BackgroundExtensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations.MethodsSirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire.ResultsNineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event.ConclusionsSirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. The main risk factors for cancers of the oral cavity, larynx, oropharynx, and hypopharynx are alcohol and tobacco use. In addition, the human papillomavirus (HPV) is an established cause of oropharyngeal cancer. An experienced multidisciplinary team is necessary for adequate management and optimal outcome. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy, but despite this aggressive multimodal treatment, 40% to 60% of the patients will relapse. In this report, we will discuss recent advances in the management of SCCHN, including new developments in molecular biology, imaging, and treatment.

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Chemoradiotherapy has emerged as a gold standard in advanced squamous cell carcinoma of the head and neck (SCCHN). Because 50% of advanced stage patients relapse after nonsurgical primary treatment, the role of salvage surgery (SS) is critical because surgery is generally regarded as the best treatment option in patients with recurrent resectable SCCHN. Surgeons are increasingly confronted with considering operation among patients with significant effects of failed non-surgical primary treatment. Wide local excision to achieve clear margins must be balanced with the morbidity of the procedure, the functional consequences of organ mutilation, and the likelihood of success. Accurate selection of patients suitable for surgery is a major issue. It is essential to establish objective criteria based on functional and oncologic outcomes to select the best candidates for SS. The authors propose first to understand preoperative prognostic factors influencing survival. Predictive modeling based on preoperative information is now available to better select patients having a good chance to be successfully treated with surgery. Patients with a high comorbidity index, advanced oropharyngeal or hypopharyngeal primary tumors, and both local and regional recurrence have a very limited likelihood of success with salvage surgery and should be strongly considered for other treatments. Following SS, identifying patients with postoperative prognostic factors predicting high risk of recurrence is essential because those patients could benefit of adjuvant treatment or be included in clinical trials. Finally, defining HPV tumor status is needed in future studies including recurrent oropharyngeal SCC patients.

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PurposeTo investigate if cetuximab induces epithelial to mesenchymal transition (EMT) and activation of cancer associated fibroblast (CAF) in the tumors of patients with squamous cell carcinoma of the head and neck (SCCHN).MethodsCetuximab was administered for two weeks prior to surgery to 20 treatment-naïve patients. Five untreated patients were included as controls. Tumor biopsies were performed at baseline and before surgery. Gene expression profiles and quantitative real-time PCR (qRT-PCR) analysis of the pre-and post-treatment biopsies were compared. To further investigate EMT and CAF, correlations between previously described EMT and CAF markers and our microarray data set were calculated.ResultsGene expression profile analyses and qRT-PCR showed that some of the genes modified by cetuximab were related to CAFs and EMT (ZNF521, CXCL12, ASPN, OLFML3, OLFM1, TWIST1, LEF1, ZEB1, FAP). We identified 2 patient clusters with different EMT and CAF characteristics. Whereas one cluster showed clear upregulation of expression of genes implicated in CAF and EMT including markers of embryologic pathways like NOTCH and Wnt, the other did not.ConclusionEven if EMT and CAFs are implicated in cetuximab resistance in pre-clinical models, we demonstrate for the first time that these molecular processes may occur clinically early on.

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