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1.
JMIR Res Protoc ; 10(1): e24414, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33480862

RESUMO

BACKGROUND: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. OBJECTIVE: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. METHODS: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. RESULTS: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. CONCLUSIONS: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. TRIAL REGISTRATION: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24414.

2.
Gynecol Oncol ; 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33514483

RESUMO

OBJECTIVE: To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). MATERIALS & METHODS: This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis. RESULTS: The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy. CONCLUSION: Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.

3.
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).

4.
Cancers (Basel) ; 12(10)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003546

RESUMO

Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP) test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas (EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26% (10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted.

5.
Cancers (Basel) ; 12(6)2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545676

RESUMO

In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-a (FRa). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin avb6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FRa as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas avb6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FRa in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions.

6.
Nat Med ; 25(5): 838-849, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011202

RESUMO

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.


Assuntos
Organoides/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Genômica , Xenoenxertos , Humanos , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Medicina de Precisão
7.
J Mol Diagn ; 20(5): 600-611, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29936257

RESUMO

BRCA1/2 variant analysis in tumor tissue could streamline the referral of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer to genetic counselors and select patients who benefit most from targeted treatment. We investigated the sensitivity of BRCA1/2 variant analysis in formalin-fixed, paraffin-embedded tumor tissue using a combination of next-generation sequencing and copy number variant multiplex ligation-dependent probe amplification. After optimization using a training cohort of known BRCA1/2 mutation carriers, validation was performed in a prospective cohort in which screening of BRCA1/2 tumor DNA and leukocyte germline DNA was performed in parallel. BRCA1 promoter hypermethylation and pedigree analysis were also performed. In the training cohort, 45 of 46 germline BRCA1/2 variants were detected (sensitivity, 98%). In the prospective cohort (n = 62), all six germline variants were identified (sensitivity, 100%), together with five somatic BRCA1/2 variants and eight cases with BRCA1 promoter hypermethylation. In four BRCA1/2 variant-negative patients, surveillance or prophylactic management options were offered on the basis of positive family histories. We conclude that BRCA1/2 formalin-fixed, paraffin-embedded tumor tissue analysis reliably detects BRCA1/2 variants. When taking family history of BRCA1/2 variant-negative patients into account, tumor BRCA1/2 variant screening allows more efficient selection of epithelial ovarian cancer patients for genetic counseling and simultaneously selects patients who benefit most from targeted treatment.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Testes Genéticos , Variação Genética , Neoplasias Ovarianas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Metilação de DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética
8.
Oncotarget ; 9(1): 791-801, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416655

RESUMO

Objective: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38. Results: FRα expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRß, expressed by tumor-associated activated macrophages. Conclusions: This study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated. Methods: Immunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

9.
Health Expect ; 21(3): 659-667, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29281161

RESUMO

BACKGROUND: BRCA1/2 mutation carriers' choice between risk-reducing salpingo-oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. DESIGN: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. SETTING AND PARTICIPANTS: Pre-menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. MAIN OUTCOME MEASURES: IPDAS quality criteria, relevance, usability, clarity. RESULTS: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step-by-step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. DISCUSSION AND CONCLUSIONS: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk-reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making.


Assuntos
Neoplasias da Mama , Técnicas de Apoio para a Decisão , Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias Ovarianas , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Países Baixos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Ovariectomia/métodos , Comportamento de Redução do Risco , Salpingectomia/métodos
10.
Eur J Cancer ; 84: 159-167, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28818705

RESUMO

BACKGROUND: There has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing salpingo-oophorectomy (RRSO). METHODS: In this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data. RESULTS: Twenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = -0.40 and p < 0.001, ES = -0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT-users and the GS-group on any of the outcomes. CONCLUSION: Our results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO.


Assuntos
Menopausa Precoce/efeitos dos fármacos , Ovariectomia/efeitos adversos , Prevenção Primária/métodos , Salpingectomia/efeitos adversos , Comportamento Sexual/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/prevenção & controle , Adulto , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Risco , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Fisiológicas/fisiopatologia , Disfunções Sexuais Fisiológicas/psicologia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
11.
Gynecol Oncol ; 146(3): 449-456, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28645428

RESUMO

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.


Assuntos
Procedimentos Cirúrgicos de Citorredução/economia , Custos de Cuidados de Saúde , Laparoscopia/economia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Quimioterapia Adjuvante/economia , Análise Custo-Benefício , Técnicas de Diagnóstico por Cirurgia/economia , Feminino , Humanos , Futilidade Médica , Pessoa de Meia-Idade , Terapia Neoadjuvante/economia , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida
12.
J Clin Oncol ; 35(6): 613-621, 2017 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-28029317

RESUMO

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.


Assuntos
Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Idoso , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Laparoscopia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Resultado do Tratamento
13.
Br J Cancer ; 115(10): 1174-1178, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27755534

RESUMO

BACKGROUND: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. METHODS: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. RESULTS: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). CONCLUSIONS: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Mutação/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Prognóstico , Adulto Jovem
14.
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
15.
Mod Pathol ; 29(7): 753-63, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27056074

RESUMO

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.


Assuntos
Adenocarcinoma/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/metabolismo , Macrófagos/patologia , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adulto Jovem
16.
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
17.
Oncotarget ; 7(18): 26192-205, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27028855

RESUMO

BACKGROUND: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. RESULTS: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P=.014, disease specific survival 63.8% vs 80.0%, P=.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10-7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. METHODS: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (ß-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. CONCLUSION: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC's. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Recidiva Local de Neoplasia/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Vulvares/patologia , Idoso , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Taxa de Sobrevida , Neoplasias Vulvares/metabolismo
18.
Gynecol Oncol ; 140(3): 415-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797295

RESUMO

OBJECTIVE: Standard treatment of primary T1 squamous cell carcinoma (SCC) of the vulva <4cm consists of wide local excision (WLE) and sentinel lymph node (SLN) procedure of the groin(s). In case of a local recurrence WLE and inguino femoral lymphadenectomy (IFL) is generally recommended. In this study we assessed the feasibility of repeat SLN procedure in patients with recurrent vulvar SCC who were not able or willing to undergo IFL. METHODS: A retrospective study was performed in consecutive patients with recurrent vulvar SCC who underwent a repeat SLN procedure between 2006 and 2014. We present the clinical and pathological outcomes. The study conforms to the STROBE guidelines. RESULTS: A total number of 27 patients aged 35-87years at first diagnosis of SCC of the vulva were identified. Median follow-up after 2nd surgery was 27.4 (range 2-96) months. In 78% of patients and in 84% of the groins the repeat SLN procedure was successful. No structured questionnaires were used to describe details on the repeat SLN procedures but in general the gynecologic oncologists experienced repeat SLN procedures more challenging compared to primary procedures. There were no groin recurrences documented. CONCLUSIONS: Our findings suggest that it is feasible to perform a repeat SLN procedure in recurrent vulvar SCC, but the procedure appears technically more challenging compared to primary setting, resulting in a lower SLN identification rate.


Assuntos
Carcinoma de Células Escamosas/secundário , Recidiva Local de Neoplasia/patologia , Biópsia de Linfonodo Sentinela , Neoplasias Vulvares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Virilha , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Reoperação , Estudos Retrospectivos , Neoplasias Vulvares/cirurgia
19.
Int J Gynecol Cancer ; 26(1): 43-51, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26588231

RESUMO

OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. CONCLUSIONS: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.


Assuntos
Algoritmos , Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Guias de Prática Clínica como Assunto/normas , Idoso , Carcinoma Epitelial do Ovário , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Prognóstico , Sociedades Científicas
20.
Gynecol Oncol ; 139(3): 458-64, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26432039

RESUMO

OBJECTIVES: Treatment of groin metastasis in vulvar squamous cell carcinoma (VSCC) patients consists of surgery, often combined with (chemo)radiotherapy, and is associated with significant morbidity. Our aim was to compare the risk of groin recurrence and morbidity in patients with lymph node positive VSCC after standard full inguinofemoral lymphadenectomy (IFL) versus less radical debulking of clinically involved lymph nodes or removal of sentinel nodes only followed by radiotherapy. METHODS: A retrospective cohort study of 68 patients with primary VSCC and proven lymph node metastasis to the groin(s) was conducted. Patients were divided into three subgroups by type of initial groin surgery (84 groins): sentinel node (SN), IFL, and debulking of clinically involved nodes. Most patients (82%) received adjuvant radiotherapy. Overall survival was analyzed using time dependent cox regression. Analysis of morbidity and groin recurrence-free time was performed per groin with the generalized estimating equation model and Kaplan Meier method. RESULTS: There was no significant difference in the risk of developing a groin recurrence (SN 25%, debulking 16%, IFL 13%, p=0.495). Despite the fact that more patients received radiotherapy after debulking (90% vs 67%), the complication rate was significantly lower (p=0.003) compared to IFL, especially regarding lymphocysts and lymphedema (p=0.032 and p=0.002 respectively). CONCLUSIONS: The risk of groin recurrence was similar in all treatment groups. Debulking of clinically involved lymph nodes was related to a significant lower risk of complications compared to IFL. These findings support that the preferred treatment of patients with clinically involved lymph nodes is debulking followed by radiotherapy.


Assuntos
Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Vulvares/patologia , Neoplasias Vulvares/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/radioterapia , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Feminino , Humanos , Canal Inguinal , Excisão de Linfonodo/efeitos adversos , Metástase Linfática , Pessoa de Meia-Idade , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias Vulvares/radioterapia
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