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BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.
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Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Pirazoles , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/uso terapéutico , Adulto , Quinoxalinas/efectos adversos , Quinoxalinas/administración & dosificación , Quinoxalinas/uso terapéutico , Quinoxalinas/farmacocinética , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Japón , Anciano de 80 o más Años , Pueblos del Este de AsiaRESUMEN
AIM: Quality of care is important to reduce disease progression, and improve both survival and quality of life. The Japan Society of Gynecologic Oncology has published treatment guidelines to promote standardized high-quality care for ovarian cancer in Japan. We developed quality indicators based on the guideline recommendations and used them on large datasets of health service use to examine the quality of ovarian cancer care. METHODS: A panel of experts developed the indicators using a modified Delphi method. Adherence to each indicator was evaluated using data from a hospital-based cancer registry of patients diagnosed in 2018. All patients receiving first-line treatment at participating facilities were included. The adherence rates were returned to participating hospitals, and reasons for nonadherence were collected. A total of 580 hospitals participated, and the study examined the care received by 6611 patients with ovarian cancer and 1879 with borderline tumors using 11 measurable quality indicators. RESULTS: The adherence rate ranged from 22.6% for "Estrogen replacement within 6 months of operation" to 93.5% for "Bleomycin, etoposide, and cisplatin for germ cell tumor more than Stage II." Of 580 hospitals, 184 submitted the reasons for nonadherence. CONCLUSIONS: The quality of ovarian cancer care should be continuously assessed to encourage the use of best practices. These indicators may be a useful tool for this purpose.
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Neoplasias Ováricas , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud , Humanos , Femenino , Neoplasias Ováricas/terapia , Japón , Calidad de la Atención de Salud/normas , Adhesión a Directriz/estadística & datos numéricosRESUMEN
BACKGROUND: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose-escalation part of a first-in-human study of patients with advanced solid tumors (NCT03444701). METHODS: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21-day cycle (Q3W) or days 1 and 15 of a 28-day cycle (Q2W). Doses were escalated from 270 to 550 µg/m2 for the Q3W group or 25-400 µg/m2 for the Q2W group. The primary end point of the dose-escalation phase was safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics. RESULTS: Forty-four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment-emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3-4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment-related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 µg/m2 Q3W and 300 µg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose-dependent after initial doses of 350-480 µg/m2 . CONCLUSIONS: E7130 480 µg/m2 Q3W was chosen for the dose-expansion part over 300 µg/m2 Q2W primarily per dose-dependent biomarker results.
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Antineoplásicos , Neoplasias , Humanos , Factor A de Crecimiento Endotelial Vascular , Microambiente Tumoral , Neoplasias/patología , Antineoplásicos/efectos adversos , Biomarcadores , Microtúbulos/metabolismo , Microtúbulos/patología , Dosis Máxima ToleradaRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1-3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. METHODS: We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50 years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. RESULTS: In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n = 185) and an abemaciclib group (n = 47). At a median observation period of 607 days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14-750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. CONCLUSION: The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.
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Neoplasias de la Mama , Inhibidores de Proteínas Quinasas , Femenino , Humanos , Persona de Mediana Edad , Aminopiridinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidoresRESUMEN
Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Neoplasias del Cuello Uterino , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1 , Bevacizumab/uso terapéutico , Japón/epidemiología , Neoplasias Pulmonares/patología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/etiología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab- or lapatinib-based therapies for patients with HER2-amplified and comutated tumors. KEY POINTS: Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab- or lapatinib-based therapies but good responses to ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd). Anti-HER2 antibody-drug conjugates such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab- or lapatinib-containing therapies for patients with HER2-amplified and comutated tumors.
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Neoplasias de la Mama , Inmunoconjugados , Ado-Trastuzumab Emtansina , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Camptotecina/análogos & derivados , Femenino , Humanos , Mutación , TrastuzumabRESUMEN
BACKGROUND: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. METHODS: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. RESULTS: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. CONCLUSIONS: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Ftalazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Humanos , Japón , Dosis Máxima Tolerada , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Neoplasias/patología , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Ftalazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinéticaRESUMEN
BACKGROUND: We previously reported that in patients with HER2-positive (HER2+) locally advanced breast cancer treated with neoadjuvant trastuzumab-containing regimens, high HER2 to centromere enumerator probe 17 ratio on fluorescence in situ hybridization (HER2 FISH ratio) was an independent predictor of high pathologic complete response (pCR) rate, which translated into improved recurrence-free survival (RFS). We sought to determine whether high HER2 FISH ratio is a predictor of pCR and prognosis in patients with HER2+ nonmetastatic inflammatory breast cancer (IBC) and non-IBC treated with neoadjuvant chemotherapy with or without trastuzumab. MATERIALS AND METHODS: This study included all patients with histologically proven stage III, HER2+ primary IBC, and non-IBC treated with neoadjuvant chemotherapy with or without trastuzumab and definitive surgery during 1999-2012. Univariate and multivariate logistic regression models were applied to assess the effect of covariates on pCR. Kaplan-Meier estimates with log-rank test were employed for survival analysis. Univariate and multivariate Cox proportional hazards models were used to assess the effect of covariates on RFS and overall survival (OS). RESULTS: The study included 555 patients with stage III, HER+ breast cancer, 181 patients with IBC, and 374 with non-IBC. In the IBC cohort, HER2 FISH ratio was not significantly associated with pCR, RFS, or OS. In the non-IBC cohort, higher HER2 FISH ratio was significantly associated with higher pCR rate and longer OS. CONCLUSION: HER2 FISH ratio showed prognostic value among patients with HER2+ non-IBC but not HER2+ IBC treated with neoadjuvant chemotherapy. This disparity may be due to the underlying aggressive nature of IBC. IMPLICATIONS FOR PRACTICE: The findings of this study indicate that the HER2 to fluorescence in situ hybridization ratio as a continuous variable has promise as a predictor of pathologic complete response to neoadjuvant chemotherapy in patients with HER2-positive (HER2+) noninflammatory breast cancer (non-IBC) regardless of the results on HER2 immunohistochemical testing. In the future, some patients with HER2+ non-IBC and a high HER2 FISH ratio might even be offered personalized treatment options, such as nonsurgical treatment.
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Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Trastuzumab/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. METHODS: We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2- IBC and 677 patients with HR+/HER2- stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2- IBC and 252 patients with HR+/HER2- non-IBC to detect genes that are specifically overexpressed in IBC. RESULTS: The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2- IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. CONCLUSIONS: Higher ER expression was significantly associated with improved survival in both HR+/HER2- IBC and HR+/HER2- stage III non-IBC patients. HR+/HER2- IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2- IBC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Inflamatorias de la Mama/patología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Neoplasias Inflamatorias de la Mama/tratamiento farmacológico , Neoplasias Inflamatorias de la Mama/genética , Neoplasias Inflamatorias de la Mama/metabolismo , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Honeybee pollen foragers departing the hive carry concentrated nectar to use as fuel for flight and glue for forming pollen loads. Since nectar is concentrated by in-hive bees at the cost of time and energy, using concentrated nectar increases the cost of foraging at the colony level. This experimental study explored the potential benefit to honeybees of using concentrated nectar for pollen collection by diluting nectar carried by pollen foragers from the hive. Mass feeding with 30% sugar solution successfully reduced the crop-load-sugar concentration in putative pollen foragers departing the hive, but while those bees tended to increase the crop-load volume, such increase did not fully compensate for the decreased amount of dissolved sugars in the crop load. Feeding 30% sugar solution reduced the pollen load dry weight by approx. 10-20% compared to the unfed control and to another test group fed 60% sugar solution. In addition, the pollen load size and sugar concentration of crop load remaining in returning pollen foragers was positively correlated. These results clearly show the advantage to honeybees of using concentrated nectar for pollen foraging.
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Abejas/fisiología , Conducta Alimentaria/fisiología , Vuelo Animal/fisiología , Néctar de las Plantas/metabolismo , Polen , Animales , Abejas/metabolismo , Metabolismo EnergéticoRESUMEN
Eusocial bee foragers leave their nest with nectar as flight fuel, therewith reducing the risk of starvation during a foraging trip. Yet, the extra mass results in an increase of energetic expenditure for flight. Thus, bees should tune their fuel loads to the respective foraging situation. In the present study, we investigated the fuel adjustment in the Brazilian stingless bee Melipona subnitida (Apidae, Meliponini). Specifically, we examined whether foragers of this species increase their fuel loads when they have low expectation for nectar collection during a foraging trip. Crop load measurements revealed that nectar foragers carried significantly less fuel on departing the nest than foragers collecting either pollen, clay, or resin. Surprisingly, 75% of nectar foragers left the nest without any detectable amount of nectar, which suggests that the majority of bees collected at nearby nectar sources and avoided an increase in foraging costs. Moreover, foragers increased their fuel loading when repeatedly experiencing empty food sources that had previously been rewarding. These results support our hypothesis and demonstrate that the capability of fuel adjustment is not restricted to honey bees.
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Abejas/fisiología , Animales , Abejas/metabolismo , Conducta Animal/fisiología , Conducta Alimentaria , Vuelo Animal , Néctar de las Plantas/metabolismo , Polen/metabolismo , InaniciónRESUMEN
OBJECTIVE: Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials. METHODS: This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically. RESULTS: A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461). CONCLUSIONS: Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.
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Leiomiosarcoma/patología , Neoplasias Uterinas/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Estudios de Cohortes , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel/administración & dosificación , Femenino , Humanos , Japón/epidemiología , L-Lactato Deshidrogenasa/sangre , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/epidemiología , Leiomiosarcoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/epidemiología , Neoplasias Uterinas/cirugía , Adulto Joven , GemcitabinaRESUMEN
To determine how males of the large carpenter bee, Xylocopa appendiculata, maximize access to females while minimizing energy cost and acquiring energy for territorial flights, we investigated the times of territorial flights by males and foraging by males and females. Males were present continuously in territories from 8:00 to 12:00. They approached, chased, and excluded conspecific males from their territories. In the laboratory, males showed higher locomotor and flight activities in the morning and lower activities in the afternoon. Both males and females visited flowers from 8:00 to 16:00, but the most frequent visits were earlier in females (10:00-12:00) than in males (12:00-13:00). Relative body weights in territorial males often increased. These results indicate that the males time their territorial flights to maximize contact with females and obtain nectar as fuel between and after the territorial flights. The time-related territorial flight in males might be based on a time-keeping system in the brain. Brain levels of serotonin and its precursor tryptophan were significantly higher in males collected at 16:00 than at 11:00, suggesting a relation between time-related territorial flight and serotonin synthesis in the brain.
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Abejas/fisiología , Conducta Animal/fisiología , Vuelo Animal/fisiología , Serotonina/metabolismo , Animales , Abejas/química , Química Encefálica , Masculino , Territorialidad , Factores de TiempoRESUMEN
In Japan, the social (medical) health-care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as "cancer clinical sequencing," which uses a next-generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/genética , Guías de Práctica Clínica como Asunto , Humanos , Consentimiento Informado , Neoplasias/diagnóstico , Neoplasias/terapia , Control de CalidadRESUMEN
PURPOSE: We hypothesized that an increase in BMI category during neoadjuvant chemotherapy (NAC) would be associated with pathological complete response (pCR) rate and worse survival outcomes in primary breast cancer patients. METHODS: We reviewed the records of 4029 patients with stage I-III breast cancer who had undergone NAC and definitive surgery at our institution between May 1, 1990 and April 30, 2013. BMI values at baseline and after NAC were recorded, and the corresponding BMI category was assessed with the WHO classification. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and multivariate Cox regression models were used to estimate the effect of covariates of interest on OS and RFS. RESULTS: The median follow-up period was 3.95 years. A change in BMI category from normal to obese during NAC was independently associated with shorter OS duration than was maintaining a normal weight [hazard ratio (HR) 1.637; 95%CI 1.066-2.514; p = 0.0242]. Kaplan-Meier curves among breast cancer subtypes showed differences, and a decrease in BMI led to better RFS and OS rates in obese patients with HR+/HER2- disease; those who maintained BMI also showed better prognosis for triple-negative breast cancer (TNBC). We saw no association between BMI change and pCR rate. CONCLUSION: Our data suggest that inability to maintain normal weight during NAC is a predictive marker of poor survival but not pCR. It may be important for patients to maintain a normal weight during NAC.
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Índice de Masa Corporal , Neoplasias de la Mama/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Platelets are essential components of hemostasis and also play an important role in the tumor microenvironment. The purposes of our research were to examine the role of thrombocytosis in inflammatory breast cancer (IBC) and to know which cytokine drives thrombocytosis. METHODS: We reviewed the medical records of 3654 patients with stage I-III breast cancer treated between 1998 and 2013, including 230 patients (6%) with IBC. We used Chi-squared test or Fisher's exact test to compare the variables between patients with and without thrombocytosis. Multivariate Cox regression models were used to determine the association of thrombocytosis with overall survival. We also examined baseline serum cytokine levels in 81 patients with primary IBC to determine the association of inflammatory cytokines with thrombocytosis. RESULTS: We found that thrombocytosis was the only variable that predicted prognosis. Fifty-five patients (1.5%) had thrombocytosis. Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC (3.4% vs. 1.4%, p = 0.015). In patients with IBC, thrombocytosis was associated with worse overall survival [hazard ratio 2.38, 95% confidence interval (CI) 1.05-5.4, p = 0.0378]. Circulating levels of growth-regulated oncogene (GRO) (odds ratio 1.003, 95% CI 1.001-1.005, p = 0.0019) and transforming growth factor ß (TGF-ß) (odds ratio 1.3, 95% CI 1.128-1.499, p = 0.0003) were associated with thrombocytosis. CONCLUSIONS: Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC and it was associated with poor prognosis. GRO and TGF-ß were associated with thrombocytosis in IBC.
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Quimiocina CXCL1/sangre , Neoplasias Inflamatorias de la Mama/sangre , Trombocitosis/sangre , Factor de Crecimiento Transformador beta1/sangre , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas/patología , Citocinas/sangre , Femenino , Humanos , Neoplasias Inflamatorias de la Mama/complicaciones , Neoplasias Inflamatorias de la Mama/epidemiología , Neoplasias Inflamatorias de la Mama/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Trombocitosis/complicaciones , Trombocitosis/epidemiología , Trombocitosis/patología , Microambiente Tumoral/genéticaRESUMEN
To explore the role of the volatiles emitted from male labial gland (LG) of the bumblebee Bombus ardens ardens, we investigated the responses of virgin queens and males to volatiles using a gas chromatography-electroantennographic detector (GC-EAD) system and Y-tube olfactometer. GC-EAD analysis revealed that citronellol, the main compound detected in the male LG, caused clear electrophysiological responses in the antennae of B. a. ardens virgin queens and males although two minor compounds elicited antennal responses when applied in a high concentration. Behavioral tests using a Y-tube olfactometer showed that queens and males were significantly attracted to both LG extracts and citronellol more than to the solvent alone. This is the first study to demonstrate that citronellol as a major compound of male scent-marking pheromone in B. a. ardens functions as a sex attractant for queens. The results also suggest that this compound has another function as a trail marker used by males.
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Abejas , Animales , Cromatografía de Gases , Femenino , Himenópteros , Masculino , Feromonas , Atractivos SexualesRESUMEN
Inflammatory breast cancer is the most aggressive form of breast cancer. Identifying new biomarkers to be used as therapeutic targets is in urgent need. Messenger RNA expression profiling studies have indicated that inflammatory breast cancer is a transcriptionally heterogeneous disease, and specific molecular targets for inflammatory breast cancer have not been well established. We performed microRNA expression profiling in inflammatory breast cancer in comparison with locally advanced noninflammatory breast cancer in this study. Although many microRNAs were differentially expressed between normal breast tissue and tumor tissue, most of them did not show differential expression between inflammatory and noninflammatory tumor samples. However, by microarray analysis, quantitative reverse transcription PCR, and in situ hybridization, we showed that microRNA-205 expression was decreased not only in tumor compared with normal breast tissue, but also in inflammatory breast cancer compared with noninflammatory breast cancer. Lower expression of microRNA-205 correlated with worse distant metastasis-free survival and overall survival in our cohort. A small-scale immunohistochemistry analysis showed coexistence of decreased microRNA-205 expression and decreased E-cadherin expression in some ductal tumors. MicroRNA-205 may serve as a therapeutic target in advanced breast cancer including inflammatory breast cancer.
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Biomarcadores de Tumor/genética , Neoplasias Inflamatorias de la Mama/genética , MicroARNs/biosíntesis , Adulto , Anciano , Biomarcadores de Tumor/análisis , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Neoplasias Inflamatorias de la Mama/mortalidad , Estimación de Kaplan-Meier , MicroARNs/análisis , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
When honeybee foragers leave the nest, they receive nectar from nest mates for use as fuel for flight or as binding material to build pollen loads. We examined whether the concentration of nectar carried from the nest changes with the need for sugar. We found that pollen foragers had more-concentrated nectar (61.8 %) than nectar foragers (43.8 %). Further analysis revealed that the sugar concentration of the crop load increased significantly with waggle duration, an indicator of food-source distance, in both groups of foragers. Crop volume also increased with waggle duration. The results support our argument that foragers use concentrated nectar when the need for sugar is high and suggest that they precisely adjust the amount of sugar in the crop by altering both volume and nectar concentrations. We also investigated the impact of the area where foragers receive nectar on the crop load concentration at departure. Although nectar and pollen foragers tend to load nectar at different areas in the nest, area did not have a significant effect on crop load concentration. Departing foragers showed an average of 2.2 momentary (<1 s) begging trophallactic contacts before leaving the nest. They might be rejecting nectar with inappropriate concentrations during these contacts.