Showing papers in "International Journal of Gynecological Cancer in 2006"
TL;DR: The association between growth during childhood and the risk of breast cancer in a cohort of 117,415 Danish women found high birth weight, high stature, low BMI at 14 years of age, and peak growth at an early age were independent risk factors for breast cancer.
Abstract: Adult height and body mass index (BMI) influence the risk of breast cancer in women. Whether these associations reflect growth patterns of the fetus or growth during childhood and adolescence is unknown. We investigated the association between growth during childhood and the risk of breast cancer in a cohort of 117,415 Danish women. Birth weight, age at menarche, and annual measurements of height and weight were obtained from school health records. We used the data to model individual growth curves. Information on vital status, age at first childbirth, parity, and diagnosis of breast cancer was obtained through linkages to national registries. During 3,333,359 person-years of follow-up, 3340 cases of breast cancer were diagnosed. High birth weight, high stature at 14 years of age, low BMI at 14 years of age, and peak growth at an early age were independent risk factors for breast cancer. Height at 8 years of age and the increase in height during puberty (8-14 years of age) were also associated with breast cancer. The attributable risks of birth weight, height at 14 years of age, BMI at 14 years of age, and age at peak growth were 7%, 15%, 15%, and 9%, respectively. No effect of adjusting for age at menarche, age at first childbirth, and parity was observed. Birth weight and growth during childhood and adolescence influence the risk of breast cancer.
234 citations
TL;DR: It is concluded that a radical hysterectomy for the treatment of early-stage cervical carcinoma is associated with adverse effects mainly on sexual functioning.
Abstract: The objective of this study was to evaluate the problems with miction, defecation, and sexuality after a radical hysterectomy with or without adjuvant radiotherapy for the treatment of cervical cancer stage I-IIA. This study included an observational longitudinal study of self-reported bladder, defecation, and sexual problems with a baseline score. Ninety-four women were included in the study. An age-matched control group consisted of 224 women. The patients showed significantly more negative effects on sexual function compared with both the controls and their situation before the treatment throughout 24 months of follow-up. The problems included less lubrication, a narrow and short vagina, senseless areas around the labia, dyspareunia, and sexual dissatisfaction. Up to 12 months after the treatment, the patients complained significantly more of little or no urge to urinate and diarrhea as compared with the controls. Adjuvant radiotherapy did not increase the risk of bladder dysfunction, colorectal motility disorders, and sexual functions. We conclude that a radical hysterectomy for the treatment of early-stage cervical carcinoma is associated with adverse effects mainly on sexual functioning.
168 citations
TL;DR: TH and specialist gynecologists achieved better short-term survival of patients operated for advanced ovarian, tubal, and peritoneal cancer, and centralization and specialization of ovarian cancer surgery might improve the outcome.
Abstract: The aim of this study was to study the impact of hospital level and surgical skill on short-term survival of advanced ovarian, tubal, and peritoneal cancer patients in a prospective population-based study. All 198 women with a diagnosis of advanced epithelial invasive ovarian, tubal, and peritoneal cancer in Norway who underwent surgery during 2002 were included in this study. The data were derived from notifications to the Norwegian Cancer Registry and from medical, surgical, and histopathologic records. The hospitals were grouped into teaching and nonteaching hospitals (NTH), and the operating physicians were classified according to specialty (specialist gynecologist, gynecologist, and surgeon). The follow-up period was from 455 to 820 days. The short-term survival at 450 days was 79% for women operated at teaching hospitals (TH) and 62% at NTH (P= 0.02). After simultaneous adjustment for seven prognostic factors and residual disease, the risk of death within 600 days at NTH was unchanged compared to TH, hazard ratio 1.83. The women operated on by specialist compared to general gynecologists had a 20% increased short-term survival (P
152 citations
TL;DR: High BMI and low physical activity were strong and independent risk factors for endometrial cancer.
Abstract: Although obesity is an established risk factor for endometrial cancer, evidence linking risk to height, weight change since age 20, and physical activity is limited. In this case-cohort study, 62 573 women from The Netherlands Cohort Study on Diet and Cancer were followed up from 1986 to 1995, and 226 endometrial cancer case patients were identified. In Cox proportional hazards analyses, women 175 cm or taller had an increased risk of endometrial cancer compared with those less than 160 cm (rate ratio [RR] = 2.57, 95% confidence interval [CI] = 1.32 to 4.99). Compared with women with a body mass index (BMI; kg/m2) between 20 and 22.9, women with a BMI of 30 or greater had a higher risk (RR = 4.50, 95% CI = 2.62 to 7.72; P(trend)<.001). Moreover, BMI at age 20 and BMI gain since age 20 were positively associated with endometrial cancer risk (P(trend) = .02 and <.001, respectively). Women who spent 90 minutes per day or more doing nonoccupational physical activities had a lower risk (RR = 0.54, 95% CI = 0.34 to 0.85; P(trend) = .002) compared with those who spent less than 30 minutes per day. High BMI and low physical activity were strong and independent risk factors for endometrial cancer.
148 citations
TL;DR: Considering the fact that 80% of MCTs are diagnosed during the reproductive age, malignant transformation seems to be related to the long-term presence of nonremoved MCT in the abdomen, it is considered helpful for preventing and early detection of the malignant Transformation to have regular ovary examination through pelvic ultrasonogram during the sexual age.
Abstract: There have been few studies concerning the clinical pathology of malignant transformation arising in ovarian mature cystic teratoma (MCT). Thus, the objective of this study is to determine clinicopathologic factors affecting survival in this rare tumor. From November 1992 to December 2002, 11 patients with malignant transformation arising in ovarian MCT were treated at Department of Obstetrics and Gynecology in Chonnam National University Hospital. Demographic characteristics, symptoms, signs, stage, mode of therapy, and results of follow-up were reviewed retrospectively. There were 11 cases of the malignant transformation of ovarian MCT out of 637 cases of MCT (1.7%). The average age was 50.6 years. Histologically, 7 out of the 11 cases were squamous cell carcinoma (63.7%). There were no specific clinical symptoms, but palpable abdominal mass was the most frequent complaint (five cases, 45.4%). As for the stage of disease, eight cases were in stage IA (72.7%), and the other three cases were in stage IC, IIB, and IIC, respectively. All the patients had surgery, and seven of them had adjuvant chemotherapy and two had adjuvant chemoradiation. All the patients in stage I survived until the period of follow-up, and their average survival time was 31.8 months. One patient in stage IIC died of intestinal obstruction within 9 months from the surgery. The mechanism of the malignant transformation arising in ovarian MCT is not clear, but considering the fact that 80% of MCTs are diagnosed during the reproductive age, malignant transformation seems to be related to the long-term presence of nonremoved MCT in the abdomen. Accordingly, it is considered helpful for preventing and early detection of the malignant transformation to have regular ovary examination through pelvic ultrasonogram during the reproductive age.
139 citations
TL;DR: Targeting HER-2/neu may be beneficial for a select group of patients with UPSC, and samples are being evaluated for Herceptin-induced over expression by fluorescence in situ hybridization (FISH) and immunohistochemical analysis.
Abstract: Uterine papillary serous carcinoma (UPSC) is a highly aggressive variant of endometrial cancer with features similar to high-grade ovarian cancer. Patients tend to be elderly, thin, have a high grade tumor with extensive extrauterine disease at the time of diagnosis. The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistochemistry in <25% of ovarian cancers and 20-30% of breast cancers, and <10% of endometrial cancer. There are prognostic and therapeutic implications associated with the overexpression of this transmembrane protein. Herceptin, a humanized murine monoclonal antibody directed against the extracellular domain of the HER-2/neu protein, is being used to treat breast cancer that overexpresses HER-2/neu. We reviewed all patients diagnosed with UPSC between 1999-2001. Twenty-six patients were identified, and 19 patients had specimens available for evaluation. We performed immunohistochemical analysis (Herceptest, Dako, Carpinteria, CA) on 19 paraffin embedded blocks of UPSC tumors looking for HER-2/neu over expression. Five out of 19 (26%) stained heavily (3+) for HER-2/neu receptor protein. Four of these five patients had advanced disease at diagnosis. Two of these patients were subsequently treated with Herceptin; one with complete response and one with stable disease based on CT scan and CA-125 findings. Targeting HER-2/neu may be beneficial for a select group of patients with UPSC. We are continuing to evaluate samples for HER-2/neu over expression by fluorescence in situ hybridization (FISH).
120 citations
TL;DR: In general, women had a poor knowledge on HPV diagnosis/treatment, condyloma signs, and Pap smear test, and the main reasons for not having a Pap smeartest done before were embarrassment and fear of pain.
Abstract: The objective of the study was to assess knowledge and attitudes about human papillomavirus (HPV), cervical cancer, and Papanicolaou (Pap) smears among young women. A questionnaire was administered to 204 women aged 16–23 years, attending a public clinic. Data were gathered on sociodemographic characteristics, knowledge, and attitudes related to HPV. Overall, 92% of women reported current/previous sexual activity, 42% perceived themselves at high risk of acquiring a sexually transmitted disease, 67% did not know that HPV can cause cervical cancer/warts, and only 10% acknowledged that HPV might lead to cervical cancer. In general, women had a poor knowledge on HPV diagnosis/treatment, condyloma signs, and Pap smear test. The main reasons for not having a Pap smear test done before were embarrassment (63%) and fear of pain (61%). Knowledge of HPV infection and cervical cancer was low in this urban young population. Our findings recommend for greater HPV education of the public and health care practitioners.
119 citations
TL;DR: In vivo, E6 siRNA administration groups showed a dramatic effect in inhibiting tumor growth, suppressing expression of E6 protein, and inducing tumor necrosis and apoptosis as compared with the control group.
Abstract: Substantial studies have demonstrated that the initiation and progression of cervical cancer were closely associated with human papillomavirus (HPV) E6 and E7 oncogenes. The therapeutic strategy with ribozyme or antisense oligonucleotides to inhibit the expression of HPV E6 or E7 oncogenes showed effect to some degree, but problems such as low efficiency, short-period maintenance, and high cost still remain. The aim of this study was to investigate in vitro and in vivo the effect of HPV 16 E6 small interfering RNA (HPV 16 E6 siRNA) on cervical cancer cell line CaSki cells. The specific siRNA of HPV 16 E6 was synthesized and transfected into CaSki cells by liposome. The number of apoptotic cells, HPV 16 E6 messenger RNA (mRNA) level, and E6 protein expression were measured before and after the transfection by flow cytometry, reverse transcriptase–polymerase chain reaction, and Western blot, respectively. Cervical cancer in nude mice was established, and siRNA was injected directly into the nude mice peritoneal cavity or subcutaneous tumor. The efficiency of siRNA was evaluated by tumor volume change, HPV 16 E6 protein expression, and apoptosis of tumor cells. Apoptosis rate of CaSki cells at days 1, 2, 5, and 9 after siRNA transfection were 7.7%, 11.8%, 37.4%, and 12.6%, respectively. The mRNA level of HPV 16 E6 at the same time points were reduced by 77%, 83%, 59%, and 41%, respectively. But the mRNA level of β-actin, as an internal control, showed no significant change. The inhibition rates of E6 protein synthesis at days 1, 2, 5, and 9 after the transfection were 79.7%, 80.4%, 71.3%, and 57.4%, respectively, whereas the protein levels of Lamin A/C, as internal control, had no change. In vivo, E6 siRNA administration groups showed a dramatic effect in inhibiting tumor growth, suppressing expression of E6 protein, and inducing tumor necrosis and apoptosis as compared with the control group. Direct injection of siRNA into subcutaneous tumor resulted in tumor suppression effect similar to that via the peritoneal cavity, and with additional injection better results could be achieved in cervical cancer CaSki cells. RNA interference exists, and the interference to HPV 16 E6 is specific and highly efficient both in vitro and in vivo.
112 citations
TL;DR: The clinical characters and prognosis of ovarian cancers complicating pregnancy are similar to those of nonpregnant, reproductive-age women, and management depends on histology of the tumor, stage of the tumors, and the term of the pregnancy.
Abstract: The aim of this study was to summarize our experience of ovarian cancer diagnosed during pregnancy, to review the literature concerned, and to discuss the rationale for therapy. Twenty-two patients of ovarian malignancies complicating pregnancy were treated at Peking Union Medical College Hospital between 1985 and 2003. Data on treatment and follow-up were reviewed, and their outcomes were analyzed by survival analysis. The incidence of ovarian carcinoma complicating pregnancy in the series was 0.073/1000 pregnancies. Nine (40.9%) were found with ovarian malignant germ cell tumors, six (27.3%) with low malignant potential tumors, five (22.7%) with invasive epithelial tumors, and two (9.1%) with sex cord stromal tumors. Sixteen (72.7%) of the patients were diagnosed in stage I and had achieved complete remission. Four of the five in advanced stage died. Ascites presenting at diagnosis implies advanced disease and gloomy prognosis. The mean follow-up was 47.8 months. The prognosis was significantly related with stage and histologic type (P < 0.05). Thirteen healthy live babies were recorded in this group, and one premature newborn died of respiratory distress syndrome. The clinical characters and prognosis of ovarian cancers complicating pregnancy are similar to those of nonpregnant, reproductive-age women. Management depends on histology of the tumor, stage of the tumor, and the term of the pregnancy. In most of cases, conservative surgical treatment could be performed with adequate staging and debulking equal to the treatment of nonpregnant women. Chemotherapy is not contraindicated during the second or third trimester, but the choice of couple must be considered.
109 citations
TL;DR: Avoiding to induce long-term lymphedema or bladder-emptying difficulties would probably improve quality of life after radical hysterectomy (to cure cervical cancer).
Abstract: The aim of the study was to acquire knowledge that can be used to refine radical hysterectomy to improve quality-of-life outcome. Data were collected in 1996–1997 by means of an anonymous postal questionnaire in a follow-up study of two cohorts (patients and population controls). We attempted to enroll all 332 patients with stage IB–IIA cervical cancer registered in 1991–1992 at the seven departments of gynecological oncology in Sweden and 489 population controls. Ninety three (37%) of the 256 women with a history of cervical cancer who answered the questionnaire (77%) were treated with surgery alone. Three-hundred fifty population controls answered the questionnaire (72%). Women treated with radical hysterectomy, as compared with controls, had an 8-fold increase in symptoms indicating lymphedema (25% reported distress due to lymphedema), a nearly 9-fold increase in difficult emptying of the bladder, and a 22-fold increase in the need to strain to initiate bladder evacuation. Ninety percent of the patients were not willing to trade off survival for freedom from symptoms. Avoiding to induce long-term lymphedema or bladder-emptying difficulties would probably improve quality of life after radical hysterectomy (to cure cervical cancer). Few women want to compromise survival to avoid long-term symptoms.
105 citations
TL;DR: Vaginal stenosis is a common complication of pelvic and vaginal radiotherapy, occurring in 38% of patients and most often in the first year after treatment, where patients over the age of 50 are most at risk.
Abstract: The aim of our study was to determine the incidence, timing, and severity of vaginal stenosis in patients with carcinoma of the cervix who had received pelvic and/or vaginal radiotherapy as part of their treatment. We also sought to determine if there were any predisposing factors for the development of stenosis. A retrospective chart review was undertaken for all the patients diagnosed with carcinoma of the cervix between January 1, 1990, and December 31, 2000 and treated with pelvic and/or vaginal radiation at Westmead Hospital. Since January 1, 1990, data regarding vaginal stenosis has been prospectively recorded on all the patients. Data collected included patient demographics, stage of disease, treatments administered, and incidence, timing, and severity of vaginal stenosis. One hundred and eighty-eight patients were treated. Mean age was 58.6 years. Thirteen percent of patients had stage IB disease, 45% had stage II disease, 39.5% had stage III disease, and 1.5% had stage IV disease. One hundred and seventy-nine patients returned for follow-up, and data regarding vaginal toxicity were available in 98%. Twenty-seven percent had grade 1 toxicity (partial stenosis or shortening but not complete occlusion), and 11% had grade 2 (complete occlusion). Stenosis of any grade was noted at a mean of 9.6 months and median of 7.5 months (range, 26 days-5.6 years) from completion of treatment. The only prognostic factor associated with increased risk of stenosis was age greater than 50 years (odds ratio 2.26). Vaginal stenosis is a common complication of pelvic and vaginal radiotherapy, occurring in 38% of patients. Stenosis occurs most often in the first year after treatment. Patients over the age of 50 are most at risk.
TL;DR: Transfected BRMS1 plasmid into highly malignant ovarian carcinoma cell line, HO-8910PM, and examined cell biologic behaviors including proliferation, adhesion, invasion, and metastasis in vitro and in vivo suggested that in addition to its already described role in breast cancer and melanoma, BR MS1 functions as a metastasis-suppressor gene in ovarian carcinomas by modifying several metastatic-associated phenotypes, offering a new target for therapeutic intervention.
Abstract: Metastasis-suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. BRMS1 (breast cancer metastasis suppressor) has recently been identified as a metastasis-suppressor gene for human breast cancer and melanoma. Expression of BRMS1 messenger RNA (mRNA) in multitissue including normal prostate, ovarian, testis, and colon has been detected by northern blot analysis. We hypothesize that the role of BRMS1 in tumor progression may not be limited to breast cancer and melanoma. We previously found that BRMS1 mRNA levels in primary ovarian epithelial carcinomas were significantly lower than that in normal ovarian and benign tumors (P < 0.05), and statistical analysis of BRMS1 mRNA levels revealed that BRMS1 mRNA levels were significantly higher in early tumor stages (I, II) compared with advanced tumor stages (III, IV) in which lymph node or distant metastases were present (P < 0.01). Our data showed that reduced BRMS1 mRNA seems to influence ovarian carcinoma metastatic ability. Therefore, we transfected BRMS1 plasmid into highly malignant ovarian carcinoma cell line, HO-8910PM, and examined cell biologic behaviors including proliferation, adhesion, invasion, and metastasis in vitro and in vivo. BRMS1 expression did not alter the proliferation of HO-8910PM cells in vitro and primary tumor formation in vivo. But, BRMS1 expression significantly suppressed the cell adhesion to extracellular matrix components and in vitro cell invasion in BRMS1-transfected HO-8910PM cells compared to parental HO-8910PM and vector-only transfectants (HO-8910PM-vect). Furthermore, motility of BRMS1 transfectants was inhibited. lung colony formation of intravenously injected BRMS1 transfectants in nude mice was significantly reduced. Also, BRMS1 transfectants form significantly less metastatic to organs of peritoneal cavity in orthotopically implanted ovarian tumor nude models. We further discovered that BRMS1 expression did downregulate expression of an actin-bundling protein associated with cell motility -fascin, which perhaps is the mechanism underlying BRMS1 suppression of metastasis. These data suggested that in addition to its already described role in breast cancer and melanoma, BRMS1 functions as a metastasis-suppressor gene in ovarian carcinoma by modifying several metastatic-associated phenotypes, offering a new target for therapeutic intervention.
TL;DR: In the authors' opinion, the combination of preoperative biopsy and intraoperative frozen section is the best way to decide whether a lymphadenectomy is necessary with a low rate of understaging patients.
Abstract: The objective of this study was to determine the value of myometrial invasion by magnetic resonance imaging (MRI), histologic typing and grading by endometrial biopsy, and the intraoperative evaluation of both parameters by frozen section in the evaluation of endometrial cancer. The preoperative and intraoperative records of 180 patients with endometrial cancer were used to compare the preoperative endometrial biopsy, the myometrial invasion by MRI, and the intraoperative frozen sections, with the final histopathologic findings. The preoperative endometrial biopsy gave us the tumor histologic type and grade. MRI gave us the depth of myometrial invasion. The evaluation of intraoperative frozen sections gave us the tumor histologic type, the tumor grade, and also the myometrial invasion. Patients were classified as low risk (grade 1 and 2, and myometrial invasion 50%). Standard statistical calculations were used. Evaluation of the tumor grade by preoperative biopsy has a sensitivity and a specificity of 75% and 95%, respectively. Evaluation of the tumor grade by intraoperative biopsy has a sensitivity and a specificity of 40% and 98%, respectively. Evaluation of the depth of myometrial invasion with MRI has a sensitivity and a specificity of 79% and 82%, respectively. Evaluation of the depth of myometrial invasion with intraoperative frozen sections has a sensitivity and a specificity of 74% and 95%, respectively. Evaluation of all four of the parameters together has a sensitivity and a specificity of 80% and 82%, respectively with a kappa of 0.621. In our opinion, the combination of preoperative biopsy and intraoperative frozen section is the best way to decide whether a lymphadenectomy is necessary with a low rate of understaging patients. MRI would have a fringe benefit in these patients.
TL;DR: The use of neoadjuvant chemotherapy enabled a 28-year-old A0P1G2M0 to continue this pregnancy until the fetus was viable and only a long-term follow-up will inform her on its safety during pregnancy.
Abstract: Although cervical carcinoma is among the most frequently encountered malignancies during pregnancy, only four cases of neoadjuvant chemotherapy during pregnancy have been reported. A 28-year-old A0P1G2M0 was diagnosed at 15 weeks with stage Ib1 invasive squamous cervical cancer. Because she strongly desired the continuation of this pregnancy, after extensive counseling she was treated with 75 mg/m(2) cisplatin every 10 days starting at 17 weeks. After six cycles, clinically and radiologically stable disease with normalization of the squamous cell carcinoma tumor marker was obtained. An elective cesarean delivery followed by radical hysterectomy and lymphadenectomy was performed at 32 weeks gestation. The pathology report revealed a moderately differentiated squamous cell carcinoma of 3.5 cm, and all 33 lymph nodes were free of disease. Neonatal examination of the baby could not reveal any abnormalities, and this was confirmed at 6 months. The use of neoadjuvant chemotherapy enabled us to continue this pregnancy until the fetus was viable. Cisplatin did not influence the short-term outcome, but only a long-term follow-up will inform us on its safety during pregnancy.
TL;DR: Long-standing abnormal findings including urinary and bowel complications were presented in patients who survived for more than 5 years after initial treatment for invasive cervical cancer.
Abstract: The purpose of this study is to investigate the side effect in patients who survived for more than 5 years after initial treatment for invasive cervical cancer. Between January 1984 and December 1997, 341 patients underwent primary treatment for invasive cervical cancer. One hundred nine patients who underwent medical examinations at 5 years after primary treatment were reviewed. The patients were divided into three groups: radical surgery alone (group A), radiotherapy alone (group B), and radical surgery with postoperative radiotherapy (group C). Dysuria was seen in 8%, and positive catheterized urine culture was noted in about 20% of groups A and C. Hydronephrosis was seen in 2% and 9% of groups A and B, respectively. Colitis or ulcer detected by proctosigmoidoscopy was noted in 15%, 50%, and 43% of groups A, B, and C, respectively, frequently observed in radiotherapy group (P= 0.0029). Lymphocyst was still present in 6% of group A, and leg edema was noted in 14%, 6%, and 15% of groups A, B, and C, respectively. Long-standing abnormal findings including urinary and bowel complications were presented in this study. Periodic physical examination after treatment should be performed because complications existed over a long time.
TL;DR: An overview of the surgical mechanisms presumed to be responsible for pelvic floor denervation is presented and subsequent bladder and bowel dysfunction is described, together with future possibilities for minimizing morbidity, including less radical, more individual surgery, and nerve-sparing techniques.
Abstract: Although the survival outcome for treated, early-stage, node-negative cervical cancer is excellent, the operation of radical hysterectomy conveys major morbidity, particularly with respect to bladder and bowel function. There may be some degree of spontaneous recovery, but a significant proportion of postoperative women will have to live with the disabling effects of surgery for decades, and few seek help for their distress. As such, quality of life issues have become highly relevant in the management of this disease, and attention has turned to reducing morbidity, especially to the pelvic viscera. This review presents an overview of the surgical mechanisms presumed to be responsible for pelvic floor denervation and describes subsequent bladder and bowel dysfunction, together with future possibilities for minimizing morbidity, including less radical, more individual surgery, and nerve-sparing techniques.
TL;DR: Using p16INK4a as a bio marker of HPV oncogenic activity, it is demonstrated that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.
Abstract: Overexpression of p16(INK4a) has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16(INK4a) and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16(INK4a) overexpression was investigated immunohistochemically using a p16(INK4a)-specific monoclonal antibody (clone E6H4). In high-risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16(INK4a) overexpression. The incidence of p16(INK4a) overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16(INK4a) overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16(INK4a) as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.
TL;DR: Since the prime-boost approach in this cohort offered no significant advantages over single TA-HPV vaccination, there are no further studies planned using this protocol and future studies are warranted to define responders to immunotherapy.
Abstract: The objective of this study was to determine the clinical effectiveness of a prime-boost human papillomavirus (HPV) vaccine regimen. A nonrandomized phase II prime-boost vaccine trial was conducted. Women with biopsy-proven anogenital intraepithelial neoplasia (AGIN) 3 were vaccinated with three doses of a recombinant fusion protein comprising HPV 16, E6/E7/L2 (TA-CIN) followed by one dose of a recombinant vaccinia virus encoding HPV 16 and 18 E6/E7 (TA-HPV). Clinical responses were evaluated by serial photographs, symptomatology, and biopsies before and after vaccination. Twenty-nine women were vaccinated; 27 with vulval intraepithelial neoplasia 3 and 2 with vaginal intraepithelial neoplasia grade 3. Clinical responses were seen in five women (17%), with one complete and five partial responses. Fifteen women (62%) had symptomatic improvement. No serious adverse effects were recorded. This is the first trial of a prime-boost vaccination regimen using heterologous HPV vaccines (TA-CIN followed by TA-HPV) in the management of AGIN. Since the prime-boost approach in this cohort offered no significant advantages over single TA-HPV vaccination, there are no further studies planned using this protocol. Future studies are warranted to define responders to immunotherapy.
TL;DR: The data confirm the effectiveness of the RMI algorithm in clinical practice for the identification and subsequent referral to cancer centers of cases of potential ovarian malignancy and recommend its continued use.
Abstract: Characterization of adnexal masses to identify patients with malignant ovarian tumors preoperatively for referral to a cancer center for treatment has been extensively studied. A simple algorithm called "risk of malignancy index" (RMI) reported by Jacobs incorporated the serum CA125 level, menopausal status, and ultrasound morphologic features. This algorithm has subsequently been tested on retrospective and prospective data with encouraging results. However, these studies did not include cases that had had both their serum CA125 measurements and ultrasound examinations from a diverse range of laboratories and sonographers. The purpose of this study was to determine the effectiveness of the RMI algorithm for identifying cases of ovarian malignancy presenting at cancer units for subsequent referral to a cancer center. All cases of suspected ovarian malignancy referred to the Northern Gynaecological Oncology Centre (NGOC) during an 18-month period were identified from the NGOC database. A case note review was performed, and the following data were extracted: patient demographics, the referring physician and the operating surgeon, ultrasound morphology, serum CA125 levels, and menopausal status. All patients had their ultrasound performed by sonographers at the peripheral unit according to local protocols. A total of 182 patients with a pelvic mass were referred to the center for surgery. A total of 24% patients had benign tumors, 6% had tumors of borderline malignancy, and 70% had invasive tumors. A total of 145 cases had an RMI >200; 125 of these had ovarian or peritoneal cancers. An RMI >200 had a sensitivity of 88.5% for diagnosing invasive lesions. The overall sensitivity of this algorithm for diagnosing all borderline, invasive ovarian, or primary peritoneal lesions was 87.4%, and the positive predictive value was 86.8%. Our data confirm the effectiveness of the RMI algorithm in clinical practice for the identification and subsequent referral to cancer centers of cases of potential ovarian malignancy. We therefore recommend its continued use.
TL;DR: Elevated neopterin concentrations have been associated with anemia of chronic disease and increased urinary zinc loss in patients with gynecological malignancy, and has also been connected with depressed function of peripheral blood lymphocytes and a decrease in CD4+ T-cell numbers.
Abstract: Malignant tumors may contribute to host response that involves both the adaptive and innate immune systems. Among other biochemical indicators of systemic immune and inflammatory activity, activation of macrophages by interferon-γ induces a marked increase in the production of neopterin. Neopterin production by activated macrophages is also associated with tryptophan degradation. In addition to tumors of other primary locations, increased urinary and serum neopterin concentrations have been reported in patients with gynecological cancers, including epithelial ovarian carcinoma, cervical carcinoma, endometrial carcinoma, uterine sarcomas, and vulvar carcinoma, but not in women with benign neoplasms or precancerous disorders. Increased neopterin concentrations have been associated with poor prognosis. Elevated levels of neopterin have also been observed in the tumor microenvironment. Systemic (urinary or serum) or local (ascitic fluid) neopterin concentrations increased after therapeutic administration of cytokines. Elevated neopterin concentrations have been associated with anemia of chronic disease and increased urinary zinc loss in patients with gynecological malignancy. Elevated neopterin has also been connected with depressed function of peripheral blood lymphocytes and a decrease in CD4+ T-cell numbers.
TL;DR: While there was a positive correlation between Pap test awareness and utilization, screening uptake was very poor due to a combination of inappropriate beliefs, misapprehension, and deficient knowledge.
Abstract: Papanicolaou (Pap) smear test is considered the best approach to reduce cervical cancer incidence worldwide. We surveyed 195 female health workers with structured questionnaires to identify factors that could influence the awareness and utilization of the Pap smear as a cervical cancer screening test. More than 65% of the respondents were aware of the disease, cervical cancer, and approximately 64% were aware of the Pap smear test. Seven three (39.7%) of the respondents had their sexual debut (coitarche) before the age of 20 years, while 109 (59.9%) have had multiple sexual partners. The modal number of sexual partners was 3, range 0-8. Pap smear awareness level significantly varied among the categories of the female health workers (P < 0.001). A minority of 14.1% have had a Pap test. There was a significant variation in utilization of Pap test across the various categories of the health workers (Pearson Chi-square 14.67, P < 0.05), and a significant correlation between Pap smear awareness and utilization (P < 0.001). The majority, 89%, believed that they were not at risk of developing cervical cancer. The self-reported utilization of Pap test among health workers was low. While there was a positive correlation between Pap test awareness and utilization, screening uptake was very poor due to a combination of inappropriate beliefs, misapprehension, and deficient knowledge. There is an urgent need for an aggressive awareness campaign and the provision of a screening program nationally.
TL;DR: It is concluded that cervical impedance spectrometry provides a potentially promising real-time screening tool for CIN with similar sensitivity and specificity to currently used screening tests.
Abstract: The objective of this study was to assess the performance of cervical impedance spectroscopy in the detection of cervical intraepithelial neoplasia (CIN) using the new MKIII impedance probe. A prospective observational study recruited women referred to colposcopy with an abnormal Papanicolaou smear. A pencil probe incorporating four gold electrodes was used to measure electrical impedance spectra from cervical epithelium. Colposcopy examinations, including probe positioning, were video recorded to allow for correlation between results obtained from colposcopic impression, histopathologic examination of colposcopic punch biopsies, and impedance measurements. Cervical impedance–derived parameters R, S, R/S, C, and Fc were assessed to see if significant difference in values obtained in CIN and normal epithelium existed. The performance of the probe in identifying women with CIN was also assessed. One hundred seventy-six women were recruited and 1168 points analyzed. Parameters R, S, and Fc showed significant separation of CIN or squamous intraepithelial lesion (SIL) from squamous, mature metaplastic, and columnar epithelium. Sensitivities of 74% and specificity of 53% can be achieved in identifying CIN 2/3 (High-grade SIL) in screened women. We conclude that cervical impedance spectrometry provides a potentially promising real-time screening tool for CIN with similar sensitivity and specificity to currently used screening tests. Further research is ongoing to develop the probe for potential clinical use.
TL;DR: EMA/CO regimen is highly effective for treatment of high-risk GTN and its toxicity is well tolerated.
Abstract: The aim of this study was to evaluate the efficacy and toxicity of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen for the treatment of high-risk gestational trophoblastic neoplasia (GTN). Thirty-three patients with high-risk GTN, scored according to World Health Organization, received 159 EMA/CO treatment cycles between 1994 and 2004. Twenty-three patients were treated primarily with EMA/CO, and 10 patients were treated secondarily after failure of single agent or MAC (methotrexate, actinomycin D, cyclophosphamide, or clorambucile) III chemotherapy. Adjuvant surgery and radiotherapy were used in selected patients. Survival, response, and toxicity were analyzed retrospectively. The overall survival rate was 90.9% (30/33). Survival rates were 91.3% (21/23) for primary treatment and 90% (9/10) for secondary treatment. Six (18.2%) of 33 patients had drug resistance. Four of them underwent surgery for adjuvant therapy. Three of these patients with drug resistance died. Survival and complete response to EMA/CO were influenced by liver metastasis, antecedent pregnancy, and histopathologic diagnosis of choriocarcinoma. Survival rate was also affected by blood group. The treatment was well tolerated. The most severe toxicity was grade 3–4 leukopenia that occurred in 24.3% (8/33) of patients and 6.9% (11/159) of treatment cycles. Febrile neutropenia occurred in one patient (3%). EMA/CO regimen is highly effective for treatment of high-risk GTN. Its toxicity is well tolerated.
TL;DR: Findings confirm a high rate of loss of BRCA1 protein expression in sporadic OEC and suggest a role of BrcA1 in the progression of sporadic ovarian carcinoma.
Abstract: BRCA1 is a tumor suppressor gene that, when mutated, is associated with the development of hereditary ovarian cancer. A role for BRCA1 in the pathoetiology of sporadic ovarian epithelial cancer (OEC) development has been suggested, although spontaneous mutations of the BRCA1 gene in this disease are uncommon. Loss of gene function by epigenetic alteration is observed more commonly, while other means of gene inactivation have not been intensively investigated. We examined expression and localization of the BRCA1 gene product by immunohistochemistry and sought to clarify the relationship between protein expression and tumor stage, grade, histopathologic subtype, and outcome. Among 230 spontaneous OEC tumors, we found a statistically significant decrease in BRCA1 protein expression with advancing stages of OEC. There was no relationship between expression and tumor grade. There was a statistically significant relationship between the pathologic subtypes of OEC and BRCA1 expression. Minimal BRCA1 expression was protective for survival. These findings confirm a high rate of loss of BRCA1 protein expression in sporadic OEC and suggest a role of BRCA1 in the progression of sporadic ovarian carcinoma.
TL;DR: The promoter methylation of the p16 gene is a frequent event in cervical carcinogenesis and may have potential clinical application as a marker for the progression and prognosis of cancer.
Abstract: This study was conducted to investigate the promoter methylation status of the p16, DAPK, CDH1, and TIMP-3 genes in primary cervical cancer and its correlation with clinicopathologic characteristics. Promoter methylation was evaluated using a methylation-specific polymerase chain reaction in 78 cervical cancer tissue specimens and 24 control, normal cervical tissue specimens. Clinicopathologic parameters were obtained from medical records, and the relationship between the discrete variables and the methylation status was evaluated. The frequencies of promoter methylation of p16, DAPK, CDH1, and TIMP-3 in cervical cancer were 57%, 44.9%, 52.6%, and 9%, respectively. Primary cervical cancer had significantly higher methylation frequencies for the p16 and DAPK promoters than did the control, normal cervix (P < 0.0001). The promoter methylation of TIMP-3 was significantly higher in adenocarcinoma than in squamous cell carcinoma (41.7% vs 3%, respectively, P= 0.0175). High-stage cancers exhibited an increased promoter methylation frequency for p16 (P= 0.0061). The promoter methylation of the p16 gene is a frequent event in cervical carcinogenesis and may have potential clinical application as a marker for the progression and prognosis of cancer.
TL;DR: LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer and the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting.
Abstract: LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Twenty-six patients were enrolled in this study. Resistant disease was defined as a platinum-free interval of
TL;DR: The clinical significance of elevated VEGF ascites level in ovarian carcinomas was shown for the first time and support novel therapeutic perspectives by V EGF inhibition.
Abstract: The purpose of the study was to determine vascular endothelial growth factor (VEGF) concentrations in ascites from ovarian cancer and to correlate these data with VEGF expression in ovarian tumors, serum VEGF concentrations, and clinicopathologic characteristics. Ascites, serum, and tumor tissue from 65 ovarian carcinomas and eight borderline tumors were collected. VEGF concentration in peritoneal fluids and sera was determined using enzyme immunoassay. VEGF tumor expression was evaluated immunohistochemically. Significantly higher VEGF concentrations were found in ascites from malignant tumors (median, 2575 pg mL(-1)) compared with borderline tumors (median 181.9 pg mL(-1)) and benign peritoneal fluid (184.5 pg mL(-1)). Both VEGF ascites concentration and tumor expression correlated with advanced tumor stages and ascites volume. Elevated VEGF ascites levels were negatively correlated to patient survival. No differences between VEGF serum levels could be observed between ovarian cancer patients and patients with benign cysts. This study showed for the first time the clinical significance of elevated VEGF ascites level in ovarian carcinomas. VEGF is expressed by ovarian tumor cells and locally released in the malignant peritoneal fluid but is not increased in the serum of preoperative ovarian cancer patients. The enhanced VEGF level support novel therapeutic perspectives by VEGF inhibition.
TL;DR: It is concluded that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.
Abstract: Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.
TL;DR: The sentinel node detection rate is relatively high and depends on the tumor size and FIGO stage; however, successful identification of at least one SN was less likely in patients with tumors >2 cm compared with those with tumors ≤2 cm.
Abstract: We investigated the feasibility of sentinel lymph node (SN) identification using radioisotopic lymphatic mapping with technetium-99m-labeled nanocolloid and blue-dye injection in 100 patients with early cervical cancer (FIGO stage IB1 in 58, IB2 in 18, and IIA in 24) undergoing radical hysterectomy with pelvic lymphadenectomy. At least one SN was found in 84% on one side and in 66% on both sides. The sentinel detection rates according to the stages were as follows: 96.6% in IB1, 66.7% in IB2, and 62.5% in IIA with at least one SN on one side, and 86.2% in IB1, 38.9% in IB2, and 37.5% in IIA with at least one SN on both sides. Successful identification of at least one SN was less likely in patients with tumors >2 cm (54% of SN) compared with those with tumors ≤2 cm (96% of SN). In 15/22 patients, the SNs were the only lymph nodes that were tumor positive. The false-negative rate for the SN procedure was 3% (3/100). In all false-negative SNs, the primary cervical tumor was above 2 cm and there was an isthmus infiltration. SN detection had 86.4% sensitivity (19/22), 100% specificity (66/66), and 95.5% negative predictive value (63/68). The sentinel node detection rate is relatively high and depends on the tumor size and FIGO stage.
TL;DR: Data indicate that the ChemoFx® assay is predictive of PFI in ovarian cancer, and the incorporation of assay information into treatment selection has the potential to improve clinical outcomes in Ovarian cancer patients.
Abstract: The study objective was to determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy measured by progression-free interval (PFI) in a retrospective series of ovarian cancer patients whose tumor specimens had been tested with the ChemoFx® assay. A statistically significant correlation between assay prediction of response and PFI was observed in 256 cases with an exact or partial match between drug(s) assayed and received. In 135 cases with an exact match, the hazard ratio for progression of the resistant group was 2.9 (confidence interval [CI]: 1.4–6.3; P