic susceptibility were reduced to nonsignificance when intratumoral Hcy was controlled to the same level between groups. SIGNIFICANCE: Glioma patients with hyperhomocysteinemia and the MTHFR C677T variant were susceptible to preoperative seizures, suggesting their potential as biomarkers for the management of seizures in glioma patients. The elevation of intratumoral Hcy is a possible mechanism underlying this susceptibility.

BOB: Bayesian optimal design for biosimilar trials with co-primary endpoints.

For regulatory approval of a biosimilar product, extensive evaluations should be performed by rigorous clinical trials to establish the similarity between the reference product and the proposed biosimilar in terms of both efficacy and safety. Existing designs for biosimilar trials often use a single primary efficacy endpoint in trial monitoring, and then separately evaluate the safety of the biosimilar product in a secondary analysis at the trial completion. However, ignoring the safety endpoint and the correlation between safety and efficacy in trial monitoring may lead to a high false positive rate, or it may delay the termination of the trial when dissimilarity in safety is early detected. We propose a Bayesian optimal design for biosimilar trials by incorporating both safety and efficacy endpoints in a unified framework. Based on a Bayesian joint safety and efficacy model, we sequentially use a so-called Bayesian biosimilar probability to make go/no-go decisions. We calibrate the Bayesian design to maximize the statistical power while maintaining the frequentist type I error rate at the nominal level. We carry out extensive simulation studies to show that the design has desirable performance in terms of the false positive rate and the average sample size. We also apply the proposed design to a biosimilar trial evaluating a ranibizumab product.

Low MxA Expression Predicts Better Immunotherapeutic Outcomes in Glioblastoma Patients Receiving Heat Shock Protein Peptide Complex 96 Vaccination.

Heat shock protein peptide complex 96 (HSPPC-96) has been proven to be a safe and preliminarily effective therapeutic vaccine in treating newly diagnosed glioblastoma multiforme (GBM) (NCT02122822). However, the clinical outcomes were highly variable, rendering the discovery of outcome-predictive biomarkers essential for this immunotherapy. We utilized multidimensional immunofluorescence staining to detect CD4+ CD8+ and PD-1+ immune cell infiltration levels, MxA and gp96 protein expression in pre-vaccination GBM tissues of 19 patients receiving HSPPC-96 vaccination. We observed low MxA expression was associated with longer OS than high MxA expression (48 months vs. 20 months, p=0.038). Long-term survivors (LTS) exhibited significantly lower MxA expression than short-term survivors (STS) (p= 0.0328), and ROC curve analysis indicated MxA expression as a good indicator in distinguishing LTS and STS (AUC=0.7955, p=0.0318). However, we did not observe any significant impact of immune cell densities or gp96 expression on patient outcomes. Finally, we revealed the association of MxA expression with prognosis linked to a preexisting TCR clone (CDR3-2) but was independent of the peripheral tumor-specific immune response. Taken together, low MxA expression correlated with better survival in GBM patients receiving HSPPC-96 vaccination, indicating MxA as a potential biomarker for early recognition of responsive patients to this immunotherapy. Clinical Trial Registration: ClinicalTrials.gov (NCT02122822) http://www. chictr.org.cn/enindex.aspx (ChiCTR-ONC-13003309).

Resection of Noncontrast-Enhancing Regions Deteriorated the Immunotherapeutic Efficacy of HSPPC-96 Vaccination in Treating Glioblastoma.

Surgical resection remains a first-line therapy for glioblastoma multiforme (GBM). Increased extent of resection (EOR) of noncontrast-enhancing regions in T2-weighted MRI images (T2-EOR) provides a survival benefit for GBM patients receiving standard radio/chemotherapy. However, whether it also improves immunotherapeutic outcomes remains unclear. We calculated the T2-EOR by comparing the preoperative and postoperative MRI T2 hyperintensity outside the enhancing tumour and correlated the T2-EOR with immunological and clinical outcomes from our published early-phase trial of heat shock protein peptide complex-96 (HSPPC-96) vaccination in treating a cohort of 19 patients with newly diagnosed GBMs (NCT02122822). Patients with higher T2-EOR exhibited shorter progression-free survival (PFS) (HR 11.29, p=0.002) and overall survival (OS) (HR 6.5, p=0.003) times than patients with lower T2-EOR. T2-EOR was negatively correlated with the levels of tumour specific immune response (TSIR) post-vaccination (R=-0.725, p<0.001) and absolute TSIR increase from pre- to post-vaccination (R=-0.679, p=0.001). Multivariate Cox regression models revealed that higher T2-EOR represented an independent risk factor for PFS (HR 19.85, p=0.0068) and OS (HR 21.24, p=0.0185) in this patient cohort. Taken together, increased T2-EOR deteriorated immunotherapeutic outcomes by suppressing TSIR, suggesting the potential of T2-EOR as an early biomarker for predicting the immunotherapeutic efficacy of HSPPC-96 vaccination.

A Nomogram Predicts Individual Prognosis in Patients With Newly Diagnosed Glioblastoma by Integrating the Extent of Resection of Non-Enhancing Tumors.

BACKGROUND: The extent of resection of non-contrast enhancing tumors (EOR-NCEs) has been shown to be associated with prognosis in patients with newly diagnosed glioblastoma (nGBM). This study aimed to develop and independently validate a nomogram integrated with EOR-NCE to assess individual prognosis. METHODS: Data for this nomogram were based on 301 patients hospitalized for nGBM from October 2011 to April 2019 at the Beijing Tiantan Hospital, Capital Medical University. These patients were randomly divided into derivation (n=181) and validation (n=120) cohorts at a ratio of 6:4. To evaluate predictive accuracy, discriminative ability, and clinical net benefit, concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were calculated for the extent of resection of contrast enhancing tumor (EOR-CE) and EOR-NCE nomograms. Comparison between these two models was performed as well. RESULTS: The Cox proportional hazards model was used to establish nomograms for this study. Older age at diagnosis, Karnofsky performance status (KPS)<70, unmethylated O6-methylguanine-DNA methyltransferase (MGMT) status, wild-type isocitrate dehydrogenase enzyme (IDH), and lower EOR-CE and EOR-NCE were independent factors associated with shorter survival. The EOR-NCE nomogram had a higher C-index than the EOR-CE nomogram. Its calibration curve for the probability of survival exhibited good agreement between the identical and actual probabilities. The EOR-NCE nomogram showed superior net benefits and improved performance over the EOR-CE nomogram with respect to DCA and ROC for survival probability. These results were also confirmed in the validation cohort. CONCLUSIONS: An EOR-NCE nomogram assessing individualized survival probabilities (12-, 18-, and 24-month) for patients with nGBM could be useful to provide patients and their relatives with health care consultations on optimizing therapeutic approaches and prognosis.

Pre-operative Neurocognitive Function Was More Susceptible to Decline in Isocitrate Dehydrogenase Wild-Type Subgroups of Lower-Grade Glioma Patients.

Background: Neuropsychological deficits frequently occur in diffuse lower-grade glioma (DLGG) patients, but their relationship with molecular subgroups based on the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is unclear. Methods: All patients enrolled for this study were divided into different subgroups according to the molecular-integrated 2016 CNS WHO and morphology-centric 2007 CNS WHO to compare their neurocognitive function (NCF) dysfunction. Univariate and multivariate analyses were used to assess the independent factors for NCF decline. The performance of NCF changes for discrimination of IDH and 1p19q status was evaluated by receiver operating characteristic (ROC). Results: There was no significant difference in the clinical characteristics among the molecular and morphologic subgroups. In the molecular subgroups, significant differences in NCF alterations were found in terms of attention function, working memory and executive function in grade II glioma patients; in addition to these changes in NCF, memory function and abstract thinking were also significantly different in grade III glioma patients. The pairwise comparison further confirmed that patients with astrocytoma (A)/anaplastic astrocytoma (AA) with isocitrate dehydrogenase wild-type (IDHwt) glioma were more susceptible to severe cognitive decline in terms of the NCF performance described above. For the morphologic subgroups, only working memory was significantly different in grade III glioma patients. The distribution proportion was significantly different among each subgroup of DLGG (grade II, P = 0.001; grade III, P = 0.002). The proportion of extensive NCF decline (≥5 tests) was 4, 12, and 50% in the IDH mutant oligodendroglioma (IDHm-O), IDHm-A, and IDHwt-A subgroups, and this proportion was 33, 60, and 93% in the IDHm-AO, IDHm-AA, and IDHwt-AA subgroups, respectively. In multivariate regression analysis, molecular types were independent factors for NCF alterations after adjusted the factors of tumor and demographics (p < 0.05). ROC curves suggested combined NCF tests model showed an advantage in the differentiation of IDH status. Conclusions: NCF alteration is closely related to molecular-integrated subgroups with varying degrees and frequencies in DLGG. Patients with IDHwt gliomas are more susceptible to suffer from severe and extensive NCF decline than other subgroups.