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Negative Impact of COVID-19 Upon Primary Brain Tumor Care [Case Report]

Sarwan, Gurpreet; Mubarak, Taufif; Puello, Persis; Brisman, Michael; Grewal, Jai
Meningiomas are the most common primary central nervous system tumors, as they can account for up to one-third of all primary brain tumors. Most meningiomas are benign, although up to one-fourth of such tumors are classified as atypical or malignant. Atypical and malignant meningiomas are associated with an increased risk of local recurrence and decreased overall survival. Our patient is a 57-year-old male with a history of recurrent malignant meningioma, with metastasis to the liver. He underwent multiple surgical interventions, radiation treatments, and systemic therapies for a malignant meningioma, ultimately requiring transfer to hospice care. Not only did a positive novel coronavirus (COVID-19) infection delay his ability to receive radiation therapy, the infection in itself may have had an impact on the course of care for this patient. Treatment targeting the patient's COVID-19 infection may have suppressed the immune system, and as a result, caused the progression of metastatic disease. Palliative care was needed in the setting of losing all functional goals for quality of life due to malignant neoplasm.
PMCID:8496556
PMID: 34660010
ISSN: 2168-8184
CID: 5023322

Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial

Ballo, Matthew T; Urman, Noa; Lavy-Shahaf, Gitit; Grewal, Jai; Bomzon, Ze'ev; Toms, Steven
INTRODUCTION/BACKGROUND:Tumor Treating Fields (TTFields) are approved for glioblastoma based on improved overall survival (OS) and progression-free survival (PFS) in the phase 3 EF-14 trial of newly diagnosed glioblastoma. To test the hypothesis that increasing TTFields dose at the tumor site improves patient outcomes, we performed a simulation-based study investigating the association between TTFields dose and survival (OS and PFS) in patients treated with TTFields in EF-14. METHODS AND MATERIALS/METHODS:EF-14 patient cases (N = 340) were included. Realistic head models were derived from T1-contrast images captured at baseline. The transducer array layout on each patient was obtained from EF-14 records; average compliance (fraction of time patient was on active treatment) and average electrical current delivered to the patient were derived from log files of the TTFields devices used by patients. TTFields intensity distributions and power densities were calculated using the finite element method. Local minimum dose density (LMiDD) was defined as the product of TTFields intensity, tissue-specific conductivities, and patient compliance. The average LMiDD within a tumor bed comprising the gross tumor volume and the 3-mm-wide peritumoral boundary zone was calculated. RESULTS:: OS was 25.2 versus 20.4 months (P = .003, hazard ratio [HR] = 0.611) and PFS was 8.5 versus 6.7 months (P = .02, HR = 0.699). The median OS and PFS were longer when the average TTFields intensity was >1.06 V/cm: OS was 24.3 versus 21.6 months (P = .03, HR = 0.705) and PFS was 8.1 versus 7.9 months (P = .03, HR = 0.721). CONCLUSIONS:In this study we present the first reported analysis demonstrating patient-level dose responses to TTFields. We provide a rigorous definition for TTFields dose and set a conceptual framework for future work on TTFields dosimetry and treatment planning.
PMID: 31026557
ISSN: 1879-355x
CID: 4096982

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma [Correction]

Liau, Linda M; Ashkan, Keyoumars; Tran, David D; Campian, Jian L; Trusheim, John E; Cobbs, Charles S; Heth, Jason A; Salacz, Michael; Taylor, Sarah; D'Andre, Stacy D; Iwamoto, Fabio M; Dropcho, Edward J; Moshel, Yaron A; Walter, Kevin A; Pillainayagam, Clement P; Aiken, Robert; Chaudhary, Rekha; Goldlust, Samuel A; Bota, Daniela A; Duic, Paul; Grewal, Jai; Elinzano, Heinrich; Toms, Steven A; Lillehei, Kevin O; Mikkelsen, Tom; Walbert, Tobias; Abram, Steven R; Brenner, Andrew J; Brem, Steven; Ewend, Matthew G; Khagi, Simon; Portnow, Jana; Kim, Lyndon J; Loudon, William G; Thompson, Reid C; Avigan, David E; Fink, Karen L; Geoffroy, Francois J; Lindhorst, Scott; Lutzky, Jose; Sloan, Andrew E; Schackert, Gabriele; Krex, Dietmar; Meisel, Hans-Jorg; Wu, Julian; Davis, Raphael P; Duma, Christopher; Etame, Arnold B; Mathieu, David; Kesari, Santosh; Piccioni, David; Westphal, Manfred; Baskin, David S; New, Pamela Z; Lacroix, Michel; May, Sven-Axel; Pluard, Timothy J; Tse, Victor; Green, Richard M; Villano, John L; Pearlman, Michael; Petrecca, Kevin; Schulder, Michael; Taylor, Lynne P; Maida, Anthony E; Prins, Robert M; Cloughesy, Timothy F; Mulholland, Paul; Bosch, Marnix L
Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
PMCID:6026340
PMID: 29958537
ISSN: 1479-5876
CID: 3196472

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

Liau, Linda M; Ashkan, Keyoumars; Tran, David D; Campian, Jian L; Trusheim, John E; Cobbs, Charles S; Heth, Jason A; Salacz, Michael; Taylor, Sarah; D'Andre, Stacy D; Iwamoto, Fabio M; Dropcho, Edward J; Moshel, Yaron A; Walter, Kevin A; Pillainayagam, Clement P; Aiken, Robert; Chaudhary, Rekha; Goldlust, Samuel A; Bota, Daniela A; Duic, Paul; Grewal, Jai; Elinzano, Heinrich; Toms, Steven A; Lillehei, Kevin O; Mikkelsen, Tom; Walpert, Tobias; Abram, Steven R; Brenner, Andrew J; Brem, Steven; Ewend, Matthew G; Khagi, Simon; Portnow, Jana; Kim, Lyndon J; Loudon, William G; Thompson, Reid C; Avigan, David E; Fink, Karen L; Geoffroy, Francois J; Lindhorst, Scott; Lutzky, Jose; Sloan, Andrew E; Schackert, Gabriele; Krex, Dietmar; Meisel, Hans-Jorg; Wu, Julian; Davis, Raphael P; Duma, Christopher; Etame, Arnold B; Mathieu, David; Kesari, Santosh; Piccioni, David; Westphal, Manfred; Baskin, David S; New, Pamela Z; Lacroix, Michel; May, Sven-Axel; Pluard, Timothy J; Tse, Victor; Green, Richard M; Villano, John L; Pearlman, Michael; Petrecca, Kevin; Schulder, Michael; Taylor, Lynne P; Maida, Anthony E; Prins, Robert M; Cloughesy, Timothy F; Mulholland, Paul; Bosch, Marnix L
BACKGROUND:-L) to standard therapy for newly diagnosed glioblastoma. METHODS:After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS:For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS:Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.
PMCID:5975654
PMID: 29843811
ISSN: 1479-5876
CID: 3156362

Longitudinal sequential biventricular assessment in adults with transposition of the great arteries and relationship with adverse outcomes

Riahi, M; Claman, A; Kiess, M; Orgad, M; Human, D; Chakrabarti, S; Leipsic, J; Grewal, J
BACKGROUND:In a cohort of congenitally corrected transposition of the great arteries (cc-TGA) and transposition of the great arteries after atrial switch procedure (d-TGA) the study objectives were: 1) to assess the change of quantitative systemic right ventricle (sRV) parameters over time and; 2) to examine the relationship of quantitative sRV parameters with adverse clinical outcomes. METHODS AND RESULTS/RESULTS:Single-center cohort study that included 49 (39%) cc-TGA and 76 (61%) d-TGA patients >18years who had at least one MUGA sRV assessment, 18/39 had more than one respectively. The primary clinical endpoint was all-cause mortality, heart transplantation and/or heart failure hospitalization. At a median clinical follow-up of 7years following the first MUGA, the primary endpoint occurred more often in cc-TGA versus d-TGA patients (18 (36.7%) vs. 9 (11.8%), p=0.03). Median time between the MUGA assessments was 5.8 (cc-TGA) and 4.9years (d-TGA). At last MUGA follow-up: 6 (33%) cc-TGA/14 (36%) d-TGA patients showed a significant decline in sRVEF (>5%); 6 (33%) cc-TGA/17 (44%) d-TGA patients had a significant increase in sRVEDVi; and 7 (39%) cc-TGA/19 (49%) PA-TGA patients had a significant increase in sRVESVi. Baseline sRV parameters were not associated with the primary end point or sRV changes over time. CONCLUSIONS:An important proportion of both patient cohorts demonstrated a significant change in sRV parameters over time and these are likely related to multiple factors that vary between individuals given population heterogeneity. The TGA patients have distinct clinical trajectories with increased adverse heart failure outcomes in the cc-TGA population and sRV parameters were not related to adverse heart failure events in either group.
PMID: 28818352
ISSN: 1874-1754
CID: 5273172

A randomized, double-blind, controlled phase IIb study of the safety and efficacy of ICT-107 in newly diagnosed patients with glioblastoma multiforme following resection and chemoradiation. [Meeting Abstract]

Hawkins, Elma S.; Aiken, Robert; Chandler, James; Fink, Karen L.; Glantz, Michael J.; Grewal, Jai; Gruber, Michael L.; Kesari, Santosh; Landolfi, Joseph C.; LaRocca, Renato V.; Lesser, Glenn Jay; Markert, James; Mayer, Tina M.; O'Rourke, Donald; Peereboom, David M.; Phuphanich, Surasak; Schiff, David; Sloan, Andrew E.; Stea, Baldassarre; Zhu, Jay-Jiguang
ISI:000318009801430
ISSN: 0732-183x
CID: 3484382

Novel approaches to treating leptomeningeal metastases

Grewal, Jai; Saria, Marlon Garzo; Kesari, Santosh
Leptomeningeal metastasis is a devastating complication of the central nervous system in patients with late-stage solid or hematological cancers. Leptomeningeal metastasis results from the multifocal seeding of the leptomeninges by malignant cancer cells. Although central nervous system metastasis usually presents in patients with widely disseminated and progressive late-stage cancer, malignant cells may spread to the cerebrospinal fluid during earlier disease stages in particularly aggressive cancers. Treatment of leptomeningeal metastasis is largely palliative but will often provide stabilization and protection from further neurological deterioration and improve quality of life. There is a need to raise awareness of the impact of leptomeningeal metastases on cancer patients and its known and putative biological basis. Novel diagnostic approaches include identification of biomarkers that may stratify the risk for developing leptomeningeal metastasis. Current therapies can be used more effectively while waiting for advanced treatments to be developed.
PMID: 21874597
ISSN: 1573-7373
CID: 3484452

Eltrombopag for radiation-induced thrombocytopenia in a glioblastoma patient [Letter]

Duic, J Paul; Grewal, Jai; McConie, Kerry; Staszewski, Harry; Haas, Jonathan; Kesari, Santosh
PMID: 21833801
ISSN: 1573-7373
CID: 3484442

Neoplastic meningitis resulting from hematological malignancies: pharmacokinetic considerations and maximizing outcome

Grewal, Jai; Saria, Marlon; Grewal, Harpreet K; Kesari, Santosh
Neoplastic meningitis, also known as leptomeningeal metastases, is a complication of various types of cancer that occurs when tumor cells enter the cerebrospinal fluid (CSF), travel along CSF pathways and grow. Treatment options include drug delivery directly into the CNS or systemic administration for targeted action in the CNS. CNS drug delivery is limited by the blood-brain barrier and the blood-CSF barrier. It may be possible to partially overcome this by using high-dose systemic therapy; however, this is done at the possible expense of increased systemic toxicity. Intra-CSF drug delivery bypasses the blood-brain barrier and allows direct access of the chemotherapeutic agent to the CSF. Because neoplastic meningitis occurs in an increasingly large percentage of all cancer patients, it is imperative to optimize drug delivery to the CSF and meninges. Both the pharmacokinetic profile of the chemotherapeutic agent and the site of administration influence therapeutic efficacy. Achieving prolonged therapeutic cytotoxic drug concentrations and even distribution in the CSF will improve efficacy. In this article we summarize data on the efficacy, safety and outcome of high-dose systemic and intra-CSF treatments.
PMID: 22396850
ISSN: 2041-6792
CID: 3484472

Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system

Levin, Victor A; Bidaut, Luc; Hou, Ping; Kumar, Ashok J; Wefel, Jeffrey S; Bekele, B Nebiyou; Grewal, Jai; Prabhu, Sujit; Loghin, Monica; Gilbert, Mark R; Jackson, Edward F
PURPOSE/OBJECTIVE:To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS/METHODS:A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS:The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION/CONCLUSIONS:The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.
PMID: 20399573
ISSN: 1879-355x
CID: 3484462