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BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.
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Leucemia Linfocítica Crónica de Células B , Melanoma , Adulto , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Australia , Melanoma/patología , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
BACKGROUND: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. MATERIALS AND METHODS: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. RESULTS: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. CONCLUSIONS: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.
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Mutación , Neoplasias , Biomarcadores de Tumor , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Reproducibilidad de los Resultados , Carga TumoralRESUMEN
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
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Sarcoma , Tropomiosina , Adulto , Fusión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas , Receptor trkA/genética , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológico , Sarcoma/genéticaRESUMEN
BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m⻲ intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gonanos/uso terapéutico , Neoplasias/tratamiento farmacológico , Taxoides/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Docetaxel , Femenino , Gonanos/efectos adversos , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Taxoides/efectos adversos , Resultado del TratamientoAsunto(s)
Sarcoma , Transcriptoma , Formaldehído , Perfilación de la Expresión Génica , Humanos , Adhesión en Parafina , PronósticoRESUMEN
BACKGROUND: Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events. PATIENTS AND METHODS: We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected. RESULTS: We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA. CONCLUSION: A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.
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Fibromatosis Agresiva/complicaciones , Fibromatosis Agresiva/epidemiología , Tumores del Estroma Gastrointestinal/complicaciones , Tumores del Estroma Gastrointestinal/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Molecular markers are currently being utilized as sensitive prognosticators of cancer patient outcome. We sought to identify prognostic biomarkers for complex karyotype soft tissue sarcoma (STS). MATERIALS AND METHODS: A large (n = 205) clinically annotated tissue microarray (TMA) was constructed and immunostained for several tumor-related markers. Staining was scored via an automated Ariol image analysis system; data were statistically analyzed to evaluate the correlation of clinicopathological and molecular variables with overall survival (OS) and local recurrence. RESULTS: Multivariable analysis identified older age [hazard ratio (HR) 1.62, P < 0.0001], nonextremity location (HR 2.95, P = 0.001), high tumor grade (HR 2.5, P = 0.02), and increased matrix metalloproteinase (MMP) 2 expression (HR 1.74, P = 0.04) as predictors for poor OS. Similarly, older age (HR 1.51, P = 0.008), nonextremity location (HR 4.09, P = 0.001), and increased MMP2 expression (HR 6.28, P = 0.006) were all found to correlate with shorter local recurrence-free interval. High nuclear p53 expression was associated with shorter STS local recurrence-free interval, with a trend toward significance. CONCLUSIONS: Data presented indicate that a clinically annotated TMA can be utilized to identify STS-related prognostic markers. Specifically, MMP2 and nuclear p53 should be further evaluated for their potential inclusion in complex karyotype STS staging systems.
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Biomarcadores de Tumor/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Sarcoma/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Núcleo Celular/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Cariotipificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Estudios Prospectivos , Sarcoma/diagnóstico , Tasa de Supervivencia , Análisis de Matrices TisularesRESUMEN
BACKGROUND: Angiosarcoma (AS) is a rare soft tissue sarcoma with an enhanced propensity for local and systemic failure. The outcome of locally recurrent and metastatic AS treated at a single institution was evaluated. METHODS: Medical records of AS patients treated for local recurrence and distant metastasis (1993-2008) were retrospectively reviewed. Univariable and multivariable analyses were performed to identify prognosticators. RESULTS: Forty-four patients were treated for locally recurrent AS; the majority (59%) were
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hemangiosarcoma/secundario , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Hemangiosarcoma/terapia , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/terapia , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Decreased performance status, comorbidities, and disease natural history may erode enthusiasm for soft tissue sarcoma (STS) resection in elderly patients. Consequently, we evaluated the outcome of elderly patients amenable to complete surgical resection treated at a single institution. METHODS: Prospectively accrued data were used to identify patients with primary STS age >or=65 years (n = 325) who underwent complete macroscopic resection at our institution (1996-2007). Univariable and multivariable analyses were performed to identify prognostic factors. RESULTS: Median age at presentation was 72 years; 179 patients (55.1%) had associated comorbidities with an ASA score of >or=3. Extremity was the most common site (57.1%; n = 186), undifferentiated pleomorphic sarcoma the most common histology (60.4%; n = 197); 232 (71.2%) were high grade, 222 (68.3%) were >5 cm. Thirty-day postoperative mortality was 0.9% (n = 3); overall complication rate was 30.7% (n = 100), and mean postoperative hospital stay was 9 days (range, 1-84). Estimated median survival was 96 months, 5-year disease-specific survival (DSS) was 63%. Multivariable analysis identified age >or=75 year (HR = 2.03), tumor size: 5-15 vs <5 cm (HR = 3.54), or >15 vs <5 cm (HR = 10.33), and high-grade (HR = 5.53) as significant independent adverse prognostic factors. Compared with patients aged 65-74 years, older patients had more high grade tumors (P = .04), received chemotherapy less often (P < .0001), developed different patterns of recurrence (P < .05), and exhibited a shorter median survival (70 months; P = .05). CONCLUSIONS: Properly selected elderly patients can safely undergo extensive STS resections. Until more effective therapies become available, surgery in the elderly is indicated and remains the best means for STS control.
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Sarcoma/cirugía , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Sarcoma/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.
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Melanoma/genética , Proteínas Proto-Oncogénicas c-akt/genética , Neoplasias Cutáneas/genética , Western Blotting , Línea Celular Tumoral , ADN de Neoplasias/genética , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , TransfecciónRESUMEN
BACKGROUND: Data suggest that the current American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging criteria merit further evaluation. We sought to identify and validate factors as enhanced descriptors of STS clinical behavior. METHODS: Prospectively accrued data were analyzed for 1,091 AJCC stage I to III primary STS patients who had complete macroscopic resection at our institution from 1996 to 2007. Study factors were examined by univariable and multivariable analyses to identify independent prognostic factors for disease related mortality and overall survival (OS). RESULTS: In contrast to the current AJCC STS staging system, which stratifies size into T1 (=5 cm) and T2 (>5 cm) groups, we demonstrated three distinct cohorts (P < 0.0001): T1 (=5 cm; 5-year OS 85%), T2 (5 to 15 cm; OS 68%), and T3 (>15 cm; OS 52%). A two-category system of histologic grade was demonstrably as informative as the current four histologic grade AJCC system. A multivariable Cox proportional hazard model identified tumor size (5 to 15 cm vs. =5 cm, P = 0.03; or >15 cm vs. =5 cm; P < 0.0001), nonextremity primary site (P = 0.0016), disease of high histologic grade (P = 0.001), specific histology (P = 0.001), and margin positivity (P < 0.0001) as statistically significant adverse independent prognostic factors. Recurrence during follow-up was the most significant risk factor for STS-specific mortality (P < 0.0001). CONCLUSION: Tumor size and grade in the AJCC STS staging system need revision; moreover, primary site, histologic subtype, margin status, and recurrence offer additional relevant prognostic insight. Incorporation of these factors may enhance the AJCC staging system, thereby further facilitating individualized therapeutic strategies for STS patients.
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Recurrencia Local de Neoplasia/patología , Sarcoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Sarcoma/clasificación , Sarcoma/terapia , Tasa de SupervivenciaRESUMEN
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
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Microbioma Gastrointestinal/inmunología , Inmunoterapia , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/terapia , Animales , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/genética , Humanos , Melanoma/inmunología , Metagenoma , Ratones , Neoplasias Cutáneas/inmunologíaRESUMEN
Sebaceous tumours include hyperplasia, adenoma, sebaceoma and carcinoma. Importantly, the latter three are potential markers of Torre-Muir syndrome; the hereditary association of sebaceous neoplasia and internal malignancy, most commonly colorectal carcinoma. The diagnostic features, differential diagnosis, molecular diagnostics and recent advances in pathogenesis of this rare group of tumours are discussed along with Torre-Muir syndrome and recommendations for screening for this important association.
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Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/ß-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs. In this study we found a strong positive correlation between the activity of PAK1/2/3 and the stage of human MPNSTs. We determined that reducing Group I Pak activity diminished MPNST cell proliferation and motility, and that these effects were not accompanied by significant blockade of the Raf/Mek/Erk pathway, but rather by reductions in Akt and ß-catenin activity. Using the small molecule PAK1/2/3 inhibitor Frax1036 and the MEK1/2 inhibitor PD0325901, we showed that the combination of these two agents synergistically inhibited MPNST cell growth in vitro and dramatically decreased local and metastatic MPNST growth in animal models. Taken together, these data provide new insights into MPNST signaling deregulation and suggest that co-targeting of PAK1/2/3 and MEK1/2 may be effective in the treatment of patients with MPNSTs.
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Benzamidas/farmacología , Difenilamina/análogos & derivados , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinasas p21 Activadas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Difenilamina/farmacología , Femenino , Humanos , Ratones , Ratones SCID , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Neoplasias de la Vaina del Nervio/enzimología , Neoplasias de la Vaina del Nervio/patología , Distribución Aleatoria , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/metabolismoRESUMEN
Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24-40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.
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Liposarcoma , Terapia Neoadyuvante , Neoplasias Retroperitoneales , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Liposarcoma/mortalidad , Liposarcoma/patología , Liposarcoma/terapia , Masculino , Persona de Mediana Edad , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
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Neoplasias Óseas/metabolismo , Proteínas Portadoras/fisiología , Proliferación Celular , Metástasis de la Neoplasia , Osteosarcoma/metabolismo , Vía de Señalización Wnt , Proteínas Adaptadoras Transductoras de Señales , Animales , Neoplasias Óseas/patología , Proteínas de Unión al Calcio , Línea Celular Tumoral , Ratones , Invasividad Neoplásica , Osteosarcoma/patologíaRESUMEN
Six hundred ninety-eight patients with premature rupture of the membranes between 26 and 34 weeks were managed expectantly without the use of tocolytics or corticosteroids. Of these, 92 (13 per cent) developed chorioamnionitis. Although latency period (defined as the time from rupture of the membranes to the onset of labor) had no correlation with the incidence of chorioamnionitis, the mean latency period was significantly shorter for those gestations complicated by infection. The risk of chorioamnionitis was found to be inversely related to gestational age. The length of labor, once chorioamnionitis was diagnosed, had no correlation with neonatal outcome, but the development of chorioamnionitis led to a statistically significant increase in neonatal mortality, infection rate, incidence of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and five-minute Apgar score less than 7. Maternal endometritis and other complications of infection were increased in the presence of chorioamnionitis, especially in patients delivered by Cesarean section. Useful predictors of early chorioamnionitis were maternal leukocytosis, fetal tachycardia, and elevated maternal C-reactive protein titers.
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Corioamnionitis/complicaciones , Resultado del Embarazo , Parto Obstétrico , Endometriosis/etiología , Femenino , Rotura Prematura de Membranas Fetales , Edad Gestacional , Humanos , Recién Nacido , Enfermedades del Prematuro/etiología , Embarazo , Estudios Prospectivos , Trastornos Puerperales/etiología , Factores de Tiempo , Enfermedades Uterinas/etiologíaRESUMEN
Desmoid tumors are monoclonal proliferations that fall within a broad histologic spectrum of fibrous mesenchymal tumors that ranges from benign proliferations of scar tissue to high-grade fibrosarcomas. These low-grade tumors are extremely infiltrative locally, but lack the ability to metastasize systemically. While they are only rarely a direct cause of mortality, using current therapeutic modalities, these tumors have a high rate of local recurrence that can result in significant treatment related morbidity. Sporadic desmoids are usually associated with somatic mutations in codons 41 or 45 of exon 3 of beta-catenin (CTNNB1). Desmoid tumors occurring in the background of familial adenomatous polyposis (FAP) usually contain inactivating germline mutations in the adenomatous polyposis coli (APC) gene. CTNNB1 and APC are part of the Wnt signaling pathway and mutations in either gene result in stabilization of the beta-catenin protein and allow nuclear translocation and binding of beta-catenin to the T-cell factor/lymphoid enhancer factor (TCF/Lef) family of transcription factors, resulting in activation of target genes which may underlie desmoid tumor biology and clinical behavior. In an era of molecularly targeted therapeutics there is a real need to better grasp the molecular mechanisms behind desmoid tumorigenesis and progression. This knowledge will eventually result in the development of patient and tumor tailored therapies and assist in the control and eradication of this disease.
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Proteína de la Poliposis Adenomatosa del Colon/genética , Fibromatosis Agresiva/genética , beta Catenina/genética , Proteína de la Poliposis Adenomatosa del Colon/fisiología , Fibromatosis Agresiva/fisiopatología , Humanos , Mutación/genética , Transducción de Señal/fisiología , Proteínas Wnt/genética , Proteínas Wnt/fisiología , beta Catenina/fisiologíaRESUMEN
AIMS: There is considerable overlap between the histological features of sebaceoma and basal cell carcinoma (BCC). The distinction between these two tumours is important due to the often more locally aggressive nature of BCC and the association of sebaceoma with the Muir-Torre syndrome. The aim of this study was to describe the immunohistochemical reactivity of the cells in sebaceoma to Ber-EP4 and epithelial membrane antigen (EMA) and investigate the utility of this panel to differentiate sebaceoma from basal cell carcinoma. METHODS AND RESULTS: Immunohistochemistry of 25 sebaceomas for Ber-EP4 and EMA revealed unequivocal negative expression of Ber-EP4 in 24 of 25 sebaceomas. A single case exhibited focal weak Ber-EP4 staining, predominantly in mature sebocytes and in < 10% of the tumour cells. EMA was not expressed in the germinative cells of sebaceoma, but was expressed strongly in approximately 50% of mature sebocytes in all cases and highlighted the cytoplasmic vacuoles. We reviewed the immunoreactivity of 51 cases of nodular BCCs and found moderate or strong BerEP4 expression in all cases with never less than 20% of the tumour staining. Expression of EMA was uncommon in BCC (moderate or strong in 8%) and was confined to keratotic or squamoid areas. CONCLUSION: The use of Ber-EP4 in combination with EMA, both widely used immunomarkers in histopathology, is a helpful aid in distinguishing sebaceoma from nodular BCC.