Rosa De Vincenzo

Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

ABSTRACT Infection with high-risk (HR) human papillomavirus (HPV) is the major cause of cervical cancer. However, relatively few infections progress to malignant disease. Progression to malignancy requires the overexpression of the E6 and E7 genes in the integrated HPV genome. It follows that the E6 and E7 transcripts could be useful markers of disease progression. The study presented here tests this possibility, using data from colposcopy and from cytological and histological tests to compare RNA assays for the E6 and E7 genes with DNA testing. A total of 180 women underwent colposcopy, cytology, and biopsy of suspected lesions (143 cases). Cervical brush specimens were analyzed for HPV DNA and for E6 and E7 mRNA. DNA from HR HPV was found in 57.8% of the specimens; E6 and E7 transcripts were found in 45%. The rates of detection of HPV DNA and of E6 and E7 transcripts were 33.3% and 25%, respectively, for specimens with normal findings; 51.4% and 31.9%, respectively, for specimens with cervical intraepithelial neoplasia grade 1 (CIN1); and 61.1% and 44.2% for specimens with CIN2, respectively. All specimens with CIN3 and 95.5% of specimens from patients with squamous cell carcinoma were positive by both assays. Thirty-seven patients with normal colposcopy findings did not undergo biopsy. HPV DNA and mRNA transcripts were found in 32.4% and 18.9% of these cases, respectively. Comparisons with cytological tests produced similar results. Overall, the mRNA tests showed a higher specificity than the DNA tests for high-grade lesions (72.7% and 56.2%, respectively) and a higher positive predictive value (59.3% and 49.0%, respectively). These findings suggest that mRNA assays could be more powerful than DNA testing for predicting the risk of progression and offer a strong potential as a tool for triage and patient follow-up.

Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF‐7 human breast‐cancer cells

In this study the ability of the new pure anti‐estrogen ICI 182,780 to modulate the cytotoxic action of adriamycin (ADR) on parental and ADR‐resistant MCF‐7 (MCF‐7 ADRr) human breast‐cancer cells was investigated and compared with that of tamoxifen (TAM). TAM enhanced ADR cytotoxicity in MCF‐7 ADRr cells in a dose‐related manner, but this effect was slight or absent in MCF‐7 WT. In contrast, ICI 182,780 was able to enhance ADR toxicity both in MCF‐7 ADRr and in the parental cell line. ICI 182,780 was up to 2.5‐fold more effective than TAM in reducing the IC50 of ADR in MCF‐7 ADRr cells. Analysis of the data by the isobole method showed that the combination ADR/TAM and ADR/ICI 182,780 produced synergistic anti‐proliferative activity in MCF‐7 ADRr cells. Because ADR resistance in these cells is associated with the expression of high levels of P‐glycoprotein (Pgp), we evaluated the effect of anti‐estrogens on Pgp expression and activity. Both ICI 182,780 and TAM failed to modulate Pgp expression as assessed by flow cytometry and Western‐blot analysis, performed using the monoclonal antibodies MM4.17 and C219, which are specific for an external or an internal determinant respectively. Pgp activity was investigated by flow cytometry measuring the extrusion of ADR and the cationic dye Rhodamine 123 (Rh 123). ICI 182,780, but not TAM, reduced the activity of Pgp in MCF‐7 ADRr cells. Flow cytometry was also used to investigate cell‐cycle modifications induced by ADR in MCF‐7 ADRr cells, both in the presence and in the absence of anti‐estrogens. After 72 hr, higher doses induced an arrest of cells at the G2/M phase. The same effect was visible when lower doses of ADR were combined with ICI 182,780 or TAM. In terms of cell‐cycle‐blocking activity ICI 182,780 was largely more effective than TAM.

Synergistic antiproliferative activity of tamoxifen and cisplatin on primary ovarian tumours

We looked for the presence of the so-called type II oestrogen binding sites (EBS), in four oestrogen (ER) and progesterone (PR) receptor negative primary ovarian tumours. Moreover, the colony-forming assay was used to evaluate the response of ovarian cancer cells from these primary tumours to tamoxifen and cisplatin used alone or in combination. All tumours contained type II EBS, and tamoxifen was able to compete for [3H] oestradiol binding to these sites. Cisplatin and tamoxifen exhibited a dose-dependent inhibition of colony formation in a range of concentrations between 10 and 1000 micrograms/l and 37 and 3710 micrograms/l, respectively. The combination of the two drugs resulted in a synergistic antiproliferative activity, with a potentiation up to and beyond 50-fold. Our results show that in ovarian cancer tamoxifen interacts with type II EBS with an affinity consistent with the concentration effective both in inhibition of colony formation and in synergising cisplatin activity. Based on the experiments performed the action of tamoxifen on cell growth is independent of ER expression, and could be mediated by type II EBS. The possibility that the association of tamoxifen and cisplatin may result in an improved clinical response in ovarian cancer should be investigated.

Evaluation of quality of life and emotional distress in endometrial cancer patients: A 2-year prospective, longitudinal study

OBJECTIVES The aim of the study was to prospectively, and longitudinally assess Quality of Life (QoL) and emotional distress in a large series of endometrial cancer (EC) patients. METHODS Global Health Status of the EORTC QLQ-C30 (GHS), the EORTC QLQ-CX24 (CX24), and the Hospital Anxiety and Depression Scale (HADS) questionnaires were administered at diagnosis, and after 3, 6, 12, and 24months since surgery. The Generalized Linear Model and the Between Subject test were used to analyze QoL changes over time, and the association between factors and patient QoL. RESULTS GHS scores improved over time, although the statistical significance was not reached. Worse lymphedema scores were documented worsened over time with a trend to recover at the 12- and 24month evaluation (p-value=0.028). Scores for Menopausal Symptoms (MS) dramatically worsened over time reaching a 38.5 difference of mean±SE compared to baseline (p-value=0.011). Sexual Activity (SxA) scores improved until the 12-month evaluation (p-value=0.048), and showed a return to baseline levels at the last assessment (p-value=0.025). A significant improvement of anxiety scores was documented at the 3-month evaluation, and persisted over time. In multivariate analysis, unmarried status was associated with poor scores for sexual activity, while living with someone was associated with worse MS scores. CONCLUSIONS Menopausal and lymphedema symptoms heavily affect QoL in EC patients. Since socio-demographic features play a major role in deteriorating SxA and MS, psycho-social intervention and patient education should be considered as an integral part of EC patient treatment.

Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence.

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.

Bowel endometriosis with hemoperitoneum complicating pregnancy

Case Report We report a case of bowel endometriosis complicated by spontaneous hemoperitoneum and miscarriage in a 33-year-old primigravida at the 24th week of gestation. An emergency laparotomy showed spontaneous rupture of the left uterine artery and bowel wall endometrioma. Artery suture, bowel resection and cesarean section on demised fetus were performed. Conclusions Although pregnancy may have beneficial effects on endometriosis, rare but significant endometriosis-associated pregnancy complications may also occur.

Locally Advanced Cervical Cancer in Pregnancy: Overcoming the Challenge. A Case Series and Review of the Literature.

Objective Cervical cancer is the most common gynecological cancer occurring in pregnancy, creating a complex situation both for patient and physician. Neoadjuvant chemotherapy is an innovative way of managing cervical cancer in pregnancy. Methods In our paper, we report a retrospective case series of 4 women treated with chemotherapy for invasive cervical cancer during pregnancy in our center over the last 5 years, and we summarize the available literature and guidelines. Results All the cases were locally advanced cervical cancers that received chemotherapy with platinum and/or taxanes. All patients showed a good response to chemotherapy and a radical surgery was performed with no additional morbidities at the cesarean delivery time in 3 of 4 cases. Three of 4 patients are alive and have a good outcome with no recurrence of disease up to date. One patient died because of recurrent disease 2 years after the first-line treatment during pregnancy. All babies are alive and well up to date (maximum follow-up, 63 months). Conclusions Even if there are no standardized practices in the treatment of cervical cancer in pregnancy, in our opinion, neoadjuvant chemotherapy can be a very useful strategy for patients and physicians facing the challenge.

Real-world management of trabectedin/pegylated liposomal doxorubicin in platinum-sensitive recurrent ovarian cancer patients: A national survey

Background Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. Methods We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians’ approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. Results Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients’ choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. Conclusions This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.