ABSTRACT
T-cell large granular leukemia (T-LGL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T lymphocytes. We present a unique case of T-LGL and concurrent retroperitoneal sarcoma occurring in a patient with long-standing rheumatoid arthritis. Pathology revealed a high-grade dedifferentiated liposarcoma. The diagnosis of T-LGL with a synchronous retroperitoneal sarcoma is a case that highlights the surgical management of these two rare conditions.
ABSTRACT
Radiation therapy remains a promising modality for curative treatment of localized prostate cancer, but dose-limiting toxicities significantly limit its effectiveness. Agents that enhance efficacy at lower radiation doses might have considerable value in increasing tumor control without compromising organ function. Here, we tested the hypothesis that the PARP inhibitor ABT-888 (veliparib) can enhance the response of prostate cancer cells and tumors to ionizing radiation (IR). Following exposure of DU-145 and PC-3 prostate cancer cell lines to the combination of 10 µmol/L ABT-888 and 6 Gy, we observed similar persistence between both cell lines of DNA damage foci and in vitro radiosensitization. We have previously observed that persistent DNA damage foci formed after ABT-888 plus IR efficiently promote accelerated cell senescence, but only PC-3 cells displayed the expected senescent response of G(2)-M arrest, induction of p21 and ß-galactosidase expression, and accumulation as large flat cells. In turn, combining ABT-888 with 6 Gy resulted in delayed tumor regrowth compared with either agent alone only in PC-3 xenograft tumors, whereas DU-145 tumors continued to grow. By 7 days after treatment with ABT-888 plus IR, PC-3 tumors contained abundant senescent cells displaying persistent DNA damage foci, but no evidence of senescence was noted in the DU-145 tumors. That equivalent radiosensitization by ABT-888 plus IR in vitro failed to predict comparable results with tumors in vivo suggests that the efficacy of PARP inhibitors may partially depend on a competent senescence response to accumulated DNA damage.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms/enzymology , Aging/drug effects , Aging/radiation effects , Animals , Cell Line, Tumor , DNA Breaks, Double-Stranded/drug effects , DNA Damage/drug effects , DNA Damage/radiation effects , Female , Humans , Male , Mice , Mice, Nude , Prostatic Neoplasms/genetics , Radiation, Ionizing , Tumor Burden/drug effects , Tumor Burden/radiation effects , Xenograft Model Antitumor AssaysABSTRACT
Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy.
Subject(s)
Benzimidazoles/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Growth Processes/drug effects , Cell Growth Processes/radiation effects , Cell Line, Tumor , Cellular Senescence/drug effects , Cellular Senescence/radiation effects , Combined Modality Therapy , Dose-Response Relationship, Radiation , Female , Green Fluorescent Proteins/analysis , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Infrared Rays , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Nude , Recombinant Fusion Proteins/analysis , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Tumor Suppressor p53-Binding Protein 1 , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Soft tissue sarcomas are rare tumors with a wide clinical spectrum. Prognostic factors for survival have been identified, but they have been focused in the characteristics of the tumor. Patient related variables have not usually been considered in previous analysis. METHODS: We analyzed a group of 61 patients with soft tissue sarcomas. Tumor related variables and patient related ones were recorded. Overall and disease free survival were calculated according to the Kaplan and Meier method. Prognostic factors for survival were determined by the log-rank method for univariate analysis and the Cox method for multivariate analysis. RESULTS: Clinical and demographic characteristics are comparable to those of previous reports. Adverse prognostic factors for overall survival in multivariate analysis were advanced stage, high tumor grade, irresecability, and serum albumin. Size, high surgical risk (ASA III-IV) and a low performance status (Karnofsky less than 70) were predictive of overall survival only in univariate analysis. For disease free survival, only high tumor grade had statistical significance. CONCLUSIONS: Besides the usual tumor related prognostic factors, such as grade and stage, patient related factors, such as performance status and surgical risk should be considered when predicting survival. Specifically, serum albumin was an independent prognostic factor for overall survival.
Subject(s)
Sarcoma/blood , Serum Albumin/analysis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers , Cachexia/blood , Cachexia/etiology , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Liposarcoma/blood , Liposarcoma/mortality , Liposarcoma/therapy , Male , Mexico/epidemiology , Middle Aged , Prognosis , Retrospective Studies , Sarcoma/complications , Sarcoma/mortality , Sarcoma/therapy , Survival Analysis , Young AdultABSTRACT
Objetivo: conocer los resultados a corto y largo plazos del tratamiento quirúrgico en el carcinoma del colon y recto en el INCMNSZ. Antecedentes: el cáncer colorrectal es la segunda neoplasia maligna más frecuente del tubo digestivo en México. Su incidencia continúa en aumento, siendo primordial su identificación en estadios tempranos, en los que la cirugía puede ser curativa. Método: estudio retrolectivo, descriptivo y observacional. Se estudiaron 165 pacientes intervenidos quirúrgicamente por cáncer colorrectal entre 1985 y 1994 en el INNSZ, comparando variables de los pacientes y de la intervención quirúrgica en sí, con base en su relación con la morbilidad y mortalidad operatorias, así como supervivencia a cinco años. Resultados: la supervivencia fue mayor en cirugía con intento curativo en tumores de colon con respecto a los rectales (p < 0.05). Hubo mayor supervivencia a cinco años mientras más temprano fuera el estadio al momento del diagnóstico. La morbilidad operatoria fue de 30 por ciento, principalmente infecciones de la herida. La mortalidad operatoria fue de 3.6 por ciento, siendo sepsis la causa principal. Se encontró mayor mortalidad quirúrgica en mayores de 65 años. Hubo mayor morbilidad en la cirugía rectal con respecto a la cirugía del colon. Conclusiones: es necesario detectar a los pacientes con cáncer colorrectal en estadios más tempranos que permitan un manejo quirúrgico con fines curativos, pues el estadio al momento del diagnóstico se relaciona directamente con la supervivencia del paciente. La edad fue un factor de riesgo para mortalidad quirúrgica, y la cirugía de recto lo fue para morbilidad.
