Protein kinase C inhibitor sotrastaurin in de novo liver transplant recipients: a randomized phase II trial.

Efficacy and safety of protein kinase C inhibitor sotrastaurin (STN) with tacrolimus (TAC) was assessed in a 24-month, multicenter, phase II study in de novo liver transplant recipients. A total of 204 patients were randomized (1:1:1:1) to STN 200 mg b.i.d. + standard-exposure TAC (n = 50) or reduced-exposure TAC (n = 52), STN 300 mg b.i.d. + reduced-exposure TAC (n = 50), or mycophenolate mofetil (MMF) 1 g b.i.d. + standard-exposure TAC (control, n = 52); all with steroids. Owing to premature study termination, treatment comparisons were only conducted for Month 6. At Month 6, composite efficacy failure rates (treated biopsy-proven acute rejection episodes of Banff grade ≥1, graft loss, or death) were 25.0%, 16.5%, 20.9% and 15.9% for STN 200 mg + standard TAC, STN 200 mg + reduced TAC, STN 300 mg + reduced TAC and control groups, respectively. Median estimated glomerular filtration rates were 84.0, 83.3, 81.1 and 75.3 mL/min/1.73 m(2), respectively. Gastrointestinal events (constipation, diarrhea, and nausea), infection, and tachycardia were more frequent in STN groups. More patients in STN groups experienced serious adverse events compared with the control group (62.3-70.8% vs. 51.9%). STN-based regimens were associated with a higher efficacy failure rate and higher incidence of adverse events with no significant difference in renal function between the groups.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Age-related prevalence and morphological appearance of facial skin tumours: a prospective, cross-sectional, observational, multicentre study with special emphasis on melanocytic tumours.

BACKGROUND: The clinical and histopathological diagnosis of skin tumours arising on the face may be challenging. OBJECTIVE: An improved knowledge about the age-related patterns of facial skin tumours may aid the correct diagnosis and management. METHODS: We conducted a prospective, cross-sectional morphological study to investigate the age-related frequency and morphological variability in facial skin tumours in a cohort of consecutive subjects attending two skin lesion clinics in Italy between June and September 2011. A total of 454 consecutive subjects (249 women; 55.5%) presenting with a total of 1866 facial tumours were enrolled in the study. Of the entire cohort, 54 (11.9%) subjects had no facial lesion. RESULTS: Total body naevus count correlated significantly with the mean number of facial lesions (ρ = 0.289, P < 0.001). The majority of flat lesions were pigmented (1056; 75.70%), compared to palpable (233; 17.40%) and raised lesions (93; 6.90%), the association being statistically significant (Pearson's chi square, P < 0.001. Considering melanocytic tumours only, the frequency of flat lesions significantly decreased with increasing age, while the number of palpable and raised lesions increased with increasing age (chi-square, P < 0.001). This trend was mainly due to naevi, whereby pigmented melanocytic naevi decreased with increasing age. Conversely, the percentage of non- pigmented naevi increased with increasing age (chi-square, P < 0.001). LIMITATIONS: The study was conducted in skin lesion clinics in Italy, thus any general conclusions with respect to common traits or features based on the phenotypic and genetic diversity within the European population cannot be stated. CONCLUSIONS AND RELEVANCE: Our study suggests that a high number of facial naevi could predict a high total naevus count. Moreover, naevi present a different morphological appearance during lifetime being initially flat, small and pigmented and becoming later raised, large and hypopigmented. Instead, lentigo maligna is an intraepidermal proliferation that typically presents as flat, large pigmented macule. A given histopathological diagnosis of a junctional naevus of a flat, facial pigmented macule of an elderly should be critically reviewed and treated with caution.

Use of octogenarian donors for liver transplantation: a survival analysis.

Use of very old donors in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk for graft dysfunction and worse long-term results, especially for hepatitis C virus (HCV)-positive recipients. This was a retrospective, single-center review of primary, ABO-compatible LT performed between 2001 and 2010. Recipients were stratified in four groups based on donor age (<60 years; 60-69 years; 70-79 years and ≥80 years) and their outcomes were compared. A total of 842 patients were included: 348 (41.3%) with donors <60 years; 176 (20.9%) with donors 60-69 years; 233 (27.7%) with donors 70-79 years and 85 (10.1%) with donors ≥80 years. There was no difference across groups in terms of early (≤30 days) graft loss, and graft survival at 1 and 5 years was 90.5% and 78.6% for grafts <60 years; 88.6% and 81.3% for grafts 60-69 years; 87.6% and 75.1% for grafts 70-79 years and 84.7% and 77.1% for grafts ≥80 years (p = 0.065). In the group ≥80 years, the 5-year graft survival was lower for HCV-positive versus HCV-negative recipients (62.4% vs. 85.6%, p = 0.034). Based on our experience, grafts from donors ≥80 years may provide favorable results but require appropriate selection and allocation policies.

Melanoma detection in Italian pigmented lesion clinics.

AIM: Accuracy in melanoma detection is important to recognize early curable melanomas and to minimize the unnecessary excision of benign lesions. The aim of this paper was to evaluate melanoma screening accuracy of Italian pigmented lesion clinics in terms of number needed to excise (NNE), melanoma thickness, and number of melanomas diagnosed during patient follow-up. METHODS: Information on all skin tumors excised in 2011 were extracted from the databases of the participating centers. Information whether the lesion was excised at the baseline examination or during patient follow-up was recorded, as well as the overall number of patients examined in each center in 2011. RESULTS: After e-mail solicitation, 22 of 40 centers agreed to participate. A total of 8229 excised lesions were collected. The overall number of examined patients was 86.564, thus 9.5% of screened patients had a lesion removed. Of the excised lesions, 866 were diagnosed as melanoma (1% of examined patients) and 5311 (88.9%) were melanocytic nevi. Three NNE were calculated giving values of 7.9 excised lesions to find 1 melanoma, 7.1 melanocytic lesions to find 1 melanoma, and 3.7 lesions to find 1 skin malignancy. The median melanoma thickness was 0.6 mm, with only 15.1% of melanomas ≥ 1 mm of thickness. Melanomas detected over time were 96 (11.1%; mean thickness, 0.3 mm), with 15.6% of lesions excised after short-term follow-up and 84.4% after long-term follow-up. CONCLUSION: The NNE values comparable to those achieved in specialized clinical settings and the high number of early melanomas diagnosed at the baseline examination or during patient follow-up indicate a high level of accuracy in melanoma screening achieved by Italian pigmented lesion clinics.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Intermediate hepatocellular carcinoma: current treatments and future perspectives.

Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients managed with this technique do not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with intermediate-stage HCC may derive similar benefit from TACE, and some patients may benefit from other treatment options, which are currently approved or being explored. These include different TACE modalities, such as selective TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.

Typical and atypical dermoscopic presentations of dermatofibroma.

BACKGROUND: Dermatofibroma is a common skin neoplasm that is usually easy to recognize, but in some cases its differentiation from melanoma and other tumours may be difficult. OBJECTIVE: To describe the dermoscopic features of dermatofibromas, with special emphasis on the characteristics of atypical patterns, and to calculate pattern frequency according to the patients age and gender, anatomical site and histopathological subtype. METHODS: Two groups of patients were consecutively seen, one with dermatofibromas that were surgically excised because of clinically and/or dermoscopically equivocal aspects or following patient request, and another with non-equivocal dermatofibromas. Each lesion was scored for previously reported global dermoscopic patterns and for additional features. RESULTS: A typical pattern was observed in 92 of 130 (70.8%) lesions, whereas an atypical pattern, that we named the 'non Dermatofibroma (DF)-like' pattern, was seen in 38 of 130 (29.2%). Atypical dermatofibromas showed features reminiscent of different conditions, such as melanoma in 21(16.2%) cases, vascular tumour in six (4.6%), basal cell carcinoma in five (3.8%), collision tumour in three (2.3%) and psoriasis in three (2.3%). A significant association was found between the 'melanoma-like' pattern/'vascular tumour-like' pattern and males, whereas a trend was observed between the above-mentioned patterns and hemosiderotic/aneurysmal DFs. 'Peripheral pigment network and central white scar-like patch' pattern was found associated with females and classic histopathological variant of DF. CONCLUSION: Dermatofibromas may display different morphological faces. The typical dermoscopic patterns allow a confident diagnosis, whereas a full surgical excision is always recommended in all doubtful cases.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Seven-point checklist of dermoscopy revisited.

BACKGROUND: Most dermoscopic algorithms to diagnose melanoma were established more than 10 years ago and have been tested primarily on clear-cut melanomas and excised melanocytic naevi. OBJECTIVES: To assess the diagnostic performance of pattern analysis and seven-point checklist on lesions that reflect the current clinical setting, compared with a revised seven-point checklist with a lower threshold for excision. METHODS: Eight experienced dermatologists viewed dermoscopic images of 100 excised melanomas, 100 excised naevi and 100 monitored naevi. Each lesion was evaluated by pattern analysis and scored as naevus, melanoma or lesion to be excised. Images were then evaluated using the seven-point criteria, with both standard and revised thresholds for excision. RESULTS: Pooled data using the pattern analysis algorithm showed that 82% of melanomas and 87·5% of monitored naevi were correctly scored as lesion to be excised and benign naevus, respectively. Using the standard and revised thresholds for the seven-point checklist, excision was recommended for 77·9% and 87·8% of the lesions in the melanoma set, respectively. The standard threshold produced 'no excision' recommendations for 85·6% of the monitored naevi, compared with 74·5% using the revised threshold. Pattern analysis, standard seven-point and revised seven-point algorithms resulted in recommendations of 'excision' for 63·6%, 60·3% and 72·0% of the excised naevi, respectively. CONCLUSIONS: The diagnostic approach to naevi and melanoma should be adapted to the current clinical setting, in which patients may present with early-stage melanomas and multiple atypical naevi. To increase sensitivity, a revised seven-point checklist with a lower threshold for excision should be used.

Alcohol drinking after liver transplantation is associated with graft injury.

AIM: This was a single-center, mixed-design, cross-sectional and retrospective study to assess the performance of the 4-item, self-reported CAGE (Cut down, Annoyed, Guilty, Eye-opener) questionnaire in predicting histology-proven alcohol-related liver graft injury (ARLGI). METHODS: A total of 316 liver transplant (LT) patients between six months and five years were enrolled. Based on previous research, problem alcohol drinking (PAD) was defined as any score ≥ 1 on the CAGE, while a cut-off of 2 was assumed for alcohol dependence (AD). RESULTS: Responders were 195, 45 (23.1%) had a CAGE score ≥ 1 and 30 (15.3%) scored ≥ 2. After controlling for confounders, PAD was associated with hyperlipidemia (P=0.01), while AD with a male gender (P=0.01), hyperlipidemia (P=0.03) and alcohol as native diagnosis (P=0.03). PAD and AD were both associated with a significantly higher prevalence of ARLGI, i.e. 53.3% and 63.3%, respectively (P<0.0001). Hepatitis C virus (HCV) patients with PAD showed more steatosis (P=0.04), portal infiltrate (P=0.03), and pericellular/perivenular fibrosis (P=0.02). The likelihood ratios for CAGE scores ranging from 0 to 4 in predicting ARLGI were 0, 5.2, 7.8, 7.8, and 100, respectively. CONCLUSION: By use of a self-report instrument we found a 23.1% prevalence of PAD and a 15.3% prevalence of AD among LT patients between six months and five years. A variable degree of ARLGI was present in 53.3% of PAD and 63.3% of AD, respectively. HCV patients with PAD had more steatosis, portal inflammation, and pericellular fibrosis. Transplant physicians might improve their ability to predict the probability for ARLGI using the CAGE.

Novel and recurrent p14 mutations in Italian familial melanoma.

CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16(INK4a) and p14(ARF), and originate from different open reading frames. Exon 1alpha is specific for p16(INK4a), while exon 1beta characterizes p14(ARF). Most CDKN2A mutations are located in exons 1alpha and 2, while exon 1beta variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16(INK4a)/CDK4 germline alterations and identified 15 p16(INK4a) and 1 CDK4 point mutations. In the present work, we extended our search to p14(ARF) mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14(ARF) mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.

Successful use of extended criteria donor grafts with low to moderate steatosis in patients with model for end-stage liver disease scores below 27.

Liver transplantation may be performed using extended criteria donor grafts (ECDg). The characteristics of ECDg include age >60 years, long intensive care unit (ICU) stay, history of malignancy or steatosis. Grafts are often discarded due to steatosis, which can be macrovesicular (MaS) or microvesicular (MiS). MaS is the variety most frequently involved with unfavorable outcomes due to primary nonfunction (PNF) or primary dysfunction (PDF). As of January 2000, all livers referred to our institution were considered potentially transplantable. Steatosis was defined as the presence of fat droplets in more than 5% of hepatocytes. We observed 35 steatotic grafts. Grafts were stratified according to MaS and MiS as follows: low steatosis (5%-15%), mild steatosis (16%-30%), moderate steatosis (31%-60%), or severe steatosis (>60%). Fifteen grafts with moderate (n = 2) or severe (n = 13) MaS were discarded. Twenty grafts were harvested: 18 of them were transplanted at our institution, the remaining 2, discarded by our donor team, were transplanted by other Italian centers. Low MaS was detected in 10 grafts (50%), mild MaS in 4 (20%), and moderate MaS in 2 (10%). Low MiS was detected in 8 grafts (40%), mild MiS in 5 (25%), and moderate MiS in 1 (5%). Steatotic grafts were transplanted only into recipients with model for end-stage liver disease (MELD) scores <27. The 6-month graft survival was 80%; the PNF rate was 10%; and the PDF rate was 15%. The careful use of ECDg with low to moderate steatosis is possible if particular care is taken to avoid additional risk factors related to the recipient.

Modulation of Autophagy Influences the Function and Survival of Human Pancreatic Beta Cells Under Endoplasmic Reticulum Stress Conditions and in Type 2 Diabetes.

Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n = 17; age 65 ± 21 years; gender: 5 M/12 F; BMI 23.4 ± 3.3 kg/m2) and T2D (n = 9; age 76 ± 6 years; 4 M/5 F; gender: BMI 25.4 ± 3.7 kg/m2) organ donors. Nine ND organ donors were treated for hypertension and 1 for both hypertension and hypercholesterolemia. T2D organ donors were treated with metformin (1), oral hypoglycemic agents (2), diet + oral hypoglycemic agents (3), insulin (3) or insulin plus metformin (3) as for antidiabetic therapy and, of these, 3 were treated also for hypertension and 6 for both hypertension and hypercholesterolemia. Two days after isolation, they were cultured for 1-5 days with 10 ng/ml rapamycin (autophagy inducer), 5 mM 3-methyladenine or 1.0 nM concanamycin-A (autophagy blockers), either in the presence or not of metabolic (0.5 mM palmitate) or chemical (0.1 ng/ml brefeldin A) ER stressors. In ND islets palmitate exposure induced a 4 to 5-fold increase of beta cell apoptosis, which was significantly prevented by rapamycin and exacerbated by 3-MA. Similar results were observed with brefeldin treatment. Glucose-stimulated insulin secretion from ND islets was reduced by palmitate (-40 to 50%) and brefeldin (-60 to 70%), and rapamycin counteracted palmitate, but not brefeldin, cytotoxic actions. Both palmitate and brefeldin induced PERK, CHOP and BiP gene expression, which was partially, but significantly prevented by rapamycin. With T2D islets, rapamycin alone reduced the amount of p62, an autophagy receptor that accumulates in cells when macroautophagy is inhibited. Compared to untreated T2D cells, rapamycin-exposed diabetic islets showed improved insulin secretion, reduced proportion of beta cells showing signs of apoptosis and better preserved insulin granules, mitochondria and ER ultrastructure; this was associated with significant reduction of PERK, CHOP and BiP gene expression. This study emphasizes the importance of autophagy modulation in human beta cell function and survival, particularly in situations of ER stress. Tuning autophagy could be a tool for beta cell protection.