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BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Adenocarcinoma/tratamento farmacológico , Neoplasias PancreáticasRESUMO
Talimogene Laherparepvec (OncoVEXmGMCSF), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAFCA/+; PTENflox/flox), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEXmGMCSF. We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEXmGMCSF have decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEXmGMCSF compared to mice not treated with OncoVEXmGMCSF. Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEXmGMCSF + BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEXmGMCSF is more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEXmGMCSF had more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma.
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Antineoplásicos , Melanoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia , Melanoma/tratamento farmacológico , Camundongos , Proteínas Proto-Oncogênicas B-raf/genética , Microambiente TumoralRESUMO
BACKGROUND: Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection. METHODS: Here, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). RESULTS: Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1. CONCLUSION: This case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Adolescente , Adulto , Carcinoma Hepatocelular/cirurgia , Criança , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgiaRESUMO
Eribulin inhibits microtubule polymerization and suppresses epithelial-mesenchymal transition. Conventional pathology approaches have not identified a precise predictive biomarker for Eribulin. We performed qmIF on pre-treatment tissue from 11 patients (6 TNBC, 5 HGSOC) treated with Eribulin-LF. T-lymphocytes were the dominant immune-subset in TME, with higher levels detected in stroma vs tumor (9% vs 2%). Greater density of CD3+ (p = 0.01) and CD3 + CD8+ (p = 0.03) cells and closer proximity between CD3 + CD8+ and tumor cells was observed in the patients with disease control (PR + SD) vs. progressive disease. QmIF identified an association between TIL infiltration and Eribulin-LF sensitivity, which should be evaluated further in prospective studies.
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Biomarcadores Tumorais/imunologia , Neoplasias da Mama/tratamento farmacológico , Cistadenoma Seroso/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias da Mama/imunologia , Complexo CD3/metabolismo , Antígenos CD8 , Ensaios Clínicos Fase I como Assunto , Feminino , Imunofluorescência , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Fosfolipídeos , Análise de Sobrevida , Linfócitos T/metabolismo , Resultado do Tratamento , Microambiente TumoralRESUMO
PURPOSE: To compare the prognostic value of imaging biomarkers derived from a quantitative analysis of baseline 18F-FDG-PET/CT in patients with mucosal melanoma (Muc-M) or cutaneous melanoma (Cut-M) treated with immune checkpoint inhibitors (ICIs). METHODS: In this retrospective monocentric study, we included 56 patients with non-resectable Muc-M (n = 24) or Cut-M (n = 32) who underwent baseline 18F-FDG-PET/CT before treatment with ICIs between 2011 and 2017. Parameters were extracted from (i) tumoral tissues: SUVmax, SUVmean, TMTV (total metabolic tumor volume), and TLG (total lesion glycolysis) and (ii) lymphoid tissues: BLR (bone marrow-to-liver SUVmax ratio) and SLR (spleen-to-liver SUVmax ratio). Association with survival and response was evaluated using Cox prediction models, Student's t tests, and Spearman's correlation respectively. p < 0.05 was considered significant. RESULTS: Majority of ICIs were anti-PD1 (92.9%, n = 52/56). All 18F-FDG-PET/CT were positive. Overall (Muc-M to Cut-M), ORR was 33%:42%, DCR was 56%:69%, median follow-up was 25.0:28.9 months, median PFS was 4.7:10.7 months, and median OS was 23.9:28.3 months. In Muc-M, increased tumor SUVmax was associated with shorter OS while it was not correlated with PFS, ORR, or DCR. In Cut-M, increased TMTV and increased BLR were independently associated with shorter OS, shorter PFS, and lower response (ORR, DCR). CONCLUSION: While all Muc-M and Cut-M were FDG avid, prognostic imaging biomarkers differed. For Muc-M patients treated with ICI, the only prognostic imaging biomarker was a high baseline maximal glycolytic activity (SUVmax), whereas for Cut-M patients, baseline metabolic tumor burden or bone marrow metabolism was negatively correlated to ICI response duration.
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Melanoma , Neoplasias Cutâneas , Antígeno CTLA-4 , Fluordesoxiglucose F18 , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/tratamento farmacológico , Carga TumoralRESUMO
PURPOSE: To enhance clinician's decision-making by diagnosing hepatocellular carcinoma (HCC) in cirrhotic patients with indeterminate liver nodules using quantitative imaging features extracted from triphasic CT scans. MATERIAL AND METHODS: We retrospectively analyzed 178 cirrhotic patients from 27 institutions, with biopsy-proven liver nodules classified as indeterminate using the European Association for the Study of the Liver (EASL) guidelines. Patients were randomly assigned to a discovery cohort (142 patients (pts.)) and a validation cohort (36 pts.). Each liver nodule was segmented on each phase of triphasic CT scans, and 13,920 quantitative imaging features (12 sets of 1160 features each reflecting the phenotype at one single phase or its change between two phases) were extracted. Using machine-learning techniques, the signature was trained and calibrated (discovery cohort), and validated (validation cohort) to classify liver nodules as HCC vs. non-HCC. Effects of segmentation and contrast enhancement quality were also evaluated. RESULTS: Patients were predominantly male (88%) and CHILD A (65%). Biopsy was positive for HCC in 77% of patients. LI-RADS scores were not different between HCC and non-HCC patients. The signature included a single radiomics feature quantifying changes between arterial and portal venous phases: DeltaV-A_DWT1_LL_Variance-2D and reached area under the receiver operating characteristic curve (AUC) of 0.70 (95%CI 0.61-0.80) and 0.66 (95%CI 0.64-0.84) in discovery and validation cohorts, respectively. The signature was influenced neither by segmentation nor by contrast enhancement. CONCLUSION: A signature using a single feature was validated in a multicenter retrospective cohort to diagnose HCC in cirrhotic patients with indeterminate liver nodules. Artificial intelligence could enhance clinicians' decision by identifying a subgroup of patients with high HCC risk. KEY POINTS: ⢠In cirrhotic patients with visually indeterminate liver nodules, expert visual assessment using current guidelines cannot accurately differentiate HCC from differential diagnoses. Current clinical protocols do not entail biopsy due to procedural risks. Radiomics can be used to non-invasively diagnose HCC in cirrhotic patients with indeterminate liver nodules, which could be leveraged to optimize patient management. ⢠Radiomics features contributing the most to a better characterization of visually indeterminate liver nodules include changes in nodule phenotype between arterial and portal venous phases: the "washout" pattern appraised visually using EASL and EASL guidelines. ⢠A clinical decision algorithm using radiomics could be applied to reduce the rate of cirrhotic patients requiring liver biopsy (EASL guidelines) or wait-and-see strategy (AASLD guidelines) and therefore improve their management and outcome.
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Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico por imagem , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Aprendizado de Máquina , Tomografia Computadorizada por Raios X/métodos , Idoso , Inteligência Artificial , Carcinoma Hepatocelular/patologia , Meios de Contraste/farmacologia , Diagnóstico Diferencial , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OPINION STATEMENT: There is an unmet need for additional treatments for metastatic melanoma, besides anti-PD1 antibodies which are FDA approved for adjuvant therapy for stage III or resected stage IV melanoma. Talimogene laherparepvec (T-VEC) is the first and only FDA-approved oncolytic virus for the treatment of melanoma. New viral vectors including coxsackieviruses, HF-10, adenovirus, reovirus, echovirus, and newcastle disease virus are currently under active development and investigation with varying degrees of efficacy in targeting melanoma. The use of T-VEC as a neoadjuvant therapy is emerging, but more data is needed at this point. T-VEC has also shown promise for use in combination therapy with ipilimumab, as T-VEC plus ipilimumab has a significantly higher objective response compared to ipilimumab alone. Data comparing T-VEC in combination with PD-1 checkpoint inhibitors is awaited, and a phase III trial is underway. It is likely that oncolytic viruses will have long-term application in the treatment of melanoma and that T-VEC in particular will continue to have a role in the treatment of patients with readily accessible cutaneous lesions both for local control and synergistic induction of antitumor immunity as part of combination therapies.
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Terapia Genética , Vetores Genéticos , Melanoma/patologia , Melanoma/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Vacinas Anticâncer , Ensaios Clínicos como Assunto , Terapia Combinada , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Melanoma/etiologia , Terapia Neoadjuvante , Metástase Neoplásica , Estadiamento de Neoplasias , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Prognóstico , Resultado do TratamentoRESUMO
PURPOSE: An imaging-based stratification tool is needed to identify melanoma patients who will benefit from anti Programmed Death-1 antibody (anti-PD1). We aimed at identifying biomarkers for survival and response evaluated in lymphoid tissue metabolism in spleen and bone marrow before initiation of therapy. METHODS: This retrospective study included 55 patients from two institutions who underwent 18F-FDG PET/CT before anti-PD1. Parameters extracted were SUVmax, SUVmean, HISUV (SUV-based Heterogeneity Index), TMTV (total metabolic tumor volume), TLG (total lesion glycolysis), BLR (Bone marrow-to-Liver SUVmax ratio), and SLR (Spleen-to-Liver SUVmax ratio). Each parameter was dichotomized using the median as a threshold. Association with survival, best overall response (BOR), and transcriptomic analyses (NanoString assay) were evaluated using Cox prediction models, Wilcoxon tests, and Spearman's correlation, respectively. RESULTS: At 20.7 months median follow-up, 33 patients had responded, and 29 patients died. Median PFS and OS were 11.4 (95%CI 2.7-20.2) and 28.5 (95%CI 13.4-43.8) months. TMTV (>25cm3), SLR (>0.77), and BLR (>0.79) correlated with shorter survival. High TMTV (>25 cm3), SLR (>0.77), and BLR (>0.79) correlated with shorter survival, with TMTV (HR PFS 2.2, p = 0.02, and HR OS 2.5, p = 0.02) and BLR (HR OS 2.3, p = 0.04) remaining significant in a multivariable analysis. Low TMTV and TLG correlated with BOR (p = 0.03). Increased glucose metabolism in bone marrow (BLR) was associated with transcriptomic profiles including regulatory T cell markers (p < 0.05). CONCLUSION: Low tumor burden correlates with survival and objective response while hematopoietic tissue metabolism correlates inversely with survival. These biomarkers should be further evaluated for potential clinical application.
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Biomarcadores Tumorais/metabolismo , Imunoterapia , Melanoma/imunologia , Melanoma/terapia , Tomografia por Emissão de Pósitrons , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Fluordesoxiglucose F18 , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Transcriptoma , Resultado do Tratamento , Adulto JovemRESUMO
A correction was made to a sentence in the original article to provide additional clarification in the "Other Oncolytic Viruses" section.
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PURPOSE OF REVIEW: Oncolytic virotherapy is a new approach to the treatment of cancer and its success in the treatment of melanoma represents a breakthrough in cancer therapeutics. This paper provides a review of the current literature on the use of oncolytic viruses (OVs) in the treatment of melanoma. RECENT FINDINGS: Talimogene laherparepvec (T-VEC) is the first OV approved for the treatment of melanoma and presents new challenges as it enters the clinical setting. Several other OVs are at various stages of clinical and pre-clinical development for the treatment of melanoma. Reports from phase Ib-III clinical trials combining T-VEC with checkpoint blockade are encouraging and demonstrate potential added benefit of combination immunotherapy. OVs have recently emerged as a standard treatment option for patients with advanced melanoma. Several OVs and therapeutic combinations are in development. Immunooncolytic virotherapy combined with immune checkpoint inhibitors is promising for the treatment of advanced melanoma.
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Melanoma/terapia , Terapia Viral Oncolítica , Humanos , PrognósticoRESUMO
BACKGROUND & AIMS: Premalignant lesions and early stage tumors contain immunosuppressive microenvironments that create barriers for cancer vaccines. Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which express an activated form of Kras in pancreatic tissues, develop pancreatic intraepithelial neoplasms (PanIN) that progress to pancreatic ductal adenocarcinoma (PDA). We used these mice to study immune suppression in PDA. METHODS: We immunized KPC and Kras(G12D/+);Pdx-1-Cre mice with attenuated intracellular Listeria monocytogenes (which induces CD4(+) and CD8(+) T-cell immunity) engineered to express Kras(G12D) (LM-Kras). The vaccine was given alone or in sequence with an anti-CD25 antibody (PC61) and cyclophosphamide to deplete T-regulatory (Treg) cells. Survival times were measured; pancreatic and spleen tissues were collected and analyzed by histologic, flow cytometry, and immunohistochemical analyses. RESULTS: Interferon γ-mediated, CD8(+) T-cell responses were observed in KPC and Kras(G12D/+);Pdx-1-Cre mice given LM-Kras, but not in unvaccinated mice. Administration of LM-Kras to KPC mice 4-6 weeks old (with early stage PanINs), depleted of Treg cells, significantly prolonged survival and reduced PanIN progression (median survival, 265 days), compared with unvaccinated mice (median survival, 150 days; P = .002), mice given only LM-Kras (median survival, 150 days; P = .050), and unvaccinated mice depleted of Treg cells (median survival, 170 days; P = .048). In 8- to 12-week-old mice (with late-stage PanINs), LM-Kras, alone or in combination with Treg cell depletion, did not increase survival time or slow PanIN progression. The combination of LM-Kras and Treg cell depletion reduced numbers of Foxp3(+)CD4(+) T cells in pancreatic lymph nodes, increased numbers of CD4(+) T cells that secrete interleukin 17 and interferon γ, and caused CD11b(+)Gr1(+) cells in the pancreas to acquire an immunostimulatory phenotype. CONCLUSIONS: Immunization of KPC mice with Listeria monocytogenes engineered to express Kras(G12D), along with depletion of Treg cells, reduces progression of early stage, but not late-stage, PanINs. This approach increases infiltration of the lesion with inflammatory cells. It might be possible to design immunotherapies against premalignant pancreatic lesions to slow or prevent progression to PDA.
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Vacinas Anticâncer/uso terapêutico , Carcinoma in Situ/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Listeria monocytogenes/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígeno CD11b/metabolismo , Vacinas Anticâncer/imunologia , Carcinoma in Situ/genética , Carcinoma in Situ/imunologia , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Integrases/genética , Integrases/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/metabolismo , Fatores de Tempo , Transativadores/genética , Transativadores/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION: Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors. METHODS: Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers. RESULTS: We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count. CONCLUSION: Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.
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Biomarcadores Tumorais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Imuno-Histoquímica , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Melanoma Maligno CutâneoRESUMO
The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.
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Melanoma , Humanos , Imunoterapia , Itália , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/patologia , Melanoma/terapiaRESUMO
BACKGROUND: Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. OBJECTIVE: We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. METHODS: Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. RESULTS: Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). LIMITATIONS: Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CONCLUSIONS: CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.
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Antígenos CD2/imunologia , Melanoma/mortalidade , Melanoma/patologia , Recidiva Local de Neoplasia/mortalidade , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia por Agulha , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/cirurgia , Análise de Sobrevida , Resultado do Tratamento , Melanoma Maligno CutâneoRESUMO
The objective of this study is to describe survival outcomes in patients with metastatic melanoma in a real-world setting receiving combination and single-agent immunotherapy outside the clinical trial context. We conducted a retrospective single-institution study of patients with metastatic melanoma in a real-world setting. Survival was calculated using log-rank test. Contingency tables were analyzed using Fisher's Exact test. CD8â +â T-cell densities were measured using quantitative immunofluorescence and analyzed using Mann-Whitney U test. The median overall survival (OS) for 132 patients was 45.3 months. Brain metastasis did not confer a higher risk of death relative to liver and/or bone disease (39.53 versus 30.00 months, respectively; P â =â 0.687). Anti-PD-1 monotherapy was the most common first-line treatment, received by 49.2% of patients. There was no significant difference in OS between patients receiving single-agent anti-PD-1 and combination anti-PD-1 plus CTLA-4 (39.4 months versus undefined; P â =â 0.643). Patients treated with combination therapy were more likely to be alive without progression at the last follow-up than those who received monotherapy (70.4% versus 49.2%; P â =â 0.0408). Median OS was 21.8 months after initiation of second-line therapy after anti-PD-1 monotherapy. CD8+â T-cell densities were higher in patients who achieved disease control on first-line immunotherapy ( P â =â 0.013). In a real-world setting, patients with metastatic melanoma have excellent survival rates, and treatment benefit can be achieved even after progression on first-line therapy. Combination immunotherapy may produce more favorable long-term outcomes in a real-world setting. High pretreatment CD8+â T-cell infiltration correlates with immunotherapy efficacy.
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Melanoma , Segunda Neoplasia Primária , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Imunoterapia , Progressão da DoençaRESUMO
Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state, whereas invasiveness genes were linked with Epgn3 high-risk status. We identified the ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems, suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/Epgn3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
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Histonas , Melanoma , Humanos , Histonas/genética , Histonas/metabolismo , Melanoma/patologia , Desdiferenciação Celular/genética , Acetilação , Linhagem Celular Tumoral , Cromatina/genéticaRESUMO
Backgroundâ¯: â¯â¯Incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors (ICI). Methods: Demographics were tabulated for 194 patients treated with ICI at the Montefiore-Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. Categorical variables were analyzed by Chi-squared test, and survival was analyzed using Kaplan-Meier (KM) curves. Results: MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2%, respectively, in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and the Model for End-Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p < 0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p = 0.0017). AFP decline correlated with response (p = 0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p = 0.011). Conclusion: In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetic and environmental factors in Hispanics with HCC.
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PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , PPAR alfa , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Ácidos Graxos , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/uso terapêutico , PPAR alfa/antagonistas & inibidoresRESUMO
The approval of immunotherapy for stage II-IV melanoma has underscored the need for improved immune-based predictive and prognostic biomarkers. For resectable stage II-III patients, adjuvant immunotherapy has proven clinical benefit, yet many patients experience significant adverse events and may not require therapy. In the metastatic setting, single agent immunotherapy cures many patients but, in some cases, more intensive combination therapies against specific molecular targets are required. Therefore, the establishment of additional biomarkers to determine a patient's disease outcome (i.e., prognostic) or response to treatment (i.e., predictive) is of utmost importance. Multiple methods ranging from gene expression profiling of bulk tissue, to spatial transcriptomics of single cells and artificial intelligence-based image analysis have been utilized to better characterize the immune microenvironment in melanoma to provide novel predictive and prognostic biomarkers. In this review, we will highlight the different techniques currently under investigation for the detection of prognostic and predictive immune biomarkers in melanoma.
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BACKGROUND: Intrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRß), platelet-derived growth factor beta (PDGFß) and platelet-derived growth factor receptor beta (PDGFRß). METHODS: We included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFßR1, TGFßR2, PDGFß, and PDGFRß. RESULTS: Of the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5-22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFßR1, PDGFß, and PDGFRß, while C9, CD59 and C3 correlated with TGFßR2. CONCLUSION: This study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.