Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Two unusual cases: vulvar lipoma - description of the largest case in literature. Developing myoma with the longest pedicle.

The authors present two cases of benign tumors one located on the outer surface of the vulva, and the second extending beyond the vagina. The first, originating from the right pudendal lip, a lipoma measuring 23 cm in greatest diameter, weighing 6.6 kg, and the second a pedunculated, uterine smooth muscle myoma with a pedicle of 6.5 cm, maximum diameter 18 cm, weight 700 grams, which caused significant metroptosis. Operative procedures in each case were free of complications.

Multiple primary cancers in BRCA 1/2 carriers - A review of literature and our observations.

An increasing number of patients with diagnosed synchronous or metachronous neoplasms that arc gene as well as non-gene dependent which are associated with the development of new oncological treatment, and environmental factors, prompted the authors of this study to conduct an analysis in a narrow group of patients with multiple cancers and simultaneous BRCA1I mutations (confirmed by genetic analysis). BRCA1 mutation, as well as multiple cancers were found in seven patients treated between 2007 and 2013. The patients diagnosed with a second cancer shared a uniquely common trait - a 5382insC mutation. The study describes four patients that did not carry a BRCA 1/2 mutation, yet were diagnosed with multiple cancers. A brief review of literature was performed concerning multiple cancers in women.

A case of a 20-kg fibrothecoma.

A case report of a 50-cm diameter and 20-kg mass of benign ovarian tumor. Total abdominal hysterectomy with a bilateral salpingooophorectomy was performed with full patient recovery. Fibrothecomas can remain long asymptomatic and can grow to giant sizes.

Nanooncology in ovarian cancer treatment.

In the following review, the authors present various methods of using nanoparticles in the therapy of ovarian cancer. Nanoparticles have been shown to prolong the half-time of various chemotheurapeutics, have a lower toxicity, and increase chemosensitivity. It is their hope that this article will widen the discussion within the scientific community on the use of nanotheurapeutics in oncology.

Evaluation of residual tumor locations in advanced ovarian cancer patients after incomplete primary cytoreduction.

BACKGROUND: Nowadays complete primary cytoreduction can be achieved in a large number of patients suffering from advanced ovarian cancer. However, there is a group of patients in whom complete tumor resection remains impossible. The authors analyzed the intraoperative limiting factors in patients with residual tumor after primary surgery treated in the present institution. MATERIALS AND METHODS: Patients with advanced epithelial ovarian cancer (FIGO Stage IIIB-IV), who underwent primary incomplete surgery in the present institution between 2006 and 2008 were included in this study. Patients' records were evaluated regarding to intraoperative findings and final surgical results. RESULTS: The authors identified 39 eligible patients in their registry. Twenty-six (66.7%) patients underwent surgery with residual tumor < 1 cm and 13 (33.3%) ≥ 1 cm. The most frequent location of residual tumor limiting complete surgery was disseminated bowel carcinomatosis in 34 (87.2%) patients. Moreover significant differences in tumor residuals locations and operative time between patients with residuals < 1 cm and ≥ 1 cm were reported (p < 0.05). CONCLUSIONS: The most frequent reason for incomplete primary cytoreduction remains disseminated carcinomatosis. However, in patients with residuals under one cm, its frequency is significantly higher. The complication rate is comparable in patients independently of residual tumor < 1 cm and ≥ 1 cm. Therefore the cytoreductive efforts should be made even in primarily not completely operated patients in order to achieve residuals under one cm.

Late recurrence of ovarian cancer: a literature review and description of two cases.

Ovarian cancer is not the most frequent malignancy of female reproductive system, but it causes many deaths in women with this diagnosis. Mostly of the patients with ovarian cancer will have recurrence after first-line standard treatment containing surgery and chemotherapy. This article presents two cases with late recurrence in women with ovarian cancer; both were nine years after the first diagnosis and both were operated and received second-line chemotherapy. The authors reviewed medical literature with late recurrence of ovarian cancer.

Oxidative stress markers in uterine fibroids tissue in pre- and postmenopausal women.

UNLABELLED: Uterine fibroids are common benign tumors of the reproductive organ and occur in approximately 50-80% of women of reproductive age. The pathogenesis of uterine fibroids is multifactorial and includes: sex hormones, genetic factors, cytokines, and oxidative stress. OBJECTIVE: The aim of this study was to investigate the oxidative stress markers in tissue samples of women with uterine fibroids, with further analysis on size and menopausal status. MATERIALS AND METHODS: Fifty-nine patients with the mean age 50.6 (35 premenopausal and 24 postmenopausal) who underwent standard gynecological procedures were recruited in the study. All women had histologically proven uterine leiomyoma. Samples were collected ex vivo immediately after resection. Glutathione peroxidase (GPX), catalase (CAT), and the ferric reducing ability of plasma (FRAP) were measured. RESULTS: The activity of GPX was significantly higher in fibroid samples than in myometrium (0.070 +/- 0.042 vs. 0.057 +/- 0.027 U/mg of protein, p < 0.05), activity of CAT did not differ between samples (1.13 +/- 0.86 vs. 1.23 +/- 0.51 U/mg of protein, p > 0.05), and FRAP presented higher values in fibroid samples than in myometrium (4.58 +/- 6.29 vs. 3.04 +/- 3.81 mM Fe(+2)/mg of protein), but the difference was not statistically significant (p = 0.06). In the subgroups analyses, there were no statistically significant differences when comparing the activity of GPX, CAT, and FRAP in fibroid samples from pre- and postmenopausal women, as well as when comparing fibroid samples of small size (< 50 mm) and large size (≥ 50 mm) tumors. CONCLUSION: Oxidative stress markers are changed in fibroid tissue samples showing that oxidative stress may play an important role in this tumor formation, although without influencing menopausal status nor tumor size.

Development of antiangiogenic therapies for ovarian cancer.

Angiogenesis is a dynamic process which leads to a development of cancer and metastases. The most recognized and dominant prognostic factor is vascular endothelial growth factor (VEGF) and its receptors. VEGF was identyfied in 1989. There are three receptors for VEGF: VEGFR1 (VEGF receptor 1) and VEGFR2 that play the role in angiogenesis and development of ascites, and VEGFR3 is critical for lymphangiogenesis. There is bevacizumab--a new drug, monoclonal antibody that can block connection VEGF to its receptors. The first notification of activity of bevacizumab in ovarian cancer was in 2005. The aim of the article is to show some clinical trials in ovarian cancer and their results. The bevacizumab was registered in November 2011 in first line with standard chemotherapy in ovarian cancer. There is a new weapon against this disease.

The expression of BRCA1, P53, KAI1, and Nm23 in ovaries of BRCA1 mutation carriers after prophylactic adnexectomy.

INTRODUCTION: High mortality rate, absence of reliable methods for early diagnosis and poor prognosis of advanced ovarian cancer prompted to investigate the role of prophylactic oophorectomy in BRCA1 mutation carriers as well as evaluate the expression of BRCA1, p53, Nm23, and KAI1 proteins in ovarian tissue from these patients. MATERIALS AND METHODS: Ovaries from BRCA1 mutation carriers underwent prophylactic adnexectomy and control group of patients were operated from other than cancer reasons. The expression of selected proteins was studied using immunohistochemical staining. The intensity of immunostaining and the number of tumor cells showing the reaction for selected proteins were analyzed. RESULTS: We have analyzed ovarian tissues from 18 BRCA1 mutation carriers and 11 women included in control group. Positive expression of BRCA1 protein was presented in 83.3 % cases in BRCA1 mutation carriers and in 72.7 % in the control group (p > 0.05). Positive expression of p53 protein was observed, respectively, in 27.8 vs. 36.4 % (p > 0.05), Nm23 protein 77.7 vs. 90.9 % (p > 0.05), and KAI1 in 72.2 vs. 72.7 % (p > 0.05). Mean percent of tumor cells that showed the reaction for selected proteins as well as the intensity of immunostaining for all analyzed proteins seems to be lower in BRCA1 mutation carriers. CONCLUSIONS: However, any significant differences between study group and control group have not been found; there were similar trends showing reduced expression of studied proteins in BRCA1 mutation carriers.

Effect of cryotherapy and povidone-iodine preparation on eradication of DNA corresponding to highly oncogenic HPV in women with lesions in the uterine cervix.

In all 88 patients, 23-67 years of age (mean of 34.8 years) with abnormal cytology, lesions in the uterine cervix and presence of DNA corresponding to highly oncogenic HPV, two cycles of uterine cervix cryotherapy and local treatment with povidone-iodine resulted in eradication of the virus six months after detection of the virus.

The effect of hyaluronic acid (Cicatridine) on healing and regeneration of the uterine cervix and vagina and vulvar dystrophy therapy.

Procedures aimed at the treatment of precancerous lesions and ectopia on the uterine cervix are frequently linked to lesions of anatomical structures. The application of hyaluronic acid (Cicatridine vaginal ovules) promotes accelerated healing of the uterine cervix and acquisition of a normal shape in the uterine cervix canal. Local application of hyaluronic acid in the vagina following radiotherapy due to cancer in the uterine cervix or endometrium favourably affects the healing of post-irradiation lesions in the vagina and improves quality of life. Over 90% of patients responded positively to the application of hyaluronic acid in the form of a cream on dystrophic lesions in the vulva. Hyaluronic acid aids the healing process of post-procedural wounds in the uterine cervix, following radiotherapy applied due to cancer of the uterine cervix, endometrium and in vulvar dystrophy.

Two cases of metachronic tumours: cancers of the ovary and endometrium in young women. Case presentation and review.

Ovarian and endometrial cancers seldom develop in females under 40 years of age. Manifestation of metachronic cancers before the age of 40 is of casuistic interest. Two cases are presented in whom metachronic cancers were detected: the first localisation involved the ovary, and the second the endometrium. One of the patients had earlier delivered a baby with multiple hereditary defects and was diagnosed with secondary infertility. The second patient was diagnosed with primary infertility. Immunohistochemical tests disclosed the presence of alpha and beta type estrogen receptors and progesterone receptors in the tumour cells of the ovary and endometrium. Neither of the patients carried mutations in the BRCA 1 or NOD 2 genes.

Activity of telomerase in ovarian cancer cells. Clinical implications.

Estimation of telomerase activity in cell nuclei of ovarian malignant tumours may provide an independent prognostic index. The test for telomerase activity in tumour cell nuclei may be accepted as a useful diagnostic test with application for differential diagnoses of benign ovarian tumours vs tumours of a borderline or malignant character.

Significance of serum CA125 and TPS antigen levels for determination of overall survival after three chemotherapy courses in ovarian cancer patients during long-term follow-up.

PURPOSE OF INVESTIGATION: To evaluate the prognostic significance for overall survival rate for the marker combination TPS and CA125 in ovarian cancer patients after three chemotherapy courses during long-term clinical follow-up. METHODS: The overall survival of 212 (out of 213) ovarian cancer patients (FIGO Stages I-IV) was analyzed in a prospective multicenter study during a 10-year clinical follow-up by univariate and multivariate analysis. RESULTS: In patients with ovarian cancer FIGO Stage I (34 patients) or FIGO Stage II (30 patients) disease, the univariate and multivariate analysis of the 10-year overall survival data showed that CA125 and TPS serum levels were not independent prognostic factors. In the FIGO Stage III group (112 patients), the 10-year overall survival was 15.2%; while in the FIGO Stage IV group (36 patients) a 10-year overall survival of 5.6% was seen. Here, the tumor markers CA125 and TPS levels were significant prognostic factors in both univariate and multivariate analysis (p < 0.0001). In a combined FIGO Stage III + FIGO Stage IV group (60 patients with optimal debulking surgery), multivariate analysis demonstrated that CA125 and TPS levels were independent prognostic factors. For patients in this combined FIGO Stage III + IV group having both markers below respective discrimination level, 35.3% survived for more than ten years, as opposed to patients having one marker above the discrimination level where the 10-year survival was reduced to 10% of the patients. For patients showing both markers above the respective discrimination level, none of the patients survived for the 10-year follow-up time. CONCLUSION: In FIGO III and IV ovarian cancer patients, only patients with CA 125 and TPS markers below the discrimination level after three chemotherapy courses indicated a favorable prognosis. Patients with an elevated level of CA 125 or TPS or both markers after three chemotherapy courses showed unfavorable prognosis.

Brain metastases from epithelial ovarian cancer--report of cases.

Epithelial ovarian cancer is one of the gynecological malignancies most commonly diagnosed late and one of the principal causes of mortality among women. The majority of women present with advanced disease. However, 5-year survival of patients with ovarian cancer has improved in recent years. Brain metastases from epithelial ovarian cancer are rare but in the last few years the incidence of brain complications seems to be increasing. Among all patients registered as having epithelial ovarian cancer at the Department of Oncology, Division of Gynecological Oncology, Poznan University of Medical Sciences, Poland between August 1998 and March 2008, four patients (4/669) who developed central nervous system (CNS) metastases were identified. Patients with symptoms of the CNS were evaluated by a neurologist, with a CT scan of the brain. The most common symptom of brain metastases are headaches which occur in 40-50% of patients. Because of the rarity of these patients, the optimal treatment for brain metastases is ill-defined. Brain metastasis usually appears with a poor prognosis, however early diagnosis and aggressive multimodal treatment can improve the quality of life in patients.

Significance of hypoxia in uterine cervical cancer. Multicentre study.

PURPOSE: The aim of the study was to evaluate hypoxia markers (VEGF, GLUT-1, and HIF-1alpha) in cervical cancer tissue depending on staging (FIGO) and grading. We also analyzed the adverse effects of radiotherapy according to expression levels of hypoxic markers in the studied tissue. MATERIAL AND METHODS: Expression of hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter 1 (GLUT-1) and vascular endothelial growth factor (VEGF, also known as proangiogenic factor) were estimated in biopsy or surgical specimens from 106 patients diagnosed with uterine cervical cancer. Immunohistochemical methods with EbVision+ complex using monoclonal antibodies anti-VEGF and anti-HIF-1alpha and polyclonal antibody anti-GLUT-1 were applied. RESULTS AND CONCLUSIONS: Hypoxia features measured by percentage of cells undergoing reaction with antibodies anti-HIF-1alpha, anti-GLUT-1 and anti-VEGF were similar in all clinical stages; however the biggest hypoxia features were shown in low differentiated cancers G2 and G3. The 5-year survival for FIGO Stage III patients was shorter in cases with a high expression of hypoxic markers. We observed adverse effects in 45.3% of patients, which occurred more often in patients with higher expression of the studied factors. The presence of hypoxic cells is established as one of the most important factors affecting resistance against tumor radiotherapy and patient prognosis.

Peritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination.

This study aimed to assess the potential value of peritoneal fluid cytokine examination for the differential diagnosis of ovarian tumors and for evaluating residual or recurrent disease after treatment. The cytokines that are commonly elevated in ovarian cancer, VEGF, IL-6, bFGF, IL-8 and M-CSF, and a reference ovarian tumor marker, CA 125, were measured in peritoneal fluids of 53 previously untreated patients with epithelial ovarian cancer, 18 ovarian cancer patients after surgical treatment and chemotherapy, and 17 patients with benign epithelial ovarian tumors. Non-parametric statistical analysis of data was performed. Ovarian cancer peritoneal fluids, as compared to peritoneal fluids of patients with benign ovarian tumors, contained significantly higher concentrations of IL-6, VEGF and CA 125, and significantly lower concentrations of bFGF and M-CSF, but only the levels of IL-6 and VEGF were significantly higher in peritoneal fluids of stage I and II ovarian cancer patients than of patients with benign ovarian conditions. IL-6 at the cutoff level of 400 pg/mL discriminated benign and malignant ovarian tumors with 92% sensitivity and 60% specificity, while VEGF at the cutoff of 400 pg/mL had 90% sensitivity and 80% specificity. At the cutoff level of 1200 pg/mL, IL-6 had 84% sensitivity and 87% specificity. A radical decrease in local cytokine and CA 125 levels in patients after treatment was independent of therapy outcome. IL-6 and VEGF measurements in peritoneal fluids might be useful for the differential diagnosis of malignant and benign ovarian conditions, but not for residual or recurrent disease examination.

Preliminary results of mitomycin C local application as post-treatment prevention of vaginal radiation-induced morbidity in women with cervical cancer.

PURPOSE: To determine the usefulness of local mitomycin C application in the prophylaxis of vaginal narrowing after irradiation. MATERIAL AND METHODS: 31 patients with advanced cervical cancer qualified for the study. They underwent brachytherapy with iridium-192 isotope and external beam therapy with linear accelerators. In a blind probe method 16 patients were chosen to have an aqueous solution of mitomycin C applied to the vagina. RESULTS: Radiotherapy caused a shortening of vaginal length in both groups (study and control). In the "mitomycin C group" complete vaginal occlusion was visibly less frequent as were solid fibrotic vault changes. CONCLUSIONS: This mode of morbidity prevention can potentially diminish the occurrence of local vaginal fibrosis and thus may improve patients' quality of life. Further investigations are needed to confirm these results.

TP53 status determines clinical significance of ERBB2 expression in ovarian cancer.

ERBB2 expression has been found in 19 to 44% of ovarian carcinomas; however, its predictive value has not been demonstrated, and trastuzumab has not found clinical application in ovarian cancer patients. We evaluated clinical significance of ERBB2 expression in relation to TP53 accumulation in ovarian carcinoma patients treated with platinum-based regimens. Immunohistochemical analysis with CB11 and a novel NCL-CBE356 antibody (against the internal and external domains of ERBB2, respectively) was performed on 233 tumours (FIGO stage IIB-IV); the US Food and Drug Administration-approved grading system with 0 to 3+ scale was used for evaluation, and the results were analysed by the Cox and logistic regression models. In all, 42% of the tumours expressed (category 1+, 2+ or 3+) either CB11 or CBE356 or both (CB11/CBE356 parameter). Associations between ERBB2 expression and clinical factors were observed only if tumours with staining category 1+ were grouped together with tumours showing staining categories 2+ and 3+. CB11/CBE356 parameter had a better predictive value than CB11 alone. CB11/CBE356 expression was negatively associated with platinum sensitivity (PS) in the TP53(-) group (P=0.022) and with disease-free survival (DFS) in the TP53(+) group (P=0.009). Our results may suggest that trastuzumab should be given postoperatively to patients with TP53(-)/ERBB2(+) ovarian carcinomas to enhance PS, and after completion of chemotherapy to patients with complete remission and TP53(+)/ERBB2(+) carcinomas to extend DFS time (in total to 30.4% of all patients analysed). Thus, novel criteria for ovarian cancer patient inclusion for clinical trials with trastuzumab should be considered and tested.