RESUMO
We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45high/DNAlow) with hematological (CD45low/DNAhigh) and solid cancer cell lines (CD45neg/DNAhigh). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations.
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Citotoxicidade Imunológica , Neoplasias , Leucócitos Mononucleares , Células Matadoras Naturais , Linfócitos T , Técnicas de Cocultura , Citometria de Fluxo , Neoplasias/metabolismoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. METHODS: We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. RESULTS: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). CONCLUSIONS: Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.
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Corticosteroides/efeitos adversos , Corticosteroides/imunologia , Citocinas/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/imunologia , Imunoterapia/efeitos adversos , Melanoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Estudos RetrospectivosRESUMO
BACKGROUND: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.
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Antígeno CTLA-4/genética , Colite/tratamento farmacológico , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Vitamina D/administração & dosagem , Idoso , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Colite/induzido quimicamente , Colite/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos/efeitos dos fármacos , Masculino , Melanoma/complicações , Melanoma/patologia , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
The type I IFN (IFN-α) response is crucial for viral clearance during primary viral infections. Plasmacytoid dendritic cells (pDCs) are important early responders during systemic viral infections and, in some cases, are the sole producers of IFN-α. However, their role in IFN-α production during memory responses is unclear. We found that IFN-α production is absent during a murine viral memory response, despite colocalization of virus and pDCs to the splenic marginal zone. The absence of IFN was dependent on circulating Ab and was reversed by the transgenic expression of the activating human FcγRIIA receptor on pDCs. Furthermore, FcγRIIB was required for Sendai virus immune complex uptake by splenic pDCs in vitro, and internalization via FcγRIIb prevented cargo from accessing TLR signaling endosomes. Thus, pDCs bind viral immune complexes via FcγRIIB and prevent IFN-α production in vivo during viral memory responses. This Ab-dependent IFN-α regulation may be an important mechanism by which the potentially deleterious effects of IFN-α are prevented during a secondary infection.
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Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Memória Imunológica , Interferon Tipo I/biossíntese , Receptores de IgG/genética , Viroses/genética , Viroses/imunologia , Animais , Anticorpos Antivirais/imunologia , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Transporte Proteico , Receptores de IgG/metabolismo , Infecções por Respirovirus/genética , Infecções por Respirovirus/imunologia , Infecções por Respirovirus/metabolismo , Vírus Sendai/imunologia , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Receptor Toll-Like 9/metabolismo , Viroses/metabolismoAssuntos
Infecções por Coronavirus/prevenção & controle , Infecção Hospitalar/prevenção & controle , Desinfecção/normas , Ambiente de Instituições de Saúde/normas , Zeladoria Hospitalar/organização & administração , Controle de Infecções/normas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologiaRESUMO
Effective hospital environmental cleaning requires proper technique and training. Highlight is a novel additive that colorizes bleach wipes to help visualize wiped surfaces and fades to colorless to confirm effective cleaning. In a 401-bed hospital study, Highlight reduced fluorescent marker removal failure rates from a baseline of 12.4% to 0.6%.
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Anti-Infecciosos , Desinfetantes , Humanos , Desinfetantes/farmacologia , Desinfecção/métodos , Hospitais , Centros Médicos AcadêmicosRESUMO
Surface disinfection is critical for preventing health care-associated infections; however, sustaining high-quality cleaning technique is challenging without constant feedback and training of staff. A novel color additive to bleach wipes, Highlight, indicates where surfaces have been wiped and fades to colorless to provide real-time visual feedback of cleaning. In a multiphase interventional study, Highlight reduced failure rates of cleaning based on fluorescent marker removal (15.0%-4.5%) and adenosine triphosphate bioluminescence assay (3.6%-2.5%).
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Anti-Infecciosos , Infecção Hospitalar , Desinfetantes , Centros Médicos Acadêmicos , Infecção Hospitalar/prevenção & controle , Desinfetantes/farmacologia , Desinfecção/métodos , HumanosRESUMO
We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.
Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.
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Antineoplásicos Imunológicos , Neoplasias do Colo , Doenças do Sistema Imunitário , Linfadenite , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Citocinas , Genômica , Humanos , Imunoterapia/efeitos adversos , Linfadenite/induzido quimicamente , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Estudos RetrospectivosRESUMO
BACKGROUND: There is limited information on the management and outcomes of oligometastases (OM) in adenoid cystic carcinoma (ACC). METHODS: Retrospective study of 42 patients with metastatic ACC of the head and neck. Imaging studies were analyzed to identify patients with OM (1-5 lesions) at any point during follow-up. RESULTS: There was radiographic evidence of OM in 33/42 (79%) patients. Eighteen patients had OM when treated for metastases, with median overall survival (OS) of 36.0 versus 9.2 years for patients with polymetastases (6+ lesions, HR 0.38, 95%CI 0.14-0.89). Earlier locally ablative treatment, but not systemic treatment, of patients with OM predicted improved survival 3 years after metastasis (HR 0.15, 95%CI 0.02-0.63) and postponed systemic treatment by 80 more months (HR 0.22, 95%CI 0.07-0.71). CONCLUSIONS: There is a considerable population of ACC patients with detectable oligometastases, and early locally ablative treatment of oligometastases may be associated with improved outcomes.
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Carcinoma Adenoide Cístico , Carcinoma Adenoide Cístico/diagnóstico por imagem , Carcinoma Adenoide Cístico/terapia , Humanos , Estudos Retrospectivos , Tempo para o Tratamento , Carga TumoralRESUMO
BACKGROUND: The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. METHODS: This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. RESULTS: Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. CONCLUSION: The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.
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Carcinoma de Células Renais , Neoplasias Renais , Melanoma , Anticorpos Monoclonais Humanizados , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de FusãoRESUMO
BACKGROUND: Trimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used for locally-advanced non-small-cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses. METHODS: A retrospective analysis of patients who received planned TMT with IMRT for LA-NSCLC at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2008 and 2017 was performed. Clinical and treatment characteristics, pathologic response, and surgical toxicity were assessed. Kaplan-Meier method and log-rank test was used for survival outcomes. Cox proportional-hazards regression was used for multivariable analysis. RESULTS: Forty-six patients received less than definitive doses of <60 Gy and 30 patients received definitive doses ≥60 Gy. Surgical outcomes, pathologic complete response, and postoperative toxicity did not differ significantly between the groups. With median follow-up of 3.6 years (range: 0.4-11.4), three-year locoregional recurrence-free survival (78.0% vs. 68.3%, p = 0.51) and overall survival (OS) (61.0% vs. 69.4%, p = 0.32) was not significantly different between patients receiving <60 Gy and ≥60 Gy, respectively. On multivariable analysis, older age, clinical stage, and length of hospital stay (LOS) >7 days were associated with OS. CONCLUSIONS: With IMRT, there was no increased rate of surgical complications in patients receiving higher doses of radiation. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radioterapia de Intensidade Modulada , Idoso , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos RetrospectivosRESUMO
Introduction: To evaluate the impact of Sars-Cov-2 infection on mortality and immune checkpoint inhibitor (ICI) toxicity in patients with cancer receiving ICIs compared to those not receiving ICIs. Methods: We conducted a retrospective matched cohort study of 25 patients receiving ICIs within 1 year of coronavirus disease 2019 (COVID-19) diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute/Mass General Brigham. Cases were matched 1:1 with controls based on age, sex, and anticancer therapy within the prior 6 months. Results: Seven of 25 (28%) patients receiving ICIs died from COVID-19 as compared with nine of 25 (36%) controls. Through multivariable analysis adjusting for age, sex, and anticancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR [odds ratio] 0.36, 95% CI 0.07-1.87). Determinants of mortality included age (OR 1.14, 95% CI 1.03-1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76-85.14). Statin use was protective against mortality (OR 0.08, 95% CI 0.01-0.63). Two patients experienced persistent immune-related adverse events (irAEs) (hypophysitis); one had new-onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICIs had significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels. Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI. Conclusion: There is insufficient evidence to conclude COVID-19-related outcomes are associated with ICIs, and we did not observe an increased risk of COVID-19-related death associated with ICIs. The potential protective effect of statin therapy and role of laboratory biomarkers warrant further investigation.
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Proper disinfection using adequate disinfecting agents will be necessary for infection control strategies against coronavirus disease 2019 (COVID-19). However, limited guidance exists on effective surface disinfectants or best practices for their use against severe acute respiratory coronavirus 2. We outlined a process of fully characterizing over 350 products on the Environmental Protection Agency List N, including pH, method of delivery, indication for equipment sterilization, and purchase availability. We then developed a streamlined set of guidelines to help rapidly evaluate and select suitable disinfectants from List N, including practicality, efficacy, safety, and cost/availability. This resource guides the evaluation of ideal disinfectants amidst practical considerations posed by the COVID-19 pandemic.
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This cross-sectional study examines private equitybacked acquisitions of medical and radiation oncology clinics in the US from 2003 to 2022 using financial databases and publicly available data.
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Instituições de Assistência Ambulatorial , Atenção à Saúde , HumanosRESUMO
Bleach sprays suffer from poor surface coverage, dry out before reaching proper contact time, and can be inadvertently over-diluted to ineffective concentrations. Highlight®, a novel color additive for bleach that fades to indicate elapsed contact time, maintained >99.9% surface coverage over full contact time and checked for correct chlorine concentration.
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Cloro/farmacologia , Corantes/química , Desinfetantes/química , Hipoclorito de Sódio/química , Cloro/química , Desinfecção , Ambiente de Instituições de Saúde , Propriedades de SuperfícieRESUMO
OBJECTIVE: A novel color additive colorizes chlorine disinfectants blue to improve visibility and enhance spray surface coverage, and it fades to colorless to indicate elapsed contact time. We investigated its interactions with 3 chlorine disinfectants to determine if the additive would adversely affect the disinfectants' antimicrobial efficacy or skin safety. METHODS: We tested 0.5% sodium hypochlorite, 0.2% calcium hypochlorite, and 0.5% sodium dichloroisocyanurate (NaDCC) alone versus with color additive. An independent laboratory tested efficacy against Staphylococcus aureus, Pseudomonas aeruginosa, Vibrio cholerae, and human coronavirus 229E. An independent laboratory also tested direct skin irritation. RESULTS: Chlorine disinfectants with and without color additive achieved equal levels of efficacy against the tested pathogens. Against S. aureus, 0.5% sodium hypochlorite with and without color additive met Environmental Protection Agency criteria for disinfection success. Against human coronavirus 229E, 0.5% sodium hypochlorite alone failed disinfection success criteria, whereas 0.5% sodium hypochlorite with color additive achieved full viral inactivation (≥4.50 log10 reduction). Against V. cholerae, 0.2% calcium hypochlorite alone and with color additive achieved 5.99 log10 and >6.03 log10 reductions, respectively. Against S. aureus and P. aeruginosa, 0.5% NaDCC with and without color additive achieved >4.9 log10 and >3.54 log10 reductions, respectively. All 3 chlorine disinfectants with color additive tested as negligible skin irritants. CONCLUSIONS: This color additive can be combined with chlorine disinfectants without adversely affecting antimicrobial efficacy or skin safety.