Characteristics of AA amyloidosis patients in San Francisco.

BACKGROUND: AA amyloidosis due to subcutaneous injection of drugs of abuse has been described in the USA, but all the existing literature is from more than 20 years ago. There is more recent literature from Europe. We have observed a high incidence of AA amyloidosis in the county hospital in San Francisco. DESIGN: Here, we describe 24 patients who had kidney biopsy-proven AA amyloidosis from our hospital from 1998 to 2013. All the patients were thought to have AA amyloidosis from skin popping of illicit drugs after having exhausted the intravenous route. These patients with biopsy-proven AA amyloidosis were analysed further. RESULTS: All patients were found to have hepatitis C infection, hypertension was not common, most had advanced kidney failure, and acidosis was common as was tubulointerstitial involvement on the kidney biopsy. Other organ involvement included hepatomegaly and splenomegaly in a number of patients; direct myocardial involvement was not seen, but pulmonary hypertension, history of deep vein thrombosis and pulmonary embolism were common. The prognosis of these patients was poor. The mortality rate approached 50% 1 year after biopsy, and most of the patient needed dialysis shortly after diagnosis. Cessation of drug use seemed beneficial but rarely achievable. CONCLUSION: AA amyloidosis from skin popping is common in San Francisco. Most patients with renal involvement end up on dialysis, and mortality rates are exceedingly high.

Mortality from nonneoplastic skin disease in the United States.

BACKGROUND: The mortality burden from nonneoplastic skin disease in the United States is unknown. OBJECTIVE: We sought to estimate mortality from nonneoplastic skin disease as underlying and contributing causes of death. METHODS: Population-based death certificate data detailing mortality from nonneoplastic skin disease for years 1999 to 2009 were used to calculate absolute numbers of death and age-adjusted mortality by year, patient demographics, and 10 most commonly reported diagnoses. RESULTS: Nonneoplastic skin diseases were reported as underlying and contributing causes of mortality for approximately 3948 and 19,542 patients per year, respectively. Age-adjusted underlying cause mortality (per 100,000 persons) were significantly greater (P < .0001) for patients who were black/African American (3.4), women (1.4), and residing in the South (1.6). Most deaths occurred in patients ages 65 years and older (34,248 total deaths). Common underlying causes of death included chronic ulcers (1789 deaths/y) and cellulitis (1348 deaths/y). LIMITATIONS: Errors in death certificate data and inability to adjust for patient-level confounders may limit the accuracy and generalizability of our results. CONCLUSION: Mortality from nonneoplastic skin disease is uncommon yet potentially preventable. The elderly bear the greatest burden of mortality from nonneoplastic skin disease. Chronic ulcers and cellulitis constitute frequent causes of death.

Macroscopic tumor dimension, sentinel lymph node outcome, and survival analysis among cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is characterized by a high risk of metastasis to distant organs and a substantial mortality rate. For planning treatment and assessing outcomes, the Breslow micrometric measurement is critical. The tumor macroscopic dimension is not considered a prognostic parameter in cutaneous melanoma, although there are studies showing that tumor size is an independent prognostic factor for melanoma-specific survival. Therefore, this study aimed to evaluate the macroscopic dimension of melanoma and other known prognostic factors (i.e., Breslow index, mitoses, regression, and ulceration) as predictors of sentinel lymph node outcome and survival outcome. METHODS: We performed a retrospective cross-sectional study of 227 melanoma lesions subjected to sentinel lymph node biopsy at two Brazilian referral centers. RESULTS: On univariate analysis, there was a statistically significant correlation between the largest macroscopic tumor dimension and the sentinel lymph node result (P = 0.001); however, on multivariate analysis considering all evaluated parameters, there was no significant difference between the sentinel lymph node result and the tumor macroscopic dimension (P = 0.2689). Regarding melanoma-specific survival, the macroscopic dimension showed no significant correlation (P = 0.4632) in contrast to Breslow's dimension (P < 0.0001). CONCLUSION: The Breslow thickness was the only significant factor related to both the sentinel lymph node outcome and melanoma specific survival among the evaluated variables.

Age as a prognostic factor in patients with localized melanoma and regional metastases.

BACKGROUND: We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. MATERIALS AND METHODS: The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. RESULTS: With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. CONCLUSIONS: Melanomas in patients at the extremes of age have a distinct natural history.

Prognostic subclassifications of T1 cutaneous melanomas based on ulceration, tumour thickness and Clark's level of invasion: results of a population-based study from the Swedish Melanoma Register.

BACKGROUND: Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. OBJECTIVES: The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. METHODS: From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13,026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11,165 patients with complete data. RESULTS: Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67·9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1·5% (1·2-1·9%); an intermediate-risk group (28·6% of T1 cases) with a 10-year mortality rate of 6·1% (5·0-7·3%); and a high-risk group (3·5% of T1 cases) with a 10-year mortality rate of 15·6% (11·2-21·4%). The high- and intermediate-risk groups accounted for 66% of melanoma deaths within T1. CONCLUSIONS: Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.

Skin ulcer is a predictive and prognostic factor of acute or subacute interstitial lung disease in dermatomyositis.

The aim of this study was to determine whether skin ulcer can be used as a predictive and prognostic factor of acute/subacute interstitial lung disease (ILD) in Japanese patients with dermatomyositis (DM). We reviewed the medical records of 39 consecutive DM patients who were admitted to Tokyo Metropolitan Komagome Hospital from January 2000 to December 2009. The mean follow-up period was 63.9 ± 51.6 months. Fifteen patients had acute/subacute ILD and 11 patients had chronic ILD. Seven out of 15 acute/subacute ILD led to respiratory failure and 3 of them died due to ILD. Skin ulcers were observed in 5 out of 15 patients with acute/subacute ILD (33.3 %) and in 2 out of 24 patients without acute/subacute ILD (8.3 %). The presence of skin ulcers was revealed to be a significant predictive factor for acute/subacute ILD among various parameters by multivariate analysis. In the 15 patients with acute/subacute ILD, the presence of skin ulcers was a significant poor prognostic factor (p = 0.0231) and the cumulative survival rate of patients with skin ulcers was 53.3 % for 12 months. Skin ulcer is a significant predictive and prognostic factor of acute/subacute ILD in patients with DM.

Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity?

PURPOSE OF REVIEW: Ulceration of a primary cutaneous melanoma has for many years been recognized as a very important prognostic factor associated with increased risk for recurrence and mortality. Patients with an ulcerated melanoma do much worse than patients with a nonulcerated melanoma with the same breslow thickness. Ulceration may indicate a separate biologic entity. RECENT FINDINGS: Gene profiling studies of fresh frozen melanoma samples indicated that ulcerated melanomas have a very different profile. Analysis of the results of the two largest adjuvant interferon (IFN) trials ever conducted in 2644 patients [European Organization for Research and Treatment of Cancer (EORTC) 18952 and 18991], which used ulceration of the primary as a stratification factor, indicated that ulceration was not only a very strong prognostic factor, but more importantly a significant predictive factor for outcome of adjuvant IFN treatment. Only in patients with an ulcerated primary, was a similar and significant impact on disease-free survival, distant metastasis-free survival and overall survival observed. As a more general finding, in trials independent of ulceration used as a stratification factor, this IFN sensitivity of ulcerated melanomas has been reported in a meta-analysis in more than 3000 patients. It was also identified as a predictive factor of outcome in the Sunbelt adjuvant IFN trial in the USA. SUMMARY: These important findings regarding ulceration need biologic studies to identify the differences between ulcerated and nonulcerated melanoma at the molecular level. Moreover, the importance of ulceration will be assessed prospectively in the EORTC 18081 trial in patients with primary ulcerated melanomas more than 1  mm.

Food and Drug Administration (FDA) drug approval end points for chronic cutaneous ulcer studies.

The rising costs of caring for chronic cutaneous ulcers (CCUs) and recent appreciation of the mortality of CCUs have led to consideration of the reasons for the failure to have new drug therapies. No new chemical entities to heal CCUs have been approved by the Food and Drug Administration (FDA) in over a decade, in part due to an inability to reach the FDA accepted end point of "complete wound closure." The frequent failure to reach the complete closure end point brings forward the question of the relevance of other healing end points such as improved quality of life, or partial healing. Because CCUs carry a prognosis and mortality rate worse than many cancers, it is reasonable to compare the FDA trial end points for cancer drug approval with those for CCUs. And the difference is quite striking. While there is only one end point for CCUs, there are five surrogate and three direct end points for cancers. In contrast to cancer, surrogate end points and partial healing are not acceptable for therapies aimed at CCUs. For example, making tumors smaller is an acceptable end point, but making CCUs smaller is not and improvement in the signs and symptoms of cancer is an acceptable end point for cancers but not CCUs. As CCUs carry a prognosis and mortality rate worse than many cancers, we believe a reconsideration of end points for CCUs is highly warranted.

Precipitous Declines in Northern Gulf of Mexico Invasive Lionfish Populations Following the Emergence of an Ulcerative Skin Disease.

Invasive Indo-Pacific lionfish Pterois volitans/miles have become well-established in many western Atlantic marine habitats and regions. However, high densities and low genetic diversity could make their populations susceptible to disease. We examined changes in northern Gulf of Mexico (nGOM) lionfish populations following the emergence of an ulcerative skin disease in August 2017, when estimated disease prevalence was as high as 40%. Ulcerated female lionfish had 9% lower relative condition compared to non-ulcerated females. Changes in lionfish size composition indicated a potential recruitment failure in early summer 2018, when the proportion of new recruits declined by >80%. Remotely operated vehicle surveys during 2016-2018 indicated lionfish population density declined in 2018 by 75% on natural reefs. The strongest declines (77-79%) in lionfish density were on high-density (>25 lionfish per 100 m2) artificial reefs, which declined to similar levels as low-density (<15 lionfish per 100 m2) artificial reefs that had prior lionfish removals. Fisheries-dependent sampling indicated lionfish commercial spearfishing landings, commercial catch per unit effort (CPUE), and lionfish tournament CPUE also declined approximately 50% in 2018. Collectively, these results provide correlative evidence for density-dependent epizootic population control, have implications for managing lionfish and impacted native species, and improve our understanding of biological invasions.

Adjuvant therapy with pegylated interferon-alfa2b vs observation in stage II B/C patients with ulcerated primary: Results of the European Organisation for Research and Treatment of Cancer 18081 randomised trial.

BACKGROUND: Subgroup analyses of two large EORTC adjuvant interferon-alpha2b (IFNα-2b) vs observation randomised trials demonstrated that a treatment benefit was observed only in patients with an ulcerated melanoma without palpable nodes (hazard ratio [HR] for recurrence-free survival [RFS] was 0.69). This was confirmed by a meta-analysis of 15 adjuvant IFN trials (HR: 0.79). PATIENTS AND METHODS: In the EORTC 18081 trial, sentinel node-negative stage II patients with an ulcerated primary melanoma were 1:1 randomised between pegylated (PEG)-IFNα-2b at 3 µg/kg/week subcutaneously and observation, for 2 years, or until disease recurrence or unacceptable toxicity in spite of dose adjustments to maintain an Eastern Cooperative Oncology Group performance status of 0 or 1. Main end-point was RFS. Secondary end-points included distant metastasis-free survival (DMFS), overall survival, and safety (EudraCT Number: 2009-010273-20). RESULTS: Between February 2013 and January 2017, only 112 patients were randomised, 56 in each arm. The trial was stopped early for lack of recruitment. At a 3.4-year median follow-up, the estimated HR for the PEG-IFNα-2b group compared with the observation group regarding RFS was 0.66 (95% confidence interval [CI]: 0.32-1.37), and the 3-year RFS rate was 80.0% (95% CI: 65.7-88.8%) and 72.9% (95% CI: 58.3-83.0%), respectively. DMFS was prolonged: HR: 0.39 (95% CI: 0.15-0.97), and the 3-year DMFS rate was 90.6% (95% CI: 78.9-96.0%) vs 76.4% (95% CI: 62.1-85.9%). One patient in the PEG-IFNα-2b group died compared with 4 in the observation group. Fifty-four patients started PEG-IFNα-2b treatment, 16 (29%) completed 2 years of treatment, 2 (4%) stopped due to recurrence, 23 (43%) due to toxicity and 14 (25%) due to other reasons. CONCLUSIONS: The EORTC 18081 PEG-IFNα-2b randomised trial, observed a similar HR (0.69) for RFS as the previous EORTC trials (0.69). In countries without access to new drugs, adjuvant (PEG)-IFNα-2b treatment is an option for patients with ulcerated melanomas without palpable nodes.

Six-month mortality risks in long-term care residents with chronic ulcers.

Chronic ulcers are a common problem in long-term care. Residents with ongoing ulcers are often frail and at risk for mortality. This study evaluated the relationship between wound characteristics and other health predictors with 6-month mortality in nursing home residents. The subjects included were nursing home residents seen by the wound consult service from 1998 to 2007 with an ongoing chronic ulcer. This was a retrospective cohort study. Data were manually and electronically abstracted for each resident. Six-month mortality was collected as the primary outcome. Statistical comparisons were made using logistic regression with a final multivariant model. Four hundred and forty residents were seen with 411 records reviewed. Ulcer area was not associated with mortality; however, chronic ulcer number was associated with 6-month mortality with an odds ratio of 1.32 (95% CI 1.07-1.63). Other significant risk factors included heart failure, dementia, cancer, depression and blindness with all factors having an odds ratio greater than 1.75. Higher haemoglobin and venous insufficiency were protective of 6-month mortality. Ulcer number is an important predictor for 6-month mortality. The presence of multiple ulcers and comorbid health concerns may influence discussion of prognosis for healing and for potential end of life discussions.

Combination of therapeutic ultrasound with antibiotics interfere with the growth of bacterial culture that colonizes skin ulcers: An in-vitro study.

Staphylococcus aureus and Escherichia coli are among the major bacterial species that colonize skin ulcers. Therapeutic ultrasound (TUS) produces biophysical effects that are relevant to wound healing; however, its application over a contaminated injury is not evidence-based. The objective of this research was to analyze the effect of TUS on in vitro-isolated S. aureus and E. coli, including the combination of ultrasound and antibiotics, in order to assess their antibiotic action on bacterial susceptibility. For the experiments, the bacterial strains were suspended in saline, then diluted (10(4)CFU/mL) for irradiation (at 1 and 3MHz, 0.5 and 0.8W/cm(2) for 0 and 15min) and the combination treatment of ultrasonication and antibiotics was administered by adding nalidixic acid (S. aureus) and tetracycline (E. coli) at concentrations equivalent to 50% of the minimum inhibitory concentration (MIC). The experiments were carried out in duplicate with six repetitions. The suspensions were inoculated on to Petri plates and incubated at 37°C and the colony forming units (CFUs) were counted after 24h. The results were subjected to the Shapiro-Wilk normality test, followed by parametric ANOVA and Tukey's post hoc test at a significance level of 1%. The results demonstrated that the action of TUS at 1MHz inhibited bacterial growth while at 3MHz, bacterial growth was observed in both species. However, the synergistic combination of ultrasound and antibiotics was able to inhibit the growth of both bacteria completely after 15min of ultrasonication. The results suggest that the action of ultrasound on S. aureus and E. coli are dependent on the oscillation frequency as well as the intensity and time of application. The combination of ultrasound with antibiotics was able to inhibit bacterial growth fully at all frequencies and doses in both species.

Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry.

OBJECTIVE: Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc. METHODS: Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets-diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). RESULTS: Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynaud's phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynaud's phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes. CONCLUSIONS: Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynaud's phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients.

Skin Ulcers and Mortality Among Adolescents and Young Adults With Spina Bifida in South Carolina During 2000-2010.

The authors investigated 48 deaths (7% death rate) among 690 adolescents and young adults with spina bifida in South Carolina during 2000-2010. The authors used Medicaid and other administrative data and a retrospective cohort design that included people with spina bifida identified using ICD-9 codes. Cox regression models with time-dependent and time-invariant covariates, and Kaplan-Meier survival curves were constructed. The authors found that 21.4% of the study group had a skin ulcer during the study period and individuals with skin ulcers had significantly higher mortality than those without ulcers (P < .0001). People who had their first skin ulcer during adolescence had higher mortality than those who had the first skin ulcer during young adulthood (P = .0002; hazard ratio = 10.70, 95% confidence interval for hazard ratio: 3.01, 38.00) and those without skin ulcers, controlling for other covariates. This study showed that age at which individuals first had a skin ulcer was associated with mortality.

Chronic cutaneous ulcers: etiology and epidemiology.

The most commonly encountered chronic cutaneous ulcers in the United States are pressure ulcers and leg ulcers; this review is limited to the epidemiology of these ulcers. Chronic leg ulcers are frequently encountered in clinical practice but the extent of the problem is largely unknown. In particular, epidemiologic information within the United States is sadly lacking. Although there are more data available regarding the incidence and prevalence of pressure ulcers in acute and chronic care facilities, national surveys should be considered to obtain more accurate information on their incidence and prevalence. Multicenter studies are necessary to determine the epidemiology and cost of treating pressure ulcers by stage, setting, and other factors. Particular attention should be paid to high-risk groups such as spinal cord injury patients, the elderly, and those who are immobilized or chronically debilitated. Leg ulcers and pressure ulcers probably account for the majority of chronic cutaneous ulcers seen in the United States.

Ulcerated breast cancer. Patients and outcome.

A review of patients presenting with ulcerated breast cancer (38 women between 1976 and 1980) revealed the following. Although almost all women (82%) presented with documentable distant metastases, they were palliated most by eradication of the painful, infected, malodorous ulcer and persistent intact skin for the extent of their survival. The long-term local control rate was 82 per cent for patients who survived longer than one year despite the large underlying primary cancer masses (average = 11.7 cm). Radiation therapy followed by mastectomy was the most frequently used combination. The crude survival rates (one year, 63%; two year, 26%; three year, 19%) approximate those of patients presenting with metastatic disease. Good prognostic signs included estrogen receptor protein found in 89 per cent of the one-year survivors (and only 25% of the less than one-year survivors) and rare histology found in 85 per cent of the one-year survivors (and only 15% of the less than one-year survivors).

Infectivity and pathogenicity of the oomycete Aphanomyces invadans in Atlantic menhaden Brevoortia tyrannus.

Atlantic menhaden Brevoortia tyrannus develop characteristic skin ulcers in response to infection by the oomycete Aphanomyces invadans. To investigate pathogenicity, we conducted a dose response study. Juvenile menhaden were inoculated subcutaneously with 0, 1, 5, 10, 100, and 500 secondary zoospores per fish and monitored for 37 d post-injection (p.i.). Survival rates declined with increasing zoospore dose, with significantly different survivorship curves for the different doses. Moribund and dead fish exhibited characteristic ulcerous lesions at the injection site starting at 13 d p.i. None of the sham-injected control fish (0 zoospore treatment) died. The LD50 (lethal dose killing 50% of exposed menhaden) for inoculated fish was estimated at 9.7 zoospores; however, some fish receiving an estimated single zoospore developed infections that resulted in death. Menhaden were also challenged by aqueous exposure and confirmed that A. invadans was highly pathogenic by this more environmentally realistic route. Fish that were acclimated to culture conditions for 30 d, and presumably free of skin damage, then aqueously exposed to 100 zoospores ml(-1), exhibited 14% lesion prevalence with 11% mortality. Net-handled fish that were similarly infected had a significantly higher lesion prevalence (64%) and mortality (64%). Control fish developed no lesions and did not die. Scanning electron microscopy of fish skin indicated that zoospores adhered to intact epidermis, germinated and penetrated the epithelium with a germ tube. Our results indicate that A. invadans is a primary pathogen of menhaden and is able to cause disease at very low zoospore concentrations.

Prognostic impact of PHIP copy number in melanoma: linkage to ulceration.

Ulceration is an important prognostic factor in melanoma whose biologic basis is poorly understood. Here we assessed the prognostic impact of pleckstrin homology domain-interacting protein (PHIP) copy number and its relationship to ulceration. PHIP copy number was determined using fluorescence in situ hybridization (FISH) in a tissue microarray cohort of 238 melanomas. Elevated PHIP copy number was associated with significantly reduced distant metastasis-free survival (DMFS; P=0.01) and disease-specific survival (DSS; P=0.009) by Kaplan-Meier analyses. PHIP FISH scores were independently predictive of DMFS (P=0.03) and DSS (P=0.03). Increased PHIP copy number was an independent predictor of ulceration status (P=0.04). The combined impact of increased PHIP copy number and tumor vascularity on ulceration status was highly significant (P<0.0001). Stable suppression of PHIP in human melanoma cells resulted in significantly reduced glycolytic activity in vitro, with lower expression of lactate dehydrogenase 5, hypoxia-inducible factor 1 alpha subunit, and vascular endothelial growth factor, and was accompanied by reduced microvessel density in vivo. These results provide further support for PHIP as a molecular prognostic marker of melanoma, and reveal a significant linkage between PHIP levels and ulceration. Moreover, they suggest that ulceration may be driven by increased glycolysis and angiogenesis.

Is vasculopathy associated with systemic sclerosis more severe in men?

OBJECTIVE: To identify possible differences in morbidity and mortality between men and women with systemic sclerosis (SSc) by examining a homogeneous cohort at a single academic center. METHODS: Demographic, clinical, and outcome data for all 231 patients of Greek origin with SSc who were examined between 1995 and 2011 in our department (200 women) were recorded in consecutive 3-year intervals from disease onset; data were analyzed retrospectively. RESULTS: Factors comparable between sexes were age (yrs ± SD) at disease onset (46 ± 15 vs 46 ± 15), diffuse skin involvement (61.3% of men vs 46.4% of women), and anti-Scl-70 antibody positivity (66.6% of men vs 59.2% of women). Also comparable were prevalence of interstitial lung disease, upper or lower gastrointestinal (GI) tract involvement, and echocardiographic findings during the first, second, and third 3-year intervals from disease onset (2904 patient-yrs). In contrast, vasculopathy occurred earlier in men. During the first 3 years digital ulcers developed in 54% of men versus 31% of women (p = 0.036) and renal crisis developed in 17% of men versus 3% of women (p = 0.006). No significant differences regarding social history, smoking, medical history, or disease management were identified. After excluding non-SSc-related deaths, survival was worse in men (p = 0.005, Kaplan-Meier analysis) with significantly lower 6- and 12-year cumulative rates (77.2% and 53.8%, respectively, in men vs 97.3% and 89.2% in women). CONCLUSION: Results derived from an unselected SSc population indicate that the disease is more severely expressed in men than in women, a finding that could be related to more rapid development of vasculopathy in men. Studies are warranted in other single-center cohorts to confirm these findings.