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1.
Gynecol Oncol ; 159(3): 672-680, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33041071

RESUMO

OBJECTIVE: The aim of this study was to assess the superiority of ICG-99mTc-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using 99mTc-nanocolloid with blue dye. METHODS: In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-99mTc-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications. RESULTS: Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-99mTc-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041). CONCLUSIONS: Intraoperative visual detection of SLNs in patients with VSCC using ICG-99mTc-nanocolloid was superior compared to 99mTc-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register (Trial ID NL7443).

2.
Int J Gynecol Cancer ; 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630883

RESUMO

OBJECTIVE: To evaluate the efficacy and toxicity of primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer and to identify predictors of treatment failure and toxicity. METHODS: Retrospective analysis of 155 stage IB-IVA cervical cancer patients treated from 2008 to 2016 with chemoradiation and image-guided adaptive brachytherapy. Treatment consisted of external beam radiotherapy (45 - 48.6 Gy in 1.8 - 2 Gy fractions) with concurrent weekly cisplatin (40 mg/m2, 5 - 6 cycles) and image-guided adaptive brachytherapy (3-4 × 7 Gy high dose rate) using intracavitary or combined intracavitary-interstitial techniques according to GEC-ESTRO (Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology) recommendations. Incidences of all outcomes were calculated using Kaplan-Meier's methodology. Risk factors for treatment failure and toxicity were identified using Cox's proportional hazards model and the Kruskal-Wallis H-test respectively. RESULTS: Median follow-up was 57 months. Five-year local control was 90.4 %. Five-year para-aortic lymph node metastasis-free and distant metastasis-free survival were 85.3 % and 70.2 % respectively. Tumor size and lymph node metastasis were independent risk factors for treatment failure. Cumulative incidences of severe late bladder, rectal, bowel, and vaginal toxicity were 0.8%, 3.3%, 3.6%, and 1.4% respectively at 5 years of follow-up. Combined intracavitary-interstitial brachytherapy techniques were associated with less vaginal morbidity. CONCLUSIONS: Primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer is a highly effective local and loco-regional treatment. However, survival is compromised by the occurrence of distant metastasis. Patients with large tumors and nodal involvement at diagnosis are at increased risk and may benefit from intensified treatment. Severe late gastrointestinal and urogenital toxicity is limited and may be further reduced by increasing conformity, using combined intracavitary-interstitial techniques and lowering doses to organs at risk.

3.
Arch Gynecol Obstet ; 299(1): 159-165, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30498966

RESUMO

OBJECTIVE: To estimate the risk of uterine leiomyosarcoma in patients undergoing gynecological surgery and also to identify groups at risk for unrecognized uterine leiomyosarcoma. METHODS: A national cohort study was performed evaluating all uterine leiomyosarcoma (ULMS) diagnosed in The Netherlands between January 2000 and September 2015. Cases were identified and supplied by the nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA). Unexpected and expected ULMS were compared. Approval for this study was granted by the Medical Ethics Committee of all participating hospitals and by the review board of PALGA. RESULTS: 262 original cases were included. The overall incidence of ULMS in our study was 0.25% or 1:400 patients. The incidence of unexpected ULMS was 0.12% or 1:865 patients. Preoperatively, a malignancy was unexpected in 46% of the cases and expected in 54%. Abnormal uterine bleeding constituted most of the symptoms. 90% of women underwent abdominal hysterectomy and/or bilateral salpingo-oophorectomy. CONCLUSIONS: Leiomyosarcoma are rare. Women aged 40-50 years with abnormal uterine bleeding are most at risk for unexpected ULMS. In contrast, this risk is low in postmenopausal women. ULMS were highly uncommon in women aged under 40 years.


Assuntos
Leiomiossarcoma/epidemiologia , Neoplasias Uterinas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Histerectomia , Incidência , Laparoscopia , Leiomiossarcoma/cirurgia , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Neoplasias Pélvicas/cirurgia , Neoplasias Uterinas/cirurgia
4.
Clin Cancer Res ; 25(3): 1087-1097, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413523

RESUMO

PURPOSE: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics. EXPERIMENTAL DESIGN: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort. RESULTS: Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001). CONCLUSIONS: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.


Assuntos
Neoplasias do Endométrio/genética , Endométrio/metabolismo , Recombinação Homóloga/genética , Rad51 Recombinase/genética , Idoso , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Hibridização Genômica Comparativa , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Recombinação Homóloga/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Prospectivos , Rad51 Recombinase/metabolismo
5.
Gynecol Oncol ; 151(2): 196-201, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30262404

RESUMO

OBJECTIVE: Recently, the pattern of invasion in usual-type human papillomavirus-associated endocervical adenocarcinoma (AC) was put forward as a novel variable to select patients with favourable prognosis. Based on destructiveness of stromal invasion, three patterns were proposed: A - no destructive stromal invasion, B - focal destructive stromal invasion, and C - diffuse destructive stromal invasion. We aimed to independently validate the clinical significance of this classification-system in 82 AC patients, and explored associations between invasion pattern and somatic mutations. METHODS: All patients surgically treated for FIGO stage IB-IIA usual type AC (1990-2011, n = 82) were retrospectively reviewed and classified into pattern A, B or C. Additional immunohistochemical analyses were performed for p53, MSH6, and PMS2. Moreover, previously obtained data on somatic hotspot mutations in 13 relevant genes was integrated. RESULTS: Of 82 AC, 22% showed pattern A, 37% pattern B, and 41% pattern C. Significant differences were observed between invasion patterns and tumour size, depth of invasion (DOI), lymph-vascular invasion (LVI), and lymph-node metastasis. Significantly fewer mutations were present in tumours with pattern A morphology (p = 0.036). All pattern A patients survived (p = 0.002) without recurrent disease (p = 0.005). In multivariate regression analysis including tumour size, DOI, LVI, and lymph node metastasis, invasion pattern was a strong independent predictor for recurrence-free and disease-specific survival (HR 3.75, 95%CI 1.16-12.11, and HR 5.08, 95%CI 1.23-20.98, respectively). CONCLUSIONS: We have independently validated the clinical significance of invasion patterns for usual type endocervical AC. Pattern A predicts excellent survival, and a clinical trial should prove safety of a more conservative treatment for these patients.


Assuntos
Adenocarcinoma/mortalidade , Neoplasias do Colo do Útero/mortalidade , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
6.
Surg Endosc ; 32(10): 4357-4362, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29987561

RESUMO

BACKGROUND: To assess potential risks of new surgical procedures and devices before their introduction into daily practice, a prospective risk inventory (PRI) is a required step. This study assesses the applicability of the Health Failure Mode and Effects Analysis (HFMEA) as part of a PRI of new technology in minimally invasive gynecologic surgery. METHODS: A reference case was defined of a patient with presumed benign leiomyoma undergoing a laparoscopic hysterectomy or myomectomy including in-bag power morcellation; however, pathology defined a stage I uterine leiomyosarcoma. Using in-bag morcellation as a template, a HFMEA was performed. All steps of the in-bag morcellation technique were identified. Next, the possible hazards of these steps were explored and possible measures to control these hazards were discussed. RESULTS: Five main steps of the morcellation process were identified. For retrieval bags without openings to accommodate instruments inside the bag, 120 risks were identified. Of these risks, 67 should be eliminated. For containment bags with openings 131 risks were identified of which 68 should be eliminated. Of the 10 causes most at risk to cause spillage, two can be eliminated by using appropriate bag materials. Myomectomy appears to be more at risk for residual tissue spillage compared to total hysterectomy. CONCLUSION: The HFMEA has provided important new insights regarding potential weaknesses of the in-bag morcellation technique, particularly with respect to hazardous steps in the morcellation process as well as requirements that bags should meet. As such, this study has shown HFMEA to be a valuable method that identifies and quantifies potential hazards of new technology.


Assuntos
Histerectomia/métodos , Laparoscopia/métodos , Leiomiossarcoma/cirurgia , Morcelação/métodos , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Feminino , Análise do Modo e do Efeito de Falhas na Assistência à Saúde , Humanos , Estudos Prospectivos
7.
Histopathology ; 72(2): 248-258, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28795426

RESUMO

AIMS: POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE-mutant ECs. METHODS AND RESULTS: Fifty-one POLE-mutant endometrioid, 67 POLE-wild-type endometrioid and 15 POLE-wild-type serous ECs were included (total N = 133). An expert gynaecopathologist, blinded to molecular features, evaluated each case (two or more slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, and PMS2. POLE-mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoral lymphocytes and 59% showed tumour-infiltrating lymphocytes, as compared with 43% and 28% of POLE-wild-type endometrioid ECs, and 27% and 13% of their serous counterparts (P < 0.01, all comparisons). Of POLE-mutant ECs, 33% contained tumour giant cells; this proportion was significantly higher than that in POLE-wild-type endometrioid ECs (10%; P = 0.003), but not significantly different from that in serous ECs (53%). Serous-like features were as often (focally) present in POLE-mutant as in POLE-wild-type endometrioid ECs (6-24%, depending on the feature). The majority of POLE-mutant ECs showed wild-type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%). CONCLUSIONS: A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoral lymphocytes, MLH1, and p53 expression) can assist in prescreening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being detected from 7% to 33%. This facilitates the use of this important prognostic biomarker in routine pathology.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação
8.
Int J Gynecol Cancer ; 27(5): 1051-1057, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28498243

RESUMO

OBJECTIVE: Sexual problems among cervical cancer survivors may in part be caused by reduced vaginal blood flow due to damaged hypogastric nerves during radical hysterectomy with pelvic lymphadenectomy and/or by radiation-induced vaginal changes after pelvic radiotherapy. A nerve-sparing modification of radical hysterectomy (NSRH) may preserve vaginal blood flow. Vaginal blood flow during sexual arousal was compared between different treatment modalities. METHODS: We investigated premenopausal women treated for early-stage cervical cancer with radical hysterectomy (n = 29), NSRH (n = 28), NSRH with radiotherapy (n = 14), and controls (n = 31). Genital arousal and subjective sexual arousal in response to sexual stimuli were measured using vaginal photoplethysmography and a questionnaire. Results were compared by using a between-study (treatment groups) by within-study (stimulus) design. RESULTS: Participants were aged 29 to 51 years (mean, 42 years) and at 1 to 14 years (mean, 5 years) after treatment. Measured vaginal blood flow in women treated with NSRH was similar to controls. Women treated with radical hysterectomy had a significantly lower vaginal blood flow compared with controls overall and lower compared with the NSRH group during sexual stimulation. Women treated with radiotherapy had a vaginal blood flow intermediate between the other groups without significant differences. The erotic films were equally effective in enhancing subjective sexual arousal among treatment groups. CONCLUSIONS: Cervical cancer treatment with radical hysterectomy disrupts the vaginal blood flow response, and this may be prevented by conducting an NSRH. Treatment with radiotherapy did not significantly impact vaginal blood flow, but further investigation is needed with a larger sample.


Assuntos
Nível de Alerta/fisiologia , Sobreviventes de Câncer , Neoplasias do Colo do Útero/fisiopatologia , Vagina/irrigação sanguínea , Adulto , Feminino , Humanos , Histerectomia/métodos , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão/métodos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia
9.
Oncotarget ; 8(15): 25542-25551, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28424422

RESUMO

INTRODUCTION: Individual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC). As these molecular alterations are determined in a small tumour fraction, high intratumour heterogeneity may interfere with correct risk prediction. This study aimed to investigate to which extent intratumour heterogeneity exists for molecular markers and whether it affects the molecular risk assignment in EC. METHODS: Forty-nine ECs (three tumour blocks/case) were selected with alterations in POLE (n=10), CTNNB1 (n=8), p53 (n=10), mismatch repair (n=11), L1CAM (n=10), and ECs without any of these markers (n=9). Nine ECs carried more than one molecular marker. All 147 blocks were analysed for POLE exonuclease domain and CTNNB1 exon 3 mutations, and for p53, mismatch repair and L1CAM protein expression. All blocks were assigned to a favourable, intermediate or unfavourable risk group, based on a molecular risk assignment. RESULTS: Concordance between the three tumour blocks for POLE and CTNNB1 mutational status, and p53, mismatch repair and L1CAM protein expression was found in 100% (48/48), 95.9% (47/49), 93.9% (46/49), 98.0% (48/49), and 91.8% (45/49) of tumours, respectively. These discordances were found in a total of nine cases (18.4%). The intratumour heterogeneity impacted the risk assignment in five cases (10.2%). CONCLUSION: Intratumour heterogeneity of prognostic molecular markers in EC without morphologic heterogeneity is uncommon among three tumour fractions, affecting the molecular risk allocation in a limited number of cases. This low intratumour heterogeneity facilitates the implementation of the molecular risk assignment, advocating its use in clinical decision making.


Assuntos
Biomarcadores Tumorais , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Variação Genética , Idoso , Neoplasias do Endométrio/metabolismo , Éxons , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/genética
10.
Clin Cancer Res ; 22(12): 2929-38, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27306792

RESUMO

PURPOSE: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers. EXPERIMENTAL DESIGN: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging. RESULTS: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation. CONCLUSIONS: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929-38. ©2016 AACR.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Corantes Fluorescentes/farmacologia , Neoplasias Epiteliais e Glandulares/diagnóstico por imagem , Neoplasias Epiteliais e Glandulares/cirurgia , Imagem Óptica/métodos , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/cirurgia , Adolescente , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Receptor 1 de Folato/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Adulto Jovem
11.
Oncotarget ; 7(22): 32144-55, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27014973

RESUMO

INTRODUCTION: Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer. METHODS: Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics. RESULTS: Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification. CONCLUSIONS: FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Fluoresceína-5-Isotiocianato/administração & dosagem , Corantes Fluorescentes/administração & dosagem , Receptor 1 de Folato/análise , Ácido Fólico/análogos & derivados , Imagem Óptica/métodos , Neoplasias Ovarianas/química , Administração Intravenosa , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Reações Falso-Positivas , Estudos de Viabilidade , Feminino , Fluoresceína-5-Isotiocianato/efeitos adversos , Fluoresceína-5-Isotiocianato/farmacocinética , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Ácido Fólico/administração & dosagem , Ácido Fólico/efeitos adversos , Ácido Fólico/farmacocinética , Humanos , Cuidados Intraoperatórios , Medições Luminescentes , Pessoa de Meia-Idade , Países Baixos , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
12.
Int J Gynecol Cancer ; 26(3): 483-90, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26825822

RESUMO

OBJECTIVE: The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes. METHODS: We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor-positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up. RESULTS: There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment. CONCLUSIONS: We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Preservação da Fertilidade , Fosfatidilinositol 3-Quinases/metabolismo , Progesterona/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Estadiamento de Neoplasias , Progestinas/uso terapêutico , Prognóstico , Estudos Retrospectivos , Transdução de Sinais
13.
PLoS One ; 10(6): e0129766, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26110901

RESUMO

OBJECTIVE: In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting. METHODS: Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions. RESULTS: 6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99). CONCLUSIONS: This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16945066.


Assuntos
Metástase Neoplásica/diagnóstico , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Feminino , Corantes Fluorescentes , Humanos , Verde de Indocianina , Pessoa de Meia-Idade , Monitorização Intraoperatória , Imagem Óptica/métodos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Permeabilidade
14.
Psychooncology ; 24(4): 458-64, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25858440

RESUMO

OBJECTIVE: Many women treated for cervical cancer (CC) report sexual complaints and sexual distress. It is important to assess these women's and their partners' sexual healthcare needs. This study aims to (a) investigate the prevalence of psychosexual healthcare needs and help-seeking behaviour among CC survivors, (b) identify the association between psychosocial variables and help-seeking intentions among CC survivors and (c) assess survivors' and partners' preferences regarding psychosexual healthcare services. METHODS: A multicentre cross-sectional questionnaire study was conducted in a cohort of women with a history of CC (n=343, mean age=48.7), and their partners (n=154, mean age=50.8). Questions concerned professional healthcare needs, help-seeking behaviour, help-seeking intentions and preferences regarding sexual healthcare services. Furthermore, the questionnaire assessed social cognitive variables related to help-seeking intentions. Data were analysed with multivariate linear regression analyses with future help-seeking intention as an outcome variable. RESULTS: About 51% of the women reported a need for information and/or professional help, although only 35% of these women had initiated a conversation with a professional about sexuality. Women considering sexual functioning important, expecting relief from seeking help, perceiving social support to seek help and having positive beliefs about the quality of professional psychosexual support had higher help-seeking intentions. Women who were embarrassed to discuss sexual issues with a professional were less likely to seek help. Most participants would appreciate receiving information about sexuality and CC. CONCLUSIONS: Many CC survivors have psychosexual healthcare needs, although few seek professional help. Women and their partners should be facilitated in accessing sexual healthcare services.


Assuntos
Necessidades e Demandas de Serviços de Saúde , Disfunções Sexuais Psicogênicas/psicologia , Sexualidade/psicologia , Estresse Psicológico/psicologia , Sobreviventes/psicologia , Neoplasias do Colo do Útero/psicologia , Adulto , Estudos Transversais , Feminino , Humanos , Intenção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Aceitação pelo Paciente de Cuidados de Saúde , Saúde Reprodutiva , Comportamento Sexual , Disfunções Sexuais Psicogênicas/reabilitação , Parceiros Sexuais/psicologia , Apoio Social , Inquéritos e Questionários
15.
Clin Cancer Res ; 21(14): 3347-3355, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25878334

RESUMO

PURPOSE: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. EXPERIMENTAL DESIGN: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. RESULTS: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. CONCLUSIONS: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.


Assuntos
DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Mutação , Estudos de Coortes , Análise Mutacional de DNA , DNA Polimerase II/imunologia , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Ligação a Poli-ADP-Ribose , Reação em Cadeia da Polimerase
16.
Int J Gynecol Cancer ; 24(8): 1499-506, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25248115

RESUMO

OBJECTIVE: This study aimed to reach consensus among professional experts on patient information provision and support regarding sexual rehabilitation and vaginal dilator use after radiotherapy (RT) for gynecological cancers. METHODS: A 3-round online Delphi study was conducted among 10 radiation oncologists, 10 gynecologic oncologists, and 10 oncology nurses from 12 gynecological cancer centers providing RT for gynecological tumors. We assessed the desired content and provider of instructions and patient support regarding sexuality and vaginal dilator use. Responses were measured on a 7-point scale varying from "totally disagree" to "totally agree." Consensus was reached when 70% of participants' answers fell within 2 scale categories with an interquartile range less than or equal to 1. RESULTS: The panel agreed that information about sexual rehabilitation using vaginal dilators should be provided by radiation oncologists before treatment. Information should always be provided to sexually active cervical and vaginal cancer patients younger than 70 years. Tailored information was recommended for vulvar and endometrial cancer patients, patients older than 70 years, and sexually inactive patients. Preferably, specifically trained oncology nurses should give psychological and practical support. Participants recommended vaginal dilation to prevent vaginal adhesions, tightening, and shortening. The panel advised to start dilation around 4 weeks after treatment to perform dilation 2 to 3 times a week for 1 to 3 minutes and to continue dilation for 9 to 12 months. Plastic dilator sets were considered the most suitable type of dilator. CONCLUSIONS: Consensus was reached on patient information provision and support during sexual rehabilitation after RT for gynecological cancers. Results were used to develop a sexual rehabilitation intervention.


Assuntos
Técnica Delfos , Neoplasias dos Genitais Femininos/reabilitação , Neoplasias dos Genitais Femininos/radioterapia , Padrões de Prática Médica/estatística & dados numéricos , Comportamento Sexual/fisiologia , Vagina/patologia , Dilatação/instrumentação , Dilatação/métodos , Aconselhamento Diretivo/métodos , Aconselhamento Diretivo/estatística & dados numéricos , Feminino , Neoplasias dos Genitais Femininos/epidemiologia , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricos , Educação de Pacientes como Assunto , Pelve/efeitos da radiação , Recuperação de Função Fisiológica , Vagina/efeitos da radiação
17.
Int J Gynecol Cancer ; 23(9): 1717-25, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24172106

RESUMO

OBJECTIVE: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients. METHODS: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire. RESULTS: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina). CONCLUSIONS: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.


Assuntos
Intestinos/fisiologia , Autorrelato , Comportamento Sexual/fisiologia , Bexiga Urinária/fisiologia , Neoplasias do Colo do Útero/terapia , Adulto , Terapia Combinada/efeitos adversos , Terapia Combinada/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Morbidade , Complicações Pós-Operatórias/epidemiologia , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/estatística & dados numéricos , Inquéritos e Questionários , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/fisiopatologia
18.
Obstet Gynecol ; 119(4): 700-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22395145

RESUMO

OBJECTIVE: To estimate, after correction for patient factors, to what extent blood loss, operative time, and adverse events are decisive factors for the successful outcome of laparoscopic hysterectomy. A secondary objective was to estimate to what extent a successful outcome can be predicted from surgical experience or other measures of surgical skill. METHODS: A nationwide multivariate 1-year cohort analysis was conducted with gynecologists who perform laparoscopic hysterectomy. The primary outcomes were blood loss, operative time, and adverse events. The procedures were corrected for multiple covariates in a mixed-effects logistic regression model. Furthermore, all primary outcomes were related to experience and the influence of individual surgical skills factors. RESULTS: One thousand five hundred thirty-four laparoscopic hysterectomies were analyzed for 79 surgeons. The success of the surgical outcome was significantly influenced by uterus weight, body mass index, American Society of Anesthesiologists Physical Status Classification, previous abdominal surgeries, and the type of laparoscopic hysterectomy. Surgical experience also predicted the successful outcome of laparoscopic hysterectomy with respect to blood loss and adverse events (P=.048 and .036, respectively). A significant improvement in surgical outcomes tends to continue up to approximately 125 procedures. Independently from surgical experience, an individual surgical skills factor was identified as odds ratio 1.67 and 3.60 for blood loss and operative time, respectively. CONCLUSION: After adjusting for risk factors, it was shown that an increase in experience positively predicted a successful outcome in laparoscopic hysterectomy with respect to blood loss and adverse events. However, the independent surgical skills factor shows a large variation in proficiency between individuals. The fact that a surgeon has performed many laparoscopic hysterectomies does not necessarily guarantee good surgical outcome. LEVEL OF EVIDENCE: II.


Assuntos
Perda Sanguínea Cirúrgica/estatística & dados numéricos , Competência Clínica/estatística & dados numéricos , Histerectomia/estatística & dados numéricos , Laparoscopia/estatística & dados numéricos , Feminino , Previsões , Humanos , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Modelos Logísticos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
19.
J Minim Invasive Gynecol ; 18(5): 582-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21803663

RESUMO

STUDY OBJECTIVES: To compare preferences for laparoscopic hysterectomy (LH) over abdominal hysterectomy (AH) by gynecologists who perform LH (group 1), their colleagues (group 2), and gynecologists employed by a hospital that does not provide LH (group 3), and to estimate boundary values of patient characteristics that influence preference for mode of hysterectomy. Differences in referral tendencies between groups 2 and 3 are compared. DESIGN: Group comparison study (Canadian Task Force classification II-2). SETTING: Nationwide conjoint preference study in groups 1, 2, and 3. INTERVENTION: Web-based choice-based conjoint analysis questionnaire. MEASUREMENTS AND MAIN RESULTS: In general, group 1 preferred LH significantly more often (86.3%; 95% confidence interval [CI], 81.6-91.0) than did group 2 (70.9%; 95% CI, 63.4-78.4). Group 3 preferred LH significantly less frequently (50.3%; 95% CI, 35.7-64.9). Increases in body mass index, estimated uterus size, and number of previous abdominal surgeries caused a significant drop in shares of preferences in all groups. CONCLUSIONS: The presence of a gynecologist who performs LH positively influences the referral behavior of colleagues. The effect of an increased body mass index seems to be a restrictive parameter for choosing LH according to both referring gynecologists and those who perform LH. Level of experience does not influence preference of laparoscopists. The observed discrepancy between reported and simulated referral behavior in group 3 demonstrates that practical impediments significantly decrease referral tendencies, consequently hampering implementation of this minimally invasive approach.


Assuntos
Histerectomia/métodos , Laparoscopia , Padrões de Prática Médica , Adulto , Canadá , Feminino , Ginecologia , Pesquisas sobre Serviços de Saúde , Humanos
20.
Gynecol Surg ; 8(1): 65-70, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21461042

RESUMO

This study was conducted to assess whether women would prefer to undergo saline infusion sonography (SIS) or office hysteroscopy for the investigation of the uterine cavity. In a randomised controlled trial, 100 patients underwent SIS or office hysteroscopy for assessing patients' pain scores. After the investigation, 92 of them were asked to fill out an anonymous questionnaire addressing their preference regarding the method of evaluation and treatment of the uterine cavity. A control group, consisting of 50 women who never underwent SIS or office hysteroscopy, was also asked to complete an identical questionnaire. The questionnaire was completed by 113 women (83.7%). Twenty-four (21.2%) women would opt for SIS, whereas 52 (46.0%) would opt for office hysteroscopy, and 37 (32.7%) had no preference. If therapy would be necessary, 48.7% of the women would opt for an outpatient treatment, whereas 33.0% of the women would prefer treatment under general anaesthesia. Despite the fact that SIS is less painful, the majority of the women prefer office hysteroscopy. Additionally, therapy in an outpatient setting is preferred to a day case setting.

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