Publications by authors named "Chandan Guha"

173 Publications

Using Statistical Measures and Density Maps Generated From Chest Computed Tomography Scans to Identify and Monitor COVID-19 Cases in Radiation Oncology Rapidly.

Cureus 2021 Aug 25;13(8):e17432. Epub 2021 Aug 25.

Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, USA.

Objectives This study aimed to evaluate quantitative and qualitative screening measures for anomalous computed tomography (CT) scans in cancer patients with potential coronavirus disease 2019 (COVID-19) as an automated detection tool in a radiation oncology treatment setting. Methods We identified a non-COVID-19 cohort and patients with suspected COVID-19 with chest CT scans from February 1, 2020 to June 30, 2020. Lungs were segmented, and a mean normal Hounsfield Unit (HU) histogram was generated for the non-COVID-19 CT scans; these were used to define thresholds for designating the COVID-19-suspected histograms as normal or abnormal. Statistical measures were computed and compared to the threshold levels, and density maps were generated to examine the difference between lungs with and without COVID-19 qualitatively. Results The non-COVID-19 cohort consisted of 70 patients with 70 CT scans, and the cohort of suspected COVID-19 patients consisted of 59 patients with 80 CT scans. Sixty-two patients were positive for COVID-19. The mean HUs and skewness of the intensity histogram discriminated between COVID-19 positive and negative cases, with an area under the curve of 0.948 for positive and 0.944 for negative cases. Skewness correctly identified 57 of 62 positive cases, whereas mean HUs correctly identified 17 of 18 negative cases. Density maps allowed for visualization of the temporal evolution of COVID-19 disease. Conclusions The statistical measures and density maps evaluated here could be employed in an automated screening algorithm for COVID-19 infection. The accuracy is high enough for a simple and rapid screening tool for early identification of suspected infection in patients treated with chemotherapy and radiation therapy already receiving CT scans as part of clinical care. This screening tool could also identify other infections that present critical risks for patients undergoing chemotherapy and radiation therapy, such as pneumonitis.
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http://dx.doi.org/10.7759/cureus.17432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460489PMC
August 2021

Extracellular Vesicles for the Treatment of Radiation Injuries.

Front Pharmacol 2021 18;12:662437. Epub 2021 May 18.

Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States.

Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.
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http://dx.doi.org/10.3389/fphar.2021.662437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167064PMC
May 2021

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies.

Front Cell Dev Biol 2021 22;9:650772. Epub 2021 Apr 22.

R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.

Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.
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http://dx.doi.org/10.3389/fcell.2021.650772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100510PMC
April 2021

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

J Immunother Cancer 2021 04;9(4)

Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.
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http://dx.doi.org/10.1136/jitc-2020-002038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031689PMC
April 2021

Using CT-guided stereotactic prostate radiation therapy (CT-SPRT) to assess sustained murine prostate ablation.

Sci Rep 2021 03 22;11(1):6571. Epub 2021 Mar 22.

Department of Cell Biology, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY, 10461, USA.

The prostate is a hormone-responsive organ where testicular androgens drive the proliferation and survival of prostatic cells, ensuring the development and functioning of this gland throughout life. Androgen deprivation therapy leads to apoptosis of prostatic cells and organ regression, and is a cornerstone of prostate cancer and benign prostatic hypertrophy treatment. For several decades, androgen deprivation has been used as an adjuvant to external beam radiotherapy, however, emerging data suggests that the low rates of epithelial proliferation in the castrated prostate imparts radio-resistance. As proliferating cells exhibit increased sensitivity to radiation, we hypothesized that short bursts of synchronized epithelial proliferation, which can be achieved by exogeneous testosterone supplementation prior to targeted high-dose radiation, would maximize sustained prostate ablation, while minimizing damage to surrounding tissues. To test this hypothesis, we designed a novel computed-tomography (CT)-guided stereotactic prostate radiation therapy (CT-SPRT) technique to deliver a single high-dose 25 Gy fraction of X-ray radiation. Sustained prostatic cell ablation was assessed post CT-SPRT by measuring prostate weight, epithelial cell number, and relative contributions of luminal and basal epithelial populations in control and testosterone-pretreated glands. CT-SPRT was safely delivered with no observed damage to surrounding rectal and bladder tissues. Importantly, castrated mice that received a pulse of testosterone to induce synchronous cell proliferation prior to CT-SPRT exhibited significant sustained gland ablation compared to control mice. These results provide new insights in stereotactic radiotherapy sensitivity to maximize prostatic cell ablation and improve our understanding of prostate gland regeneration that can potentially lead to improved non-invasive therapies for benign prostatic hypertrophy and prostate cancer.
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http://dx.doi.org/10.1038/s41598-021-86067-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985301PMC
March 2021

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Int J Radiat Oncol Biol Phys 2021 08 25;110(5):1325-1340. Epub 2021 Feb 25.

Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496269PMC
August 2021

Carbon ion triggered immunogenic necroptosis of nasopharyngeal carcinoma cells involving necroptotic inhibitor BCL-x.

J Cancer 2021 1;12(5):1520-1530. Epub 2021 Jan 1.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.

To explore the potential and mechanisms of necroptosis, a form of immunogenic cell death, induced by carbon ion as compared to photon beams in established photon resistant- (PR-) and sensitive nasopharyngeal carcinoma (NPC) cells. MLKL is considered a central executor of necroptosis and phosphorylation of MLKL (p-MLKL) was a critical event of necroptosis. The clonogenic survival and DNA microarray demonstrated that after repeated photon irradiation, radiosensitive NPC cells became apoptosis-resistant but could be effectively inhibited by carbon ion irradiation. The relative biologic effectiveness (RBE) at D10 and D37 were 2.15 and 2.78 for PR-NPC cells. Carbon ion induced delayed DNA damage repair, cell cycle arrest, cytogenetic damage, morphological change and cell necrosis, indicating the possibility of necroptosis in both PR- and sensitive NPC cell types. The lower expression of necroptotic inhibitors (caspase-8 and Bcl-x) and higher level of MLKL in PR-NPC cells showed it was relatively more predisposed to necroptosis compared to the sensitive cells. Subsequent experiments demonstrated the significant upregulation of p-MLKL in the PR-NPC cells treated by carbon ion (4 Gy) compared with photon irradiation at both physical (4 Gy) and RBE (10 Gy) doses (P≤0.0001). Moreover, carbon ion induced a robust (up to 28 folds) p-MLKL in the PR-NPC cells as well as sensitive cells (up to 6-fold) coupled with a lower level of BCL-x expression and increased GM-CSF implicated in resculputure of immune system. These results suggested that carbon ion could induce necroptosis of NPC cells, especially in PR-NPC cells, and its mechanisms involve BCL-x.
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http://dx.doi.org/10.7150/jca.46316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847655PMC
January 2021

Association of Addition of Ablative Therapy Following Transarterial Chemoembolization With Survival Rates in Patients With Hepatocellular Carcinoma.

JAMA Netw Open 2020 11 2;3(11):e2023942. Epub 2020 Nov 2.

Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York.

Importance: Hepatocellular carcinoma (HCC) is a heterogeneous disease with many available treatment modalities. Transarterial chemoembolization (TACE) is a valuable treatment modality for HCC lesions. This article seeks to evaluate the utility of additional ablative therapy in the management of patients with HCC who received an initial TACE procedure.

Objective: To compare the overall survival (OS) and freedom from local progression (FFLP) outcomes after TACE alone with TACE that is followed by an ablative treatment regimen using stereotactic body radiation therapy, radiofrequency ablation, or microwave ablation for patients with HCC.

Design, Setting, And Participants: This cohort study of 289 adults at a single urban medical center examined survival outcomes for patients with nonmetastatic, unresectable HCC who received ablative therapies following TACE or TACE alone from January 2010 through December 2018. The Lee, Wei, Amato common baseline hazard model was applied for within-patient correlation with robust variance and Cox regression analysis was used to assess the association between treatment group (TACE vs TACE and ablative therapy) and failure time events (FFLP per individual lesion and OS per patient), respectively. In both analyses, the treatment indication was modeled as a time-varying covariate. Landmark analysis was used as a further sensitivity test for bias by treatment indication.

Exposures: TACE alone vs TACE followed by ablative therapy.

Main Outcomes And Measures: Freedom from local progression and overall survival. Hypotheses were generated before data collection.

Results: Of the 289 patients identified, 176 (60.9%) received TACE only and 113 (39.1%) received TACE plus ablative therapy. Ablative therapy included 45 patients receiving stereotactic body radiation therapy, 39 receiving microwave ablation, 20 receiving radiofrequency ablation, and 9 receiving a combination of these following TACE. With a median (interquartile range) follow-up of 17.4 (9.5-29.5) months, 242 of 512 (47.3%) lesions progressed, 211 in the group with TACE alone and 31 in the group with TACE plus ablative therapy (P < .001). Over 3 years, FFLP was 28.1% for TACE alone vs 67.4% for TACE with ablative therapy (P < .001). The 1-year and 3-year OS was 87.5% and 47.1% for patients with lesions treated with TACE alone vs 98.7% and 85.3% for patients where any lesion received TACE plus ablative therapy, respectively (P = .01), and this benefit remained robust on landmark analyses at 6 and 12 months. The addition of ablative therapy was independently associated with OS on multivariable analysis for all patients (hazard ratio, 0.26; 95% CI, 0.13-0.49; P < .001) and for patients with Barcelona clinic liver cancer stage B or C disease (hazard ratio, 0.31; 95% CI, 0.14-0.69; P = .004).

Conclusions And Relevance: Adding ablative therapy following TACE improved FFLP and OS among patients with hepatocellular carcinoma. This study aims to guide the treatment paradigm for HCC patients until results from randomized clinical trials become available.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.23942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645696PMC
November 2020

Who Benefits the Most From Adjuvant Durvalumab After Chemoradiotherapy for Non-small Cell Lung Cancer? An Exploratory Analysis.

Pract Radiat Oncol 2021 Mar-Apr;11(2):e172-e179. Epub 2020 Oct 27.

Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, The Bronx, New York.

Purpose: Adjuvant durvalumab is now recommended for most patients with locally advanced non-small cell lung cancer after concurrent chemoradiotherapy. Herein, we explore the clinical factors that may be associated with the benefit from adjuvant durvalumab.

Methods And Materials: Patients with non-small cell lung cancer who were treated with definitive concurrent chemoradiotherapy at our institution between August 2013 and May 2019 were included in this analysis. Clinical and treatment characteristics were tested for associations with progression-free survival (PFS) in Cox models. Interaction terms were added to the PFS Cox models to explore factors that may modulate the effects of adjuvant durvalumab. PFS and overall survival (OS) rates were estimated using the Kaplan-Meier method, and comparisons between patient subgroups were performed using log rank testing.

Results: A total of 105 patients met the eligibility criteria. Thirty-five patients (33%) received adjuvant durvalumab. Treatment with durvalumab was associated with significant improvement in PFS (1-year PFS: 67% vs 39%; log rank P = .006) and OS (1-year OS: 88% vs 76%; log rank P = .041). Exploratory analyses identified the neutrophil-to-lymphocyte ratio (NLR) after radiation therapy (RT) as a factor that may be associated with a benefit from durvalumab. For patients with post-RT NLR exceeding the cohort's median value of 4.3, receipt of adjuvant durvalumab was not associated with a significant PFS improvement (1-year PFS: 45% vs 36%; log rank P = .702). For patients with post-RT NLR <4.3, durvalumab receipt was associated with improved PFS (69% vs 41%; P = .009). High mean RT doses delivered to the heart and esophagus were associated with high post-RT NLR.

Conclusions: We identified low NLR after chemoradiotherapy as a factor that may be associated with a benefit from adjuvant durvalumab. Validation studies are warranted.
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http://dx.doi.org/10.1016/j.prro.2020.09.010DOI Listing
August 2021

The Technical and Clinical Implementation of LATTICE Radiation Therapy (LRT).

Radiat Res 2020 Dec;194(6):737-746

Department of Radiation Oncology Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.
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http://dx.doi.org/10.1667/RADE-20-00066.1DOI Listing
December 2020

Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

Radiat Res 2020 11;194(5):452-464

National Council on Radiation Protection and Measurements, Bethesda, Maryland.

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.
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http://dx.doi.org/10.1667/RADE-20-00211.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009137PMC
November 2020

Association of Race and Ethnicity With Comorbidities and Survival Among Patients With COVID-19 at an Urban Medical Center in New York.

JAMA Netw Open 2020 09 1;3(9):e2019795. Epub 2020 Sep 1.

Department of Pediatrics, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York.

Importance: As of May 11, 2020, there have been more than 290 000 deaths worldwide from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). Risk-adjusted differences in outcomes among patients of differing ethnicity and race categories are not well characterized.

Objectives: To investigate whether presenting comorbidities in patients with COVID-19 in New York City differed by race/ethnicity and whether case fatality rates varied among different ethnic and racial groups, controlling for presenting comorbidities and other risk factors.

Design, Setting, And Participants: This cohort study included 5902 patients who presented for care to the Montefiore Medical Center, a large urban academic medical center in the Bronx, New York, between March 14 and April 15, 2020, and tested positive for SARS-CoV-2 on reverse transcription quantitative polymerase chain reaction assay. Final data collection was April 27, 2020.

Exposures: Patient characteristics, including self-identified ethnicity/race, age, sex, socioeconomic status, and medical comorbidities, were tabulated.

Main Outcomes And Measures: Overall survival. Associations between patient demographic characteristics, comorbidities, and race/ethnicity were examined using χ2 tests, and the association with survival was assessed using univariable and multivariable Cox proportional hazards regression, based on time from positive COVID-19 test.

Results: Of 9268 patients who were tested, 5902 ethnically diverse patients (63.7%) had SARS-CoV-2. Of these, 3129 patients (53.0%) were women, and the median (interquartile range) age was 58 (44-71) years. A total of 918 patients (15.5%) died within the study time frame. Overall, 1905 patients (32.3%) identified as Hispanic; 1935 (32.8%), non-Hispanic Black; 509 (8.6%), non-Hispanic White; and 171 (2.9%), Asian; the death rates were 16.2% (309), 17.2% (333), 20.0% (102), and 17.0% (29), respectively (P = .25). Hispanic and non-Hispanic Black patients had a higher proportion of more than 2 medical comorbidities with 654 (34.3%) and 764 (39.5%), respectively, compared with 147 (28.9%) among non-Hispanic White patients (P < .001). Hispanic and non-Hispanic Black patients were also more likely to test positive for COVID-19 than White patients, with 1905 of 2919 Hispanic patients (65.3%), 1935 of 2823 non-Hispanic Black patients (68.5%), and 509 of 960 non-Hispanic White patients (53.0%) having positive test results for SARS-CoV-2 (P < .001). While controlling for age, sex, socioeconomic status and comorbidities, patients identifying as Hispanic (hazard ratio, 0.77; 95% CI, 0.61-0.98; P = .03) or non-Hispanic Black (hazard ratio, 0.69; 95% CI, 0.55-0.87; P = .002) had slightly improved survival compared with non-Hispanic White patients.

Conclusions And Relevance: In this cohort study of patients with COVID-19 who presented for care at the same urban medical center, non-Hispanic Black and Hispanic patients did not experience worse risk-adjusted outcomes compared with their White counterparts. This finding is important for understanding the observed population differences in mortality by race/ethnicity reported elsewhere.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.19795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519416PMC
September 2020

Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy.

EBioMedicine 2020 Sep 3;59:102973. Epub 2020 Sep 3.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Stereotactic body radiotherapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). This study sought to identify differentially expressed plasma metabolites in HCC patients at baseline and early during SBRT, and to explore if changes in these metabolites early during SBRT may serve as biomarkers for radiation-induced liver injury and/or tumour response.

Methods: Forty-seven HCC patients were treated with SBRT on previously published prospective trials. Plasma samples were collected at baseline and after one to two fractions of SBRT, and analysed by GC/MS and LC/MS for untargeted and targeted metabolomics profiling, respectively.

Findings: Sixty-nine metabolites at baseline and 62 metabolites after one to two fractions of SBRT were differentially expressed, and strongly separated the Child Pugh (CP) B from the CP A HCC patients. These metabolites are associated with oxidative stress and alterations in hepatic cellular metabolism. Differential upregulation of serine, alanine, taurine, and lipid metabolites early during SBRT from baseline was noted in the HCC patients who demonstrated the greatest increase in CP scores at three months post SBRT, suggesting that high protein and lipid turnover early during SBRT may portend increased clinical liver toxicity. Twenty annotated metabolites including fatty acids, glycerophospholipids, and acylcarnitines were differentially upregulated early during SBRT from baseline and separated patients with complete/partial response from those with stable disease at three months post SBRT.

Interpretation: Dysregulation of amino acid and lipid metabolism detected early during SBRT are associated with subsequent clinical liver injury and tumour response in HCC.
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http://dx.doi.org/10.1016/j.ebiom.2020.102973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484529PMC
September 2020

Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

Stem Cell Res Ther 2020 08 27;11(1):371. Epub 2020 Aug 27.

Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France.

Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality.

Methods: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods.

Results: We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium.

Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.
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http://dx.doi.org/10.1186/s13287-020-01887-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457304PMC
August 2020

Reply to Chowdhary et al.

Adv Radiat Oncol 2020 Jul-Aug;5(4):713-714. Epub 2020 Aug 3.

Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York.

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http://dx.doi.org/10.1016/j.adro.2020.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397987PMC
August 2020

Extent of Prior Lung Irradiation and Mortality in COVID-19 Patients With a Cancer History.

Adv Radiat Oncol 2020 Jul-Aug;5(4):707-710. Epub 2020 May 20.

Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York.

Purpose: There have been nearly 200,000 deaths worldwide so far from coronavirus disease 2019 (COVID-19), which is caused by a coronavirus called SARS-CoV-2. Cancer history appears to be a poor prognostic factor for COVID-19 patients, although the reasons for this are unclear. In this report, we assess whether extent of prior lung irradiation is a risk factor for death as a result of COVID-19 infection.

Methods And Materials: Patients who tested positive for COVID-19 between March 14 and April 15, 2020, at our institution and who previously received radiation therapy for cancer in our department were included in this analysis. Patient characteristics and metrics describing the extent of lung irradiation were tabulated. Cox regression models were used to identify predictors of death after COVID-19 diagnosis. A logistic model was used to characterize the association between mean lung radiation therapy dose and 14-day mortality risk after COVID-19 diagnosis.

Results: For the study, 107 patients met the inclusion criteria. With a median follow-up of 7 days from COVID-19 diagnosis for surviving patients, 24 deaths have been observed. The actuarial survival rate 14 days after COVID-19 testing is 66%. Increasing mean lung dose (hazard ratio [HR] per Gy = 1.1, = .002), lung cancer diagnosis (HR = 3.0, = .034), and receiving radiation therapy between 1 month and 1 year before COVID-19 testing (HR = 3.4, = .013) were associated with increased risk of death. Our survival model demonstrates a near linear relationship between mortality risk after COVID-19 diagnosis and mean lung radiation therapy dose.

Conclusions: COVID-19 patients with a history of radiation therapy for cancer have a poor prognosis, and mortality risk appears to be associated with extent of lung irradiation. Validation of these findings will be critical as the COVID-19 pandemic continues.
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http://dx.doi.org/10.1016/j.adro.2020.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239013PMC
May 2020

The thrombopoietin mimetic JNJ-26366821 increases megakaryopoiesis without affecting malignant myeloid proliferation.

Leuk Lymphoma 2020 10 24;61(10):2453-2465. Epub 2020 Jun 24.

Department of Oncology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.
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http://dx.doi.org/10.1080/10428194.2020.1775213DOI Listing
October 2020

Mechanistic dissection of the PD-L1:B7-1 co-inhibitory immune complex.

PLoS One 2020 4;15(6):e0233578. Epub 2020 Jun 4.

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, United States of America.

The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge for defining the biological contribution of each specific interaction. We developed a strategy for addressing these challenges by combining cell microarray and high-throughput FACS methods to screen for promiscuous binding events, map binding interfaces, and generate functionally selective reagents. Applying this approach to the interactions of mPD-L1 with its receptor mPD-1 and its ligand mB7-1, we identified the binding interface of mB7-1 on mPD-L1 and as a result generated mPD-L1 mutants with binding selectivity for mB7-1 or mPD-1. Next, using a panel of mB7-1 mutants, we mapped the binding sites of mCTLA-4, mCD28 and mPD-L1. Surprisingly, the mPD-L1 binding site mapped to the dimer interface surface of mB7-1, placing it distal from the CTLA-4/CD28 recognition surface. Using two independent approaches, we demonstrated that mPD-L1 and mB7-1 bind in cis, consistent with recent reports from Chaudhri A et al. and Sugiura D et al. We further provide evidence that while CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. These observations offer new functional insights into the regulatory mechanisms associated with this group of B7 family proteins and provide new tools to elucidate their function in vitro and in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272049PMC
August 2020

Snai2 Maintains Bone Marrow Niche Cells by Repressing Osteopontin Expression.

Dev Cell 2020 06 14;53(5):503-513.e5. Epub 2020 May 14.

Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. Electronic address:

Bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) are a critical constituent of the hematopoietic stem cell (HSC) niche. Previous studies have suggested that the zinc-finger epithelial-mesenchymal transition transcription factor Snai2 (also known as Slug) regulated HSCs autonomously. Here, we show that Snai2 expression in the BM is restricted to the BM stromal compartment where it regulates the HSC niche. Germline or MSPC-selective Snai2 deletion reduces the functional MSPC pool and their mesenchymal lineage output and impairs HSC niche function during homeostasis and after stress. RNA sequencing analysis revealed that Spp1 (osteopontin) expression is markedly upregulated in Snai2-deficient MSPCs. Genetic deletion of Spp1 in Snai2-deficient mice rescues MSPCs' functions. Thus, SNAI2 is a critical regulator of the transcriptional network maintaining MSPCs by the suppression of osteopontin expression.
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http://dx.doi.org/10.1016/j.devcel.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299199PMC
June 2020

Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy.

Semin Radiat Oncol 2020 04;30(2):187-193

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY.

There is now strong clinical and preclinical evidence that lymphocytes, for example, CD8 T cells, are key effectors of immunotherapy and that irradiation of large blood vessels, the heart, and lymphoid organs (including nodes, spleen, bones containing bone marrow, and thymus in children) causes transient or persistent lymphopenia. Furthermore, there is extensive clinical evidence, across multiple cancer sites and treatment modalities, that lymphopenia correlates strongly with decreased overall survival. At the moment, we lack quantitative evidence to establish the relationship between dose-volume and dose-rate to critical normal structures and lymphopenia. Therefore, we propose that data should be systematically recorded to characterise a possible quantitative relationship. This might enable us to improve the efficacy of radiotherapy and develop strategies to predict and prevent treatment-related lymphopenia. In anticipation of more quantitative data, we recommend the application of the principle of As Low As Reasonably Achievable to lymphocyte-rich regions for radiotherapy treatment planning to reduce the radiation doses to these structures, thus moving toward "Lymphocyte-Sparing Radiotherapy."
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http://dx.doi.org/10.1016/j.semradonc.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412054PMC
April 2020

Trials and Tribulations of Radio-Immuno-Oncology.

Authors:
Chandan Guha

Semin Radiat Oncol 2020 04;30(2):108-112

Departments of Radiation Oncology, Pathology and Urology, and Institute of Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY. Electronic address:

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http://dx.doi.org/10.1016/j.semradonc.2020.01.001DOI Listing
April 2020

Evaluating dosimetric constraints for carbon ion radiotherapy in the treatment of locally advanced pancreatic cancer.

Radiat Oncol 2020 May 7;15(1):101. Epub 2020 May 7.

Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, 4365 Kangxin Road, Shanghai, 201318, China.

Objective: To identify a safe carbon ion radiotherapy (CIRT) regimen for patients with locally advanced pancreatic cancer (LAPC).

Methods: We generated treatment plans for 13 consecutive, unselected patients who were treated for LAPC with CIRT at our center using three dose and fractionation schedules: 4.6 GyRBE × 12, 4.0 GyRBE × 14, and 3.0 GyRBE × 17. We tested the ability to meet published dose constraints for the duodenum, stomach, and small bowel as a function of dose schedule and distance between the tumor and organs at risk.

Results: Using 4.6 GyRBE × 12 and 4.0 GyRBE × 14, critical (high-dose) constraints could only reliably be achieved when target volumes were not immediately adjacent to organs at risk. Critical constraints could be met in all cases using 3.0 GyRBE × 17. Low-dose constraints could not uniformly be achieved using any dose schedule.

Conclusion: While selected patients with LAPC may be treated safely with a CIRT regimen of 4.6 GyRBE × 12, our dosimetric analyses indicate that a more conservative schedule of 3.0 GyRBE × 17 may be required to safely treat a broader population of LAPC patients, including those with large tumors and tumors that approach gastrointestinal organs at risk. The result of this work was used to guide an ongoing clinical trial.
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http://dx.doi.org/10.1186/s13014-020-01515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204055PMC
May 2020

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 07 13;107(4):766-778. Epub 2020 Apr 13.

Division of Cancer Treatment and Diagnosis, Rockville, Maryland.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.028DOI Listing
July 2020

Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity.

Theranostics 2020 10;10(8):3397-3412. Epub 2020 Feb 10.

Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74074.

: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. : Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. : CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% . that seen in untreated controls, and >~50% . CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. : CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.
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http://dx.doi.org/10.7150/thno.42243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069083PMC
April 2021

Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer.

EClinicalMedicine 2019 Nov 22;16:23-29. Epub 2019 Oct 22.

Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Background: There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database.

Methods: LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM).

Findings: Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT ( = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% ( = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21,  = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT ( = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36,  = 0•13) or negative CRM (OR = 1•77,  = 0•19) in multivariable logistic regression modelling.

Interpretation: With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.
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http://dx.doi.org/10.1016/j.eclinm.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890979PMC
November 2019

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma.

Int J Hyperthermia 2019 11;36(sup1):64-73

Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.

The success of melanoma immunotherapy is dependent on the presence of activated and functional T-cells in tumors. The objective of this study was to investigate the impact of local-focused ultrasound (FUS) heating (∼42-45 °C) and in-situ anti-CD-40 agonistic antibody in enhancing T-cell function for melanoma immunotherapy. We compared the following groups of mice with bilateral flank B16 F10 melanoma: (1) Control, (2) FUS, (3) CD-40, and (4) CD-40 + FUS (FUS40). FUS heating was applied for ∼15 min in right flank tumor, and intratumoral injections of CD-40 were performed sequentially within 4 h. A total of 3 FUS and 4 anti-CD-40 treatments were administered unilaterally 3 days apart. Mice were sacrificed 30 days post-inoculation, and the treated tumor and spleen tissues were profiled for T-cell function and macrophage polarization. Compared to all other groups, histology and flow cytometry showed that FUS40 increased the population of tumor-specific CD-4+ and CD-8+ T cells rich in Granzyme B+, interleukin-2 (IL-2) and IFN-γ production and poor in PD-1 expression. In addition, FUS40 promoted the infiltration of tumor-suppressing M1 phenotype macrophages in the treated mice. The resultant immune-enhancing effects of FUS40 suppressed B16 melanoma growth at the treated site by 2-3-folds compared to control, FUS, and CD-40, and also achieved significant abscopal effects in untreated tumors relative to CD40 alone. Additionally, the local FUS40 prevented adverse liver toxicities in the treated mice. Our study suggests that combined FUS and CD-40 can enhance T-cell and macrophage functions to aid effective melanoma immunotherapy.
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http://dx.doi.org/10.1080/02656736.2019.1663280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897315PMC
November 2019

Postablation Modulation after Single High-Dose Radiation Therapy Improves Tumor Control via Enhanced Immunomodulation.

Clin Cancer Res 2020 02 22;26(4):910-921. Epub 2019 Nov 22.

Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York.

Purpose: Radiotherapy (RT) is frequently used for local control of solid tumors using equal dose per fraction. Recently, single high-dose radiation has been used for ablation of solid tumors. In this report, we provide a novel immunological basis for radiation dose fractionation consisting of a single high-dose radiotherapy, followed by postablation modulation (PAM) with four daily low-dose fractions (22 Gy + 0.5 Gy × 4) to reprogram the tumor microenvironment by diminishing immune suppression, enabling infiltration of effector cells and increasing efficacy of tumor control.

Experimental Design: Palpable 3LL and 4T1 tumors in C57Bl/6 and Balb/c mice were irradiated with the Small-Animal Radiation Research Platform irradiator, and tumor growth and survival were monitored. Immunomodulation of tumor and immune cells and characterization of tumor-infiltrating immune effector cells were performed by FACS. For systemic application of PAM-RT, whole-lung irradiation was administered in 4T1-bearing Balb/c mice.

Results: We report significant tumor growth delays and increased survival in 3LL tumor-bearing mice with PAM. Primary tumor PAM-RT increased infiltration of immune effector cells and decreased Treg in irradiated tumors and secondary lymphoid organs. In a model of murine metastatic breast cancer (4T1), we demonstrated that systemic PAM-RT to the whole lung, 12 days after primary tumor ablative radiotherapy, increased survival with suppression of pulmonary metastases.

Conclusions: We provide a novel immunologic basis for radiation dose fractionation consisting of a single high dose of radiotherapy followed by daily low-dose PAM-RT fractionation to improve the immunogenic potential of ablative radiotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3518DOI Listing
February 2020

Non-Invasive Targeted Hepatic Irradiation and SPECT/CT Functional Imaging to Study Radiation-Induced Liver Damage in Small Animal Models.

Cancers (Basel) 2019 Nov 15;11(11). Epub 2019 Nov 15.

Department of Radiation Oncology, Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging.
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http://dx.doi.org/10.3390/cancers11111796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896151PMC
November 2019

Low Intensity Focused Ultrasound (LOFU)-mediated Acoustic Immune Priming and Ablative Radiation Therapy for in situ Tumor Vaccines.

Sci Rep 2019 10 29;9(1):15516. Epub 2019 Oct 29.

Departments of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.

Focal ablative therapies have been primarily used for local tumor ablation. However, they often fail to impact systemic disease. Here we propose the use of low intensity focused ultrasound (LOFU), a noninvasive, nontoxic, conformal therapy, to deliver acoustic stress to the tumor for immune priming. We demonstrate that LOFU significantly induces expression and cell surface localization of heat shock proteins in murine breast (4T1) and prostate adenocarcinoma (TPSA23) cancer cell lines. In vivo LOFU followed by ablative radiation therapy (RT) results in primary tumor cure, upregulation of a cytotoxic immune response and induction of immunological memory by inhibiting secondary tumor growth upon re-challenge with tumor cells. We, therefore, describe a regimen of a combination therapy with noninvasive, acoustic immune priming and ablative radiation therapy to generate an in situ tumor vaccine, induce CD8+ T cells against tumor-associated antigens and provide a viable oncologic treatment option for solid tumors.
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http://dx.doi.org/10.1038/s41598-019-51332-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820551PMC
October 2019
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