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Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.
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A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
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Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
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Antineoplásicos , Melanoma , Células Supresoras de Origen Mieloide , Neoplasias Cutáneas , Humanos , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Melanoma/tratamiento farmacológico , Antineoplásicos/farmacología , Linfocitos T CD8-positivos/metabolismo , Células Supresoras de Origen Mieloide/metabolismoRESUMEN
The Castleman triad has been described in a select few patients presenting with a retroperitoneal mass, mucocutaneous pemphigus vulgaris, and bronchiolitis obliterans. Here, we describe the Castleman triad in a 19-year-old male with unicentric hyaline vascular type Castleman disease (HV-CD). This patient presented with an array of positive antibodies, including anti-cyclic citrullinated peptide, anti-double-stranded DNA, and Sjogren's IgG. Interestingly, the patient's rheumatologic symptoms resolved after tumor resection, while his antibody profile remained relatively unchanged. HV-CD, with a triad presentation, was thought to be from a paraneoplastic syndrome secondary to an underlying lymphoproliferative disorder. The findings presented here identify multiple autoantibodies potentially contributing to this patient's presentation with HV-CD.
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We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.
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Epidermis , Melanocitos , Pigmentación de la Piel , Vitíligo , Vitíligo/patología , Vitíligo/radioterapia , Vitíligo/metabolismo , Humanos , Epidermis/patología , Epidermis/metabolismo , Epidermis/efectos de la radiación , Pigmentación de la Piel/efectos de la radiación , Melanocitos/patología , Melanocitos/metabolismo , Melanocitos/efectos de la radiación , Terapia Ultravioleta/métodos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Rayos Ultravioleta , Femenino , Masculino , Vía de Señalización Wnt , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genéticaRESUMEN
Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1 S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1 S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1's promotion of stem-like function. Further, the SASH1 S519N variant is in a bona fide Tankyrase-binding motif, and SASH1 S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.
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Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.
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Linfocitos T CD8-positivos , Lisofosfolípidos , Monitorización Inmunológica , Lisofosfolípidos/metabolismo , Transducción de Señal , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismoRESUMEN
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased CTLA4 mRNA was associated with a poorer prognosis in metastatic melanoma. To investigate further, we measured blood CTLA4 mRNA in 273 whole-blood samples from an Australian cohort and found that it was lower in metastatic melanoma than in healthy controls and associated with worse patient survival. We confirmed these findings using Cox proportional hazards model analysis and another cohort from the US. Fractionated blood analysis revealed that Treg cells were responsible for the downregulated CTLA4 in metastatic melanoma patients, which was confirmed by further analysis of published data showing downregulated CTLA-4 surface protein expression in Treg cells of metastatic melanoma compared to healthy donors. Mechanistically, we found that secretomes from human metastatic melanoma cells downregulate CTLA4 mRNA at the post-transcriptional level through miR-155 while upregulating FOXP3 expression in human Treg cells. Functionally, we demonstrated that CTLA4 expression inhibits the proliferation and suppressive function of human Treg cells. Finally, miR-155 was found to be upregulated in Treg cells from metastatic melanoma patients compared to healthy donors. Our study provides new insights into the underlying mechanisms of reduced CTLA4 expression observed in melanoma patients, demonstrating that post-transcriptional silencing of CTLA4 by miRNA-155 in Treg cells may play a critical role. Since CTLA-4 expression is downregulated in non-responder melanoma patients to anti-PD-1 immunotherapy, targeting miRNA-155 or other factors involved in regulating CTLA4 expression in Treg cells without affecting T cells could be a potential strategy to improve the efficacy of immunotherapy in melanoma. Further research is needed to understand the molecular mechanisms regulating CTLA4 expression in Treg cells and identify potential therapeutic targets for enhancing immune-based therapies.
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Melanoma , MicroARNs , Neoplasias Primarias Secundarias , Humanos , Linfocitos T Reguladores , Antígeno CTLA-4 , Australia , Pronóstico , MicroARNs/metabolismoRESUMEN
PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.
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Melanoma , Células Supresoras de Origen Mieloide , Neoplasias Primarias Secundarias , Humanos , Células Supresoras de Origen Mieloide/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Melanoma/patología , Tretinoina/efectos adversos , Neoplasias Primarias Secundarias/tratamiento farmacológicoRESUMEN
Importance: Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)-DR alleles in conferring irAE risk has not been well studied. Objective: To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma. Design, Setting, and Participants: This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis. Exposures: Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma. Main Outcomes and Measures: The association between irAEs and response to therapy, survival, and HLA-DR alleles. Results: Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4. Conclusions and Relevance: These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.
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Antineoplásicos Inmunológicos , Antígenos HLA-DR , Inhibidores de Puntos de Control Inmunológico , Melanoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Casos y Controles , Antígenos HLA-DR/genética , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma Cutáneo MalignoRESUMEN
INTRODUCTION: Primary hip and knee arthroplasty represent two of the most successful orthopaedic surgical interventions in the past century. Similarly, lumbar fusion (LF) remains a valuable, evidence-based option to relieve pain and disability related to spinal degenerative conditions. This study evaluates the relative improvements in 1-year health-related quality of life (HRQOL) measures among patients undergoing primary single-level LF, primary total hip arthroplasty (THA), and primary total knee arthroplasty (TKA). METHODS: Patients older than 18 years who underwent primary single-level posterior LF (posterolateral decompression and fusion with or without transforaminal lumbar interbody fusion, involving any single lumbar level), TKA, and THA at a single academic institution were retrospectively identified. Patient demographics and surgical characteristics were collected. HRQOL measures were collected preoperatively and at 1-year postoperative time point including Short-Form 12 Physical Component Score (PCS) and Mental Component Score (MCS) along with subspecialty-specific outcomes. RESULTS: A total of 2,563 patients were included (346 LF, 1,035 TKA, and 1,182 THA). Change in MCS-12 and PCS-12 after LF did not vary markedly by preoperative diagnosis. LF patients had a significantly lower preoperative MCS-12 (LF: 50.8, TKA: 53.9, THA: 52.9, P < 0.001), postoperative MCS-12 (LF: 52.5, TKA: 54.8, THA: 54.5, P < 0.001), postoperative PCS-12 (LF: 40.1, TKA: 44.0, THA: 43.9, P < 0.001), ΔPCS-12 (LF: 7.9, TKA: 10.8, THA: 11.9, P < 0.001), and PCS-12 recovery ratio (LF: 10.7%, TKA: 15.1%, THA 16.6%, P < 0.001) compared with TKA and THA patients. In regression analysis, both TKA and LF were found to be independently associated with a smaller ΔPCS-12 improvement (TKA: ß = -1.36, P = 0.009; LF: ß = -4.74, P < 0.001) compared with THA. TKA (ß = -1.42, P = 0.003) was also independently associated with a smaller ΔMCS-12 improvement compared with THA. CONCLUSIONS: Patients undergoing single-level LF, TKA, and THA demonstrate notable improvements in HRQOL outcomes at 1 year postoperatively compared with preoperative baseline scores. The greatest improvements were found among THA patients, followed subsequently by TKA and LF patients. Both LF and TKA were independently associated with markedly less improvement in physical disability at 1 year postoperatively compared with THA. STUDY DESIGN: Retrospective Cohort Study.
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Artroplastia de Reemplazo de Rodilla , Fusión Vertebral , Humanos , Estudios Retrospectivos , Calidad de Vida , Resultado del Tratamiento , Artroplastia de Reemplazo de Rodilla/efectos adversosRESUMEN
Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. SIGNIFICANCE: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Rayos Ultravioleta , Genómica , Mutación , Melanoma Cutáneo MalignoRESUMEN
There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers.
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STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The objective of this study was to determine if the degree of interbody cage lordosis and cage positioning are associated with changes in postoperative sagittal alignment after single-level transforaminal lumbar interbody fusion (TLIF). SUMMARY OF BACKGROUND DATA: Ideal sagittal alignment and lumbopelvic alignment have been shown to correlate with postoperative clinical outcomes. TLIF is one technique that may improve these parameters, but whether the amount of cage lordosis improves either segmental or lumbar lordosis (LL) is unknown. METHODS: A retrospective review was performed on patients who underwent single-level TLIF with either a 5-degree or a 12-degree lordotic cage. LL, segmental lordosis (SL), disk height, center point ratio, cage position, and cage subsidence were evaluated. Correlation between center point ratio and change in lordosis was assessed using the Spearman correlation coefficient. Secondary analysis included multiple linear regression to determine independent predictors of change in SL. RESULTS: A total of 126 patients were included in the final analysis, with 51 patients receiving a 5-degree cage and 75 patients receiving a 12-degree cage. There were no differences in the postoperative minus preoperative LL (∆LL) (12-degree cage: -1.66 degrees vs. 5-degree cage: -2.88 degrees, P =0.528) or ∆SL (12-degree cage: -0.79 degrees vs. 5-degree cage: -1.68 degrees, P =0.513) at 1-month follow-up. Furthermore, no differences were found in ∆LL (12-degree cage: 2.40 degrees vs. 5-degree cage: 1.00 degrees, P =0.497) or ∆SL (12-degree cage: 1.24 degrees vs. 5-degree cage: 0.35 degrees, P =0.541) at final follow-up. Regression analysis failed to show demographic factors, cage positioning, or cage lordosis to be independent predictors of change in SL. No difference in subsidence was found between groups (12-degree cage: 25.5% vs. 5-degree cage: 32%, P =0.431). CONCLUSION: Lordotic cage angle and cage positioning were not associated with perioperative changes in LL, SL, or cage subsidence after single-level TLIF. LEVEL OF EVIDENCE: Level III.
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Lordosis , Fusión Vertebral , Humanos , Lordosis/cirugía , Fusión Vertebral/métodos , Vértebras Lumbares/cirugía , Estudios Retrospectivos , Periodo Posoperatorio , Resultado del TratamientoRESUMEN
OBJECTIVES: While much of the research concerning factors associated with responses to immune checkpoint inhibitors (ICIs) has focussed on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are an abundant population of innate-like T cells expressing a semi-invariant T-cell receptor restricted to the MHC class I-like molecule, MR1, presenting vitamin B metabolites derived from bacteria. We sought to characterise MAIT cells in melanoma patients and determined their association with treatment responses and clinical outcomes. METHODS: In this prospective clinical study, we analysed the frequency and functional profile of circulating and tumor-infiltrating MAIT cells in human melanoma patients. Using flow cytometry, we compared these across metastatic sites and between ICI responders vs. non-responders as well as healthy donors. RESULTS: We identified tumor-infiltrating MAIT cells in melanomas across metastatic sites and found that the number of circulating MAIT cells is reduced in melanoma patients compared to healthy donors. However, circulating MAIT cell frequencies are restored by ICI treatment in responding patients, correlating with treatment responses, in which patients with high frequencies of MAIT cells exhibited significantly improved overall survival. CONCLUSION: Our results suggest that MAIT cells may be a potential predictive marker of responses to immunotherapies and provide rationale for testing MAIT cell-directed therapies in combination with current and next-generation ICIs.
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STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The goal of this study is to evaluate the outcomes of patients with cervical degenerative spondylolisthesis (DS) undergoing anterior cervical discectomy and fusion (ACDF), specifically comparing surgeries that include versus exclude the DS level. SUMMARY OF BACKGROUND DATA: DS has been extensively studied in the lumbar spine associated with both back and leg pain leading to worse patient quality of life measures. Conversely, there is a relative dearth of literature regarding surgical and clinical outcomes in the setting of cervical DS. MATERIALS AND METHODS: A total of 315 patients undergoing ACDF between 2014 and 2018 with minimum of 1-year postoperative patient-reported outcome measures (PROMs) were retrospectively reviewed. Forty-six patients were found to have DS and were categorized based on whether an ACDF was performed at the same level (SL) or at a different level (DL) than the spondylolisthesis. Patient demographics, surgical parameters, preoperative and postoperative radiographs, and PROMs were compared between groups. RESULTS: Of the 315 patients, a total of 46 met the inclusion criteria including 21 SL and 25 DL patients. There were no significant differences in patient demographics between the groups. The SL cohort had a significantly worse preoperative sagittal vertical axis (SL: 34.4 vs. 26.1, P=0.025) but no difference in postoperative or delta sagittal vertical axis. Both patient cohorts reported significant postoperative improvement in all PROMs, except Short-Form 12 Mental Component Score in the SL group. There were no differences between the groups regarding Visual Analog Scale Neck, Visual Analog Scale Arm, Neck Disability Index, or Short-Form 12 Physical Component Score. Regression analysis demonstrated SL to be a significant negative predictor for improvement in Short-Form 12 Mental Component Score (ß: -11.27, P=0.10). CONCLUSION: Patients treated only at their neurologically symptomatic levels, excluding asymptomatic listhesis in their construct, can expect equivalent radiographic as well as physical function, disability, and pain outcomes 1 year after ACDF compared with patients whose listhetic level was included in their construct. LEVEL OF EVIDENCE: Level III.
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Enfermedades de la Médula Espinal , Fusión Vertebral , Espondilolistesis , Vértebras Cervicales/cirugía , Discectomía/efectos adversos , Humanos , Dolor de Cuello/cirugía , Calidad de Vida , Estudios Retrospectivos , Enfermedades de la Médula Espinal/cirugía , Fusión Vertebral/efectos adversos , Espondilolistesis/diagnóstico por imagen , Espondilolistesis/cirugía , Resultado del TratamientoRESUMEN
Uveal melanoma (UM) is a subtype of melanoma. Although they share a melanocytic origin with cutaneous melanoma (CM), patients with UM have few treatment options. BCL2 homologous 3 mimetics are small-molecule drugs that mimic proapoptotic BCL2 family members. We compared BCL2 family member expression between UM and CM using immunoblot and The Cancer Genome Atlas transcriptomic analysis. UM has a unique signature of low BFL1 and high PUMA proteins compared with CM and 30 other cancer types, making them an attractive candidate for BCL2 homologous 3 protein mimetics. We tested the efficacy of a BCL2 inhibitor and MCL1 inhibitor (MCL1i) in UM, with viability assays, live-cell imaging, sphere assays, and mouse xenograft models. UM had a higher sensitivity to MCL1i than CM. Overexpression of BFL1 or knockdown of PUMA made the UM more resistant to MCL1i. In contrast, MAPK/extracellular signalâregulated kinase inhibitor treatment in CM made them more sensitive to MCL1i. However, MCL1i-alone treatment was not very effective to reduce the UM initiating cells; to overcome this, we employed a combination of MCL1i with BCL2 inhibitor that synergistically inhibited UM initiating cell's capacity to expand. Overall, we identify a distinct expression profile of BCL2 family members for UM that makes them susceptible to BCL2 homologous 3 mimetics.
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Antineoplásicos , Melanoma , Neoplasias Cutáneas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Ratones , Proteínas Proto-Oncogénicas c-bcl-2 , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias de la Úvea , Melanoma Cutáneo MalignoRESUMEN
INTRODUCTION: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND. METHODS: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively. Nodal recurrence, recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival were evaluated. RESULTS: Among 90 patients, 56 (62%) received adjuvant therapy and 34 (38%) underwent observation alone. Patients who received adjuvant therapy were younger (mean age: 53 vs. 65, p < 0.001) and had higher overall stage (Stage IIIb/c 75% vs. 54%, p = 0.041). Disease recurred in 12 of 34 patients (35%) in the observation group and 11 of 56 patients (20%) in the adjuvant therapy group. The most common first site of recurrence was distant recurrence alone (5/34 patients) in the observation group and nodal recurrence alone (8/90 patients) in the adjuvant therapy group. Despite more adverse nodal features in the adjuvant therapy group, 24-month nodal recurrence rate and RFS were not significantly different between the adjuvant and observation cohorts (nodal recurrence rate: 26% vs. 20%, p = 0.68; RFS: 75% vs. 61%, p = 0.39). Among patients with stage IIIb/c disease, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%, p = 0.04). CONCLUSIONS: In this early report, modern adjuvant therapy in patients who forego CLND is associated with longer DMFS among patients with stage IIIb/c disease.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Escisión del Ganglio Linfático , Melanoma/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/cirugíaRESUMEN
Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
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Mastocitosis Sistémica/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase I como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , Triazinas/administración & dosificación , Triazinas/efectos adversos , Triazinas/farmacocinéticaRESUMEN
Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials.