Alessandra Felici

The 5′ sequence of human Factor XII gene contains transcription regulatory elements typical of liver specific, estrogen-modulated genes

The human Factor XII gene codes for a serine proteinase synthesized in liver that activates both the coagulation and the fibrinolytic cascades. The nucleotide sequence analysis of a HincII-HincII 3129 bp fragment was performed showing that the FXII promoter region contains neither CAAT and TATA regulatory elements, nor GC islands, but revealing the presence of two tandemly repeated sequences in opposite orientation, two LF-A1 elements typical of the liver specific genes and one estrogen responsive element, that substantiates the observation of Factor XII gene modulation by estrogens.

Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting

AIM The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Functional and pharmacodynamic evaluation of metronomic cyclophosphamide and docetaxel regimen in castration-resistant prostate cancer

AIM The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC). MATERIALS & METHODS CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC. RESULTS Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients. CONCLUSION Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation

BACKGROUND We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Progression-free survival (PFS) and overall survival (OS) in patients receiving three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC).

431 Background: In recent years, TTs have improved the prognosis of mRCC patients (pts). Despite a non-negligible number of pts received 3 TTs in clinical practice, no TTs have been evaluated as third-line. Aim of this study is to investigate the clinical outcome in pts who received 3 TTs. METHODS Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was sent to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type and length of first-, second- and third-line were collected; MSKCC risk class was calculated before starting the first-line. Sequences were evaluated by class (TKI-TKI-mTOR vs. TKI-mTOR-TKI) or by drug (Su-So-Ev vs. Su-Ev-So). Median PFS, OS and Time to Strategy Failure (TTSF: from start of first- to end of thrid-line) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. Cox model was used to explore predictors of TTSF and OS. The study had the ethical approval. RESULTS 2,065 pts were screened and 281 pts (13%) were treated with 3 TTs. No differences were found between TKI-TKI-mTOR and TKI-mTOR-TKI groups. The TTSF was 36.5 (30.5-42.6) mos vs. 29.3 (23.6-34.9) mos (p=0.059), and the OS was 50.7 (40.6-60.8) vs. 37.8 (34.2-41.5) mos (p=0.004), for TKI-TKI-mTOR and and TKI-mTOR-TKI, respectively. TTSF for Su-So-Ev was 32.1 vs. 30.4 mos for Su-Ev-So (p=0.006). The median OS was not reached in the group treated with Su-So-Ev compared to 35.6 (95%CI, 31.6-39.6) mos in the group treated with Su-Ev-So (p<0.001). The univariate and multivariable Cox analyses for TTSF and OS showed that the only predictive factor is the primary resistance to 1st line (HR: 3.15, 95%CI, 1.98-4.99; p<0.001). The Prognostic factors are the initial MSKCC group (HR: 2.07, 95% CI, 1.41 -3.05; p<0.001), the sequence of therapy (HR: 2.59, 95% CI, 1.59-4.22; p<0.001) and the primary resistance to first line (HR: 2.20, 95% CI, 1.16-4.11; p<0.001). CONCLUSIONS We report as the sequential treatment with two antiangiogenic inhibitors followed by an mTOR inhibitor could increase survival and the control disease in metastatic renal cell carcinoma.

Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan–Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient’s median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.