Toxicological assessment of electronic cigarette vaping: an emerging threat to force health, readiness and resilience in the U.S. Army.

The U.S. Army and U. S. Army Public Health Center are dedicated to protecting the health, and readiness of Department of the Army Service Members, civilians, and contractors. Despite implementation of health programs, policies and tobacco control interventions, the advent of electronic nicotine delivery systems (ENDS), including electronic cigarettes (e-cigs), represent unregulated and poorly defined systems to supplant or substitute use of conventional nicotine products (e.g., cigarettes and pipe tobacco). E-cigs present unique challenges to healthcare officials vested in preventive medicine. The health impact of an e-cig and vaping on an individual's acute or chronic disease susceptibility, performance and wellness, is fraught with uncertainty. Given the relatively recent emergence of e-cigs, high-quality epidemiological studies, and applied biological research studies are severely lacking. In sparsely available epidemiological studies of short-term cardiovascular and respiratory health outcomes, any attempt at addressing the etiology of acute and chronic health conditions from e-cig use faces incredible challenges. Until relatively recently, this was complicated by an absent national regulatory framework and health agency guidance on the manufacture, distribution, selling and use of e-cigs or similar ENDS devices and their chemical constituents. Two key issues underpin public health concern from e-cig use: 1) continued or emergent nicotine addiction and potential use of these devices for vaping controlled substances; and 2) inadvertent sudden-onset or chronic health effects from inhalational exposure to low levels of complex chemical toxicants from e-cig use and vaping the liquid. Herein, the health impacts from e-cig vaping and research supporting such effects are discussed.

Subungual Melanoma of the Hand.

BACKGROUND: The diagnosis of subungual melanoma (SUM) can be challenging and SUMs generally have a worse prognosis than melanomas arising elsewhere. Due to their rarity, the evidence to guide management is limited. This study sought to identify clinicopathological features predictive of outcome and to provide guidelines for management. METHODS: From a large, single-institution database, 103 patients with in situ (n = 9) or invasive (n = 94) SUMs of the hand treated between 1953 and 2014 were identified and their features analyzed. RESULTS: The most common site of hand SUMs was the thumb (53%). Median tumor thickness was 3.1 mm, and SUMs were commonly of the acral subtype (57%), ulcerated (58%), amelanotic (32%), and had mitoses (73%). Twenty-one patients reported prior trauma to the tumor site. Twenty-two patients were stage III at diagnosis; 7 underwent therapeutic lymph node dissection and 22 underwent elective lymph node dissection (5 positive), while 36 had sentinel node biopsy (SNB), 28% of which were positive. Forty percent of SNB-positive patients had involved non-sentinel nodes (SNs) in their completion lymph node dissection. Five-year melanoma-specific survival (MSS) and disease-free survival (DFS) rates were 70% and 52%, respectively. On multivariate analysis, regional node metastasis and right-hand tumor location were significant predictors of shorter DFS and MSS, whereas mitoses negatively impacted DFS only and increasing Breslow thickness impacted MSS only. CONCLUSIONS: This study confirms that SUMs on the hand usually present at an advanced stage. Distal amputation appears safe for invasive SUMs, and SNB should be considered as these patients have a high risk of both SN and non-SN metastasis.

Multiple environmental stressors induce complex transcriptomic responses indicative of phenotypic outcomes in Western fence lizard.

BACKGROUND: The health and resilience of species in natural environments is increasingly challenged by complex anthropogenic stressor combinations including climate change, habitat encroachment, and chemical contamination. To better understand impacts of these stressors we examined the individual- and combined-stressor impacts of malaria infection, food limitation, and 2,4,6-trinitrotoluene (TNT) exposures on gene expression in livers of Western fence lizards (WFL, Sceloporus occidentalis) using custom WFL transcriptome-based microarrays. RESULTS: Computational analysis including annotation enrichment and correlation analysis identified putative functional mechanisms linking transcript expression and toxicological phenotypes. TNT exposure increased transcript expression for genes involved in erythropoiesis, potentially in response to TNT-induced anemia and/or methemoglobinemia and caused dose-specific effects on genes involved in lipid and overall energy metabolism consistent with a hormesis response of growth stimulation at low doses and adverse decreases in lizard growth at high doses. Functional enrichment results were indicative of inhibited potential for lipid mobilization and catabolism in TNT exposures which corresponded with increased inguinal fat weights and was suggestive of a decreased overall energy budget. Malaria infection elicited enriched expression of multiple immune-related functions likely corresponding to increased white blood cell (WBC) counts. Food limitation alone enriched functions related to cellular energy production and decreased expression of immune responses consistent with a decrease in WBC levels. CONCLUSIONS: Despite these findings, the lizards demonstrated immune resilience to malaria infection under food limitation with transcriptional results indicating a fully competent immune response to malaria, even under bio-energetic constraints. Interestingly, both TNT and malaria individually increased transcriptional expression of immune-related genes and increased overall WBC concentrations in blood; responses that were retained in the TNT x malaria combined exposure. The results demonstrate complex and sometimes unexpected responses to multiple stressors where the lizards displayed remarkable resiliency to the stressor combinations investigated.

Neuromuscular anomalies following oral exposure to 3-nitro-1,2,4-triazol-5-one (NTO) in a one-generation study with Japanese quail (Coturnix japonica).

Substances used as explosives in munitions by the military often result in environmental releases through manufacturing, testing, training, and combat activities. The toxicity of 3-nitro-1,2,4-triazol-5-one (nitrotriazolone or NTO) was evaluated following oral exposure in Japanese quail (Coturnix japonica) to determine if environmental releases result in unacceptable risks to avian populations. In an acute test at the limit dose (2000 mg/kg), one female was ataxic, exhibited tremors, and showed signs of neurological toxicity approximately 24 h after dosing. In a subsequent one-generation study, parental generation (F0) birds were exposed orally to 1000, 500, 100, or 20mg/kg-day NTO suspended in corn oil. After 5 consecutive days of dosing, 2-week-old birds receiving 1000 mg/kg-day displayed ataxia, convulsions, backward arching of the neck (opisthotonos), and alternated between prostrate inactivity and ataxic wing activity. Birds in the 500 mg/kg-day group exhibited neuromuscular anomalies after 17 days exposure. Ultimately, all of the 1000 mg/kg-day birds and all but one of the 500 mg/kg-day birds met euthanasia criteria and were humanely euthanized prior to behavioral and reproductive evaluation. As such, first-generation (F1) birds were exposed to 100 or 20 mg/kg-day NTO. Mild neuromuscular anomalies occurred in 10% of F1 birds from the 100 mg/kg-day group, but not in birds from 20 mg/kg-day or controls in either generation. Vacuolization of cerebellum and/or the brainstem was observed on histopathologic examination in a dose-dependent manner. Therefore, brain vacuoles and neuromuscular anomalies were identified as critical endpoints in this study. A mean Benchmark Dose (BMD) for brain vacuoles of 62 mg/kg-day was derived for male and female F0-generation quail, which corresponded to a Benchmark Dose Low (BMDL10) of 35 mg/kg-day.

Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies.

Acute systemic toxicity data are used by a number of U.S. federal agencies, most commonly for hazard classification and labeling and/or risk assessment for acute chemical exposures. To identify opportunities for the implementation of non-animal approaches to produce these data, the regulatory needs and uses for acute systemic toxicity information must first be clarified. Thus, we reviewed acute systemic toxicity testing requirements for six U.S. agencies (Consumer Product Safety Commission, Department of Defense, Department of Transportation, Environmental Protection Agency, Food and Drug Administration, Occupational Safety and Health Administration) and noted whether there is flexibility in satisfying data needs with methods that replace or reduce animal use. Understanding the current regulatory use and acceptance of non-animal data is a necessary starting point for future method development, optimization, and validation efforts. The current review will inform the development of a national strategy and roadmap for implementing non-animal approaches to assess potential hazards associated with acute exposures to industrial chemicals and medical products. The Acute Toxicity Workgroup of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), U.S. agencies, non-governmental organizations, and other stakeholders will work to execute this strategy.

Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center.

Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins ≥8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence.

The Impact of an International Network (Gynecologic Cancer InterGroup) for Clinical Research on Global Capacity for Gynecologic Cancer Clinical Trials.

OBJECTIVE: The objective of this study was to demonstrate that the construction of the Gynecologic Cancer InterGroup (GCIG) has increased collaboration and accrual to high-quality phase 3 trials at a global level. MATERIALS AND METHODS: The GCIG is a collaboration of 29 international cooperative clinical trial groups committed to conduct of high-quality phase 3 trials among women with gynecologic cancer. A complete bibliography of the reported phase 3 trials has been developed and is available on the GCIG Web site http://www.gciggroup.com. A "GCIG trial" is a trial in which any 2 or more GCIG member groups are formally involved. We reviewed the output of the GCIG from 1997 to 2015 with respect to member participation and quality of publication (impact factor and citation index). The publications are considered in 3 cohorts, 1997 to 2002, 2003 to 2008, and 2009 to 2014, for the purposes of comparison and progress. A social network map has been developed for these publications to identify how the GCIG has increased capacity for clinical trials globally. RESULTS: Using a global map, the number of member groups in the GCIG has increased in each of the 3 periods. The total annual number of publications and citations within the 1997 to 2015 period has increased significantly. The average number of citations per publication is demonstrated in each of the 3 periods. The steady increase in the number of citations is used as a proxy for the impact of the publications. The impact factor of the journal and the number of citations are reported for the 10 most highly cited publications. Finally, using a social networking methodology, networking has visibly and numerically increased in each of the 3 periods. CONCLUSIONS: Evidence supports that the construction of the GCIG has increased collaboration and accrual to high-quality phase 3 trials at a global level among women with gynecologic cancer.

The Association Between Excision Margins and Local Recurrence in 11,290 Thin (T1) Primary Cutaneous Melanomas: A Case-Control Study.

BACKGROUND: At presentation, most primary cutaneous melanomas are "thin" (Breslow thickness ≤1 mm, designated T1 in the American Joint Committee on Cancer staging system) and local recurrence (LR) is rare. Most current management guidelines recommend 1 cm surgical excision margins for T1 melanomas, but evidence to support this recommendation is sparse. We sought to identify clinical and pathologic factors associated with LR in patients with T1 melanomas that might guide primary tumor management. METHODS: From a large, prospectively collected, single-institution database, patients with primary cutaneous melanomas ≤1 mm thick diagnosed between 1970 and 2011 who developed LR were identified and matched with controls. Clinical and pathologic parameters were analyzed for their association with LR. RESULTS: From 11,290 primary melanomas ≤1 mm thick, 176 (1.56 %) cases with LR were identified and 176 controls (without LR) were selected. LR occurred after a median time of 37 months (range 3-306 months) and was associated with narrower excision margins (hazard ratio = 0.95, 95 % confidence interval 0.92-0.98, p = 0.001), desmoplastic, acral, and lentigo maligna melanoma subtypes (p = 0.008), and melanomas composed predominantly of spindle cells (p = 0.005). However, Breslow thickness, Clark level, ulceration, mitotic rate, regression, and lymphovascular invasion were not. CONCLUSIONS: LR was associated with <8 mm histologic excision margins (corresponding to <1 cm margins in vivo) and desmoplastic, acral, and lentigo maligna melanoma subtypes. This study provides evidence that a ≥1 cm clinical excision margin for thin (T1) primary melanomas reduces the risk of LR.

Minimum Safe Pathologic Excision Margins for Primary Cutaneous Melanomas (1-2 mm in Thickness): Analysis of 2131 Patients Treated at a Single Center.

OBJECTIVE: This study was designed to determine the minimum safe pathologic excision margin for primary cutaneous melanomas 1.01-2.00-mm thick (T2) and to identify prognostic factors that influence survival in these patients. BACKGROUND: Several studies have shown previously that "narrow" clinical excision margins (1-2 cm in vivo) are as safe as "wide" excision margins (4-5 cm) for management of primary T2 melanomas. However, pathologic margins are likely to be a better predictor of recurrence than clinical margins. METHODS: Clinicopathologic and follow-up data for 2131 T2 melanoma patients treated at Melanoma Institute Australia between January 1992 and May 2012 were analyzed. RESULTS: Of the 2131 patients, those who had a pathologic excision margin of <8 mm (equivalent to 1 cm in vivo) had poorer prognosis in terms of disease-free survival compared with the 8-16-mm group (equivalent to 1-2 cm in vivo; P = 0.044). When comparing 8-mm with 16-mm pathologic margins, no differences were observed in any of the survival outcomes. Only the deep margin proved to be an independent predictor of local and in-transit recurrence-free survival (P = 0.003) in all excision margin categories. Pathologic excision margins <8 mm were associated with worse regional node recurrence-free survival and distant recurrence-free survival compared with margins ≥8 mm (P = 0.049 and P = 0.045; respectively). However, these results failed to translate into a statistically significant difference in melanoma-specific survival. CONCLUSIONS: The results of this study suggest that if a peripheral/radial pathologic excision margin for a T2 primary cutaneous melanoma is <8 mm consideration should be given to performing a wider excision.

Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite.

BACKGROUND: A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60 d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. RESULTS: As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. CONCLUSION: Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.

Melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases.

BACKGROUND: Primary melanomas of the vulva and vagina are rare. As a result, it has been difficult to develop evidence-based guidelines for their management. By analyzing a large series of patients with vulval and vaginal melanomas, this study sought to document the most common presenting features, identify clinical and pathologic predictors of outcome, and provide management guidelines. METHODS: A clinicopathologic analysis of 85 patients with primary melanomas of the vulva or vagina diagnosed and treated at Melanoma Institute Australia and associated units in Sydney, Australia, between 1960 and 2011 was performed. Predictors of disease-free and melanoma-specific survival (MSS) were determined. RESULTS: Patients with American Joint Committee on Cancer (AJCC) stage 0-II had a significantly better MSS (5Y MSS = 63.6 %, n = 59) compared with those with stage III disease (5Y MSS = 0 %, n = 12, p < 0.001). Tumor thickness, ulceration status, and pathologic clearance margin were significant predictors of MSS. Disease-free survival was predicted by these factors and additionally by tumor mitotic rate. CONCLUSIONS: The results of this study provide evidence to support the appropriateness of utilizing the AJCC (7th edition) cutaneous melanoma staging system for vulval and vaginal melanomas. Detection and removal of these melanomas at an early stage with pathologically confirmed clear margins confers the best chance of cure.

In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy.

PURPOSE: To analyze a large, single-institution database to further understanding of melanoma in-transit metastases (ITM) with regard to incidence, prognosis, and the role of lymphadenectomy. METHODS: A total of 11,614 patients with single primary cutaneous melanomas were treated at Melanoma Institute Australia between January 1994 and December 2009. Of these, 505 developed ITM. Clinicopathologic characteristics, sentinel node (SN) status, patterns of disease progression, and outcomes were analyzed. RESULTS: In the 505 patients with ITM, the median primary tumor thickness was 2.95 mm, and 39.4 % were ulcerated. The ITM rates for patients with primary melanomas <1 or ≥1 mm in size and in those who underwent sentinel node biopsy were 0.4, 7.8, and 7.2 %, respectively. The ITM rates for SN-positive and SN-negative patients were 21.6 and 4.7 %, respectively. The median time from primary diagnosis to the development of ITM was 17.9 months. After ITM diagnosis, the median survival time was 19.9 months, 5-year survival was 32.8 %, and 10-year survival was 27.5 %. After ITM diagnosis, primary tumor site (head/neck, trunk) and ulceration were predictors of poorer survival. Five-year survival from the time of ITM ranged from 47.9 % for nonulcerated limb primary lesions to only 13.6 % for ulcerated trunk primary lesions. Elective lymph node dissection in clinically node-negative patients with ITM did not significantly alter overall survival. CONCLUSIONS: This large study demonstrates that the diagnosis of melanoma ITM carries serious adverse prognostic implications and will assist in improving the accuracy of staging and prognostic estimates as well as treatment in these patients.

SOUND: a structured handoff tool improves patient handoffs in a pediatric emergency department.

INTRODUCTION: Handoff communication is an important contributor to safety and quality in the emergency department (ED). Breakdowns in this process may lead to unsafe conditions or adverse events. The purpose of this study was to test the hypothesis that the quality of patient handoffs in the pediatric ED would improve after implementation of a structured handoff method. METHODS: In this prospective, observational study, we evaluated the implementation of a structured handoff tool, SOUND, which we developed to standardize the format of handoffs. The tool contains 5 components as follows: Synthesis, Objective Data, Upcoming Tasks, Nursing Input, and Double Check. SOUND was implemented through an online module and provider education. Handoffs were observed before and after implementation of SOUND. Statistical process control was used to measure the effects of the intervention. A successful handoff was defined as one in which 4 of the 5 components were included. As a balancing measure, we calculated mean time per handoff. RESULTS: We observed 638 handoffs. The implementation of SOUND significantly increased the percentage of successful handoffs. Statistical process control demonstrated continued improvement over time. This improvement was associated with a modest increase in the mean time per patient discussed (52.9 vs 73.0 seconds, P < 0.01). CONCLUSIONS: It is feasible to standardize patient handoffs in the pediatric ED. The implementation of SOUND improved completeness of handoffs with only a modest increase in the mean time spent discussing each patient. Future study is required to determine if SOUND will prove effective in other ED settings.

Outcome following sentinel node biopsy plus wide local excision versus wide local excision only for primary cutaneous melanoma: analysis of 5840 patients treated at a single institution.

OBJECTIVE: Worldwide, sentinel node biopsy (SNB) is now a standard staging procedure for most patients with melanomas 1 mm or more in thickness, but its therapeutic benefit is not clear, pending randomized trial results. This study sought to assess the therapeutic benefit of SNB in a large, nonrandomized patient cohort. METHODS: Patients with primary melanomas 1.00 mm or more thick or with adverse prognostic features treated with wide local excision (WLE) at a single institution between 1992 and 2008 were identified. The outcomes for those who underwent WLE plus SNB (n = 2909) were compared with the outcomes for patients in an observation (OBS) group who had WLE only (n = 2931). Median follow-up was 42 months. RESULTS: Melanoma-specific survival (MSS) was not significantly different for patients in the SNB and OBS groups. However, a stratified univariate analysis of MSS for different thickness subgroups indicated a significantly better MSS for SNB patients with T2 and T3 melanomas (>1.0 to 4.0 mm thick) (P = 0.011), but this was not independently significant in multivariate analysis. Compared with OBS patients, SNB patients demonstrated improved disease-free survival (DFS) (P < 0.001) and regional recurrence-free survival (P < 0.001). There was also an improvement in distant metastasis-free survival (DMFS) for SNB patients with T2 and T3 melanomas (P = 0.041). CONCLUSIONS: In this study, the outcome for the overall cohort after WLE alone did not differ significantly from the outcome after additional SNB. However, the outcome for the subgroup of patients with melanomas more than 1.0 to 4.0 mm in thickness was improved if they had a SNB, with significantly improved disease-free and DMFS.

The optimum excision margin and regional node management for primary cutaneous T3 melanomas (2-4 mm in Thickness): a retrospective study of 1587 patients treated at a single center.

OBJECTIVE: To determine the optimum excision margin and nodal management for patients with primary cutaneous melanomas 2.01- to 4.00-mm thick (T3 melanomas). BACKGROUND: Currently available evidence does not reliably define the minimum safe excision margin and best nodal management for patients with primary cutaneous T3 melanomas. METHODS: A retrospective study was conducted, analyzing data on 1587 patients with melanomas 2.01- to 4.00-mm thick treated at a single center. RESULTS: A histopathologic excision margin of 8 mm or more (equivalent to a ≥1 cm surgical margin) was associated with increased local and in-transit recurrence-free survival [hazard ratio (HR) = 0.54; P = 0.008] and disease-free survival (DFS) (HR = 0.59; P = 0.001) compared with a less than 8-mm margin. The <8-mm group had reduced distant recurrence-free survival (DRFS) compared with the 8- to 16-mm group (HR = 1.63; P = 0.038). On multivariate analysis, patients with a positive sentinel lymph node (SLN) had significantly reduced melanoma-specific survival (MSS), DFS, regional node recurrence-free survival (RNRFS) and DRFS compared with patients with a negative SLN, unless an immediate completion lymph node dissection was performed. Patients in whom an SLN biopsy was not performed had significantly reduced MSS (HR = 2.10; P < 0.001), DFS (P < 0.001), RNRFS (P < 0.001), and DRFS (P = 0.010) compared with patients who received an SLN biopsy. CONCLUSIONS: A histopathologic excision margin of 8 mm or more (corresponding to a ≥1 cm surgical excision margin) combined with SLN biopsy (followed by an immediate completion lymph node dissection if positive) provided T3 melanoma patients with optimum local, regional, and distant disease control and resulted in enhanced melanoma-specific survival.

Primary melanoma location on the scalp is an important risk factor for brain metastasis: a study of 1,687 patients with cutaneous head and neck melanomas.

BACKGROUND: Primary cutaneous head and neck melanomas (HNM) are reported to be associated with a higher incidence of brain metastasis than trunk and limb melanomas (TLM). In this study, the incidence of brain metastases in patients with HNM and risk factors for the development of brain metastases were analyzed. METHODS: From a large, prospectively-collected database, 1,687 HNM patients and 8,793 TLM patients who presented with American Joint Committee on Cancer (AJCC) stage I and II disease were identified. Survival was assessed using the Kaplan-Meier method and multivariate Cox regression analysis. Independent risk factors were determined by binary logistic regression analysis. RESULTS: The incidence of brain metastases 5 years after diagnosis of HNM was 6.7 % compared with 4.7 % for brain metastases from TLM (p = 0.003). Patients with scalp melanomas were most likely to develop brain metastases (12.7 %). Independent risk factors for brain metastasis in patients with HNM were Breslow thickness, ulceration, and scalp location. CONCLUSION: Patients with primary scalp melanomas had a much higher incidence of brain metastasis than patients with melanomas on other head and neck sites, who in turn had a higher incidence than patients with melanomas on sites elsewhere on the body. More intensive monitoring of patients with scalp melanomas, who are at particularly high risk of brain metastasis, might lead to earlier discovery of metastatic disease in the brain, offering the prospect of earlier intervention and better outcomes.

Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease.

BACKGROUND: Several reports in the literature suggest a difference in outcome between melanoma patients with macroscopic (clinically palpable) nodal disease from an unknown primary (MUP) and a known primary (MKP). The purpose of this study was to compare the outcomes for MUP and MKP patients after therapeutic lymph node dissection (TLND) for macroscopic nodal disease. METHODS: From a large, prospective, single-institution database, the details of melanoma patients who first presented with macroscopic nodal disease and underwent TLND between 1971 and 2010 were extracted and analyzed. RESULTS: There were 287 MUP patients and 264 MKP patients who fulfilled the study selection criteria. MUP patients had better disease-free, distant metastasis-free, and melanoma-specific survival after their TLND than MKP patients (all p < 0.001). Extranodal melanoma extension, >3 positive lymph nodes, and administration of adjuvant radiotherapy were all independent predictors of reduced disease-free and melanoma-specific survival (all p < 0.05). MUP patients also had a better prognosis than MKP patients whose primary melanoma had regression (p = 0.001). CONCLUSIONS: The occurrence and improved outcome of MUP patients may be due to immune-induced total regression of the primary tumor and better immunologic prevention or control of distant metastatic disease. Alternatively, in some MUP patients, melanoma may not be metastatic but may originate de novo from nevus cells in lymph nodes, with the more favorable prognosis attributable to their primary nodal origin and complete surgical resection.

Threshold for increased liver weight is protective of other effects in Peromyscus exposed to PFNA.

Perfluorononanoic acid (PFNA) is a commercially relevant, long-chain (8 fully fluorinated carbon) perfluorinated carboxylic acid. PFNA has limited terrestrial ecotoxicity data and is detected in humans, animals, and the environment. This study is the fourth in a series with the objective of investigating the toxicity of a suite of per- and polyfluoroalkyl substances (PFAS) detected on military installations in a mammal indigenous to North America. Peromyscus leucopus (white-footed mice, ∼25/sex/dose) were exposed via oral gavage to either 0, 0.03, 0.14, 1, or 3 mg PFNA/kg-d for 112 consecutive days (4 wk premating exposure followed by an additional 12 wk of exposure after onset of mating). Parental generation animals were assessed for potential reproductive and developmental effects, organ weight changes, thyroid modulation, and immunotoxicity. Pup weight and survival were assessed at postnatal days 0, 1, 4, 7, and 10. Change in liver weight was determined to yield the most sensitive dose response according to benchmark dose analysis, and serves as the most protective point of departure (BMDL = 0.37 mg/kg-d PFNA). Other effects of PFNA exposure included reduced formation of plaque-forming cells, which are indicative of functional immune deficits (BMDL = 2.31 mg/kg-d); decreased serum thyroxine (BMDL = 0.93 mg/kg-d) without changes in some other hormones; and increased stillbirths (BMDL = 0.61 mg/kg-d PFNA). Pup weight and survival were not affected by PFNA exposure. Combined with data from previous studies, data from Peromyscus provide a One Health perspective on health effects of PFAS.

The importance of adequate primary tumor excision margins and sentinel node biopsy in achieving optimal locoregional control for patients with thick primary melanomas.

OBJECTIVE: This study sought to investigate the impact of histopathologically measured excision margins and SNB on local and locoregional disease control in patients with primary cutaneous melanomas more than 4 mm thick. BACKGROUND: Most current guidelines recommend at least a 2-cm surgical margin (which corresponds to a 16-mm histopathologic margin). These guidelines are based on limited evidence, mostly obtained in patients who did not have an SNB. METHODS: Histopathologic tumor excision margins for clinically lymph node-negative patients with melanomas more than 4 mm thick, treated at Melanoma Institute Australia (1992-2009), were determined. Clinicopathologic predictors of local and locoregional disease-free survival were investigated. RESULTS: There were 632 patients eligible for the study; of these, 397 (62.8%) had an SNB. The median histopathologic excision margin was 15 mm (interquartile range, 11.0-19.5 mm). After a median follow-up of 37 months, local and locoregional recurrences were observed in 48 (7.6%) and 159 (25.2%) patients, respectively. Excision margin as a continuous variable was a significant predictor of local [hazard ratio (HR), 0.91; P < 0.001) and locoregional (HR, 0.97; P = 0.042) tumor control on multivariate analyses. Patients with histopathologic margins 16 mm or less had worse local disease-free survival (HR, 2.41; P = 0.01). Patients who did not have an SNB were at higher risk of locoregional recurrence (HR, 1.67; P = 0.003). CONCLUSIONS: Histopathologically determined primary tumor excision margins more than 16 mm, corresponding to 2-cm surgical margins, were associated with better local control in patients with melanomas more than 4 mm thick. Patients achieved the best local and locoregional control when SNB was coupled with a more than 16-mm histologic excision margin.

Interspecific effects of 4A-DNT (4-amino-2,6-dinitrotoluene) and RDX (1,3,5-trinitro-1,3,5-triazine) in Japanese quail, Northern bobwhite, and Zebra finch.

The purpose of this study was to assess the toxicological effects of two munition compounds, 4-amino-2,6-dinitrotoluene (4A-DNT) and 1,3,5-trinitro-1,3,5-triazine (RDX), on three different bird species: two common toxicological model species-the Northern Bobwhite (Colinus virginianus) and the Japanese Quail (Coturnix japonica), and a representative passerine-the Zebra Finch (Taeniopygia guttata). Bobwhite were exposed to 4A-DNT at 0, 8, 15, 30, 60, or 150 mg/kg body weight (bw) d by oral gavage for seven days; because the high dose of 4A-DNT was lethal to bobwhite, the maximum dose was changed to 100 mg/kg bw d for Japanese quail and finches to ensure tissue could be used for future toxicogenomic work. RDX was similarly administered at 0, 0.5, 1.5, 3, 6, or 12 mg/kg bw d. Blood was drawn prior to euthanasia for blood cellularity and chemistry analyses. Finches were clearly least affected by 4A-DNT as evidenced by a lack of observable effects. Bobwhite appeared to be the most sensitive species to 4A-DNT as observed through changes in blood cellularity and plasma chemistry effects. Bobwhite appeared to be more sensitive to RDX than Japanese Quail due to increased effects on measures of plasma chemistries. Finches exhibited the greatest sensitivity to RDX through increased mortality and seizure activity. This study suggests that sensitivity among species is chemical-specific and provides data that could be used to refine current avian sensitivity models used in ecological risk assessments.