RESUMO
PURPOSE: This case report describes the use of a trachelectomy and adjuvant vaginal brachytherapy for pediatric clear cell adenocarcinoma as definitive fertility-sparing treatment. METHODS AND MATERIALS: A previously healthy 8-year-old female presented with abdominal cramping and heavy vaginal bleeding. Diagnostic imaging revealed a 3.5 cm circumscribed cervical mass, with subsequent biopsy revealing clear cell adenocarcinoma. Fertility preserving treatment was requested. RESULTS: The patient underwent a radical trachelectomy, with final pathology demonstrating a close radial margin. Due to close margin, adjuvant radiotherapy with a vaginal cylinder was delivered to a total dose of 18 Gray in three fractions prescribed to a depth of 5 mm from the vaginal surface using iridium-192. With 2 years of follow-up, the patient continues to do well with no evidence of recurrence or late toxicity from treatment. CONCLUSIONS: Pediatric clear cell adenocarcinoma of the cervix is a rare occurrence that lacks clinical trials to guide effective treatment. Adjuvant vaginal brachytherapy following trachelectomy in a pediatric patient with clear cell adenocarcinoma of the cervix is feasible and well-tolerated.
Assuntos
Adenocarcinoma de Células Claras , Braquiterapia , Traquelectomia , Neoplasias do Colo do Útero , Feminino , Criança , Humanos , Adenocarcinoma de Células Claras/radioterapia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma de Células Claras/patologia , Braquiterapia/métodos , Traquelectomia/métodos , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Colo do Útero/patologia , Estadiamento de NeoplasiasRESUMO
PURPOSE: LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, has been found to radiosensitize various human cancer cells. However, its potential to act as an effective therapeutic agent is diminished by its toxicity levels. The purposes of this study were to determine the mechanism by which LY294002 radiosensitizes. MATERIALS AND METHODS: Cell growth curves and clonogenic assays were performed with increasing LY294002 exposure times proximate to the radiation dose. Protein levels of downstream PI3K effectors were analyzed. Detection of phosphorylated histone H2AX (gammaH2AX) was used to identify DNA double-strand breaks at various time points post-radiation. RESULTS: LY294002 significantly radiosensitized HeLa cervical cancer cells when administered for just 12 h following radiation. Cell growth curves also decreased with brief LY294002 application. DNA double-strand breaks are typically repaired within 2-6 h following radiation. Interestingly, at 48, 72, and 96 h post-irradiation, gammaH2AX was still significantly elevated in cells radiated in combination with LY294002. Protein expressions of ATM and ATR downstream effectors showed no differences among the treated groups, however, DNA-PK activity was significantly inhibited by LY294002. CONCLUSIONS: These results lead us to conclude that the central mechanism by which LY294002 radiosensitizes is via DNA-PK inhibition which induces DNA double-strand break repair inhibition. We are currently investigating radiosensitization induced by DNA-PK-specific inhibition in efforts to find a less toxic, yet equally effective, chemotherapeutic agent than LY294002.
Assuntos
Cromonas/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Morfolinas/farmacologia , Tolerância a Radiação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapia , Divisão Celular , Inibidores Enzimáticos/farmacologia , Feminino , Citometria de Fluxo , Células HeLa , Humanos , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki). EXPERIMENTAL DESIGN: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 micromol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnett's t Test. Microarray gene expression analysis was done on the HeLa cell line. RESULTS: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P < 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression. CONCLUSIONS: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix.
Assuntos
Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Feminino , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias do Colo do Útero/terapiaRESUMO
PURPOSE: We sought to test the hypothesis that the presence of telomerase activity in peritoneal washings of patients treated for ovarian carcinoma is a sensitive and specific indicator of the presence of residual disease. We hypothesized that this test, if added to second-look procedure protocols, could help determine whether residual disease is present or not in patients who have completed their adjuvant chemotherapy for ovarian carcinoma. EXPERIMENTAL DESIGN: Peritoneal washings were obtained from 100 consecutive patients undergoing a second-look procedure after treatment for ovarian carcinoma (cases) and from 100 patients undergoing surgery for benign gynecological conditions (controls). The washings were assayed for telomerase activity using the telomerase repeat amplification protocol. The results were compared to the histological and cytological findings. RESULTS: Among our 100 cases, 82 (82%) had either positive second-look procedures or expressed telomerase in their peritoneal washings. Fifty-three (53%) had positive second-look procedures, whereas 66 (66%) tested positive for telomerase. Twenty-nine of the 47 patients (62%) with negative second-look procedures tested positive for telomerase. Of the 53 patients with positive second-look procedures, 37 (70%) tested positive for telomerase. None of the 100 controls (0%) expressed telomerase in their peritoneal washings. CONCLUSIONS: Telomerase activity in peritoneal washings of patients treated for ovarian carcinoma and undergoing a second-look procedure may provide a means of increasing the sensitivity of such procedures for the detection of residual disease while maintaining a high level of specificity.
Assuntos
Líquido Ascítico/patologia , Quimioterapia Adjuvante , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Lavagem Peritoneal , Peritônio/metabolismo , Sensibilidade e Especificidade , Manejo de Espécimes , Telomerase/genética , Telomerase/metabolismoRESUMO
PURPOSE: The purpose of this study was to examine a variety of biomarkers in carcinoma of the cervix to better characterize (1). the natural history of the disease, (2). response to radiotherapy (RT), and (3). potential for new therapeutic strategies. MATERIALS AND METHODS: Fifty-five patients with Stage IB-IVA carcinoma of the cervix, treated with definitive intent RT, and on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Immunohistochemistry was performed for epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD34, topoisomerase II alpha (topo-II), and cyclooxygenase-2 (COX-2). Univariate and multivariate Cox proportional hazards modeling was performed with disease-free survival (DFS) and overall survival (OS) as the end points. Biomarkers were evaluated for correlation between various prognostic factors. RESULTS: In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p < 0.0001). On univariate analysis, increasing FIGO stage (p < 0.0001) and membranous staining of EGFR (p < 0.037) indicated diminished OS. On multivariate analysis for DFS, COX-2, VEGF, and stage were significant (p = 0.012, p = 0.014, and p = 0.03, respectively), with increased expression indicating a worse prognosis. For OS, multivariate analysis revealed that VEGF, EGFR, and FIGO stage were significant (p = 0.005, p = 0.011, and p < 0.0001, respectively). Significant direct correlations were identified between VEGF and CD34 (p = 0.04), COX-2 and topo-II (p = 0.04), COX-2 and grade (p = 0.04), and tumor size and clinical stage (p = 0.04). CONCLUSION: Multivariate analysis revealed that increased staining for VEGF and COX-2 indicated diminished DFS, and VEGF and EGFR identified patients at increased risk of death. A significant direct correlation between VEGF and CD34 implicates the process of angiogenesis. Topo-II is a proliferative marker and it correlated directly with COX-2, indicating that expression of COX-2 may be greater in more proliferative tumors. Increased expression of EGFR, VEGF, and COX-2 has identified patients with a worse prognosis in cancer of the cervix. These data support the investigation of therapeutics that target these proteins in carcinoma of the cervix.
Assuntos
Biomarcadores Tumorais/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Receptores ErbB/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfocinas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Ciclo-Oxigenase 2 , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Isoenzimas/metabolismo , Proteínas de Membrana , Análise Multivariada , Estadiamento de Neoplasias , Prostaglandina-Endoperóxido Sintases/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
OBJECTIVE: The role of post-operative radiotherapy (RT) in women with early-stage, low to intermediate risk cancer of the uterine corpus remains controversial. The primary objective of this analysis was to evaluate the survival outcomes of women with early-stage endometrial cancer treated with surgery alone or surgery followed by RT. METHODS: Data from two institutions were collected from 1990 to 2003. The 608 eligible women had FIGO stage IA to IIA endometrial cancer and underwent primary surgery +/-RT. Univariate and multivariate analyses of pertinent variables were performed for the end points of disease-free survival (DFS) and overall survival (OS). RESULTS: The median age for all women was 64 years. RT was delivered to 133 women (22%). Unfavorable histologic grade (P < 0.0001) and stage (P < 0.0001) were significantly more prevalent in the adjuvant RT group. At a median follow-up of 5.2 years, 26 pelvic (11 vaginal) and 16 distant failures occurred along with 110 deaths (with no significant differences between women undergoing surgery alone or followed by RT). Adjuvant RT, younger age, and lower stage predicted for improved DFS and OS on multivariate analysis. Stratified analysis revealed that adjuvant RT conferred a survival benefit in women with stage IC or IIA disease. CONCLUSIONS: Adjuvant RT was associated with improved disease-free and overall survival in women with higher risk disease. Despite significantly worse disease characteristics among women in the adjuvant RT group, the analyzed end points were equivalent among the two groups. These findings suggest that adjuvant radiotherapy has a significant benefit in reducing mortality and disease progression in early-stage carcinoma of the uterine corpus.
Assuntos
Adenocarcinoma/radioterapia , Neoplasias do Endométrio/radioterapia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate treatment outcomes in women with early-stage endometrial cancer (FIGO IA, IB, IC, or IIA) surgically managed by a general gynecologist (GYN) or a gynecologic oncologist (GYO). METHODS AND RESULTS: 349 women treated from 1990-2003 were studied. Median follow-up was 3.7 years. Ninety-five were classified as high-intermediate risk (HIR: stages IB grade III, IC grade II or III, any stage IIA). 110 women received adjuvant radiotherapy. The GYO group had more unfavorable tumor characteristics based on stage and grade (P<0.0001), shorter follow-up (median 3.1 vs. 5.1 years, P=0.0002), and an absolute 12% less likelihood of receiving adjuvant radiotherapy (P=0.04). Local and distant failures were not significantly different. Overall survival favored GYN patients (P=0.02) with no difference in disease-specific survival (P=0.38). Multivariate analysis for disease-free survival revealed HIR disease (P=0.04) and GYO treatment (P=0.049) to be significant, with a trend for ageAssuntos
Adenocarcinoma/cirurgia
, Neoplasias do Endométrio/cirurgia
, Adenocarcinoma/patologia
, Idoso
, Neoplasias do Endométrio/patologia
, Feminino
, Procedimentos Cirúrgicos em Ginecologia/normas
, Ginecologia
, Humanos
, Oncologia
, Pessoa de Meia-Idade
, Estadiamento de Neoplasias
, Especialidades Cirúrgicas
, Resultado do Tratamento
RESUMO
OBJECTIVE: To investigate prognostic significance of and correlations between HER1 (EGFR), HER2 (c-erb-B2), HER3 (c-erb-B3), HER4 (c-erb-B4), and phosphorylated Akt (P-Akt) in patients treated with radiation for cervical carcinoma. METHODS: Fifty-five patients with stages I-IVA cervical carcinoma were treated with definitive radiotherapy. Tumor expression of each biomarker was quantitatively scored by an automated immunohistochemical imaging system. Parametric correlations were performed between biomarkers. Univariate and multivariate analysis was performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints. RESULTS: Correlations were observed between expression of HER2 and HER4 (P = 0.003), and HER3 and HER4 (P = 0.004). Decreased HER2, HER4, and P-Akt expressions were significant for diminished DFS on univariate analysis (P = 0.04, P = 0.008, and P = 0.02, respectively). Increased EGFR, and diminished HER2, HER4, and P-Akt expression were significant or showed trends toward significance for diminished OS on univariate analysis (P = 0.07, P = 0.008, P = 0.09, and P = 0.08, respectively). After controlling for pretreatment factors, multivariate analysis revealed HER2 associated with improved OS (P = 0.05). CONCLUSIONS: These data emphasize that significant correlations exist between the differential expression of various HER family receptors. Multivariate analysis revealed only increased HER2 expression associated with improved OS after controlling for pretreatment clinical factors. These data emphasize the importance of continued basic and translational research on the HER family of receptors in cervical carcinoma.
Assuntos
Biomarcadores Tumorais/biossíntese , Receptores ErbB/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/radioterapia , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Intervalo Livre de Doença , Feminino , Humanos , Análise Multivariada , Estadiamento de Neoplasias , Fosforilação , Receptor ErbB-2/biossíntese , Receptor ErbB-3/biossíntese , Receptor ErbB-4 , Resultado do Tratamento , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVES: To evaluate HER2neu and epidermal growth factor receptor (EGFR) expression with respect to overall survival and disease-free survival (DFS), and correlate expression with pretreatment factors. Comparative evaluations of manual and automated immunohistochemical imaging systems for HER2neu and EGFR expression were made. METHODS: Fifty-five patients with stages I-IVA carcinoma of the cervix were treated with definitive radiation therapy. Immunohistochemistry was performed for HER2neu and EGFR, and scored by both manual and automated methods. Univariate and multivariate analyses were performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints, and biomarkers were evaluated for correlation between prognostic factors. RESULTS: Strong correlations in HER2neu and EGFR protein expression were observed between digitally and manually analyzed staining (P <== 0.0001). Increased FIGO stage and decreased HER2neu expression were significant for reduced DFS on univariate analysis (P <== 0.001 and P = 0.03, respectively). Increased FIGO stage, decreased HER2neu expression, and increased membranous staining of EGFR were significant for diminished OS on univariate analysis (P <== 0.0001, P = 0.002, and P = 0.043, respectively). Multivariate analysis revealed only increased membranous staining of EGFR associated with diminished DFS and OS (P = 0.046 and P = 0.012, respectively). Overexpression of HER2neu correlated significantly with adenocarcinoma, and overexpression of EGFR correlated significantly with squamous cell carcinoma histology (P = 0.038 and P = 0.035). Inverse correlations were observed between HER2neu expression and clinical stage, EGFR membranous staining, and EGFR distribution (P = 0.007, P = 0.006, and P = 0.034, respectively). CONCLUSIONS: Increased expression of HER2neu and decreased EGFR membranous staining identified patients with improved DFS and OS on univariate analysis, although only decreased EGFR membranous staining was significant on multivariate analysis. We also found strong correlation of results between manually and automated imaging methods.