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1.
Oncoimmunology ; 10(1): 1863631, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33643689

RESUMO

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).

2.
Cancer Res ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514514

RESUMO

Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ER)α-negativity. Here we explored the role of the second ER subtype, ERß, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERß in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERß was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERß by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. Based on these findings, we propose ERß as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality.

3.
Biomaterials ; 267: 120463, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130321

RESUMO

The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one of the challenges for effective bench-to-bedside translation of nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (Tex) pH-triggered NM that can maintain the micellar structure with the entrapped-drug during systemic circulation and progressively release drug in the tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), a derivative of potent anticancer drug vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)-b-poly(amino acid) copolymer and the hydrolytic stability of the derived hydrazone bond was efficiently tailored by exploiting the compartmentalized structure of polymer micelle. We confirmed an effective and safe therapeutic application of Tex pH-sensitive DAVBNH-loaded micelle (Tex-micelle) in orthotopic glioblastoma (GBM) models, extending median survival to 1.4 times in GBM xenograft and 2.6 times in GBM syngeneic model, compared to that of the free DAVBNH. The work presented here offers novel chemical insights into the molecular design of smart NMs correctly sensing Tex-pH via programmed functionalities. The practical engineering strategy based on a clinically relevant NM platform, and the encouraging therapeutic application of Tex-micelle in GBM, one of the most lethal human cancers, thus suggests the potential clinical translation of this system against other types of common cancers, including GBM.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33223046

RESUMO

PURPOSE: The effects of thoracic radiation therapy (RT) on physical functioning and quality of life (QoL) are incompletely defined. We determined the associations between thoracic RT dose volume metrics, physical activity, and QoL in patients with cancer. METHODS AND MATERIALS: Participants with breast cancer, lung cancer, or mediastinal lymphoma treated with radiation with or without chemotherapy were enrolled in a prospective, longitudinal cohort study. Data were collected pre-RT, immediately post-RT, and 5 to 9 months post-RT. At each timepoint, self-reported physical activity was assessed via the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and QoL metrics were assessed via Functional Assessment of Chronic Illness Therapy Fatigue and Dyspnea Scales. Multivariable adjusted linear regression models were stratified by breast cancer alone and lung cancer and lymphoma combined. RESULTS: One hundred thirty participants were included in the study. In breast cancer (n = 80), each 1-Gy increase in mean heart dose was associated with worse Functional Assessment of Chronic Illness Therapy Fatigue scores (-1.0; 95% confidence interval [CI], -1.9 to -0.2; P = .021); similar associations were observed between V5 and fatigue (-2.5; 95% CI, -4.4 to -0.6; P = .010 for each 10% increase in V5). In lung cancer and lymphoma (n = 50), each 10% increase in V5 was associated with decreased physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire score -2.3; 95% CI, -4.3 to -0.4; P = .017). Although the associations between baseline levels of physical activity and fatigue and dyspnea were of borderline significance in breast cancer alone (P < .10), increased physical activity over time was associated with improvements in fatigue and dyspnea across all cancer types (P < .05 for all). CONCLUSIONS: Higher cardiac RT dose was associated with worse fatigue and physical activity across breast cancer, lung cancer, and mediastinal lymphoma. Longitudinal increases in physical activity were associated with concurrent improvements in QoL measures. Strategies to increase physical activity and decrease cardiac RT dose may improve physical functioning and QoL for patients with cancer.

5.
JAMA Dermatol ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112366

RESUMO

Importance: Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed. Objective: To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ. Design, Setting, and Participants: This is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4+ SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT. Interventions: Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT. Main Outcomes and Measures: To characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli. Results: Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1. Conclusions and Relevance: We describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32866566

RESUMO

PURPOSE: Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT. METHODS AND MATERIALS: Within an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT. RESULTS: A total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation. CONCLUSIONS: PT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.

7.
ACS Nano ; 14(8): 10127-10140, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32806051

RESUMO

Glioblastoma (GBM) is resistant to immune checkpoint inhibition due to its low mutation rate, phosphatase and tensin homologue (PTEN)-deficient immunosuppressive microenvironment, and high fraction of cancer stem-like cells (CSCs). Nanomedicines fostering immunoactivating intratumoral signals could reverse GBM resistance to immune checkpoint inhibitors (ICIs) for promoting curative responses. Here, we applied pH-sensitive epirubicin-loaded micellar nanomedicines, which are under clinical evaluation, to synergize the efficacy of anti-PD1antibodies (aPD1) against PTEN-positive and PTEN-negative orthotopic GBM, the latter with a large subpopulation of CSCs. The combination of epirubicin-loaded micelles (Epi/m) with aPD1 overcame GBM resistance to ICIs by transforming cold GBM into hot tumors with high infiltration of antitumor immune cells through the induction of immunogenic cell death (ICD), elimination of immunosuppressive myeloid-derived suppressor cells (MSDCs), and reduction of PD-L1 expression on tumor cells. Thus, Epi/m plus aPD1 eradicated both PTEN-positive and PTEN-negative orthotopic GBM and provided long-term immune memory effects. Our results indicate the high translatable potential of Epi/m plus aPD1 for the treatment of GBM.

8.
Phys Med Biol ; 65(16): 165002, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32413889

RESUMO

This paper aims to demonstrate the difference in biological effectiveness of proton monoenergetic arc therapy (PMAT) compared to intensity modulated proton therapy (IMPT) and conventional 6 MV photon therapy, and to quantify this difference when exposing cells of different radiosensitivity to the same experimental conditions for each modality. V79, H1299 and H460 cells were cultured in petri dishes placed in the central axis of a cylindrical and homogeneous solid water phantom of 20 cm in diameter. For the PMAT plan, cells were exposed to 13 mono-energetic proton beams separated every 15° over a 180° arc, designed to deliver a uniform dose of higher LET to the petri dishes. For the IMPT plans, 3 fields were used, where each field was modulated to cover the full target. Cells were also exposed to 6 MV photon beams in petri dishes to characterize their radiosensitivity. The relative biological effectiveness of the PMAT plans compared with those of IMPT was measured using clonogenic assays. Similarly, in order to study the quantity and quality of the DNA damage induced by the PMAT plans compared to that of IMPT and photons, γ-H2AX assays were conducted to study the relative amount of DNA damage induced by each modality, and their repair rate over time. The clonogenic assay revealed similar survival levels to the same dose delivered with IMPT or x-rays. However, a systematic average of up to a 43% increase in effectiveness in PMAT plans was observed when compared with IMPT. In addition, the repair kinetic assays proved that PMAT induces larger and more complex DNA damage (evidenced by a slower repair rate and a larger proportion of unrepaired DNA damage) than IMPT. The repair kinetics of IMPT and 6 MV photon therapy were similar. Mono-energetic arc beams offer the possibility of taking advantage of the enhanced LET of proton beams to increase TCP. This study presents initial results based on exposing cells with different radiosensitivity to other modalities under the same experimental conditions, but more extensive clonogenic and in-vivo studies will be required to confirm the validity of these results.


Assuntos
Imagens de Fantasmas , Fótons , Terapia com Prótons , Radiobiologia , Planejamento da Radioterapia Assistida por Computador/métodos , Humanos , Fótons/uso terapêutico , Dosagem Radioterapêutica , Eficiência Biológica Relativa
9.
Semin Radiat Oncol ; 30(2): 173-180, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32381296

RESUMO

Immune checkpoint inhibitors have shown remarkable clinical benefit across a variety of cancer types. However, the majority of patients do not respond or develop relapse after therapy. Radiation can favorably modulate the immune system and enhance tumor antigen recognition and rejection. Thus, the combination of radiation and immune checkpoint blockade (ICB) has been recognized as a promising strategy to improve tumor response and broaden the clinical utility of immunotherapy. In this review, we highlight the preclinical and clinical experience at our institution aimed at understanding and promoting the immunostimulatory effect of radiation. We discuss the rationale, design, results, and lessons from our clinical trials in combining radiation with anti-CTLA4 and/or anti-PD-1 therapy. In parallel, our studies to understand the resistance mechanism to radiation and ICB have converged on interferon (IFN) signaling as a key regulatory pathway. Persistent IFN-γ signaling impairs anti-tumor immune responses which can be reversed by using JAK inhibitor to disrupt the IFN signaling. Lastly we discuss remaining challenges, ongoing studies, and future directions in combining radiation with immunotherapy.

10.
Int J Radiat Oncol Biol Phys ; 108(1): 178-188, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32446950

RESUMO

PURPOSE: CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration-approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach. METHODS AND MATERIALS: Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT. RESULTS: Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099). CONCLUSIONS: Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.

11.
Haematologica ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414850

RESUMO

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

12.
J Natl Cancer Inst ; 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32294209

RESUMO

BACKGROUND: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was pre-specified. The primary outcome was overall survival (OS) and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous (IV) steroids. All statistical tests were two-sided. RESULTS: There were 568 patients in our database, of which 114 received antibiotics prior to ICI. 35.9% of patients had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.27-2.57, p<.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR 2.78, 95% CI 1.31-5.87, p=.007). When limited to only patients who received adjuvant ICI (N = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR 4.84, 95% CI 1.09-21.50, p=.04). The antibiotic group had a greater incidence of colitis (HR 2.14, 95% CI 1.02-4.52, p=.046). CONCLUSION: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.

13.
Oncogene ; 39(22): 4344-4357, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32335582

RESUMO

We explore a novel strategy of activating immune signaling through increased micronuclei formation utilizing a cell cycle checkpoint inhibitor to drive cell cycle progression following ionizing radiation. The Chk1/2 inhibitor AZD7762 is used to abrogate radiation therapy (RT)-induced G2/M cell cycle arrest in multiple cell lines and, we find that this therapeutic combination promotes increased micronuclei formation in vitro and subsequently drives increased type I interferon signaling and cytotoxic T-cell activation. In vivo studies using B16-F10 melanoma cancer cells implanted in C57/BL6 mice demonstrate improved rates of tumor control at the abscopal (unirradiated) site, located outside of the radiation field, only in the AZD7762 + RT group, with a corresponding reduction in mean tumor volume, increase in the CD8 T-cell population, and immune activated gene signaling. Our results demonstrate that targeted inhibition of cell cycle checkpoint activation following ionizing radiation drives increased production of immunogenic micronuclei, leading to systemic tumor response with potential future clinical benefit.


Assuntos
Núcleo Celular/efeitos dos fármacos , Núcleo Celular/efeitos da radiação , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase do Ponto de Checagem 2/antagonistas & inibidores , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Melanoma Experimental/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Tiofenos/farmacologia , Ureia/análogos & derivados , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Interferon beta/biossíntese , Interferon beta/genética , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/radioterapia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Testes para Micronúcleos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT1/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Radiat Oncol Biol Phys ; 106(2): 440-448, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928642

RESUMO

PURPOSE: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. METHODS AND MATERIALS: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation. RESULTS: The double scattering and collimation apparatus was dosimetrically validated with dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection in MH641905 pancreatic cancer flank tumors after 12 or 18 Gy irradiation. CONCLUSIONS: We have designed and dosimetrically validated a FLASH-PRT system with accurate control of beam flux on a millisecond time scale and online monitoring of the integral and dose delivery time structure. Using this system, we found that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities.


Assuntos
Órgãos em Risco/efeitos da radiação , Terapia com Prótons/instrumentação , Lesões Experimentais por Radiação/prevenção & controle , Proteção Radiológica/instrumentação , Radioterapia Guiada por Imagem/instrumentação , Abdome/efeitos da radiação , Animais , Proliferação de Células/efeitos da radiação , Desenho de Equipamento/métodos , Estudos de Viabilidade , Feminino , Fibrose , Raios gama , Intestino Delgado/patologia , Intestino Delgado/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Tratamentos com Preservação do Órgão/instrumentação , Tratamentos com Preservação do Órgão/métodos , Órgãos em Risco/patologia , Neoplasias Pancreáticas/radioterapia , Terapia com Prótons/métodos , Proteção Radiológica/métodos , Radiometria/métodos , Radioterapia Guiada por Imagem/métodos , Espalhamento de Radiação , Células-Tronco/efeitos da radiação , Tomografia Computadorizada por Raios X
15.
Leuk Lymphoma ; 61(4): 905-911, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876204

RESUMO

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%, n = 13) of the patients had extranodal disease. Frontline approaches included surgical intervention/complete excision (n = 5, 33%), rituximab monotherapy (n = 5, 33%), observation (n = 3, 20%), and radiation (n = 2, 13%). Two of the five patients underwent surgical excision and were subsequently treated with rituximab. Of the 7 patients who were given rituximab, 64% remained progression free 24 months after the initial rituximab administration. Our review parallels previous reports and highlights rituximab as a favorable option for therapy if ineligible for surgery or radiation.

16.
Radiat Res ; 193(1): 46-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675265

RESUMO

D-dimer plasma levels were evaluated to determine whether they are altered by radiation. D-dimer levels were measured in radiation oncology patients, who were diagnosed with prostate, breast or lung cancer, or leukemia, as well as in healthy subjects serving as controls. Blood samples from radiotherapy patients were taken at three different time points: pre-, on- and post-radiotherapy. For the patients, considered together, differences between the D-dimer levels at these three time points compared to controls were statistically significant. Compared to the pre-radiotherapy measurements, radiation exposure was associated with a significant increase in the D-dimer levels at the on- and post-radiotherapy time points. At the post-radiotherapy time point, D-dimer levels in the patients were not significantly reduced compared to the on-radiotherapy levels, indicating that the risk for developing disseminated intravascular coagulation (DIC) may be increased in some radiation oncology patients. Of particular concern are the post-radiotherapy results observed for the D-dimer levels in the leukemia patients, in which the average fold increase in the D-dimer levels was 5.43 (compared to the pre-radiotherapy levels). These results suggest that leukemia patients might benefit from frequent assessment of their D-dimer levels after their total-body irradiation-conditioning regimen to detect early signs of DIC development. It is hoped that the results described here will lead to heightened awareness in the radiation oncology community that the risk of DIC development is greatly increased in some of these patients.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Neoplasias/sangue , Humanos , Neoplasias/radioterapia , Radioterapia (Especialidade)
17.
Med Phys ; 47(1): 201-212, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31665544

RESUMO

BACKGROUND: Total skin electron therapy (TSET) utilizes high-energy electrons to treat malignancies on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interactions between the high-energy electron beam and tissue. METHODS AND MATERIALS: With a time-gated intensified camera system, the Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real time. Fifteen patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. Each patient was monitored during TSET via in vivo detectors (IVD) in nine locations. For accurate Cherenkov imaging, a comparison between IVD and Cherenkov profiles was conducted using a polyvinyl chloride board to establish the perspective corrections. RESULTS AND DISCUSSION: With proper corrections developed in this study including the perspective and inverse square corrections, the Cherenkov imaging provided two-dimensional maps proportional to dose and projected on patient skin. The results of ratio between chest and umbilicus points were in good agreement with in vivo point dose measurements, with a standard deviation of 2.4% compared to OSLD measurements. CONCLUSIONS: Cherenkov imaging is a viable tool for validating patient-specific dose distributions during TSET.


Assuntos
Elétrons/uso terapêutico , Imagem Óptica , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica
18.
Indian J Otolaryngol Head Neck Surg ; 71(Suppl 3): 1821-1826, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31763253

RESUMO

Conidiobolomycosis is a rare mycotic disease caused by Conidiobolus coronatus. Very few cases have been reported in English literature. Often it is clinically misdiagnosed as soft tissue tumour. A prospective case study was done from 2006 to 2015 in a tertiary care hospital of West Bengal, India. The objectives of our study were to describe the epidemiological and clinical features and treatment of Conidiobolomycosis to prevent disfigurement. Patients clinically suspected to be suffering from Conidiobolomycosis were subjected to biopsy followed by histopathological and mycological examinations. Then they were treated with oral saturated solution of potassium iodide along with other drugs. Total six cases were histopathologically proved to be suffering from Conidiobolomycosis. Fungus was isolated and identified in one case. Complete resolution was seen in five patients. Conidiobolomycosis should be brought into mind as differential diagnosis of subcutaneous swelling in the rhinofacial region.

19.
Neurooncol Pract ; 6(4): 297-304, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31386046

RESUMO

Background: The interaction between immune checkpoint blockade (ICB) and radiation (RT) for brain metastases has not been well understood. Given that acute neurotoxicity from this combination is not well characterized, we reviewed patients receiving ICB and RT for brain metastases. Methods: Patients treated with ICB and cranial RT from 2010 through 2017 were reviewed. ICB and RT must have been administered within 30 days of each other. Treatment parameters, performance status, symptoms prior to treatment, and toxicity were extracted from the electronic medical record. Survival was calculated from the end of RT to last follow-up or death. Results: Seventy-eight patients were included. Median follow-up was 177 days (range, 12-1603). Median age was 64 years old (range, 29-98) and 47 (63%) were male. The main tumor types were melanoma (n = 47) and nonsmall-cell lung cancer (n = 19). Fifty-seven patients were treated with stereotactic radiosurgery (SRS) and 21 with whole-brain radiotherapy (WBRT). Most patients received single-agent ICB, though 4 patients received nivolumab and ipilimumab. Forty-one (53%) patients reported no neurologic toxicity. Grade 2 or greater neurologic toxicities were reported in 12 (21%) and 8 (38%) patients in the SRS and WBRT groups, respectively. WBRT was associated with a greater risk of any neurotoxicity, though there was no correlation between ICB agent and toxicity. Sequencing of ICB and RT (ie, <30 days vs <7) did not influence rates of toxicity. Conclusions: ICB during SRS or WBRT does not appear to worsen acute neurotoxicity compared to historical controls of RT alone.

20.
JAMA Oncol ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436839

RESUMO

Importance: Local failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor. Objective: To evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival. Design, Setting, and Participants: This prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors. Interventions: Oral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT. Main Outcomes and Measures: Graded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Thirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). The cumulative incidence of local failure was 39% (95% CI, 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI, 6.2-17.1 months). Median overall survival for all patients was 41.1 months (95% CI, 19.0-63.1 months); the 5-year mean (SE) overall survival rate was 37.1% (8.2%). Conclusions and Relevance: This study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT. Trial Registration: ClinicalTrials.gov identifier: NCT00589056.

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