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BACKGROUND: Understanding co-occurrence patterns and prognostic implications of immune-related adverse events is crucial for immunotherapy management. However, previous studies have been limited by sample size and generalisability. In this study, we leveraged a multi-institutional cohort and a population-level database to investigate co-occurrence patterns of and survival outcomes after multi-organ immune-related adverse events among recipients of immune checkpoint inhibitors. METHODS: In this retrospective study, we identified individuals who received immune checkpoint inhibitors between May 31, 2015, and June 29, 2022, from the Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Cancer Institute (Boston, MA, USA; MGBD cohort), and between April 30, 2010, and Oct 11, 2021, from the independent US population-based TriNetX network. We identified recipients from all datasets using medication codes and names of seven common immune checkpoint inhibitors, and patients were excluded from our analysis if they had incomplete information (eg, diagnosis and medication records) or if they initiated immune checkpoint inhibitor therapy after Oct 11, 2021. Eligible patients from the MGBD cohort were then propensity score matched with recipients of immune checkpoint inhibitors from the TriNetX database (1:2) based on demographic, cancer, and immune checkpoint inhibitor characteristics to facilitate cohort comparability. We applied immune-related adverse event identification rules to identify patients who did and did not have immune-related adverse events in the matched cohorts. To reduce the likelihood of false positives, patients diagnosed with suspected immune-related adverse events within 3 months after chemotherapy were excluded. We performed pairwise correlation analyses, non-negative matrix factorisation, and hierarchical clustering to identify co-occurrence patterns in the MGBD cohort. We conducted landmark overall survival analyses for patient clusters based on predominant immune-related adverse event factors and calculated accompanying hazard ratios (HRs) and 95% CIs, focusing on the 6-month landmark time for primary analyses. We validated our findings using the TriNetX cohort. FINDINGS: We identified 15 246 recipients of immune checkpoint inhibitors from MGBD and 50 503 from TriNetX, of whom 13 086 from MGBD and 26 172 from TriNetX were included in our propensity score-matched cohort. Median follow-up durations were 317 days (IQR 113-712) in patients from MGBD and 249 days (91-616) in patients from TriNetX. After applying immune-related adverse event identification rules, 8704 recipients of immune checkpoint inhibitors were retained from MGBD, of whom 3284 (37·7%) had and 5420 (62·3%) did not have immune-related adverse events, and 18 162 recipients were retained from TriNetX, of whom 5538 (30·5%) had and 12 624 (69·5%) did not have immune-related adverse events. In both cohorts, positive pairwise correlations of immune-related adverse events were commonly observed. Co-occurring immune-related adverse events were decomposed into seven factors across organs, revealing seven distinct patient clusters (endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological). In the MGBD cohort, the patient clusters that predominantly had endocrine (HR 0·53 [95% CI 0·40-0·70], p<0·0001) and cutaneous (0·61 [0·46-0·81], p=0·0007) immune-related adverse events had favourable overall survival outcomes at the 6-month landmark timepoint, while the other clusters either had unfavourable (respiratory: 1·60 [1·25-2·03], p=0·0001) or neutral survival outcomes (gastrointestinal: 0·86 [0·67-1·10], p=0·23; musculoskeletal: 0·97 [0·78-1·21], p=0·78; hepatic: 1·20 [0·91-1·59], p=0·19; and neurological: 1·30 [0·97-1·74], p=0·074). Similar results were found in the TriNetX cohort (endocrine: HR 0·75 [95% CI 0·60-0·93], p=0·0078; cutaneous: 0·62 [0·48-0·82], p=0·0007; respiratory: 1·21 [1·00-1·46], p=0·044), except for the neurological cluster having unfavourable (rather than neutral) survival outcomes (1·30 [1·06-1·59], p=0·013). INTERPRETATION: Reliably identifying the immune-related adverse event cluster to which a patient belongs can provide valuable clinical information for prognosticating outcomes of immunotherapy. These insights can be leveraged to counsel patients on the clinical impact of their individual constellation of immune-related adverse events and ultimately develop more personalised surveillance and mitigation strategies. FUNDING: US National Institutes of Health.
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Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/imunologiaRESUMO
Cutaneous imaging is a central tenant to the practice of dermatology. In this article, the authors explore various noninvasive and invasive skin imaging techniques, as well as the latest deployment of these technologies in conjunction with the use artificial intelligence and machine learning. The authors also provide insight into the benefits, limitations, and challenges around integrating these technologies into dermatologic practice.
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Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal and other cells within the tumor microenvironment (TME). Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize molecular, cellular and spatial properties of TMEs for various malignancies. This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of TMEs using multiplexed single-cell data. The source code and tutorials are available at https://semenovlab.github.io/SpatialCells. SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion and metastasis.
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Análise de Célula Única , Software , Microambiente Tumoral , Análise de Célula Única/métodos , Humanos , Neoplasias/patologia , Aprendizado de Máquina , Biologia Computacional/métodosRESUMO
In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.
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Linfócitos T CD8-Positivos , Vacinas Anticâncer , Carboximetilcelulose Sódica/análogos & derivados , Células Dendríticas , Glioma , Interferons , Poli I-C , Polilisina/análogos & derivados , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Glioma/imunologia , Glioma/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Poli I-C/administração & dosagem , Poli I-C/farmacologia , Adulto , Receptores Toll-Like/agonistas , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Idoso , Vacinação , Monócitos/imunologia , Monócitos/efeitos dos fármacos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunoterapia/métodos , Agonistas do Receptor Semelhante a TollRESUMO
BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVES: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. RESULTS: Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.
Cutaneous immune-related adverse events (cirAEs) are the most common complications to occur for oncology patients treated with immune checkpoint inhibitors (ICIs). cirAEs can lead to increased use of healthcare resources and significant morbidity. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. In this study, we aimed to investigate the influence of cancer organ system and histology on the development of cirAEs and survival outcomes. To do this, we included a cohort of patients retrospectively between 1 December 2011 and 30 October 2020. We identified 3668 ICI recipients who were seen at Massachusetts General Brigham and Dana-Farber in Boston, Massachusetts. Of these, 669 people developed cirAEs. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI start, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. We found that, compared with other nonepithelial cancers, patients with cutaneous squamous cell carcinoma (cSCC) and melanoma were at significantly higher risk of cirAEs. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma and cSCC. This study improves our understanding of patients who are at highest risk of developing cirAEs those with melanoma and cSCC. Therefore, many patients could benefit from appropriate counselling and close monitoring by their oncologists and dermatologists throughout ICI therapy.
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Inibidores de Checkpoint Imunológico , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/mortalidade , Neoplasias/imunologia , Neoplasias/terapia , Toxidermias/etiologia , Toxidermias/patologia , Toxidermias/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/tratamento farmacológico , AdultoRESUMO
Background: Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal, and other cells within the tumor microenvironment. Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize the molecular, cellular, and spatial properties of tumor microenvironments for various malignancies. Results: This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of tumor microenvironments using multiplexed single-cell data. Conclusions: SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion, and metastasis.
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Biosynthesis of gold nanoparticles (AuNPs) using algal polysaccharides is a simple, low-cost, and an eco-friendly approach. In the current study, different concentrations of Arthospira platensis exopolysaccharides (EPS) were used to synthetize AuNPs via the reduction of gold ions. The biologically synthesized AuNPs (AuNPs1, AuNPs2, AuNPs3) were prepared in 3 different forms through the utilization of three different ratios of EPS-reducing agents. AuNPs analysis confirmed the spherical shape of the EPS-coated AuNPs. Furthermore, AuNPs prepared by EPS and L-ascorbic acid (AuNPs3) showed more stability than the AuNPs colloidal solution that was prepared using only L-ascorbic acid. Analysis of the antimicrobial effects of AuNPs showed that E. coli was the most sensitive bacterial species for AuNPs3 and AuNPs1 with inhibition percentages of 88.92 and 83.13%, respectively. Also, safety assay results revealed that AuNPs3 was the safest biogenic AuNPs for the tested noncancerous cell line. The anticancer assays of the biogenic AuNPs1, AuNPs2, and AuNPs3 against MCF-7 cell line indicated that this cell line was the most sensitive cell line to all treatments and it showed inhibition percentages of 66.2%, 57.3%, and 70.2% to the three tested AuNPs, respectively. The AuNPs also showed abilities to arrest MCF-7 cells in the S phase (77.34%) and increased the cellular population in the sub G0 phase. Gene expression analysis showed that AuNPs3 down regulated Bcl2, Ikapα, and Survivn genes in MCF-7 treated-cells. Also, transmission electron microscopy (TEM) analysis of MCf-7 cells revealed that AuNPs 3 and AuNPs2 were localized in cell vacuoles, cytoplasm, and perinuclear region.
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Neoplasias da Mama , Nanopartículas Metálicas , Antibacterianos/farmacologia , Ácido Ascórbico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Escherichia coli , Feminino , Ouro/farmacologia , Química Verde/métodos , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/farmacologiaRESUMO
OBJECTIVES: Living donor liver transplant is the gold standard therapy for patients with terminal hepatic disorders for whom no alternative therapy is available. The primary aim was to assess different intraoperative factors that may predict early death after adult-to-adult living donor liver transplant. The secondary aim was to assess the effect of small-for-size syndrome on mortality. MATERIALS AND METHODS: This retrospective multicenter cohort study was performed on records from 145 adults with cirrhosis who had received a right lobe living donor liver transplant. Patients were divided according to the occurrence of short-term mortality (death within the first month after transplant). The primary intraoperative parameters included graft weight, surgical duration, mean blood pressure, serum lactate and sodium bicarbonate, transfusions, durations of cold and warm ischemia and anhepatic phase, input and output during surgery, and portal venous pressures. RESULTS: There were statistically significant variations between both cohorts for number of units of packed red blood cells, durations of cold and warm ischemia and anhepatic phase, preclamp and postreperfusion portal venous pressures, average urine output, mean serum lactate, mean blood pressure, and surgical duration (P ⟨ .001). Also, there were significant differences in the number of platelets, units of fresh frozen plasma, and mean sodium bicarbonate (P = .025, .003, and .035, respectively). Of the 25 patients who died within the early postoperative period, 20 had developed small-for-size syndrome (P ⟨ .001). CONCLUSIONS: A variety of intraoperative risk factors may affect early posttransplant mortality, which suggests the high complexity of living donor liver transplants and the need for well-trained experienced teams to perform these surgeries.