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Objectives: This study aimed to evaluate the vagina clinically, cytologically, and histologically before and after treating genitourinary syndrome of menopause (GSM) with fractional microablative carbon dioxide LASER (CO2L), radiofrequency (RF), and estrogen vaginal cream (CT). Methods: Women with moderate-to-severe symptoms of GSM, denoted by a GSM Visual analog scale (VAS) score of >4, were eligible for this study. The patients were randomized into treatment groups. In the energy groups, three vulvovaginal applications were administered monthly. The CT group used 0.5 mg vaginal estriol cream for 14 consecutive days, followed by twice a week for 4 months. The follow-up visits occurred 120 days after the beginning of the treatments. The same parameters obtained at the first visit were re-evaluated: GSM VAS score, Incontinence Quality of Life Questionnaire (I-QOL), gynecological examination determining Vaginal Health Index (VHI), vaginal smear for Vaginal Maturation Value (VMV), and vaginal biopsy. Results: Seventy-one women were included, 48 completed the study and provided adequate samples for analysis (CO2L [21 patients], RF [15 patients], and CT [12 patients]). GSM symptoms, I-QOL, and VHI significantly improved after all proposed treatments, with no significant differences between them. VMV did not change after any treatment; however, only 22.9% of the patients presented with cytological atrophy before treatment. Histological vaginal atrophy was identified in 6 (12.5%) pretreated vaginal samples. After the intervention, all histological parameters were normalized, no tissue damage was observed, and no major clinical complications were observed. Conclusion: CO2L and RF seem to be good alternatives to CT for GSM treatment, with no tissue damage.
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Lasers de Gás , Menopausa , Vagina , Humanos , Feminino , Lasers de Gás/uso terapêutico , Pessoa de Meia-Idade , Vagina/efeitos da radiação , Síndrome , Doenças Urogenitais Femininas/terapia , Qualidade de Vida , Cremes, Espumas e Géis Vaginais/uso terapêutico , IdosoRESUMO
OBJECTIVE: This study aimed to compare the efficacy of CO 2 laser, radiofrequency, and promestriene in treating genitourinary syndrome of menopause in women with breast cancer receiving adjuvant therapy and to analyze the clinical and histological findings of the vulvar vestibule. METHODS: Women with moderate-to-severe symptoms of vulvar atrophy were enrolled. The participants were evaluated according to pretreatment and posttreatment protocols using the visual analog scale and clinical assessments, which included a gynecological examination and vestibular biopsy. Participants were randomly assigned into the laser, radiofrequency, or promestriene groups. Participants in the energy treatment groups underwent three consecutive monthly outpatient vulvovaginal treatment sessions, whereas those in the control group were administered promestriene for 4 months. During a follow-up visit 30 days posttreatment, the participant global posttreatment impression of improvement was evaluated using a Likert scale. RESULTS: Seventy women completed treatment. Histological vulvar atrophy was identified in four (5.7%) of the pretreatment vulvar samples. Postintervention, all histological parameters were normalized. Significant improvements in symptoms were observed, as all three groups showed a reduction in the visual analog scale score, with no statistically significant differences among them. A high level of satisfaction was reported posttreatment in all groups. No damage to the histological structure of the vulvar vestibule or relevant clinical adverse events were identified posttreatment. CONCLUSIONS: Laser, radiofrequency, and promestriene delivered comparable, significant symptom improvements among women with breast cancer receiving adjuvant therapy. These treatments did not cause structural tissue damage or other clinical complications.
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Neoplasias da Mama , Sobreviventes de Câncer , Lasers de Gás , Feminino , Humanos , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Menopausa , Lasers de Gás/uso terapêutico , Atrofia/patologia , Resultado do Tratamento , Vagina/patologiaRESUMO
BACKGROUND: Mammography screening has become widely spread and provided a marked increase in ductal carcinoma in situ (DCIS) diagnosis. In DCIS, the ductal epithelium proliferates without invasion through the basal cell membrane. However, histologic underestimation can happen in some cases. OBJECTIVE: To analyze the rate of histologic underestimation (histopathologic results upgraded to invasive carcinoma after surgery) and the rate of positive results of sentinel lymph node biopsy (SLNB) in patients diagnosed with DCIS in a Brazilian public hospital. METHODS: We reviewed medical records of all consecutive patients admitted between 2009 and 2013 whose initial diagnosis was DCIS through core needle biopsy. DCIS cases with a high risk of invasion underwent SLNB. We excluded cases with invasion or micro-invasion components in the first biopsy. RESULTS: A total of 86 women were included, most with microcalcifications as the primary radiological lesion (73.2%), and underwent preoperative biopsy, with an invasive component in 21 (24.4%) in the final pathology report. Most had invasive carcinoma of no special type (NST): 52.3% (n = 11) and microinvasive tumors (7 cases, 33.3%). The main factors associated with histologic underestimation were nodular lesion (61.9%, p<0.001) and an ultra-sonography-guided biopsy (71.4%, p=0.0005). The positivity rate of SLNB was 4.3%. All these patients underwent mastectomy, and the initial histologic pattern was solid DCIS. CONCLUSION: The "histologic underestimation" rate among patients with DCIS was not low, and less than 5% of patients who underwent SLNB had axillary positivity. This result suggests that patients who have DCIS and a high risk of invasion and undergoing mastectomy should have SLNB. As to the patients who will undergo lumpectomy, SLNB could be omitted and could be performed if patients have upgraded to invasive breast cancer.
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Altered cell metabolism is a hallmark of cancer and critical for its development. Particularly, activation of one-carbon metabolism in tumor cells can sustain oncogenesis while contributing to epigenetic changes and metabolic adaptation during tumor progression. We assessed whether increased one-carbon metabolism activity is a metabolic feature of invasive ductal carcinoma (IDC). Differences in the metabolic profile between biopsies from IDC (n = 47) and its adjacent tissue (n = 43) and between biopsies from different breast cancer subtypes were assessed by gas spectrometry in targeted (Biocrates Life Science ® ) and untargeted approaches, respectively. The metabolomics data were statistically treated using MetaboAnalyst 4.0, SIMCA P+ (version 12.01), Statistica 10 software and t test with p < 0.05. The Cancer Genome Atlas breast cancer dataset was also assessed to validate the metabolomic profile of IDC. Our targeted metabolomics analysis showed distinct metabolomics profiles between IDC and adjacent tissue, where IDC displayed a comparative enrichment of metabolites involved in one-carbon metabolism (serine, glycine, threonine, and methionine) and a predicted increase in the activity of pathways that receive and donate carbon units (i.e., folate, methionine, and homocysteine). In addition, the targeted and untargeted metabolomics analyses showed similar metabolomics profiles between breast cancer subtypes. The gene set enrichment analysis identified different transcription-related functions between IDC and non-tumor tissues that involved one-carbon metabolism. Our data suggest that one-carbon metabolism may be a central pathway in IDC and even in general breast tumors, representing a potential target for its treatment and prevention.
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We evaluated whether the excluded stomach (ES) after Roux-en-Y gastric bypass (RYGB) can represent a premalignant environment. Twenty obese women were prospectively submitted to double-balloon enteroscopy (DBE) with gastric juice and biopsy collection, before and 3 months after RYGB. We then evaluated morphological and molecular changes by combining endoscopic and histopathological analyses with an integrated untargeted metabolomics and transcriptomics multiplatform. Preoperatively, 16 women already presented with gastric histopathological alterations and an increased pH (≥4.0). These gastric abnormalities worsened after RYGB. A 90-fold increase in the concentration of bile acids was found in ES fluid, which also contained other metabolites commonly found in the intestinal environment, urine, and faeces. In addition, 135 genes were differentially expressed in ES tissue. Combined analysis of metabolic and gene expression data suggested that RYGB promoted activation of biological processes involved in local inflammation, bacteria overgrowth, and cell proliferation sustained by genes involved in carcinogenesis. Accumulated fluid in the ES appears to behave as a potential premalignant environment due to worsening inflammation and changing gene expression patterns that are favorable to the development of cancer. Considering that ES may remain for the rest of the patient's life, long-term ES monitoring is therefore recommended for patients undergoing RYGB.
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Obesidade/patologia , Estômago/patologia , Adolescente , Adulto , Feminino , Derivação Gástrica/métodos , Suco Gástrico/fisiologia , Expressão Gênica/fisiologia , Humanos , Inflamação/patologia , Inflamação/cirurgia , Metabolômica/métodos , Pessoa de Meia-Idade , Obesidade/cirurgia , Estômago/cirurgia , Transcriptoma/fisiologia , Redução de Peso/fisiologia , Adulto JovemRESUMO
Molecular phenotyping and tissue microarray (TMA) studies have identified distinct invasive breast carcinoma subtypes: Luminal A, luminal B, enriched with overexpressed human epidermal growth factor receptor 2 (HER-2) and triple-negative, i.e., negative for HER-2, as well as for estrogen and progesterone receptor (ER and PR, respectively) expression. These subtypes are useful in clinical management, since they bear distinct prognoses and predictive responses to targeted therapy. However, although molecular profiling provides important prognostic indicators, breast cancer risk stratification remains a challenge in triple-negative cases. What is referred to as claudin-low subtype was identified as a triple-negative subset that is associated with more aggressive tumor behavior and worse prognosis. However, the immunohistochemical expression of claudins has not yet been standardized. Our objective was to verify whether the immunoexpression of claudins 4 and 7 (the main claudins specifically expressed in human breast tissue) in TMA is associated with survival and prognosis in luminal A, HER-2 and triple-negative molecular subtypes. In this diagnostic study, we investigated ER/PR receptor status, HER-2, claudin 4 and 7 expression and stem cell CD44/24 profiles, and verified the association with prognosis and survival outcomes in 803 invasive breast carcinoma cases arranged in four TMAs. Among these, 503 (62.6%) were positive for claudin 4 and 369 (46.0%) for claudin 7. Claudin 4 exhibited the lowest expression in luminal A and triple-negative subtypes, and the highest frequency of expression in HER-2-enriched subtypes, whereas claudin 7 staining was not associated with any subtype. The stem cell phenotype was not associated with subgroups or claudins 4 and 7. Claudin immunoexpression profile was not able to distinguish between patients with better or worse prognosis, and it was not correlated to triple-negative cases. Therefore, it may be concluded that the immunoexpression of claudins 4 and 7, individually or within the usual immunohistochemical context (ER, PR and HER-2), does not provide additional prognostic information on breast cancer subtypes.
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Malnutrition is associated with the delay or failure of healing. We assessed the effect of experimental malnutrition and early enteral feeding with standard diet or diet supplemented with arginine and antioxidants on the levels of mRNA encoding growth factors in acute, open wound healing. Standardised cutaneous dorsal wounds and gastrostomies for enteral feeding were created in malnourished (M, n = 27) and eutrophic control (E, n = 30) Lewis male adult rats. Both M and E rats received isocaloric and isonitrogenous regimens with oral chow and saline (C), standard (S) or supplemented (A) enteral diets. On post-trauma day 7, mRNA levels of growth factor genes were analysed in wound granulation tissue by reverse transcription polymerase chain reaction (RT-PCR). M(C) rats had significantly lower transforming growth factor ß(TGF-ß1 ) mRNA levels than E(C) rats (2·58 ± 0·83 versus 3·53 ± 0·57, P < 0·01) and in comparison with M(S) and M(A) rats (4·66 ± 2·49 and 4·61 ± 2·11, respectively; P < 0·05). VEGF and KGF-7 mRNA levels were lower in M(A) rats than in E(A) rats (0·74 ± 0·16 versus 1·25 ± 0·66; and 1·07 ± 0·45 versus 1·79 ± 0·89, respectively; P≤ 0·04), but did not differ from levels in E(C) and M(C) animals. In experimental open acute wound healing, previous malnutrition decreased local mRNA levels of TGF-ß1 genes, which was minimised by early enteral feeding with standard or supplemented diets.
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Nutrição Enteral , Desnutrição/metabolismo , Desnutrição/terapia , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização/fisiologia , Adulto , Animais , Antioxidantes/uso terapêutico , Arginina/uso terapêutico , Suplementos Nutricionais , Humanos , Masculino , Modelos Animais , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Pele/lesões , Ferimentos e Lesões/metabolismoRESUMO
BACKGROUND: The role of estrogen receptor beta (ER-ß) in breast cancer (BC) remains unclear. Some studies have suggested that ER-ß may oppose the actions of estrogen receptor alpha (ER-α), and clinical evidence has indicated that the loss of ER-ß expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-ß and the ER-α/ER-ß ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-ß expression levels. METHODS: Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-ß, ER-α and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p ≤ 0.05. RESULTS: The frequency of ER-ß expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-ß-negative cases (p = 0.45), but in the ER-ß-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-α and ER-ß expression levels. Only patients with an ER-α/ER-ß expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026). CONCLUSIONS: Our results provide additional data that indicate that the measurement of ER-ß in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-α/ER-ß expression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89801719.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Nitrilas/administração & dosagem , Tamoxifeno/uso terapêutico , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Nitrilas/uso terapêutico , Pós-Menopausa , Prognóstico , Tamoxifeno/administração & dosagem , Resultado do Tratamento , Triazóis/uso terapêuticoRESUMO
PURPOSE: To evaluate the immunohistochemical expression of p16, Ki-67, p53 and Bcl-2 proteins in gastrointestinal stromal tumors (GIST); to assess the possible association between these variables and clinical and histopathological factors of cancer; and to check for prognostic value of these variables (survival and recurrence). METHODS: A sample of 55 patients treated surgically for GIST in three hospitals was studied. The surgically excised tumors were confirmed as GIST by KIT, vimentin, desmin S100 protein, CD117, 1A4 and CD34 assessment in paraffin blocks. RESULTS: Only 9 (16%) cases of GIST were positive for p53, p16 was positive among 43.6%; 80% of GISTs showed staining for Bcl-2. The proliferative index (expressed as the proportion of positive cells) assessed by immunohistochemical expression of Ki-67 was high in 49% of cases. Elevated Ki-67 scores were associated to high histological grade (p=0.0026) and mitosis index, MI (p=0.0001). High Ki-67 index was associated to death. Expression of p53, p16 and Bcl-2 did not correlate to morphological or clinical variables. CONCLUSIONS: Ki-67 immunohistochemical evaluation should be included in preoperative evaluation of GIST biopsies or surgical specimens as a prognostic tool for clinical staging; and all other proteins studied (Bcl-2, p53 and p16) did not play a role in GIST metabolic or carcinogenic process, remaining without prognostic value.
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Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Antígeno Ki-67/metabolismo , Proteínas de Neoplasias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Feminino , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
PURPOSE: To evaluate the immunohistochemical expression of p16, Ki-67, p53 and Bcl-2 proteins in gastrointestinal stromal tumors (GIST); to assess the possible association between these variables and clinical and histopathological factors of cancer; and to check for prognostic value of these variables (survival and recurrence). METHODS: A sample of 55 patients treated surgically for GIST in three hospitals was studied. The surgically excised tumors were confirmed as GIST by KIT, vimentin, desmin S100 protein, CD117, 1A4 and CD34 assessment in paraffin blocks. RESULTS: Only 9 (16%) cases of GIST were positive for p53, p16 was positive among 43.6%; 80% of GISTs showed staining for Bcl-2. The proliferative index (expressed as the proportion of positive cells) assessed by immunohistochemical expression of Ki-67 was high in 49% of cases. Elevated Ki-67 scores were associated to high histological grade (p=0.0026) and mitosis index, MI (p=0.0001). High Ki-67 index was associated to death. Expression of p53, p16 and Bcl-2 did not correlate to morphological or clinical variables. CONCLUSIONS: Ki-67 immunohistochemical evaluation should be included in preoperative evaluation of GIST biopsies or surgical specimens as a prognostic tool for clinical staging; and all other proteins studied (Bcl-2, p53 and p16) did not play a role in GIST metabolic or carcinogenic process, remaining without prognostic value.
OBJETIVO: Avaliar a expressão imunoistoquímica de p16, Ki-67, p53 e Bcl-2 proteínas em tumores gastrointestinais estromais (GIST); determinar a possível associação entre essas variáveis e fatores clínicos e histopatológicos de câncer, e para verificar o valor prognóstico destas variáveis (sobrevivência e recorrência). MÉTODOS: Uma amostra de 55 pacientes tratados cirurgicamente para GIST em três hospitais foi estudada. Os tumores extirpados cirurgicamente foram confirmados como GIST por KIT, vimentina, proteína desmina S100, CD117, 1A4 e avaliação de CD34 em blocos de parafina. RESULTADOS: Apenas nove (16%) casos de GIST foram positivos para p53, p16 foi positiva em 43,6%, 80% dos GIST apresentaram coloração para Bcl-2. O índice proliferativo (expresso como a proporção de células positivas), avaliado pela expressão imunoistoquímica de Ki-67, foi elevado em 49% dos casos. Escores de Ki-67 elevados foram associados com alto grau histológico (p=0,0026) e índice de mitose, MI (p=0,0001). Alto índice de Ki-67 foi associado à morte. Expressão da p53, p16 e Bcl-2 não se correlacionou com as variáveis morfológicas ou clínicas. CONCLUSÕES: A avaliação imunoistoquímica de Ki-67 deve ser incluída na avaliação pré-operatória de biópsias ou peças cirúrgicas de GIST como uma ferramenta prognóstica para o estadiamento clínico, e todas as outras proteínas estudadas (Bcl-2, p53 e p16) não desempenharam um papel no processo metabólico ou carcinogênico em GIST, mantendo-se sem valor prognóstico.