Clinical and pathological characteristics of patients
A total of 76 decedents (49 males, ages 23-80 years old at initial diagnosis, were enrolled prospectively with initial diagnoses as GBM (N=53), grade III glioma (N=8), brain metastasis (BM, N=8), grade II glioma (N=5), and spinal glioma (N=2) (grades III and IV, respectively). At autopsy, 4 grade II and 5 grade III gliomas had progressed to secondary GBMs (Table 1). The swimmer plot is presented in Figure 1. The average time from death to postmortem examination at MHH-TMC/UTHealth was 35.3±3.7 hours (range: 7-100 hours, calculated from 38 cases with accurate documentation of timing of death).
Kidney ultrastructure examination
EM studies were performed in 14 subjects to understand the ultrastructural changes in those who had HTN and proteinuria due to BEV therapy. An interval from death to tissue collection was not available from five decedents at Tufts Medical Center; the interval from death to tissue collection was 19.8±7.5 hours from nine glioma decedents at MHH-TMC/UTHealth. To differentiate true microscopic findings from possible artifacts from autolysis, interventional radiologist (AKP) biopsied cadaver kidney under ultrasound guidance on 4 decedents #22 (3 hrs), #20 (6 hrs), #17 (7 hrs), and #49 (9 hrs). The EM results of podocyte effacement with basement membrane detachment were observed in subjects exposed to BEV and naïve to BEV. making observation inconclusive due to autolysis.
Clinical myelosuppression on active therapies
Analysis showed that 41.7% (5/12), 16.7% (2/12), and 20% (10/37) of decedents experienced grade III or worse CM during active therapies in groups 2, 3, and 4, respectively. Compared to group 4, ORs were 1.93 (95% CI: 0.50-7.50, P=0.343) and 0.54 (95% CI: 0.10-2.91, P=0.473) for groups 2 and 3, respectively (Table 3). The CM rates were 57.1% and 47.6% in IRI infusion subgroups who received 1-6 cycles (N=14) and 1-12 cycles (N=21), respectively. The ORs in these two groups were 7.67 (95% CI: 1.71-34.33, P=0.008) and 5.23 (95% CI: 1.34-20.45, P=0.018) (Table 3). By contrast, the likelihoods of CM for patients treated with 7-12, 13-18, 19-24, and 25-47 cycles of TMZ were not significantly increased compared to those receiving 1-6 cycles (all P>0.05) (Table 3).
Bone marrow examinations at autopsy
Bone marrow exams were performed in 39 decedents. BM study in 4 decedents (case #9, 46, 65 and 69) showed as hypocellular, but not conclusive if they are appropriate for age or indicative of treatment-related changes. Nine severe hypocellularity cases were identified: two from group 2 (case #17 and 23), three from group 4 (case #29, 52 and 59), and four from the BM group (case #71, 73, 74 and 76). Three severe hypocellular bone marrow specimens (#17, 23, and 52) matched antemortem CM history. Subject # 36's (group 4, SOC) bone marrow, who had a history of leukocytopenia and thrombocytopenia, was hypercellular. There was no evidence of postmortem BM abnormality among decedents in groups 1 and 3.
Five patients (#29, 32, 38, 62, and 63) discontinued TMZ due to severe CM during CCRT. But CM in glioma patients did not develop permanent bone marrow damage as often as seen among BM decedents treated with chemotherapy. Patients exposed to extended TMZ (Figure 2C) or TIB regimens (Figure 2D) still had normal bone marrow.
Other clinical adverse events
The three most common AEs in group 4 were grade III HTN (37.5%), weight loss (29.7%), and venous thromboembolism (VTE, 24.3%). Grade III HTN (41.7%) was also the most common AE among patients who received TIB (groups 2 and 3 combined). The grade III CM was 33.3% and 21.6% among TIB and group 4, respectively. However, no grade IV thrombocytopenia was observed in the TIB group, while the rate was 13.5% in group 4. All AEs grade III or above are listed in Table 2.
Cause of death (COD) for recurrent/progressive glioma patients including GBM patients
Among the 68 glioma decedents, disease progression was the most common COD (N=43, 63.2%) (Table 2). The second most common COD was aspiration pneumonia (N=33, 48.5%) among glioma cases. Herniation with brain swelling was detected in 12 (17.6%) subjects, while cerebral or intraventricular hemorrhages were documented in 7 glioma cases. Uncommon CODs include decedent #67, who died at home from sudden death with autopsy finding of cardiomyopathy; descendants #26 and #76 expired from cerebral herniation soon after decompression surgeries. Three subjects (#52, 57, and 60) passed away in hospital due to severe adverse events while on active anti-cancer treatments.