G. Vlachos

Hormonal therapy with letrozole for relapsed epithelial ovarian cancer: Long-term results of a phase II study

Objective: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer. Methods: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors. Results: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression. Conclusion: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated.

Management of ureteric injuries during gynecological operations: 10 years experience

OBJECTIVE(S) To present our 10 years experience in the management of ureteric injuries occurring during gynecological surgery. STUDY DESIGN Seventy-six patients had a variety of injuries. In 29 cases, the ureteric damage was diagnosed intraoperatively. Management of early-diagnosed injuries included suturing, ligature removal, end-to-end anastomosis, and reimplantation of the ureter. In 47 cases, the injury was diagnosed postoperatively. Ureteric catheterization was attempted in all cases presenting with obstruction. Catheterization failures were managed with ureterolysis, and reimplantation. Small ureteric fistula were managed with catheterization, and large communications with reimplantation. Two cases with urinomas were treated with surgical evacuation and anastomoses. RESULTS Management of early-diagnosed injuries was relatively easy in most cases. Postoperatively-diagnosed injuries were more difficult to treat. Catheterization failed in 28/44 (65.9%) ureters and surgical re-exploration was necessary. Long-term morbidity was minimal and no relapses occurred. CONCLUSION(S) Early recognition of a ureteric injury is the key to a complications-free repair. Unrecognized injuries cause prolonged morbidity, and their management can be difficult. Treatment of these injuries by experienced teams may minimize long-term consequences.

Risk factors in women 40 years of age and younger with endometrial carcinoma

Objective. To identify and compare risk factors among endometrial cancer patients ≤40 years of age, postmenopausal women with the same malignancy and women ≤40 years without malignancy. Design. Retrospective case–control study. Setting. Athens University, department of obstetrics and gynecology of a tertiary hospital serving a mainly urban population. Population. Endometrial cancer patients ≤40 years (study group, n = 40), postmenopausal women with the same malignancy (positive controls, n = 40) and women ≤40 (negative controls, n = 40) without endometrial cancer. Methods. Clinical history, treatment and follow‐up of patients were evaluated. Factors studied included age, histology, stage, grade, lymphovascular space involvement, body mass index (BMI), cytology, lymph node status, parity, smoking, family history, hypertension recurrence and survival. Main outcome measures. Differences in risk factors and characteristics. Results. Nulliparity, smoking and hypertension were significantly related with endometrial cancer in the study group compared to positive controls (p = 0.001, p < 0.01 and p < 0.001, respectively). BMI >30 significantly characterized patients in the study group compared to negative controls (p = 0.006). Finally, irregular menstruation and family history of cancer were observed more often in the study group compared to both control groups. Stage, grade, myometrial invasion, lymphovascular space involvement and lymph node status were comparable between the study and positive control groups. Conclusion. Nulliparity, obesity, unstable menstruation, smoking and cancer in the family are strongly correlated with endometrial cancer risk in women ≤40 years.

Nevirapine induces growth arrest and premature senescence in human cervical carcinoma cells

OBJECTIVE The aim of this study was to assess the impact of nevirapine on a cervix carcinoma cell line. METHODS HeLa cells were cultured in Dulbeccos modified Eagle medium supplemented with 20% fetal bovine serum at 37 degrees C and humidified 10% CO(2) in air. Nevirapine was purified from commercially available Viramune (Boehringer-Ingelheim), diluted in dimethyl sulfoxide (DMSO, Sigma-Aldrich) in 350 microMu final concentration and added to cell cultures 5 h after seeding. The same DMSO volume (0.2% final concentration) was added to controls. RESULTS We found that nevirapine treatment induces reversible growth arrest and produces morphological changes in treated cells. In contrast with previous reports the observed effects of nevirapine did not correlate with promotion of differentiation, but with induction of premature senescence. Premature senescence as a response to anti-tumour treatment is a common effect of the most anti-cancer chemotherapeutics. Nevirapine treated cells strongly accumulated SA-b-Gal activity and also expressed increased levels of p53 and p21 when analyzed via RT-PCR. In order to further explore the potent mechanisms of premature senescence induction we performed pChk2-Thr68 immunofluorescence analysis and found that nevirapine treated cells exhibited increased number of nuclear foci, indicating activated DNA damage response. CONCLUSION We propose that at least in HeLa cell line nevirapine treatment exerts an effect far from the differentiation process, by introducing the cells into premature senescence. Based on these data, the effects of RT inhibitors should be further investigated since they may represent an additional agent against human cancer.

Fetal alcohol spectrum disorders and cognitive functions of young children

Abstract Fetal alcohol spectrum disorder (FASD) is one of the main causes of mental retardation worldwide. Nearly 1% of children in North America are affected from antenatal exposure to ethanol. Its economic burden in industrialized countries is increasing. It is estimated that, in the United States, 4.0 billion dollars are annually expended in the treatment and rehabilitation of these patients. As a pathologic entity, they present with a broad symptomatology. Fetal alcohol syndrome (FAS) is the most readily recognized clinical manifestation of these disorders. Various factors seem to contribute in the pathogenesis of FASD-related cognitive disorders. During the last 20 years, several potential pretranslational and posttranslational factors have been extensively studied in various experimental animal models. Research has specifically focused on several neurotransmitters, insulin resistance, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, abnormal glycosylation of several proteins, oxidative stress, nutritional antioxidants, and various epigenetic factors. The purpose of the present review is to summarize the clinical manifestations of this disorder during childhood and adolescence and to summarize the possible pathophysiologic and epigenetic pathways that have been implicated in the pathophysiology of FASD.

High-dose melphalan and autologous stem cell transplantation as consolidation treatment in patients with chemosensitive ovarian cancer: Results of a single-institution randomized trial

The role of high-dose chemotherapy (HDCT) in epithelial ovarian cancer (EOC) remains controversial. This study was initiated to compare the efficacy and tolerability of HDCT as a consolidation approach in women with chemosensitive advanced EOC (FIGO stages IIC–IV). Patients who had achieved their first clinical complete remission after six cycles of conventional paclitaxel and carboplatin combination chemotherapy were randomly assigned to receive or not high-dose melphalan. The primary objective was to compare time to disease progression (TTP). A total of 80 patients were enrolled onto the trial. Patients who were randomized to receive HDCT were initially treated with cyclophosphamide 4 g/m2 for PBPC mobilization. HDCT consisted of melphalan 200 mg/m2. Of the 37 patients who were allocated to HDCT, 11 (29.7%) did not receive melphalan either due to patient refusal (n=5) or due to failure of PBPC mobilization (n=6). In an intent-to-treat analysis, there were no significant differences between the two arms in TTP (P=0.059) as well as in overall survival (OS) (P=0.38).

Laparoscopically assisted vaginal radical hysterectomy: systematic review of the literature.

Laparoscopically assisted vaginal radical vaginal hysterectomy (LAVRH), a minimally invasive technique that seems to be an attractive alternative to traditional surgery, remains unexplored in the treatment of cervical cancer. We searched Medline (1966-2013) and Scopus (2004-2013) search engines, as well as reference lists from all included studies. Ten studies were retrieved; including 6 retrospective cohort studies, 2 prospective cohort studies, 1 retrospective randomized trial, and a phase II randomized control trial. LAVRH provided equal recurrence-free rates when performed in patients with tumors not exceeding 2 cm in greatest diameter. Its main advantages seem to be less intraoperative blood loss and more radical pelvic lymphadenectomy. The primary disadvantages of the technique are a higher rate of disease-positive surgical margins, resulting in the need for adjuvant therapy, and the slow learning curve required for a surgeon to gain expertise. With use in minimally invasive surgery of newer techniques such as total laparoscopic radical hysterectomy and robotic-assisted radical hysterectomy, and possible future adoption of more conservative techniques such as cervical conization with pelvic lymphadenectomy, the question remains as to whether LAVRH will be adopted by the surgical community or lost to oblivion.

Diabetes mellitus and functional sperm characteristics: A meta-analysis of observational studies.

OBJECTIVE Insulin resistance and diabetes mellitus (DM) are well defined causes of female infertility. Animal studies present evidence for decreased sperm quality, but conflicting results have been presented in clinically-orientated studies. We sought to evaluate whether DM affects functional sperm characteristics. STUDY DESIGN We searched the Medline, Scopus, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials databases. RESULTS DM seems to decrease the seminal volume (MD -0.66ml, 95% CI -1.10, -0.22) and the percentage of motile cells (MD -14.29%, 95% CI -22.76, -5.82) and increase the FSH values (MD 0.47mIU/ml, 95% CI 0.01, 0.93) of men who were screened for infertility. It does not, however, influence the total sperm count (MD 13.16 106 cells, 95% CI -22.75, 49.07), the percentage of normal sperm morphology (-3.06%, 95% CI -6.25, 0.14), or LH (MD 0.65mIU/ml, 95% CI -0.84, 2.13 Supp. Fig. 2) and testosterone values (MD -0.18ng/ml, 95% CI -0.60, 0.24). CONCLUSION Current evidence suggests that the presence of DM seems to influence functional sperm characteristics. Firm results are, however, precluded due to the significant heterogeneity of the included studies. Future prospective studies will clarify whether the DM affects semen quality and IVF outcome.

Uterine fibroid in an adolescent: An unlikely diagnosis?

treatment was contraindicated due to her severe asthma. The combined oral contraceptive pill is also used as first-line treatment for primary dysmenorrhoea. Once again, this treatment was also unsuitable for this patient due to her Factor V Leiden mutation and her family history of venous thromboembolic disease. We are not aware of any studies to date describing the use of the POP in the treatment of primary dysmenorrhoea. Long-term continuous progestogen therapy is known to have an antimitotic effect on the endometrium thus inhibiting proliferation (Moyer and Felix 1998). It would seem logical that a reduction in endometrial activity would lead to lighter and less painful periods. Ideally, continuous progestogens would induce endometrial atrophy leading to an absence of menstruation and associated pain. After 9 months’ treatment with Micronor , our patient had no change in her menstrual blood loss or dysmenorrhoea. We then decided to try other hormonal methods of menstrual suppression similar to those suggested by the National Institute of Clinical Excellence (NICE), for the treatment of heavy menstrual bleeding (NICE 2007). Long acting injectable medroxyprogesterone acetate (DepoProvera ) has been reported to be effective in reducing symptoms of dysmenorrhoea in up to two thirds of adolescents (Harel et al. 1995). There are however, concerns that the use of Depo-Provera can reduce bone mineral density. In 2004 Pfizer, the manufacturer of Depo-Provera , issued a black box warning indicating that the use of the drug by adolescents was associated with a significant decline in bone mineral density from baseline (FDA 2004). We felt in this particular patient, the potential advantages of DepoProvera outweighed these risks and she was started on treatment. Although this treatment ultimately failed, its initial positive effect prompted the consideration of other methods to suppress endometrial activity. The use of Mirena as a treatment for primary dysmenorrhoea in adolescents has not been previously considered. The Mirena is thought to produce a local progestogenic effect within the uterine cavity, mainly in the form of decidualisation of the stroma and atrophy of endometrial glands (Phillips et al. 2003), and also a reduction in endometrial proliferation (Silverberg et al. 1986). The Mirena has no demonstrated effect on either bone mineral density or peak bone mass in contrast to Depo-Provera . This would indicate that a predominantly local steroid administration to the endometrium might be a safer option for women in the adolescent age group who are particularly susceptible to a reduction in peak bone mass from systemic steroids such as medroxyprogesterone acetate. Potential problems with using a Mirena in adolescents would be with insertion and the size of the uterine cavity. Our patient had not been sexually active and opted for insertion under a general anaesthetic. At this time, she was noted to have a normal sized uterine cavity.

The Impact of Underweight Status on the Prognosis of Ovarian Cancer Patients: A Meta-Analysis

ABSTRACT Malnutrition and underweight status pose an unfavorable prognosis for cancer patients. Several studies have addressed the impact of a low body mass index (BMI) (<18.5 kg/m2) on ovarian cancer progression. However, their results seem to be conflicting. The present meta-analysis investigates whether the underweight status negatively affects the progress of ovarian cancer. We conducted a systematic review searching the Medline (1966–2014), Scopus (2004–2014), Popline (1974–2014), ClinicalTrials.gov (2008–2014), and Cochrane Central Register of Controlled Trials (CENTRAL) (1999–2014) databases together with reference lists from included studies. All prospective and retrospective observational cohort studies were included. Statistical meta-analysis was performed using the RevMan 5.1 software. Current evidence suggests that the stage of the disease does not differ between underweight and normal-weight patients [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.46–1.39 for stage I; OR 1.27, 95% CI 0.71–2.27 for stage II; OR 1.03, 95% CI 0.71–1.51 for stage III; and OR 1.05, 95% CI 0.63–1.76 for stage IV disease]. Concurrently, the risk of residual disease after surgery (OR 1.03, 95% CI 0.69–1.52) and the risk of dying due to ovarian cancer (OR 1.08, 95% CI 0.64–1.85) seem to be similar. According to the findings of our systematic review, the underweight status does not seem to have a detrimental impact on ovarian cancer prognosis. However, the methodological limitations of published studies and the small number of enrolled underweight patients preclude firm results. Thus, future research in this field is necessary.