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1.
Anticancer Res ; 42(2): 1099-1106, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35093912

RESUMEN

BACKGROUND/AIM: This study investigated the efficacy of continuing cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) after disease progression on prior-palbociclib combined with endocrine therapy (ET). PATIENTS AND METHODS: This retrospective study based on 25 ER+/HER2- MBC patients reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib. RESULTS: The overall response rate and clinical benefit rate were 16.0% and 44.0%, respectively. The median progression-free survival (PFS) was 5.3 months. In multivariate analysis, the best overall response (BOR) to prior-palbociclib was the only independent predictive factor for PFS (p=0.015). The median time to chemotherapy was 33.9 months. The median PFS in patients treated with next-line chemotherapy after progression on subsequent-abemaciclib was 6.2 months. CONCLUSION: BOR to prior-palbociclib was the only independent predictive factor for PFS in ER+/HER2- MBC patients undergoing subsequent-abemaciclib after disease progression on prior-palbociclib.


Asunto(s)
Aminopiridinas/uso terapéutico , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Japón , Persona de Mediana Edad , Metástasis de la Neoplasia , Piperazinas/administración & dosificación , Supervivencia sin Progresión , Piridinas/administración & dosificación , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Resultado del Tratamiento
2.
Clin Breast Cancer ; 22(3): 235-243, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34289949

RESUMEN

BACKGROUND: The efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel combined with S-1 in patients with operable breast cancer is uncertain. We evaluated the feasibility of this combination followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy in such patients. PATIENTS AND METHODS: This was an open-label, single-arm, phase II, single-institution prospective study of 4 cycles of nab-paclitaxel (260 mg/m2) administered intravenously on day 1 in combination with S-1 (65 mg/m2 orally twice daily) on days 1 to 14 every 21 days followed by EC as neoadjuvant chemotherapy. RESULTS: Of 30 patients, 1 required a dose interruption for nab-paclitaxel combined with S-1; 4 required a dose reduction for nab-paclitaxel, 1 for S-1, and 4 for EC. Mean relative dose intensities of nab-paclitaxel, S-1, and EC were 98.0%, 99.3%, and 98.2%, respectively. Overall clinical response rate was 96.7%. In histological response, grade 3, pathological complete response (pCR; ypT0/is and ypN0) rate was 63.3% and grade 2b (near pCR) was 3.3%. pCR was observed in 57.1% of luminal B human epidermal growth factor receptor type 2 (HER2)-negative patients, 55.6% of luminal B HER2-positive patients, 100% of HER2-positive patients, and 57.1% of triple-negative breast cancer patients. Grade 3/4 neutropenia was observed in 1 patient during nab-paclitaxel combined with S-1 and in 7 during EC treatments. The most frequent nonhematological severe adverse events were grade 3 peripheral neuropathy in 2 patients and grade 3 arthralgia in 2 patients during nab-paclitaxel combined with S-1. CONCLUSION: Tri-weekly nab-paclitaxel with S-1 followed by EC is effective and well tolerated as neoadjuvant chemotherapy in patients with operable breast cancer.


Asunto(s)
Neoplasias de la Mama , Nanopartículas , Neoplasias de la Mama Triple Negativas , Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Ciclofosfamida , Epirrubicina , Estudios de Factibilidad , Femenino , Humanos , Terapia Neoadyuvante , Paclitaxel , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico
3.
Oncol Lett ; 17(2): 1883-1888, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30675251

RESUMEN

The mitochondrial DNA (mtDNA) displacement loop (D-loop) is often altered in various cancer types, including with regard to simple sequence repeat number variation (SSRNV), which includes the C-tract and CA-tract. However, because of mitochondrial heteroplasmy and slippage errors by the Taq DNA polymerase used in polymerase chain reaction (PCR) analysis, it is difficult to precisely evaluate mtDNA D-loop SSRNV experimentally. In this study, to precisely determine cancer-specific variants in mtDNA SSRNV, various microscopic portions of cancerous tissues and normal control tissues were obtained from a patient with breast cancer, followed by laser-capture microdissection of formalin-fixed paraffin-embedded specimens. Regions containing (CA)7 repeats (positions 514-523) and (C)8 repeats (positions 303-315) of the mitochondria DNA D-loop were amplified and sequenced. Variant signals of mtDNA SSRs of (CA)7 and (C)8 were observed in normal and cancerous tissues, with the content of minor alleles (CA)6 and (C)7/(C)9 differing among samples. These results were confirmed by PCR using various primers and proofreading DNA polymerases. PCR of genomic SSRs of (CA)7 in the NAALD2 gene and (C)8 in the BMP6 gene showed a simple repeat in all samples that was different from the observed mtDNA SSRNV. The present study suggests a reliable procedure for determining cancer-specific variants in mtDNA SSRNV: Using a proofreading DNA polymerase for PCR, the background of slippage by PCR is determined by PCR of the same genomic sequence as the target. Due to the varied heteroplasmy level of mtDNA SSRNV among normal tissues, the second background of polymorphic variations should be determined by several normal tissue DNA as PCR templates. Finally, the cancer-specific variant, including its variation frequency, is determined by subtracting the two background signals from the variant signals in cancer. However, care must be taken, as normal heteroplasmy drifts observed in mtDNA SSRNV may complicate such estimations.

4.
Arch Virol ; 163(4): 855-865, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29248968

RESUMEN

We found a HLA class II histocompatibility antigen gene, DQ alpha 1 chain (HLA-DQA1), that was expressed more than 9-fold higher in high-load hepatitis C virus (HCV) livers than low-load HCV livers using transcriptomics of chronic HCV-infected livers. To further investigate this finding, we examined which cells were positive for HLA-DQA1 and what liver immune responses were different between HCV-high and -low livers. HLA-DQA1-positive cells were significantly increased in the HCV-high group, and most positive cells were identified as non-parenchymal sinusoid cells and lymphocytic infiltrates in the portal area. Parenchymal hepatocytes were negative for HLA-DQA1. HLA-DQA1-positive cells in the liver sinusoid were positive for CD68 (macrophages or Kupffer cells); those in the lymphocytic infiltrates were positive for CD20 (B cells) or CD3 (T cells). mRNA levels of antigen-presenting cell (APC) markers such as CD68 and CD11c were significantly upregulated in the HCV-high group and were correlated with HLA-DQA mRNA levels. CD8B mRNA (CD8+ T cells) was upregulated in both HCV-positive livers compared with HCV-negative livers, whereas CD154 mRNA (CD4+ T helper cell) was upregulated in the HCV-high group compared with the HCV-low group. The immune regulatory molecules FOXP3 mRNA (regulatory T cell, T reg) and programmed cell death ligand-1 (PD-L1) mRNA were significantly increased in the HCV-high group. HCV-high livers had two molecular immune responses: increased APC numbers and adaptive immunity and the induction of immune tolerance. The local hepatic imbalance of contradictory immune responses might be responsible for high HCV loads.


Asunto(s)
Carcinoma Hepatocelular/genética , Cadenas alfa de HLA-DQ/genética , Hepatitis C Crónica/genética , Neoplasias Hepáticas/genética , Carga Viral/genética , Inmunidad Adaptativa , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD20/genética , Antígenos CD20/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Antígeno CD11c/genética , Antígeno CD11c/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Ligando de CD40/genética , Ligando de CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/virología , Células Dendríticas/inmunología , Células Dendríticas/virología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica , Cadenas alfa de HLA-DQ/inmunología , Hepacivirus/crecimiento & desarrollo , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Hepatocitos/inmunología , Hepatocitos/virología , Humanos , Tolerancia Inmunológica , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/virología , Hígado/inmunología , Hígado/virología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , Transducción de Señal , Transcriptoma/inmunología , Carga Viral/inmunología
5.
PLoS One ; 12(5): e0176280, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28498833

RESUMEN

Formalin-fixed, paraffin-embedded (FFPE) tissues used for pathological diagnosis are valuable for studying cancer genomics. In particular, laser-capture microdissection of target cells determined by histopathology combined with FFPE tissue section immunohistochemistry (IHC) enables precise analysis by next-generation sequencing (NGS) of the genetic events occurring in cancer. The result is a new strategy for a pathological tool for cancer diagnosis: 'microgenomics'. To more conveniently and precisely perform microgenomics, we revealed by systematic analysis the following three details regarding FFPE DNA compared with paired frozen tissue DNA. 1) The best quality of FFPE DNA is obtained by tissue fixation with 10% neutral buffered formalin for 1 day and heat treatment of tissue lysates at 95°C for 30 minutes. 2) IHC staining of FFPE tissues decreases the quantity and quality of FFPE DNA to one-fourth, and antigen retrieval (at 120°C for 15 minutes, pH 6.0) is the major reason for this decrease. 3) FFPE DNA prepared as described herein is sufficient for NGS. For non-mutated tissue specimens, no artifactual mutation occurs during FFPE preparation, as shown by precise comparison of NGS of FFPE DNA and paired frozen tissue DNA followed by validation. These results demonstrate that even FFPE tissues used for routine clinical diagnosis can be utilized to obtain reliable NGS data if appropriate conditions of fixation and validation are applied.


Asunto(s)
ADN/análisis , Formaldehído/química , Secuenciación de Nucleótidos de Alto Rendimiento , Adhesión en Parafina , Proteínas Adaptadoras Transductoras de Señales , Animales , Moléculas de Adhesión Celular , Moléculas de Adhesión Celular Neuronal/genética , Quinasa de Punto de Control 2/genética , ADN/genética , Guanilato-Quinasas , Inmunohistoquímica , Hígado/metabolismo , Masculino , Mutación/genética , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética
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