RESUMEN
INTRODUCTION: Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated. METHODS: Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls. RESULTS: All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes. CONCLUSION: MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.
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Linfoma de Células B de la Zona Marginal/inmunología , Linfoma de Células B de la Zona Marginal/patología , Organoides/inmunología , Organoides/patología , Células T Auxiliares Foliculares/inmunología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Student-athletes (SAs) have an increased skin cancer risk on account of significant ultraviolet exposure; however, their sun-protective practices are suboptimal. A novel program, Stanford University Network for Sun Protection, Outreach, Research, and Teamwork (SUNSPORT), was designed to target SAs, coaches, and athletic trainers (ATs). OBJECTIVE: To measure the impact of educational intervention on sun protection beliefs and practices of SAs. METHODS: A survey of sun protection beliefs and practices was administered to National Collegiate Athletic Association athletes before and after intervention. SUNSPORT dermatologists educated SAs, coaches, and ATs regarding skin cancer risk and prevention methods. The main outcome was frequency of sunscreen use by SAs before versus after intervention. RESULTS: A total of 846 National Collegiate Athletic Association athletes were surveyed between September 23, 2012, and September 20, 2015. After intervention, significant increases were observed in sunscreen use 4 or more days per week by SAs (from 26% to 39% [P = .02]), SAs spoken to by their coach about sun safety (from 26% to 57% [P = .0001]), and SA recognition of higher skin cancer risk (from 54% to 67% [P = .04]). LIMITATIONS: Intervention in only 1 West Coast university and no paired data. CONCLUSIONS: Following the SUNSPORT intervention, SAs were significantly more likely to use sunscreen, especially if encouraged by their coach. This study emphasizes that education directed to SAs, ATs, and coaches can improve sun-protective practices in SAs.
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Educación en Salud/métodos , Conocimientos, Actitudes y Práctica en Salud , Promoción de la Salud/métodos , Deportes , Protectores Solares/uso terapéutico , Universidades , Adolescente , Femenino , Humanos , Masculino , Tutoría/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Factores Sexuales , Estudiantes/estadística & datos numéricos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND/AIMS: This study examined the role of random normal skin biopsy in the diagnosis of intravascular lymphoma (IVL) in adult Western patients with clinically diagnosed hemophagocytic lymphohistiocytosis (HLH). METHODS: In a retrospective chart review study, we analyzed a total of 59 skin biopsies that were performed to diagnose IVL in 21 adult patients with HLH seen at Stanford Hospital between 2004 and 2016. RESULTS: Out of the 59 skin biopsies, 42 were taken from clinically normal-appearing skin and 17 from clinically abnormal-appearing skin. None of the 59 biopsies revealed a diagnosis of primary or metastatic malignancy, regardless of the malignancy history, clinical presentation, and biopsy and histopathologic characteristics. A review of 8 positive IVL cases at Stanford Hospital including 1 case associated with HLH showed 1 positive diagnosis by a targeted skin biopsy and other positive diagnoses by bone marrow (n = 4), lung (n = 2), brain (n = 2), muscle (n = 1), and nerve (n = 1). CONCLUSION: Random skin biopsies have a limited role in diagnosing IVL in adult patients with HLH, in the setting of a single academic institution in the USA. A review of the literature emphasizes the role of a full body skin exam with a selective skin biopsy in these patients.
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Linfohistiocitosis Hemofagocítica/diagnóstico , Piel/patología , Neoplasias Vasculares/diagnóstico , Adolescente , Adulto , Anciano , Femenino , Ferritinas/análisis , Humanos , Subunidad alfa del Receptor de Interleucina-2/análisis , Linfohistiocitosis Hemofagocítica/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Vasculares/patología , Adulto JovenRESUMEN
BACKGROUND: Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial. METHODS: In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35-75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229. FINDINGS: Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36-36). Patients treated with vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 0·12] new surgically eligible basal-cell carcinomas per patient per year vs 34 [1·32] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). In the 11 patients initially assigned to placebo, mean cross over to vismodegib reduced the development of new surgically eligible basal-cell carcinomas compared with placebo (0·4 [SD 0·2] new surgically eligible basal-cell carcinomas per patient per year vs 30·0 [7·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Only three (17%) of 18 patients tolerated vismodegib continuously for the full 36 months. Fewer new surgically eligible basal-cell carcinomas developed in patients receiving vismodegib continuously than in those who interrupted dosing (mean 0·6 [0·72] new surgically eligible basal-cell carcinomas per patient per year vs 1·7 [1·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Treatment-related grade 3-4 adverse events included weight loss of 20% or more (n=6) and muscle cramps (n=2). Two patients died during the course of the trial, one each from laryngeal and metastatic prostate cancer, deemed probably unrelated to drug. INTERPRETATION: Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence. FUNDING: Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.
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Anilidas/uso terapéutico , Síndrome del Nevo Basocelular/tratamiento farmacológico , Proteínas Hedgehog/antagonistas & inhibidores , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anilidas/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridinas/efectos adversosRESUMEN
BACKGROUND: Sun exposure is a major risk factor for skin cancer; however, the relative contribution of ultraviolet (UV) exposure during childhood versus adulthood on skin cancer risk remains unclear. OBJECTIVE: Our goal was to determine the impact of residential UV, measured by AVerage daily total GLObal solar radiation (AVGLO), exposure during childhood (birth, 15 years) versus adulthood (35, 50 years, and present) on incident non-melanoma skin cancer (NMSC) and malignant melanoma (MM) in postmenopausal women. METHODS: Women were followed with yearly surveys throughout the duration of their participation in the Women's Health Initiative Observational study, a multicenter study from 1993 to 2005. A total of 56,557 women had data on all observations and were included in the baseline characteristics. The main exposure, residential UV (as measured by AVGLO), was measured by geographic residence during childhood and adulthood. Outcome was risk of incident NMSC and MM. RESULTS: Over 11.9 years (median follow-up), there were 9,195 (16.3 %) cases of NMSC and 518 (0.92 %) cases of MM. Compared with the reference group (women with low childhood and low adulthood UV), women with low childhood and high adulthood UV had a 21 % increased risk of NMSC (odds ratio 1.21, 95 % confidence interval 1.12, 1.31). Women with high childhood and high adulthood UV had a 19 % increased risk of NMSC (odds ratio 1.19, 95 % confidence interval 1.11, 1.27). Surprisingly, women with high childhood UV and low adulthood UV did not have a significant increase in NMSC risk compared with the reference group (odds ratio 1.08, 95 % confidence interval 0.91, 1.28) in multivariable models. Residential UV exposure in childhood or adulthood was not associated with increased melanoma risk. CONCLUSION: This study reveals an increase in NMSC risk associated with adulthood residential UV exposure, with no effect for childhood UV exposure.
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Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Melanoma/epidemiología , Neoplasias Cutáneas/epidemiología , Rayos Ultravioleta , Población Blanca , Factores de Edad , Anciano , Femenino , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Posmenopausia , Factores de Riesgo , Salud de la MujerRESUMEN
AIMS: The p63 gene shares structural and functional homologies with the p53 family of transcriptional activators, but differs in exhibiting a consistent expression pattern in normal tissues. Although p63 is rarely mutated in malignancy studies of primary human tumours and cell lines suggest that p63 may promote tumour development. In non-Hodgkin's nodal lymphoma, TAp63 expression in follicular lymphoma (54%) and diffuse large B cell lymphoma (34%) has been described and correlated with the proliferative index. In this study, we analysed a series of primary cutaneous B cell lymphomas for immunohistochemical expression of p63. METHODS AND RESULTS: Thirty cases of diffuse large B cell lymphoma leg type (pcDLBCLL) and 34 cases of follicle centre cell lymphoma (pcFCCL) were stained using a generic antibody to p63, and a subset of these with an antibody specific for delta-Np63 isoform. The results indicate a significant difference between pcDLBCLL (21 of 30) and pcFCCL (four of 34) in p63 expression (P = 0.000); expression correlated strongly with the proliferation rate as assessed by Ki-67 (P = 0.015). None of the p63((+)) cases tested expressed the delta-Np63 isoform, suggesting that expression is of the TAp63 isoform. CONCLUSIONS: Functional studies are required to clarify the significance of p63 overexpression in primary cutaneous B cell lymphoma.
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Biomarcadores de Tumor/metabolismo , Linfoma Folicular/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Neoplasias Cutáneas/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Biomarcadores de Tumor/genética , Humanos , Inmunohistoquímica , Linfoma Folicular/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Dominios Proteicos , Isoformas de Proteínas , Neoplasias Cutáneas/diagnóstico , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
OBJECTIVE: Evidence for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on non-melanoma skin cancer (NMSC) risk is inconsistent. We prospectively examined whether regular, inconsistent, or no/low-use of NSAIDs is associated with lower NMSC risk among 54,728 postmenopausal Caucasian women in the Women's Health Initiative Observational Study enrolled between 1993 and 1998. METHODS: Logistic regression models were used to assess odds of NMSC after adjusting for skin type, sun exposure history and indication for NSAID use. RESULTS: There were 7652 incident cases of NMSC (median follow-up: 6.9years). There was no association between regular NSAID-use and NMSC risk relative to no/low-users. However, in a subgroup analysis of 5325 women with a history of skin cancer (incident NMSC: 1897), odds of NMSC were lower among regular NSAID users whether <5years (OR 0.82, 95% CI: 0.70-0.95) or ≥5years (OR 0.82, 95% CI: 0.69-0.98) of use compared to no/low-users. Inconsistent NSAID use and acetaminophen use were not associated with NMSC risk. CONCLUSION: Overall, NSAID use was not associated with NMSC risk. However, in women with a history of skin cancer, regular NSAID use was associated with 18% lower odds of NMSC. Future studies on potential chemopreventative effects of NSAIDs should focus on subjects with prior history of NMSC.
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Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Cutáneas/prevención & control , Acetaminofén/efectos adversos , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Aspirina/uso terapéutico , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Neoplasias Cutáneas/inducido químicamente , Encuestas y Cuestionarios , Población Blanca , Salud de la MujerRESUMEN
BACKGROUND: Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis. OBJECTIVE: We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib. METHODS: This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability. RESULTS: Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4±2 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery. LIMITATIONS: Short follow-up time and no placebo control are limitations. CONCLUSION: Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Cirugía de Mohs/efectos adversos , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alopecia/inducido químicamente , Anilidas/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma Basocelular/patología , Carcinoma Basocelular/cirugía , Quimioterapia Adyuvante , Disgeusia/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calambre Muscular/inducido químicamente , Terapia Neoadyuvante , Piridinas/efectos adversos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Carga TumoralRESUMEN
Cutaneous T-cell lymphomas (CTCL) account for almost 65-92% of all cutaneous lymphomas, many of which usually present with multiple lesions. However, a number of well-recognized and rare types of CTCL, including mycosis fungoides, can present in isolated fashion. These solitary lesions often run a relatively indolent clinical course but often pose diagnostic difficulties. We review histopathologically challenging solitary cutaneous T-cell lymphomas, including criteria for diagnosis, clinical course and prognosis, particularly for primary cutaneous CD4+ small/medium pleomorphic lymphoma and indolent CD8+ lymphoid proliferation of acral sites. In addition, we suggest an algorithm and nomenclature to aid in the diagnosis of such problematic lesions.
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Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/patología , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , PronósticoRESUMEN
The authors report six further cases of a cutaneous lymphoid proliferation that share many of the features of a case series previously described as indolent CD8-positive lymphoid proliferation of the ear. Previous reports of this entity have described the slow growth of cutaneous papules and nodules, with a predilection for the ear, associated with specific histopathologic and immunophenotypic features and a benign clinical course. These include the presence of a clear Grenz zone without epidermotropism, and a CD8(+) granzyme B- immunophenotype with a low proliferative index. The current case series presents some atypical clinical features, including site of disease beyond the ear and recurrent disease. Despite this, indolent clinical evolution is apparent. Histopathologically, three of the six cases showed a moderate-high proliferative index, while two cases had very focal epidermotropism and Pautrier collections. A single example had significant granzyme B expression. These previously unreported features add to our understanding of this rare entity, which is not currently recognized in the World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) classification.
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Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Linfocitos T/patología , Adulto , Anciano , Antígenos CD8/biosíntesis , Antígenos CD8/inmunología , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Linfoma Cutáneo de Células T/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: CD4+ small/medium-sized pleomorphic T-cell lymphoma (SMPTCL) is a controversial primary cutaneous lymphoma, in which the candidate neoplastic cells express a follicular T-helper phenotype. We describe 16 cases of SMPTCL and compare expression of PD-1, CXCL-13 and ICOS in these tumors with 40 dermatitis cases. METHODS: Histopathologic examination and immunocytochemistry were performed for 16 tumors and 40 assorted dermatitis cases. RESULTS: All but one patient presented with solitary lesions. Each biopsy revealed a dense nodular non-epitheliotropic infiltrate of atypical T-cells. Neoplastic cells were CD3+/CD4+/CD8(-)/CD30(-). Cutaneous recurrence occurred in one patient over a median follow up of 8 months (range 5-36). All tumors widely expressed PD-1 and ICOS to a lesser extent. CXCL-13 stained much fewer cells. Of the dermatitis cases, PD-1 (most numerous) and ICOS labeled lymphoid cells in all cases, albeit fewer than in the tumors, and CXCL-13 was negative in 32. A rosette pattern of PD-1 expression was identified in all the SMPTCL cases but not in dermatitis. CONCLUSIONS: There remains uncertainty about the appropriate nosological status of SMPTCL, which some authors consider to be a pseudolymphoma. However, this study suggests a significant difference in the prevalence and pattern of follicular T-helper cell markers between this tumor and lymphoid proliferations known to be reactive.
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Dermatitis , Regulación Neoplásica de la Expresión Génica , Linfoma Cutáneo de Células T , Proteínas de Neoplasias/biosíntesis , Neoplasias Cutáneas , Linfocitos T Colaboradores-Inductores , Adulto , Anciano , Quimiocina CXCL13/biosíntesis , Dermatitis/metabolismo , Dermatitis/patología , Femenino , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/biosíntesis , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/biosíntesis , Estudios Retrospectivos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), accounting for almost 50% of all primary cutaneous lymphomas. The occurrence of solitary lesions, which are clinically and histopathologically indistinguishable from classic MF has been described. OBJECTIVE: We describe 15 cases of solitary MF and discuss the relationship to classic MF, "reactive" processes and to other, rarer forms of CTCL that may present with solitary lesions. METHODS: We conducted a retrospective chart review and a PubMed search to identify all reported cases of solitary MF to date, as well as information about other CTCLs presenting as a solitary lesion. RESULTS: Fifteen patients were identified. Follow-up data were available on 10 patients with a median follow-up of 10 months (range, 1 to 48 months). Clinical, pathological, immunocytochemical, and molecular-genetic features were analyzed. Five cases were diagnosed as folliculotropic MF (FMF). Of the 10 cases with follow-up, 2 were treated with topical steroids, 2 were completely excised, 5 received radiotherapy, and 1 received tacrolimus. One hundred twenty-eight cases of solitary MF were identified in the literature and reviewed for commonalities to and differences with our cases and other CTCLs. LIMITATIONS: This study was retrospective; follow-up data were not available in some cases and were only short term in others. CONCLUSIONS: Solitary MF appears to have a good prognosis. In lesions that are not completely excised, curative radiotherapy can be used. Long-term follow up is advised.
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Micosis Fungoide/patología , Micosis Fungoide/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenAsunto(s)
Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Neoplasias Faciales/tratamiento farmacológico , Recurrencia Local de Neoplasia , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/patología , Carcinoma Basocelular/cirugía , Quimioterapia Adyuvante , Neoplasias Faciales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Cirugía de Mohs , Terapia Neoadyuvante , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Carga TumoralRESUMEN
OBJECTIVE: To assess the dose-dependent relationship between smoking history and cancer screening rates or staging of cancer diagnoses. DESIGN: Prospective, population-based cohort study. SETTING: Questionnaire responses from the Women's Health Initiative (WHI) Observational Study. PARTICIPANTS: 89 058 postmenopausal women. OUTCOME MEASURES: Logistic regression models were used to assess the odds of obtaining breast, cervical, and colorectal cancer screening as stratified by smoking status. The odds of late-stage cancer diagnoses among patients with adequate vs inadequate screening as stratified by smoking status were also calculated. RESULTS: Of the 89 058 women who participated, 52.8% were never smokers, 40.8% were former smokers, and 6.37% were current smokers. Over an average of 8.8 years of follow-up, current smokers had lower odds of obtaining breast (OR 0.55; 95% CI 0.51 to 0.59), cervical (OR 0.53; 95% CI 0.47 to 0.59), and colorectal cancer (OR 0.71; 95% CI 0.66 to 0.76) screening compared with never smokers. Former smokers were more likely than never smokers to receive regular screening services. Failure to adhere to screening guidelines resulted in diagnoses at higher cancer stages among current smokers for breast cancer (OR 2.78; 95% CI 1.64 to 4.70) and colorectal cancer (OR 2.26; 95% CI 1.01 to 5.05). CONCLUSIONS: Active smoking is strongly associated with decreased use of cancer screening services and more advanced cancer stage at the time of diagnosis. Clinicians should emphasise the promotion of both smoking cessation and cancer screening for this high-risk group.
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Fumar Cigarrillos , Neoplasias , Estudios de Cohortes , Detección Precoz del Cáncer , Femenino , Humanos , Estudios Prospectivos , Factores de Riesgo , Salud de la MujerRESUMEN
CpG island methylation in the promoter regions of tumor suppressor genes has been shown to occur in normal colonic tissue and can distinguish between subjects with and without colorectal neoplasms. It is unclear whether this relationship exists in other tissues such as blood. We report the relationship between estrogen receptor gene (estrogen receptor alpha) methylation in leukocyte and normal colonic tissue DNA in subjects with and without colorectal neoplasia. DNA was extracted from frozen stored whole blood samples of 27 subjects with cancer, 30 with adenoma, 16 with hyperplastic polyps, and 57 disease-free subjects. DNA methylation in seven CpG sites close to the transcription start of estrogen receptor alpha was quantitated using pyrosequencing and expressed as a methylation index (average methylation across all CpG sites analyzed). Estrogen receptor alpha methylation in leukocyte DNA was compared with estrogen receptor alpha methylation in normal colonic mucosa DNA that had been previously determined in the same subjects. Estrogen receptor alpha was partially methylated (median, 4.3%; range, 0.0-12.6%) in leukocyte DNA in all subjects, with no significant difference between disease groups (P>0.05). Estrogen receptor alpha methylation in leukocytes was 60% lower than estrogen receptor alpha methylation in normal colonic tissue (P<0.001). Estrogen receptor alpha methylation in colonic tissue (P<0.001) and smoking (P=0.016) were determinants of estrogen receptor alpha methylation in leukocytes, independent of age, body mass index, gender, and disease status. In conclusion, there was a positive relationship between estrogen receptor alpha methylation in leukocytes and colonic tissue in subjects with and without colorectal tumors. However, unlike in colonic tissue, estrogen receptor alpha methylation in leukocytes was unable to distinguish between disease groups.
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Pólipos del Colon/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Mucosa Intestinal/metabolismo , Leucocitos/metabolismo , Adenoma/genética , Adenoma/metabolismo , Anciano , Análisis de Varianza , Biomarcadores/sangre , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Pólipos del Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Islas de CpG/genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Ácido Fólico/sangre , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estadísticas no ParamétricasRESUMEN
IMPORTANCE: Patients with basal cell nevus syndrome (BCNS) have a greater risk of developing numerous basal cell carcinomas (BCCs). Risk factors influencing the wide variation in tumor burden are poorly understood. OBJECTIVE: To describe the burden of BCCs in patients with BCNS in the United States and identify potential risk factors for BCCs. DESIGN, SETTING, AND PARTICIPANTS: Prospective clinical registry with data collected from September 2014 to March 2016. Participants were recruited from a mailing list of patients with BCNS at Children's Hospital Oakland Research Institute and Basal Cell Carcinoma Nevus Syndrome Life Support Network. Patients of all ages with a diagnosis of BCNS were eligible for enrollment. Participants completed a clinical questionnaire on their disease characteristics and risk factors. MAIN OUTCOMES AND MEASURES: Number of BCCs in the past 2 years and over lifetime (disease burden), risk factors for BCCs. RESULTS: A consecutive sample of the first 141 participants was included (34% [100 of 297] response rate from paper survey, 23% [41 of 179] from online survey; 85 [60%] female; mean age at start of study, 53 [range, 8-83] years; 131 [93%] white). In the previous 2 years, participants reported a mean of 25 BCCs (median, 11; range, 0-250). Over their lifetime, participants reported a mean of 257 BCCs (median, 160; range, 0-2200). Univariate analysis identified age (odds ratio [OR], 1.05; 95% CI, 1.03-1.07; P < .001), number of sunburns (OR, 1.05; 95% CI, 1.00-1.10; P = .047), and history of radiation exposure (OR, 2.26; 95% CI, 1.02-5.03; P = .046) as potential risk factors for lifetime BCC severity. On multivariate analysis, only age (OR, 1.04; 95% CI, 1.02-1.07; P < .001) and number of sunburns (OR, 1.06; 95% CI, 1.00-1.11; P = .04) were statistically significant. In our adjusted models, BCC burden increased by 4% per year of age and by 6% per number of sunburns. CONCLUSIONS AND RELEVANCE: Patients with BCNS have a high burden of BCCs. Age and number of sunburns were significantly associated with the severity of lifetime BCC. Further interventions to prevent and treat BCCs in patients with BCNS are needed.
RESUMEN
IMPORTANCE: Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors. OBJECTIVE: To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples. DESIGN, SETTING, AND PARTICIPANTS: Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability. RESULTS: Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients. CONCLUSIONS AND RELEVANCE: Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Factores de Transcripción/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Trióxido de Arsénico , Arsenicales/administración & dosificación , Carcinoma Basocelular/patología , Resistencia a Antineoplásicos , Estudios de Seguimiento , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Itraconazol/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Óxidos/administración & dosificación , ARN Mensajero/metabolismo , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Proteína con Dedos de Zinc GLI1RESUMEN
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.