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BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
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Neoplasias Primarias Desconocidas , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Inestabilidad de Microsatélites , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Nivolumab/efectos adversos , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Nivolumab/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anciano , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Resultado del Tratamiento , Carga TumoralRESUMEN
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
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Neoplasias Esofágicas , Humanos , Asia , Consenso , Manejo de la Enfermedad , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/secundario , Neoplasias Esofágicas/terapia , Sociedades MédicasRESUMEN
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
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Neoplasias Gástricas , Humanos , Asia , Consenso , Manejo de la Enfermedad , Sociedades Médicas , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/secundario , Neoplasias Gástricas/terapiaRESUMEN
The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
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Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/terapia , Pueblo Asiatico , China , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/patología , Humanos , Malasia , Metástasis de la Neoplasia , República de Corea , TaiwánRESUMEN
The influence of the structure of ionic liquids on the crystallinity of aluminum hydroxide (Al(OH)3) prepared by a sol-gel process with aluminum isopropoxide (Al(OPr(i))3) in imidazolium-based ionic liquids was investigated. When Al(OH)3 was prepared in ionic liquids having long alkyl chains, such as 1-butyl-3-methylimidazolium salts and 1-methyl-3-octylimidazolium salts, highly crystalline products were obtained. In contrast, Al(OH)3 obtained using the 1-ethyl-3-methylimidazolium salt was an amorphous material, indicating that hydrophobic interaction of the alkyl tail of the imidazolium cation of the ionic liquid strongly affects the crystallinity of sol-gel products and the local structure of the ionic liquid. Moreover, the crystallinity of Al(OH)3 prepared in ionic liquids increased relative to the amount of additional water (ionic liquid/water = 1.28/2.0-3.5/0.2, w/w). In the case of addition of a small amount of water (ionic liquid/water = 3.5/0.2, w/w), the product was amorphous. These results implied that the presence of an ionic liquid and a sufficient amount of water was crucial for the successful synthesis of sol-gel products with high crystallinity. (1)H NMR analyses revealed a shift of the peak associated with the imidazolium cation upon addition of water, which suggested that the molecular orientation of the ionic liquid was similar to that of a micelle.
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BACKGROUND: The purpose of this study was to investigate the usefulness of a hydrocolloid dressing containing ceramide for hand-foot skin reaction (HFSR) on the soles of the feet in metastatic renal cell carcinoma (RCC) patients treated with sorafenib. PATIENTS AND METHODS: Patients with grade 1 HFSR on the soles of the feet were randomly assigned in to two groups. One group received a hydrocolloid dressing containing ceramide (arm A) and the other received 10% urea cream (arm B). Patients in both groups applied treatment to the affected sites on the soles of the feet, but not to the hands. The primary end point was the incidence of grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks. RESULTS: Thirty-three patients were assessed (17 in arm A and 16 in arm B), and there were no significant differences in baseline characteristics between the two groups. During the observation period of this study, grade 2 or 3 HFSR on the soles of the feet was found in 29% of patients in arm A and was significantly less than the 69% in arm B (P=0.03). The incidence of HFSR on the hands, however, was similar in both arms. The median time to grade 2 or 3 HFSR on the soles of the feet was also significantly longer in arm A than in arm B (P=0.03). CONCLUSIONS: These results indicate that a hydrocolloid dressing containing ceramide prevented the worsening of HFSR caused by sorafenib in metastatic RCC patients. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002016.
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Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Ceramidas/administración & dosificación , Síndrome Mano-Pie/terapia , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Anciano , Antineoplásicos/uso terapéutico , Vendas Hidrocoloidales , Carcinoma de Células Renales/secundario , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Sorafenib , Propiedades de Superficie , Resultado del TratamientoRESUMEN
Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.
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Anticuerpos Monoclonales Humanizados/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ciclina D1/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Anciano , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/cirugía , Fosfatidilinositol 3-Quinasa Clase I , Ciclina D1/genética , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante , Fosfatidilinositol 3-Quinasas/genética , Valor Predictivo de las Pruebas , Trastuzumab , Resultado del TratamientoRESUMEN
Endoscopic diagnostics of early squamous cell carcinoma (SCC) in the laryngo-esophageal region have dramatically improved together with development of less invasive endoscopic treatment. It is essential for gastrointestinal endoscopists to detect lesions when they are still endoscopically treatable, especially in this region since surgical approach can still be extremely invasive. Pioneers have found some notable fundamental alterations in early SCC and created several classifications. Inoue [Dig Endosc 2001;13(suppl): 40-41] proposed the intrapapillary capillary (IPCL) classification, which focused on the microvascular change of the mucosal surface. One of the significances of this classification is that it clearly distinguished the lesions that require further pathological evaluation by categorizing the diameter change of the IPCLs. On the other hand, Arima et al. [Esophagus 2005;2:191-197] advocated the alteration of microvessels as well as change of the vascular arrangement in the area. Most recently, the Japan Esophageal Society constructed a new classification uniting these two exemplary classifications as the 'Japanese Classification of Magnifying Endoscopy for Early Squamous Cell Carcinoma'. This classification was intended to be simple and easily applicable in general clinical practice. Brownish color change between the IPCLs has reported to be one of the useful findings in distinguishing early SCC from benign changes such as inflammatory change and low-grade intraepithelial neoplasia. Nevertheless, the exact cause of this phenomenon remains unclear. We recently examined the association of color change with hemoglobin (Hb) in cancer tissue, since NBI exclusively detects the wavelength of Hb in superficial vessels in the gastrointestinal tract. This review article also describes our examination of a distinct finding in esophageal cancer, namely, 'background coloration'.
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Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Esofagoscopía , Carcinoma de Células Escamosas/clasificación , Color , Neoplasias Esofágicas/clasificación , Humanos , Yoduros , Microvasos/patologíaRESUMEN
BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Neoplasias de Cabeza y Cuello , Paclitaxel , Humanos , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Cetuximab/farmacología , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificaciónRESUMEN
BACKGROUND: We evaluated the efficacy of aprepitant plus granisetron and an increased dose of dexamethasone in selected patients undergoing moderately emetogenic chemotherapy (MEC). METHODS: Nondrinking women <70 years undergoing MEC were randomly assigned to aprepitant (day 1, 125 mg; days 2 and 3, 80 mg) or placebo. Dexamethasone on days 1-3 was 12, 4, and 4 mg with aprepitant and 20, 8, and 8 mg with placebo. The primary end point was complete response (CR; no emesis or rescue therapy) during 120 h of the first cycle. Logistic regression analysis was performed to identify predictors of overall CR. RESULTS: Of the 94 patients enrolled, 91 were assessable. Most received carboplatin-based chemotherapy. In the aprepitant (n=45) and placebo (n=46) groups, the overall, acute (day 1), and delayed (days 2-5) CR rates were 62% and 52%, 98% and 96%, and 62% and 52%, respectively. Although not statistically significant, the overall CR rate was 10% higher in the aprepitant group. Both regimens were well tolerated. On multivariate analysis, advanced ovarian cancer (OR, 0.26 (0.10-0.72)) was independently associated with a lower CR. CONCLUSION: Even with an increased dose of dexamethasone, aprepitant seemed more effective than placebo in these selected patients undergoing MEC; however, delayed phase management remains a significant problem.
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Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Morfolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Templanza , Vómitos/prevención & control , Adulto , Anciano , Aprepitant , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Dexametasona/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Granisetrón/uso terapéutico , Humanos , Irinotecán , Modelos Logísticos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Resultado del Tratamiento , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológicoRESUMEN
In order to determine if the mesa geometry might affect the properties of the coherent terahertz (THz) radiation emitted from the intrinsic Josephson junctions in mesas constructed from single crystals of the high-temperature superconductor, Bi2Sr2CaCu2O8+δ, we studied triangular mesas. For equilateral triangular mesas, the observed emission was found to be limited to the single mesa TM(1,0) mode. However, tunable radiation over the range from 0.495 to 0.934 THz was found to arise from an acute isosceles triangular mesa. This 47% tunability is the widest yet observed from the outer current-voltage characteristic branch of such mesas of any geometry. Although the radiation at a few of the frequencies in the tunable range appear to have been enhanced by cavity resonances, most frequencies are far from such resonance frequencies, and can only be attributed to the ac-Josephson effect.
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Cerámica/química , Iluminación/instrumentación , Semiconductores , Radiación Terahertz , Cerámica/efectos de la radiación , Diseño de Equipo , Análisis de Falla de EquipoRESUMEN
Magnification endoscopy enables in vivo evaluation of gastrointestinal mucosa. Furthermore, endocytoscopy (ECS) with ultra-high magnification enables in vivo observation of cellular atypia during routine endoscopic examination. The purpose of this study is to clarify the efficacy of ECS and endocytoscopic atypia (ECA) classification in various types of benign and malignant pathology in the esophagus. Consecutive 110 patients, who underwent ECS in our institution from March 2003 to December 2009, were included in this study. One hundred and forty-six esophageal lesions were classified according to ECA classification, and these endocytoscopic images were compared with histological images. We categorized endocytoscopic images into five categories according to size and uniformity of nuclei, number of cells and regularity of cellular arrangement. Eighty-one out of 89 ECA-1 to ECA-3 lesions (91.0%) corresponded to Vienna categories 1 to 3. Seventy-one out of 84 ECA-4 or ECA-5 lesions (91.2%) corresponded to Vienna category 4 or 5. Overall accuracy of ECS was 91.3%, providing images similar to conventional hematoxylin and eosin staining. In addition, with ECS, we can take an 'optical biopsy' even in patients with cardiovascular disease without interrupting anticoagulant therapy. A newly designed single charge-coupled device endocytoscope allows observation of target tissue noninvasibly from regular magnification to ultra-high magnification. The development of ECS has opened the door to in vivo cellular imaging, enabling endoscopic diagnosis of tissue cytological atypia during routine endoscopic examination.
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Carcinoma de Células Escamosas/clasificación , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/clasificación , Neoplasias Esofágicas/patología , Esófago/patología , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Células Escamosas/cirugía , Recuento de Células , Núcleo Celular/patología , Colorantes , Neoplasias Esofágicas/cirugía , Esofagoscopía/instrumentación , Esófago/cirugía , Femenino , Violeta de Genciana , Humanos , Masculino , Azul de Metileno , Persona de Mediana Edad , Membrana Mucosa/patología , Membrana Mucosa/cirugía , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Docetaxel , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Taxoides/administración & dosificación , Taxoides/efectos adversos , Tegafur/administración & dosificación , Tegafur/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: Although the concentration of α1-acid glycoprotein (AGP) in serum increases under some conditions, the behavior of the individual genetic variants is not well understood. Therefore, we studied the relative changes in AGP variants pre- and postoperatively in patients with cancer and patients with chronic inflammatory disease states, as well as the distribution of AGP phenotypes in a Japanese population. METHODS: Serum samples were taken before and after surgery from 25 female patients with early breast cancer. Serum samples were also obtained from 134 patients with rheumatoid arthritis (RA) and 33 with systemic lupus erythematosus (SLE), and from 103 healthy subjects. The relative concentrations of the individual genetic variants in the serum samples were determined by isoelectric focusing after desialylation with neuraminidase. RESULTS: The postoperative AGP concentrations in patients with early breast cancer were 2-fold higher than before surgery. The relative concentrations of the F1 and S variants were significantly increased, whereas that of the A variant was not changed significantly. The relative concentrations of all the AGP variants in patients with RA and SLE were significantly higher than those in healthy subjects. The distribution of the AGP phenotypes did not differ significantly among the groups examined in this study. CONCLUSIONS: The F1/S variants of AGP, but not the A variant, were significantly increased after early breast cancer surgery, but all the variants were increased in patients with chronic inflammatory states such as RA and SLE. The distribution of the AGP phenotypes did not differ significantly among the disease groups studied.
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Neoplasias de la Mama/metabolismo , Inflamación/metabolismo , Orosomucoide/metabolismo , Adolescente , Adulto , Artritis Reumatoide/metabolismo , Neoplasias de la Mama/cirugía , Enfermedad Crónica , Femenino , Variación Genética , Humanos , Focalización Isoeléctrica , Japón/epidemiología , Lupus Eritematoso Sistémico/metabolismo , Persona de Mediana Edad , Orosomucoide/química , Orosomucoide/genética , Fenotipo , Procedimientos Quirúrgicos Operativos , Adulto JovenRESUMEN
BACKGROUND: The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. MATERIALS AND METHODS: We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). RESULTS: Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 microg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 microM CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype. CONCLUSIONS: PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.
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Antineoplásicos/administración & dosificación , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Fosfatidilinositol 3-Quinasas/genética , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromonas/administración & dosificación , Cromonas/farmacología , Fosfatidilinositol 3-Quinasa Clase I , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Activación Enzimática/genética , Femenino , Amplificación de Genes/fisiología , Humanos , Morfolinas/administración & dosificación , Morfolinas/farmacología , Mutación Missense/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Fosforilación/efectos de los fármacos , Fosforilación/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , TrastuzumabRESUMEN
BACKGROUND AND STUDY AIMS: Carbon dioxide (CO (2)) insufflation for endoscopy has been reported to provide superior recovery and is expected to reduce the risk of serious complications, including air embolism and tension pneumothorax, whereas general anesthesia offers some advantages not found under intravenous sedation. Little is known about the effect of prolonged CO (2) insufflation into gastrointestinal tracts on arterial CO (2) tension (PaCO (2)). Here we introduce the use of general anesthesia with CO (2) insufflation for esophagogastroduodenal endoscopic submucosal dissection (ESD). PATIENTS AND METHODS: A prospective observational study was conducted in a university-affiliated hospital. A total of 100 patients were scheduled for esophagogastroduodenal ESD under general anesthesia with CO (2) insufflation, using standardized anesthesia techniques and unchanged ventilatory settings. Arterial blood gas analyses were repeated at predetermined time intervals. RESULTS: Of the initial 100 participants, 94 patients undergoing ESD and four patients undergoing endoscopic mucosal resection completed the study. The median procedure time was 122 minutes (range 29â-â309 minutes). The median baseline PaCO (2) of 28 mmHg increased to a median peak PaCO (2) of 39 mmHg ( P < 0.001), with marked inter-individual variability in the time courses of changes in PaCO (2). The correlation coefficient of PaCO (2) with the procedure time was low (r = 0.194; n = 577, P < 0.0001). FEV (1.0)â% (forced expiratory volume in 1 second/forced vital capacity) of < 70â% and esophagoscopy vs. gastroduodenoscopy were relative enhancement factors of PaCO (2). CONCLUSION: Increases of PaCO (2) during esophagogastroduodenal ESD under general anesthesia with CO (2) insufflation remained within acceptable or readily controllable ranges, and are little enhanced by prolongation of the procedure. Esophagogastroduodenal ESD can be performed safely and feasibly with this procedure.
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Dióxido de Carbono/administración & dosificación , Duodenoscopía/métodos , Esofagoscopía/métodos , Gastroscopía/métodos , Insuflación , Anciano , Anciano de 80 o más Años , Anestesia General , Dióxido de Carbono/efectos adversos , Dióxido de Carbono/fisiología , Disección , Duodenoscopía/efectos adversos , Esofagoscopía/efectos adversos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Mucosa Gástrica/cirugía , Gastroscopía/efectos adversos , Humanos , Mucosa Intestinal/cirugía , Masculino , Persona de Mediana Edad , Presión Parcial , Estudios Prospectivos , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
BACKGROUND: Peroral endoscopic myotomy (POEM) was developed by our group to provide a less invasive permanent treatment for esophageal achalasia. PATIENTS AND METHODS: POEM was performed in 17 consecutive patients with achalasia (10 men, 7 women; mean age 41.4 years). A long submucosal tunnel was created (mean length 12.4 cm), followed by endoscopic myotomy of circular muscle bundles of a mean total length of 8.1 cm (6.1 cm in distal esophagus and 2.0 cm in cardia). Smooth passage of an endoscope through the gastroesophageal junction was confirmed at the end of the procedure. RESULTS: In all cases POEM significantly reduced the dysphagia symptom score (from mean 10 to 1.3; P = 0.0003) and the resting lower esophageal sphincter (LES) pressure (from mean 52.4 mmHg to 19.9 mmHg; P = 0.0001). No serious complications related to POEM were encountered. During follow-up (mean 5 months), additional treatment or medication was necessary in only one patient (case 17) who developed reflux esophagitis (Los Angeles classification B); this was well controlled with regular intake of protein pump inhibitors (PPIs). CONCLUSIONS: The short-term outcome of POEM for achalasia was excellent; further studies on long-term efficacy and on comparison of POEM with other interventional therapies are awaited.
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Acalasia del Esófago/cirugía , Esofagoscopía , Esófago/cirugía , Adulto , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC-D) as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40 mg/m2 plus cyclophosphamide 500 mg/m2), D (60 mg/m2), or alternating treatment with AC-D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks. RESULTS: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC-D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P = 0.13 for AC versus D, P = 0.14 for AC versus AC-D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P = 0.09 for AC versus D, P = 0.13 for AC versus AC-D) in the AC, D, and AC-D, respectively. CONCLUSION: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.