Resilience in Radiotherapy Services During the COVID-19 Emergency: Collaboration Between the Regional Radiation Oncology Departments of Lazio, Abruzzo and Molise.

AIM: Radiation therapy is a cornerstone of oncological treatment and oncological patients show greater risk of developing complications related to COVID-19 infection. Stringent social restrictions have ensured a significant reduction in the spread of the virus, but also gave rise to a number of critical issues for radiation oncology wards. For this reason, the Directors of the Radiation Oncology Departments (RODs) of Lazio, Abruzzo and Molise regions shared their experience and ideas in order to create a common document that may assist in facing the negative impacts of the pandemic on radiation oncology wards and patients. PATIENTS AND METHODS: The study was conducted according to the Estimate-Talk-Estimate method. Five issues were proposed and rated. Among approved issues, statements were proposed anonymously, then harmonized and finally voted on according to a Likert scale from 1 to 9. Those for which an agreement of 7-9 was observed were finally approved. RESULTS: The document was developed with 42 statements dealing about safety measures for patients and staff, organization of clinical and work activities, usage of Information Technology systems for meetings/smart working. An agreement was recorded for 34 statements. CONCLUSION: This document sets out some recommendations for RODs and can provide valuable management information for Oncological Radiotherapy wards.

The Masturbation Erection Index (MEI): validation of a new psychometric tool, derived from the six-item version of the International Index of Erectile Function (IIEF-6) and from the Erection Hardness Score (EHS), for measuring erectile function during masturbation.

OBJECTIVES: To validate a psychometric instrument, the Masturbation Erection Index (MEI) able to evaluate erectile function (EF) during masturbation. In fact, although the evaluation of EF during masturbation is pivotal in evaluating erectile dysfunction (ED), to date no specific psychometric tools have been developed to measure it both in the routine clinical practice and in the experimental setting. PATIENTS AND METHODS: Of 560 men attending our andrological outpatient clinic for the first time, 99 (17.7%) had ED. As a control group, we enrolled 102 sexually healthy men. All the men were requested to complete both the six-item version of the International Index of Erectile Function (IIEF-6) and the MEI. The MEI was used together with a standardised tool, the Erection Hardness Score (EHS). The MEI was validated in terms of content validity. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC). Internal consistency was evaluated by Cronbach's α. The comparability between the MEI and IIEF-6 in measuring EF was tested by Bland-Altman analysis. The concordance correlation coefficient (CCC) between the two questionnaires was also determined. RESULTS: Internal consistency of the MEI was >0.93. Test-retest reliability was 0.982 (95% confidence interval [CI] 0.975-0.987). Bland-Altman analysis showed a good level of agreement between the IIEF-6 and MEI in the whole ED population, with stronger agreement in the organic-ED subpopulation. The estimated area under the curve of the MEI was 0.983 (P < 0.001; 95% CI 0.954-0.996), with a score of ≤27 as the optimal threshold to discriminate between the presence and absence of ED during self-induced masturbation. The CCC, Pearson ρ and bias correction factor (Cb) were 0.951 (95% CI 0.936-0.962), 0.968, and 0.982, respectively. CONCLUSION: The MEI showed good internal consistency and a good level of agreement with the IIEF-6. Hence, the MEI fulfills the major psychometric requirements for measuring EF during masturbation.

The possible prognostic role of histone deacetylase and transforming growth factor ß/Smad signaling in high grade gliomas treated by radio-chemotherapy: a preliminary immunohistochemical study.

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-ß/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome.  The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-ß/Smad pathway, with high levels of IL-13, Smad2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in Smad 7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-ß/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease.

Oral Platelet Gel Supernatant Plus Supportive Medical Treatment Versus Supportive Medical Treatment in the Management of Radiation-induced Oral Mucositis: A Matched Explorative Active Control Trial by Propensity Analysis.

OBJECTIVES: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. MATERIALS AND METHODS: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. RESULTS: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. CONCLUSIONS: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials.

Is Testosterone a Food for the Brain?

INTRODUCTION: Testosterone is fundamental for psychological, sexological, cognitive, and reproductive aspects, and its lack or reduction largely impacts the quality of life in males and females. AIM: Therefore, the aim of this review is to describe the role of testosterone in the neurophysiology of the brain and related aspects regarding the quality of general and sexual life. METHODS: We listed and discussed the principal studies on the role of testosterone in the brain regarding sexual health, psychopathological conditions, and the elderly. The search strategies were composed by the insertion of specific terms in PubMed regarding the main studies from January 2000 to June 2015. MAIN OUTCOME MEASURES: Using a psychoneuroendocrinologic perspective, we considered 4 main sections: brain and testosterone, sexuality and testosterone, psychopathology and testosterone, and cognitive impairment and testosterone. RESULTS: Much evidence on the neuroendocrinology of testosterone regarding brain activity, sexual function, psychological health, and senescence was found. In any case, it is known that testosterone deficiency negatively impacts quality of life, first, but not exclusively, through a central effect. Moreover, testosterone and androgen receptors are differently expressed according to age and gender. This aspect contributes to gender differences and to the dimorphic physiological role of this hormone. CONCLUSION: A universal role for testosterone can be recognized: low levels of testosterone are associated with mental disorders, sexual dysfunction, and cognitive impairment in both sexes. Hence, physicians should carefully assess testosterone levels, not only in the management of sexual dysfunctions but also when seeking to help patients with severe mental or organic diseases.

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells.

Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

Sexual dysfunctions in people with first-episode psychosis assessed according to a gender perspective.

AIM: Patients with chronic mental disorders often can suffer from sexual dysfunction. Nevertheless, the sexual functioning of new patients with first-episode psychosis has been little explored. The aim of this study was to investigate gender differences in sexual functioning in people with first-episode psychosis. METHODS: A group of 40 males and 37 females with first-episode psychosis took part in the research. We administered a psychiatric protocol composed of the PANSS, UKU and SCID-DSM-IV diagnosis. RESULTS: We found that the 42.5% of the male group had sexual dysfunctions while the percentage of the female group was 37.8%. The correlation between sexual dysfunctions and psychopathology did not reveal any association in males. However, in females, general psychopathology and positive symptoms are linked to the alteration of vaginal lubrication: (r=0.547; p=0.003) and (r=0.485; p=0.011), although orgasm alteration was also associated with general psychopathology (r=0.500; p=0.013). Moreover, we found a relation between the alteration of vaginal lubrication with depression(r=0.627; p<0.0001) and disorder of volition (r=0.600; p<0.001). DISCUSSION AND CONCLUSIONS: These data suggest that the association between sexual dysfunctions and psychopathology regarded only women. Therefore, during the taking charge of patients it is fundamental to consider the gender-specific relationship between psychopathology and sexual problems.

Italian Validation of Homophobia Scale (HS).

INTRODUCTION: The Homophobia Scale (HS) is a valid tool to assess homophobia. This test is self-reporting, composed of 25 items, which assesses a total score and three factors linked to homophobia: behavior/negative affect, affect/behavioral aggression, and negative cognition. AIM: The aim of this study was to validate the HS in the Italian context. METHODS: An Italian translation of the HS was carried out by two bilingual people, after which an English native translated the test back into the English language. A psychologist and sexologist checked the translated items from a clinical point of view. We recruited 100 subjects aged18-65 for the Italian validation of the HS. The Pearson coefficient and Cronbach's α coefficient were performed to test the test-retest reliability and internal consistency. MAIN OUTCOME MEASURES: A sociodemographic questionnaire including the main information as age, geographic distribution, partnership status, education, religious orientation, and sex orientation was administrated together with the translated version of HS. RESULTS: The analysis of the internal consistency showed an overall Cronbach's α coefficient of 0.92. In the four domains, the Cronbach's α coefficient was 0.90 in behavior/negative affect, 0.94 in affect/behavioral aggression, and 0.92 in negative cognition, whereas in the total score was 0.86. The test-retest reliability showed the following results: the HS total score was r = 0.93 (P < 0.0001), behavior/negative affect was r = 0.79 (P < 0.0001), affect/behavioral aggression was r = 0.81 (P < 0.0001), and negative cognition was r = 0.75 (P < 0.0001). CONCLUSIONS: The Italian validation of the HS revealed the use of this self-report test to have good psychometric properties. This study offers a new tool to assess homophobia. In this regard, the HS can be introduced into the clinical praxis and into programs for the prevention of homophobic behavior.

Post-traumatic stress disorder, coping strategies and type 2 diabetes: psychometric assessment after L'Aquila earthquake.

AIM: After natural and collective catastrophes, many behavioral phenomena can occur through psychobiological responses that involve also the diabetic condition.The aim of this study was to investigate post-traumatic stress disorder (PTSD) and coping strategies in type 2 diabetic patients after L'Aquila earthquake, with a particular attention to the newly diagnosed patients and to the gender differences. METHODS: Among the local diabetic population, we recruited 100 diabetic patients (46 women and 54 men). Sixty of these had diabetes before the earthquake (pre-quake patients), and other 40 received diabetes diagnosis after the earthquake (post-quake patients). A psychometric protocol composed by Davidson Trauma Scale for PTSD and Brief-COPE for coping strategies was administered. RESULTS: We found significant differences in the levels of PTSD when comparing both post-quake with pre-quake patients (post-quake = 51.72 ± 26.05 vs. pre-quake = 31.65 ± 22.59; p < 0.05) and the female patients with males (women = 53.50 ± 27.01 vs. men = 31.65 ± 23.06; p < 0.05) and also in the prevalence [post-quake = 27/40 (67.5 %) vs. pre-quake = 20/60 (33.3 %); p < 0.05], [women = 27/46 (58.69 %) vs. men = 16/54 (29.62 %); p < 0.05]. Moreover, maladaptive coping was a predictive factor for PTSD in the post-quake group only (OR 1.682; 95 % CI 1.155-2.450; p = 0.006). CONCLUSIONS: Our results revealed that PTSD may be considered an important comorbidity factor in newly diagnosed patients and in diabetic women. Hence, a psychological support seems particularly important in these patients after a collective traumatic event to help them react to both PTSD and diabetes and to help them improve their coping skills.

Challenges to treat hypogonadism in prostate cancer patients: implications for endocrinologists, urologists and radiotherapists.

The literature suggests that the serum testosterone level required for maximum androgen receptor (AR) binding may be in the range of nanomolar and above this range of concentrations; this sexual hormone may not significantly affect tumour biology. This assumption is supported by clinical studies showing that cell proliferation markers did not change when serum T levels increased after exogenous T treatment in comparison to subjects treated with placebo. However, a considerable part of the global scientific community remains sceptical regarding the use of testosterone replacement therapy (TRT) in men suffering from hypogonadism and prostate cancer (Pca). The negative attitudes with respect to testosterone supplementation in men with hypogonadism and Pca may be justified by the relatively low number of clinical and preclinical studies that specifically dealt with how androgens affect Pca biology. More controversial still is the use of TRT in men in active surveillance or at intermediate or high risk of recurrence and treated by curative radiotherapy. In these clinical scenarios, clinicians should be aware that safety data regarding TRT are scanty limiting our ability to draw definitive conclusions on this important topic. In this review we critically discuss the newest scientific evidence concerning the new challenges in the treatment of men with hypogonadal condition and Pca providing new insights in the pharmacological and psychological approaches.

Platelet-derived growth factor regulation of type-5 phosphodiesterase in human and rat penile smooth muscle cells.

INTRODUCTION: Relaxation of cavernous smooth muscle cells (SMCs) is a key component in the control of the erectile mechanism. SMCs can switch their phenotype from a contractile differentiated state to a proliferative and dedifferentiated state in response to a change of local environmental stimuli. Proliferation and contraction are both regulated by the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are degraded by phosphodiesterases (PDEs). The most abundant PDE present in corpora cavernosa is the electrolytic cGMP-specific phosphodiesterase type 5 (PDE5). AIM: We investigated the cellular localization of PDE5 in in vitro cultured corpora cavernosa cells and the effect of mitogenic stimulation on PDE5 expression. METHODS: Biochemical ad molecular techniques on cultured SMCs from human and rat penis. MAIN OUTCOME MEASURES: We studied the ability of the quiescent SMC phenotype vs. the proliferating phenotype in modulation of PDE5 expression. RESULTS: We demonstrated that PDE5 is localized in the cytoplasm, in the perinuclear area, and in discrete cytoplasmic foci. As previously demonstrated in human myometrial cells, the cytoplasmic foci may correspond to centrosomes. In corpora cavernosa, PDE5 protein levels are strongly regulated by the mitotic activity of the SMCs, as they were increased in quiescent cultures. In contrast, treatment with platelet-derived grow factor (PDGF), one of the most powerful mitogenic factors for SMCs, reduces the expression of PDE5 after 24 hours of treatment. CONCLUSION: We found that PDGF treatment downregulates PDE5 expression in proliferating SMCs, suggesting that PDE5 may represent one of the markers of the contractile phenotype of the SMCs of corpora cavernosa.

Strategies for imaging androgen receptor signaling pathway in prostate cancer: implications for hormonal manipulation and radiation treatment.

Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

Angiotensin-converting-enzyme inhibition counteracts angiotensin II-mediated endothelial cell dysfunction by modulating the p38/SirT1 axis.

OBJECTIVE: Oxidative stress has been linked to endothelial dysfunction and angiotensin II stimulates the reactive oxygen species production contributing to several cardiovascular diseases. We have studied the chain of events induced by angiotensin-converting-enzyme (ACE) activation in vascular umbilical vein endothelial cells (HUVECs) by using an ACE inhibitor such as zofenoprilat. METHODS: We used specific assay to measure the superoxide anion production, tetrazolium bromide (MTT) assay for cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, and western blot for protein analysis in the study. RESULTS: Zofenoprilat counteracts the superoxide anion production and cell apoptosis induced by angiotensin I treatment by blocking the extrinsic caspase cascade, NF-kB and p38 activation. p38 inhibitor SB203580 reverted the angiotensin II oxidant effects while the p38 constitutively activation, by MKK6 transfection, abrogated the zofenoprilat effects. Characterizing the zofenoprilat downstream effector we found that zofenoprilat reverted the SirT-1 downregulation induced by angiotensin II. p38 activation by angiotensin II was strictly correlated with SirT1 protein downregulation; SB203580 significantly prevented SirT1 downregulation induced by angiotensin II while the p38 constitutive activation abolished SIRT1 protein basal levels. p38 directly bound SirT1 sequestering it in the cytoplasm. SirT1 inhibition by sirtinol annulled zofenoprilat action while SirT1 overexpression reverted the cytotoxic effects of angiotensin II. Finally, zofenoprilat negatively controlled angiotensin I receptor protein expression through SirT1. CONCLUSION: The p38-SirT1 axis is found markedly relevant in modulating the cardiovascular benefit deriving from ACE-inhibitors and might represent a novel target for innovative drugs in cardiovascular prevention.

Is testosterone a friend or a foe of the prostate?

INTRODUCTION: Is there any unequivocal evidence that testosterone (T) can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer (PCa)? This is not a controversial point: the answer is yes. However, this evidence does not imply that PCa is a result of T or therapy with T (TTh) of hypogonadal men. Furthermore, currently adequately powered and optimally designed long-term prostate disease data are not available to determine if there is an additional risk from normal T values in cured patients for PCa. METHODS: This Controversy is introduced by an endocrinologist, the section editor (E.A.J.) with G.L.G., a fellow urologist and radiotherapist expert in basic research on PCa. Two outstanding urologists, A.M and W.J.G.H., debate clinical data and clinical guidelines, respectively. Finally, other controversial issues are discussed by another leader in the field (A.M.) and a radiation oncologist and sexologist who is actually president of the International Society for Sexuality and Cancer (L.I.). MAIN OUTCOME MEASURE: Expert opinion supported by the critical review of the currently available literature. RESULT: The answer to the main question "is the prostate a really T-dependent tissue?" is definitively yes, but T stimulates the prostatic tissue in a dose-dependent fashion only to a saturation point, achieved at low T concentrations. At these low T concentrations, stimulation is near maximal, and T supplementation above this level would not lead to significantly greater stimulation. Furthermore, there is no conclusive evidence that TTh increases the risk of PCa or even prostatic hyperplasia. There is also no evidence that TTh will convert subclinical PCa to clinically detectable PCa. However, there is a limited clinical experience of TTh after successful treatment of PCa. So far, just 48 patients have been studied in the three published articles. CONCLUSIONS: It is evident that the issue is still controversial and much more research is needed. However, the available data suggest to the expert in sexual medicine that TTh can be cautiously considered in selected hypogonadal men previously treated for curative intent of low-risk PCa and without evidence of active disease.

Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation.

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic agents or radiation for targeting DNA-protein complex. The positive results obtained with these combined approaches in preclinical cancer models demonstrate the potential impact DNMT inhibitors may have in treatments of different cancer types. Therefore, as the emerging interest in use of DNMT inhibitors as a potential chemo- or radiation sensitizers is constantly increasing, further clinical investigations are inevitable in order to finalize and confirm the consistency of current observations.The present article will provide a brief review of the biological significance and rationale for the clinical potential of DNMT inhibitors in combination with other chemotherapeutics or ionizing radiation. The molecular basis and mechanisms of action for these combined treatments will be discussed herein.

Late morbidity and oncological outcome after radical hypofractionated radiotherapy in men with prostate cancer.

OBJECTIVE: To test the hypothesis that three-dimensional hypofractionated radiotherapy (3D-HFRT) is well tolerated and not worse than 3-D conventional RT (3D-CRT) for oncological outcome. PATIENTS AND METHODS: In all, 162 men with hystologically confirmed prostate adenocarcinoma were included in the analysis. In all, 82 men were treated with 3D-HFRT (15 fractions of 3.62 Gy delivered 3 times/week; a total dose of 54.3 Gy). This group was retrospectively compared with 80 men who met the same inclusion criteria and who were treated with 3D-CRT (39 fractions of 2 Gy delivered daily; a total dose of 78 Gy). A short course of hormone therapy was administered concomitantly with the RT. RESULTS: Only one (1.7%) patient in the 3D-CRT group and two (4.0%) in the 3D-HFRT group had Grade 3 genitourinary toxicity. There was late gastrointestinal morbidity of ≥ grade 3 in only 5.1% of men treated with 3D-HFRT and in 4.0% of men treated with 3D-CRT. In both groups there was no Grade 4 toxicity. At the median (range) follow-up of 45 (39.4-51) months for the 3D-HFRT group and 57.5 (54.9-59.1) months for 3D-CRT group the progression rate was 18/82 (21.9%) and 20/80 (25.0%), respectively, with no significant worsening in the risk of biochemical failure (BCF; log-rank test, P= 0.222). CONCLUSIONS: In the present study, men with clinically localized prostate cancer had similar levels of morbidity irrespective of whether they received HFRT or CRT without any worsening in the early risk of BCF. Thus, the present data provide some clinical evidence to justify trends already emerging toward HF regimens for treating clinically localised prostate cancer.

Cavoatrial tumor thrombectomy with systemic circulatory arrest and antegrade cerebral perfusion.

Renal carcinoma extending into the inferior vena cava can be excised with a good early-term and long-term prognosis. Cardiopulmonary bypass and deep hypothermic circulatory arrest are used to resect intracardiac extension of the tumor. We propose antegrade selective cerebral and cardiac perfusion associated with systemic circulatory arrest to protect the brain and the abdominal viscera while obtaining a bloodless surgical field for tumor thrombus removal.

Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathways.

Valproic acid is a well-known antiepileptic drug that was recently discovered to have a wide-spectrum antitumoral action in several tumors. In our work, we tested the proapoptotic activity of valproic acid in prostate cancer. Valproic acid-induced apoptosis was described by several in-vitro assays in three prostate cancer cell lines: two representing the prototype of advanced, clinically untreatable stages of prostate progression, PC3 and DU145, and one resembling a more differentiated androgen-sensitive tumor, LNCaP. We observed that valproic acid was a potent and early apoptotic inducer, mainly in less-differentiated prostate cancer cell lines. The molecular analysis of the apoptotic machinery involved in valproic acid action revealed a central role in Bcl-2 downmodulation. When prostate cancer cells were treated for a longer time with valproic acid, we detected an enhancement of Fas-dependent apoptosis associated with an overexpression in Fas and Fas ligand. Our data indicate that the use of valproic acid may be a suitable therapeutic agent in the control of prostate cancer progression and its action appears particularly relevant in the control of refractory stages of prostate cancer.