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Epistaxis, or nosebleed, is bleeding from the nostril(s), nasal cavity, or nasopharynx. Anterior nasal bleeding is the most common location for spontaneous nontraumatic epistaxis and is commonly treated with manual compression to the nasal alae. Cryotherapy is also routinely recommended in conjunction with manual compression in the first aid and ED setting. We performed a scoping review on behalf of the International Liaison Committee on Resuscitation First Aid Task Force guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR). We searched Embase, Cochrane, and PubMed databases for published studies, without date restrictions, and we searched the gray literature using Google.com and Google Scholar. The websites of selected resuscitation councils were searched for guidelines relating to the management of epistaxis. References from included studies were hand-searched. Our published and gray literature search identified 1255 and 61,315 records, respectively. After removing duplicates and following selection criteria, we included 21 records from the published literature and 11 records from the gray literature. Our scoping review found that most of the published studies and website documents focused on managing nontraumatic epistaxis in the first aid setting. They provide recommendations for the use of cryotherapy based on expert opinion or indirect evidence extrapolated from cryotherapy-associated changes in nasal submucosal temperature, nasal blood flow, and nasal blood volume in healthy subjects (three studies). We did not identify any prospective, randomized trials comparing the efficacy of cryotherapy as an intervention for nontraumatic epistaxis in the first aid setting. The limited literature identified in this scoping review does not support the development of a systematic review but highlights the need for future research to better understand the role of cryotherapy in the first aid setting.
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OBJECTIVES: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. MATERIALS AND METHODS: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". RESULTS: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). CONCLUSIONS: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.
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AIM: Develop and apply a comprehensive and accurate next-generation sequencing based assay to help clinicians to match oncology patients to therapies. MATERIALS & METHODS: The performance of the CANCERPLEX® assay was assessed using DNA from well-characterized routine clinical formalin-fixed paraffin-embedded (FFPE) specimens and cell lines. RESULTS: The maximum sensitivity of the assay is 99.5% and its accuracy is virtually 100% for detecting somatic alterations with an allele fraction of as low as 10%. Clinically actionable variants were identified in 93% of patients (930 of 1000) who underwent testing. CONCLUSION: The test's capacity to determine all of the critical genetic changes, tumor mutation burden, microsatellite instability status and viral associations has important ramifications on clinical decision support strategies, including identification of patients who are likely to benefit from immune checkpoint blockage therapies.
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HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2 positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P < .001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Amplificación de Genes , Receptor ErbB-2/genética , Análisis de Secuencia de ADN , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias Colorrectales/química , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/análisis , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC). METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC. RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy. CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.
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Alelos , Neoplasias Colorrectales/genética , Bases de Datos Genéticas , Exoma , Genes Relacionados con las Neoplasias , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Medicina de Precisión , Pueblo Asiatico , Femenino , Humanos , Japón , MasculinoRESUMEN
Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8(+) T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8(+) T cell activity, permitting growth of FAK-expressing tumors. Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Furthermore, FAK's immuno-modulatory nuclear activities may be specific to cancerous squamous epithelial cells, as normal keratinocytes do not have nuclear FAK. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8(+) T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities.
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Carcinoma de Células Escamosas/inmunología , Quimiocina CCL5/genética , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Escape del Tumor , Aminopiridinas/administración & dosificación , Animales , Carcinoma de Células Escamosas/metabolismo , Quimiocina CCL5/inmunología , Modelos Animales de Enfermedad , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Humanos , Queratinocitos/metabolismo , Ratones , Ratones Desnudos , Neoplasias Cutáneas/metabolismo , Transcripción GenéticaRESUMEN
Cancer stem cells (CSC) have been implicated in disease recurrence, metastasis, and therapeutic resistance, but effective targeting strategies for these cells are still wanting. VS-5584 is a potent and selective dual inhibitor of mTORC1/2 and class I PI 3-kinases. Here, we report that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSC compared with non-CSC in solid tumor cell populations. VS-5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Likewise, VS-5584 treatment ex vivo preferentially reduced CSC in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel and cisplatin were less effective in targeting CSC than bulk tumor cells. Mechanistic investigations revealed that preferential targeting of CSC required inhibition of multiple components of the PI3K-mTOR pathway: coordinate RNAi-mediated silencing of PI3Kα, PI3Kß, and mTOR phenocopied the effect of VS-5584, exhibiting the strongest preferential targeting of CSC, while silencing of individual PI3K isoforms or mTOR failed to replicate the effect of VS-5584. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small-cell lung cancer. Taken together, the preferential targeting of CSC prompts a new paradigm for clinical testing of VS-5584: clinical trials designed with CSC-directed endpoints may facilitate demonstration of the therapeutic benefit of VS-5584. We suggest that combining VS-5584 with classic chemotherapy that debulks tumors may engender a more effective strategy to achieve durable remissions in patients with cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Morfolinas/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Distribución Aleatoria , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell-cycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/ß-catenin signaling by destabilizing ß-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.
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Aminopiridinas/farmacología , Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Mieloma Múltiple/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Adhesión Celular/efectos de los fármacos , Adhesión Celular/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Progresión de la Enfermedad , Femenino , Quinasa 2 de Adhesión Focal/genética , Quinasa 2 de Adhesión Focal/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Immunoblotting , Mediciones Luminiscentes , Ratones SCID , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition lack expression of the neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells underlie their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated aldehyde dehydrogenase as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response through reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.
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Antineoplásicos/farmacología , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Neurofibromina 2/deficiencia , Inhibidores de Proteínas Quinasas/farmacología , Aldehído Deshidrogenasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mesotelioma/enzimología , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma Maligno , Ratones , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Neurofibromina 2/genética , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D's selective cytotoxic activity. Here we show that the selective cytotoxic action of austocystin D arises from its selective activation by cytochrome P450 (CYP) enzymes in specific cancer cell lines, leading to induction of DNA damage in cells and in vitro. The potency and selectivity of austocystin D is lost upon inhibition of CYP activation and does not require MDR1 expression or activity. Furthermore, the pattern of cytotoxicity of austocystin D was distinct from doxorubicin and etoposide and unlike aflatoxin B(1), a compound that resembles austocystin D and is also activated by CYP enzymes to induce DNA damage. Theses results suggest that austocystin D may be of clinical benefit for targeting or overcoming chemoresistance.
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Aflatoxina B1/farmacología , Aflatoxinas/aislamiento & purificación , Aflatoxinas/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Aspergillus/química , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/efectos de los fármacos , Aflatoxinas/química , Antineoplásicos/química , Sistema Enzimático del Citocromo P-450/metabolismo , Daño del ADN/efectos de los fármacos , Daño del ADN/fisiología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura MolecularRESUMEN
The alpha6beta4 integrin has been widely implicated in carcinoma function in vitro; however, in vivo data are scarce. To determine the importance of alpha6beta4 in tumor progression, a SUM-159 breast carcinoma cell line that is essentially devoid of alpha6beta4 expression was generated using an RNA interference strategy. Loss of alpha6beta4 expression inhibits colony formation in soft agar assays, suggesting a vital role for alpha6beta4 in survival signaling and anchorage-independent growth. Orthotopic injection of the beta4-deficient cell line into the mammary fat pad of immunocompromised mice yielded significantly fewer and smaller tumors than the control cell line, revealing a role for the alpha6beta4 integrin in tumor formation. Under conditions that mimicked the in vivo environment, decreased expression of the alpha6beta4 integrin led to enhanced apoptosis as determined by the percentage of Annexin V-FITC+, PI- cells and the presence of caspase-3 cleavage products. Recombinant vascular endothelial growth factor (VEGF) significantly inhibited the cell death observed in the beta4-deficient cell line, demonstrating the importance of VEGF expression in this survival pathway. Furthermore, loss of alpha6beta4 expression leads to enhanced apoptosis and reduced expression of VEGF in breast carcinoma cells in vivo. Importantly, the specificity of alpha6beta4 in both the in vitro and in vivo assays showed that reexpression of the beta4 subunit into the beta4-deficient cell line could rescue the functional phenotype. Taken together, these data implicate the alpha6beta4 integrin in tumor formation by regulating tumor cell survival in a VEGF-dependent manner.