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OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.
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Melanoma , Estadificación de Neoplasias , Nivolumab , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos Inmunológicos/uso terapéutico , Quimioterapia Adyuvante/métodos , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/patología , Melanoma/cirugía , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Resultado del TratamientoRESUMEN
We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 - 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 - 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.
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Neoplasias , Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Humanos , Antígenos HLA-A , Papillomavirus Humano 16 , Leucocitos Mononucleares , Neoplasias/complicaciones , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/complicacionesRESUMEN
PURPOSE OF REVIEW: To review recent advancements in the genetic understanding, diagnosis, prognosis, and treatment of uveal melanoma (UM). RECENT FINDINGS: UM is a molecularly distinct melanocytic malignancy driven by mutations in GNAQ or GNA11, with mitogen-activated protein kinase pathway upregulation. Earlier diagnosis and treatment are important factors for improving life prognosis. These goals can be aided by more objective multimodal imaging risk factors for the prediction of malignant nevus transformation and novel treatment strategies such as customized radiation fields and nanoparticle therapy to reduce vision-threatening treatment side effects. The risk for metastatic disease can be reliably predicted through gene expression profiling or the Cancer Genome Atlas project classification, and combined use of clinical tumor features with molecular data allows for highly individualized patient prognosis. Patients with high-risk UM should be considered for clinical trials of adjuvant therapy to prevent metastatic disease. For patients with clinically evident metastasis, combination immunotherapy regimens, T cell-based therapies, and focal adhesion kinase inhibitors offer hope for improved clinical response rates. SUMMARY: Improved understanding of UM molecular pathogenesis and clinical trials of targeted therapy for prevention and treatment of metastatic disease may improve patient survival for this challenging disease.
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Melanoma/diagnóstico , Melanoma/terapia , Atención al Paciente/tendencias , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/terapia , Transformación Celular Neoplásica/patología , Tratamiento Basado en Trasplante de Células y Tejidos , Diagnóstico Precoz , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Humanos , Inmunoterapia , Laboratorios , Melanoma/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Úvea/genéticaRESUMEN
INTRODUCTION: Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab. METHODS: A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis. RESULTS: A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab (n = 22) or ipilimumab in combination with nivolumab (n = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p = 0.81. CONCLUSIONS: In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/métodos , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Melanoma/terapia , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Anciano , Terapia Combinada , Bases de Datos Factuales , Registros Electrónicos de Salud , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
AIMS: Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI ), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods have not yet been described. METHODS AND RESULTS: Clinicopathological characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in-situ hybridisation and RNA-based digital molecular analysis assays were performed on archival tissue from 173 stage III and 192 stage IV tumours. ALKATI was identified in 12.7 and 4.8% stage III and IV tumours, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (n = 20) and mixed ALKATI (combined ALKATI and ALKWT ; n = 7). Isolated ALKWT expression (n = 4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression compared to those with ALKWT or no expression [5-year survival 80, 95% confidence interval (CI) = 57-100% versus 43%, 95% CI = 34-55%, P = 0.013]. Clinicopathological characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (n = 12) has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI . CONCLUSION: Presence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.
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Quinasa de Linfoma Anaplásico/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/genética , Estudios Retrospectivos , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: There is currently no FDA or EMA-approved standard of care for metastatic uveal melanoma. MATERIAL AND METHODS: A systematic review of all interventional uveal melanoma trials on the ClinicalTrials.gov database and EU Clinical Trials Register was conducted from January 15, 2019 through November 30, 2019. Categorical data analysis and descriptive statistics were generated. RESULTS: A total of 119 trials met inclusion criteria for this systematic review, of which 39 were active. Of all trials, 47% were NIH-funded while 59% of active trials were industry funded. Of all trials, 86% were concerned with treatment of metastasis, 7% with adjuvant therapy, and 8% with treatment of primary tumor. In trials treating metastasis, 62% reported response rates as their primary outcome measure. Non-randomized patient allocation to treatment arms was reported in 73% of trials, and 8% of trials were in phase 3. Pharmaceutical drugs were utilized by 69% of trials. Of the 6 negative randomized trials, all reported no significant effect from intervention compared to a control arm and were usually initiated on preclinical or early phase data. CONCLUSION: Given decreased NIH funding for uveal melanoma trials, clinicians should consider industry funding partnerships. Standardization of primary outcome measures between trials will also allow for statistical meta-analyses of results in this rare patient population. Finally, clinicians should use single arm studies to establish significant treatment response rates before proceeding with randomized trials.
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Melanoma , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Nivel de Atención , Neoplasias de la Úvea/tratamiento farmacológicoRESUMEN
Background: Pembrolizumab (P) and nivolumab (N) are commonly used therapies for advanced melanoma. However, their effectiveness has never been directly compared, leaving little guidance for clinicians to select the best therapy. Therefore, we sought to retrospectively compare the overall survival of patients with metastatic melanoma treated with front line P or N in the real-world setting.Material and methods: This study included patients with advanced melanoma, diagnosed between 1 January 2011 and 31 July 2018, treated with frontline P or N who were included in a nationwide, longitudinal de-identified electronic health record (EHR)-derived database. Overall survival (OS) was estimated for each treatment group using Kaplan-Meier curves with a log-rank test. Comparison of OS was estimated using an inverse probability weighting model to reduce bias between the groups. The model was adjusted using age, sex, ECOG, LDH (elevated or not), BRAF (mutated or not), Kit (mutated or not), NRAS (mutated or not), PD-L1 expression (0% or greater), Body Mass Index, and primary site.Results: 888 patients with advanced disease who received treatment with frontline P (n = 486) or N (n = 402) were identified. Median OS for all patients treated with P was 22.6 months (m) and was 23.9 m for those treated with N (p = 0.91). In the inverse probability weight analysis there was no difference in survival between patients treated with P or N 1.06 (95% CI 0.84-1.33).Concluding Statement: In our retrospective, real-world analysis of patients with advanced melanoma, no statistical difference in OS was noted between patients treated with frontline P compared to N. This supports the current practice of choosing either P or N based on patient and provider preference.
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Antineoplásicos Inmunológicos/uso terapéutico , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Humanos , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nivolumab/administración & dosificación , Estudios Retrospectivos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Melanoma is an aggressive cancer that arises from melanocytes that can both locally invade surrounding tissues as well as metastasize systemically. If detected early, melanoma can be curable with surgical resection. However, despite complete removal, high-risk resected melanomas have a significant rate of both local and distant recurrence. Curative treatment options are typically limited for patients who develop distant recurrence after resections of their primary melanoma. Therefore, adjuvant therapy is typically given after complete resection of high-risk melanomas to try and reduce the risk of recurrent disease. Adjuvant therapy for high-risk resected melanoma has changed considerably over the past couple of years due to the availability of new melanoma therapies that are active in the metastatic setting. Here, we review the new treatment options and ongoing clinical research for adjuvant therapy.
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Procedimientos Quirúrgicos Dermatologicos/métodos , Melanoma/terapia , Estadificación de Neoplasias , Neoplasias Cutáneas/terapia , Quimioterapia Adyuvante/métodos , Humanos , Melanoma/diagnóstico , Radioterapia Adyuvante/métodos , Neoplasias Cutáneas/diagnósticoRESUMEN
c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0years; interquartile range, 61-75) had epithelioid (n=97), biphasic (n=18), or sarcomatoid (n=34) MPM. Median follow-up was 10.1months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes (P=.015; P=.0001, and P=.0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio=2.81; 95% confidence interval, 1.21-6.51; P=.01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression.
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Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Mesotelioma/diagnóstico , Mesotelioma/metabolismo , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Anciano , Femenino , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ , Masculino , Mesotelioma Maligno , Persona de Mediana Edad , Pronóstico , Sarcoma/diagnóstico , Sarcoma/metabolismoRESUMEN
Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
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K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O 2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O 2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O 2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O 2.-, and treatment with the small molecule O 2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O 2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.
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Proliferación Celular , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismo , Proteínas ras/metabolismo , Animales , Western Blotting , Óxidos N-Cíclicos , Citosol/enzimología , Espacio Extracelular/enzimología , Fluorescencia , Humanos , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Desnudos , Mitocondrias/enzimología , NADPH Oxidasa 2 , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Neoplasias Pancreáticas/metabolismo , Fenantridinas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , ARN Interferente Pequeño/genética , Marcadores de Spin , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/genética , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre , Proteínas ras/genéticaRESUMEN
A 66-year-old female with a history of two renal transplants due to recurrent thrombotic thrombocytopenic purpura presented to clinic with multiple lesions identified to be non-metastatic cutaneous squamous cell carcinoma (CSCC). The patient previously underwent multiple Mohs procedures and radiation therapy treatment but continued to develop CSCC lesions with increasing frequency. After discussing multiple treatment options, it was elected to pursue treatment with Talimogene laherparepvec (T-VEC) given the systemic immune responses it can cause, with low theoretical risk of graft rejection. After starting intratumoral T-VEC injections, treated lesions began to decrease in size, and a reduction in the rate of new CSCC lesions was observed. Treatment was held due to unrelated renal complications during which time new CSCCs developed. Patient was restarted on T-VEC therapy with no recurrent renal issues. Upon reinitiating treatment, injected and non-injected lesions showed reduction in size, and the development of new lesions again ceased. One injected lesion was resected via Mohs micrographic surgery due to its size and discomfort. On sectioning, this demonstrated an exuberant lymphocytic perivascular infiltrate which was consistent with treatment response to T-VEC, with little active tumor. With high rates of non-melanoma skin cancer in renal transplant patients, their transplant status significantly limits treatment options, specifically with regards to anti-PD-1 therapy. This case suggests T-VEC can generate local and systemic immune responses in the setting of immunosuppression and that T-VEC may be a beneficial therapeutic option for transplant patients with CSCC.
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Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.
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PURPOSE: The purpose of this study was to analyze the prevalence of an activating mutation in the B-Raf proto-oncogene (BRAF) V600E immunoreactivity in pediatric conjunctival lesions. METHODS: This retrospective case-control study included 32 pediatric patients who underwent surgical excision of conjunctival lesions between Jan 2019 and May 2022. The collected data included demographic data, clinical features, and histopathologic characteristics of the lesion, including BRAF V600E positivity. The Student t test and the Fisher exact test were used to determine the significance of the associations between clinical variables and BRAF positivity. RESULTS: BRAF immunoreactivity was positive in 11/32 lesions (34%). Age at diagnosis did not correlate with BRAF positivity, with a mean age at diagnosis of 131.7 months for patients with BRAF+ lesions and 134.7 months for those with BRAF- lesions (P > 0.1). No clinical or pathological features were found to be significantly correlated with BRAF positivity, although there was a trend toward BRAF positivity in the presence of cysts (P = 0.072). CONCLUSIONS: BRAF reactivity was present in approximately one-third of pediatric conjunctival nevi but does not correlate significantly with unique clinical or histopathological features.
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Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.
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Antimitóticos , Neoplasias Encefálicas , Terapia por Estimulación Eléctrica , Glioblastoma , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , HumanosRESUMEN
OBJECTIVES: Optimal sequence of therapy for patients with metastatic pancreatic ductal adenocarcinoma is unknown. Combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel + gemcitabine (nab-p/gem) are standard first-line (1L) therapies. They have never been prospectively compared. We retrospectively compared overall survival (OS) of patients treated with 1L nab-p/gem and second-line (2L) FOLFIRINOX with those treated with the reverse sequence. METHODS: Patients with metastatic pancreatic ductal adenocarcinoma treated with 1L FOLFIRINOX and 2L nab-p/gem or vice versa were identified using an electronic health record-derived real-world database. Using an intent-to-treat analysis, we compared OS from initiation of 1L therapy. A Cox model, stratified by deciles of propensity score, estimated the effect of treatment sequence on OS. RESULTS: The study included 3027 patients. The median OS for 1L FOLFIRINOX versus nab-p/gem was 8.6 versus 6.1 months (hazard ratio, 0.77; 95% confidence interval, 0.70-0.84). The median OS for 1L FOLFIRINOX and 2L nab-p/gem versus 1L nab-p/gem and 2L FOLFIRINOX was 11.9 versus 11.5 months (hazard ratio, 0.97; 95% confidence interval, 0.79-1.18). CONCLUSIONS: In this analysis of real-world data, 1L FOLFIRINOX was associated with increased OS in propensity analysis. For patients who received both FOLFIRINOX and nab-p/gem, median OS was similar regardless of sequence.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Albúminas/administración & dosificación , Carcinoma Ductal Pancreático/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Evaluación de Resultado en la Atención de Salud/métodos , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , GemcitabinaRESUMEN
Immune checkpoint inhibitors (ICIs), monoclonal antibodies to cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1 or its ligand PD-L1 are rapidly changing the treatment landscape and prognosis of many cancer types. Following their initial approval in melanoma in 2011, ICIs are now approved in many other cancers. Despite the long-term, durable response that can be noted with ICIs, the majority of patients do not respond to ICIs and some of the initial responders develop relapsed disease during their treatment course. In order to improve the response rate to ICIs, an understanding of the mechanisms of resistance is critical. Given the number of different ways cancers can become resistant to ICIs, patient-rather than population-based strategies to reverse resistance will likely be needed. We review the currently defined mechanisms of resistance to ICIs and discuss possible methods to overcome these mechanisms.
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Antineoplásicos Inmunológicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Humanos , Melanoma/inmunología , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
The rapid expansion of modern cancer immunotherapeutics has led to a dramatic improvement in patient survival and sustained remission for otherwise refractory malignancies. However, a significant limitation behind these current treatment modalities is an irregularity in clinical response, which is especially pronounced among checkpoint inhibition. This unpredictability leads to significant side effects, financial costs, and health care burden, with unsatisfactory clinical benefit in the majority of treated patients. Additionally, although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit. This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting. Herein, we discuss current advantages of predictive biomarkers, as well as limitations in their clinical use and application. We also review future directions, ideal characteristics, and trial design needed for proper precision immuno-oncology and biomarker development.
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Biomarcadores de Tumor/inmunología , Inmunoterapia/métodos , Medicina de Precisión/métodos , Proteómica/métodos , HumanosRESUMEN
Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Tumores Neuroendocrinos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/metabolismo , Ratones Noqueados , Tumores Neuroendocrinos/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Análisis de la Célula Individual , Carcinoma Pulmonar de Células Pequeñas/metabolismoRESUMEN
BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi. METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.