Clinical decision making in the era of immunotherapy for high grade-glioma: report of four cases

Abstract Background Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. Case presentation We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. Conclusions A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques. Trial registration ClinicalTrials.gov NCT02311920. Registered 8 December 2014

Family history as the strongest predictor of aortic and peripheral aneurysms in patients with intracranial aneurysms

Objective: Intracranial aneurysms (IA) and aortic aneurysms (AA) are both abnormal dilations of arteries with familial predisposition and have been proposed to share co-prevalence and pathophysiology. Associations of IA and non-aortic peripheral aneurysms are less well-studied. The goal of the study was to understand the patterns of aortic and peripheral (extracranial) aneurysms in patients with IA, and risk factors associated with the development of these aneurysms. Methods: 4701 patients were included in our retrospective analysis of all patients with intracranial aneurysms at our institution over the past 26 years. Patient demographics, comorbidities, and aneurysmal locations were analyzed. Univariate and multivariate analyses were performed to study associations with and without extracranial aneurysms. Results: A total of 3.4% of patients (161 of 4701) with IA had at least one extracranial aneurysm. 2.8% had thoracic or abdominal aortic aneurysms. Age, male sex, hypertension, coronary artery disease, history of ischemic cerebral infarction, connective tissues disease, and family history of extracranial aneurysms in a 1st degree relative were associated with the presence of extracranial aneurysms and a higher number of extracranial aneurysms. In addition, family history of extracranial aneurysms in a second degree relative is associated with the presence of extracranial aneurysms and atrial fibrillation is associated with a higher number of extracranial aneurysms. Conclusion: Significant comorbidities are associated with extracranial aneurysms in patients with IA. Family history of extracranial aneurysms has the strongest association and suggests that IA patients with a family history of extracranial aneurysms may benefit from screening.</p

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas

PURPOSE: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide (TMZ) in patients with recurrent high-grade astrocytoma. EXPERIMENTAL DESIGN: This two-stage phase 1 trial determined the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) TMZ using a Bayesian Optimal Interval design; then a randomized cohort-expansion compared the progression-free survival rate at 4 month (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with zotiraciclib at MTD. Pharmacokinetics (PK) and pharmacogenomic (PG) profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. RESULTS: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250mg in both arms and thus selected for the cohort expansion. Dose-dense TMZ plus zotiraciclib (PSF4 40%) compared favorably with metronomic TMZ (PFS4 25%). Symptom burden worsened at Cycle 2 but stabilized by Cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. PK/PG analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUC(inf) value. CONCLUSIONS: Zotiraciclib combined with TMZ is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas

PurposeTo investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and methodsThis two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.ResultsFifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T&gt;C (rs2470890) polymorphism was associated with higher AUCinf value.ConclusionsZotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib

Ancient DNA from Coral-Hosted Symbiodinium Reveal a Static Mutualism over the Last 172 Years

Ancient DNA (aDNA) provides powerful evidence for detecting the genetic basis for adaptation to environmental change in many taxa. Among the greatest of changes in our biosphere within the last century is rapid anthropogenic ocean warming. This phenomenon threatens corals with extinction, evidenced by the increasing observation of widespread mortality following mass bleaching events. There is some evidence and conjecture that coral-dinoflagellate symbioses change partnerships in response to changing external conditions over ecological and evolutionary timescales. Until now, we have been unable to ascertain the genetic identity of Symbiodinium hosted by corals prior to the rapid global change of the last century. Here, we show that Symbiodinium cells recovered from dry, century old specimens of 6 host species of octocorals contain sufficient DNA for amplification of the ITS2 subregion of the nuclear ribosomal DNA, commonly used for genotyping within this genus. Through comparisons with modern specimens sampled from similar locales we show that symbiotic associations among several species have been static over the last century, thereby suggesting that adaptive shifts to novel symbiont types is not common among these gorgonians, and perhaps, symbiotic corals in general