RESUMO
OBJECTIVES: Parturients are at increased risk for difficult airway management with subsequent fetal complications. Videolaryngoscopy was opined to be the new standard of airway care to facilitate orotracheal intubation under urgent care conditions. We examined in parturients requiring general anesthesia for urgent cesarean delivery the association of the type of laryngoscopy technique and time required to facilitate orotracheal intubation with the incidence of subsequent neonatal intensive care unit (NICU) admission. METHODS: Following institutional review board approval, 431 parturients aged 18 years and older who underwent urgent cesarean section requiring general anesthesia were entered into this study. Patient characteristics, maternal comorbidities, and indications for urgent cesarean delivery were collected from the electronic medical records from January 2013 to November 2018. Orotracheal intubation times by type of laryngoscopy (video or direct) and NICU admission rates also were collected. A measure of effect size, risk differences with 95% confidence intervals (CIs), were calculated for the likelihood of NICU admission by difficult orotracheal intubation and by type of laryngoscopy used to secure the airway. RESULTS: Videolaryngoscopy as the primary type of laryngoscopy was used in 24.1% (95% CI 20.3%-28.3%) of general anesthetics. The incidence of difficult orotracheal intubation was 4.4% (95% CI 2.8%-6.7%), with a higher incidence observed with videolaryngoscopy (8.7%) than with direct laryngoscopy (3.1%) and a risk difference of 5.6% (95% CI 0.001%-11.3%). The incidence of NICU admission was 38.4% (95% CI 34.0%-43.1%). Times for successful orotracheal intubation were longer with videolaryngoscopy. Videolaryngoscopy had a higher association for NICU admission (47%) than for direct laryngoscopy (36%), with a risk difference of 11.4% (95% CI 0.01%-22.3%). CONCLUSIONS: Videolaryngoscopy did not decrease the incidence of difficult orotracheal intubation, and it did not decrease the time associated with orotracheal intubation. Videolaryngoscopy was associated with a higher association of NICU admission. These results suggest that videolaryngoscopy does not supplant direct laryngoscopy as the standard of care for orotracheal intubation under urgent care conditions of general anesthesia for cesarean section.
Assuntos
Cesárea , Unidades de Terapia Intensiva Neonatal , Intubação Intratraqueal , Laringoscopia , Humanos , Laringoscopia/métodos , Laringoscopia/estatística & dados numéricos , Feminino , Cesárea/métodos , Cesárea/estatística & dados numéricos , Gravidez , Intubação Intratraqueal/métodos , Intubação Intratraqueal/estatística & dados numéricos , Adulto , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Recém-Nascido , Anestesia Geral/métodos , Anestesia Geral/estatística & dados numéricos , Manuseio das Vias Aéreas/métodos , Estudos Retrospectivos , Gravação em VídeoRESUMO
INTRODUCTION: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. METHODS: Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. RESULTS: A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. CONCLUSIONS: ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. TRIAL REGISTRATION: ACTRN12605000588695.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Isoenzimas/metabolismo , Retinal Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Docetaxel , Esquema de Medicação , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
Hydrogen peroxide was employed as the terminal oxidant in the osmium tetroxide mediated oxidative cleavage of olefins, producing the corresponding aldehyde and ketone products. Aryl olefins are cleaved in good to excellent yield regardless of arene electronics. Alkyl olefins cleave in moderate to good yield for di- and tri-substituted alkenes.
Assuntos
Alcenos/química , Peróxido de Hidrogênio/química , Tetróxido de Ósmio/química , Catálise , Estrutura Molecular , Oxirredução , Ácidos Sulfúricos/químicaRESUMO
INTRODUCTION: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. RESULTS: Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. CONCLUSIONS: Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto , Idoso , Antraciclinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Quimioterapia Adjuvante , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
Spread of invasive carcinoma throughout breast tissue is believed to occur at supramolecular levels, beyond the range of standard histopathology identification. Small angle x-ray scattering (SAXS) is capable of characterizing the structural properties of collagen and tissue found in the breast at the scale of tens to hundreds of nanometers. Fifty-six patients who were treated with wide-local excision or mastectomy had tissue biopsy samples analyzed at 2 cm intervals along two perpendicular axes over their excised mass, up to 6 cm away from the primary site of the tumor. Two SAXS parameters, the integrated amorphous scatter and the third order collagen axial d spacing, showed significant differences between the center (0 cm) and distant tissues (2, 4, or 6 cm from the primary lesion). There was no evidence of directional trends (superior, inferior, or lateral sides of the nipple) of these two parameters over the breast. Mapping of these two variables over a two-dimensional grid showed good matching with independent histopathology diagnosis. These results suggest that SAXS may be capable of identifying areas of invasion or directional spread of disease as well as providing more information at the supramolecular level for aiding tissue diagnosis.
Assuntos
Doenças Mamárias/diagnóstico por imagem , Doenças Mamárias/patologia , Mama/patologia , Mamografia/métodos , Espalhamento de Radiação , Raios X , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Humanos , Modelos BiológicosRESUMO
BACKGROUND: When a papillary lesion is identified on core biopsy of an impalpable breast lesion, standard practice involves excisional biopsy. Recent literature has questioned the need for surgical excision in patients with benign core biopsy and radiological concordance. Our aim was to assess whether surgical excision is required by targeting this concordant group in a large screen-detected population. METHODS: A retrospective review of a prospectively collected database of all benign papillary core biopsies between February 1995 and September 2007 at North Western Breast Screen and Monash Breast Screen in Melbourne, Australia was performed. All patients had surgical excision, enabling correlation between core and final excisional biopsy results on all lesions. All histology reports were reviewed and the radiology was reassessed. RESULTS: During a 14-year period, 5783 core biopsies were performed from 633,163 screening mammograms. Eighty patients (0.01%) had benign papilloma on core biopsy, no patients had atypia on core biopsy, and all patients had benign radiological features. Of the 80 patients, 15 patients were found to have ductal carcinoma in situ (8) or invasive ductal carcinoma (7) on final pathology, yielding a 19% malignant rate. CONCLUSION: Core biopsy showing benign papillary lesion, even where radiology is also suggestive of a benign process, cannot exclude malignancy, and therefore surgical excision is required.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Papiloma/patologia , Papiloma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Mama/cirurgia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos RetrospectivosRESUMO
BACKGROUND: Screen-detected ductal carcinoma in situ (DCIS) usually presents as clinically impalpable microcalcification. Although core biopsy is well established as a diagnostic modality for invasive breast cancers, few reports address its impact on the management of screen-detected DCIS. We examined the sensitivity of core biopsy in diagnosing screen-detected DCIS, as well as its role in facilitating one-step surgery in the community, especially a breast-conserving approach. METHODS: Through the Monash BreastScreen database, we reviewed the management of 148 patients diagnosed with pure DCIS over a 4-year period. Particular attention was paid to the sensitivity and surgical margin status of 63 patients who underwent initial assessment with core biopsy, compared to patients who underwent excisional biopsy or fine needle aspiration cytology (FNAC). RESULTS: Core specimens in 63 patients yielded positive histology in 57 (90%), allowing for breast-conserving surgery in 45 and mastectomy in 12. Negative margins were obtained in 73% of those treated by breast-conserving surgery, compared to 51% negative margins among those who underwent excisional biopsy initially. Overall, 45 of 57 patients with a positive core biopsy histology (79%) underwent one-step surgery. Those assessed by FNAC had a 48% incidence of non-diagnostic/benign cytology. CONCLUSIONS: Core biopsy facilitates one-step surgery for screen-detected DCIS, and potentially reduces the number of surgical procedures. Stereotactic core biopsy for suspicious microcalcifications should replace hookwire-guided excisional biopsy and FNAC as the diagnostic modality of choice.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Biópsia por Agulha , Feminino , HumanosRESUMO
BACKGROUND: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity. METHODS: Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1-100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 microM) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured. RESULTS: Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC(50) = 14.9 nM), arcaine (IC(50) = 37.9 nM), agmatine (IC(50) = 41.5 nM), and DFMO (IC(50) = 0.6 nM). NMDA (5 microM) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity. CONCLUSIONS: These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions.
Assuntos
Poliaminas Biogênicas/metabolismo , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Hipocampo/metabolismo , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
BACKGROUND: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. RESULTS: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. CONCLUSIONS: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.
Assuntos
Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Maleato de Dizocilpina/farmacologia , Feminino , Hipocampo/metabolismo , Masculino , N-Metilaspartato/farmacologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
BACKGROUND: Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD-induced neurotoxicity in organotypic hippocampal slice cultures. METHODS: A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-D-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N-acetyl homotaurine or Na-acamprosate). A comparison of the effects of 100 microM guanosine 5'-triphosphate on unlabeled glutamate, trans-ACPD, and Na-acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 microM -ACPD or 50 microM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone. RESULTS: Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD. The presence of 100 microM guanosine 5'-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-acamprosate. Na-acamprosate (200-1000 microM) and SIB-1893 (20-500 microM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity. CONCLUSIONS: Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.