RESUMEN
The extracellular matrix (ECM) is the basis for virtually all cellular processes and is also related to tumor metastasis. Fibronectin (FN), a major ECM macromolecule expressed by different cell types and also present in plasma, consists of multiple functional modules that bind to ECM-associated, plasma, and cell-surface proteins such as integrins and FN itself, thus ensuring its cell-adhesive and modulatory role. Here we show that FN constitutes an immune checkpoint. Thus, FN was identified as a physiological ligand for a tumor/leukemia/lymphoma- as well as autoimmune-associated checkpoint, ILT3/LILRB4 (B4, CD85k). Human B4 and the murine ortholog, gp49B, bound FN with sub-micromolar affinities as assessed by bio-layer interferometry. The major B4-binding site in FN was located at the N-terminal 30-kDa module (FN30), which is apart from the major integrin-binding site present at the middle of the molecule. Blockade of B4-FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. The unexpected nature of the B4-FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.
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Enfermedades Autoinmunes/metabolismo , Fibronectinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Comunicación Celular/inmunología , Línea Celular Tumoral , Células Cultivadas , Fibronectinas/inmunología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Glicoproteínas de Membrana/inmunología , Ratones , Fagocitosis/inmunología , Células RAW 264.7 , Receptores Inmunológicos/inmunología , Células THP-1/inmunología , Células THP-1/metabolismoRESUMEN
The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.
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Neoplasias de la Mama/genética , Ácidos Nucleicos Libres de Células , Fosfatidilinositol 3-Quinasa Clase I/genética , ADN de Neoplasias , Receptor alfa de Estrógeno/genética , Mutación , Proteínas Proto-Oncogénicas c-akt/genética , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Estimación de Kaplan-Meier , PronósticoRESUMEN
BACKGROUND: ESR1 mutations have attracted attention as a potentially important marker and treatment target in endocrine therapy-resistant breast cancer patients. The E380Q mutation, which is one of the ESR1 mutations, is associated with estradiol (E2) hypersensitivity, increased DNA binding to the estrogen response element, and E2-independent constitutive trans-activation activity, but its frequency in ESR1 mutations remains unknown. The present study aimed to investigate the E380Q mutation in comparison with the other representative ESR1 mutations. METHODS: We screened a total of 62 patients (66 tumor tissues and 69 plasma cell-free DNA (cfDNA)) to detect ESR1 mutations (E380Q, Y537S, Y537N, Y537C, and D538G) using droplet-digital polymerase chain reaction. Plasma was collected at more than two points of the clinical course, in whom changes of ESR1 mutations under treatment were investigated. RESULTS: We detected ESR1 mutations in 21% (12/57) of MBCs. The E380Q ESR1 mutation was found in 16% (2/12) and the other ESR1 LBD mutations were five (41.6%) of Y537S, and four each (33.3%) of D538G, Y537N, and Y537C, in 12 ESR1 mutant breast cancer patients. Five tumors had multiple ESR1 mutations: three had double ESR1 mutations; Y537S/E380Q, Y37S/Y537C, and Y537S/D538G, and two had triple ESR1 mutations; Y537S/Y537N/D538G. In plasma cfDNA analysis, the E380Q mutation was not detected, but increases in other ESR1 mutations were detected in 46.2% (6/13) of MBC patients under treatment. CONCLUSIONS: We have shown that there are distinct populations of ESR1 mutations in metastatic tissue and plasma. Each ESR1 mutation may have different clinical significance, and it will be necessary to investigate them all.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , ADN Tumoral Circulante , Femenino , Frecuencia de los Genes , Humanos , Japón , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de NeoplasiasRESUMEN
PURPOSE: Single-photon emission computed tomography (SPECT)/computed tomography (CT) improves the anatomical identification of sentinel lymph nodes (SNs). We aimed to evaluate the possibility of predicting the SN status using SPECT/CT. METHODS: SN mapping using a SPECT/CT system was performed in 381 cases of clinically node-negative, operable invasive breast cancer. We evaluated and compared the values of SN mapping on SPECT/CT, the findings of other modalities and clinicopathological factors in predicting the SN status. RESULTS: Patients with SNs located in the Level I area were evaluated. Of the 355 lesions (94.8 %) assessed, six cases (1.6 %) were not detected using any imaging method. According to the final histological diagnosis, 298 lesions (78.2 %) were node negative and 83 lesions (21.7 %) were node positive. The univariate analysis showed that SN status was significantly correlated with the number of SNs detected on SPECT/CT in the Level I area (P = 0.0048), total number of SNs detected on SPECT/CT (P = 0.011), findings of planar lymphoscintigraphy (P = 0.011) and findings of a handheld gamma probe during surgery (P = 0.012). According to the multivariate analysis, the detection of multiple SNs on SPECT/CT imaging helped to predict SN metastasis. CONCLUSIONS: The number of SNs located in the Level I area detected using the SPECT/CT system may be a predictive factor for SN metastasis.
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Neoplasias de la Mama/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Biopsia del Ganglio Linfático Centinela , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Anciano , Neoplasias de la Mama/patología , Femenino , Humanos , Metástasis Linfática , Linfocintigrafia , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
The development and characterization of enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols using chiral alkoxyamines as precatalysts are described. A number of chiral alkoxyamines have been synthesized, and their structure-enantioselectivity correlation study in OKR has led us to identify a promising precatalyst, namely, 7-benzyl-3-n-butyl-4-oxa-5-azahomoadamantane, which affords various chiral aliphatic secondary alcohols (ee up to >99%, k(rel) up to 296). In a mechanistic study, chlorine-containing oxoammonium species were identified as the active species generated in situ from the alkoxyamine precatalyst, and it was revealed that the chlorine atom is crucial for high reactivity and enantioselectivity. The present OKR is the first successful example applicable to various unactivated aliphatic secondary alcohols, including heterocyclic alcohols with high enantioselectivity, the synthetic application of which is demonstrated by the synthesis of a bioactive compound.
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Alcoholes/química , Aminas/química , Adamantano/análogos & derivados , Adamantano/química , Catálisis , Óxidos N-Cíclicos/química , Cinética , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
Cylindromatosis (CYLD) is a tumor suppressor gene that is mutated in familial cylindromatosis, a rare autosomal dominant disorder associated with numerous benign skin adnexal tumors. CYLD is now known to regulate various signaling pathways, including transforming growth factor-ß signaling, Wnt/ß-catenin signaling, and NF-κB signaling by deubiquitinating upstream regulatory factors. Downregulation of CYLD has been reported in several malignancies; however, the clinical significance of CYLD expression in many malignancies, including breast cancer, remains to be elucidated. This study investigated the clinical significance of CYLD in breast cancer and its roles in tumor progression. We evaluated CYLD expression in matched normal breast tissue samples and tumor breast tissue samples from 26 patients with breast cancer and in a series of breast cancer cell lines. In addition, by means of immunohistochemistry, we investigated CYLD protein expression and its clinical significance in 244 breast cancer cases. We also analyzed the effects of CYLD repression or overexpression on breast cancer cell viability, cell migration, and NF-κB activity with or without receptor activator of NF-κB ligand (RANKL) stimulation. Breast cancer tissues demonstrated significantly reduced CYLD mRNA expression compared with normal breast tissues. Downregulation of CYLD promoted cell survival and migratory activities through NF-κB activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells. As an important finding, CYLD overexpression also inhibited RANKL-induced NF-κB activation. Our immunohistochemical analysis revealed that reduced CYLD protein expression was significantly correlated with estrogen receptor negativity, high Ki-67 index, high nuclear grade, decreased disease-free survival, and reduced breast cancer-specific survival in primary breast cancer. Moreover, reduced CYLD expression was an independent factor for poor prognosis in breast cancer. CYLD downregulation may promote breast cancer metastasis via NF-κB activation, including RANKL signaling.
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FN-kappa B/genética , Transducción de Señal/genética , Neoplasias de la Mama Triple Negativas/genética , Proteínas Supresoras de Tumor/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Enzima Desubiquitinante CYLD , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Ligando RANK/metabolismo , Neoplasias de la Mama Triple Negativas/patología , beta Catenina/genéticaRESUMEN
Little is known about how the solubility and chemical speciation of phosphorus (P) in poultry litters are altered during the composting period. This study investigated the quantitative and qualitative changes in organic P (Po) and inorganic P (Pi) compositions in poultry litters during the seven-day composting period using sequential extraction in combination with P K-edge X-ray absorption near-edge structure (XANES) and solution (31)P nuclear magnetic resonance (NMR) spectroscopy. The result of sequential extraction illustrated that the significant decrease of H2O-P by 55% in poultry litters occurred concomitantly with the increase of HCl-Pi and HCl-Po during the composting period (p < 0.05). X-ray diffraction results for poultry litter samples showed three distinct peaks indicative of hydroxyapatite. Phosphorus K-edge XANES confirmed the increase of hydroxyapatite during the composting period, corresponding to the increase of HCl-Pi determined by the sequential extraction. The NaOH-EDTA extraction for solution (31)P NMR revealed that myo-inositol hexakisphosphate (IHP) constituted about 80% of phosphate monoesters and was increased from 16 to 28% in the poultry litter during the composting period. The combined applications of chemical extraction and molecular-spectroscopic techniques determined that water-soluble P in poultry litter was transformed into less soluble phases, primarily hydroxyapatite and IHP, during the composting period.
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Fraccionamiento Químico/métodos , Durapatita/química , Espectroscopía de Resonancia Magnética , Fósforo/química , Ácido Fítico/química , Suelo/química , Residuos/análisis , Espectroscopía de Absorción de Rayos X/métodos , Animales , Estiércol , Isótopos de Fósforo , Aves de Corral , Soluciones , Análisis Espectral/métodos , Difracción de Rayos XRESUMEN
The patient was 77-year-old woman whose breast cancer had metastasized to the bone and soft tissue 5 years after surgery. Although she had been sequentially treated with endocrine therapies following chemotherapies, new metastatic lesions in the pleura and skin appeared 8 years after recurrence. The biopsied skin tissue showed high positivity for estrogen receptor(ER), was negative for human epidermal growth factor receptor 2(HER2), and had a low Ki-67 labeling index. Following the treatment with exemestane(EXE)for 3 months, ethinyl estradiol(EE2)was administered at 3mg/day. After 4 months of treatment, the lymph nodes shrunk to 35% of their size and pleural effusion disappeared. The efficacy of EE2 was observed for 10 months. Subsequently, fulvestrant was administered because the skin lesions showed progressive disease. Adverse events such as nausea and general fatigue were observed at the beginning of EE2 therapy. Pigmentation of the nipple and areola and cystic swelling of the cervical canal were observed after a few months. This therapy can be considered to be effective in patients with ER-positive metastatic breast cancer who have been heavily treated with endocrine therapies and chemotherapies.
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Neoplasias de la Mama/tratamiento farmacológico , Estrógenos/uso terapéutico , Etinilestradiol/uso terapéutico , Receptor ErbB-2/análisis , Anciano , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Femenino , Humanos , Metástasis de la Neoplasia , Posmenopausia , RecurrenciaRESUMEN
BACKGROUND: Breast elastography (EG), which can objectively evaluate tumor stiffness, has been useful for differentiation of benign and malignant breast lesions. However, the value of EG for prediction of response to systemic therapy is poorly understood. METHODS: The baseline evaluations of EG in 55 patients who received neoadjuvant chemotherapy were reviewed. We investigated the correlation between tumor stiffness and response to neoadjuvant chemotherapy. Tumor stiffness was evaluated by the Tsukuba elasticity scoring system. RESULTS: The mean EG scores were significant lower for the clinical and pathologic complete response (pCR) groups than for the others. When we categorized patients into two groups according to tumor stiffness, 26 patients were assigned to the low EG group (soft, scores from 1 to 3) and 29 patients were assigned to the high EG group (hard, score 4 and 5). The low EG group had significantly higher clinical complete response and pCR rates than the high EG group (clinical complete response, low EG group 38 % vs. high EG group 10 %, P = 0.024; pCR, low EG group 50 % vs. high EG group 14 %, P = 0.003, respectively). Furthermore, multivariate analysis indicated that estrogen receptor, human epidermal growth factor receptor 2, and low EG (odds ratio 13.04, 95 % confidence interval 1.19-458.28, P = 0.035) were independent predictive factors of pCR. CONCLUSIONS: Tumor stiffness evaluated by EG bears predictive potential for response to neoadjuvant chemotherapy. Stiffness evaluated by EG may be recognized as a clinically significant tumor characteristic, comparable to other data obtained by functional imaging techniques.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/tratamiento farmacológico , Diagnóstico por Imagen de Elasticidad , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Femenino , Humanos , Antígeno Ki-67/metabolismo , Modelos Logísticos , Persona de Mediana Edad , Terapia Neoadyuvante , Valor Predictivo de las Pruebas , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Insulin-like growth factor-1 receptor (IGF1R) plays a key role in the initiation and progression of breast cancer. However, its prognostic relevance to breast cancer patients has long been a matter of debate. In a series of 325 primary invasive breast cancer patients, we performed a comprehensive analysis of IGF1R at the levels of gene copy number, mRNA expression and protein expression. The relationship between the IGF1R status and the clinicopathological characteristics and prognosis was evaluated. IGF1R mRNA levels not only correlated with protein expression, but also were significantly associated with several clinicopathological parameters and prognosis. Patients with low nuclear grade, negative axillary lymph nodes, positive hormone receptor, negative Her2, negative Ki67, and luminal subtype tumors showed higher expression levels of IGF1R mRNA, which was shown to be a significant univariate parameter for both relapse-free survival and breast cancer-specific survival (BCSS) as well as a significant multivariate parameter for BCSS. IGF1R protein expression showed an association with a prolonged BCSS in univariate analysis. In contrast, IGF1R gene copy number was not correlated with mRNA and protein expression, and harbored no prognostic value. When studied in the luminal tumor subtype groups, IGF1R mRNA level was still significantly associated with a better BCSS. Overall, our data indicated a correlation between IGF1R mRNA expression and protein expression in primary breast cancer. In particular, IGF1R mRNA expression appeared to be a good prognostic marker both in the entire cohort and in the luminal subtype group. These data may serve as background information for IGF1R-targeted therapy.
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Neoplasias de la Mama/mortalidad , Dosificación de Gen , Receptor IGF Tipo 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Expresión Génica , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Receptor IGF Tipo 1/metabolismo , Adulto JovenRESUMEN
The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC(50) values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC(50)=0.032µM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Glicósido Hidrolasas , Iminofuranosas/química , Iminofuranosas/farmacología , alfa-Glucosidasas/metabolismo , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Inhibidores Enzimáticos/síntesis química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Iminofuranosas/síntesis química , RatasRESUMEN
OBJECTIVES: There are few scales that reflect the function of the stroke-affected arm as it relates to the performance of daily activities while also indicating the difficulty of scale items. In this study, we developed the Activities Specific Upper-extremity Hemiparesis Scale (ASUHS) to evaluate daily activities performable by the affected arm after stroke. We also clarified the validity, reliability, and item difficulty of the scale. METHODS: The participants were 145 patients with stroke who were consecutively admitted to a convalescent rehabilitation ward. The unidimensionality of ASUHS was assessed by principal component analysis. Analyses of item discrimination and content validity were conducted to assess the overall validity. Reliability was evaluated by assessing internal consistency and inter-rater reliability. Item difficulties were determined by Rasch analysis. RESULTS: Unidimensionality, high discrimination, and good content validity were shown for all items. ASUHS consists of a dominant hand scale and non-dominant hand scale. Both scales showed good internal consistency (Cronbach's α coefficient = 0.99) and substantial inter-rater reliability (Cohen's Kappa coefficient = 0.74 and 0.75, respectively). Item difficulty was determined as being in the range -8.71 to +5.18 logit. CONCLUSIONS: This study suggested good validity and reliability of ASUHS. Furthermore, because the item difficulties of daily activities performed by the affected arm were clarified, therapists can use ASUHS to identify the process that should be the next focus for training. Consequently, therapists may be able to train patients in daily activities that match the affected arm's ability step by step rather than determining training activities empirically.
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BACKGROUND: The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients. METHODS: The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients. We developed multiplex droplet digital PCR assays to verify the clinical significance of ESR1 and PIK3CA mutations both in a snapshot and serially in these patients. RESULTS: cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6 % of MBC patients, respectively. The relation between ESR1 or PIK3CA mutations and clinical features showed that ESR1 mutations occurred mostly in patients previously treated by ET, which was not the case for PIK3CA mutations. The analysis of the clinical impact of those mutations on subsequent lines of treatment for the 69 MBC patients revealed that both ESR1 and PIK3CA mutations detection were related to a shorter duration of ET effectiveness in univariate analysis but only for ESR1 mutations in multivariate analysis. The monitoring of cfDNA in a subset of 52 patients showed that loss of ESR1 mutations was related to a longer duration of response, which was not the case for PIK3CA mutations. CONCLUSIONS: We have demonstrated the clinical significance of on-treatment ESR1 mutations both in a snapshot and serially in comparison with PIK3CA mutations.
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BACKGROUND: ESR1 mutation in circulating cell-free DNA (cfDNA) is emerging as a noninvasive biomarker of acquired resistance to endocrine therapy, but there is a paucity of data comparing the status of ESR1 gene in cfDNA with that in its corresponding tumor tissue. The objective of this study is to validate the degree of concordance of ESR1 mutations between plasma and tumor tissue. METHODS: ESR1 ligand-binding domain mutations Y537S, Y537N, Y537C, and D538G were analyzed using droplet digital PCR in 35 patients with metastatic breast cancer (MBC) (35 tumor tissue samples and 67 plasma samples). RESULTS: Of the 35 paired samples, 26 (74.3%) were concordant: one patient had detectable ESR1 mutations both plasma (ESR1 Y537S/Y537N) and tumor tissue (ESR1 Y537S/Y537C), and 25 had WT ESR1 alleles in both. Nine (25.7%) had discordance between the plasma and tissue results: five had mutations detected only in their tumor tissue (two Y537S, one Y537C, one D538G, and one Y537S/Y537N/D538G), and four had mutations detected only in their plasma (one Y537S, one Y537N, and two Y537S/Y537N/D538G). Furthermore, longitudinal plasma samples from 19 patients were used to assess changes in the presence of ESR1 mutations during treatment. Eleven patients had cfDNA ESR1 mutations over the course of treatment. A total of eight of 11 patients with MBC with cfDNA ESR1 mutations (72.7%) had the polyclonal mutations. CONCLUSION: We have shown the independent distribution of ESR1 mutations between plasma and tumor tissue in 35 patients with MBC.
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The radiation recall phenomenon (RRP) is an acute inflammatory reaction at a site previously treated with radiation, and is triggered by anti-cancer therapies such as chemotherapy or antibiotics. A 48-year-old Japanese woman with primary breast cancer underwent partial mastectomy and sentinel lymph node biopsy followed by postoperative radiotherapy. Subsequent to breast-conserving surgery, adjuvant chemotherapy, including docetaxel in combination with cyclophosphamide (TC), was administrated after 16 days of radiotherapy involving the right breast. The patient experienced the RRP with erythema and burning pain at the site of the irradiation fields at 6 days after the administration of TC. The skin symptoms resolved after treatment with topical corticosteroid therapy over a few days. After the second course of TC, the patient had only mild symptoms relative to the first course. She successfully completed four cycles of TC without dose reduction and treatment delay. We report this case involving the RRP induced by TC together with a review of the literature.
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Glycosylphosphatidylinositol-anchored proteins (GPI-APs) can be shed from the cell membrane by GPI cleavage. In this study, we report a novel GPI-processing enzyme, termed post-glycosylphosphatidylinositol attachment to proteins 6 (PGAP6), which is a GPI-specific phospholipase A2 mainly localized at the cell surface. CRIPTO, a GPI-AP, which plays critical roles in early embryonic development by acting as a Nodal coreceptor, is a highly sensitive substrate of PGAP6, whereas CRYPTIC, a close homologue of CRIPTO, is not sensitive. CRIPTO processed by PGAP6 was released as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D. CRIPTO shed by PGAP6 was active as a coreceptor in Nodal signaling, whereas cell-associated CRIPTO activity was reduced when PGAP6 was expressed. Homozygous Pgap6 knockout mice showed defects in early embryonic development, particularly in the formation of the anterior-posterior axis, which are common features with Cripto knockout embryos. These results suggest PGAP6 plays a critical role in Nodal signaling modulation through CRIPTO shedding.
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Proteínas Ligadas a GPI/metabolismo , Glicosilfosfatidilinositoles/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína Nodal/metabolismo , Fosfolipasas A2/metabolismo , Animales , Tipificación del Cuerpo , Células CHO , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario , Células HEK293 , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Noqueados , Modelos Biológicos , Mutación/genética , Monoéster Fosfórico Hidrolasas/genética , Fosfotransferasas/genética , Transducción de SeñalRESUMEN
BACKGROUND: Ki67 has been identified as a prognostic and predictive marker for breast cancer and it was suggested that it may contribute to pathologic complete response (pCR) after neoadjuvant chemotherapy. It is unclear whether expression of Ki67 is particularly helpful for prediction of pCR across tumor subtypes. METHODS: Pretherapeutic Ki67 was evaluated in a series of 121 breast cancer core biopsies. After neoadjuvant chemotherapy, we used postoperative specimens to evaluate the pCR status. Several parameters predictive of pCR were identified using logistic regression analysis. We investigated subgroups defined by estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, in which predicting pCR with Ki67 might be feasible. RESULTS: Ki67 was found to be an independent predictor of pCR in multivariate analysis (odds ratio [OR], 3.62; 95% CI, 1.21-10.8). When stratified by ER, the above significance was exclusive to ER-positive tumors (OR, 6.24; 95% CI, 1.40-27.7). Using an receiver-operating characteristic curve, we obtained moderate discriminative accuracy with an area under the curve of 0.7752 for Ki67 prediction of pCR in ER-positive tumors. In subgroup analysis, patients with high Ki67 showed significantly improved pCR rate in luminal-type disease, with a median Ki67 value of 43% in the patients who achieved pCR, versus 29% for those without pCR (P = .018), whereas no associations were observed in other subtypes. CONCLUSION: Our results suggest that stratification according to Ki67 levels might improve predictive significance of the response in hormone-responsive breast cancer. Even in these subtypes assumed to be less chemosensitive, some patients with highly proliferative tumors derive a significant benefit from chemotherapy, and consequently it is important to identify them.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia , Antígeno Ki-67/metabolismo , Terapia Neoadyuvante , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Survivin plays a key role in the initiation and progression of breast cancer. However, its prognostic relevance to breast cancer patients has long been a matter of debate. The purpose of this study was to examine the expression of survivin and its role in predicting clinical outcome in a series of human breast cancer cases both at the mRNA and protein level. METHODS: Formalin-fixed paraffin-embedded tumor tissues from 245 female patients with invasive breast cancer and 13 patients with ductal carcinoma in situ were examined for survivin mRNA by quantitative real-time RT-PCR (RT-qPCR). In addition, 237 of these tumors with invasive breast cancer were available for immunohistochemistry (IHC). The relationship between survivin status and clinicopathological characteristics and prognosis was evaluated. RESULTS: RT-qPCR revealed that high levels of survivin mRNA were strongly associated with high nuclear grade, positive axillary lymph nodes, negative hormone receptor status, positive Her2 amplification, higher Ki67 labeling index, and presence of vascular invasion. In the Cox proportional regression model analysis, survivin mRNA was shown to be a significant univariate parameter for relapse-free survival (RFS), distant relapse-free survival (DRFS), and breast cancer-specific survival (BCSS) as well as a significant multivariate parameter for RFS, DRFS, and BCSS. In hormone receptor (HR)-positive/Her2-negative subtype cases, survivin mRNA expression was also an independent predictor in terms of DRFS. Immunohistochemically, positive staining was seen in the cytoplasm and/or nucleus of cancer cells, although this did not correlate with the mRNA level, and harbored no prognostic value. CONCLUSIONS: High mRNA expression of survivin was an independent marker of poor prognosis both in the entire cohort and in the HR-positive/Her2-negative subtype, whereas the protein expression of survivin was not. These findings suggest that RT-qPCR can provide more reliable data than IHC in validating the prognostic significance of survivin for breast cancer patients.