Radical Nephroureterectomy Tetrafecta: A Proposal Reporting Surgical Strategy Quality at Surgery.

Background: Standardized methods for reporting surgical quality have been described for all the major urological procedures apart from radical nephroureterectomy (RNU). Objective: To propose a tetrafecta criterion for assessing the quality of RNU based on a consensus panel within the Young Association of Urology (YAU) Urothelial Group, and to test the impact of this tetrafecta in a multicenter, large contemporary cohort of patients treated with RNU for upper tract urothelial carcinoma (UTUC). Design setting and participants: This was a retrospective analysis of 1765 patients with UTUC treated between 2000 and 2021. Outcome measurements and statistical analysis: We interviewed the YAU Urothelial Group to propose and score a list of items to be included in the "RNU-fecta." A ranking was generated for the criteria with the highest sum score. These criteria were applied to a large multicenter cohort of patients. Kaplan-Meier curves were built to evaluate differences in overall survival (OS) rates between groups, and a multivariable logistic regression model was used to find the predictors of achieving the RNU tetrafecta. Results and limitations: The criteria with the highest score included three surgical items such as negative soft tissue surgical margins, bladder cuff excision, lymph node dissection according to guideline recommendations, and one oncological item defined by the absence of any recurrence in ≤12 mo. These items formed the RNU tetrafecta. Within a median follow-up of 30 mo, 52.6% of patients achieved the RNU tetrafecta. The 5-yr OS rates were significantly higher for patients achieving tetrafecta than for their counterparts (76% vs 51%). Younger age, lower body mass index, and robotic approach were found to be independent predictors of tetrafecta achievement. Conversely, a higher Eastern Cooperative Oncology Group score, higher clinical stage, and bladder cancer history were inversely associated with tetrafecta. Conclusions: Herein, we present a "tetrafecta" composite endpoint that may serve as a potential tool to assess the overall quality of the RNU procedure. Pending external validation, this tool could allow a comparison between surgical series and may be useful for assessing the learning curve of the procedure as well as for evaluating the impact of new technologies in the field. Patient summary: In this study, a tetrafecta criterion was developed for assessing the surgical quality of radical nephroureterectomy in patients with upper tract urothelial carcinoma. Patients who achieved tetrafecta had higher 5-yr overall survival rates than those who did not.

68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.

OBJECTIVE: To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. MATERIAL AND METHODS: We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. RESULTS: The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. CONCLUSIONS: We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

Trace elements in scalp hair of children living in differing environmental contexts in Sicily (Italy).

We present here data about trace elements in human scalp hair samples to test whether they are valuable to reflect environmental exposure and contamination by trace elements. The study compares contents of trace elements in scalp hair from a total of 336 children, aged 11-13 years old, living in various geographical areas of Sicily (southern Italy) characterized by differing environmental conditions. Nineteen elements (Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Coverage intervals (CI) formulated by the elemental composition of hair samples from the Palermo subjects were compared with the median content of hair from children living in the other study areas. Statistical analysis showed that Al, Ba, Sr and Zn concentrations differed significantly between gender, higher concentrations being observed in girls' hair. Children living close to the volcanic area had higher concentrations of As, Cr, Mn, Ni, Rb, Sb, U, V and Zn. Those living in an area with several old quarries had higher levels of Al, As, Pb, Rb and U. The hair of children living near the Pace del Mela industrial area contained higher levels of As, Ba, Mn, Pb, Rb, Sr and U. Linear discriminant analysis (LDA) between Palermo and the other sites allowed to better assess which variables contribute towards differentiating the groups. Our observations suggest that human hair can be used to monitor exposure to several metals, provided that sampling and analytical procedures, together with statistical treatment of data, are carried out according to standardized protocols.

Histological findings of a surgically excised myopic choroidal neovascular membrane after photodynamic therapy. A case report.

BACKGROUND: The authors describe a myopic choroidal neovascular membrane excised 4 months after photodynamic therapy (PDT). METHODS: A 68-year-old woman with classic choroidal neovascularization (CNV) due to pathologic myopia underwent PDT with verteporfin in the left eye. Four months after treatment a full-thickness macular hole was diagnosed in the same eye and the patient underwent vitrectomy with submacular membranectomy. The subfoveal membrane was studied by light microscopy and immunohistochemical techniques. RESULTS: Light microscopy showed a thin fibrovascular membrane covered by residual retinal pigment epithelium. The membrane contained homogeneous matrix with small collagen bundles, fibroblasts and small blood vessels. The distribution of blood vessels was nonuniform: extravasated red blood cells, macrophages and other inflammatory elements were not present in the fibrous matrix. Endothelial cells were highlighted by CD34 immunostaining and did not show any significant alteration. There was no evidence of inflammatory cells or thrombosis inside vascular lumina. CONCLUSIONS: Histologic examination of the neovascular membrane showed features similar to those of surgically excised myopic CNV without PDT treatment. Our findings suggest that PDT-induced occlusion is temporary. Fluorescein leakage from CNV after a single PDT treatment can be considered as an sign of blood vessel regrowth or recanalization indicating that multiple treatments are necessary.

Long-lasting antithrombotic effects of a single dose of human recombinant, active site-blocked factor VII: insights into possible mechanism(s) of action.

Tissue factor (TF) is important in initiating intravascular thrombosis. We demonstrated that active-site blocked factor VII (FVIIai) inhibits intravascular thrombosis for at least 6 h following a single injection, despite FVIIai plasma half-life was approximately 45 min. The aims of the present study were: (a) to determine the duration of the antithrombotic effects of a single injection of FVIIai; and (b) to assess whether FVIIai prolonged effects can be explained by a slow dissociation rate from TF in the arterial wall. Cyclic flow variations (CFVs), obtained in stenotic rabbit carotid arteries with endothelial injury, were abolished by either FVIIai (100 micro g kg-1 min-1 for 10 min) or hirudin (1 mg kg-1). After CFVs were abolished, carotid blood flow velocity was recorded continuously for 24 h. CFVs restored in all hirudin-treated animals after 2.1 +/- 0.3 h, while they restored in only four of nine FVIIai-treated rabbits in 10.1 +/- 2.2 h. Five animals in this group did not show restoration of CFVs up to 24 h. Immunohistochemistry revealed that FVIIai was still bound to the arterial wall 24 h following its administration, despite at this time FVIIai plasma levels were undetectable. Prothrombin time and partial thromboplastin time did not change significantly. FVIIai exerts potent, long-lasting antithrombotic effects without affecting systemic hemostatic parameters; a possible mechanism is a slow dissociation rate of FVIIai from TF. These proprieties make FVIIai particularly attractive as an antithrombotic intervention.

Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries.

OBJECTIVES: The aim of the present study was to test the hypothesis that retrovirus-mediated in vivo tissue factor pathway inhibitor (TFPI) gene transfer to the arterial wall would efficiently inhibit thrombosis without causing significant changes in systemic hemostatic variables. BACKGROUND: Acute coronary syndromes (unstable angina and acute myocardial infarction) are usually caused by atherosclerotic plaque rupture, with consequent activation of the coagulation cascade and circulating platelets. Tissue factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and thrombin formation. Tissue factor pathway inhibitor is a naturally occurring inhibitor of the extrinsic pathway. METHODS: In the present study, the gene coding for rabbit TFPI was inserted in a retroviral vector under control of a tetracycline-inducible promoter. Replication-defective, infectious, recombinant retroviruses were used to transfect rabbit carotid arteries with either TFPI or a reporter gene--green fluorescent protein (GFP). RESULTS: Retroviral-mediated arterial gene transfer of TFPI resulted in potent inhibition of intravascular thrombus formation in stenotic and injured rabbit carotid arteries, whereas transfection of the contralateral carotid artery with GFP had no effect on thrombosis. No significant changes in systemic hemostatic variables (prothrombin time and partial thromboplastin time) were observed when thrombosis was inhibited. CONCLUSIONS: These data suggest that retroviral-mediated transfection of the arterial wall with TFPI might represent an attractive approach for the treatment of thrombotic disorders.

Effects of recombinant active site-blocked activated factor VII in rabbit models of carotid stenosis and myocardial infarction.

We tested the effects of human recombinant active site-blocked activated factor VII (rFVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. After 30 min of CFV, the animals received rFVIIai. If CFVs were abolished, animals were observed for 30 additional minutes, after which human recombinant activated factor VII was infused into the carotid artery to determine whether it could displace rFVIIai from tissue factor (TF), thus restoring CFV. An additional group of animals received rFVIIai to determine its duration of action. Recombinant FVIIai abolished CFVs in 8 of 9 rabbits (P < 0.01). This effect was reversible, as rFVIIa administration restored CFVs in all animals. A further study was initiated to assess whether TF-dependent reductions in coronary blood flow might contribute to the occurrence of myocardial injury during postischaemic reperfusion of rabbit hearts. Recombinant FVIIai resulted in significant reductions in both infarct size and no-reflow area, while rFVIIa produced a significant increase in both infarct size and no-reflow area. These data suggest that rFVIIai might be beneficial in patients with acute myocardial infarction undergoing reperfusion therapies.

Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.

The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequence of vascular injury. Increasing evidence indicates that this TF-dependent activation of the coagulation plays an important role in the pathophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site-blocked activated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. Carotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 microg x kg(-1) x min(-1) intracarotid infusion for 10 minutes, n=9). If CFVs were abolished, animals were followed for 30 additional minutes, after which recombinant human activated FVII (FVIIa) was infused into the carotid artery (100 microg x kg(-1) x min(-1) for 10 minutes) to determine whether FVIIai could be displaced from TF by FVIIa, thus restoring CFVs. To establish the duration of action of FVIIai, an additional group of animals received FVIIai at the same dose as above, and after CFVs were inhibited, they were followed until CFVs were restored or for up to 6 hours. To determine whether CFVs could be restored by epinephrine after their abolition with FVIIai, increasing doses of epinephrine were administered to a third group of 6 animals. FVIIai abolished CFVs in 8 of 9 rabbits (P<.01). This effect was reversible, as FVIIa administration restored CFVs in all animals. Prothrombin times and activated partial thromboplastin times did not change significantly throughout the study. One single 10-minute infusion exerted complete antithrombotic effects for at least 6 hours, despite the fact that at this time point, plasma FVIIai levels were well below threshold concentrations. Epinephrine restored CFVs in 3 of 6 animals in which CFVs were inhibited by FVIIai. FVIIai exerts potent antithrombotic effects in this model; these effects were prolonged even after FVIIai was almost completely cleared from the circulation, probably as a result of the tight binding of FVIIai to TF. Thus, FVIIai might represent an antithrombotic substance of potential interest.

The role of class I and class II HLA antigens in primary open angle glaucoma (POAG).

Several clinical and epidemiological studies have shown the role of genetic factors in the pathogenesis of primary open angle glaucoma (POAG). In this study, 30 patients affected by this disease were tissue-typed for HLA Class I and Class II antigens. The results pointed up an increased incidence of some antigens and, particularly, a statistically significant association with DQ1 and DR11 alleles.

Clinical use of a topical carbonic anhydrase inhibitor in patients affected by chronic simple glaucoma.

The aim of this study is to evaluate the ocular hypotensive efficacy of a topical carbonic anhydrase inhibitor (dorzolamide) in primary open-angle glaucoma patients, administered alone or in association with beta-blockers or with beta-blockers and miotics, in a one-year follow-up.

Oxygen radicals can induce preconditioning in rabbit hearts.

Indirect evidence suggests that oxygen radicals may contribute to ischemic preconditioning. We directly investigated whether exposure to oxygen radicals per se, in the absence of ischemia, could reproduce the beneficial effects of ischemic preconditioning on infarct size and on postischemic contractile dysfunction. In one branch of the study, isolated rabbit hearts underwent 30 minutes of total global ischemia and 45 minutes of reperfusion (n=6, control group). A second group, before ischemia/reperfusion, was exposed for 5 minutes to a low flux of oxygen radicals generated by purine/xanthine oxidase (P/XO), followed by a 15-minute washout (n=6). Oxygen radical pretreatment significantly improved postischemic recovery of contractile function. We then investigated in another branch of the study whether this preconditioning effect would also reduce infarct size and whether it was mediated by protein kinase C activation. Control hearts were subjected to coronary artery occlusion for 30 minutes, followed by 2.5 hours of reperfusion (n=6). A second group, before coronary occlusion, was exposed to oxygen radicals and washout as described (n=8). A third group was subjected to oxygen radical infusion, but an inhibitor of protein kinase C (polymyxin B, 50 micromol/L) was administered throughout subsequent ischemia (n=7). A fourth group was exposed to oxygen radicals in the presence of scavengers (superoxide dismutase, 250 U/mL; catalase 500, U/mL; n=8). Pretreatment with oxygen radicals markedly reduced infarct size, from 65+/-19% of risk region in controls to 12+/-4% (P<.05). Protein kinase C inhibition significantly attenuated this effect (infarct size, 37+/-9% of risk region; P<.05 versus P/XO; P=NS versus controls). Oxygen radical-induced preconditioning was prevented by scavengers (infarct size, 55+/-14% of risk region; P<.05 versus P/XO; P=NS versus P/XO+polymyxin B). Our data show that in the absence of ischemia, exposure to low concentrations of oxygen radicals can reproduce the beneficial effects of ischemic preconditioning on infarct size and postischemic recovery of left ventricular function. Thus, oxygen radicals might be potential contributors to ischemic preconditioning.

Structural features of nephritogenic lupus autoantibodies.

We have identified monoclonal antibodies derived from MRL-lpr/lpr lupus-prone mice that produced nephritis after passive transfer to normal mice. Our present goal was to elucidate the structural and immunochemical features of nephritogenic Ig that facilitate immune deposition. For this purpose the antigen binding properties, capacity to form immune deposits, and nucleotide sequence of a genetically related autoantibody subgroup were compared. The prototype, H147 (an IgG encoded by 7183/81X VH gene), produced glomerular and tubular basement membrane, mesangial immune deposits, and proliferative glomerulonephritis after passive transfer to normal mice. For comparison three other 7183/81X encoded anti-DNA IgG (H257, H171, and H8a) were evaluated (predicted heavy chain aa homology >75%). H257 produced similar types of immune deposits as H147, and this was associated with nephritis; H8a produced predominantly mesangial deposits, whereas H171 did not produce significant deposits. Although their antigen binding profile to a panel of soluble autoantigens was variable, only H147 and H257 bound to both mesangial and aortic endothelial cell surfaces. V gene sequence analysis of the IgG suggests that individual residues, motifs, and conformations influence the autoantigen binding specificities that contributed to the observed differences in immune deposit formation.