Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling.

Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood. Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema. Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury. Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema.

Skin cancers of the hand: a series of 541 malignancies.

BACKGROUND: Skin cancers of the hand are uncommon and poorly documented. The objective of this study was to review a large cohort of patients with hand skin malignancies to determine tumor characteristics, management techniques, and outcomes. METHODS: A retrospective review of consecutive patients with surgically excised primary cutaneous hand malignancies at the John Radcliffe Hospital between 1993 and 2010 was performed. Records were reviewed to determine tumor characteristics, demographics, and management details. Outcome parameters included margins and completeness of excision, recurrence, metastatic spread, and survival. RESULTS: A total of 407 patients (65.8 percent male; mean age, 72.2 ± 0.7 yr) presented with 541 primary cutaneous hand malignancies and were followed up for a mean period of 24 months. Half the cohort had previous skin cancers and almost one in five developed further hand skin cancers. Squamous cell carcinoma comprised 78.0 percent, basal cell carcinoma 11.3 percent, and melanoma 3.9 percent of cases. Incidence was highest on the dorsum of the hand. Surgical margins were proportionate to tumor size, and most defects required soft-tissue reconstruction. Recurrence was uncommon in melanoma and rare in squamous and basal cell carcinomas. Lymph node metastasis and death were rare in patients with squamous cell carcinoma but relatively common in those with melanoma. CONCLUSIONS: Squamous cell carcinomas are the most common skin malignancy of the hand, frequently require soft-tissue reconstruction, and those occurring in the web spaces or on the dorsum of the proximal phalanges are more sinister malignancies with a greater propensity for metastatic spread. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.