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Introduction: For decades, endocrine therapy has been the cornerstone of management for luminal breast cancer. Despite the substantial benefit derived by patients from endocrine therapy, primary and secondary resistances to endocrine therapy are serious clinical issues.Areas covered: Today, in the advanced setting, three distinct classes of targeted agents mTOR, CDK 4/6, and PI3K inhibitors, are approved for use. CDK 4/6 inhibitors have improved outcomes substantially, changing the natural history of advanced luminal breast cancer. Current studies seek to bring CDK 4/6 inhibitors to the early setting. This review will cover all available data on target therapy combinations with endocrine therapy for both the early and advanced settings, including approved drugs and agents in development.Expert opinion: Combined endocrine and target therapy has changed the landscape in advanced disease. In early disease, it is possible to have a large impact, particularly in patients with higher risk of relapse. Trials like ADAPTCYCLE seek to leverage neoadjuvant data to de-escalate treatment, substituting chemotherapy for CDK 4/6 inhibitors. In advanced diseases, studies such as PADA-1 point toward a future in which ctDNA will be used to define management before clinical progression occurs.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quinase 4 Dependente de Ciclina , Feminino , Humanos , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2RESUMO
The study evaluated an echo-guided oocyte recovery technique in owl monkeys. Twelve females were selected for the transabdominal ovum retrieval technique. This procedure collected twenty-six follicles, of which nine oocytes were recovered, without harm to the animals. The technique is feasible and is a minimally invasive protocol for neotropical primates.
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Aotidae/fisiologia , Oócitos/fisiologia , Ultrassonografia/métodos , Animais , FemininoRESUMO
BACKGROUND: Takotsubo syndrome (TTS), also known as stress cardiomyopathy, apical ballooning syndrome and broken heart syndrome, is characterized by acute-onset chest pain, electrocardiographic (ECG) abnormalities and reversible left ventricular (LV) disfunction in the absence of a culprit obstructive lesion in the coronary arteries; therefore, myocardial infarction is the most important differential diagnosis. Usually induced by emotional/physical stress, its treatment consists in hemodynamic support until complete and spontaneous recovery occurs, which is generally achieved within a few days to weeks. Cervical malignancies are an important public health issue in low/middle-income countries and, in the setting of locally advanced disease, concurrent chemoradiation followed by brachytherapy is considered the standard treatment, harboring curative potential. CASE REPORT: We report a case of a 38-year-old woman who underwent concurrent chemoradiotherapy and developed cardiopulmonary arrest in ventricular fibrillation during a brachytherapy session. Complementary tests disclosed altered ECG and cardiac biomarkers, no evidence of coronary artery obstruction, as well as LV disfunction consistent with TTS on echocardiogram and cardiac MRI. After few days of supportive therapy, complete recovery of heart function was observed. CONCLUSIONS: Especially for cancer patients, who usually experience intense emotional/physical stress intrinsically associated with their diagnosis and aggressive treatments, considering TTS as a differential diagnosis is warranted. Intracavitary brachytherapy procedure may represent a trigger for TTS.
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Purpose: The goal was to compare the micronucleus (MN) and dicentric plus ring chromosomes (D + R) assays for dose assessment in cases of partial body irradiations (PBI). Materials and methods: We constructed calibration curves for each assay at doses ranging from 0 to 5 Gy of X-rays at dose rate of 0.275 Gy/min. To simulate partial-body exposures, blood samples from two donors were irradiated with 0.5, 1, 2 and 4 Gy and the ratios of irradiated to unirradiated blood were 25, 50, and 100%. Different tests were used to confirm if all samples were overdispersed or zero-inflated and for partial-body dose assessment we used the Qdr, Dolphin and Bayesian model. Results: In our samples for D + R calibration curve, practically all doses agreed with Poisson assumption, but MN exhibited overdispersed and zero-inflated cellular distributions. The exact Poisson tests and zero-inflated tests demonstrate that virtually all samples of D + R from PBI simulation fit the Poisson distribution and were not zero-inflated, but the MN samples were also overdispersed and zero-inflated. In the partial-body estimation, when Qdr and Dolphin methods were used the D + R results were better than MN, but the doses estimation defined by the Bayesian methodology were more accurate than the classical methods. Conclusions: Dicentric chromosomes continue to prove to be the best biological marker for dose assessment. However exposure scenarios of partial-body estimation, overdispersion and zero-inflation may not occur, it being a critical point not only for dose assessment, but also to confirm partial-body exposure. MN could be used as alternative assay for partial-body dose estimation, but in case of an accident without any information, the MN assay could not define whether the accident was a whole-body irradiation (WBI) or a PBI.
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Testes para Micronúcleos , Doses de Radiação , Cromossomos em Anel , Aberrações Cromossômicas , Relação Dose-Resposta à Radiação , Humanos , Distribuição de PoissonRESUMO
BACKGROUND: and Purpose: Post-operative radiation therapy (PORT) is usually indicated for patients with breast cancer (BC) after neoadjuvant chemotherapy (NAC) and surgery. However, the optimal timing to initiation of PORT is currently unknown. MATERIAL AND METHODS: We retrospectively evaluated data from patients with BC who received PORT after NAC and surgery at our institution from 2008 to 2014. Patients were categorized into three groups according to the time between surgery and PORT: <8 weeks, 8-16 weeks and >16 weeks. RESULTS: A total of 581 patients were included; 74% had clinical stage III. Forty-three patients started PORT within 8 weeks, 354 between 8 and 16 weeks and 184 beyond 16 weeks from surgery. With a median follow-up of 32 months, initiation of PORT up to 8 weeks after surgery was associated with better disease-free survival (DFS) (<8 weeks versus 8-16 weeks: HR 0.33; 95% CI 0.13-0.81; p = 0.02; <8 weeks versus >16 weeks: HR 0.38; 95% CI 0.15-0.96; p = 0.04) and better overall survival (OS) (<8 weeks versus 8-16 weeks: HR 0.22; 95% CI 0.05-0.90; p = 0.036; <8 weeks versus >16 weeks: HR 0.28; 95% CI 0.07-1.15; p = 0.08). CONCLUSION: PORT started up to 8 weeks after surgery was associated with better DFS and OS in locally-advanced BC patients submitted to NAC. Our findings suggest that early initiation of PORT is critically important for these patients. However, the low numbers of patients and events in this study prevent us from drawing firm conclusions.
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Neoplasias da Mama/radioterapia , Mastectomia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
In the present study, we aimed to assess the influence of different social contexts on the seminal coagulation and sperm quality in captive tufted capuchin monkeys. For this, males were housed either individually, in mixed-sex groups (with females), or in male-only groups. Monkeys were housed in cages and each cage type (i.e., individual or group cage) was placed in a different room. Forty-one males were subjected to semen collection by rectal electroejaculation. The degree of seminal coagulation was determined on a scale of I-IV. Seminal volume, sperm concentration, sperm motility, vigor, and plasma membrane integrity were evaluated for all ejaculate samples. All ejaculates collected showed degrees of coagulation between II and IV, where the majority presented coagulation degree IV, when collected from animals housed in groups. No statistical differences among percentages of coagula degree when samples were collected from males housed individually. Animals housed in group cages (male-only groups and mixed-sex groups) showed a significantly higher percentage of ejaculates at degree IV than males housed individually. Seminal volume was not affected by the coagula degree but by the housing system, where animals housed individually showed the highest volume (543 µl) when compared with those animals from male (273 µl) and mixed-sex (318 µl) groups. No differences were observed in semen volume when comparing male-only groups with mixed-sex groups. Sperm motility was affected by both housing system and coagula degree. Samples with coagula degree IV from animals housed individually showed the highest (72%) sperm motility percentages. Sperm plasma membrane integrity was lower when samples were presenting coagula degree II + III and collected from male- (17%) or mixed-sex (23%) groups. However, this housing system effect was not observed when sperm was obtained from coagula degree IV semen. Sperm vigor was neither affect by housing system or coagula degree.
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Cebus , Comportamento Social , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Animais , Feminino , Masculino , Sêmen , EspermatozoidesRESUMO
Cervical cancer remains a prevalent and deadly disease in low-income countries, especially among young and otherwise healthy women. Multimodality treatment has led to a significant improvement in outcomes for patients with locally advanced disease, and this is mainly because of the incorporation of platinum-based chemoradiotherapy in current treatment protocols. However, locally advanced tumors are associated with a greater risk for para-aortic lymph node (PALN) involvement, which is an important adverse prognostic factor. Most staging techniques have low accuracy for detection of disease in this area, which could lead to understaging and undertreatment. Meanwhile, patients with PALN disease are underrepresented in trials addressing the treatment of advanced cervical cancer and a few studies have been directed at this population. The aim of this review is to analyze the current data regarding staging and treatment of cervical cancer with PALN disease to determine which strategy is best when managing these patients.
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Linfonodos/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Linfonodos/efeitos da radiação , Linfonodos/cirurgia , Metástase Linfática , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/diagnósticoRESUMO
BACKGROUND: Weekly paclitaxel has been shown more effective and less toxic than the conventional three-weekly administration. The GEICAM 9906 demonstrated effectiveness and safety of a dose-dense schedule of 100 mg/m(2) of paclitaxel given over 8 weeks (w). This schedule has been adopted at our institution in 2009 for HER2-negative disease, and herein, we present the first off-trial experience and compare its safety profile with that of a historical cohort of patients treated with the conventional 80 mg/m(2) over 12 w schedule. METHODS: Retrospective single-center chart review of patients with locally advanced breast cancer treated with (neo)adjuvant paclitaxel-based therapy from 2008 to 2012 with (1) 80 mg/m(2) for 12 w or (2) 100 mg/m(2) for 8 w. Adverse events were graded according to common terminology criteria for adverse events (CTCAE) 4.0. RESULTS: A total of 326 patients were analyzed. Median age was 52 (±10.9). Seventy and 256 patients received schedule (1) and (2), respectively. No significant difference was observed in the incidence of grade (G) 3/4 toxicity: pneumonitis (2.8 vs 0.3 % p = 0.097); neuropathy (2.8 vs 0.7 % p = 0.303); hand-foot syndrome (1.4 vs 0.3 % p = 0.538); anemia (0 vs 0.6 % p = 0.624); and neutropenia (5.7 vs 6.2 % p = 0.408). Also, no significant difference was seen when comparing all grades toxicity. Schedule (2) had higher dose intensity: 97.72 vs 77.07 mg/m(2) per week (p < 0.0001). CONCLUSIONS: Weekly paclitaxel given according to GEICAM 9906 is pragmatic and well tolerated, with safety profile consistent with the conventional schedule. In addition to being convenient to patients, it may also be cost-effective because of a lower number of clinic visits and infusions.
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Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/uso terapêutico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Brasil , Neoplasias da Mama/patologia , Esquema de Medicação , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
There is a paucity of efficient cryopreservation protocols for primordial follicles enclosed in the ovarian tissue from non-human primates (NHP), in special New World primates. Our objective was to establish an optimal procedure for the recovery of ovarian biopsies from capuchin monkeys. To this end, we adapted a trap door biopsy method. Follicular density and quality of the biopsies were evaluated and ultrasound analysis was performed before and continuously after surgery to assess ovarian structure. Ovarian tissue biopsies recovered by the trap door technique allowed the successful harvesting of primordial follicles from capuchin monkeys, and no complication was recorded. The female cycle was not affected by surgery and no adherence was found thereafter. In conclusion, the adaptation of a trap door biopsy method is a safe procedure and allows recovery of healthy primordial follicles.
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Folículo Ovariano/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Animais , Biópsia , Cebus , Feminino , Humanos , Microscopia , Folículo Ovariano/citologia , Folículo Ovariano/diagnóstico por imagem , Ultrassonografia Doppler DuplaRESUMO
The efficiency of in vitro fertilization (IVF) depends on the viability of spermatozoa. For capuchin monkeys (Cebus apella), in vitro capacitation of spermatozoa is challenging because of their unique seminal coagulum. Motile spermatozoa can be obtained after liquefaction of the semen coagulum in coconut water-based solution. The objective of the present study was to establish an optimal in vitro maturation (IVM) protocol for capuchin monkeys and to observe the effect of follicle stimulating hormone (FSH) and luteinising hormone (LH) on IVF and parthenogenetic activation (PA) of oocytes collected from unstimulated females. We assessed spermatozoa quality after recovery from seminal coagulum using the solution ACP-118® as an extender. Oocytes were matured in vitro for 36 or 40 h and subjected to IVF or PA by applying ionomycin combined either with 6-dimethylaminopurine (6-DMAP) or roscovitine. In total, 87% of oocytes reached metaphase II (MII) after 40 IVM and 4-cell embryo production was obtained after IVF and parthenogenesis using ionomycin/6-DMAP. ACP-118® was used successfully to harvest viable spermatozoa from semen coagulum and in the preservation of spermatozoa, which were able to fertilize oocytes in vitro.
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Embrião de Mamíferos/citologia , Fertilização in vitro , Metáfase/efeitos dos fármacos , Oócitos/citologia , Partenogênese/fisiologia , Espermatozoides/citologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Cebus , Células Cultivadas , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/farmacologia , Hormônios/farmacologia , Hormônio Luteinizante/farmacologia , Masculino , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Roscovitina , Espermatozoides/efeitos dos fármacosRESUMO
OBJECTIVE: To study the protein profile of oocytes and cumulus cells from different sized follicles throughout the follicular phase and to asses the ability of oocytes to progress from the dictyate to metaphase II (MII) stage. DESIGN: Animal model study. SETTING: Five academic basic research laboratories and the National Primate Centre. ANIMAL(S): Eleven normal, cycling capuchin monkey (Cebus apella) females. INTERVENTION(S): Cumulus-oocyte complexes and denuded oocytes were recovered by antral follicle aspiration. MAIN OUTCOME MEASURE(S): Protein profile analysis of denuded or intact oocytes. RESULT(S): The protein profiles of 25 denuded or intact oocytes recovered on days 5 (six denuded, five intact), 7 (four denuded, four intact), or 9 (one denuded, five intact) of the menstrual cycle were analyzed; in a second experiment, 40 intact oocytes were cultured for 24 (n = 20) or 36 hours (n = 20). The oocytes were denuded, fixed, stained, and microscopically examined to reveal the meiotic stage. The protein profile in each compartment within the cumulus-oocyte complex varied along the follicular development with a predominance of low-molecular-weight proteins in both oocyte and cumulus cells at final stages. No differences were found in the protein profile among oocytes pertaining to different sized follicles that were in the same day of the follicular phase. Oocyte MII competence was achieved only after incubation for 36 hours, and the highest maturation rate occurred in those becoming from dominant follicles. CONCLUSION(S): Our study shows, for the first time in a New World primate species, that the proteins contained in oocytes and cumulus cells reach an identical profile in the late follicular phase. This phenomenon could be related to the oocyte's ability to progress to the MII stage.
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Cebus , Células do Cúmulo/metabolismo , Fase Folicular/metabolismo , Meiose , Oócitos/metabolismo , Proteínas/metabolismo , Animais , Células Cultivadas , Feminino , Fatores de TempoRESUMO
The aim this study was to evaluate the efficiency of in natura coconut water solution at 37º C as seminal extender. Were analyzed fifteen ejaculates collected from 5 adult Cebus apella by electroejaculation. The means volumes of liquid and coagulated fractions were 0.26 + 0.06 mL and 0.98 + 0.02 mL, respectively. The sperm concentration in the liquid fraction (2.1 x 108 + 0.5 108 mL) was lower than liquefied fraction (1.6 x 109+ 0.9 109 mL) (p = 0.05). The mean percentage of live spermatozoa after 7 hours incubated at 37 C was 72 + 3%. Only in one sample was observed sperm motility (20%) and vigor (2). The results suggest that electroejaculation protocol using 100mA maximum amperage is efficient to obtain semen from adult Cebus apella. The coconut water extender can be used to maintain sperm viability for up to 7 hours at 37 C. However, studies are necessary to evaluate the sperm functionality extended in natura coconut water based solution.KEY WORDS: Cebus apella, electroejaculation water, extender, semen.
O objetivo deste estudo foi avaliar a eficiência de um diluidor de sêmen à base de água de coco in natura a 37 C na dissolução da fração coagulada e conservação do sêmen de macacos-prego. Analisaram-se quinze ejaculados colhidos de cinco (n=5) machos adultos de Cebus apella através de eletroejaculação. Os volumes médios das frações líquida e coagulada foram 0,26 + 0,06 mL e 0,98 + 0,02 mL, respectivamente. A fração líquida apresentou baixa concentração média de espermatozoides (210. 106 + 50 106 mL) em relação à fração coagulada (1600. 106+ 900 106 mL) (p ? 0,05). O percentual médio de espermatozoides vivos após sete horas de incubação a 37C foi 72 + 3%. Em apenas uma amostra observaram-se 20% de motilidade e vigor 2. Os resultados sugerem que o protocolo de eletroejaculação utilizando amperagem máxima de 100 mA é eficaz para a obtenção de sêmen de Cebus apella e que o diluidor à base de água de coco pode ser utilizado para manter a viabilidade dos espermatozoides a 37 C por até sete horas. Contudo, são necessários testes adicionais para avaliar a funcionalidade desses espermatozoides após a diluição do sêmen em água de coco in natura. Palavras chave: Água de coco, Cebus apella, diluidor, eletroejaculação, sêmen.
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The aim this study was to evaluate the efficiency of in natura coconut water solution at 37º C as seminal extender. Were analyzed fifteen ejaculates collected from 5 adult Cebus apella by electroejaculation. The means volumes of liquid and coagulated fractions were 0.26 + 0.06 mL and 0.98 + 0.02 mL, respectively. The sperm concentration in the liquid fraction (2.1 x 108 + 0.5 108 mL) was lower than liquefied fraction (1.6 x 109+ 0.9 109 mL) (p = 0.05). The mean percentage of live spermatozoa after 7 hours incubated at 37 C was 72 + 3%. Only in one sample was observed sperm motility (20%) and vigor (2). The results suggest that electroejaculation protocol using 100mA maximum amperage is efficient to obtain semen from adult Cebus apella. The coconut water extender can be used to maintain sperm viability for up to 7 hours at 37 C. However, studies are necessary to evaluate the sperm functionality extended in natura coconut water based solution.KEY WORDS: Cebus apella, electroejaculation water, extender, semen.
O objetivo deste estudo foi avaliar a eficiência de um diluidor de sêmen à base de água de coco in natura a 37 C na dissolução da fração coagulada e conservação do sêmen de macacos-prego. Analisaram-se quinze ejaculados colhidos de cinco (n=5) machos adultos de Cebus apella através de eletroejaculação. Os volumes médios das frações líquida e coagulada foram 0,26 + 0,06 mL e 0,98 + 0,02 mL, respectivamente. A fração líquida apresentou baixa concentração média de espermatozoides (210. 106 + 50 106 mL) em relação à fração coagulada (1600. 106+ 900 106 mL) (p ? 0,05). O percentual médio de espermatozoides vivos após sete horas de incubação a 37C foi 72 + 3%. Em apenas uma amostra observaram-se 20% de motilidade e vigor 2. Os resultados sugerem que o protocolo de eletroejaculação utilizando amperagem máxima de 100 mA é eficaz para a obtenção de sêmen de Cebus apella e que o diluidor à base de água de coco pode ser utilizado para manter a viabilidade dos espermatozoides a 37 C por até sete horas. Contudo, são necessários testes adicionais para avaliar a funcionalidade desses espermatozoides após a diluição do sêmen em água de coco in natura. Palavras chave: Água de coco, Cebus apella, diluidor, eletroejaculação, sêmen.