RESUMEN
PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.
RESUMEN
BACKGROUND: Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs. OBJECTIVE: The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments. RESULTS: MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials. CONCLUSIONS: Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.
RESUMEN
Background: Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants. Methods: We employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression. Results: The murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acids in vivo to form self-assembled nanoparticles of â¼55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways. Conclusions: These results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.
RESUMEN
Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/terapia , Neurofibromatosis 1/patología , Neoplasias de la Vaina del Nervio/terapia , Neoplasias de la Vaina del Nervio/patologíaRESUMEN
Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.
RESUMEN
"Xanthogranulomatous epithelial tumor" (XGET) and "keratin-positive giant cell-rich soft tissue tumor" (KPGCT), two recently described mesenchymal neoplasms, likely represent different aspects of a single entity. Both tumors are composed of only a small minority of tumor cells surrounded by large numbers of non-neoplastic inflammatory cells and histiocytes, suggesting production of a paracrine factor with resulting "landscape effect," as seen in tenosynovial giant cell tumor. Recent evidence suggests that the paracrine factor in XGET/KPGCT may be CSF1, as in tenosynovial giant cell tumor. We hypothesized that CSF1 is overexpressed in XGET/KPGCT. To test our hypothesis, we performed quantitative real time PCR (qPCR) for CSF1 expression and CSF1 RNAscope chromogenic in situ hybridization (CISH) on 6 cases of XGET/KPGCT. All cases were positive with CSF1 CISH and showed increased expression of CSF1 by qPCR. Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.
Asunto(s)
Carcinoma , Tumor de Células Gigantes de las Vainas Tendinosas , Tumores de Células Gigantes , Neoplasias de los Tejidos Blandos , Humanos , Factor Estimulante de Colonias de Macrófagos/genética , Queratinas , Tumores de Células Gigantes/metabolismo , Tumores de Células Gigantes/patología , Neoplasias de los Tejidos Blandos/patología , Células Gigantes/patologíaRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.
Asunto(s)
Neurofibrosarcoma , Humanos , Transducción de Señal , Ciclo Celular , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/genéticaRESUMEN
PURPOSE: Soft tissue sarcomas (STS) are rare mesenchymal neoplasms that frequently show complex chromosomal aberrations such as amplifications or deletions of DNA sequences or even whole chromosomes. We recently found that gain of chromosome (chr) 8 is associated with worse overall survival (OS) in STS as a group. We therefore aimed to investigate the overall copy number profile of rhabdomyosarcoma (RMS) to evaluate for prognostic signatures. METHODS: Fluorescence in situ hybridization (FISH) testing was performed on a cohort of STS to assess for chr8 gain. Copy number variation (CNV) data from the National Cancer Institute were analyzed to assess for prognostically significant CNV aberrations in FOXO1 fusion-negative (FN)- versus fusion-positive (FP)-RMS. FISH testing was performed on a cohort of FN-RMS to assess for chr3q loss and correlate with outcomes. RESULTS: Chr8 gain is a highly prevalent CNV in embryonal RMS and shows slightly improved prognosis. Meanwhile, loss of chr3q was associated with worse outcome in FN-RMS compared with FP-RMS. CONCLUSION: The pathogenesis of STS including FN-RMS remains poorly understood, emphasizing the need for new therapeutic advances and adequate risk stratification. Our data demonstrate that loss of chr3q is associated with poor OS in FN-RMS, supporting it as an important tool for risk stratification.
Asunto(s)
Variaciones en el Número de Copia de ADN , Rabdomiosarcoma , Humanos , Hibridación Fluorescente in Situ , Pronóstico , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/genética , CromosomasRESUMEN
PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGN: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. RESULTS: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CONCLUSIONS: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
Asunto(s)
Neurofibrosarcoma , Ratones , Humanos , Animales , Neurofibrosarcoma/tratamiento farmacológico , Células Plasmáticas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Línea Celular Tumoral , Microambiente Tumoral , Quinasa 4 Dependiente de la CiclinaRESUMEN
Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.
Asunto(s)
Neurofibroma Plexiforme , Neurofibromatosis 1 , Niño , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibroma Plexiforme/tratamiento farmacológico , Calidad de Vida , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). METHODS: Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. RESULTS: We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to "robust" or "good" microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. CONCLUSIONS: These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Neurofibrosarcoma , Humanos , Neurofibrosarcoma/patología , Medicina de Precisión , Neurofibromatosis 1/patología , Neoplasias de la Vaina del Nervio/patología , MutaciónRESUMEN
BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols. METHODS: We conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected. RESULTS: Seventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors. CONCLUSIONS: DDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.
RESUMEN
The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.
RESUMEN
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its anti-proliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable anti-tumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.
RESUMEN
PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. RESULTS: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. CONCLUSIONS: These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Neurofibrosarcoma , Humanos , Ratones , Animales , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Línea Celular , Apoptosis , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismo , Línea Celular Tumoral , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismo , TYK2 Quinasa/farmacologíaRESUMEN
Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Neurofibrosarcoma , Humanos , Neurofibrosarcoma/genética , Neurofibrosarcoma/diagnóstico , Neurofibrosarcoma/patología , Histonas/metabolismo , Metilación de ADN , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neurofibromatosis 1/genética , Genómica , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismoRESUMEN
Granular cell tumors (GrCTs) are mesenchymal neoplasms of presumed schwannian differentiation that may present as solitary or multifocal lesions with excision usually being curative. A minority of cases, however, show histological features associated with an increased risk for metastasis and are highly aggressive leading to death in about a third of cases. While benign and malignant cases have been shown to harbor mutations in the H + ATPase genes, there is only limited data examining molecular aberrations associated with malignancy. The departmental archives were searched for cases of atypical/malignant GrCTs. Clinical and histopathological features were noted. Whole-exome sequencing was performed. Three cases of malignant GrCTs and one case of atypical GrCTs were included. All three malignant tumors metastasized to distant sites with a median disease-free survival of 16 months and an overall follow-up time of 35 months. Whole-exome sequencing showed mutations involving TGFß and MAPK pathways in all four tumors. Although the cohort size is small, our preliminary findings suggest that mutations involving the TGFß and MAPK pathways may be associated with tumor progression or malignant transformation in GrCT pathogenesis.
Asunto(s)
Tumor de Células Granulares , Humanos , Tumor de Células Granulares/genética , Mutación , Factor de Crecimiento Transformador beta/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. RESULTS: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. CONCLUSIONS: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.
Asunto(s)
Neoplasias de Células Epitelioides Perivasculares , Femenino , Humanos , Mutación , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patología , Estudios Retrospectivos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
BACKGROUND: Chemotherapy is associated with decreased quality of life (QOL), fatigue, depression, and weight gain in patients with breast cancer. Weight gain is associated with poorer prognosis. Yoga improves QOL, fatigue, and mood in women with breast cancer but its effect on treatment-related weight gain has not been studied. The aim of this trial was to determine the feasibility of personalized yoga therapy in women receiving treatment for early-stage or locally advanced breast cancer and assess its impact on weight gain. METHODS: Thirty women were randomized 1:1 to receive yoga therapy by a certified yoga therapist during treatment or a control group. Participants in the yoga arm were asked to complete three 30 minute yoga sessions weekly (which included movement, breath work, mindfulness, and relaxation) throughout adjuvant or neoadjuvant chemotherapy (N = 29) or endocrine (N = 1); the control arm received breast cancer treatment without yoga. For comparability between participants randomized to yoga therapy, the single patient treated with endocrine therapy was excluded from the analysis. Primary outcomes were feasibility and weight change. Additional outcomes were mood, fatigue, QOL, serum tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) as immune mediator biomarkers. RESULTS: Mean age was 51.6 years, 75.9% were white and 24.1% were people of color, reflecting the cancer center population. 80% had stage II-III disease. Enrollment was completed in 9 months. Compliance was lower than predicted; however, participants participated in on average 1.7 yoga sessions/week for a mean 15.6 weeks duration. There were no adverse events. Control arm participants gained on average 2.63% body weight during treatment while yoga participants lost 0.14% body weight (weight change = -0.36 in yoga arm vs. 2.89 in standard of care arm, Wilcoxon rank sum test P = .024). Control participants reported increased fatigue and decreased QOL, while yoga participants reported no change in QOL. No significant change in TNF-alpha or CRP was noted in either arm. CONCLUSION: This feasibility study suggests that personalized yoga therapy is beneficial for QOL and weight maintenance among women undergoing chemotherapy for early-stage or locally advanced breast cancer. Weight maintenance associated with yoga therapy may be of clinical significance in this population given the poorer prognosis associated with weight gain in breast cancer survivors. TRIAL REGISTRATION: NIH Clinicaltrials.gov #NCT03262831; August 25, 2017. https://clinicaltrials.gov/ct2/show/NCT03262831.
Asunto(s)
Neoplasias de la Mama , Yoga , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Calidad de Vida , Factor de Necrosis Tumoral alfa , Fatiga/inducido químicamente , Fatiga/terapia , Peso Corporal , Aumento de PesoRESUMEN
OBJECTIVES: The optimal frequency and modality of sarcoma surveillance imaging are uncertain, and current practices vary substantially. While efforts to develop evidence-based guidelines are ongoing, patient perspectives regarding surveillance imaging have not been reported. The primary goal of this study was to pilot the novel Sarcoma Surveillance Survey to assess patient concerns regarding sarcoma surveillance. METHODS: In this single-center, cross-sectional study, patients receiving surveillance imaging after surgical sarcoma treatment were administered the 10-item Sarcoma Surveillance Survey, the validated Appraisal Scale, measuring positive and negative emotional reactions to imaging, and the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Short Form 8a as a measure of anxiety. RESULTS: Patients expressed highest levels of concern about cost and radiation exposure associated with surveillance, and most (87.6%) did not express a preference for more or less frequent imaging. Younger patients and those living further away from the imaging center were more concerned about cost of surveillance. Female patients had higher levels of concern compared to males regarding radiation, IV contrast, and overall levels of concern about surveillance. Higher levels of anxiety were correlated with preference for more frequent imaging (rs = 0.274, p = 0.027) and higher overall level of concern about surveillance (rs = 0.259, p = 0.037). Higher negative appraisal scores were also correlated with higher overall concerns (rs = 0.323; p = 0.012). CONCLUSIONS: Patient perspectives should be considered when developing sarcoma surveillance strategies. Identifying patients with greater anxiety and concerns regarding imaging may create opportunities for improved surveillance practices as well as counseling and survivorship interventions.