How staging of thin melanoma is changed after the introduction of TNM 7th edition: a population-based analysis.

INTRODUCTION: In 2009, the American Joint Committee on Cancer (AJCC) incorporated the tumor mitotic rate in the melanoma pathological TNM staging system. To investigate the effect of this change on the pT1 substaging of primary cutaneous melanomas, we reclassified the cases collected by a cancer registry according to the 6th and the 7th editions of AJCC melanoma staging. METHODS: Patients with pathological T1 melanoma diagnosed in the period 2000-2008 were selected from Tuscan Cancer Registry. The histological reports were reviewed and pT1 melanomas classified according to both the 6th and the 7th editions of the AJCC staging system. The shift of melanomas between pT1 substages was analyzed. RESULTS: Among the 242 pT1 melanomas collected in the study period and with mitotic index available, there were 202 (83 % of all pT1) and 175 (72 %) pT1a, according to the 6th and the 7th editions of the AJCC melanoma staging, respectively. When the 7th edition was used, 20 % of all pT1a melanomas shifted to pT1b, and 32 % of all pT1b melanomas shifted to pT1a. A poor level agreement between the two TNM staging systems, measured by the Cohen's kappa coefficient, was found (K = 0.37). CONCLUSIONS: The addition of mitotic activity to the pathological staging resulted in an increase in pT1b proportion and in a change in the classification of some cases. This modification could influence the clinical approach, with a different use of the sentinel lymph node biopsy, and underlines the role of mitosis evaluation in the management of thin melanoma patients.

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.

Dermoscopic features of cutaneous melanoma are associated with clinical characteristics of patients and tumours and with MC1R genotype.

BACKGROUND: Several algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors. OBJECTIVES: To investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes. METHODS: A total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations. RESULTS: A lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P = 0.019), due to reduced dermoscopic structures (P < 0.0001). Thicker melanomas showed higher TDS values (P = 0.021) due to sharper borders (P < 0.0001) and higher number of colors (P = 0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P = 0.010), in individuals with dark skin (P = 0.043) and hair color (P = 0.001). An atypical vascular pattern was more frequent in nodular (P < 0.0001) and thick (P < 0.0001) melanomas, in individuals with skin type I-II (P = 0.037), blond or red hair color (P = 0.032) and blue or green eyes (P = 0.014). Melanomas of MC1R R carriers showed lower TDS value (P = 0.037), reduced dermoscopic structures (P = 0.001) and lower prevalence of atypical pigment network (P = 0.001). No differences were identified between BRAF-mutated or wild-type melanomas. CONCLUSIONS: We suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals.

Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation.

Numerous epidemiological studies have shown an association between pesticide exposure and the increased risk of developing Parkinson's disease. Previously we have reported that Dichlorvos exposure can induce oxidative stress, resulting in over-expression of pro-apoptotic genes and finally caspase-dependent nigrostriatal dopaminergic neuronal cell death in rat brain. Here, we examined the effect of caspase inhibition on PC12 cell death induced by Dichlorvos (30 µM). Reactive oxygen species (ROS) generation followed by protein carbonylation, lipid peroxidation, decreased antioxidant defenses (decreased Mn-superoxide dismutase (MnSOD) activity and decreased glutathione levels) and subsequent caspase activation mediated the apoptosis. Inhibition of caspase cascade with Boc-aspartyl(OMe)-fluoromethylketone (BAF) enhanced the Dichlorvos-induced PC12 cell death, as assessed by the increased cellular efflux of lactate dehydrogenase (LDH). This increase in cell death was accompanied by a marked increase in poly(ADP-ribose) polymerase-1 (PARP1) activity, increased oxidative stress, a reduction in the mitochondrial membrane potential and reduced cellular NAD and ATP levels. Pretreatment of cells with PJ34, a PARP1 inhibitor prevented the cells from undergoing cell death and preserved intracellular NAD and ATP levels. Subsequent release of the apoptosis-inducing factor (AIF) from mitochondria and its translocation into the nucleus was also prevented by PJ34 pretreatment. In conclusion, the results of the present study show that caspase inhibition without concurrent inhibition of PARP1 is unlikely to be effective in preventing cell death because in the presence of the caspase inhibitor, caspase-independent cell death predominates due to PARP activation. These results suggest that combined therapeutic strategies directed at multiple cell death pathways may provide superior neuroprotection than those directed at a single mechanism.

Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase.

BACKGROUND AND PURPOSES: Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH: Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS: In male rats with tMCAO, HYDAMTIQ (0.1-10 mg·kg(-1)) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS: Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.

Familial and sporadic melanoma: different clinical and histopathological features in the Italian population - a multicentre epidemiological study - by GIPMe (Italian Multidisciplinary Group on Melanoma).

BACKGROUND: Having a familial member affected by cutaneous melanoma is a risk factor for this neoplasm. Only a few epidemiological case-control studies have been carried out to investigate whether familial and sporadic melanomas show different clinical and histopathological features. OBJECTIVE: The aim of this study was to evaluate eventual different features and risk factors in subjects affected by familial and sporadic cutaneous melanoma. METHODS: A case-control multicentre study interesting 1407 familial (n = 92) and sporadic (n = 1315) melanomas in the Italian population. The analysis was made using t-test for continuous variables and chi-squared test for categorized ones. The variables which have shown statistically significant differences in the two groups in the univariate analysis were included in a multivariate model. RESULTS: The results showed some main significantly clinical differences between the two groups investigated: earlier age at diagnosis, a greater proportion of sunburns and a higher number of naevi were observed for the familial cases compared with sporadic ones. Nevertheless, we did not find a diagnostic anticipation in familial melanomas, in fact the invasion level and the thickness of melanomas was similar in the two groups. CONCLUSION: Some relevant clinical differences are observed between the two groups examined. The familial melanoma members, although carriers of constitutional risk factors, are not careful enough to primary and secondary prevention.

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury.

The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia.

Sensitivity to ultraviolet B is a risk factor for cutaneous melanoma in a Mediterranean population: results from an Italian case-control study.

BACKGROUND: Sun sensitivity is one of the predictors of melanoma risk, together with other individual characteristics such as skin and eye colour and number of naevi. However, it is unclear how best to measure sun sensitivity in order to quantify the individual risk of melanoma. OBJECTIVES: In this case-control study, the relationship between minimal erythema dose (MED) and skin colour (both instrumentally assessed) was investigated, and their possible role as independent risk factors for melanoma in a Mediterranean population evaluated. METHODS: In total, 143 patients with cutaneous melanoma and 102 controls were enrolled in the study. Skin colour was assessed using a Minolta CR-200 chromameter. For MED calculation, a fluorescent lamp (Philips TL 4W/12) was used as a source of ultraviolet B light. MED was defined as the lowest dose that produced an increase of 2.5 in the redness value, expressed by the parameter a* of the Commission Internationale d'Eclairage (CIE) L*a*b* colour space (Deltaa* = 2.5). RESULTS: A significant excess of risk was associated with increasing L* values of skin colour (P < 0.05; OR = 1.12; 95% CI 1.01-1.24) for each unit of change. Low MED values were also associated with an increasing risk of melanoma, with an excess of risk of 18% (OR = 1.18, 95% CI 1.04-1.35) for every 10 mJ/cm(2) of MED reduction. Compared with the highest MED values (> 97.7 mJ/cm(2)), subjects with MED values 2-fold increased risk of melanoma (OR = 2.37, 95% CI 1.05-5.38). The effect of decreasing MED value as a melanoma risk factor persisted after adjustment for skin colour and atypical naevi in a multivariate model. CONCLUSIONS: In conclusion, both instrumentally assessed skin colour and MED are significant risk factors for malignant melanoma in a Mediterranean population. MED seems be an independent variable in establishing the subject's risk profile.

High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo.

High mobility group proteins are chromatin binding factors with key roles in maintenance of nuclear homeostasis. The evidence indicates that extracellularly released high mobility group box 1 (HMGB1) protein behaves as a cytokine, promoting inflammation and participating to the pathogenesis of several disorders in peripheral organs. In this study, we have investigated the expression levels and relocation dynamics of HMGB1 in neural cells, as well as its neuropathological potential. We report that HMGB1 is released in the culture media of neurons and astrocytes challenged with necrotic but not apoptotic stimuli. Recombinant HMGB1 prompts induction of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor alpha, and increases excitotoxic as well as ischemic neuronal death in vitro. Dexamethasone reduces HMGB1 dependent immune glia activation, having no effect on the protein's neurotoxic effects. HMGB1 is expressed in the nucleus of neurons and astrocytes of the mouse brain, and promptly (1 h) translocates into the cytoplasm of neurons within the ischemic brain. Brain microinjection of HMGB1 increases the transcript levels of pro-inflammatory mediators and sensitizes the tissue to the ischemic injury. Together, data underscore the neuropathological role of nuclear HMGB1, and point to the protein as a mediator of post-ischemic brain damage.

Predictors of skin self-examination in subjects attending a pigmented lesion clinic in Italy.

BACKGROUND: Skin self-examination (SSE) is associated with thinner melanomas in both North American and Italian patients. The knowledge of conditions associated with SSE may help in refining educational strategies for the prevention of melanoma. OBJECTIVE: The aim of the study was to investigate the frequency of SSE and the factors associated with SSE in subjects followed at a specialized pigmented lesion clinic (PLC) in Italy. PATIENTS/METHODS: A series of 299 consecutive subjects who visited the Florence PLC was investigated by means of a self-administered questionnaire regarding SSE habits. The statistical association between SSE and selected variables was examined by univariate and multivariate analyses. RESULTS: In the univariate analysis, variables significantly associated with SSE were: green/blue eyes, phototype I/II, the presence of large numbers of common acquired and atypical melanocytic naevi, sunscreen use, having had a previous PLC examination, and having received a leaflet explaining SSE. SSE was less frequent in women using sunbeds and more frequent in those performing breast self-examination. Using the multivariate model, which included all the variables associated with SSE in the previous analysis, we found that, among males, the only variable significantly associated with SSE was the report of having received a leaflet explaining SSE [odds ratio (OR) 3.02, 95% confidence interval (CI) 1.24-7.38]. Among females, having had a previous consultation at a PLC was significantly associated with SSE (OR 4.84, 95%CI 1.57-14.93); this might be because of the explanation and advice about skin cancer prevention customarily provided as a part of the PLC consultation at our department. CONCLUSION: Educational tools, including a leaflet explaining SSE and counselling given within previous PLC visits, seem to play a crucial role in promoting SSE habits in subjects followed at a specialized PLC consultation.

Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case-case-control study.

We directly compared risk factors between 214 histologically confirmed melanomas (CMM), 215 basal-cell carcinomas (BCC) and 139 squamous-cell carcinomas (SCC) in a multiple case-case-control study with 349 controls from patients without dermatological disease admitted to the same hospitals. Subjects with fair hair had a significant risk increase for all types of tumours at a comparable level (OR(adj) for blonde hair: CMM 2.3; SCC 2.4; BCC 2.3). The effect of pale eyes was significant and similar for CMM and BCC (OR(adj) 2.6). Intermittent sun exposure measured in hours spent at beach during holidays was significant for both CMM (OR(adj) 2.6 for more than 7000 lifelong hours) and BCC (OR(adj) 2.1 for more than 7000 lifelong hours), while SCC exhibited a significant risk increase for chronic exposure to sunlight measured in hours of outdoor work (OR(adj) 2.2 for more than 6000 lifelong hours). In the case-case comparison using a multinomial logistic regression model, we found a statistically significant risk difference for pale eyes, and number of naevi in the CMM group, compared to other skin cancers. For intermittent sun exposure, there was a significant risk difference of BCC when compared to the risk of SCC. Factors influencing risk of SCC are different, with chronic exposure to sun playing a major role in causing this type of carcinoma.

Improvement of malignant/benign ratio in excised melanocytic lesions in the 'dermoscopy era': a retrospective study 1997-2001.

BACKGROUND: Because of the many limitations of studies based on the diagnostic setting of excised lesions, the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) in melanoma screening during practice remains to be established. OBJECTIVES: We assumed that effects of the use of dermoscopy on some indicators of diagnostic performance in melanoma screening should be traceable retrospectively; therefore, we analysed the impact of routine dermoscopy use on the malignant/benign ratio in excised melanocytic lesions. METHODS: Preoperative and histological diagnosis of 3053 melanocytic lesions [319 melanomas (10.4%)] consecutively diagnosed and excised at the Department of Dermatology, University of Florence in the period 1997-2001 inclusive were retrieved. Six dermatologists who selected the lesions to excise and who performed preoperative diagnosis were divided into two groups according to their use of dermoscopy in routine activity (n = 2 dermoscopy users and n = 4 nonusers). The study period was divided into a predermoscopy period (1997), a shift phase (1998) and a dermoscopy period (1999-2001). RESULTS: During the study period, the malignant/benign ratio improved in dermoscopy users only (from 1 : 18 to 1 : 4.3, P = 0.037). No significant difference was found for nonusers (from 1 : 11.8 to 1 : 14.4). Dermoscopy users were more likely to have a melanoma diagnosed within a series of excised lesions than nonusers, even taking into account potential confounders such as sex, age and study period by means of multivariate analysis (odds ratio 1.55, 95% confidence interval 1.17-2.01). The percentage of 'problem' naevi (naevi with architectural disorder with or without cytological atypia and Spitz or Reed naevi) over the total number of excised lesions was higher in dermoscopy users than in nonusers (year 2001, 51.6% vs. 40.9%, P = 0.014). Similar findings were obtained after exclusion from the data set of lesions excised for cosmetic reasons. CONCLUSIONS: The adoption of dermoscopy in routine melanoma screening is followed by an improvement of the malignant/benign ratio in excised lesions, suggesting a more appropriate selection of pigmented lesions referred to surgery. Because of the possible limitations of a retrospective study design, future confirmation of this finding by means of a prospective, randomized study is advisable. The introduction of dermoscopy in routine practice may have major implications in large-scale melanoma screening with cost savings and a reduction of the dermosurgery workload.

Delayed inflammation in rat meninges: implications for migraine pathophysiology.

Nitric oxide (NO) has been implicated in migraine pathogenesis based on the delayed development of typical migraine headache 4-6 h after infusing the NO donor nitroglycerin [glyceryl trinitrate (GTN)] to migraineurs. Furthermore, inhibiting the synthesis of NO by treatment with a NO synthase (NOS) inhibitor attenuates spontaneous migraine headaches in 67% of subjects. Because NO has been linked to inflammation and cytokine expression, we investigated the delayed consequences of brief GTN infusion (30 min) on the development of meningeal inflammation in a rat model using doses relevant to the human model. We found dose-dependent Type II NOS [inducible NOS (iNOS)] mRNA upregulation in dura mater beginning at 2 h and an increase in the corresponding protein expression at 4, 6 and 10 h after infusion. Type II NOS immunoreactivity was expressed chiefly within resident meningeal macrophages. Consistent with development of a delayed inflammatory response, we detected induction of interleukin 1beta in dura mater at 2 and 6 h and increased interleukin 6 in dural macrophages and in rat cerebrospinal fluid at 6 h after GTN infusion. Myeloperoxidase-positive cells were rarely found. Leakage of plasma proteins from dural blood vessels was first detected 4 h after GTN infusion, and this was suppressed by administering a specific Type II NOS inhibitor [L-N(6)-(1-iminoethyl)-lysine (L-NIL)]. In addition to cytokine induction, macrophage iNOS upregulation and oedema formation after GTN infusion, dural mast cells exhibited granular changes consistent with secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages following topical GTN, and in the spleen after intravenous injection, the data suggest that the inflammatory response is mediated by direct actions on the dura and does not develop secondary to events within the brain. Our findings point to the importance of new gene expression and cytokine expression as fundamental to the delayed response following GTN infusion, and support the hypothesis that a similar response develops in human meninges after GTN challenge.

Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages.

We studied the regulation of the kynurenine pathway of tryptophan metabolism in human monocyte-derived macrophages (MDM) with the aim of evaluating macrophage involvement in inflammatory neurological disorders. Cultured MDM metabolized tryptophan and released kynurenine metabolites, including the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) or the pro-inflammatory cytokines INFgamma and TNFalpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release of QUIN. The incubation media of INFgamma-exposed MDM caused neuronal death in primary cultures of mixed cortical cells. Glutamate receptor antagonists or poly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuroinflammatory disorders.

Serum imbalance of cytokines in melanoma patients.

The cytokines interleukin (IL)6 and IL10 appear to be involved in the progression of melanoma because they are secreted by malignant cells and their serum levels are associated with poor survival and with advanced stages of the disease. Antitumour immunity is considered to be a T-cell response, mediated mainly by type 1 cytokines such as IL12 and interferon-gamma (IFNgamma). We evaluated the serum levels of cytokines involved in the host response against tumour (IL12, IFNgamma) and/or the progression of melanoma (IL6, IL10) in 45 melanoma patients with localized and metastatic disease and in 45 controls, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. In the controls, IL6 and IL12 were nearly undetectable, whereas the IL10 and IFNgamma ranges were 0.5-9 pg/ml and 2-4.8 pg/ml, respectively. In the melanoma patients, pathologically high values were found in 44.4% for IL6, in 24.4% for IL10, and in 60% for IL12. Significantly higher values were found for IL6 and IL12, and lower values for IFNgamma. This study highlights a significant difference in serum cytokine profiles between controls and melanoma patients, which is mainly due to the high levels of IL6 and IL12 and the low levels of IFNgamma.

Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid.

3OH-Kynurenine and quinolinic acid are tryptophan metabolites able to cause, at relatively elevated concentrations, neuronal death in vitro and in vivo. In primary cultures of mixed cortical cells, the minimal concentration of these compounds leading to a significant degree of neurotoxicity decreased from 100 to 1 microM, when the exposure time was prolonged from 24 to 72 h. NMDA receptor antagonists and inhibitors of nitric oxide synthase or poly(ADP-ribose) polymerase reduced quinolinic acid, but not 3OH-kynurenine toxicity. In contrast, scavengers of free radicals, caspase inhibitors and cyclosporin preferentially reduced 3OH-kynurenine neurotoxicity. These observations suggest that quinolinic acid causes necrosis, whereas 3OH-kynurenine-exposed neurons primarily die in apoptosis. In line with this possibility, we found that ATP levels decreased more rapidly in quinolinate- than in 3OH-kynurenine-exposed cultures and that poly(ADP-ribose) polymer, the product of poly(ADP-ribose) polymerase activity, was more abundant in the nuclei of quinolinic acid than in those of 3OH-kynurenine-exposed neurons. Because minor changes in the physiological concentrations of 3OH-kynurenine and quinolinic acid may cause neuronal death, our data suggest that these metabolites play a key role in the pathogenesis of several neurological disorders.

Correlation of Ki-67 expression in cutaneous primary melanoma with prognosis in a prospective study: different correlation according to thickness.

BACKGROUND: The proliferative activity of melanoma cells, evaluated as MIB-1 immunoreactivity against a Ki-67 epitope, has been considered an indicator of poor prognosis in thick primary melanomas. OBJECTIVE: The aim of the study was to assess the correlation between the growth fraction of primary melanomas, assessed by means of Ki-67 immunoreactivity, and metastatic relapse. METHODS: Ki-67 reactivity in primary melanomas was evaluated as at least 5% of positive neoplastic cells and was assessed on fresh specimens of 55 primary lesions at the time of excision. Such reactivity was correlated with metastatic relapse of patients in a prospective study, by means of multivariate Cox regression models (follow-up, 3-120 months). RESULTS: Ki-67 immunoreactivity was associated with increasing thickness (P =.003). Positive correlation was found between Ki-67 reactivity and metastatic dissemination in primary melanomas less than 1.5 mm thick (n = 23; mean thickness, 0.75 +/- 0.3 mm; P =.002). On the contrary, a negative correlation was found between Ki-67 reactivity and metastatic activity in primary melanomas thicker than 1.5 mm (n = 32; mean thickness, 4.0 +/- 1.6 mm; P =.019). CONCLUSION: Ki-67 proliferative activity appears to be a possible predictor of metastasis in primary melanomas, in particular, an indicator of poor prognosis in lesions less than 1.5 mm thick.

Oral carcinoma in a young man: a case of dyskeratosis congenita.

We report a 28-year-old male with a voluminous growth of the tongue, present for 6 months. The histological examination revealed a squamous cell carcinoma. The patient was also affected by oral leukoplakia, nail dystrophy, reticulated poikiloderma of the neck and hyperkeratosis of palms and soles. On the basis of clinical features and histological findings, as well as findings from the family, the diagnosis of dyskeratosis congenita (DKC) was made.

Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages.

We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon-gamma (IFN-gamma)-activated macrophages of the murine BACl.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammatory neurological disorders. IFN-gamma induced indoleamine 2,3-dioxygenase (IDO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QUIN, and NO that accumulated in the incubation medium where they reached neurotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, resulted in a decreased formation of not only the kynurenine metabolites but also NO. The inhibition of NO synthesis could not be ascribed to reduced NADPH availability or decreased NOS induction. Norharmane inhibited NOS activity also in coronary vascular endothelial cells and in isolated aortic rings. Our findings suggest that activated macrophages release large amounts of neurotoxic molecules and that norharmane may represent a prototype compound to study macrophage involvement in inflammatory brain damage.