BackgroundDNA methyl transferase 1 (DNMT-1) is a key epigenetic enzyme in cancer cells which inactivates proliferation terminating genes and downregulates the expression of cancer related proteins ...and neoantigens by hypermethylation. Prolonged exposure of tumor cells to DAC is required for sufficient demethylation. Clinical use of decitabine to target DNMT-1 is restricted by its short in vivo half-life (about 10 minutes) due to rapid inactivation by the enzyme cytidine deaminase (CDA) present in tissues. Tetrahydrouridne(THU), an oral inhibitor of CDA can overcome the pharmacokinetic (PK) limitation.HypothesisNovel pharmacologic combination of THU with micro-doses of DAC can significantly increase half-life of DAC allowing sufficient interaction between DNMT-1 and decitabine to overcome epigenetic repression by DNMT-1. This could lead to enhanced expression of epigenetically silenced cancer-related proteins and antigens, attracting a robust immune response in the tumor milieu. Increased lymphocytic infiltrate in the tumor post the immune priming by decitabine can augment response to immune checkpoint inhibitor MPDL3280A, an anti PD-L1 antibody.Study designThis is a proof-of-concept Phase II single arm open label prospective clinical trial in patients with advanced non-small cell lung cancer (NSCLC) with at least one prior chemotherapy (Figure 1).Figure 1MethodsThe study treatment would be DAC 0.002 mg/m2 and THU at a dose of 400 mg/m2 at a fixed dose administered orally 2X/week for 8 weeks followed by treatment with 1200mg MPDL3280A every 3 weeks until progression. The THU-DAC regimen for immune priming is selected based on ongoing Phase I clinical trial in nonmalignant disease, and IND enabling GLP toxicology studies. Doubling in the number of activated TILs in the tumor compared to pre-treatment biopsy will be considered evidence of immune induction by DAC. The trial will be conducted in two stages. The first stage will be an assessment of the immunologic effect of the combination. The second stage, which will occur only if THU-DAC is shown to have a significant priming effect, will assess the ability of the immunologic response to translate to clinical efficacy. Based on our previous studies we anticipate in advanced stage NSCLC approximately 25% patients will have high TILs and hypothesize that THU-DAC will increase that proportion to >50%. With 24 patients there will be at least 90% power to detect such a difference. Assuming the combination does indeed prime the immune system, stage 2 will be implemented and a two-stage accrual design will be used to assess clinical efficacy, with the 24 patients already accrued.
Overexpression/amplification of the HER2 gene in advanced gastric cancer is a predictor of response to adjuvant therapy with monoclonal antibodies.
To determine the frequency of HER2 gene ...overexpression and amplification in advanced gastric cancer.
One hundred nine advanced gastric cancer biopsy specimens, from 76 men and 33 women aged 67 ± 14 and 62 ± 12 years respectively, were selected. Three histological patterns (diffuse, intestinal and mixed) were recognized. Automated immunohistochemistry was performed with monoclonal c-erbB-2 (NCL-356) Novocastra. Fluorescent in situ hybridization (FISH) for HER2 was performed in positive cases.
In 39% of cases, immunohistochemical staining was negative. It was 1+, 2+ and 3+ positive in 15, 36 and 11% of cases, respectively. It was positive in 16% and 3% of intestinal type and mixed carcinomas, respectively. It was negative in all diffuse carcinomas. FISH was performed in 39 (2 +) cases and in 11 (3 +) cases. The gene amplification was positive in two (2 +) and 11 (3 +) cases (11.9%). The overall concordance between immunohistochemical staining and in situ hybridization was 85%.
In advanced gastric cancer, HER2 gene overexpression or amplification was observed in 11% and 12% of cases, respectively.
The quality of the archival samples stored at pathology services could be a limiting factor for molecular biology studies.
To determine the quality of DNA extracted from gallbladder cancer samples at ...different institutions.
One hundred ninety four samples coming from five medical centers in Chile, were analyzed. DNA extraction was quantified determining genomic DNA concentration. The integrity of DNA was determined by polymerase chain reaction amplification of different length fragments of a constitutive gene (β-globin products of 110, 268 and 501 base pairs).
The mean DNA concentration obtained in 194 gallbladder cancer samples was 48 ± 43.1 ng/µl. In 22% of samples, no amplification was achieved despite obtaining a mean DNA concentration of 58.3 ng/ul. In 81, 67 and 22% of samples, a DNA amplification of at least 110, 268 or 501 base pairs was obtained, respectively. No differences in DNA concentration according to the source of the samples were demonstrated. However, there were marked differences in DNA integrity among participating centers. Samples from public hospitals were of lower quality than those from private clinics.
Despite some limitations, in 80% of cases, the integrity of DNA in archival samples from pathology services in our country would allow the use of molecular biology techniques.
Actinomices es una bacteria oportunista gram positiva no formadora de esporas que aparece ocasionalmente en los genitales femeninos. La infección pélvica es infrecuente, de difícil diagnóstico y se ...ha demostrado asociación con uso de dispositivos intrauterinos. Material y Método: Se analizaron 36 casos entre 1995 y 2002. Se consideraron edad, tipo y subtipo de método anticonceptivo usado, tiempo de uso del mismo y presencia de síntomas. Resultados: La edad media fue 42 años, con 69% entre los 36 y los 47. 92% usuarias de DIU que presentaron un tiempo medio de uso de 11 años, 52% eran usuarias de Lippes y 48% de T de Cobre. Sólo 44% presentaron algún síntomas. Conclusiones: La detección de Actinomices ocurre casi exclusivamente en usuarias de DIU, más frecuentemente en aquellas entre 35 y 47 años y que presentan un tiempo de uso menor a 15 años. La presencia de síntomas, no parece ser un elemento clínico relevante. No se encontraron diferencias entre usuarias de Lippes y T de Cu en este estudioBackground: Actynomices is an opportunistic gram positive bacteria that can occasionally be detected in the female genital tract. The pelvic form is rare and it is related to use of intrauterine devices. Material and Method: 36 cases between 1995 and 2002 were analysed. We considered age at the time of the diagnosis, type and subtype of birth-control method used, length of use and symptoms atributable to their condition. Results: The mean age of presentation was 42 years. 69% were between the 36 and 47 years. 92% were users of IUD and they presented a mean time of use of 11 years. 52% were users of Lippes and 48% of Copper T. Only 44% presented symptoms. Conclusions: The presence of Actinomyces is detectable almost exclusively in IUD users, more frecuently in patients between 35 and 47 years and with less than 15 years of use. The presence of symptoms does not appear to be a relevant clinical aspect. We found no difference between Lippes and Copper T users in this study
Actinomices es una bacteria oportunista gram positiva no formadora de esporas que aparece ocasionalmente en los genitales femeninos. La infección pélvica es infrecuente, de difícil diagnóstico y se ...ha demostrado asociación con uso de dispositivos intrauterinos. Material y Método: Se analizaron 36 casos entre 1995 y 2002. Se consideraron edad, tipo y subtipo de método anticonceptivo usado, tiempo de uso del mismo y presencia de síntomas. Resultados: La edad media fue 42 años, con 69% entre los 36 y los 47. 92% usuarias de DIU que presentaron un tiempo medio de uso de 11 años, 52% eran usuarias de Lippes y 48% de T de Cobre. Sólo 44% presentaron algún síntomas. Conclusiones: La detección de Actinomices ocurre casi exclusivamente en usuarias de DIU, más frecuentemente en aquellas entre 35 y 47 años y que presentan un tiempo de uso menor a 15 años. La presencia de síntomas, no parece ser un elemento clínico relevante. No se encontraron diferencias entre usuarias de Lippes y T de Cu en este estudio
Actinomicosis es una enfermedad infecciosa poco frecuente. La forma pélvica es rara y de difícil diagnóstico. Se ha mencionado que su aparición en la pelvis podría estar relacionada con el uso de ...DIU. Se busca asociación entre Actinomyces y el uso de DIU en nuestro medio, así como otros factores relacionados. Se incluyó 1.774 informes de PAP del Hospital de Florida entre 1996 y 2001. Se consideraron método anticonceptivo y edad. Se utilizó dócima no paramétrica, Chi cuadrado de homogeneidad e independencia. Los casos positivos para Actinomyces fueron 15, correspondientes al 0,84%. Un 86,7% eran usuarias de DIU. La edad media de presentación fue de 33,2 años. En 9 casos hubo presencia de Actinomyces sin respuesta inflamatoria a diferencia de los 6 casos restantes, dondo hubo inflamación específica. Actinomyces es un patógeno poco habitual en los genitales femeninos. Existe asociación positiva con el uso de DIU (p < 0,0001). No se encontró asociación con edad.Actinomycosis is an infrequent infecious disease. The pelvic form is rare and of difficult diagnosis. It has been mentioned that its appearance in female genital tract could be related to the use of IUD. Association between Actinomyces and use of IUD is assesed in our environment, as well as other related factors. 1774 reports of PAP of the Florida Hospital between 1996 and 2001 were included. It were considered birth-control method and age. It was used non parametric test, Chi test for homogeneity and independence of Mann-Whitney. The Actinomyces positive cases were 15, corresponding to 0.84%; 86.7% were IUD users. The median age of presentation was of 33.2 years. In 9 cases there was presence of Actinomyces without inflammatory reaction and the other six presented specific inflammation. Actinomyces is a very uncommon bacteria in the female genital tract. There is a positive association with IUD use (p < 0.0001). We found no association with age.
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