Will the mininvasive approach challenge the old paradigms in oral cancer surgery?

In the genome era, the achievement of a safe and complete resection of oral cancers remains a challenge for surgeons. Margin length at histopathological examination is still considered the main indicator of oncological radicality. However, this parameter is fraught by major limitations. Cancer aggressiveness, and in particular its ability to spread in the surrounding tissue, most probably influences loco-regional control and prognosis more than margin length. Unfortunately, no molecular markers are currently available to predict tumor aggressiveness pre-operatively. However, additional histopathological parameters, beside margin length, could be considered to better stratify oral tumors, including depth of invasion (DOI), perineural invasion or composite scores. Recent advances in laser technology have established a novel surgical trend toward a minimalist approach, named transoral laser microsurgery (TLM). TLM provides a local control rate comparable to the one achieved by larger resections if the margin appears disease free, independent from its length. In addition, the clinical availability of innovative optical technologies, such as narrow band imaging (NBI) or autofluorescence, allows more precise and tailored resections, not simply based on clinical observation and ruler measurement. This review will propose the possible implementation of novel procedures toward a mini-invasive surgical approach, providing a satisfactory control rate but significantly improving the quality of life of the patients compared to conventional surgery.

VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans.

Tumor angiogenesis depends on the vascular endothelial growth factor (VEGF), which exists in multiple splicing isoforms, including the most abundant VEGF165 and VEGF121. We have previously shown that the differential capacity of these two VEGF isoforms to bind Neuropilin-1 accounts for their diverse ability to recruit Nrp1-expressing monocytes (NEMs), resulting in a different arteriogenic potential. Here we measure the expression of VEGF165 and VEGF121 in human cancer and their influence on tumor growth and vascularization. We measured the expression levels of VEGF165 and VEGF121 in human colorectal cancer and found that VEGF121 was more expressed than VEGF165, particularly in patients with extensive lymph node infiltration. Overexpressing either VEGF165 or VEGF121 in a cancer mouse model, we observed that the former decreased, whereas the latter increased tumor growth. In both clinical and experimental tumors, VEGF165 expression resulted in the recruitment of NEMs, paralleled by maturation of the tumor vascular network. Finally, hypoxia induced a shift toward the VEGF165 isoform in the central core of human cancers, as well as in various types of cultured cells. These results demonstrate that the two VEGF splicing isoforms are differentially expressed in colorectal cancers, exerting opposite effects on tumor growth and vessel maturation.

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.

Evaluation of nutritional status in head and neck radio-treated patients affected by oral mucositis: efficacy of class IV laser therapy.

PURPOSE: To retrospectively evaluate the role of class IV laser therapy in the amelioration of nutritional status of patients affected by oral mucositis due to radiotherapy of the head and neck region during oncological treatment. METHODS: Sixty-three oncological patients were included in this study. All patients were affected by tumors in the head and neck region and had developed oral mucositis during radiotherapy. Forty-two patients had been treated by high-power laser therapy whereas 21 patients had been managed with traditional medications. Data collection included weight measurement (kilogram) and body mass index (BMI) calculation (mass (kilogram)/(height) (square meter)) on the first and last day of radiotherapy. In addition, gender, age, pathology, and the kind of oncological treatment have been considered. RESULTS: Laser-treated patients decreased less in BMI during radiotherapy (p=0.000). Patients treated by combined oncological treatments (radiotherapy and/or chemotherapy and/or surgery) had a higher weight loss during radiotherapy (p=0.015). According to a multivariate regression analysis, the only variable which significantly influenced the reduction of BMI was laser treatment (p=0.000). CONCLUSIONS: Laser therapy is actually considered one of the recommended remedies for the healing of oral mucositis due to cancer treatments. Healing of mucositis can deeply influence the feeding capacity of patients, through reduction of pain and improvement of chewing and swallowing capacities. It also allows lowering the costs for hospitalization and supportive care. Laser therapy should become part of nutritional interventions in oncological patients affected by oral mucositis.

Effect of vascular endothelial growth factor gene therapy on post-traumatic peripheral nerve regeneration and denervation-related muscle atrophy.

Functional recovery after peripheral nerve injury depends on both improvement of nerve regeneration and prevention of denervation-related skeletal muscle atrophy. To reach these goals, in this study we overexpressed vascular endothelial growth factor (VEGF) by means of local gene transfer with adeno-associated virus (AAV). Local gene transfer in the regenerating peripheral nerve was obtained by reconstructing a 1-cm-long rat median nerve defect using a vein segment filled with skeletal muscle fibers that have been previously injected with either AAV2-VEGF or AAV2-LacZ, and the morphofunctional outcome of nerve regeneration was assessed 3 months after surgery. Surprisingly, results showed that overexpression of VEGF in the muscle-vein-combined guide led to a worse nerve regeneration in comparison with AAV-LacZ controls. Local gene transfer in the denervated muscle was obtained by direct injection of either AAV2-VEGF or AAV2-LacZ in the flexor digitorum sublimis muscle after median nerve transection and results showed a significantly lower progression of muscle atrophy in AAV2-VEGF-treated muscles in comparison with muscles treated with AAV2-LacZ. Altogether, our results suggest that local delivery of VEGF by AAV2-VEGF-injected transplanted muscle fibers do not represent a rational approach to promote axonal regeneration along a venous nerve guide. By contrast, AAV2-VEGF direct local injection in denervated skeletal muscle significantly attenuates denervation-related atrophy, thus representing a promising strategy for improving the outcome of post-traumatic neuromuscular recovery after nerve injury and repair.

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond.

Despite the enormous progress made in terms of prevention and early intervention, a pressing need remains to develop innovative therapeutic strategies for ischemic cardiovascular disorders, including acute myocardial infarction, chronic cardiac ischemia, peripheral artery disease and stroke. The induction of new blood vessel formation by delivering angiogenic genes to ischemic tissues continues to appear as a promising, alternative strategy to currently available therapies. In aspiring to induce therapeutic angiogenesis, the members of the vascular endothelial growth factor (VEGF) family have long been recognized as major molecular tools. Remarkably, VEGF family members have recently been recognized to also exert multiple, non-angiogenic effects on various cell types, including neurons, skeletal muscle and cardiac cells. Here, we critically review the VEGF-based therapies that have already reached clinical experimentation and highlight the pleiotropic activities of VEGF factors that might create new opportunities for therapeutic application.