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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Long-term follow-up reveals that ulceration and sentinel lymph node status are the strongest predictors for survival in patients with primary cutaneous melanoma.

PURPOSE: To assess the long-term outcome after sentinel lymph node biopsy (SLNB) in melanoma patients. METHODS: Between 1995-2009 450 melanoma patients underwent SLNB in a single center. Survival and prognostic factors were analyzed for 429 patients. RESULTS: Median age was 53 (range 11-84) years. Median Breslow thickness was 2.4 (range 1-20) mm and 36% were ulcerated melanomas. Median follow-up time was 64.8 (range 2-174) months. A tumor-positive SLN was present in 140 patients (31%). Completion lymph node dissection (CLND) was performed in 119 patients and these patients were analyzed for recurrence and survival. 124 Patients (29%) relapsed during follow-up; 55 in the node-positive group who underwent CLND (55/119; 46%) and 69 in the node-negative group (69/310; 22%; p < 0.001). In the node-negative group 17 patients developed recurrence in the regional node field; false-negative rate 11%. On multivariate analysis strongest prognostic factors for disease free survival (DFS) were primary melanoma ulceration and SLN positivity (Hazard Ratio (HR) of 2.2 and 2.3; p < 0.001). For disease specific survival (DSS) the same was found to be true with an HR of 2.1 for ulceration and 2.0 for SLN positivity (p = 0.001 and p = 0.002 respectively). 10-Year DFS was 71% for node-negative patients compared with 48% for node-positive patients (p < 0.001). 10-Year DSS was 77% for node-negative patients compared to 60% for node-positive patients (p < 0.001). CONCLUSIONS: This study shows a remarkably high percentage of tumor-positive SLN. The long-term follow-up data confirm that tumor-positive SLN patients have a worse DFS and DSS than tumor-negative SLN patients. Ulceration and SLN status proved to be the strongest prognostic factors for long-term DFS and DSS.

Cancer-testis antigen expression in primary cutaneous melanoma has independent prognostic value comparable to that of Breslow thickness, ulceration and mitotic rate.

To determine the effect of Cancer-Testis Antigen (CTAg) expression on the natural history of primary cutaneous melanoma we compared its impact on prognosis with that of known prognostic factors and its relationship with other clinicopathologic characteristics. The immunohistochemical expression of three CTAgs (MAGE-A1, MAGE-A4 and NY-ESO-1) in 348 cases of stage I and stage II primary cutaneous melanoma was analysed and correlated with clinicopathologic characteristics, relapse free survival (RFS) and overall survival (OS). A Cox proportional hazards regression model was used to analyse factors which independently predicted RFS. All three CTAgs were significantly co-expressed with each other (p < 0.001). The median RFS for patients with CTAg-negative tumours and CTAg-positive tumours was 72 months and 45 months, respectively, (P = 0.008). Univariate analysis demonstrated that the impact of CTAg expression on RFS was comparable in magnitude to that of Breslow thickness, ulceration and tumour mitotic rate. Multivariate Cox regression analysis indicated that CTAg expression was a powerful independent predictor of RFS (risk ratio (RR) = 1.715, 95% confidence interval (CI) = 0.430-0.902, P = 0.010). In contrast, CTAg expression was demonstrated to have no prognostic impact on overall survival. This study demonstrates that CTAg expression in primary cutaneous melanoma is a strong independent predictor of RFS and it is comparable to other known important prognostic factors. CTAg expression has no relationship with overall survival, suggesting anti-melanoma immunity directed towards CTAg expression may contribute to the natural history of the disease. In view of these results, further investigation of the function of CTAgs and their potential use in therapeutic targeting is warranted.

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.

Pathogenicity studies with the fungi Aphanomyces invadans, Achlya bisexualis, and Phialemonium dimorphosporum: induction of skin ulcers in striped mullet.

Based on isolations from naturally infected fish in Florida, we investigated the role of the fungi Aphanomyces invadans, Achlya bisexualis, and Phialemonium dimorphosporum in the etiology of ulcerative mycosis (UM) in striped mullet Mugil cephalus. We injected healthy striped mullet subcutaneously with secondary zoospores of four oomycete isolates: two concentrations (50 and 115 zoospores/mL) of SJR (an endemic isolate of Aphanomyces invadans in American shad Alosa sapidissima from the St. Johns River); two concentrations each of CAL (25 and 65 zoospores/mL) and ACH (1,400 and 2,000 zoospores/mL; endemic isolates of Aphanomyces invadans and Achlyva bisexualis, respectively, in striped mullet from the Caloosahatchee River); and two concentrations of the ascomycete culture MTZ (2,500 and 3,500 zoospores/mL; endemic isolate of P. dimorphosporum from whirligig mullet M. gyrans in the Matanzas Inlet). All fish injected with either concentration of SJR developed granulomatous ulcers after 8 d and died within 21 d. Eighty percent (8/10) of fish injected with the high dose of CAL developed ulcers after 13 d and died within 28 d, but only 30% (3/10) of fish injected with the low dose of CAL developed ulcers. Four of the ulcerated fish died within 28 d, and the remaining fish were terminated after 32 d. Fish injected with zoospores of Aphanomyces invadans developed ulcers that were grossly and histologically similar to those observed in naturally infected striped mullet with UM from several estuaries or rivers in Florida. These hemorrhagic skin ulcers were characterized by myonecrosis and the presence of mycotic granulomas. None of the fish injected with ACH, MTZ, or sterile water developed ulcers. This study fulfilled Koch's postulates and demonstrated that ulcers could be experimentally induced in striped mullet after exposure via injection to secondary zoospores of an endemic Florida strain of Aphanomyces invadans.

Pathological and microbiological findings from incidents of unusual mortality of the common frog (Rana temporaria).

In 1992 we began an investigation into incidents of unusual and mass mortalities of the common frog (Rana temporaria) in Britain which were being reported unsolicited to us in increasing numbers by members of the public. Investigations conducted at ten sites of unusual mortality resulted in two main disease syndromes being found: one characterized by skin ulceration and one characterized by systemic haemorrhages. However, frogs also were found with lesions common to both of these syndromes and microscopic skin lesions common to both syndromes were seen. The bacterium Aeromonas hydrophila, which has been described previously as causing similar lesions, was isolated significantly more frequently from haemorrhagic frogs than from those with skin ulceration only. However, as many of the latter were euthanased, this may have been due to differences in post mortem bacterial invasion. An iridovirus-like particle has been identified on electron microscopical examination of skin lesions from frogs with each syndrome and iridovirus-like inclusions have been detected in the livers of frogs with systemic haemorrhages. Also, an adenovirus-like particle has been cultured from one haemorrhagic frog. A poxvirus-like particle described previously from diseased frogs has now been found also in control animals and has been identified as a melanosome. Both the prevalence of the iridovirus-like particle and its association with lesions indicate that it may be implicated in the aetiology of the disease syndromes observed. Specifically, we hypothesize that primary iridovirus infection, with or without secondary infection with opportunistic pathogens such as A. hydrophila, may cause natural outbreaks of 'red-leg', a disease considered previously to be due to bacterial infection only.

A follow-up study of leg and foot ulcer patients.

Three hundred and fifty patients treated in 1980 at the Department of Dermatology for leg and foot ulcers were asked to come for an interview concerning the development of their ulcerations up to the end of 1983. Forty-five of 186 patients were free from ulcers from 1981 to 1983. Thirty patients had leg ulcers continuously throughout the period and their ulcers were not healed at any time. Ninety-six patients had died during the follow-up period, and the total mortality rate compared to an age-matched population was shown to be approximately doubled for both men and women. When analysing the causes of death, it was found that the ischemic heart disease mortality rate was twice that of the age-matched population but the mortality rate for malignant diseases was about the same.

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).