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Introduction Quality in medical care must be measured in order to be improved. Trauma management is part of health care, and by definition, it must be checked constantly. The only way to measure quality and outcomes is to systematically accrue data and analyze them. Material and methods A systematic revision of the literature about quality indicators in trauma associated to an international consensus conference Results An internationally approved base core set of 82 trauma quality indicators was obtained: Indicators were divided into 6 fields: prevention, structure, process, outcome, post-traumatic management, and society integrational effects. Conclusion Present trauma quality indicator core set represents the result of an international effort aiming to provide a useful tool in quality evaluation and improvement. Further improvement may only be possible through international trauma registry development. This will allow for huge international data accrual permitting to evaluate results and compare outcomes.

Introduction Apomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. Methods Sixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. Results After injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. Conclusion These results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

OBJECTIVES: To evaluate the prevalence of diarrhea and its association with drug use in elderly outpatients. METHODS: The study was carried out by 133 general practitioners (GPs) who referred to 24 geriatric units in Italy. The demographic data, disability, gastrointestinal symptoms, and current medications were evaluated using a structured interview, including the evaluation of the activities of daily living (ADL), the instrumental activities of daily living (IADL), and the gastrointestinal symptoms rating scale (GSRS). RESULTS: The study included 5,387 elderly subjects who regularly completed the structured interview. In total, 488 patients (9.1% of the whole population, 210 men and 278 women, mean age 75.6 6.2 yr, range 65–100 yr) reported diarrhea, that is, items 11 and 12 of the GSRS, during the 7-day period before the interview. The prevalence of diarrhea significantly increased with older age (P= 0.025), the severity of ADL (P < 0.0001) and IADL disability (P < 0.0001), and the number of drugs taken (P= 0.0002). A multivariate analysis demonstrated that the presence of diarrhea was significantly associated with the use of antibiotics (odds ratio [OR] 4.58, 95% confidence interval [CI] 1.95–10.73), proton pump inhibitors (OR 2.97, 95% CI 2.03–4.35), allopurinol (OR 2.19, 95% CI 1.26–3.81), psycholeptics (OR 1.82, 95% CI 1.26–2.61), selective serotonin reuptake inhibitors (OR 1.71, 95% CI 1.01–2.89), and angiotensin II receptor blockers (OR 1.46, 95% CI 1.08–1.99), also accounting for sex, age, and the use of antidiarrheal agents and drugs for functional gastrointestinal disorders. CONCLUSION: Diarrhea is a common problem in elderly outpatients. Its prevalence increases with old age, the severity of disability, and the number of drugs. Monitoring the presence of diarrhea and its complications in elderly patients who need treatments with drugs significantly associated with diarrhea may be clinically useful.

OBJECTIVE: This study aimed to evaluate the surgical treatment of acute pancreatitis in Italy and to assess compliance with international guidelines. METHODS: A series of 1173 patients in 56 hospitals were prospectively enrolled and their data analysed. RESULTS: Twenty-nine patients with severe pancreatitis underwent surgical intervention. Necrosectomy was performed in 26 patients, associated with postoperative lavage in 70% of cases. A feeding jejunostomy was added in 37% of cases. Mortality was 21%. Of the patients with mild pancreatitis, 714 patients with a biliary aetiology were evaluated. Prophylactic treatment of relapses was carried out in 212 patients (36%) by cholecystectomy and in 161 using a laparoscopic approach. Preoperative endoscopic retrograde cholangiopancreatography was associated with cholecystectomy in 83 patients (39%). Forty-seven patients (22%) were treated at a second admission, with a median delay of 31 days from the onset of pancreatitis. Eighteen patients with severe pancreatitis underwent cholecystectomy 37.9 days after the first admission. There were no deaths. DISCUSSION: The results indicate poor compliance with published guidelines. In severe pancreatitis, early surgical intervention is frequently performed and enteral feeding is seldom used. Only a small number of patients with mild biliary pancreatitis undergo definitive treatment (i.e. cholecystectomy) within 4 weeks of the onset of pancreatitis.

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

Background Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. Objective To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Design, setting, and participants Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Outcome measurements and statistical analysis Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Results and limitations Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37–0.72; p p 50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p Conclusions Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. Patient summary We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

Key points Age per se does not influence outcome in CLL patients on ibrutinib, whereas CIRS score is predictive of treatment management, PFS, and EFS.ECOG-PS and neutropenia resulted as the only baseline parameters affecting overall survival., Visual Abstract, Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Introduction. Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC. Patients and methods. In this translational study, we employed flow cytometry to assess total, PTEN–, and AR-V7+ CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide. Results. CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN– CTC, and AR-V7+ CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN– CTC count was 2 (0; 4) and median (interquartile range) AR-V7+ CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P=.021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P =.003), whereas ≥ 2 versus < 2 PTEN– CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P=.001) and OS (HR, 2.36; 95% CI, 1.12-5; P=.025). Finally, ≥ 1 versus < 1 AR-V7+ CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

The management of portosystemic shunts in liver transplant recipients relies on appropriate perioperative study. There are several strategies for shunt handling, ranging from preoperative interventional procedures to intraoperative surgical interruption or embolization. Appropriate management often results in a successful outcome, although wrong decisions could lead to serious consequences. Here, we report a liver transplant recipient with grade 2 portal vein thrombosis associated with 2 large portosystemic shunts (coronary and mesocaval), which were managed intraoperatively via thrombectomy without shunt ligation. Acute portal vein thrombosis developed early after transplant due to portal steal syndrome. The patient underwent a successful endovascular shunt embolization, with prompt restoration of hepatopetal portal flow and resolution of the portal steal. Use of interventional radiology in perioperative management of transplant patients has recently gained wider importance; our case reported here is particularly suggestive of the good outcomes of a multidisciplinary approach to a threatening complication such as postoperative acute portal vein thrombosis.

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan&ndash, Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51&ndash, 10.88) and 11.57 months (95% CI 10.90&ndash, not reached (NR)) as second-line and 11.38 months (95% CI 5.79&ndash, NR) and NR (95% CI 11.51&ndash, NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib&ndash, nivolumab and 25.64 months and NR with nivolumab&ndash, cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39, 95% CI 1.24&ndash, 4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04&ndash, 2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33, 95%CI, 1.16&ndash, 4.69, p = 0.018) and Hb levels (HR = 3.12, 95%CI 1.18&ndash, 8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72, 95%CI 1.04&ndash, 7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.

Background No compelling evidence is available about surveillance and follow-up of patients with testicular germ cell tumour (TGCT). Methods In the light of the best clinical evidence, the Italian Germ cell cancer Group (IGG) and the Associazione Italiana di Oncologia Medica (AIOM) set up a multidisciplinary national consensus conference, involving 42 leading experts and 3 TGCT survivors. A minimum of 50% of votes was required in order to achieve a consensus recommendation on 29 questions. Results Recommendations have been summarized in three tables, divided by stage I seminoma, stage I nonseminoma and the advanced disease, which may be useful for clinicians to appropriately choose the clinical investigation and its timing during the surveillance and follow-up of TGCT patients based on an accurate estimation of their risk of disease relapse. Conclusions The IGG-AIOM consensus recommendations may help clinicians to choose appropriate clinical investigations for the surveillance and follow-up of TGCT patients.

Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1a (HIF-1a) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1a regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1α (HIF-1α) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1α regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. © 2011 Società Italiana di Nefrologia.

The major toxic components in the outer membranes of gram-negative bacteria are lipopolysaccharides (LPS) (endotoxins) and porins. The latter are hydrophobic proteins (mass, about 35,000 Da) that account for more than 50% (18, 35) of the total membrane proteins and that are named porins for their ability to form transmembrane channels for the passive diffusion of small molecules across the cell membrane (26, 27). Purified porins possess immunomodulatory and procoagulant activities and are considered pathogenicity determinants. Depending on the dose, LPS and porins are either frankly toxic to a number of target cells or significantly alter normal cell functions (10, 45). By acting on human polymorphonuclear leukocytes (PMNs), subtoxic concentrations of porins, for example, inhibit phagocytosis and intracellular killing of Salmonella typhimurium (45), decrease oxidative burst and cell hydrophobicity, and cause significant morphological changes in the target cells (46). Subcutaneous injection of porins in rat hind paws causes local inflammation without complement activation (12, 13), a process that is known to be triggered in vitro by these proteins. Finally, it has recently been demonstrated that nontoxic concentrations of porins stimulate the synthesis and release of platelet-activating factor from different types of human cells (PMNs and mesangial and endothelial cells) (6, 41, 42) and promote proinflammatory and immunomodulatory cytokine release from immunocompetent cells or other cellular sources (11). Porins from different microorganisms have similar effects (8, 23, 43, 44). The cell damage from severe infections by gram-negative bacteria comes mainly from exotoxins and enterotoxins, even though the occurrence of LPS and porins in the bacterial microenvironment contributes significantly. Exposure of target cells to high concentrations of these substances leads to a rapid lytic death of the cells (1, 5, 10, 34, 45). In contrast, lower concentrations of LPS produce a less dramatic type of death: programmed cell death (PCD), or apoptosis (49). Classic morphological and biochemical signs of apoptosis in the toxin-injured cells are cell shrinkage, extensive blebbing of the cell surface, disappearance of microvilli, chromatin condensation, internucleosomal DNA fragmentation, presence of large intracytoplasmic vacuoles, increase of intracellular calcium ion and free radical levels, enhancement of endonuclease and protease activities, cell cycle arrest, and modified transcriptional activity of different apoptosis-linked genes (p53, bcl-2, c-myc, etc.) (2, 7). An increase in the expression of type II transglutaminase (tissue transglutaminase [tTGase]) has also been reported to be associated with apoptosis in several cell types, and an important role for tTGase in this process has been proposed (15). The ability of bacterial endotoxin to kill cells by necrosis and/or apoptosis has been found to play a key role in the pathogenesis of many alterations occurring in subjects with infections by gram-negative bacteria, including disseminated intravascular coagulation, septic shock, degenerative processes in different tissues, and reduced fertility or sterility (4, 10, 24, 48). The tissue lesions produced by Pseudomonas aeruginosa are of particular interest. P. aeruginosa is an opportunistic pathogen that commonly invades immunocompromised patients. The main targets of the LPS and porin released by this gram-negative rod during its lysis or active growth are the endothelial and epithelial cells present in many anatomical regions, including the skin, eyes, genitourinary tract, and heart valves. In particular, it has been reported that low levels of natural porin or LPS in patients with mild chronic infections severely damage the human spermatozoa in vitro and lead to reduced fertility or sterility (29). On the basis of these data and considerations, and taking into account the scarce information available on the cytotoxic effects of very low concentrations of LPS or porin on specific target cells, we were prompted to investigate the possible involvement of these substances in the induction of apoptosis in a cell line (SVC1) derived from the rat seminal vesicle secretory epithelium (36, 37, 49).

Rationale PSA responses have been associated with a survival benefit in patients treated with enzalutamide in retrospective analyses. Patient concerns However the prognostic value of PSA declines in highly pretreated patients receiving enzalutamide remains to be defined. Diagnoses and interventations Medical records of patients with documented mCRPC treated with enzalutamide between September 2011 and August 2016 were reviewed at multiple participating centers and assessed for overall survival (OS), PSA variations, and other variables of interest. Univariable and multivariable analyses were conducted. Outcomes A total of 129 patients received enzalutamide. PSA response rates (>50% PSA declines) were 58/119 (48.7%), 58/115 (50.4%), 54/110 (49.1%), and 47/91 (51.7%) at weeks 4, 8, 12, and 16, respectively. Having a PSA response was a statistically significant prognostic factor of improved OS at 8 and 12 weeks in univariable analysis, whereas it was significant at 12 weeks in the multivariable analysis. Patients treated with enzalutamide had a median OS of 7.8 months. Lessons Our study supports the prognostic value of PSA declines in heavily treated patients receiving enzalutamide.

The effect of nontoxic, low concentrations (10 −8 M) of retinoic acid (RA) for a relatively long time (28 days) on a Kirsten ras-virus transformed cell line (Ki-SVC1), derived from the rat seminal vesicle epithelium, was investigated. In these experimental conditions, the cell treatment with RA induced a decrease of the proliferation rate, apoptosis and a marked reduction of both anchorage-independent growth and tumorigenicity. These biological responses were either preceded or associated with important changes in adenylate cyclase/protein kinase C signaling pathways, the activation of important apoptosis-linked genes and a marked decrease of the v-Ki-ras p21 protein. The significance of these findings is discussed.

The aim of the study was to evaluate the effect of the protein Seminal Vesicle Protein No. 4 (SV-IV), a potent inhibitor of antithrombin III (antithrombin), on the coagulation of blood obtained from patients affected by hemophilia A. In the coagulating blood of these patients, the antithrombin/thrombin ratio was found to be markedly higher (about 44) than in normal individuals (about 4. 4). This high ratio was related to the low efficiency of thrombin-generating reactions induced by the factor VIII deficiency and to the high levels of free (not bound to serine proteases) antithrombin present in the hemophilic serum (antithrombin concentration was the same in normal and hemophilic plasma). The elevated concentration of free antithrombin in hemophiliacs was primarily a consequence of a reduced consumption caused by the scarce availability in the hemophilic serum of factors Xa and IIa, which are serine proteases possessing strong binding affinity for antithrombin. Addition of SV-IV to coagulating hemophilic blood reduced markedly the serum antithrombin and thrombin-antithrombin complexes, normalizing, as a consequence, the clotting time and other coagulation parameters. Similar results were obtained by using appropriate concentration of factor VIII.

Statins are a class of drugs that inhibit the rate-limiting step in the cholesterol biosynthetic pathway and show an anticancer effect, probably through the inhibition of cells proliferation. To date, the exact mechanism at basis of cancer cells growth arrest induced by statins is not known. Here we reported that simvastatin is able to induce apoptosis in melanoma cells but not in normal cells and also able to contrast the growth of tumor in an experimental melanoma murine model. In particular, we observed an interesting delay in the tumor development in almost the 50% of the simvastatin administered animals and a strong reduction of the tumor volume with a differences of about 150% respect to the controls. Also the survival rate was significantly higher in mice that received the drug with a survival increase of about the 130% respect to the controls. The tumor growth reduction in mice was supported by the results of cells migration assay, confirming that simvastatin clearly reduced the cells migration. Lastly, simvastatin induced a strong down regulation of Non0 gene-expression, an important growth factor involved in the splicing regulation. This result could explain the decrease of melanoma cells proliferation, suggesting a possible action mechanism. The results derived from our experimentation may sustain the many reports on the anticancer inhibitory property of statins and encourage new studies on this drug for a possible use in therapy, probably in combination with the conventional chemotherapy.

Objective The authors determined the impact of a positive cytotoxic crossmatch on the outcome of liver transplantation. Summary Background Data Liver allografts rarely undergo hyperacute rejection, but transplants performed across a positive cytotoxic crossmatch tend to follow a different clinical course, with higher intraoperative blood use, postoperative graft dysfunction, and, in some cases, graft loss. How this affects overall graft survival has not been determined. Methods The authors provide a retrospective analysis of 1520 liver transplants performed between November 1989 and December 1993, with a minimum follow-up of 1 year. All cases had a cytotoxic crossmatch using serum pretreated with dithiothreitol. Results There were 1390 negative crossmatch and 130 positive crossmatch cases. There was no difference in overall graft survival, although early survival rates were lower in the positive crossmatch group, with the maximum difference at 6 months: 0.76 (95% confidence interval, 0.74-0.78) for a negative crossmatch versus 0.68 (95% confidence interval, 0.61-0.77) for a positive crossmatch. These differences become negligible by the 2-year mark. Using stepwise logistic regression, the authors identified seven variables independently associated with outcome: 1) donor age, 2) donor gender, 3) prior liver transplant, 4) medical urgency status, 5) ischemia time, 6) indication for transplantation, and 7) primary immunosuppressant. Conclusions The cytotoxic crossmatch is not statistically associated with overall graft survival after liver transplantation. However, early failure rates are higher in the positive crossmatch cases, a difference that disappears by the second year.

Organisms exposed to ionizing radiation are mainly damaged by free radicals, which are generated by the radiolysis of water contained in the cells. Recently a significant reduction of tissue injury from irradiation damage was demonstrated by using MnSOD-plasmid/liposome treatments in the protection of murine lung. In this study we show that a new active recombinant human MnSOD (rMnSOD), easily administered in vivo, not only exerts the same radioprotective effect on normal cells and organisms as any MnSOD, but it is also radiosensitizing for tumor cells. In addition, we show how healthy animals, exposed to lethal doses of ionizing radiation and daily injections with rMnSOD, were protected from radiodamage and were still alive 30 days after the irradiation, while animals treated with only PBS solution, in the absence of rMnSOD, died after 7-8 days from the radiotreatments. The molecular analysis of all irradiated tissues revealed that the antiapoptotic AVEN gene appeared activated only in the animals treated in the presence of rMnSOD. The data suggest that rMnSOD deserves to be considered as a pharmaceutical tool for making radiotherapy more selective on cancer cells and to prevent and/or cure the accidental damage derived from exposure to ionizing radiation.

The involvement of brain deoxyribonucleic acid (DNA) synthesis in adaptive neural events was studied in the adult rat during long-term habituation (LTH) or potentiation (LTP) of the perforant path-granule cell synapse. Male Long-Evans rats were given 50 muCi [3H]thymidine intraventricularly under urethane anesthesia. Soon thereafter, field excitatory postsynaptic potential (EPSP) slope and population spike were monitored from the right dentate gyrus before and at various times (5, 10, 15, 60 min) following the delivery to the ipsilateral perforant bundle of a low frequency (LFS: 1.0 Hz, 160 s) or a high-frequency train (HFS: 400 Hz, 200 ms), repeated once after 5 min. Unstimulated implanted rats served as controls. DNA synthesis was evaluated by the incorporation of the radioactive precursor into DNA of several brain areas at the end of a 1 h incorporation period. In CA1, LTH and LTP increased DNA synthesis by 30% on the stimulated side. In the entorhinal cortex, LTH but not LTP increased DNA synthesis (by 30%) on the stimulated side. Conversely, in the frontal cortex, LTP but not LTH increased DNA synthesis (by 100%) on both sides. Long-lasting changes in synaptic efficacy covaried non-linearly with DNA synthesis in mono- and polysynaptically stimulated hippocampal regions, and in functionally associated neocortical areas. The co-variations of population spike amplitude were positive for LTH and negative for LTP in the dentate gyrus and frontal cortex of both sides, and in CA3/CA1 of the stimulated side, indicating higher DNA synthesis at lower values of LTH and LTP, and viceversa. Further, regional cross-correlation analyses revealed a high degree of synchronization among brain sites, following low- or high-frequency train pulses, indicating that (i) extra-target sites participate on the stimulated and on the contralateral side, and (ii) small distributed changes take place across the sampled neural networks. A modulatory role of information flow on brain DNA synthesis is inferred to take place in a diffuse, distributed manner.

We studied the expression of 33 human homeobox genes belonging to four complex HOX loci in embryonal carcinoma NT2/D1 cells. These cells can be induced to differentiate by culturing them in media containing retinoic acid. Northern blot analysis reveals that no expression of these genes was detectable in NT2/D1 stem cells, whereas 22 HOX genes are well expressed in NT2/D1 cells treated with 10 microM retinoic acid for 14 days. The 11 HOX genes the expression of which remained undetectable in NT2/D1 cells after this treatment are located at the 5' end of their loci: four in HOX1, five in HOX3 and two in HOX4. The boundary between induced and silent genes roughly corresponds to the HOX genes constituting the homology group 5, related to the Abdominal-B homeotic gene of Drosophila. All nine identified HOX2 genes are well expressed in fully induced NT2/D1 cells and none of them maps 5' genes of this homology group. We conclude that HOX genes are differentially activated by retinoic acid in these cells according to their physical location within the four chromosomal loci.

Human telomerase reverse transcriptase (hTERT) gene expression in resected specimens of oral squamous cell carcinoma (OSCC) and their surrounding tissue, either apparently normal or clearly histologically dysplastic, was evaluated by both real-time RT-PCR and immunohisto-chemical protein analyses. The expression level of hTERT in oral dysplasia and in OSCC was markedly higher than in normal tissues. The correlation between hTERT expression in OSCC and clinico-pathological parameters or survival of OSCC patients was statistically analyzed. Our study demonstrates that there is no significant relationship between hTERT expression and classical clinico-pathological parameters. Interestingly, survival analysis showed both overexpressing cases and lower survival rate in the early stage of OSCC (p=0.03 for immunohistochemistry; p=0.04 for RT real-time PCR). The histological location of hTERT in these tumors has been discussed in the context of the cancer stem cell theory.

Ochratoxin A (OTA) is a mycotoxin produced by fungal of Aspergillus species absorbed in human through contaminate food in gastrointestinal tract. OTA has been demonstrated to be teratogenic in a number of species including mice and potentially human. Mice exposed in uterus to OTA develop craniofacial abnormalities such as exencephaly, microencephaly, microphthalmia and facial clefts. An important role in differentiation of maxillofacial are exerted by the Hox related genes Dlx and Msx. In the present investigation we have confirmed that 2.75 mg/kg body weight OTA, given at gestational day 7.5, induces significant developmental craniofacial anomalies in mice and we have demonstrated the down expression of Dlx5, a member of Dlx gene family, that seems to be responsible of the observed deformities. These results support the hypothesis that Dlx5 is a target for ochratoxin and the inhibition of its function, directly or indirectly, could be at origin of the observed differentiation defects.