RESUMEN
BACKGROUND: Tranexamic acid (TXA) is increasingly being used to prevent hemorrhagic complications after dermatologic surgery. Interpolated flap repairs following Mohs micrographic surgery are at risk for increased bleeding events and unplanned health care utilization, particularly among patients on antithrombotic medication. OBJECTIVE: To assess bleeding events after interpolated flap repair in patients receiving TXA compared with those who did not. MATERIALS AND METHODS: A retrospective review identified interpolated flap repairs in a 5-year period. Hemorrhagic complications were analyzed, defined as major bleeding events, which included all unplanned medical visits, and minor bleeding events, which included any unplanned patient phone calls or messages through electronic medical record. RESULTS: One hundred fifteen patients had interpolated flap repair during the 5-year period, of which 21 (18.3%) received TXA postprocedure. Twenty-seven bleeding events were identified in the non-TXA group compared with 1 event in the TXA-treated group. Patients who received TXA were less likely to have had a bleeding event (28.7% vs 4.8%, p < .01). CONCLUSION: Patients undergoing interpolation flap repair were less likely to experience a bleeding event after subcutaneous injection of TXA.
Asunto(s)
Antifibrinolíticos , Ácido Tranexámico , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Hemorragia/inducido químicamente , Hemorragia/prevención & controlRESUMEN
PURPOSE: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vß) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vß would eliminate the malignant clone while having minimal effects on healthy T cells. EXPERIMENTAL DESIGN: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vß13.3. We developed a panel of anti-Vß13.3 antibodies to test for binding and elimination of the malignant T-cell clone. RESULTS: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vß13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vß13.3 were also killed by antibody administration in an in vivo murine model. CONCLUSIONS: This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024.
Asunto(s)
Linfoma de Células T , Receptores de Antígenos de Linfocitos T , Humanos , Ratones , Animales , Rituximab , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunologíaRESUMEN
The current standard for investigating tumors is surgical biopsy, which is costly, invasive, and difficult to perform serially. As an adjunct, circulating tumor cells (CTCs)-cells that have broken away from the primary tumor or metastatic sites-can be obtained from a blood draw and offer the potential for obtaining serial genetic information and serving as biomarkers. Here, we detail the potential for melanoma CTCs to serve as biomarkers and discuss a clinically viable methodology for single-cell CTC isolation and analysis that overcomes previous limitations. We explore the use of melanoma CTC biomarkers by isolating and performing single-cell RNA sequencing on CTCs from melanoma patients. We then compared transcriptional profiles of single melanoma CTCs against A375 cells and peripheral blood mononuclear cells to identify unique genes differentially regulated in circulating melanoma tumor cells. The information that can be obtained via analysis of these CTCs has significant potential in disease tracking.
RESUMEN
In this study, we report a differential response of mitogen-activated protein kinase-kinase (MEK) inhibitor trametinib in 20 head and neck squamous cell carcinoma (HNSCC) patients' tumor-derived cell cultures. Relatively sensitive and resistant cases to trametinib were identified using high throughput metabolic assays and validated in extended dose response studies in vitro. High throughput metabolic assays exploring combination therapies with trametinib were subjected to synergy models and maximal synergistic dose analyses. These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume). Sensitivity was validated in vivo in a patient-derived xenograft (PDX) model in which trametinib as a single agent effected reduction in tumor volume up to 72%. Reverse Phase Protein Arrays (RPPA) demonstrated differentially expressed proteins and phosphoproteins upon trametinib treatment. Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.
Asunto(s)
Neoplasias de Cabeza y Cuello , Proteómica , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Piridonas , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
The varicella-zoster virus (VZV), a member of the Herpesviridae family (HHV-3), is the pathogen responsible for causing herpes zoster, the skin eruption known as shingles. This report describes a rare presentation of herpes zoster involving cutaneous vasculitis in the unilateral upper extremity in an immunocompetent patient. Histologic evaluation confirmed a diagnosis of leukocytoclastic vasculitis and yielded a positive VZV immunoperoxidase stain. An approach to histologic evaluation of this case is discussed.
RESUMEN
Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/metabolismo , Supervivencia Celular/genética , Progresión de la Enfermedad , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Receptor EphA6/antagonistas & inhibidores , Receptor EphA6/metabolismo , Receptor EphA7/antagonistas & inhibidores , Receptor EphA7/metabolismo , Transducción de Señal/genética , Neoplasias Cutáneas/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Secuenciación del Exoma/métodosAsunto(s)
Antígenos CD19/metabolismo , Inmunoterapia Adoptiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Preescolar , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMEN
Vismodegib is a small molecule inhibitor of the Hedgehog signaling pathway that has shown efficacy in the control of locally advanced or metastatic basal cell carcinoma, although proof of its effectiveness in the elimination of aggressive tumors is lacking. We report a case and provide complete histological evidence of a 69-year-old gentleman who presented with a recurrent, infiltrative, and sclerosing (morpheiform) basal cell carcinoma on his left upper lip that was entirely eradicated with a three-month course of vismodegib 150 mg daily. Complete histologic clearance of a tumor in a recurrent, infiltrative, and sclerosing basal cell carcinoma with vismodegib is uncommon.
Asunto(s)
Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Carcinoma Basocelular/patología , Carcinoma Basocelular/cirugía , Cicatriz , Terapia Combinada , Humanos , Masculino , Cirugía de Mohs , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Piel/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal "rule of twos and threes," but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: "melanoma dominant" and "melanoma subordinate." Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the "rule of twos and threes" for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.
Asunto(s)
Melanoma/genética , Melanoma/terapia , Algoritmos , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Melanoma/diagnósticoRESUMEN
About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF(V600E/K)) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.
Asunto(s)
Melanoma/tratamiento farmacológico , Melanoma/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Resistencia a Antineoplásicos/genética , Receptores Frizzled/antagonistas & inhibidores , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Humanos , Indoles/farmacología , Melanoma/metabolismo , Mutación , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Sulfonamidas/farmacología , Regulación hacia Arriba/efectos de los fármacos , Proteínas Wnt/antagonistas & inhibidores , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt-5a , beta Catenina/metabolismoRESUMEN
Because the Wnt/ß-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome small interfering RNA (siRNA) screen in melanoma cells to expand our understanding of the kinases that regulate this pathway. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAF(V600E) mutation, inhibits Wnt/ß-catenin signaling in human melanoma cells. Because inhibitors of BRAF(V600E) show promise in ongoing clinical trials, we investigated whether altering Wnt/ß-catenin signaling might enhance the efficacy of the BRAF(V600E) inhibitor PLX4720. We found that endogenous ß-catenin was required for PLX4720-induced apoptosis of melanoma cells and that activation of Wnt/ß-catenin signaling synergized with PLX4720 to decrease tumor growth in vivo and to increase apoptosis in vitro. This synergistic enhancement of apoptosis correlated with reduced abundance of an endogenous negative regulator of ß-catenin, AXIN1. In support of the hypothesis that AXIN1 is a mediator rather than a marker of apoptosis, siRNA directed against AXIN1 rendered resistant melanoma cell lines susceptible to apoptosis in response to treatment with a BRAF(V600E) inhibitor. Thus, Wnt/ß-catenin signaling and AXIN1 may regulate the efficacy of inhibitors of BRAF(V600E), suggesting that manipulation of the Wnt/ß-catenin pathway could be combined with BRAF inhibitors to treat melanoma.
Asunto(s)
Apoptosis/fisiología , Proteína Axina/fisiología , Melanoma/metabolismo , Proteínas Proto-Oncogénicas B-raf/fisiología , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Humanos , Melanoma/enzimología , Melanoma/genética , Melanoma/patología , MutaciónRESUMEN
In cancer, Wnt/beta-catenin signaling is ubiquitously referred to as an "oncogenic" pathway that promotes tumor progression. This review examines how the regulation and downstream effects of Wnt/beta-catenin signaling in cancer varies depending on cellular context, with a focus on malignant melanoma. We emphasize that the cellular homeostasis of Wnt/beta-catenin signaling may represent a more appropriate concept than the simplified view of the Wnt/beta-catenin pathway as either oncogenic or tumor-suppressing. Ultimately, a more refined understanding of the contextual regulation of Wnt/beta-catenin signaling will be essential for addressing if and how therapeutic targeting of this pathway could be leveraged for patient benefit.
Asunto(s)
Melanoma/metabolismo , Oncogenes/fisiología , Transducción de Señal , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Humanos , Melanoma/patologíaRESUMEN
The collecting duct of the kidney is composed of two morphologically and physiologically distinct cell types, principal and intercalated cells. To better understand intercalated cell function we generated a transgenic mouse expressing Cre recombinase under the control of a cell type- specific promoter. We used 7 kb of the ATP6V1B1 5' untranslated region (B1 promoter), a gene found in the intercalated cells of the kidney and the male reproductive tract. We first crossed these B1-Cre transgenic mice with the ROSA26-loxP-stop-loxP-yellow fluorescent protein reporter mice to assess the specificity of Cre expression. Immunohistochemistry and confocal fluorescence microscopy showed that Cre is selectively active in all intercalated cells (type A, type B, and non-A/B cells) within the collecting duct and most cells of the connecting segment. About half of the principal cells of the connecting segment also expressed Cre, a pattern also seen in B1-driven enhanced green fluorescent protein transgenic mice. Cre was found to be active in the male reproductive tract and at a low level in limited non-ATP6V1B1 expressing tissues. The B1-Cre transgenic mice are healthy, breed normally, produce regular sized litters, and transmit the transgene in Mendelian fashion. This new cell-specific Cre expressing mouse should prove useful for the study of intercalated cell physiology and development.