Older melanoma patients have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in over 1000 patients, and high technecium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to ECM degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding rHAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-Cadherin junctions, whereas endothelial permeability was increased following HAPLN1-knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics.

In the largest study to date of patients with angiosarcoma, risk factors for poor OS were identified to create a clinically useful risk model that can prognosticate patients with localized disease following surgical resection. J. Surg. Oncol. 2016;114:557-563. © 2016 Wiley Periodicals, Inc.

IMPORTANCE More than half of all new melanoma diagnoses present as clinically localized T1 melanoma, yet sentinel lymph node biopsy (SLNB) is controversial in this population given the overall low yield. Guidelines for SLNB have focused on pathologic factors, but patient factors, such as age, are not routinely considered.OBJECTIVES To identify indicators of lymph node (LN) metastasis in thin melanoma in a large, generalizable data set and to evaluate the association between patient age and LN positivity. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study using the National Cancer Database, an oncology database representing patients from more than 1500 hospitals throughout the United States, was performed (2010)(2011)(2012)(2013). Data analysis was conducted from October 1, 2016, to January 15, 2017. A total of 8772 patients with clinical stage I 0.50 to 1.0 mm thin melanoma undergoing wide excision and surgical evaluation of regional LNs were included for study. MAIN OUTCOME AND MEASURESThe primary outcome of interest was presence of melanoma in a biopsied regional LN. Clinicopathologic factors associated with LN positivity were characterized, using logistic regression. Age was categorized as younger than 40 years, 40 to 64 years, and 65 years or older for multivariable analysis. Classification tree analysis was performed to identify high-risk groups for LN positivity.RESULTS Among the study cohort (n = 8772), 333 patients had nodal metastases, for an overall positivity rate of 3.8% (95% CI, 3.4%-4.2%). A total of 4087 (54.0%) patients were women. Median age was 56 years (interquartile range [IQR], 46-67) in patients with negative LNs and 52 years (IQR, 41-61) in those with positive LNs (P < .001). In multivariable analysis, younger age, female sex, thickness of 0.76 mm or larger, increasing Clark level, mitoses, ulceration, and lymphovascular invasion were independently associated with LN positivity. In decision tree analysis, patient age was identified as an important risk stratifier for LN metastases, after mitoses and thickness. Patients younger than 40 years with category T1b tumors 0.50 to 0.75 mm, who would generally not be recommended for SLNB, had an LN positivity rate of 5.6% (95% CI, 3.3%-8.6%); conversely, patients 65 years or older with T1b tumors 0.76 mm or larger, who would generally be recommended for SLNB, had an LN positivity rate of only 3.9% (95% CI, 2.7%-5.3%). CONCLUSIONS AND RELEVANCEPatient age is an important factor in estimating lymph node positivity in thin melanoma independent of traditional pathologic factors. Age therefore should be taken into consideration when selecting patients for nodal biopsy.

ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.

Norepinephrine, histamine, adenosine, glutamate, and depolarizing agents elicit accumulations of radioactive cyclic AMP from adenine-labeled nucleotides in particulate fractions from Krebs-Ringer homogenates of guinea pig cerebral cortex. The particulate fractions contain sac-like entities, which apparently are associated with a significant portion of the membranal adenylate cyclase. Particulate fractions from sucrose homogenates are a less effective source of such responsive entities. Activation of the adenine-labeled cyclic AMP-generating systems by norepinephrine is by means of alpha-adrenergic receptors, while activation by histamine is through H1- and H2-histaminergic receptors. Adenosine responses are potentiated by the amines and are antagonized by alkylxanthines. Glutamate and depolarizing agents appear to elicit accumulations of cyclic AMP via "release" of endogenous adenosine. It is proposed, based on the virtual absence of an alpha-adrenergic or H1-histaminergic response in the presence of a combination of potent adenosine and H2-histaminergic antagonists, that alpha-adrenergic and H1-histaminergic receptor mechanisms do not activate adenylate cyclase directly in brain slices or Krebs-Ringer particulate fractions, but merely facilitate activation by beta-adrenergic, H2-histaminergic, or adenosine receptors.