Effectiveness of guselkumab in patients with facial and/or genital psoriasis: Interim analysis results at Week 12 from the GULLIVER study.

BACKGROUND: Facial (FP) and genital psoriasis (GP) significantly affect patients' quality of life. Despite the advances in treatments, limited data on efficacy and safety are available on these difficult-to-treat areas. Guselkumab is an interleukin (IL)-23 inhibitor which has been proven effective in treating patients with moderate-to-severe plaque psoriasis. OBJECTIVES: The aim of this interim analysis was to report the efficacy and safety of guselkumab in the treatment of patients with FP and/or GP. MATERIALS AND METHODS: GULLIVER is a 52-week Italian observational study to evaluate the effectiveness and safety of guselkumab in a real-life setting in patients with FP and/or GP. Adult patients with facial and/or genital moderate-to-severe psoriasis (sPGA score ≥ 3) were included. The primary endpoint of this analysis was the percentage of patients achieving a facial or genital sPGA score of 0 (clear) or 1 (almost clear), at Week 12. The change in the score of the facial or genital sPGA components in patients with a score ≥3 for each sPGA component was assessed. PASI score in patients with a baseline PASI above or below 10 was evaluated. RESULTS: Overall, 351 patients were included in the study; 83.3% of FP and 76.5% of GP patients achieved the primary endpoint. Similar response rates were observed for the facial or genital sPGA components in patients with a baseline facial or genital sPGA score ≥3 in each component. Among patients with a baseline PASI score >10, mean PASI score improved from 19.0 (SD 8.3) to 2.2 (SD 4.8). Forty-four AEs were observed in 32 patients; two mild and transient AEs (fatigue and nausea) were considered treatment related. No SAEs were observed. CONCLUSIONS: Guselkumab, showing to be effective and safe in treating FP and GP, may be a valid therapeutic option for patients with psoriasis localized in these difficult-to-treat areas.

Radical metastasectomy followed by sorafenib versus observation in patients withclear cell renal cell carcinoma: extended follow -up of efficacy results from the randomized phase II RESORT trial.

Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data.Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint.Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis . At a median follow-up of 42 months (interquartile range 31-58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42-76%) at 24 and 44% (95% CI 30-65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34-71%) at 24 and 32% (95% CI 18-57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72-2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site.Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival.Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480.

Multidisciplinary approach to obesity.

UNLABELLED: Obesity, associated with morbidity and mortality, is a complex disorder, characterised by an increase in fat mass (FM). Most authors agree in considering essential an integrated treatment made up of nutritional intervention, physical reconditioning programme and cognitive-behavioural psychotherapy. However, the feasibility is problematic and data in literature confirming the validity of this approach are poor. AIM: To verify the efficacy of a multidimensional approach (Nutritional Psycho-Physical Reconditioning - NPPR) in obesity treatment. METHODS: All patients admitted from June 2002 to June 2004 (464 subjects) ranged from 18 to 65 years old, with a body mass index (BMI) >30 kg/m2 were included in the programme. After the nutritional status evaluation a standard dietetic treatment (group N) or an integrated and multidisciplinary obesity treatment (group NPPR) was proposed. RESULTS: In group NPPR treatment duration was significantly higher (142.6+/-26 vs 48.6+/-55 days - p=0.000), while the drop-out amount was definitely lower (5.5 vs 54.4%; p=0.000). Weight loss compared to the initial weight and the difference between initial and final FM resulted significantly higher in group NNPR. Subjects in NPPR obtained a higher increase in the distance covered in a 6-minute walk test (59.9+/-19 vs 40.5+/-17 m; p=0.04) and in muscular strength. State and trait anxiety, mood and quality of life scores improved in NPPR subjects while remained substantially stable in group N. CONCLUSIONS: An integrated approach to obesity is the way to be pursued in order to obtain important and at least short-term results.

Botulinum toxin type-A for the treatment of inverse psoriasis.

OBJECTIVE: To evaluate the efficacy of botulinum toxin type-A (BoNTA) for the treatment of inverse psoriasis. BACKGROUND: The use of BoNTA in inverse psoriasis would be a novel approach compared with conventional treatments and may act at the neuroglandular junction level to reduce local sweating with its consequent skin maceration and secondary infection and at the extra-junction level to inhibit the liberation of neuropeptides and other pro-algogenic substances responsible for inflammation, hyperkeratosis and pain transmission. PATIENTS: Fifteen patients with a confirmed diagnosis of inverse psoriasis were enrolled into the study. The psoriasis was located in several areas: armpits (7 patients), submammary sulcus (6 patients), intergluteal folds (7 patients), inguinal folds (5 patients) and umbilicus (1 patient). METHODS: BoNTA treatment comprised individual injections 2.8 cm apart of 2.4 U BoNTA, with a total dosage between 50 and 100 U per patient depending on the extent and severity of the psoriasis. Patient assessments were done pre-treatment and at 2, 4 and 12 weeks post-treatment. The erythematous area was defined using objective photographic evidence, and subjective patient assessment of pain and itch was assessed using a 10-point visual analogue scale scale. RESULTS: Subjective symptomatology improved in all patients and erythema extension, intensity and infiltration improved in 13 of 15 patients (87%). Treatment was well tolerated with no reported adverse events. CONCLUSIONS: BoNTA therapy resulted in improvements in subjective patient symptomatology and objective reductions in erythema and maceration in the treated areas according to photographic evidence. Further large-scale methodologically rigorous studies are required to investigate the safety and efficacy of BoNTA in this indication.

TiO2-coated luminescent porous silicon micro-particles as a promising system for nanomedicine.

Porous silicon (pSi) is a sponge-like material obtained by electrochemical etching of a crystalline silicon wafer. Due to quantum confinement effects, this material is photoluminescent and this is a fundamental property from the perspective of bioimaging applications. Limitations in nanomedicine to the use of photoluminescent pSi structures are mainly due to optical quenching in an aqueous environment and to the adverse effects of reactive groups introduced by etching procedures. In this work, we exploited an inorganic TiO2 coating of pSi microparticles by Atomic Layer Deposition (ALD) that resulted in optical stability of pSi particles in a biological buffer (e.g. PBS). The use of a rotary reactor allows deposition of a uniform coating on the particles and enables a fine tuning of its thickness. The ALD parameters were optimized and the photoluminescence (PL) of pSi-TiO2 microparticles was stabilized for more than three months without any significant effect on their morphology. The biocompatibility of the coated microparticles was evaluated by analyzing the release of cytokines and superoxide anion (O2 -) by human dendritic cells, which play an essential role in the regulation of inflammatory and immune responses. We demonstrated that the microparticles per se are unable to significantly damage or stimulate human dendritic cells and therefore are suitable candidates for nanomedicine applications. However, a synergistic effect of the microparticles with bacterial products, which are known to stimulate immune-response, was observed, indicating that a condition unfavorable to the use of inorganic nanomaterials in biological systems is the presence of infection diseases. These results, combined with the proved PL stability in biological buffers, open the way for the use of pSi-TiO2 microparticles as promising materials in nanomedicine, but their ability to increase immune cell activation by other agonists should be considered and even exploited.

Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg).

The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.

Monocytes of patients wiht systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion.

It has been suggested that toxic oxygen free radicals can be involved in the pathogenesis of systemic sclerosis (scleroderma) (SSc). Because the cells that contribute to the generation of free radicals are not known, our aim was (i) to evaluate the ability of unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes and polymorphonucleate neutrophils of SSc patients to generate superoxide anion (O2*-); and (ii) to investigate whether the O2*- produced by these cells involved the activation of nicotinamide-adenine dinucleotide diphosphate oxidase biochemical pathway. Employing the superoxide dismutase-inhibitable reduction of cytochrome c to evaluate the generation of O2*-, unmanipulated monocytes of SSc patients generated more O2*- than primary Raynaud's phenomenon patients and normal control monocytes (p = 0.0001), and the release was higher in patients with diffuse cutaneous involvement and 5 y or less disease duration (p = 0.02). The involvement of nicotinamide-adenine dinucleotide diphosphate oxidase in the enhanced 02*- production was demonstrated by the finding that the cytosolic components of the enzyme, p47phox and p67phox, were both translocated to the plasma membrane of enriched but otherwise unmanipulated monocytes of SSc patients. The involvement of mitochondrial oxidases was excluded by the lack of inhibition of O2*- production when monocytes were incubated in the presence of rotenone, a mitochondrial oxidase inhibitor. Upon stimulation with phorbol 12-myristate 13-acetate, monocytes of SSc patients produced more O2*- than controls. In SSc patients untreated polymorphonucleate neutrophils generated significantly less O2*- than monocytes (p = 0.0001) and only slightly more than polymorphonucleate neutrophils of primary Raynaud's phenomenon patients and normal controls (p = 0.03). In conclusion, we demonstrate that in patients with scleroderma, unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes release in vitro increased amounts of superoxide anion through the activation of nicotinamide-adenine dinucleotide diphosphate oxidase and, thus, contribute to the oxidative stress found in this disease.

Tyrosine phosphorylation and subcellular redistribution of p125 ras guanosine triphosphatase-activating protein in human neutrophils stimulated with FMLP.

In this paper, we show that the p125 ras guanosine triphosphatase-activating protein (p125 GAP) is present in the cytosol of human neutrophils and is transiently tyrosine phosphorylated and translocated to the membranes upon cell activation with formyl-methionyl-leucyl-phenylalanine (FMLP). When concanavalin A (ConA) or phorbol 12-myristate 13-acetate (PMA), which both induced a long-lasting respiratory burst, were used as stimuli, tyrosine phosphorylation and translocation of p125 GAP did not occur.

Latent class analysis of DSM-IV schizotypal personality disorder criteria in psychiatric patients.

The aim of the study was to evaluate the latent structure of DSM-IV schizotypal personality disorder (SPD) diagnostic criteria. The sample consisted of 564 consecutively admitted inpatients and outpatients. Exploratory latent class analysis identified a four-class model as the best fitting model for DSM-IV SPD criteria. The first of the SPD latent classes was mainly characterized by odd thinking, inappropriate affect, and interpersonal features; the second class by cognitive/perceptual difficulties; the third class by paranoid features; and the fourth class by absence of SPD features. The conditional probability pattern of the fourclass solution could be safely replicated across confounder strata. Unlike previous findings, oddness, aloofness, and social withdrawal, rather than positive symptoms, best characterized SPD even in clinical samples.

Temperament, character, and attachment patterns in borderline personality disorder.

The aim of this study was to assess the specificity of the association between temperamental vulnerability, character deficits, and Borderline personality disorder (BPD), controlling for the effects of attachment patterns. A total of 44 BPD patients were compared with 98 non-BPD patients with other cluster B Personality Disorder (PD) diagnoses, 39 patients with any cluster A or cluster C PD diagnoses, 70 patients with no PD diagnosis, and 206 nonclinical patients. All patients were administered the Temperament and Character Inventory, the Parental Bonding Instrument, and the Attachment Style Questionnaire. Multivariate and univariate tests showed that BPD patients differed significantly from all control groups on Novelty Seeking and Cooperativeness. These differences remained significant when controlling for the effect of attachment.

Brief communication: criterion validity of the Personality Diagnostic Questionnaire-4+ (PDQ-4+) in a mixed psychiatric sample.

Three hundred consecutively admitted in- and outpatients were administered the Personality Diagnostic Questionnaire-4+ (PDQ-4+). The Structured Clinical Interview for DSM-IV Axis II Personality Disorders, Version 2.0 (SCID-II) was used as the external diagnostic standard for personality disorder (PD) assessment. SCID-II was administered blind to PDQ-4+ scores. Low agreement between PDQ-4+ and SCID-II was observed for both dimensional and categorical PD evaluations. Receiver operating characteristic (ROC) analysis showed a definitively satisfactory discriminatory capability only for two PDQ-4+ PD scales (dependent, and antisocial). In agreement with previous studies, these results showed that PDQ-4+ was not a substitute for a structured diagnostic interview.

A psychometric study of DSM-IV passive-aggressive (negativistic) personality disorder criteria.

The passive-aggressive (negativistic) personality disorder (PAPD) is one of the most controversial personality disorders. In order to assess DSM-IV PAPD psychometric properties and comorbidity pattern in a mixed psychiatric sample, 379 consecutively admitted in- and outpatients were administered SCID-II, Version 2.0. Confirmatory factor analysis showed that DSM-IV PAPD is a unidimensional construct with adequate internal consistency (K-R 20 = .85). A strong, specific association (odds ratio = 10.38, 95% CI = 4.83-22.30) was observed between DSM-IV PAPD and narcissistic personality disorder (NPD). Confirmatory factor analysis showed that DSM-IV PAPD should be considered as a subtype of a broader narcissistic disorder.

Influence of radiotherapy on intestinal microflora in cancer patients.

We investigated in 15 patients with carcinoma of the uterine cervix or endometrium, who were undergoing postoperative radiation therapy, the effects of different fractionated radiation exposures on counts of fecal bacteria, on the growth of Clostridium difficile and Clostridium perfringens enterotoxin production. We observed a generally significant decrease in intestinal microflora after the first radiation exposure, whereas at the end of radiotherapy all bacteria increased and reached basal values except Enterococcus faecium 1, lactobacilli and total anaerobes. In some patients we observed an overgrowth of some Clostridium spp. which were potential pathogens associated with clinical symptoms. We did not observe an influence of multiple radiations on C. perfringens enterotoxin fecal contents. We conclude that patients receiving radiotherapy may benefit from the intake of oral bacteriotherapy, i.e. live beneficial bacteria such as Bacillus subtilis at the beginning of the irradiation exposure.

Orange and blue luminescence emission to track functionalized porous silicon microparticles inside the cells of the human immune system.

Porous silicon micro-particles (micro-pSi) with size in the range of 1-10 µm are obtained by etching of silicon wafers followed by sonication. The derivatization of the micro-pSi surface by wet chemistry (silylation and coupling with a diamine) yields an interface, which exposes negative (carboxylic) or positive (amine) groups at pH 7.4. The surface modification, beyond the introduction of groups for the drug loading by covalent or electrostatic interactions, stabilizes the intense orange luminescence characteristic of the silicon nano-crystallites. Derivatization by amines introduces also a second emission in the blue region, which follows a different excitation pathway and can be attributed to the interface defects. The micro-pSi are efficiently internalized by human dendritic cells and do not show any toxic effect even at a concentration of 1 mg mL-1. The intrinsic luminescence of the differently functionalized micro-pSi is preserved inside the cells and permits the selective and efficient tracking of the microparticles without using molecular tags and thus leaving the organic coating available for the interaction with the drug. The results obtained suggest that the functionalized micro-pSi are an efficient platform for simultaneous imaging and delivery of therapeutic agents to the disease site.

Mechanisms of NADPH oxidase activation in human neutrophils: p67phox is required for the translocation of rac 1 but not of rac 2 from cytosol to the membranes.

NADPH oxidase is the enzyme complex responsible for the production of oxygen radicals in phagocytes. On neutrophil stimulation, the cytosolic components of NADPH oxidase, p67phox and p47phox, as well as the Ras-related G-protein rac 2, are translocated from the cytosol to cell membranes where they associate with a flavocytochrome b to form a functional complex. Besides rac 2, rac 1 G-protein is also involved in the activation of the NADPH oxidase, but, to date, it has not been documented whether it is also translocated in activated neutrophils. In this paper we show that: (a) in neutrophils stimulated with formylmethionyl-leucylphenylalanine, concanavalin A or phorbol 12-myristate 13-acetate, both rac 1 and rac 2 are translocated from cytosol to the membranes; (b) in neutrophils from a patient with a form of chronic granulomatous disease in which p67phox is absent, rac 2 and p47phox were translocated as in normal neutrophils on stimulation with the above agonists, but rac 1 failed to be translocated from the cytosol to the membranes. This is the first demonstration that, in activated neutrophils, rac 1 is translocated from the cytosol to the membranes and this translocation requires p67phox. These results, coupled with those showing that rac 2 is not translocated in activated neutrophils lacking p47phox [El Benna, Ruedi and Babior (1994) J. Biol. Chem. 269, 6729-6734], may suggest that the assembly of the cytosolic components of NADPH oxidase on the plasma membrane takes place through selective coupling of activated rac 1 and rac 2 with p67phox and p47phox respectively.

Tyrosine phosphorylation and activation of NADPH oxidase in human neutrophils: a possible role for MAP kinases and for a 75 kDa protein.

Challenge of neutrophils with concanavalin A (ConA), formyl-methionyl-leucyl-phenylalanine (FMLP), and phorbol 12-myristate 13-acetate (PMA) induced the tyrosine phosphorylation of several proteins. Among these proteins we have identified two mitogen-activated protein kinase (MAPK) isoforms of 43 kDa (p43 MAPK) and 45 kDa (p45 MAPK) molecular mass. Moreover here we show that: (1) FMLP induced the tyrosine phosphorylation of the p43 MAPK, and ConA that of p45 MAPK, while PMA induced the tyrosine phosphorylation of both p43 and p45 MAPK; all these agonists induced the tyrosine phosphorylation of a 75 kDa protein (p75). (2) With FMLP or ConA as agonists, tyrosine phosphorylations of MAPK and p75 can be involved in the process of NADPH oxidase activation. On the contrary, PMA can activate the respiratory burst independently of these phosphorylations. (3) In Ca(2+)-depleted neutrophils, where phospholipid hydrolysis did not take place, ConA or FMLP did not activate the respiratory burst, but while ConA induced the tyrosine phosphorylation of p45 MAPK and p75, FMLP was not able to phosphorylate p43 MAPK and p75. (4) As previously observed in our laboratory, a double stimulation of Ca(2+)-depleted neutrophils with ConA plus FMLP induced a respiratory burst in the absence of activation of second messengers derived from phospholipase C, D and A2 activity. This respiratory burst was accompanied by tyrosine phosphorylation of both p43 and p45 MAPKs. These results indicate that when FMLP is the agonist, both the tyrosine phosphorylation of p43 MAPK and p75, and the activation of NADPH oxidase, are coupled to Ca(2+)-dependent mechanisms. On the contrary, ConA can induce the tyrosine phosphorylation of p45 MAPK and p75 independently of calcium, but an unknown Ca(2+)-dependent mechanism is necessary for the activation of NADPH oxidase by this agonist. This mechanism could be substituted by the induction of tyrosine phosphorylation of both p43 MAPK and p45 MAPK when Ca(2+)-depleted neutrophils are stimulated with ConA plus FMLP.

Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2 from the cytosol to the membranes in human neutrophils lacking p47phox or p67phox.

On neutrophil stimulation, the cytosolic components of NADPH oxidase, p67phox, p47phox, p40phox, as well as the Ras-related G-proteins Rac1 and Rac2, are translocated from the cytosol to cell membranes where they associate with a flavocytochrome b, forming a functional complex responsible for the production of oxygen radicals in phagocytes. In this paper we show that (a) in neutrophils from a patient with a form of chronic granulomatous disease (CGD) in which p67phox is absent, p47phox and Rac2, but not p40phox and Rac1 were translocated from the cytosol to the membrane on stimulation with formylmethionyl-leucylphenylalanine (fMLP) or phorbol 12-myristate 13-acetate (PMA); (b) in neutrophils from a patient with a form of CGD in which p47phox is absent, p67phox, p40phox and Rac1 failed to associate with the membrane on stimulation with fMLP or PMA, whereas Rac2 was translocated as in normal neutrophils. We also show that in neutrophils from a patient lacking p67phox, the amount of cytosolic p40phox was decreased by about 40%. These findings indicate that, on neutrophil stimulation, p67phox mediates the translocation of p40phox and Rac1 from the cytosol to cell membranes and that Rac2 associates with the membranes independently of p47phox and p67phox.

Interleukin-10 decreases tyrosine phosphorylation of discrete lipopolysaccharide-induced phosphoproteins in human granulocytes.

Although Interleukin-10 (IL-10) has been recently shown to modulate lipopolysaccharide (LPS)-induced release of cytokines in human granulocytes, the intracellular signalling pathways of LPS have been only partially defined, while those of IL-10 remain unknown. The present study shows that LPS induces an increase in tyrosine phosphorylation of a discrete number of proteins, in a time- and concentration-dependent manner. In addition, IL-10 negatively influenced protein tyrosine phosphorylation in LPS-treated human polymorphonuclear leukocytes (PMN). The effect of IL-10 was evident only after 60 min LPS-stimulation and was detected by analysing either cell lysates or lysates which were previously immunoprecipitated with anti-phosphotyrosine antibodies. Amongst the tyrosine phosphoproteins mostly affected by IL-10 in LPS-stimulated cells were the species with molecular weights ranging from 46 to 49 kDa. The identity and possible function of these proteins remain unknown. Taken together, our results suggest that tyrosine phosphorylation may constitute one of the intracellular events that mediate LPS and IL-10 responses in granulocytes.