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BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.
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Neoplasias da Mama , Camptotecina/análogos & derivados , Imunoconjugados , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Anticorpos Monoclonais Humanizados , Trastuzumab/efeitos adversos , Imunoconjugados/efeitos adversos , Ado-Trastuzumab Emtansina , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. RESULTS: A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.
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BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.
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Neoplasias Nasofaríngeas , Platina , Humanos , Neoplasias Nasofaríngeas/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Docetaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
We dedicate this manuscript in memory of a dear friend and colleague Bella Kaufman. The fifth International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October 2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with incorporation of new evidence to inform the guidelines. Areas of research priorities as well as specificities in different geographic and minority populations were identified. This manuscript summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Oncologia , ConsensoRESUMO
BACKGROUND: Resistance to standard chemotherapy in metastatic triple-negative breast cancer (mTNBC) is associated with upregulation of the mitogen-activated protein kinase (MAPK) pathway. Cobimetinib, an MAPK/extracellular signal-regulated kinase (MEK) inhibitor, may increase sensitivity to taxanes and programmed death-ligand 1 inhibitors. COLET is a three-cohort phase II study evaluating first-line cobimetinib plus chemotherapy, with or without atezolizumab, in patients with locally advanced or mTNBC. PATIENTS AND METHODS: Patients were ≥18 years with locally advanced or mTNBC. Following a safety run-in, patients in cohort I were randomized 1:1 to cobimetinib (60 mg, D3-D23 of each 28-day cycle) or placebo, plus paclitaxel (80 mg/m2, D1, 8, and 15). Additional patients were randomized (1:1) to cohort II or III to receive cobimetinib plus atezolizumab (840 mg, D1 and D15) and either paclitaxel (cohort II) or nab-paclitaxel [cohort III (100 mg/m2, D1, D8, and D15)]. Primary endpoints were investigator-assessed progression-free survival (PFS) (cohort I) and confirmed objective response rate (ORR) (cohorts II/III). Safety and tolerability were also assessed. RESULTS: In the expansion stages, median PFS was 5.5 months for cobimetinib/paclitaxel versus 3.8 months for placebo/paclitaxel in cohort I [hazard ratio 0.73; 95% confidence interval (CI) 0.43-1.24; P = 0.25]. In cohort I, ORR was 38.3% (95% CI 24.40-52.20) for cobimetinib/paclitaxel and 20.9% (95% CI 8.77-33.09) for placebo/paclitaxel; ORRs in cohorts II and III were 34.4% (95% CI 18.57-53.19) and 29.0% (95% CI 14.22-48.04), respectively. Diarrhea was the most common grade ≥3 adverse events across all cohorts. CONCLUSIONS: Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend toward a numerical increase was observed. Cobimetinib plus atezolizumab and a taxane did not appear to increase ORR. This demonstrates the potential activity of a combinatorial MEK inhibitor, chemotherapy, and immunotherapy in this difficult-to-treat population.
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Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas , Humanos , Paclitaxel/efeitos adversos , Piperidinas , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.
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Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (ν[over ¯]_{e}) disappearance taking place between six 2.8 GW_{th} reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor ν[over ¯]_{e} oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin^{2}2θ_{14} in the 10^{-4}â²|Δm_{41}^{2}|â²0.5 eV^{2} region, free from reactor ν[over ¯]_{e} flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at |Δm_{41}^{2}|â²0.002 eV^{2} using the ν[over ¯]_{e} disappearance channel.
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BACKGROUND: Treatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries. PATIENTS AND METHODS: In this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation. RESULTS: A total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48-0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%). CONCLUSIONS: Consistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01856478.
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Afatinib/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Afatinib/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Povo Asiático , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: Although stromal tumor-infiltrating lymphocytes (sTILs) have been considered an important prognostic factor in early-stage triple-negative breast cancer (TNBC), there have been limited data on their prognostic value in the absence of adjuvant chemotherapy. PATIENTS AND METHODS: A pooled analysis was carried out using four cohorts of TNBC patients not treated with chemotherapy. sTILs were evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. RESULTS: We analyzed individual data of 476 patients from 4 centers diagnosed between 1989 and 2015. Their median age was 64 years. The median tumor size was 1.6 cm and 83% were node-negative. The median level of sTILs was 10% (Q1-Q3, 4%-30%). Higher grade was associated with higher sTILs (P < 10-3). During follow-up, 107 deaths, and 173 and 118 events for iDFS and D-DFS were observed, respectively. In the multivariable analysis, sTILs obtained an independent prognostic value for all end points (likelihood ratio χ2 = 7.14 for iDFS; P < 10-2; χ2 = 9.63 for D-DFS, P < 10-2; χ2 = 5.96 for OS, P = 0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 [95% confidence interval (CI) 0.82 - 0.97] for iDFS, 0.86 (95% CI 0.77 - 0.95) for D-DFS, and 0.88 (95% CI 0.79 - 0.98) for OS, respectively. In patients with pathological stage I tumors with sTILs ≥30% (n = 74), 5-year iDFS was 91% (95% CI 84% to 96%), D-DFS was 97% (95% CI 93% to 100%), and OS was 98% (95% CI 95% to 100%). CONCLUSION: sTILs add important prognostic information in systemically untreated early-stage TNBC patients. Notably, sTILs can identify a subset of stage I TNBC patients with an excellent prognosis without adjuvant chemotherapy.
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Biomarcadores Tumorais/sangue , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
We report a fuel-dependent reactor electron antineutrino (ν[over ¯]_{e}) yield using six 2.8 GW_{th} reactors in the Hanbit nuclear power plant complex, Yonggwang, Korea. The analysis uses 850 666 ν[over ¯]_{e} candidate events with a background fraction of 2.0% acquired through inverse beta decay (IBD) interactions in the near detector for 1807.9 live days from August 2011 to February 2018. Based on multiple fuel cycles, we observe a fuel ^{235}U dependent variation of measured IBD yields with a slope of (1.51±0.23)×10^{-43} cm^{2}/fission and measure a total average IBD yield of (5.84±0.13)×10^{-43} cm^{2}/fission. The hypothesis of no fuel-dependent IBD yield is ruled out at 6.6σ. The observed IBD yield variation over ^{235}U isotope fraction does not show significant deviation from the Huber-Mueller (HM) prediction at 1.3 σ. The measured fuel-dependent variation determines IBD yields of (6.15±0.19)×10^{-43} and (4.18±0.26)×10^{-43} cm^{2}/fission for two dominant fuel isotopes ^{235}U and ^{239}Pu, respectively. The measured IBD yield per ^{235}U fission shows the largest deficit relative to the HM prediction. Reevaluation of the ^{235}U IBD yield per fission may mostly solve the reactor antineutrino anomaly (RAA) while ^{239}Pu is not completely ruled out as a possible contributor to the anomaly. We also report a 2.9 σ correlation between the fractional change of the 5 MeV excess and the reactor fuel isotope fraction of ^{235}U.
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The RENO experiment reports more precisely measured values of θ_{13} and |Δm_{ee}^{2}| using â¼2200 live days of data. The amplitude and frequency of reactor electron antineutrino (ν[over ¯]_{e}) oscillation are measured by comparing the prompt signal spectra obtained from two identical near and far detectors. In the period between August 2011 and February 2018, the far (near) detector observed 103 212 (850 666) ν[over ¯]_{e} candidate events with a background fraction of 4.8% (2.0%). A clear energy and baseline dependent disappearance of reactor ν[over ¯]_{e} is observed in the deficit of the measured number of ν[over ¯]_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.0896±0.0048(stat)±0.0047(syst) and |Δm_{ee}^{2}|=[2.68±0.12(stat)±0.07(syst)]×10^{-3} eV^{2}.
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SMAP (Soil Moisture Active and Passive) radiometer observations at ~40 km resolution are routinely assimilated into the NASA Catchment Land Surface Model to generate the 9-km SMAP Level-4 Soil Moisture product. This study demonstrates that adding high-resolution radar observations from Sentinel-1 to the SMAP assimilation can increase the spatio-temporal accuracy of soil moisture estimates. Radar observations were assimilated either separately from or simultaneously with radiometer observations. Assimilation impact was assessed by comparing 3-hourly, 9-km surface and root-zone soil moisture simulations with in situ measurements from 9-km SMAP core validation sites and sparse networks, from May 2015 to December 2016. The Sentinel-1 assimilation consistently improved surface soil moisture, whereas root-zone impacts were mostly neutral. Relatively larger improvements were obtained from SMAP assimilation. The joint assimilation of SMAP and Sentinel-1 observations performed best, demonstrating the complementary value of radar and radiometer observations.
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The RENO experiment has analyzed about 500 live days of data to observe an energy dependent disappearance of reactor ν[over ¯]_{e} by comparing their prompt signal spectra measured in two identical near and far detectors. In the period between August of 2011 and January of 2013, the far (near) detector observed 31 541 (290 775) electron antineutrino candidate events with a background fraction of 4.9% (2.8%). The measured prompt spectra show an excess of reactor ν[over ¯]_{e} around 5 MeV relative to the prediction from a most commonly used model. A clear energy and baseline dependent disappearance of reactor ν[over ¯]_{e} is observed in the deficit of the observed number of ν[over ¯]_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.082±0.009(stat)±0.006(syst) and |Δm_{ee}^{2}|=[2.62_{-0.23}^{+0.21}(stat)_{-0.13}^{+0.12}(syst)]×10^{-3} eV^{2}.
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BACKGROUND: HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations [subcutaneous (s.c.) and intravenous (i.v.)] in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s.c. versus i.v. trastuzumab in terms of serum concentration (Ctrough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months. PATIENTS AND METHODS: Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s.c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i.v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out. RESULTS: s.c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s.c. treatment {64 [21.5%; 95% confidence interval (CI) 17.0%-26.7%] versus 42 (14.1%; 95% CI 10.4%-18.6%) in the i.v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure. CONCLUSIONS: Overall, the safety profile of s.c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i.v. trastuzumab. EFS rates were comparable between the i.v. and s.c. groups. CLINICAL TRIAL NUMBER: NCT00950300.
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Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/administração & dosagem , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias da Mama/genética , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Trastuzumab/efeitos adversosRESUMO
BACKGROUND: The survival of patients with head and neck squamous cell carcinoma (HNSCC) can be affected by noncancer health events (NCHE) as well as by index cancer progression and second primary cancer (SPC). This study aimed to investigate the risk factors for NCHE and noncancer mortality (NCM) in patients with advanced-stage HNSCC. PATIENTS AND METHODS: This cohort study involved 600 consecutive patients with overall stage III to IV HNSCC who were treated between 2001 and 2010 at our tertiary referral hospital. NCHE was defined as re-admission (i.e. after the primary treatments for the index tumors) due to noncancer-related causes. The incidences of NCHE and NCM and their risk factors were analyzed by using cumulative incidence and cause-specific hazard functions. RESULTS: During a median follow-up period of 54 months, 224 (37.3%) and 55 (9.2%) of the 600 patients had NCHE and NCM, respectively. The 5-year index cancer mortality, SPC mortality, and NCM rates were 23.8%, 4.2%, and 8.9%, respectively. Multivariate analyses revealed that body mass index <20 kg/m(2) (P = 0.018), Charlson comorbidity index (CCI) ≥1 (P < 0.001), tumor recurrence (P < 0.001), SPC occurrence (P < 0.001), and initial chemotherapy (P = 0.049) were independent NCHE predictors. Older age (P < 0.001), CCI ≥1 (P = 0.008), tumor recurrence (P < 0.001), and SPC occurrence (P = 0.047) were independent NCM predictors. Patients with respiratory NCHE were at a higher risk of NCM than patients with other NCHE types (P < 0.001). CONCLUSIONS: One or more comorbidities, tumor recurrence, and SPC occurrence were independent predictors of both NCHE and NCM. Patients with respiratory NCHE had a particularly high risk of NCM.
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Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/epidemiologia , Comorbidade , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Segunda Neoplasia Primária/epidemiologia , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.
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Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Adulto , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Letrozol , MicroRNAs/sangue , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Pós-Menopausa , Qualidade de Vida , Receptores de Estrogênio/metabolismo , Triazóis/administração & dosagemRESUMO
OBJECTIVES: HIV-associated neurocognitive disorder (HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine the prevalence of and risk factors for HAND in HIV-infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological (NP) tests for diagnosing HAND. METHODS: HIV-infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, the International HIV Dementia Scale (IHDS) and Montreal Cognitive Assessment (MoCA)-K were also assessed as potential tools for screening for HAND. RESULTS: Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment and minor neurocognitive disorder accounted for 52.9 and 47.1% of the patients with HAND, respectively. In multivariate analysis, haemoglobin (Hb) level ≤ 13 g/dL (P = 0.046) and current use of a protease inhibitor-based regimen (P = 0.031) were independent risk factors for HAND. The sensitivity and specificity of the IHDS were 72.6 and 60.8%, and those of MoCA-K were 52.9 and 73.4%, respectively. The IHDS (P < 0.001) and MoCA-K (P < 0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2 and 72.0%, and those of the Wisconsin Card Sorting Test were 61.2 and 84.4%, respectively. CONCLUSIONS: HAND is a prevalent comorbidity in HIV-infected Koreans. Active screening and diagnosis with effective tools, such as the IHDS, MoCA-K and Grooved Pegboard Test, could be used to identify this important complication.
Assuntos
Complexo AIDS Demência/diagnóstico , Complexo AIDS Demência/epidemiologia , Testes Neuropsicológicos , Adulto , Idoso , Feminino , Hospitais de Ensino , Humanos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Sensibilidade e Especificidade , Adulto JovemRESUMO
AIMS: To monitor bacterial diversity of ISO Class 8 pharmaceutical clean room environment using conventional culture-based methods and pyrosequencing analysis. METHODS AND RESULTS: Bacterial isolates were obtained through viable particulate air monitoring, passive air monitoring and surface-monitoring procedures. A total of 157 bacterial isolates were obtained and assigned to four different phyla, Actinobacteria, Firmicutes, Proteobacteria and Deinococcus-Thermus, encompassing 52 species of 24 genera based on 16S rRNA gene sequence analysis. The genera Micrococcus and Staphylococcus were found as the main bacterial groups among the isolates. However, a big discrepancy was found between the culture based and pyrosequencing results. A total of 11 409 quality reads were obtained from the pyrosequencing analysis, and the subsequent phylogenetic analysis indicated that Proteobacteria was the most abundant group at phylum level, followed by Actinobacteria and Firmicutes. Bacillus, Propionibacterium and Acinetobacter were identified as the most abundant genera by the pyrosequencing analysis. CONCLUSIONS: The culture-based results were in line with previous reports on the airborne bacterial composition of various environments, but the pyrosequencing analysis revealed a unique diversity of bacteria in this case. No significant pathogens above Riskgroup 2 were found from either culture based or pyrosequencing studies. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of various bacterial taxa including a number of groups, whose presence in air is previously unknown, was confirmed through this analysis. The main source of bacteria in the indoor air environment of pharmaceutical processes is likely human, but no significant primary pathogens were detected. Culture-based analysis may give limited information on the bacterial diversity of air environment.