Caterina Ricci

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.

Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial

BACKGROUND Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. METHODS We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. FINDINGS Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. INTERPRETATION Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. FUNDING National Cancer Institute of Napoli and GlaxoSmithKline.

Quality of life and psychological distress in locally advanced cervical cancer patients administered pre-operative chemoradiotherapy

OBJECTIVE The aim of the study was to analyze the Quality of life (QoL) scores in a single institution series of locally advanced cervical cancer patients (LACC) administered preoperative chemoradiation, compared to early stage disease (ECC) patients undergoing radical surgery. METHODS The following criteria were required in order to enroll patients: age between 18 and 65years at initial diagnosis, at least 12 months from the end of treatment, no evidence of recurrence/second malignancy. The SF-36 questionnaire on general health, and the HADS questionnaire on mental distress were utilized. RESULTS 93 subjects were available for the analysis. At time of analysis, median follow-up was 30 months (range 12-120). LACC patients showed QoL scores comparable to ECC patients with the exception of physical functioning (mean+/-SD=69.0+/-13.1 versus mean+/- SD=85.4+/-16.2, p value=0.0007). In the group of LACC patients, the presence of co-morbidities was significantly associated with the impairment of almost all subscales of QoL. A low education level and the status of unemployment were documented to negatively impact on the vast majority of SF-36 subscale scores. In the multivariate analysis, the presence of co-morbidities, low educational level, age> 50 years, and unemployment maintained their independent negative association with poor QoL scores. The percentage of cases with high levels HADS-anxiety was higher in LACC than ECC patients (27.6% versus 8.6%, p value=0.034). CONCLUSIONS LACC patients administered preoperative chemoradiation showed QoL scores comparable to EEC patients, and a higher proportion of anxiety disorders; low educational level and unemployment status were mainly associated with poor QoL scores.

Vascular Involvement in Inflammatory Bowel Disease: Pathogenesis and Clinical Aspects

Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a microvascular and also macrovascular involvement. Chronically inflamed intestinal microvessels of IBD patients have demonstrated significant alterations in their physiology and function compared with vessels from healthy and uninvolved IBD intestine. Recently, some studies have revealed that the poor mucosal healing, refractory inflammatory ulcerations and damage in the IBD intestine could depend on microvascular dysfunction, resulting in diminished vasodilatory capacity and tissue hypoperfusion in the IBD gut. Furthermore, several data show that the activation of intestinal endothelium plays a critical role in the pathogenesis and/or in perpetuating and amplifying the inflammatory process in IBD and, consequently, it is now emerging as a potential use of anticoagulant or coagulation-related drugs in treating IBD. IBD is also associated with an increased risk of macrovascular venous and arterial thrombosis. Thrombotic events occur prevalently as deep vein thrombosis and pulmonary embolism. They happen at an earlier age than in non-IBD patients. Prothrombotic risk factors in IBD patients could be distinguished as acquired, such as active inflammation, immobility, surgery, steroid therapy, and use of central venous catheters, and inherited. Furthermore, it has been found that IBD, per se, is an independent risk factor for thrombosis. The prevention of thromboembolic events in IBD patients includes the elimination of removable risk factors and, if thrombosis occurs, a pharmacological therapy similar to that used for thromboembolic events occurring in the general population.

HPV vaccine cross-protection: Highlights on additional clinical benefit

Prophylactic human papillomavirus (HPV) vaccines are administered in vaccination programs, targeted at young adolescent girls before sexual exposure, and in catch-up programs for young women in some countries. All the data indicate that HPV-virus-like particles (VLPs) effectively prevent papillomavirus infections with a high level of antibodies and safety. Since non-vaccine HPV types are responsible for about 30% of cervical cancers, cross-protection would potentially enhance primary cervical cancer prevention efforts. High levels of specific neutralizing antibodies can be generated after immunization with HPV VLPs. Immunity to HPV is type-specific. However, if we consider the phylogenetic tree including the different HPV types, we realize that a certain degree of cross-protection is possible, due to the high homology of some viral types with vaccine ones. The assessment of cross-protective properties of HPV vaccines is an extremely important matter, which has also increased public health implications and could add further value to their preventive potential. The impact of cross-protection is mostly represented by a reduction of cervical intraepithelial neoplasia CIN2-3 more than what expected. In this article we review the mechanisms and the effectiveness of Bivalent (HPV-16/-18) and Quadrivalent (HPV-6/-11/-16/-18) HPV vaccine cross-protection, focusing on the critical aspects and the potential biases in clinical trials, in order to understand how cross-protection could impact on clinical outcomes and on the new perspectives in post-vaccine era.

Treatment of cervical cancer in Italy: Strategies and their impact on the women

Treatment of cervical cancer greatly varies according to the stage of the disease. Laparoscopic surgical staging is emerging as a valid approach, compared to clinical and imaging staging, to better identify the treatment plan. Minimally invasive surgery plays the greatest role in the treatment of early cervical carcinoma (ECC). Laparoscopically assisted radical vaginal hysterectomy (LARVH) is an alternative surgical strategy in this subset of patients. Interest has been increasing in using conservative fertility-sparing surgery such as laparoscopic vaginal radical trachelectomy (LVRT) or chemo-conization, options to be preferred in selected patients, with early-stage disease and asking for future fertility. Chemoradiotherapy currently represents the gold standard in the treatment of patient with locally advanced cervical cancer (LACC). In Italy, neoadjuvant chemotherapy (NACT) followed by radical surgery is today emerging as a valid alternative to the standard chemoradiation and the paclitaxel, ifosfamide and cisplatin (TIP) regimen is one of the most active neoadjuvant chemotherapeutic treatments. Moreover, the combination of different strategies to maximize local control should be considered. Among different approaches to this issue the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery has been investigated. Our data on a large single-institutional series of LACC patients treated with chemoradiation followed by radical surgery confirm that this three-modality treatment can achieve overall survival (OS) and Disease Free Survival (DFS) rates at least comparable to chemoradiation alone, with an acceptable rate of complications. Tailoring of radical surgery, on the basis of intraoperative findings, such as lympho-nodes status, might play an important role in diminishing the overall rate of complications and eventually improve quality of life (QoL) of these patients. Cervical cancer generally has an aggressive impact on relatively young women and, as we experienced, the relevance of psychosocial aspects in gynaecologic oncology has become a main issue.

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.