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1.
Clin Cancer Res ; 26(20): 5400-5410, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32737030

RESUMO

PURPOSE: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a "one-size-fits-all" approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas-inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. EXPERIMENTAL DESIGN: IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk POLE mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. RESULTS: A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes (P < 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. CONCLUSIONS: EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype-specific management recommendations for patients with ENOC; for example, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials.

2.
Acta Obstet Gynecol Scand ; 99(7): 925-932, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31955408

RESUMO

INTRODUCTION: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. MATERIAL AND METHODS: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications. RESULTS: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss. CONCLUSIONS: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss.


Assuntos
Histerectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/cirurgia , Adulto , Feminino , Humanos , Excisão de Linfonodo , Países Baixos/epidemiologia , Estudos Prospectivos , Sistema de Registros
3.
Acta Obstet Gynecol Scand ; 99(2): 213-221, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31538662

RESUMO

INTRODUCTION: The likelihood of survival after cancer treatment among young women with cancer has increased considerably, quality of life after treatment has drawn more attention. However, in young fertile women, fertility preservation is an important issue with regard to quality of life. One of the options of fertility preservation is ovarian tissue cryopreservation. The purpose of this follow-up study is to present our clinical experiences and evaluate the long-term follow up of ovarian cryopreservation to improve future patient selection. MATERIAL AND METHODS: From July 2002 to December 2015 at the Leiden University Hospital, the Netherlands, 69 young women underwent ovarian tissue cryopreservation when they were at risk of iatrogenic premature ovarian insufficiency. Follow-up data with regard to ovarian function were obtained until October 2018, from medical records and questionnaires. RESULTS: Of the 69 women in whom ovarian tissue cryopreservation was performed, 12 died (15.9%), 57 were approached to participate, of which 6 were lost to follow up. The indications for ovarian tissue cryopreservation were malignant (81.1%) and benign (18.9%) diseases in which gonadotoxic treatment was scheduled. In total, twenty women (39.2%) are known to have premature ovarian insufficiency due to gonadotoxic treatment. Fifteen women conceived spontaneously, and delivered 25 babies. In this cohort, the usage rate of autotransplantation is 8.7% (7/69). In total, nine autotransplantations of cryopreserved ovarian tissue were performed in seven patients (of which 1 ovarian tissue cryopreservation was performed in another hospital) after which 6 babies were born to four women, giving a live-birth rate of 57%. CONCLUSIONS: Ovarian tissue cryopreservation followed by autotransplantation is an effective method to restore fertility (live-birth rate of 57%). The usage rate of 8.7% (6/69) indicates that more knowledge about the risk of premature ovarian insufficiency after gonadotoxic treatment is needed to be able to offer ovarian tissue cryopreservation more selectively.


Assuntos
Antineoplásicos/efeitos adversos , Coeficiente de Natalidade , Criopreservação/métodos , Preservação da Fertilidade/métodos , Ovário/transplante , Adolescente , Adulto , Criança , Feminino , Humanos , Países Baixos , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/cirurgia , Qualidade de Vida , Transplante Autólogo
4.
Cancer Immunol Immunother ; 68(11): 1759-1767, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31616965

RESUMO

Resistance to chemotherapy is widely recognized as one of the major factors limiting therapeutic efficacy and influences clinical outcomes in patients with cancer. Many studies on various tumor types have focused on combining standard-of-care chemotherapy with immunotherapy. However, for cervical cancer, the role of neoadjuvant chemotherapy (NACT) on the local immune microenvironment is largely unexplored. We performed a pilot study on 13 primary cervical tumor samples, before and after NACT, to phenotype and enumerate tumor-infiltrating T-cell subpopulations using multiplex immunohistochemistry (CD3, CD8, FoxP3, Ki67, and Tbet) and automated co-expression analysis software. A significant decrease in proliferating (Ki67+) CD3+CD8- T cells and FoxP3+(CD3+CD8-) regulatory T cells was observed in the tumor stroma after cisplatin and paclitaxel treatment, with increased rates of cytotoxic CD8+ T cells, including activated and CD8+Tbet+ T cells. No effect was observed on the number of tumor-infiltrating T cells in the cervical tumor microenvironment after treatment with cisplatin only. Therefore, we conclude that patients treated with cisplatin and paclitaxel had more tumor-infiltrating T-cell modulation than patients treated with cisplatin monotherapy. These findings enhance our understanding of the immune-modulating effect of chemotherapy and warrant future combination of the standard-of-care therapy with immunotherapy to improve clinical outcome in patients with cervical cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante/métodos , Linfócitos T Reguladores/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Adulto , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Adulto Jovem
5.
Clin Cancer Res ; 25(24): 7517-7526, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31492746

RESUMO

PURPOSE: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. EXPERIMENTAL DESIGN: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic." RESULTS: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). CONCLUSIONS: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Adulto , Idoso , Estudos de Coortes , Neoplasias do Endométrio/classificação , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores
6.
Eur J Surg Oncol ; 45(8): 1328-1340, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30857878

RESUMO

OBJECTIVE: To investigate the ovarian survival (OS) after ovarian transposition (OT) and pelvic radiation. DESIGN: Systematic review. Electronic databases were searched to identify studies on OT prior to external beam radiation therapy (EBRT, to the pelvic). Primary outcome was the ovarian function after radiotherapy and ovarian transposition. Secondary outcomes were complication-rate. Only studies in English, German or French were included. SETTING: Not applicable. PATIENTS: Fertile women undergoing ovarian transposition prior to pelvic radiation therapy. INTERVENTIONS: We included all studies, containing >5 patients, treated with OT prior to radiation therapy. MAIN OUTCOME MEASURE: Ovarian function. RESULTS: Our search yielded a total of 1130 studies of which 38 were eligible with a total of 765 patients. All studies were cohort studies or case-series. Heterogeneity among studies could not be rejected hence meta-analysis could not be performed. OS after OT and EBRT ranged from 20% to 100%. The median follow-up ranged from 7 to 102 months. OS was higher after OT and brachytherapy (OS 63.6-100%) when compared to OT and EBRT (20-100%) and OT concomitant chemoradiotherapy (0-69.2%). Only 22 studies (with 112 patients) reported on complications: among these studies the complication-rate was 0%-28.6%. CONCLUSION: From our systematic review of literature we conclude that the preservation of ovarian function after OT prior to EBRT is successful in 20-100% of patients. Most favorable outcome with regard to preservation of ovarian function is seen in patients after OT and BT, followed by OT and EBRT and OT and RT combined with chemotherapy.


Assuntos
Braquiterapia/efeitos adversos , Ovário/efeitos da radiação , Neoplasias Pélvicas/radioterapia , Lesões por Radiação/prevenção & controle , Idoso , Braquiterapia/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Testes de Função Ovariana/métodos , Ovário/patologia , Ovário/cirurgia , Neoplasias Pélvicas/patologia , Dosagem Radioterapêutica , Recuperação de Função Fisiológica , Medição de Risco
7.
Arch Gynecol Obstet ; 298(5): 1001-1007, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30218184

RESUMO

PURPOSE: To evaluate the effectiveness of ovarian transposition (OT) prior to radiation therapy (RT) and to evaluate the effect of age on ovarian survival (OS) after OT. METHODS: We performed a retrospective control study, with women (aged < 45 years) who underwent OT prior to pelvic radiation, versus women diagnosed with cervical cancer and treated with hysterectomy/trachelectomy and radiation therapy. All women were treated between 1989 and 2010. The 5 years OS rate was calculated, with a sub-analysis for age (25-30; 31-35 and 36-40 years). Ovarian failure was defined as climacteric complaints (with or without starting hormone replacement therapy) and/or laboratory measurements (FSH > 40 IU/L and/or estradiol < 100 pmol/L), or bilateral salpingo oophorectomy. Women were censored at recurrence. RESULTS: Twenty-seven women after OT and 29 controls were included. The radiation dose was 44.8 Gy (25.0-63.0 Gy) and 46.3 Gy (45.0-50.0 Gy), respectively. The 5-year ovarian survival rate was 60.3% versus controls 0% (p < 0.001 95% CI 3.48-11.50). Despite the decrease in ovarian survival after OT with increasing age, in all age groups (25-30, 30-35 and 35-40) ovarian survival after OT was significantly better compared to women without OT (p = 0.001; p = 0.004 and p = 0.000, respectively). Neither intra-vaginal radiation therapy of concomitant chemotherapy in addition to pelvic radiation significantly altered ovarian survival. CONCLUSIONS: Our data shows that ovarian transposition prior to pelvic radiation is effective in women until the age of 35 years and needs to be discussed in patients aged 36-40 years.


Assuntos
Procedimentos Cirúrgicos em Ginecologia/métodos , Ovário/efeitos da radiação , Insuficiência Ovariana Primária/prevenção & controle , Qualidade de Vida , Lesões por Radiação/prevenção & controle , Neoplasias do Colo do Útero/radioterapia , Adulto , Fatores Etários , Carcinoma de Células Escamosas/radioterapia , Estudos de Casos e Controles , Feminino , Preservação da Fertilidade/métodos , Humanos , Histerectomia , Recém-Nascido , Menopausa , Insuficiência Ovariana Primária/etiologia , Estudos Retrospectivos , Taxa de Sobrevida , Traquelectomia , Neoplasias do Colo do Útero/cirurgia
8.
Int J Gynecol Cancer ; 28(4): 757-763, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29595758

RESUMO

OBJECTIVE: This study aimed to describe the pattern of recurrence and survival related to prognostic variables, including type of surgery as a clinical variable, in patients surgically treated for early cervix cancer. METHODS: Records of 2124 patients who underwent a radical hysterectomy for International Federation of Gynaecology and Obstetrics stage I/IIA cervical cancer between 1982 and 2011 were reviewed. Clinical-pathologic prognostic variables, also including extent of parametrectomy, were identified and used in a multivariable Cox proportional hazard model to explore associations between disease-free survival (DFS) and prognostic variables. RESULTS: The 5-year DFS for the total group was 86%. Large tumor diameter, nonsquamous histology, lymph node metastases, parametrial involvement, lymph vascular space invasion, deep stromal invasion, and less radical surgery were independent poor prognostic variables for survival. Disease-free survival was independently associated with the type of radical hysterectomy with pelvic lymphadenectomy in favor of more radical parametrectomy (hazard ratio, 2.0; 95% confidence interval, 1.6-2.5). This difference was not found in tumors with a diameter of at least 20 mm. CONCLUSIONS: This study confirms that variables such as large tumor diameter, nonsquamous histology, lymph vascular space invasion, deep stromal invasion, positive lymph nodes, and parametrial infiltration are poor prognostic variables in early cervix cancer treated by surgery. The extent of parametrectomy had no influence on survival in tumors of 20 mm or less. For larger tumors, a more radical hysterectomy might be associated with better DFS. Taking into account the possible bias in this study as a result of its retrospective design, ideally a prospective cohort study with clear definition of radicality is necessary to answer this important clinical question.


Assuntos
Adenocarcinoma/cirurgia , Carcinoma de Células Escamosas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias do Colo do Útero/cirurgia , Adenocarcinoma/mortalidade , Adulto , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos , Neoplasias do Colo do Útero/mortalidade
9.
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.

10.
Oncotarget ; 8(50): 87568-87581, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29152102

RESUMO

Background: L1 cell adhesion molecule (L1CAM) has been shown to be a prognostic marker in various cancer types, and has been suggested to play a role in epithelial mesenchymal transition (EMT). Here, we determined the prognostic significance of L1CAM in cervical cancer and its association with vimentin expression on tumor cells, indicative of EMT. Methods: Formalin-fixed, paraffin-embedded primary tumor samples from 372 cervical cancer patients were collected for immunohistochemical analysis of L1CAM expression. In 109 FFPE specimens, the percentage of vimentin expressing tumor cells was determined by flow cytometry. Results: Positive L1CAM expression (≥10% of tumor cells) was associated with disease-free survival, validated using RNAseq TCGA data. L1CAM expression was independently associated with locoregional recurrence-free survival (hazard ratio 2.62, 95% CI 1.33 - 5.17, P = 0.006), and strongly associated with percentage of vimentin expressing tumor cells (P = 0.003). Expression of both L1CAM and vimentin indicated a subgroup with the highest risk of recurrence (hazard ratio 3.15, 95% CI 1.25 - 7.92, P = 0.015). Conclusion: L1CAM might be a promising new prognostic marker for locoregional recurrences in cervical cancer, and its association with vimentin expression suggests that L1CAM might affect tumor aggressiveness, possibly through EMT.

11.
Int J Gynecol Cancer ; 27(2): 350-356, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27984376

RESUMO

OBJECTIVE: To compare long-term morbidity and quality of life after primary surgery or primary radiotherapy for stage IB/II cervical cancer. METHODS: A cross-sectional study was performed. Patients treated for stage IB/II cervical cancer between 2000 and 2010 were approached to participate. Primary treatment consisted of radical hysterectomy with pelvic lymphadenectomy (RHL), for selected cases followed by adjuvant (chemo-)radiotherapy, or primary (chemo)radiotherapy (PRT). European Organization for Research and Treatment of Cancer-C30 and European Organization for Research and Treatment of Cancer-CX24 questionnaires were administered. A multivariable analysis was performed to identify factors associated with morbidity/quality of life. In a subgroup analysis, we compared patients with RHL + adjuvant radiotherapy with those after PRT. RESULTS: Three hundred twenty-three cervical cancer survivors were included (263 RHL/60 PRT). In the PRT group, International Federation of Gynecology and Obstetrics stage was higher and women were older. In the RHL group, more women had a partner. Women treated with PRT reported lower physical (ß, -6.01) and social functioning (ß, -15.2), more financial problems (ß, 10.9), diarrhea (ß, 9.98), symptom experience (ß, 6.13), sexual worry (ß, 11.3), and worse sexual/vaginal functioning (ß, 11.4). Women treated with RHL reported significantly more lymphedema (ß, -16.1). No differences in global health were found. In the subgroup analysis, women after PRT (n = 60) reported poorer social functioning, less sexual enjoyment, and higher symptoms experience than women after RHL and adjuvant radiotherapy (n = 60). The latter reported more lymphedema. CONCLUSIONS: Although global health scores are not significantly different, women after PRT report more physical, social, and sexual symptoms. These results can be well used by physicians to inform their patients about treatment-related morbidity.


Assuntos
Sobreviventes de Câncer , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Histerectomia , Excisão de Linfonodo , Pessoa de Meia-Idade , Morbidade , Estadiamento de Neoplasias , Qualidade de Vida , Autorrelato , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/fisiopatologia
12.
Int J Gynecol Cancer ; 26(8): 1538-43, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27465892

RESUMO

OBJECTIVE: This study aimed to compare urinary and bowel symptoms and quality of life (QoL) among women treated with a Wertheim-Meigs (WM, type III) or Wertheim-Okabayashi (WO, type IV) radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. METHODS: In this cross-sectional observational study, patients treated with a WO or a (nerve sparing) WM radical hysterectomy (with or without adjuvant radiotherapy) between January 2000 and December 2010 in the Center for Gynaecological Oncology Amsterdam or Leiden University Medical Center were included. To assess QoL, urinary and bowel symptoms we used the EORTC QLQ-C30, EORTC QLQ-CX24, and Leiden Questionnaire. We performed a multivariate analysis to identify factors associated with urinary symptoms. RESULTS: Two hundred sixty-eight women were included (152 WO and 116 WM). Quality of life was not significantly different in patients treated by WO or WM. Urinary symptoms were more often reported by patients in the WO group compared to the WM group: "feeling of urine retention" (53% vs 32%), "feeling less/no urge to void" (59% vs 14%), and "timed voiding" (49% vs 10%). With regard to bowel symptoms, there was no difference between both. Multivariate analysis showed that surgical technique was an independent factor for differences in urinary symptoms. CONCLUSIONS: Patients undergoing more radical surgery for early-stage cervical cancer report significantly more urinary dysfunction, whereas bowel function and health-related QoL are not decreased.


Assuntos
Diafragma da Pelve/fisiopatologia , Neoplasias do Colo do Útero/fisiopatologia , Neoplasias do Colo do Útero/cirurgia , Estudos Transversais , Feminino , Humanos , Histerectomia/efeitos adversos , Histerectomia/métodos , Intestinos/fisiopatologia , Excisão de Linfonodo/efeitos adversos , Excisão de Linfonodo/métodos , Pessoa de Meia-Idade , Qualidade de Vida , Bexiga Urinária/fisiopatologia , Neoplasias do Colo do Útero/patologia
13.
Oncotarget ; 6(36): 38681-94, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26299617

RESUMO

Cervical cancer is typically well infiltrated by immune cells. Because of the intricate relationship between cancer cells and immune cells, we aimed to identify both cancer cell and immune cell expressed biomarkers. Using a novel approach, we isolated RNA from flow-sorted viable EpCAM+ tumor epithelial cells and CD45+ tumor-infiltrating immune cells obtained from squamous cell cervical cancer samples (n = 24). Total RNA was sequenced and differential gene expression analysis of the CD45+ immune cell fractions identified TCL1A as a novel marker for predicting improved survival (p = 0.007). This finding was validated using qRT-PCR (p = 0.005) and partially validated using immunohistochemistry (p = 0.083). Importantly, TCL1A was found to be expressed in a subpopulation of B cells (CD3-/CD19+/CD10+/CD34-) using multicolor immunofluorescence. A high TCL1A/CD20 (B cell) ratio, determined in total tumor samples from a separate patient cohort using qRT-PCR (n = 52), was also correlated with improved survival (p = 0.027). This is the first study demonstrating the prognostic value of separating tumor epithelial cells from tumor-infiltrating immune cells and determining their RNA expression profile for identifying putative cancer biomarkers. Our results suggest that intratumoral TCL1A+ B cells are important for controlling cervical cancer development.


Assuntos
Linfócitos B/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Microambiente Tumoral , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
14.
PLoS One ; 10(6): e0129119, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26066796

RESUMO

Galectins are proteins that bind ß-galactoside sugars and provide a new type of potential biomarkers and therapeutic targets in cancer. Galectin-1, -3 and -9 have become the focus of different research groups, but their expression and function in cervical cancer is still unclear. The aim of this study was to determine the phenotype of galectin-1, -3 and -9 expressing cells and the association with clinico-pathological parameters in cervical cancer. Galectin expression was scored in tumor cells, tumor epithelium infiltrating immune cells and stromal cells in squamous cervical cancer (n = 160). Correlations with clinico-pathological parameters and survival were studied according to the REMARK recommendations. We additionally investigated whether the galectins were expressed by tumor cells, fibroblasts, macrophages and T cells. Galectin-1 and -9 were both expressed by tumor cells in 11% of samples, while 84% expressed galectin-3. Strong galectin-1 expression by tumor cells was an independent predictor for poor survival (hazard ratio: 8.02, p = 0.001) and correlated with increased tumor invasion (p = 0.032) and receiving post-operative radiotherapy (p = 0.020). Weak and positive tumor cell galectin-3 expression were correlated with increased and decreased tumor invasion, respectively (p = 0.012). Tumor cell expression of galectin-9 showed a trend toward improved survival (p = 0.087). The predominant immune cell type expressing galectin-1, -3 and -9 were CD163+ macrophages. Galectin-1 and -3 were expressed by a minor population of T cells. Galectin-1 was mainly expressed by fibroblasts in the tumor stroma. To conclude, while tumor cell expression of galectin-9 seemed to represent a beneficial response, galectin-1 expression might be used as a marker for a more aggressive anti-cancer treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Galectinas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Fibroblastos/metabolismo , Galectinas/genética , Humanos , Macrófagos/metabolismo , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
15.
Mol Cancer ; 14: 71, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25889974

RESUMO

BACKGROUND: The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma. METHODS: The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level. RESULTS: We identified four immune response clusters: 'T cells' (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), 'Macrophages' (CD4/CD14/CD163), 'Th2' (IL4/IL5/IL13/IL12) and 'Inflammation' (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: 'Angiogenesis' (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and 'Vessel maturation' (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The 'T cells' module was correlated with all modules except for 'Inflammation', while 'Inflammation' was most significantly correlated with 'Angiogenesis' (p < 0.001). High expression of the 'T cells' cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010). CONCLUSIONS: 'Inflammation' marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.


Assuntos
Carcinoma de Células Escamosas/imunologia , Expressão Gênica/imunologia , Neovascularização Patológica/imunologia , Neoplasias do Colo do Útero/imunologia , Adulto , Idoso , Feminino , Humanos , Inflamação/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Adulto Jovem
16.
Cancer Immunol Immunother ; 64(6): 745-53, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25795131

RESUMO

Cervical adenocarcinoma comprises approximately 15 % of cervical cancer cases. This histological subtype has different characteristics than cervical squamous cell carcinoma, which may influence disease progression. To study whether the infiltration of T cell subpopulations was correlated with cervical adenocarcinoma patient survival, similar to squamous cell carcinoma, the tumor-infiltrating T cells, Tregs, Th17 cells and IL-17(+) cell frequencies were analyzed in a cohort of cervical adenocarcinoma patients (n = 67). Intraepithelial, stromal and total cell frequencies were scored using triple immunofluorescence. The majority of Tregs were present in the tumor stroma, while other T cells and IL-17(+) cells infiltrated the tumor epithelium three times more frequently. A high total number of Tregs were significantly correlated with improved disease-specific and disease-free survival (p = 0.010, p = 0.007). Within the tumor epithelium, a high T cell frequency was significantly correlated with improved disease-free survival (p = 0.034). In particular, a low number of both Tregs and IL-17(+) cells were correlated with poor disease-specific survival (p = 0.007). A low number of Tregs combined with Th17 cells present were also correlated with poor survival (p = 0.018). An increased number of IL-17(+) cells were significantly correlated with the absence of vaso-invasion (p = 0.001), smaller tumor size (p = 0.030) and less infiltration depth (p = 0.021). These results suggest that Tregs and IL-17(+) cells represent a beneficial immune response, whereas Th17 cells might represent a poor response in cervical adenocarcinoma. This contrasts with the correlations described in squamous cell carcinoma, suggesting that the local immune response in cervical adenocarcinoma contributes differently to tumor growth than in squamous cell carcinoma.


Assuntos
Adenocarcinoma/imunologia , Interleucina-17/metabolismo , Neoplasias do Colo do Útero/imunologia , Adenocarcinoma/patologia , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Inclusão em Parafina , Prognóstico , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fixação de Tecidos , Microambiente Tumoral , Neoplasias do Colo do Útero/patologia
17.
Gynecol Oncol ; 127(1): 126-30, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22796548

RESUMO

OBJECTIVE: Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone. METHODS: Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 µM ICG:HSA or 500 µM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation. RESULTS: SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P=.72) or average number of detected SLNs (2.9 vs 2.7, P=.84) was found between the ICG:HSA group and the ICG alone group, respectively. CONCLUSIONS: In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.


Assuntos
Verde de Indocianina , Linfonodos/patologia , Microscopia de Fluorescência/métodos , Biópsia de Linfonodo Sentinela/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Corantes/química , Diagnóstico por Imagem/métodos , Método Duplo-Cego , Feminino , Corantes Fluorescentes/química , Humanos , Verde de Indocianina/química , Raios Infravermelhos , Cuidados Intraoperatórios/métodos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Albumina Sérica/química , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/cirurgia
18.
Int J Gynecol Cancer ; 20(11 Suppl 2): S39-41, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20975361

RESUMO

Radical hysterectomy with pelvic lymphadenectomy is considered to be the cornerstone in the treatment of early-stage cervical cancer. Although survival in early-stage cervical cancer is up to 95%, long-term morbidity with regard to bladder, bowel, and sexual function is considerable. Damage to the pelvic autonomic nerves may be the cause of these long-term complications following radical hysterectomy. Some authors have presented surgical techniques to preserve the autonomic nerves (ie, the hypogastric nerves and the splanchnic nerves) without compromising radicality. Safety, efficacy, and the surgical techniques of nerve-sparing radical hysterectomy are presented, and data confirm that whenever the decision is made to perform a radical hysterectomy, nerve-sparing techniques should be considered.


Assuntos
Plexo Hipogástrico , Histerectomia/métodos , Complicações Pós-Operatórias/prevenção & controle , Nervos Esplâncnicos , Neoplasias do Colo do Útero/cirurgia , Feminino , Humanos , Plexo Hipogástrico/lesões , Excisão de Linfonodo , Estadiamento de Neoplasias , Pelve/inervação , Pelve/cirurgia , Nervos Esplâncnicos/lesões , Neoplasias do Colo do Útero/patologia
19.
Int J Gynecol Cancer ; 20(7): 1160-5, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21495218

RESUMO

OBJECTIVE: To evaluate the diagnostic accuracy of power Doppler area (PDA) in the detection of endometrial cancer in women with postmenopausal bleeding. DESIGN: Prospective diagnostic study. SETTING: University hospital. POPULATION: Seventy-four consecutive women presenting with postmenopausal bleeding and a total endometrial thickness of more than 4 mm. METHODS: The PDA was measured by pelvic ultrasound. Endometrial cancer and hyperplasia with complex atypia were considered abnormal. MAIN OUTCOME MEASURES: A receiver operating characteristic curve was constructed and area under curve (AUC) calculated as well as positive and negative likelihood ratios (LR+ and LR-). RESULTS: Eighteen women (24%) had abnormal results of their histological specimen. The AUC of the PDA was 0.88 (95% confidence interval [CI], 0.80-0.98). The LR+ and LR- of the PDA were, respectively, 14.5 (95% CI, 4.69-44.9) and 0.23 (95% CI, 0.09-0.55). In women with total endometrial thickness of 4 to 10 mm, the AUC, LR+, and LR- were, respectively, 0.91 (95% CI, 0.78-1.00), 23.9 (95% CI, 3.29-175.0), and 0.34 (95% CI, 0.13-0.86). CONCLUSIONS: The PDA is an effective measure in the diagnosis and exclusion of endometrial cancer.


Assuntos
Hiperplasia Endometrial/diagnóstico por imagem , Neoplasias do Endométrio/diagnóstico por imagem , Endométrio/diagnóstico por imagem , Ultrassonografia Doppler , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Pós-Menopausa , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Taxa de Sobrevida
20.
J Minim Invasive Gynecol ; 16(1): 47-51, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18990612

RESUMO

STUDY OBJECTIVE: The purpose of this study was to estimate the influence of alternatives to hysterectomy for abnormal uterine bleeding (AUB) on hysterectomy rates. DESIGN: Retrospective cohort study. Canadian Task Force II-2. SETTING: University hospital. PATIENTS: Premenopausal patients with AUB. INTERVENTIONS: Medical records of all premenopausal patients treated for AUB in our university clinic between January 1, 1995, and December 31, 2004, were reviewed. Patients were identified based on (specific) diagnostic and therapy codes used in the registry system of the hospital. The total number of placements of levonorgestrel-releasing intrauterine device (LNG-IUD), hysteroscopic surgery, and hysterectomies performed/year was estimated. In addition, the course of treatment of each patient was assessed. MEASUREMENTS AND MAIN RESULTS: A total of 640 patients received surgery and 246 LNG-IUDs were placed. The proportion of endometrial ablations decreased significantly over time (p <.001), whereas hysteroscopic polyp or myoma removal (p =.030) and insertion of LNG-IUD (p <.001) both increased. The proportion of patients receiving hysterectomy for AUB as their first therapy decreased significantly (p =.005) from 40.6% to 31.4%, although the total number of patients receiving hysterectomy remained similar (p =.449). The 5-year intervention-free percentage for LNG-IUD was 70.6% (SD = 3.3%), for hysteroscopic polyp or myoma removal 75.5% (SD = 3.3%), and for endometrial ablation 78.0% (SD = 4.3%; p =.067). CONCLUSION: Despite the introduction of alternative therapies, the total hysterectomy rate in the management of AUB did not decrease in our clinic.


Assuntos
Histerectomia/estatística & dados numéricos , Histeroscopia/estatística & dados numéricos , Dispositivos Intrauterinos Medicados/estatística & dados numéricos , Levanogestrel/administração & dosagem , Metrorragia/tratamento farmacológico , Adulto , Estudos de Coortes , Feminino , Humanos , Histerectomia/tendências , Histeroscopia/tendências , Dispositivos Intrauterinos Medicados/tendências , Metrorragia/cirurgia , Pessoa de Meia-Idade , Países Baixos , Estudos Retrospectivos
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