RESUMEN
Up to 95% of all anal cancers are associated with infection by human papillomavirus (HPV); however, no established preclinical model exists for high-grade anal disease and cancer mediated by a natural papillomavirus infection. To establish an infection-mediated model, we infected both immunocompromised NSG and immunocompetent FVB/NJ mice with the recently discovered murine papillomavirus MmuPV1, with and without the additional cofactors of UV B radiation (UVB) and/or the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Infections were tracked via lavages and swabs for MmuPV1 DNA, and pathology was assessed at the endpoint. Tissues were analyzed for biomarkers of viral infection and papillomavirus-mediated disease, and the localization of viral infection was investigated using biomarkers to characterize the anal microanatomical zones. IMPORTANCE We show, for the first time, that MmuPV1 infection is sufficient to efficiently mediate high-grade squamous intraepithelial lesions in the anal tract of mice using the NSG immunocompromised strain and that MmuPV1, in combination with the chemical carcinogen DMBA, has carcinogenic potential. We further show that MmuPV1 is able to persist for up to 6 months in the anal tract of FVB/NJ mice irradiated with UVB and contributes to high-grade disease and cancer in an immunocompetent strain. We demonstrate that MmuPV1 preferentially localizes to the anal transition zone and that this localization is not an artifact of infection methodology. This study presents a valuable new preclinical model for studying papillomavirus-mediated anal disease driven by a natural infection.
Asunto(s)
Canal Anal/patología , Canal Anal/virología , Neoplasias del Ano/virología , Modelos Animales de Enfermedad , Ratones , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/complicaciones , Animales , Antracenos/administración & dosificación , Neoplasias del Ano/inducido químicamente , Femenino , Masculino , Ratones Endogámicos NOD , Ratones SCID , Infecciones por Papillomavirus/patología , Piperidinas/administración & dosificación , Lesiones Intraepiteliales Escamosas/patología , Lesiones Intraepiteliales Escamosas/virología , Rayos UltravioletaRESUMEN
BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. METHODS: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. RESULTS: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p < 0.01). CONCLUSION: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation.
Asunto(s)
Neoplasias del Ano/inducido químicamente , Carcinoma de Células Escamosas/complicaciones , Quimioradioterapia/efectos adversos , Infecciones por VIH/complicaciones , Inhibidores de Proteasas/efectos adversos , Adulto , Carcinoma de Células Escamosas/tratamiento farmacológico , Quimioradioterapia/métodos , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , VeteranosRESUMEN
With the discovery of v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, new treatment possibilities arose against metastatic melanoma. A frequent adverse effect of BRAF inhibitor therapy is the induction of epithelial proliferations such as cutaneous squamous cell carcinoma and verrucous papilloma. Here, we describe a case in which a patient developed extensive anal epithelial proliferations resembling condylomata acuminata, after starting vemurafenib treatment. This adverse effect has rarely been reported in the literature. Interestingly, the lesions in our patient were negative for human papillomavirus, and mutations in BRAF, Neuroblastoma rat sarcoma viral oncogene homolog (NRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Harvey rat sarcoma viral oncogene homolog (HRAS) were not detected. Different pathways can contribute to these epithelial proliferations resembling condylomata acuminata. We show the relevance of a detailed history at the beginning and during treatment, instructions, education, and dermatological follow-up (including the genital area) for patients treated with BRAF inhibitors. Condylomata acuminata can influence the quality of life and are treated, in an early stage, with cryotherapy, coagulation, imiquimod, and/or CO2 laser therapy.
Asunto(s)
Neoplasias del Ano/diagnóstico , Proliferación Celular , Condiloma Acuminado/diagnóstico , Melanoma/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico , Vemurafenib/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/genética , Condiloma Acuminado/inducido químicamente , Diagnóstico Diferencial , GTP Fosfohidrolasas/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Neoplasias Glandulares y Epiteliales/inducido químicamente , Neoplasias Glandulares y Epiteliales/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Human papillomavirus (HPV) infection is the major risk factor for anal dysplasia that may progress to squamous cell carcinoma of the anus. We have previously shown that systemic administration of a PI3K/mTOR inhibitor (BEZ235), an autophagic inducer, results in decreased squamous cell carcinoma of the anus in our HPV mouse model. In this study, we investigate the effect of the local, topical application of a BEZ235 on tumor-free survival, histopathology, PI3K/mTOR, and autophagy. The rationale for investigating a topical formulation is the localized nature of anal dysplasia/cancer and the goal for creating a clinically translatable formulation to decrease anal carcinogenesis. In this study, HPV transgenic mice were given no treatment, topical BEZ235, topical 7,12 dimethylbenz[a]anthracene (DMBA) (carcinogen), or both topical DMBA + BEZ235. Mice were assessed for tumor development and treatment-related toxicities. Tissue was evaluated for histology, PI3K/mTOR inhibition (pS6 and pAkt), and autophagy (LC3ß and p62). DMBA-alone mice had an average of 16.9 weeks tumor-free survival, whereas mice receiving both DMBA+topical BEZ235 had 19.3 weeks (P < 0.000001). Histopathology revealed a significant decrease in dysplasia/carcinoma with the addition of topical BEZ235 to DMBA (P < 0.000001). Comparing DMBA versus DMBA + BEZ235, topical BEZ235 resulted in a significant decrease in both pS6 and pAkt (P < 0.001). Compared with no-treatment mice, both BEZ235-treated and DMBA + BEZ235-treated mice had significantly higher LC3ß expression, signifying autophagic induction (P < 0.01), whereas DMBA-treated, BEZ235-treated, and DMBA+BEZ235-treated mice had a significantly lower p62 expression, signifying active autophagy (P < 0.0005). In conclusion, consistent with systemic delivery, topical application of BEZ235 shows decreased anal carcinogenesis through the activation of autophagy.
Asunto(s)
Neoplasias del Ano/prevención & control , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Imidazoles/administración & dosificación , Infecciones por Papillomavirus/complicaciones , Fosfatidilinositol 3-Quinasas/química , Quinolinas/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Tópica , Animales , Antracenos/toxicidad , Antineoplásicos/administración & dosificación , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/patología , Neoplasias del Ano/virología , Apoptosis , Carcinógenos/toxicidad , Proliferación Celular , Humanos , Ratones , Papillomaviridae/fisiología , Infecciones por Papillomavirus/virología , Piperidinas/toxicidadRESUMEN
PURPOSE: Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), encoded by the Pik3ca gene, are detected in approximately 20% of human anal cancers.Experimental Design: We asked if common activating mutations in Pik3ca contribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in Pik3ca genes, Pik3caH1047R or Pik3caE545K , were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes. RESULTS: Both mutant forms of Pik3ca increased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and Pik3ca mutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids in vitro and reduced the growth rates of anal cancer-derived tumor grafts in vivo. CONCLUSIONS: These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.
Asunto(s)
Neoplasias del Ano/genética , Carcinogénesis/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Papillomavirus Humano 16/patogenicidad , Neoplasias Experimentales/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Canal Anal/efectos de los fármacos , Canal Anal/patología , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/tratamiento farmacológico , Neoplasias del Ano/virología , Benzoxazoles/administración & dosificación , Carcinogénesis/efectos de los fármacos , Carcinógenos/toxicidad , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Mutación con Ganancia de Función , Humanos , Ratones , Ratones Transgénicos , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/virología , Cultivo Primario de Células , Pirimidinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: The Marginal Structural Cox Model (Cox-MSM), an alternative approach to handle time-dependent confounder, was introduced for survival analysis and applied to estimate the joint causal effect of two time-dependent nonrandomized treatments on survival among HIV-positive subjects. Nevertheless, Cox-MSM performance in the case of multiple treatments has not been fully explored under different degree of time-dependent confounding for treatments or in case of interaction between treatments. We aimed to evaluate and compare the performance of the marginal structural Cox model (Cox-MSM) to the standard Cox model in estimating the treatment effect in the case of multiple treatments under different scenarios of time-dependent confounding and when an interaction between treatment effects is present. METHODS: We specified a Cox-MSM with two treatments including an interaction term for situations where an adverse event might be caused by two treatments taken simultaneously but not by each treatment taken alone. We simulated longitudinal data with two treatments and a time-dependent confounder affected by one or the two treatments. To fit the Cox-MSM, we used the inverse probability weighting method. We illustrated the method to evaluate the specific effect of protease inhibitors combined (or not) to other antiretroviral medications on the anal cancer risk in HIV-infected individuals, with CD4 cell count as time-dependent confounder. RESULTS: Overall, Cox-MSM performed better than the standard Cox model. Furthermore, we showed that estimates were unbiased when an interaction term was included in the model. CONCLUSION: Cox-MSM may be used for accurately estimating causal individual and joined treatment effects from a combination therapy in presence of time-dependent confounding provided that an interaction term is estimated.
Asunto(s)
Modelos de Riesgos Proporcionales , Algoritmos , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/epidemiología , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Resultado del TratamientoRESUMEN
INTRODUCTION: Autophagy is an intracellular catabolic process that removes and recycles unnecessary/dysfunctional cellular components, contributing to cellular health and survival. Autophagy is a highly regulated cellular process that responds to several intracellular signals, many of which are deregulated by human papillomavirus (HPV) infection through the expression of HPV-encoded oncoproteins. This adaptive inhibitory response helps prevent viral clearance. A strong correlation remains between HPV infection and the development of squamous cell carcinoma (SCC) of the anus, particularly in HIV positive and other immunosuppressed patients. We hypothesize that autophagy is inhibited by HPV-encoded oncoproteins thereby promoting anal carcinogenesis (Fig 1). MATERIALS AND METHODS: HPV16 transgenic mice (K14E6/E7) and non-transgenic mice (FVB/N), both of which do not spontaneously develop anal tumors, were treated topically with the chemical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), to induce anal cancer. The anuses at different time points of treatment (5, 10, 15 and 20 weeks) were analyzed using immunofluorescence (IF) for two key autophagy marker proteins (LC3ß and p62) in addition to histological grading. The anuses from the K14E6/E7 mice were also analyzed for visual evidence of autophagic activity by electron microscopy (EM). To see if there was a correlation to humans, archival anal specimens were assessed histologically for grade of dysplasia and then analyzed for LC3ß and p62 protein content. To more directly examine the effect of autophagic inhibition on anal carcinogenesis, nontransgenic mice that do not develop anal cancer with DMBA treatment were treated with a known pharmacologic inhibitor of autophagy, chloroquine, and examined for tumor development and analyzed by IF for autophagic proteins. RESULTS: Histologically, we observed the progression of normal anoderm to invasive SCC with DMBA treatment in K14E6/E7 mice but not in nontransgenic, syngeneic FVB/N background control mice. With the development of low-grade dysplasia in the K14E6/E7 mice, there was an increase in both punctate LC3ß and p62 expression while EM revealed increased autophagosomes without evidence of autophagolysosomes. These observations are consistent with autophagy being inhibited at a later stage in the autophagic process. In contrast, in high-grade dysplasia and SCC in the DMBA-treated K14E6/E7 mice, there were decreased levels of p62 with a continued increase in punctate LC3ß expression by IF, while autophagolysosomes were seen on EM, consistent with the process of autophagy proceeded to completion. Similar findings, including histological grade dependent changes in LC3ß and p62 expression, were noted with human samples upon analysis of IF. Finally, with pharmacologic inhibition of autophagy in DMBA-treated, nontrangenic FVB/N mice, there was a significant increase in anal cancer development similar to that observed in DMBA- treated K14E6/E7 mice. CONCLUSION: Autophagic dysregulation is noted early on in HPV-associated anal carcinogenesis (low-grade dysplasia), with normalization of the autophagic process arising in late stages of HPV-associated anal carcinogenesis (high-grade dysplasia and invasive carcinoma).
Asunto(s)
Neoplasias del Ano/patología , Carcinoma de Células Escamosas/patología , Papillomavirus Humano 16/patogenicidad , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/patología , Proteínas de Unión al ARN/metabolismo , 9,10-Dimetil-1,2-benzantraceno/efectos adversos , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/metabolismo , Neoplasias del Ano/virología , Autofagia , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Regulación Neoplásica de la Expresión Génica , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Ratones , Ratones Transgénicos , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/metabolismoAsunto(s)
Adenocarcinoma/inducido químicamente , Neoplasias del Ano/inducido químicamente , Etanercept/efectos adversos , Psoriasis/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/antagonistas & inhibidores , Adenocarcinoma/patología , Adenocarcinoma/terapia , Neoplasias del Ano/patología , Neoplasias del Ano/terapia , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Biopsia con Aguja , Quimioradioterapia/métodos , Colectomía/métodos , Etanercept/uso terapéutico , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Psoriasis/diagnóstico , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Medición de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The treatment of anal cancer in human immunodeficiency virus (HIV) patients-as in the general population-is primarily with chemoradiotherapy (CRT), and abdominoperineal resection of residual or recurrent primary disease. The aim of this study was to evaluate the extent of residual primary disease and local recurrence as well as the outcome of salvage surgery after CRT for anal carcinoma in HIV-positive individuals. METHODS: We retrospectively studied HIV-positive anal carcinoma patients treated between February 1989 and November 2012 in a specialist London unit. Extent of residual primary disease, local recurrence after CRT, postoperative complications, and survival after salvage surgery were evaluated. RESULTS: Complete response was experienced in 44 of 53 (83%) of HIV patients treated with CRT for anal carcinoma. One patient (2.3%) developed local recurrence. Nine patients (eight residual primary disease after CRT and one local recurrence) underwent salvage surgery after CRT. There were no perioperative deaths, and perioperative CD4 counts were sustained. Complications occurred in five patients (55%). Median interval to complete perineal healing was 4 months (range 2-11 months), and median hospital stay was 29 days. Survival (median 16 months) was 25% at 2 years from salvage surgery. CONCLUSIONS: Results in HIV-positive patients receiving highly active antiretroviral therapy (HAART) suggest that loss of HIV sensitivity to HAART can be avoided, but that there is increased postoperative morbidity that may be related to HIV disease. Survival was comparable to that for salvage therapy after optimal CRT in non-HIV anal carcinoma patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Ano/cirugía , Carcinoma de Células Escamosas/cirugía , Quimioradioterapia , Infecciones por VIH/complicaciones , Recurrencia Local de Neoplasia/cirugía , Terapia Recuperativa , Adulto , Anciano , Terapia Antirretroviral Altamente Activa/efectos adversos , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/mortalidad , Neoplasias del Ano/terapia , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , VIH/patogenicidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: The incidence of certain non-AIDS-defining cancers (NADCs) in HIV patients has been reported to have increased in the combination antiretroviral therapy (ART) era. Studies are needed to directly evaluate the effect of ART use on cancer risk. DESIGN: We followed 12 872 HIV-infected Kaiser Permanente members whose complete ART history was known for incident cancers between 1996 and 2008. METHODS: Cancers, identified from Surveillance, Epidemiology, and End Results (SEER)-based cancer registries, were grouped as ADCs, infection-related NADCs, or infection-unrelated NADCs. We also evaluated the most common individual cancer types. Rate ratios for ART use (yes/no) and cumulative duration of any ART, protease inhibitor, and nonnucleotide reverse transcriptase inhibitor (NNRTI) therapy were obtained from Poisson models adjusting for demographics, pretreatment or recent CD4 cell count and HIV RNA levels, years known HIV-infected, prior antiretroviral use, HIV risk, smoking, alcohol/drug abuse, overweight/obesity, and calendar year. RESULTS: The cohort experienced 32 368 person-years of ART, 21 249 person-years of protease inhibitor therapy, and 15 643 person-years of NNRTI therapy. The mean follow-up duration was 4.5 years. ADC rates decrease with increased duration of ART use [rate ratio per year = 0.61 (95% confidence interval 0.56-0.66)]; the effect was similar by therapy class. ART, protease inhibitor, or NNRTI therapy duration was not associated with infection-related or infection-unrelated NADC [rate ratio per year ART = 1.00 (0.91-1.11) and 0.96 (0.90-1.01), respectively], except a higher anal cancer risk with longer protease inhibitor therapy [rate ratio per year = 1.16 (1.02-1.31)]. CONCLUSION: No therapy class-specific effect was found for ADC. ART exposure was generally not associated with NADC risk, except for long-term use of protease inhibitor, which might be associated with increased anal cancer risk.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/efectos adversos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Inhibidores de Proteasas/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Adulto , Fármacos Anti-VIH/administración & dosificación , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/epidemiología , Recuento de Linfocito CD4 , California/epidemiología , Estudios de Cohortes , Comorbilidad , Femenino , Estudios de Seguimiento , VIH-1/aislamiento & purificación , Humanos , Incidencia , Masculino , Neoplasias/virología , Inhibidores de Proteasas/administración & dosificación , Sistema de Registros , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Factores de Riesgo , Programa de VERF , Carga ViralRESUMEN
Ninety percent of anal cancer is associated with human papilloma viruses (HPVs). Using our previously established HPV transgenic mouse model for anal cancer, we tested the role of the individual oncogenes E6 and E7. K14E6 and K14E7 transgenic mice were treated with dimethylbenz[a]anthracene (DMBA) to the anal canal and compared to matched nontransgenic and doubly transgenic K14E6/E7 mice. K14E7 and K14E6/E7 transgenic mice developed anal tumors (papillomas, atypias and carcinomas combined) at significantly higher rates (88% and 100%, respectively) than either K14E6 or NTG mice (18% and 19%, respectively). Likewise, K14E7 and K14E6/E7 transgenic mice developed frank cancer (carcinomas) at significantly higher rates (85% and 85%, respectively) than either K14E6 or NTG mice (18% and 10%, respectively). These findings indicate that E7 is the more potent oncogene in anal cancer caused by HPVs.
Asunto(s)
Neoplasias del Ano/virología , Transformación Celular Neoplásica , Papillomavirus Humano 16/patogenicidad , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Represoras/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Canal Anal/efectos de los fármacos , Canal Anal/patología , Animales , Neoplasias del Ano/inducido químicamente , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Proteínas Oncogénicas Virales/biosíntesis , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/biosíntesis , Proteínas E7 de Papillomavirus/genética , Proteínas Represoras/biosíntesis , Proteínas Represoras/genéticaRESUMEN
The incidence of anal cancer is increasing especially among HIV-infected persons in the HAART era. Treatment of this cancer is based upon traditional chemoradiotherapeutic approaches, which are associated with high morbidity and of limited effectiveness for patients with high-grade disease. The mammalian target of rapamycin (mTOR) pathway has been implicated in several human cancers, and is being investigated as a potential therapeutic target. In archival human anal cancers, we observed mTOR pathway activation. To assess response of anal cancer to mTOR inhibition, we utilized two newly developed mouse models, one in which anal cancers are induced to arise in HPV16 transgenic mice and the second a human anal cancer xenograft model. Using the transgenic mouse model, we assessed the preventative effect of rapamycin on neoplastic disease. We saw significant changes in the overall incidence of tumors, and tumor growth rate was also reduced. Using both the transgenic mouse and human anal xenograft mouse models, we studied the therapeutic effect of rapamycin on preexisting anal cancer. Rapamycin was found to significantly slow, if not stop, the growth of both mouse and human anal cancers. As has been seen in other cancers, rapamycin treatment led to an activation of the MAPK pathway. These results provide us cause to pursue further the evaluation of rapamycin as a therapeutic agent in the control of anal cancer.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias del Ano/prevención & control , Transformación Celular Neoplásica/efectos de los fármacos , Modelos Animales de Enfermedad , Papiloma/prevención & control , Sirolimus/farmacología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/patología , Western Blotting , Carcinógenos/toxicidad , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Ratones Transgénicos , Proteínas Oncogénicas Virales/fisiología , Papiloma/inducido químicamente , Papiloma/patología , Papillomaviridae/genética , Proteínas E7 de Papillomavirus/fisiología , Proteínas Represoras/fisiologíaRESUMEN
Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer.
Asunto(s)
Neoplasias del Ano/patología , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Proteínas Oncogénicas Virales/fisiología , Proteínas E7 de Papillomavirus/fisiología , Proteínas Represoras/fisiología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/virología , Western Blotting , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/virología , Femenino , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Masculino , Ratones , Ratones Transgénicos , Papillomaviridae/genética , FenotipoRESUMEN
In the present paper, we report the case of a patient with long-standing Crohn s disease and multiple complications that, after receiving treatment with infliximab, was diagnosed with an adenocarcinoma of the rectum and anus that required radical surgery, later presenting multiple metastases. In the discussion, characteristics and major risk factors for colorectal cancer in patients with inflammatory bowel disease will be largely reviewed, and current studies will be analyzed in connection with the appearance of neoplasms in patients being treated with biologics.
Asunto(s)
Adenocarcinoma/inducido químicamente , Anticuerpos Monoclonales/efectos adversos , Neoplasias del Ano/inducido químicamente , Enfermedad de Crohn/tratamiento farmacológico , Neoplasias del Recto/inducido químicamente , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Humanos , Infliximab , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Squamous cell cancer of the anus is associated with multiple risk factors, including infection with human papillomavirus, immunosuppression, chronic inflammation, and tobacco smoking, although there is little data on these factors for the prediction of recurrent disease. Here, we evaluated the risk of recurrence and mortality of anal carcinoma in association with tobacco smoking. METHODS: We conducted a retrospective review of cases of anal carcinoma from two local hospitals. We obtained information on treatment response and cancer recurrence, as well as tobacco usage from medical records. RESULTS: We identified 64 patients with squamous cell cancer of the anus, and 34 of these (53%) had a tobacco smoking history. Current smokers had higher carcinoma recurrence rates (11/34, 32%) than non-smokers (6/30, 20%). Overall mortality was 33% (21/64), and cancer-related mortality was 23% (15/64). Smokers were more likely to die from recurrence than non-smokers, with 45% of smokers dead compared to only 20% of non-smokers by 5 years after treatment. CONCLUSION: Tobacco smoking appears to be associated with anal carcinoma disease recurrence, and is related to increased mortality. This data suggests that patients should be cautioned about tobacco smoking once a diagnosis of anal carcinoma is made in attempt to improve their long-term outcome.
Asunto(s)
Neoplasias del Ano/epidemiología , Carcinoma de Células Escamosas/epidemiología , Recurrencia Local de Neoplasia/epidemiología , Fumar/efectos adversos , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/patología , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de Riesgo , TiempoRESUMEN
Two case reports of anal cancer developing during chronic therapeutic immunosuppression for systemic lupus erythematosus (SLE) and their cancer management are presented. The complex issues of delivery of curative chemoradiation treatment for anal cancer in the context of co-existing autoimmune connective tissue disease (AICD) are discussed. These two cases show that combined chemotherapy and radiation regimens are possible in patients with SLE. However, frequent, careful assessment with judicious and prompt management of haematological and other complications during treatment is important.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Ano/inducido químicamente , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Adulto , Neoplasias del Ano/tratamiento farmacológico , Neoplasias del Ano/radioterapia , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
In the present study, we examined the ability of chymostatin, a highly specific inhibitor of chymotrypsin, to suppress dimethylhydrazine-induced colon carcinogenesis, and the dose-response relationship for an extract of soybeans containing the Bowman-Birk inhibitor (BBI) to suppress dimethylhydrazine-induced colon carcinogenesis, when added to the diet of mice. Our results showed that: (i) diets containing 0.1% BBI reduced the incidence of adenocarcinomas of the colon approximately 50%, but had no effect on the incidence of squamous cell carcinomas of the anal gland; (ii) the suppressive effect requires protease inhibitor activity, as the autoclaved BBI, in which all protease inhibitory activity has been destroyed, was ineffective at suppressing the incidence of adenocarcinomas; (iii) chymostatin suppressed the incidence of squamous cell carcinomas of the anal gland, but not adenocarcinomas of the colon; and (iv) the growth rates of the animals were the same in each of the experimental groups. Our results indicate that the levels of anticarcinogenic protease inhibitors present in the diets of these animals do not have any adverse effects on the growth or general health of the animals.
Asunto(s)
Neoplasias del Ano/prevención & control , Neoplasias del Colon/prevención & control , Oligopéptidos/farmacología , Inhibidor de la Tripsina de Soja de Bowman-Birk/farmacología , Inhibidores de Tripsina/farmacología , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Colon/inducido químicamente , Dimetilhidrazinas , Relación Dosis-Respuesta a Droga , Humanos , Masculino , RatonesRESUMEN
Treatment of human colonic cancer in early stages when the process is still limited to the colonic wall is primarily surgery. We wished to see if maltose tetrapalmitate (MTP) immunotherapy alone or in combination with radiotherapy (R) and cyclophosphamide (C) chemotherapy would be effective against primary colon cancer in a fashion similar to that reported by us for primary liver cancer (Anticancer Research 6: 245-250, 1986). One hundred female CD1 mice were subjected to dimethylhydrazine (DMH) treatment once a week for 26 weeks, a period one week before which, colon cancer was histologically documented in each animal of a group that was sacrificed. Surprisingly, many of the animals harboured early anal cancer as well. At 28 weeks, 85 of the available animals were divided into 6 groups that received: Gr. 1, no treatment; Gr. 2, MTP alone (M); Gr. 3, radiotherapy alone (R); Gr. 4, cyclosphophamide alone (C); Gr. 5, R + C; Gr. 6, M + R + C. Criteria of treatment efficacy were: number, size and staging of colorectal tumors and the incidence and the size of anal tumors at death. Mean survival time was also determined although it remained a questionable criterium since most animals died due to complication (hepatic toxicity, pyelonephritis, thrombose) elicited by DMH, R and C toxicities and not as a result of colonic tumor size or metastases. As a single therapy, M appeared to be superior to either R or C alone. However, R + C combination was effective and was further improved upon by its association with M. With the triple combination, (M + R + C), lesions of both cancers decreased in size and/or number and the colon cancer histologically eclipsed from 46% of the treated animals.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Neoplasias del Ano/terapia , Neoplasias del Colon/terapia , Ciclofosfamida/uso terapéutico , Glucolípidos/uso terapéutico , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/tratamiento farmacológico , Neoplasias del Ano/radioterapia , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/radioterapia , Terapia Combinada , Dimetilhidrazinas/toxicidad , Masculino , Ratones , Ratones EndogámicosRESUMEN
This paper reports on the investigation of the effect of medroxyprogesterone acetate (MPA) on foreign body tumorigenesis that resulted from sc implantation of a glass cylinder. Adult BALB/c mice of both sexes bearing the foreign body were separated into groups. Group 1 received 40 mg MPA sc every 2 months during 1 year, in the vicinity of the glass cylinder; group 2 received the same MPA treatment in the contralateral flank; and group 3 received no hormonal treatment. Sarcomas developed in 4 of 39, 9 of 41, and 17 of 39 mice, respectively. With the use of an evaluation based on the number of high-risk mice per time interval, the MPA inhibitory effect was found to be statistically significant in both groups: 26, 53, and 79% tumor incidence, respectively. A decrease in the rate of tumor development also was observed but only in mice treated with MPA in situ. An unexpected side effect of continuous MPA administration in females was the appearance of adenocarcinomas.
Asunto(s)
Reacción a Cuerpo Extraño/prevención & control , Medroxiprogesterona/farmacología , Sarcoma Experimental/prevención & control , Adenocarcinoma/inducido químicamente , Animales , Neoplasias del Ano/inducido químicamente , Femenino , Vidrio , Masculino , Neoplasias Mamarias Experimentales/inducido químicamente , Medroxiprogesterona/toxicidad , Ratones , Ratones Endogámicos BALB C , Sarcoma Experimental/etiología , Sarcoma Experimental/patología , Factores SexualesRESUMEN
Because epidermal growth factor (EGF) can modify cell proliferation in the gastrointestinal tract, effects of EGF were studied on the development of colonic, rectal, and anal neoplasms in male mice treated with 1,2-dimethylhydrazine (DMH) (20 mg/kg/wk for 20 weeks). DMH treatment caused a 13% increase in colonic RNA content, a 16% increase in DNA content, and 28% greater crypt depth. EGF (5 micrograms on alternate days during weeks 20 to 22) administered to DMH-treated mice produced no additional changes in colonic mucosa. At 30 weeks colorectal tumors were present in 13 of 20 mice treated with DMH (mean number of tumors per mouse 2.3 +/- 0.5) and 18 of 24 mice (mean 2.6 +/- 0.7) treated with DMH and EGF. Anal tumors were present in two of 20 DMH-treated mice (mean 0.1 +/- 0.07) but in eight of 24 DMH-EGF-treated mice (mean 0.33 +/- 0.1) (X2 = 4.84; p less than 0.05 for prevalence). Although EGF in this dose has no effect on the frequency of colorectal adenocarcinomas, the frequency of anal squamous cell carcinomas is increased more than three fold.