Publications by authors named "Daniel Markowitz"

9 Publications

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Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.

Nat Med 2021 Sep 14. Epub 2021 Sep 14.

Center for Neuroinflammation and Experimental Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.
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http://dx.doi.org/10.1038/s41591-021-01507-2DOI Listing
September 2021

Identifying breast cancer recurrence histories via patient-reported outcomes.

J Cancer Surviv 2021 Apr 14. Epub 2021 Apr 14.

Fred Hutchinson Cancer Research Center, Public Health Sciences, Biostatistics Program, 1100 Fairview Avenue North, M2-B500, Seattle, WA, 98109, USA.

Purpose: To test accuracy of patient self-report of breast cancer recurrence for enhancing standard population-based cancer registries that do not routinely collect cancer recurrence data despite the importance of this outcome.

Methods: Potential research subjects were identified in the Breast Cancer Research Database (BCRD) of the Swedish Cancer Institute (SCI). The BCRD has collected data within 45 days of each medical encounter on new primary breast cancer patients receiving all or part of their initial care at SCI. Females diagnosed with a new primary breast cancer 2004-2016, Stages I-III, and alive at the time of study initiation (2018) were identified. Recurrent breast cancer patients were matched 1:1 to surviving non-recurrent patients by patient age, date of diagnosis, and single or multiple primary tumors. Consented research subjects were surveyed about their initial and subsequent diagnostic, therapeutic, and recurrent events. PRO survey responses were compared with BCRD information for each individual participant. Discrepancies were reviewed in medical records.

Results: A matched sample of 88 recurrent and 88 non-recurrent patients were used in analyses. Respondents correctly identified the date of diagnosis of first primary breast cancer within 1 year 94% (165/176). Recurrence was reported by 97% (85/88) of recurrent patients. No recurrence was reported by 100% (88/88) of non-recurrent patients. Recurrence date within 1 year was correctly identified in 79% (67/85). Recurrence site was correctly identified in 82% (70/85). Medical record review of survey-registry discrepancies led to BCRD corrections in 4.5% (8/176) of cases.

Implications For Cancer Survivors: Breast cancer patients can accurately report their disease characteristics, treatments, and recurrence history. Patient-reported information would enhance cancer registry data.
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http://dx.doi.org/10.1007/s11764-021-01033-7DOI Listing
April 2021

Correction: Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

JMIR Cancer 2020 Sep 24;6(2):e23821. Epub 2020 Sep 24.

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

[This corrects the article DOI: 10.2196/18143.].
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http://dx.doi.org/10.2196/23821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545323PMC
September 2020

Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

JMIR Cancer 2020 Aug 17;6(2):e18143. Epub 2020 Aug 17.

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: There is a need for automated approaches to incorporate information on cancer recurrence events into population-based cancer registries.

Objective: The aim of this study is to determine the accuracy of a novel data mining algorithm to extract information from linked registry and medical claims data on the occurrence and timing of second breast cancer events (SBCE).

Methods: We used supervised data from 3092 stage I and II breast cancer cases (with 394 recurrences), diagnosed between 1993 and 2006 inclusive, of patients at Kaiser Permanente Washington and cases in the Puget Sound Cancer Surveillance System. Our goal was to classify each month after primary treatment as pre- versus post-SBCE. The prediction feature set for a given month consisted of registry variables on disease and patient characteristics related to the primary breast cancer event, as well as features based on monthly counts of diagnosis and procedure codes for the current, prior, and future months. A month was classified as post-SBCE if the predicted probability exceeded a probability threshold (PT); the predicted time of the SBCE was taken to be the month of maximum increase in the predicted probability between adjacent months.

Results: The Kaplan-Meier net probability of SBCE was 0.25 at 14 years. The month-level receiver operating characteristic curve on test data (20% of the data set) had an area under the curve of 0.986. The person-level predictions (at a monthly PT of 0.5) had a sensitivity of 0.89, a specificity of 0.98, a positive predictive value of 0.85, and a negative predictive value of 0.98. The corresponding median difference between the observed and predicted months of recurrence was 0 and the mean difference was 0.04 months.

Conclusions: Data mining of medical claims holds promise for the streamlining of cancer registry operations to feasibly collect information about second breast cancer events.
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http://dx.doi.org/10.2196/18143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459434PMC
August 2020

Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism.

Onco Targets Ther 2017 24;10:5633-5642. Epub 2017 Nov 24.

Hofstra Northwell School of Medicine, Hempstead.

Background: The cytotoxic effects of microtubule-targeting agents (MTAs) are often attributed to targeted effects on mitotic cells. In clinical practice, MTAs are combined with DNA-damaging agents such as ionizing radiation (IR) with the rationale that mitotic cells are highly sensitive to DNA damage. In contrast, recent studies suggest that MTAs synergize with IR by interfering with the trafficking of DNA damage response (DDR) proteins during interphase. These studies, however, have yet to demonstrate the functional consequences of interfering with interphase microtubules in the presence of IR. To address this, we combined IR with an established MTA, mebendazole (MBZ), to treat glioma cells exclusively during interphase.

Materials And Methods: To test whether MTAs can sensitize interphase cells to IR, we treated GL261 and GBM14 glioma cells with MBZ during 3-9 hours post IR (when the mitotic index was 0%). Cell viability was measured using a WST-1 assay, and radiosensitization was quantified using the dose enhancement factor (DEF). The effect of MBZ on the DDR was studied via Western blot analysis of H2AX phosphorylation. To examine the effects of MTAs on intracellular transport of DDR proteins, Nbs1 and Chk2, cytoplasmic and nuclear fractionation studies were conducted following treatment of glioma cells with MBZ.

Results: Treatment with MBZ sensitized interphase cells to the effects of IR, with a maximal DEF of 1.34 in GL261 cells and 1.69 in GBM14 cells. Treatment of interphase cells with MBZ led to more sustained γH2AX levels post IR, indicating a delay in the DDR. Exposure of glioma cells to MBZ resulted in a dose-dependent sequestration of Chk2 and Nbs1 in the cytoplasm.

Conclusion: This study demonstrates that MBZ can sensitize cancer cells to IR independently of the induction of mitotic arrest. In addition, evidence is provided supporting the hypothesis that MTA-induced radiosensitization is mediated by inhibiting DDR protein accumulation into the nucleus.
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http://dx.doi.org/10.2147/OTT.S143096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703169PMC
November 2017

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia.

JCI Insight 2017 10 19;2(20). Epub 2017 Oct 19.

Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York, USA.

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.
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http://dx.doi.org/10.1172/jci.insight.96411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846717PMC
October 2017

Compact Intraoperative MRI: Stereotactic Accuracy and Future Directions.

Stereotact Funct Neurosurg 2017 15;95(3):197-204. Epub 2017 Jun 15.

Department of Neurosurgery, Northwell Health, Manhasset, NY, USA.

Background: Intraoperative imaging must supply data that can be used for accurate stereotactic navigation. This information should be at least as accurate as that acquired from diagnostic imagers.

Objectives: The aim of this study was to compare the stereotactic accuracy of an updated compact intraoperative MRI (iMRI) device based on a 0.15-T magnet to standard surgical navigation on a 1.5-T diagnostic scan MRI and to navigation with an earlier model of the same system.

Methods: The accuracy of each system was assessed using a water-filled phantom model of the brain. Data collected with the new system were compared to those obtained in a previous study assessing the older system. The accuracy of the new iMRI was measured against standard surgical navigation on a 1.5-T MRI using T1-weighted (W) images.

Results: The mean error with the iMRI using T1W images was lower than that based on images from the 1.5-T scan (1.24 vs. 2.43 mm). T2W images from the newer iMRI yielded a lower navigation error than those acquired with the prior model (1.28 vs. 3.15 mm).

Conclusions: Improvements in magnet design can yield progressive increases in accuracy, validating the concept of compact, low-field iMRI. Avoiding the need for registration between image and surgical space increases navigation accuracy.
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http://dx.doi.org/10.1159/000475673DOI Listing
September 2017

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors.

Mol Med 2017 04 5;23:50-56. Epub 2017 Apr 5.

Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.
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http://dx.doi.org/10.2119/molmed.2017.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403762PMC
April 2017

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.

Mol Cancer Ther 2016 08 20;15(8):1799-808. Epub 2016 May 20.

Center of Oncology and Cell Biology, Feinstein Institute, Manhasset, New York.

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0849DOI Listing
August 2016
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