Journal of Neurology, Neurosurgery, and Psychiatry, 1999
Previous study has shown that the anti-Hu antibody titre of serum samples from patients with para... more Previous study has shown that the anti-Hu antibody titre of serum samples from patients with paraneoplastic encephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) was significantly higher than that from patients with small cell lung cancer without neurological disturbances (non-PEM/PSN). The aims of this study were (1) to identify the fine epitopes on HuD recognised by the anti-Hu antibody, (2) to determine if the pattern of epitopic reactivity diVered between antibodies from patients with and without PEM/PSN, and (3) to determine if the pattern of epitopic reactivity correlated with the clinical features. Recombinant full length HuD and nine deletion fragments were constructed and immunoreacted by western blot analysis with 14 anti-Hu serum samples from eight patients with PEM/PSN and six without PEM/PSN. All anti-Hu serum samples reacted with the deletion fragments containing amino acids (aa) 90-101 or aa 171-206. Some anti-Hu samples reacted with the deletion fragments containing aa 223-234, aa 235-252, or aa 354-373. There was no diVerence in the pattern of epitopic reactivity between patients with and without PEM/PSN. There was no correlation between the pattern of epitopic reactivity and the clinical features. The anti-Hu antibody titre from patients with PEM/ PSN was significantly higher than from patients without PEM/PSN, but there was overlap of their titre concentrations. In conclusion, aa 90-101 and aa 171-206 are the major epitopes with which all anti-Hu serum samples react, and aa 223-234, aa 235-252, and aa 354-373 are the minor epitopes with which only some anti-Hu serum samples react. The analyses suggested that the pattern of epitopic reactivity of the anti-Hu antibody on HuD was not a critical factor for the development or clinical features of PEM/PSN.
Diffuse midline gliomas are aggressive tumors centered in midline structures of the brain that mo... more Diffuse midline gliomas are aggressive tumors centered in midline structures of the brain that most commonly occur in children and young adults . They are genetically defined by the presence of K27M mutation in either the H3F3A or HIST1H3B genes, which encode the histone H3 variants H3.3 and H3.1, respectively . Given their poor prognosis, the 2016 WHO Classification includes "Diffuse midline glioma, H3 K27M-mutant" as a WHO grade IV entity, even in cases where only lower-grade histologic features are present . In all cases reported to date, H3 K27M mutation has been a clonal alteration in all regions of tumors assessed by sequencing, and immunostaining with antibodies against H3 K27M mutant protein has revealed uniform expression in all tumor cells ]. Thus, it has been
Twenty-three patients with malignant central nervous system tumors were treated with fludarabine ... more Twenty-three patients with malignant central nervous system tumors were treated with fludarabine phosphate (2-FAMP) on a 5 day bolus schedule. One brief partial response was observed in 20 malignant astrocytoma patients. 2FAMP as given in this protocol is inactive in previously treated patients with recurrent malignant astrocytomas.
Intravascular malignant lymphomatosis is a rare disease that is uniformly fatal when disseminated... more Intravascular malignant lymphomatosis is a rare disease that is uniformly fatal when disseminated. Chemotherapeutic and radiation therapy regimens have provided short-term amelioration of symptoms but have not affected overall survival. We describe a patient with diffuse neurological symptoms who responded transiently but dramatically to plasmapheresis. This marked response warrants further evaluation of this therapy in intravascular malignant lymphomatosis.
We obtained serial cranial computed tomography (CT) scans from 25 patients with documented leptom... more We obtained serial cranial computed tomography (CT) scans from 25 patients with documented leptomeningeal metastases in orders to correlate the course of clinical symptoms and cerebrospinal fluid abnormalities with the evolution of CT abnormalities. In almost one‐third of patients, relatively specific CT finding such as enhancement of the meninges, obliteration of cisterns or sulci, and hydrocephalus with transependymal edema preceded clinical symptoms. By the time patients became symptomatic, 10 of 25 (40%) had specific abnormalities, and 4 more became specifically abnormally with time. The first scan after cerebrospinal fluid tumor cells were discovered showed specific abnormalities in only 6 patient, but 7 more became specifically abnormal with time. Ventriculomegaly occurred in 18 of 25 patients (72%) and was associated with sulcal and/or cisternal obliteration in one‐half of the patients. In 4 patients sulcal and cisternal obliteration developed prior to ventricular enlargement. Multiple small, enhancing cortical nodules were detected prior to symptom onset and discovery of leptomeningeal tumor in 5 patients.
We studied 85 cancer patients with lumbosacral plexopathy and documented pelvic tumor by CT or bi... more We studied 85 cancer patients with lumbosacral plexopathy and documented pelvic tumor by CT or biopsy. Three clinical syndromes were delineated: lower (L4-S1), 51%; upper (L1-L4), 31%; and pan-plexopathy (L1-S3), 18%. Seventy percent of patients had the insidious onset of pelvic or radicular leg pain, followed weeks to months later by sensory symptoms and weakness. The quintet of leg pain, weakness, edema, rectal mass, and hydronephrosis suggests plexopathy due to cancer. CT showed pelvic tumor in 96%. On myelography, epidural extension, usually below the conus medullaris, was seen in 45%. With treatment, only 28% of patients had objective responses on CT and 17% on examination.
Current therapy for leptomeningeal metastases is predominantly palliative. In an effort to improv... more Current therapy for leptomeningeal metastases is predominantly palliative. In an effort to improve disease control and patient outcome, new strategies are being developed to target the cerebrospinal space. These include new intrathecal formulations of systemic chemotherapy as well as the development of radiolabeled immunoconjugates and antitumor antibodies. Furthermore, there is debate as to the optimal strategy of drug delivery for leptomeningeal tumor.
Neuro-Oncology RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-br... more Neuro-Oncology RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized,
age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tu... more age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with international sites opening imminently.
Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from... more Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology There is increasing interest in cognitive function as an outcome measure in brain-tumor clinical trials. Instruments used to measure cognition must be carefully selected to include requisite reliability, representative normative data, and population-specific validity. A 3-test cognitive battery has been recommended for this purpose 1,2 that includes the Trail Making Test Parts A and B (TMT-A and TMT-B), 3 the Hopkins Verbal Learning Test-Revised (HVLT-R), 4 and Controlled Oral Word Association (COWA). 5 This battery has been used in multiple completed and ongoing clinical trials. 6,7 The tests have well-established psychometric properties and clinical utility, 8 and use of the battery across
Background. There is an extensive literature highlighting the utility of blood-based liquid biops... more Background. There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring. Methods. The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF. Results. ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome. Conclusions. There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
2019 Background: There is a lack of biomarkers to predict outcome or monitor antiangiogenetic the... more 2019 Background: There is a lack of biomarkers to predict outcome or monitor antiangiogenetic therapies. We investigated whether SNPs or CECs could predict treatment efficacy/toxicity in rGBM pts treated with BEV/SOR. METHODS Blood was obtained for SNP and CEC analyses from rGBM pts enrolled in the Phase II trial N0776 (Galanis et al., ASCO. 2010). VEGF, VEGFR2, and HIF-1alpha SNPs were analyzed by Taqman or direct sequencing. Blood for CECs was collected at baseline, cycle 1 day 3, prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and at the time pt went off study. CECs were enumerated by flow cytometry. Unequal variance two-sample and paired t-tests were performed to compare values between pt outcome groups and serial measurements within a pt, respectively. RESULTS All 53 eligible pts had DNA available for SNP analyses. Significant differences (Chi-square or Fisher's exact, p<0.05) were observed between genotypes and either progression free survival at 6 months (PFS6) (VEGF rs1005230, rs1570360, rs699947 , rs833061 , VEGFR2 rs2071559) or grade 3+ adverse events (AEs) fatigue (VEGF rs10434, rs1005230, rs699947 , rs833061 ) or hypertension (rs1005230, rs699947 , rs833061 ). After correcting for multiple comparisons (method of Benjamini & Hochberg), none of the p-values remained significant (p>0.05). CEC analysis was performed on 49 of 53 pts. Median baseline CECs (bCEC) were 83.3 (mean: 136; range: 6.5-594) cells/mL; there was no correlation between bCEC values and PFS6 (p=0.19). Absolute differences between bCECs and other time points were not significant; yet, the CEC log2-fold change (FC) from bCECs decreased during treatment and reached significance at cycles 2, 7, 9, and 11 (0.03, 0.047, 0.005, and 0.005, respectively). Differences in log2-FC from bCECs to off study CECs (≤ 14 days) for pts off study for progression was higher compared to pts off study for other reasons (p=0.02, t-test). CONCLUSIONS Based upon this 53 pt cohort, further biomarker studies examining the utility of SNPs for predicting PFS and AEs and use of CEC monitoring for predicting pt progression in rGBM pts treated with BEV appear warranted.
Hematology-oncology Clinics of North America, Feb 1, 2022
Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade glioma... more Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.
2024 Background: The high response rates observed in recent trials of GBM patients (pts) treated ... more 2024 Background: The high response rates observed in recent trials of GBM patients (pts) treated with VEGF inhibitors, and the ongoing search for early endpoints which facilitate the efficient evaluation of new agents, have renewed the focus on tumor response as a potential surrogate for survival. Methods: In newly diagnosed (N=1,359) and recurrent (N=357) GBM pts treated prospectively on NCCTG phase II or III trials, we correlated best response (BR) category (responder or non-responder) with survival endpoints (PFS, TTP and OS). A responder was defined by standard NCCTG criteria as CR, PR or REGR (regression), and non-responder defined as STAB (stable) or PROG (progression) following treatment. Log-rank tests and Cox proportional hazard models were used to compare differences between survival and progression for each category. Landmark analyses at different cut-points were used for OS (newly diagnosed: 26 wks; recurrent: 9 and 13 wks) and TTP/PFS (newly diagnosed: 13 wks; recurrent: 6 and 9 wks). Results...
2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therape... more 2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported. No significant financial relationships to disclose.
Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and ang... more Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.
The purpose of this study is to determine prognostic factors in patients with high-grade recurren... more The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n 5 469, 1980-2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n 5 596, 1998-2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.
Supplementary Table 1 - PDF file 37K, Most Common (incidence &gt;10%) Grade 3/4 Toxicities pe... more Supplementary Table 1 - PDF file 37K, Most Common (incidence &gt;10%) Grade 3/4 Toxicities per Dose Group
expression are decreased with RG2833 treatment. We have also confirmed through Western blot that ... more expression are decreased with RG2833 treatment. We have also confirmed through Western blot that RG2833 treatment induces p16, p21, and p27 expression, which negatively regulate cell cycle progression, in multiple DIPG cell lines. RNAseq data showed that PI3K/mTOR pathway is upregulated in DIPG after RG2833 treatment. Paxalisib is a brain penetrant PI3K/mTOR inhibitor currently in clinical trials for DIPG. We hypothesized that RG2833 and paxalisib combination treatment would yield synergistic effects. RG2833 synergizes with paxalisib to suppress growth as measured by CellTiterBlue. ZIP synergy scores calculated by SynergyFinder were 10.5 for SUDIPG06 and 9.2 for HSJD007. Western blot demonstrated that combination treatment induced c-PARP and FOXO1 in the SUDIPG06 cell line, and decreased p-RB expression in HSJD007 cell line. Induction of c-PARP indicates increased apoptosis, and decreased p-RB expression indicates decreased cell proliferation. In vivo experiments evaluating the efficacy of combination treatment are in progress. Our data suggest the combination of RG2833 and paxalisib may be a promising treatment option for DIPG.
Journal of Neurology, Neurosurgery, and Psychiatry, 1999
Previous study has shown that the anti-Hu antibody titre of serum samples from patients with para... more Previous study has shown that the anti-Hu antibody titre of serum samples from patients with paraneoplastic encephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) was significantly higher than that from patients with small cell lung cancer without neurological disturbances (non-PEM/PSN). The aims of this study were (1) to identify the fine epitopes on HuD recognised by the anti-Hu antibody, (2) to determine if the pattern of epitopic reactivity diVered between antibodies from patients with and without PEM/PSN, and (3) to determine if the pattern of epitopic reactivity correlated with the clinical features. Recombinant full length HuD and nine deletion fragments were constructed and immunoreacted by western blot analysis with 14 anti-Hu serum samples from eight patients with PEM/PSN and six without PEM/PSN. All anti-Hu serum samples reacted with the deletion fragments containing amino acids (aa) 90-101 or aa 171-206. Some anti-Hu samples reacted with the deletion fragments containing aa 223-234, aa 235-252, or aa 354-373. There was no diVerence in the pattern of epitopic reactivity between patients with and without PEM/PSN. There was no correlation between the pattern of epitopic reactivity and the clinical features. The anti-Hu antibody titre from patients with PEM/ PSN was significantly higher than from patients without PEM/PSN, but there was overlap of their titre concentrations. In conclusion, aa 90-101 and aa 171-206 are the major epitopes with which all anti-Hu serum samples react, and aa 223-234, aa 235-252, and aa 354-373 are the minor epitopes with which only some anti-Hu serum samples react. The analyses suggested that the pattern of epitopic reactivity of the anti-Hu antibody on HuD was not a critical factor for the development or clinical features of PEM/PSN.
Diffuse midline gliomas are aggressive tumors centered in midline structures of the brain that mo... more Diffuse midline gliomas are aggressive tumors centered in midline structures of the brain that most commonly occur in children and young adults . They are genetically defined by the presence of K27M mutation in either the H3F3A or HIST1H3B genes, which encode the histone H3 variants H3.3 and H3.1, respectively . Given their poor prognosis, the 2016 WHO Classification includes "Diffuse midline glioma, H3 K27M-mutant" as a WHO grade IV entity, even in cases where only lower-grade histologic features are present . In all cases reported to date, H3 K27M mutation has been a clonal alteration in all regions of tumors assessed by sequencing, and immunostaining with antibodies against H3 K27M mutant protein has revealed uniform expression in all tumor cells ]. Thus, it has been
Twenty-three patients with malignant central nervous system tumors were treated with fludarabine ... more Twenty-three patients with malignant central nervous system tumors were treated with fludarabine phosphate (2-FAMP) on a 5 day bolus schedule. One brief partial response was observed in 20 malignant astrocytoma patients. 2FAMP as given in this protocol is inactive in previously treated patients with recurrent malignant astrocytomas.
Intravascular malignant lymphomatosis is a rare disease that is uniformly fatal when disseminated... more Intravascular malignant lymphomatosis is a rare disease that is uniformly fatal when disseminated. Chemotherapeutic and radiation therapy regimens have provided short-term amelioration of symptoms but have not affected overall survival. We describe a patient with diffuse neurological symptoms who responded transiently but dramatically to plasmapheresis. This marked response warrants further evaluation of this therapy in intravascular malignant lymphomatosis.
We obtained serial cranial computed tomography (CT) scans from 25 patients with documented leptom... more We obtained serial cranial computed tomography (CT) scans from 25 patients with documented leptomeningeal metastases in orders to correlate the course of clinical symptoms and cerebrospinal fluid abnormalities with the evolution of CT abnormalities. In almost one‐third of patients, relatively specific CT finding such as enhancement of the meninges, obliteration of cisterns or sulci, and hydrocephalus with transependymal edema preceded clinical symptoms. By the time patients became symptomatic, 10 of 25 (40%) had specific abnormalities, and 4 more became specifically abnormally with time. The first scan after cerebrospinal fluid tumor cells were discovered showed specific abnormalities in only 6 patient, but 7 more became specifically abnormal with time. Ventriculomegaly occurred in 18 of 25 patients (72%) and was associated with sulcal and/or cisternal obliteration in one‐half of the patients. In 4 patients sulcal and cisternal obliteration developed prior to ventricular enlargement. Multiple small, enhancing cortical nodules were detected prior to symptom onset and discovery of leptomeningeal tumor in 5 patients.
We studied 85 cancer patients with lumbosacral plexopathy and documented pelvic tumor by CT or bi... more We studied 85 cancer patients with lumbosacral plexopathy and documented pelvic tumor by CT or biopsy. Three clinical syndromes were delineated: lower (L4-S1), 51%; upper (L1-L4), 31%; and pan-plexopathy (L1-S3), 18%. Seventy percent of patients had the insidious onset of pelvic or radicular leg pain, followed weeks to months later by sensory symptoms and weakness. The quintet of leg pain, weakness, edema, rectal mass, and hydronephrosis suggests plexopathy due to cancer. CT showed pelvic tumor in 96%. On myelography, epidural extension, usually below the conus medullaris, was seen in 45%. With treatment, only 28% of patients had objective responses on CT and 17% on examination.
Current therapy for leptomeningeal metastases is predominantly palliative. In an effort to improv... more Current therapy for leptomeningeal metastases is predominantly palliative. In an effort to improve disease control and patient outcome, new strategies are being developed to target the cerebrospinal space. These include new intrathecal formulations of systemic chemotherapy as well as the development of radiolabeled immunoconjugates and antitumor antibodies. Furthermore, there is debate as to the optimal strategy of drug delivery for leptomeningeal tumor.
Neuro-Oncology RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-br... more Neuro-Oncology RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized,
age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tu... more age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with international sites opening imminently.
Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from... more Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology There is increasing interest in cognitive function as an outcome measure in brain-tumor clinical trials. Instruments used to measure cognition must be carefully selected to include requisite reliability, representative normative data, and population-specific validity. A 3-test cognitive battery has been recommended for this purpose 1,2 that includes the Trail Making Test Parts A and B (TMT-A and TMT-B), 3 the Hopkins Verbal Learning Test-Revised (HVLT-R), 4 and Controlled Oral Word Association (COWA). 5 This battery has been used in multiple completed and ongoing clinical trials. 6,7 The tests have well-established psychometric properties and clinical utility, 8 and use of the battery across
Background. There is an extensive literature highlighting the utility of blood-based liquid biops... more Background. There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring. Methods. The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF. Results. ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome. Conclusions. There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
2019 Background: There is a lack of biomarkers to predict outcome or monitor antiangiogenetic the... more 2019 Background: There is a lack of biomarkers to predict outcome or monitor antiangiogenetic therapies. We investigated whether SNPs or CECs could predict treatment efficacy/toxicity in rGBM pts treated with BEV/SOR. METHODS Blood was obtained for SNP and CEC analyses from rGBM pts enrolled in the Phase II trial N0776 (Galanis et al., ASCO. 2010). VEGF, VEGFR2, and HIF-1alpha SNPs were analyzed by Taqman or direct sequencing. Blood for CECs was collected at baseline, cycle 1 day 3, prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and at the time pt went off study. CECs were enumerated by flow cytometry. Unequal variance two-sample and paired t-tests were performed to compare values between pt outcome groups and serial measurements within a pt, respectively. RESULTS All 53 eligible pts had DNA available for SNP analyses. Significant differences (Chi-square or Fisher's exact, p<0.05) were observed between genotypes and either progression free survival at 6 months (PFS6) (VEGF rs1005230, rs1570360, rs699947 , rs833061 , VEGFR2 rs2071559) or grade 3+ adverse events (AEs) fatigue (VEGF rs10434, rs1005230, rs699947 , rs833061 ) or hypertension (rs1005230, rs699947 , rs833061 ). After correcting for multiple comparisons (method of Benjamini & Hochberg), none of the p-values remained significant (p>0.05). CEC analysis was performed on 49 of 53 pts. Median baseline CECs (bCEC) were 83.3 (mean: 136; range: 6.5-594) cells/mL; there was no correlation between bCEC values and PFS6 (p=0.19). Absolute differences between bCECs and other time points were not significant; yet, the CEC log2-fold change (FC) from bCECs decreased during treatment and reached significance at cycles 2, 7, 9, and 11 (0.03, 0.047, 0.005, and 0.005, respectively). Differences in log2-FC from bCECs to off study CECs (≤ 14 days) for pts off study for progression was higher compared to pts off study for other reasons (p=0.02, t-test). CONCLUSIONS Based upon this 53 pt cohort, further biomarker studies examining the utility of SNPs for predicting PFS and AEs and use of CEC monitoring for predicting pt progression in rGBM pts treated with BEV appear warranted.
Hematology-oncology Clinics of North America, Feb 1, 2022
Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade glioma... more Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.
2024 Background: The high response rates observed in recent trials of GBM patients (pts) treated ... more 2024 Background: The high response rates observed in recent trials of GBM patients (pts) treated with VEGF inhibitors, and the ongoing search for early endpoints which facilitate the efficient evaluation of new agents, have renewed the focus on tumor response as a potential surrogate for survival. Methods: In newly diagnosed (N=1,359) and recurrent (N=357) GBM pts treated prospectively on NCCTG phase II or III trials, we correlated best response (BR) category (responder or non-responder) with survival endpoints (PFS, TTP and OS). A responder was defined by standard NCCTG criteria as CR, PR or REGR (regression), and non-responder defined as STAB (stable) or PROG (progression) following treatment. Log-rank tests and Cox proportional hazard models were used to compare differences between survival and progression for each category. Landmark analyses at different cut-points were used for OS (newly diagnosed: 26 wks; recurrent: 9 and 13 wks) and TTP/PFS (newly diagnosed: 13 wks; recurrent: 6 and 9 wks). Results...
2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therape... more 2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported. No significant financial relationships to disclose.
Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and ang... more Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.
The purpose of this study is to determine prognostic factors in patients with high-grade recurren... more The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n 5 469, 1980-2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n 5 596, 1998-2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.
Supplementary Table 1 - PDF file 37K, Most Common (incidence &gt;10%) Grade 3/4 Toxicities pe... more Supplementary Table 1 - PDF file 37K, Most Common (incidence &gt;10%) Grade 3/4 Toxicities per Dose Group
expression are decreased with RG2833 treatment. We have also confirmed through Western blot that ... more expression are decreased with RG2833 treatment. We have also confirmed through Western blot that RG2833 treatment induces p16, p21, and p27 expression, which negatively regulate cell cycle progression, in multiple DIPG cell lines. RNAseq data showed that PI3K/mTOR pathway is upregulated in DIPG after RG2833 treatment. Paxalisib is a brain penetrant PI3K/mTOR inhibitor currently in clinical trials for DIPG. We hypothesized that RG2833 and paxalisib combination treatment would yield synergistic effects. RG2833 synergizes with paxalisib to suppress growth as measured by CellTiterBlue. ZIP synergy scores calculated by SynergyFinder were 10.5 for SUDIPG06 and 9.2 for HSJD007. Western blot demonstrated that combination treatment induced c-PARP and FOXO1 in the SUDIPG06 cell line, and decreased p-RB expression in HSJD007 cell line. Induction of c-PARP indicates increased apoptosis, and decreased p-RB expression indicates decreased cell proliferation. In vivo experiments evaluating the efficacy of combination treatment are in progress. Our data suggest the combination of RG2833 and paxalisib may be a promising treatment option for DIPG.
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Papers by Kurt Jaeckle