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Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.
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BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.
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Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/efeitos adversos , Bacteroides fragilis , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Epirubicina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Despite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer. METHODS: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1-14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151-2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%). CONCLUSION: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT02362958 ) on 13/02/2015.
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Neoplasias da Mama , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Receptor ErbB-2 , Trastuzumab , Resultado do TratamentoRESUMO
Granulomatous lobular mastitis (GLM) is a chronic inflammatory breast condition that is characterized by granulomatous inflammation. GLM remains a refractory disease due to its failure to respond to routine anti-inflammatory therapies and its high recurrence rate. Thus, the present study aimed to investigate the application of local heat therapy in GLM as a potential therapeutic strategy. The results revealed that the application of local heat therapy was associated with a shortened remission time for GLM, while the remission and recurrence rates were similar to those of existing therapies. The median first remission time following local heat therapy was significantly decreased compared with that following corticosteroid therapy (5.30 months vs. 11.27 months; P<0.05). The remission rates were not significantly different between the local heat therapy (76.9%), extensive excision (90.4%) and the corticosteroid therapy (85.7%) groups (P>0.05). In addition, the recurrence rates were not statistically different between the groups (local heat therapy, 8.3%; extensive excision, 10%; and corticosteroid therapy, 10%; P>0.05). The local heat therapy showed mild adverse effects and shortened healing times compared to the other therapies; however, further confirmation is required.
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Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.
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Capecitabina/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Capecitabina/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Síndrome Mão-Pé/etiologia , Humanos , Quimioterapia de Manutenção , Mastectomia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasia Residual , Observação , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgiaRESUMO
BACKGROUND: To investigate the effect of intraoperative radiotherapy (IORT) in the perioperative period of patients after breast-conserving surgery (BCS). METHODS: The clinical data of 100 patients with early breast cancer undergoing breast-conserving surgery (BCS) followed by treatment with IORT using the Intrabeam system (Carl Zeiss Meditec, Oberkochen, Germany) (BCS + IORT group, n=100) between June 2016 and December 2019 were analyzed and compared with the data of 60 matched patients who only underwent breast-conserving therapy over the same period (BCS group, n=60). The surgical settings and postoperative acute complications between the groups were assessed. RESULTS: There was no significant statistical difference between the groups in terms of age, tumor size, grading, lymph node status, hormone receptor status, and human epidermal growth factor receptor 2 (HER-2) status (P>0.05). The BCS + IORT group had a significantly longer surgery duration (P<0.05), but there was no significant statistical difference in terms of intraoperative blood loss, amount of bleeding, drainage tube removal time, postoperative length of hospitalization, incision suture removal time, or incidence of postoperative complications (P>0.05). CONCLUSIONS: IORT using the Intrabeam system safely delivers radiation therapy, is well-tolerated, has acceptable acute toxicity, and does not significant increase the risk of surgery or the incidence of perioperative complications.
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Buckwheat sprouts (BS) becomes popular due to its' health-promoting properties as food product. The effects of fermentation with Saccharomyces cerevisiae and Lactobacillus plantarum on antioxidant and hypolipidemic activities as well as functional composition in common BS cultivated in maifanite mineral water were investigated here. DPPH and ·OH results showed higher antioxidant potential in fermented BS compared to unfermented BS, due to the higher rutin, orientin, isoorientin, vitexin, isovitexin, and total phenolic and flavonoid contents. The S. cerevisiae-fermented BS also exhibited 113% and 110% higher DPPH and ·OH scavenging activities than the L. plantarum-fermented BS, respectively. In hyperlipidemic mice, blood lipid parameters were improved as dose-dependent manner when supplemented the food with S. cerevisiae-fermented BS. Fermented BS also restored liver antioxidant levels significantly. The fermented BS had greater effect on different parameters than those of unfermented BS. Therefore, fermentation is a valuable method to enhance the bioactive potential of BS.
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Antioxidantes/análise , Fagopyrum/química , Fagopyrum/crescimento & desenvolvimento , Alimentos Fermentados/análise , Águas Minerais , Animais , Antioxidantes/farmacologia , Apigenina/análise , Fagopyrum/metabolismo , Fermentação , Flavonoides/análise , Glucosídeos/análise , Hiperlipidemias/dietoterapia , Lactobacillus plantarum , Masculino , Camundongos , Fenóis/análise , Rutina/análise , Saccharomyces cerevisiae , Plântula/crescimento & desenvolvimentoRESUMO
BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day -1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided. RESULTS: In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001). CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/complicações , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Gangliosídeos/uso terapêutico , Ácido N-Acetilneuramínico/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Taxoides/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Seguimentos , Humanos , Fármacos Neuroprotetores/uso terapêuticoRESUMO
BACKGROUND: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. MATERIALS AND METHODS: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. RESULTS: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. CONCLUSION: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.
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Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/fisiologia , Proteínas de Ligação a RNA/fisiologia , Receptor EphA3/fisiologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Receptor EphA3/genéticaRESUMO
PIWI-interacting RNA (piRNA) silences the transposons in germlines or induces epigenetic modifications in the invertebrates. However, its function in the mammalian somatic cells remains unknown. Here we demonstrate that a piRNA derived from Growth Arrest Specific 5, a tumor-suppressive long non-coding RNA, potently upregulates the transcription of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a proapoptotic protein, by inducing H3K4 methylation/H3K27 demethylation. Interestingly, the PIWIL1/4 proteins, which bind with this piRNA, directly interact with WDR5, resulting in a site-specific recruitment of the hCOMPASS-like complexes containing at least MLL3 and UTX (KDM6A). We have indicated a novel pathway for piRNAs to specially activate gene expression. Given that MLL3 or UTX are frequently mutated in various tumors, the piRNA/MLL3/UTX complex mediates the induction of TRAIL, and consequently leads to the inhibition of tumor growth.
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Proteína de Leucina Linfoide-Mieloide/genética , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , RNA Nucleolar Pequeno/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Histona-Lisina N-Metiltransferase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: To investigate the applicability of inbred Wuzhishan (WZS) miniature pigs for porcine islet isolation and purification. METHODS: Islet isolation and purification was conducted on adult (1-yr-old), male inbred WZS miniature pigs and age- and sex-matched market pigs obtained from a local slaughterhouse (control group). Pancreata were excised, and islet isolation was carried out by static digestion and discontinuous gradient centrifugation. Viability of the purified islets was tested by radioimmunochemistry assay to measure glucose-induced insulin release in culture and transplantation in an in vivo study. RESULTS: The anatomical structure of the WZS miniature pig pancreas was more similar to the human pancreas than that of the market pig. Islet yield of the WZS miniature pigs' pancreata was significantly higher than that of the market pigs (6078 ± 1105 vs. 2500 ± 625 islet equivalents [IEQ]/g). In vitro study demonstrated that the islets isolated from WZS miniature pigs were viable, as they efficiently responded to glucose challenge. In vivo study showed that the islets from both groups could cure the diabetic rat with the survival varied from 3 to 5 days (median, 4.3 days) and 2-4 days (median, 3.6 days) in experimental group and control group, respectively. CONCLUSION: Wuzhishan miniature pig pancreas may be a feasible source of islets for xenotransplantation.