[show abstract][hide abstract] ABSTRACT: Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed.
European review for medical and pharmacological sciences 08/2013; 17(16):2145-58. · 1.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective:The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival.Methods:A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were analysed. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence.Results:A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months (range 6-498). Of these, 33 patients had at least one episode of disease recurrence, with a median time to recurrence of 53 months (range 9-332). Also, 47% of recurrences occurred after 5 years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment outside MITO centres and incomplete surgical staging retained significant predictive value for recurrence in both univariate and multivariate analyses.Conclusions:This study confirms the generally favourable prognosis of GCTs of the ovary, with 5-year overall survival approaching 97%. Nevertheless, prognosis after 20 years was significantly poorer, with 20-year survival rate of 66.8% and a global mortality of 30-35. These findings support the need for lifelong follow-up even in early-stage GCT.British Journal of Cancer advance online publication 11 June 2013; doi:10.1038/bjc.2013.241 www.bjcancer.com.
British Journal of Cancer 06/2013; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.
Proceedings of the National Academy of Sciences 05/2013; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters. METHODS: Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: "d[CA-125]/dt = (KPROD * exp (BETA*t)) * Effect -KELIM*[CA-125]" with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors. RESULTS: Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P<0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR = 0.53; 95% CI 0.45-0.61; P<0.001). CONCLUSIONS: Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To identify a phenotype that could be informative and prognostic in patients with renal cell carcinoma (RCC) peripheral blood was evaluated for TH1, TH2, regulatory T cells (Tregs), natural killer (NK) and NKT cells and for cytokines/chemokines. PATIENTS AND METHODS: Peripheral blood from 77 patients with RCC and 40 healthy controls was evaluated by flow cytometry using monoclonal antibodies against CD4, CD25, FoxP3, CD45RA, CD45RO, CD152, CD184, CD279, CD3, CD16, CD56, CD161, CD158a, CD4, CD26, CD30, CD183 and CD184. A concomitant evaluation of 38 molecules was conducted in patients' serum using a multiplex biometric ELISA-based immunoassay. RESULTS: The number of NK cells CD3(-) /CD16(+) , CD3(-) /CD16(+) /CD161(+) (NK) and CD3(-) /CD16(+) /CD161(+) /CD158a(+) (NK- Kir 2+) was greater in the patients with RCC (P < 0.05); and the number of Treg cells CD4(+) /CD25(high) (+) /FOXP3(+) and the subset CD4(+) /CD25(high) (+) /FOXP3(+) /CD45RA(+) (naïve) and CD45R0(+) (memory) cells, were greater in the patients with RCC (P < 0.001). An increase in the following was observed in the serum of patients with RCC compared with healthy controls: interleukin (IL)-4, IL-6, IL-8, IL-10, G-CSF, CXCL10, CXCL11, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF). According to Ingenuity Pathway Analysis (IPA), CXCL10, IL-6, IL-8, epidermal growth factor (EGF), HGF and VEGF were associated with a network that controls cellular movement, tissue development and cellular growth. Kaplan-Meier analysis for disease-free survival showed that high numbers of CD4(+) /CD25(high) (+) /FOXP3(+) /CD45RA(+) (Treg naïve) and low numbers of CD3(-) /CD16(+) /CD161(+) /CD158a(+) (NK-Kir+) cells predict short disease-free survival in patients with RCC. CONCLUSION: Concomitant evaluation of Treg (CD4(+) /CD25(high) (+) /FOXP3(+) and CD4(+) /CD25(high) (+) /FOXP3(+) /CD45RA(+) ) and of six soluble factors (IL-6, IL-8 ,VEGF, CXCL10, CXCL11, EGF, HGF) might be a surrogate marker of host immunity in patients with RCC.
[show abstract][hide abstract] ABSTRACT: Purpose
The single-arm OCTAVIA study evaluated front-line bevacizumab plus weekly paclitaxel and q3w carboplatin.
Patients and methods
Patients with newly diagnosed ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IIb–IV or grade 3/clear-cell stage I/IIA) received bevacizumab (7.5 mg/kg, day 1), weekly paclitaxel (80 mg/m2 days 1, 8, 15) and carboplatin (area under the curve 6 [AUC6], day 1) intravenously q3w for 6–8 cycles, followed by single-agent bevacizumab (total 1 year). The primary objective was to demonstrate median progression-free survival (PFS) > 18 months according to the lower 90% confidence limit. Secondary end-points included objective response rate, overall survival, safety and tolerability.
Most (74%) of the 189 treated patients had stage IIIC/IV disease, similar to the ICON7 population. Patients received a median of six chemotherapy and 17 bevacizumab cycles. At the predefined cutoff 24 months after last patient enrolment, 99 patients (52%) had progressed and 19 (10%) had died, all from ovarian cancer. Median PFS was 23.7 months (95% confidence interval [CI], 19.8–26.4 months), 1-year PFS rate was 85.6%, Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 84.6% and median response duration was 14.7 months. Most patients (⩾90%) completed at least six chemotherapy cycles. Grade ⩾3 peripheral sensory neuropathy occurred in 5% and febrile neutropenia in 0.5%. Grade ⩾3 adverse events typical of bevacizumab were no more common than in phase III bevacizumab ovarian cancer trials. There was one case of gastrointestinal perforation (0.5%) and no treatment-related deaths.
OCTAVIA met its primary objective, demonstrating median PFS of approximately 2 years. This bevacizumab-containing regimen is active and tolerable.
European Journal of Cancer. 01/2013; 49(18):3831–3838.
[show abstract][hide abstract] ABSTRACT: Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.
[show abstract][hide abstract] ABSTRACT: Urinary bladder cancer is a common malignancy in industrialized countries. More than 90% of bladder cancer originates in the transitional cells. Bladder transitional cancer prognosis is, according to the most recent definition related to the level of tumor infiltration, characterized by two main phenotypes, Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC). Either the genetic profile and the clinical course of the two subtypes are completely different, however among NMIBC the prognosis is not completely predictable, since 20% of the cases experience a relapse, even in the form of MIBC. It has recently been reported that the chromosomal region 12q13-15, containing crucial cancer genes such as MDM2, CDK4, GLI and an entire cluster of HOX genes, is amplified in bladder cancer. Moreover, it was also described the strong involvement of HOX B13 in particular in several tumors of urogenital system. HOX genes codify for transcriptionl factor, involved in embryonal development and cancer progression, with main nuclear expression. Particularly it was also described the strong involvement of HOX B13 in several tumors of urogenital system. In this study we have been investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX B13 expression in bladder cancer evolution and progression, evaluating its ability to discriminate between NMIBC and MBCI phenotypes. Cytoplasmic HOX B13 delocalization significantly relates with muscle invasion (p 0.004) . In addition in the series of NMIBC nuclear HOX B13 expression loss is significantly associated to shorter disease free survival (p-value=0.038) defining a potential prognostic role. Overexpression of HOX B13 in more aggressive phenotype is also demonstrate at gene level by quantitative RT-PCR. The de-regulation and delocalization of HOX B13 in urinary bladder cancer supports again the important role of HOX genes in tumor evolution and represents a starting point to establish an integrated analysis, in which HOX genes represent important prognostic and predictive markers for bladder cancer.
Current Medicinal Chemistry 12/2012; · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.
Anti-cancer agents in medicinal chemistry 11/2012;
[show abstract][hide abstract] ABSTRACT: Neoplasms in the testis and in the testicular adnexa of elderly patients are completely different from those observed in younger patients. Indeed, although conventional seminomas and nonseminomas are mainly observed in the age range of 20-45 years, spermatocytic seminoma, malignant Leydig tumors, and lymphomas in the testis and sarcomas in the paratesticular region are encountered in individuals older than 60 years of age. Here, we discuss the testis and paratesticular region neoplasm more commonly diagnosed in elderly men.
[show abstract][hide abstract] ABSTRACT: Introduction: Ovarian cancer is the most important cause of gynecological cancer-related mortality. Conventional treatments for advanced or recurrent disease offer limited results in terms of long-term responses and survival. Researches have recently focused on target therapies, which represent a new, promising, therapeutic approach, able to maximizing tumor kill and minimizing toxicity. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is currently one of the most hopeful and investigated alternatives. Areas covered: Preclinical and clinical studies of Olaparib , the most investigated PARP inhibitor in ovarian cancer, are analyzed and discussed. Data were obtained by searching for all English peer-reviewed articles on Medline, on Cochrane Database and all on-going Phase I and II studies registered on National Cancer Institute Clinical Trials; also any related abstracts recently presented on Olaparib at major international congresses will be included. Expert opinion: Bad prognosis and drug resistance usually affect ovarian cancer. Recent trends toward the knowledge of molecular-specific pathways have produced new target drugs. PARP inhibition mediated by Olaparib in BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2)-mutated and in sporadic ovarian cancer represents a promising field of investigation. Further studies are needed to confirm initial exciting results.
[show abstract][hide abstract] ABSTRACT: Ovarian cancer is the leading cause of death from gynecological cancers. Primary treatment of advanced ovarian cancer (FIGO stages III and IV) until recently consisted of cytoreductive surgery and paclitaxel/carboplatin chemotherapy. The results of two randomized studies, showing prolongation of progression-free survival (PFS) by the addition of the anti-VEGF monoclonal antibody, bevacizumab, led to the approval of this agent for first-line treatment of this disease and indicate that angiogenesis is a promising therapeutic target. Angiogenesis is essential for oncogenesis but also the viability and expansion of ovarian cancer. Specifically, VEGF is involved in the formation of ascites and has a direct effect on ascites tumor cells as well as an immunosuppressive function. Apart from VEGF, PDGF, FGF and angiopoietins present a therapeutic interest. We are reviewing the results of published clinical studies using anti-angiogenic factors in advanced ovarian cancer.
Critical reviews in oncology/hematology 05/2012; · 5.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: Almost 30% of the sunitinib-treated patients for metastatic renal carcinoma (mRCC) do not receive a clinical benefit. Convincing evidences demonstrated a cross talk between the VEGF and CXCR4 pathways. It was hypothesized that CXCR4 expression in primary renal cancer could predict sunitinib responsiveness.
In this exploratory study sixty-two mRCC patients receiving sunitinib as first-line treatment were evaluated for CXCR4 expression through immunohistochemistry (IHC). Correlations between CXCR4 expression, baseline patients and tumour characteristics were studied by contingency tables and the chi-square test. Univariable analysis was performed with the log-rank test, and the Cox model was applied for multivariable analysis.
The objective response rate of sunitinib first-line therapy was 35.5% (22/62) with a disease control rate (response and stable disease) of 62.9% (39/62). CXCR4 expression was absent/low in 30 (48.4%), moderate in 17 (27.4%), and high in 15 (24.2%) tumors respectively. Low or absent CXCR4 expression predicted response to sunitinib therapy. Moreover, Fuhrman grading and concomitant, CXCR4 and Fuhrman grading, strongly predicted sunitinib first line therapy responsiveness on progression-free survival and overall survival.
High CXCR4 expression correlates with sunitinib poor response in metastatic renal cancer.
Current cancer drug targets 03/2012; 12(6):693-702. · 5.13 Impact Factor