Advanced/metastatic bladder cancer: current status and future directions.

In 2015 bladder cancer was the fourth most frequent malignancy and the eighth cause of death for cancer. At diagnosis, about 30% of bladder cancer (BC) patients present a muscle-invasive bladder cancer (MIBC) and 5% a metastatic bladder carcinoma (MBC). For fit MBC patients, combination chemotherapy (CC) is the standard of care for first-line treatment. CC includes both the treatment with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) either the classical or the dose-dense MVAC regimen, and the doublet therapy with cisplatin and gemcitabine (CG). Median progression free survival (PFS) was 7 months and median overall survival (OS) was 15 months. The present review provides an update on the management of MBC, with focus on target therapies, immune checkpoint inhibition, looking for prognostic and predictive factors.

Penile cancer: prognostic and predictive factors in clinical decision-making.

Penile cancer (PC) is a typical tumor of non-industrialized countries. The incidence is 20-30 times higher in Africa and South America, considering the elevated prevalence of sexually transmitted diseases. Histologically, PC includes squamous cell carcinoma (SCPC), the most frequent, and nonsquamous carcinoma (NSCPC). Early diagnosis is the goal, whereas later diagnosis relates to poor functional outcomes and worse prognosis. The 5-year survival rate is 85% for patients with histologically regional negative lymph nodes, compared to 29%-40% for those with histologically regional positive lymph nodes. To date no new drugs are approved, and there are few new data about molecular mechanisms underlying tumorigenesis. The SCPC remains a rare tumor and the current therapeutic algorithm is based principally on retrospective analysis and less on prospective trials. In this review article, biomarkers of prognosis and efficacy of current treatments are summarized with a focus on those that have the potential to affect treatment decision-making in SCPC.

Prognostic and predictive factors in testicular cancer.

OBJECTIVE: Testicular cancer is a relatively rare neoplasia, with an incidence of about 1,5% among male malignancies, usually in the third and fourth decade of life. Although several histological variants are known, with some histotypes affecting older patients (e.g., spermatocytic seminoma), there is a clear predominance (90-95%) of germ cell tumors among young adults patients1. Testicular Germ Cell Tumor (TGCT), undoubtedly the seminoma histological variant more than non-seminoma one, is definitely a highly curable disease, with a distinctive sensitivity to cisplatin-based therapy (and for seminomas to radiotherapy) and an outstanding cure rate of nearly 80% even for patients with advanced disease. So far, clinical and pathohistological features supported our efforts to choose the best treatment option for patients suffering from this malignancy, but we don't clearly enough know molecular and pathological features underlying different clinical behaviors, mostly in early-stage disease: by improving this knowledge, we should better "shape" therapeutic or surveillance programs for each patient, also in order to avoid unnecessary, if not harmful, treatments.

Health-related quality of life and psychosocial implications in testicular cancer survivors. A literature review.

OBJECTIVE: In this review, we focused our attention on Quality of Life (QoL) of testicular cancer survivors (TCSs), in general and in the most relevant areas. Several key findings have been highlighted in our review. MATERIALS AND METHODS: PubMed, MEDLINE and PsycINFO databases were consulted to find published studies, from 1980 to May 2017, that met our inclusion criteria. RESULTS: The majority of studies investigated older adult TCSs, while few studies on adolescent and young adult patients were available. Many studies indicate that health-related QoL (HRQoL) is similar among the TCSs and the general population. Even if QoL deteriorates so clear at the time of diagnosis and throughout treatment, afterward returns to normal levels, as defined by the matched controls. However, there are numerous chronic conditions consequent to diagnosis and treatment of testicular cancer that plague survivors and affect QoL, like Raynaud-like phenomena, peripheral neuropathy, fatigue, anxiety, sexual, fertility and body image problems. Even if these problems can have no effects on the measures of global QoL, they have an impact on the quality of life. Differences between TCSs with and without a partner bring to different outcomes in the adjustments to cancer. CONCLUSIONS: It is necessary to identify TCSs with higher risks of poorer QoL outcomes, to focus interventions on the areas with the greatest impairments. Further researches should consider the effects of testicular cancer on the impaired areas, collecting more data to better identify survivor's needs and consequent interventions, with a special focus on adolescent and young adult TCSs. Other works are requested on therapies, preventive and ameliorative, to reduce chronic side effects of testicular cancer treatment.

Rectal/urinary toxicity after hypofractionated vs. conventional radiotherapy in high risk prostate cancer: systematic review and meta analysis.

OBJECTIVE: The aim of our report was to review the literature concerning the toxicity of radiation therapy in patients treated for high-risk prostate cancer, and to evaluate the differences in toxicity between conventional fractionation and hypofractionated treatments, in view of different techniques used in high-risk prostate cancer patients. MATERIALS AND METHODS: PubMed database has been explored for studies concerning acute and late urinary/gastrointestinal toxicity in high-risk prostate cancer patients treated with radiotherapy. Prospective studies, concerning potential relationship between acute/late genitourinary (GU)/gastrointestinal (GI) toxicity and prostate radiotherapy in patients with high-risk prostate cancer, were included in the final analysis. Data collected from single arm, phase II non-randomized and randomized studies have been evaluated to perform odds ratio for toxicity risk. Furthermore, meta-analysis randomized prospective trials were considered suitable because they had recruited high-risk prostate cancer patients who didn't undergo surgery, with available data on ≥ G2 toxicity frequency. RESULTS: The initial search provided 606 results, but only 35 manuscripts met all eligibility requirements and were included in this report. In order to perform odds ratio we observed a decrease in late gastrointestinal toxicity for patients treated with hypofractionated schemes compared to CV treated ones. Among patients who underwent conventional treatment, SIB seemed to decrease acute genitourinary side effects; SIB-Hypo treated patients suffered less toxicity than patients treated with hypofractionated- sequential boost schemes. Hypo-SIB schemes would seem less toxic in terms of acute gastrointestinal and late genitourinary side effects than CV-SIB. Therefore, our focus shifted to 6 clinical trials evaluating genitourinary and gastrointestinal toxicity in patients who had been randomized to receive conventional fractionation or hypofractionated treatment, in both cases with IMRT technology. Our meta-analysis of these randomized trials involving patients with high-risk prostate cancer showed a statistically significant increase in late genitourinary toxicity for hypo-treated patients; no difference was observed in acute genitourinary/gastrointestinal toxicity, and in late gastrointestinal toxicity. CONCLUSIONS: Our analysis doesn't want to establish a definitive truth; very few trials assessed only high risk-class patients. Our purpose is to stimulate further randomized prospective trials focusing both on the effectiveness and toxicity profile (toxicity/effectiveness ratio), taking into account the use of different technologies and doses.

Analysis of apoptosis induced by Caprine Herpesvirus 1 in vitro.

It is known that Caprine Herpesvirus 1 (CpHV-1) causes apoptosis in mitogen-stimulated as well as not stimulated caprine peripheral blood mononuclear cells (PBMC). Initial experiments in Madin Darby bovine kidney (MDBK) cells revealed that CpHV-1 infection induced apoptotic features like chromatin condensation and DNA laddering. Thus, to characterize in more detail this apoptotic process, activation of caspase-8, -9 and -3 in MDBK cells CpHV-1 infected was investigated and demonstrated. In addition, CpHV-1 infection resulted in disruption of mitochondrial membrane potential, cytochrome c release and alterations in the pro- and anti-apoptotic proteins of Bcl-2 family. Proteolytic cleavage of poly(ADP-ribose) polymerases (PARP), confirming the activation of downstream caspases, was also observed. Our data indicated that a "cross-talk" between the death-receptor (extrinsic) pathway and the mitochondrial (intrinsic) pathway occurred in CpHV-1-induced apoptosis in vitro.

Bovine papillomavirus type 1 DNA and E5 oncoprotein expression in water buffalo fibropapillomas.

Papillomas and fibropapillomas may occur in the skin and in different organs in animals. Ten different genotypes of bovine papillomavirus (BPV) have been identified. BPV-1 through BPV-10 are all strictly species-specific, but BPV-1/2 may also infect other species such as equids, inducing fibroblastic tumors. BPV-1 and BPV-2 are associated with fibropapillomas in cattle; these tumors are formed by excessive proliferation of virus-infected dermal fibroblasts and epidermal keratinocytes. Nine water buffalo (Bubalus bubalis) were examined for the presence of multiple cutaneous and perivulvar tumors. Cutaneous and perivulvar fibropapillomatosis were confirmed histologically. Negative-stain transmission electron microscopic examination revealed papillomavirus-like particles in the fibropapillomas, and papillomaviral DNA was also detected by the polymerase chain reaction. The amplified long control region (LCR) DNA sequence was identical to that of BPV-1. The BPV-1 E5 oncoprotein was strongly expressed in the tumor cells thus confirming a causal role of the virus. This article represents the first report of cutaneous, perivulvar, and vulvar fibropapilloma associated with BPV-1 infection in the water buffalo and describes another example of cross-species infection by BPV-1.

Bovine herpesvirus type 1 (BHV-1) up-regulates telomerase activity in MDBK cells.

The proliferative capacity of mammalian cells is regulated by telomerase, an enzyme uniquely specialised for telomeric DNA synthesis. The critical role of telomerase activation in tumor progression and maintenance has been well established in studies of cancer and of oncogenic transformation in cell culture. Experimental data suggest that telomerase activation has an important role in normal somatic cells, and that failure to activate sufficient telomerase also promotes disease. Evidence regarding the role of telomerase in the pathogenesis of several viruses including human immunodeficiency virus has led to an increased interest in the role of telomerase activity in other virus infections. In this research we evaluated the telomerase modulating activity of Bovine herpesvirus 1 (BHV-1) in MDBK cells. MDBK cells were infected at different multiplicity of infection with BHV-1 Cooper strain and telomerase activity at different times post-infection was measured by the TRAP assay. Our data indicate that BHV-1 significantly up-regulates telomerase activity at 3 and 6h post-infection decreasing after the 24h post-infection. Our data, showed that the effect was mediated by an immediate-early or early viral gene, and use of the protein translation inhibitor cycloheximide confirmed that an immediate early gene is primarily responsible.

The involvement of oxidative stress in bovine herpesvirus type 4-mediated apoptosis.

Bovine herpesvirus type 4 (BHV-4) belongs to the gamma-2-herpesviruses of the Gammaherpesvirinae subfamily. BHV-4 has a worldwide distribution and has been isolated in a variety of clinical diseases as well as from healthy cattle. In this report we demonstrate that BHV-4 induces apoptosis in MDBK cells. In the early phases of apoptosis, cells show an increase in the intracellular level of reactive oxygen species, which is indicative of oxidative stress. This precedes DNA fragmentation, a hallmark typical of apoptosis. Cells were protected from apoptosis only by certain antioxidants (butylated hydroxyanisole and ebselen), whereas N-acetylcysteine turned out to be ineffective. Antioxidants that protected cells from apoptosis prevented oxidative stress but failed to block virus growth. These observations suggest that oxidative stress may be a crucial event in the sequence leading to apoptotic cell death but apoptosis is not required for the multiplication of BHV-4.

Modulation of anthracycline activity in canine mammary tumour cells in vitro by medroxyprogesterone acetate.

Failure of chemotherapy with anthracyclines as a result of drug resistance and toxicity is a major problem in the clinical management of neoplasia. The aim of the present study was to evaluate the activity of medroxyprogesterone acetate (MPA) as a chemosensitiser on anthracycline cytotoxicity. The study investigated whether such an effect could be related to an increase in lipid peroxidation, nitric oxide production, membrane fluidity and intracellular anthracycline concentration. The results showed that anthracyclines decreased nitric oxide production but increased membrane viscosity (polarisation constant) and lipid hydroperoxide formation in canine mammary tumour cells. Moreover, it was found that both drug-induced cytotoxicity and membrane viscosity increased in the presence of MPA. Conversely, lipid hydroperoxides decreased in MPA-supplemented cells. Medroxyprogesterone acetate did not show any effect on nitric oxide production. The two anthracyclines used (doxorubicin and idarubicin) showed differential intranuclear accumulation in canine mammary tumour cells, and MPA significantly modified intracellular concentration of anthracyclines.

Role of Pasteurella multocida porin on cytokine expression and release by murine splenocytes.

The aim of this study was to verify whether Pasteurella multocida porin can affect the expression and release of IL-1alpha, IL-6, TNF-alpha, IL-4, IFN-gamma, IL-10 and IL-12 by murine splenocytes in vitro. P. multocida porin and lipopolysaccharide (LPS) were able to induce the release of IL-1alpha, IL-6, TNF-alpha, IFN-gamma and IL-12 in a dose-dependent fashion. The greatest release of these cytokines was obtained using P. multocida porin at a concentration of 5 microg ml(-1) and LPS at a concentration of 1 microg ml(-1). The time-courses of release showed that P. multocida LPS was able to stimulate the production of IL-1alpha, IL-6, TNF-alpha, IFN-gamma and IL-12 earlier than porin and at a greater rate. No effect was observed on IL-4 and IL-10 release under the same experimental conditions. P. multocida porin and LPS were also able to up-regulate the mRNA expression of IL-1alpha, IL-6, TNF-alpha, IFN-gamma and IL-12 p40. Our findings suggest that P. multocida porin is able to modulate inflammatory and immunological responses by affecting the release of several cytokines and the expression of their genes.