Combined proteomic and transcriptomic approaches reveal externalized keratin 8 as a potential therapeutic target involved in invasiveness of head and neck cancers.

Keratin 8 (K8) expressed at the surface of cancer cells, referred as externalized K8 (eK8), has been observed in a variety of carcinoma cell lines. K8 has been previously reported to be expressed in poorly differentiated head and neck squamous cell carcinoma (HNSCC); however, its role during the invasive phase of upper aerodigestive tract tumorigenesis is unknown. Cohorts of HNSCC tumors for protein and mRNA expression and panel of cell lines were used for investigation. K8 was found to be externalized in a majority of HNSCC cell lines. Among the two main K8 protein isoforms only the 54 kDa was found to be present at the plasma membrane of HNSCC cells. The plasminogen-induced invasion of HNSCC cells was inhibited by the anti-eK8 D-A10 antagonist monoclonal antibody. Overexpression of K8 mRNA and protein were both correlated with tumor aggressive features and poor outcome. The effect of eK8 neutralization on invasion, its presence exclusively in cancer cells and the association of K8 expression with aggressive features and poor clinical outcome in HNSCC unravel eK8 as key player in invasion and a promising therapeutic target in HNSCC.

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial.

BACKGROUND: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults. METHODS: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2. DISCUSSION: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.

Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design.

BACKGROUND: Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. OBJECTIVE: The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. METHODS/DESIGN: This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). DISCUSSION: The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Use of cutting guides during craniosynostosis sequelae surgery: A comparative study between computer-assisted planning and post-operative results.

BACKGROUND: The authors compared results of craniofacial reconstruction surgery using cutting guides with planned reconstruction on patients presenting craniosynostosis surgery sequelae. METHODS: This is a retrospective study performed on seven patients who had undergone craniofacial reconstructive surgery in University Hospital Center of Tours (France) in 2015. Patients had long-term sequelae of trigonocephaly and anterior plagiocephaly surgery. 3D computer model was constructed, based on CT scans and used for surgical planning. Cutting guides were realized to use patient autologous bone. Post-operative 3D cranioplasty was superimposed to the 3D pre-operative to determine the minimal distance between each point of the post-operative flap and its pre-operative point corresponding. RESULTS: Mean of minimal distances calculated per patient ranged from 0.89 mm to 1.85 mm. The best result for percentage of points having the minimal distance inferior to 1.8 mm was 98.2 percent; the worst result was 55 percent. This value ranged from 77.5 to 98.2 percent for trigonocephaly cases. This value ranged from 55 to 77.5 percent for plagiocephaly cases. No significant difference was found between pre and post-operative areas and volumes of each flap, p = 0.12 and p = 0.19 respectively. CONCLUSION: Using cutting guides facilitates complex craniofacia reconstructions with patient autologous bone and obtains precise and reproducible results.

Distally Based Medial Hemisoleus Muscle Flap: Anatomic and Angiographic Study of 18 Lower Limbs.

BACKGROUND: The distally based medial hemisoleus (MHS) flap was found useful for repairing soft-tissue defects of the lower third of the leg; however, its reliability is controversial. We used a combination of static and dynamic techniques to investigate the vascular supply of distally based MHS muscle flaps to better establish their use in repair of lower-third leg defects. METHODS: We performed an anatomic study of 18 cadaver legs. For 6 legs, we performed dynamic angiography, which allowed for obtaining MHS muscle radiographs after pulsed injection of contrast medium in distal pedicles. RESULTS: The mean length of MHS muscle was 25.4 cm, the mean width was 6.9 cm, and the mean surface area was 87.5 cm. A mean of 3 distal posterior tibial vascular pedicles was directly connected to this medial subunit. These pedicles were present in all 18 cadaver legs. We observed complete opacification of the 6 MHS muscles through distal pedicles. Radiography revealed opacification of a vascular path from 1 distal pedicle to 1 proximal vascular pedicle of the MHS muscle. The mean level of this main distal pedicle was 14.5 cm to the tip of the medial malleolus. The level was at 38.2%, on average, from the bottom of the entire tibia. CONCLUSIONS: The distally based MHS muscle flap has constant blood supply, so it could be a useful flap to repair soft-tissue defects of the lower third of the leg. Moreover, knowledge of the average location of the main distal pedicle can help in increasing the use of the distally based MHS flap.

Cystathionine ß-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations.

BACKGROUND: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways. OBJECTIVE: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism. METHODS: We performed a case-control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls). RESULTS: In the discovery study on 'mothers', the CBS locus reached array-wide significance (p=9.13×10-6; Bonferroni p=4.77×10-3; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10-4; Bonferroni p=2.00×10-2; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10-5; Bonferroni p=7.80×10-3; OR 0.40 (0.25 to 0.63)). In the 'children' group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele). CONCLUSIONS: The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies.

Long-Term Assessment of Suturectomy in Trigonocephaly and Anterior Plagiocephaly.

INTRODUCTION: Techniques for treating trigonocephaly and anterior plagiocephaly have evolved from the initial suturectomy technique to frontal cranioplasty. The authors evaluated the suturectomy technique in adolescent patients with these craniosynostoses, by carrying out a retrospective, long-term assessment at the end of growth. METHODS: Patients with anterior plagiocephaly or trigonocephaly were included. All had undergone coronal or metopic suturectomy with bilateral orbitofrontal bandeau resection between 1997 and 2005. The primary endpoint was the Whitaker classification. The secondary endpoints were anthropometric measurement, assessments of the bone defects on computed tomography scan, and the comments of patients and their relatives concerning the final skull outcome. Patients with anterior plagiocephaly also attended an ophthalmological consultation. RESULTS: Seventeen patients were included in the study: 8 with anterior plagiocephaly and 9 with trigonocephaly. Mean age at the time of surgery was 6.91 months. Mean age at the time of craniofacial consultation was 14 years. Fourteen patients (82%) were classified as Whitaker Class III and IV, corresponding to poor esthetic results and persistent bone defects. Seven patients requested further surgery. CONCLUSION: This study shows that suturectomy seems to yield poor esthetic results in the long term and patients should be followed up throughout adolescence to correct any craniofacial deformities.

[Oral angiomas]. / Angiomes de la bouche.

Hemangiomas are benign tumors that occur after a few days of life. The capillary malformations are isolated or constitute part of a complex angiomatosis. Venous malformations are low flow malformations with a blue color. They are of different types. The arteriovenous malformations are high flow lesions. They are difficult to treat. Lymphatic malformations are micro- or macrocystic. MRI is the gold standard for explorations. Some patients undergo maxillofacial surgical procedures and interventional radiology techniques for venous malformations, macrocystic lymphatic malformations, arteriovenous malformations.

Frontofacial Monobloc Advancement With Simultaneous Frontal Cranioplasty in Adolescents With Residual Apert Syndrome Deformations.

INTRODUCTION: The treatment of faciocraniosynostosis has steadily evolved since the introduction of craniofacial surgery in the 1950s. The aim of this study is to demonstrate the positive results obtained by frontofacial monobloc advancement with simultaneous frontal cranioplasty in adolescents with adult facial bones and residual Apert syndrome deformations. MATERIALS AND METHODS: Three adolescents underwent surgery between September 1, 2010 and March 31, 2011. All had faciocraniosynostosis in the context of Apert syndrome and had undergone brain decompression surgery during the first year of life. However, they presented intracranial hypertension. The authors carried out frontofacial monobloc advancement with internal distraction and frontal cranioplasty. RESULTS: The mean frontal advancement was 13.8 mm. The mean maxillary advancement was 16.3 mm. About exorbitism, 2 patients had grade III and 1 had grade I before surgery. After monobloc advancement, 2 patients had no exorbitism and 1 had grade I. About dental occlusion, 3 patients had class III before surgery and were overcorrected in class II after advancement. DISCUSSION: Frontofacial monobloc advancement yields satisfactory functional and esthetic results in these cases. In conclusion, simultaneous frontofacial monobloc advancement and cranioplasty appears to be a promising technique for the treatment of adolescents with residual craniofacial deformations.

Efficacy and safety of embolization in arteriovenous malformations of the extremities and head and neck: a retrospective study of 32 cases.

BACKGROUND: Definitive treatment of arteriovenous malformations (AVMs) consists of complete surgical excision. When not possible, embolization may be performed. OBJECTIVES: We aimed to evaluate the efficacy and safety of embolization for AVMs of the extremities and head and neck. MATERIALS AND METHODS: This retrospective study included all patients undergoing embolization for AVMs of skin and soft tissues on the limbs, head and neck, in the University Hospital Center of Tours between January 1996 and December 2009. The main outcome was efficacy, assessed by two independent assessors, as the percentage of AVM devascularized at the end of embolization. Secondary outcomes were patient satisfaction, evolution of symptoms and safety of embolization. RESULTS: We included 32 AVMs in 31 patients, for 66 embolizations evaluated. In 18 AVMs (56.3%), devascularization was greater than 75% of the initial vascularization. Efficacy was lower for AVMs of the upper limbs than other body parts (p = 0.003). For 18 patients who could be contacted by telephone, the mean global satisfaction was 6.0 ± 2.7 on a scale of 0 to 10, and 13 (72.2%) reported an improvement of the symptoms linked to the AVM. Severe adverse events were reported after 4 embolizations, all located on the head and neck. CONCLUSION: Embolization can lead to good devascularization and improve symptoms linked to AVMs, especially in lower limbs. Minor complications are frequent, and severe adverse events may occur, especially after procedures on the head and neck.

Orbitofrontal monobloc advancement for Crouzon syndrome.

INTRODUCTION: Usually, patients suffering from Crouzon syndrome have synostosis of coronal sutures, exophthalmia, hypertelorism, and hypoplasia of the middle third of face. Sometimes maxillary retrusion is absent, so these patients have class I or II relationship. In these cases, frontofacial monobloc advancement, which is the gold standard, increases the maxillo-mandibular dysmorphia. Therefore we propose orbitofrontal monobloc advancement minus dental arch, without splits of the pterygoid plates. CASE REPORT: A 12-year-old girl with Crouzon syndrome had intracranial hypertension, exophthalmia, a middle third retrusion and a class II occlusion. We achieved orbitofrontal monobloc advancement which is frontofacial monobloc advancement minus maxillary dental arch. Four distractors KLS Martin were used. After 20 days of distraction, the final advancement was 10.2 mm for cranial distractors and 10.5 mm at fronto-zygomatic. Distractors were removed after 8 months. DISCUSSION: We offer patients suffering from Crouzon syndrome with class I or II relationship a change from the classic frontofacial monobloc advancement leaving the maxillary dental arch in place, thus avoiding the worsening of the maxillo-mandibular dysmorphia related to surgery. The idea of associating Le Fort I osteotomy with a frontofacial monobloc advancement or Le Fort III osteotomy has already been described, mainly by Tessier and Obwegeser, however they probably achieved a complete Le Fort I osteotomy while we don't split the pterygoid plates. The patient's morphology and his surgical history determine the choice between Le Fort III and monobloc advancement. Dental occlusion needs to be taken into account for surgical indication.

Resistance of the sheep skull after a monocortical cranial graft harvest.

INTRODUCTION: Cranial bone grafts are commonly used for preimplant or facial reconstructive surgery. However, removing bone may weaken the parietal bone and lead to a loss of strength. This loss has never been quantified. Bone harvest site reconstruction is being carried out more frequently than in the past, but its effect on the strength of the donor site is unknown. The aim of our study is to quantify the loss of strength due to a monocortical cranial bone graft harvest in sheep. MATERIALS AND METHODS: Thirty-four fresh sheep cadaver heads were used for the study. We performed a monocortical bone graft harvest on the posterior part of the right frontal bone. We used a surgical navigation system with optoelectronic tracking to measure bone thickness. To evaluate the resistance of the skull to an impact we developed a pendulum Charpy impact testing machine. The impact force hit a defined target frontal area. RESULTS: The total thickness on both sides ranged from 3 mm to 10 mm with a mean of 6 mm (SD = 1.4 mm). The loss of strength between the intact left side and the harvested right side varied with a mean of 49% (SD = 17%) and was significant (p = 6.10(-10)). CONCLUSION: This study has demonstrated that there is a loss of strength in the skull on the side where a bone graft has been harvested. Reconstruction of the harvested site using biomaterials reduces the poor aesthetic outcome due to depression at the site, but we do not know its effects on strength. This kind of study cannot be performed in humans for ethical reasons. Data obtained from this study will allow us to carry out a study in sheep to evaluate strength of the frontal area of a skull with a harvest site reconstructed with hydroxyapatite cement.

Reconstruction of large defects of the lips and commissure using a composite radial forearm palmaris longus free flap associated with a lengthening temporalis myoplasty.

We performed a single-stage operation to reconstruct a large defect of the lips and commissure using a composite radial forearm-palmaris longus free flap. To obtain cranial traction and a voluntary smile, independently from any jaw movement, traction was achieved by using a lengthening temporalis myoplasty. The tendon attached to the coronoid process was fixed to the palmaris longus tendon, recreating a new commissure and a "neo-modiolus." Physical therapy was started on the 21st postoperative day to facilitate progress from a "mandibular smile," to ideally a spontaneous and symmetric smile after 3 months of therapy. This procedure was able to obtain good oral continence and a good commissural movement during smile which has not previously been mentioned in the published literature.

Mechanical characterization and optoelectronic measurement of parietal bone thickness before and after monocortical bone graft harvest: design and validation of a test protocol.

Parietal bone grafts are commonly used in craniomaxillofacial surgery. However, bone removal may weaken the parietal bone and lead to deleterious complications. The aim of our study was to design a test protocol for characterization of the impact resistance of parietal bone before and after monocortical bone graft harvest and to validate an optoelectronic measurement of parietal bone thickness. Twelve fresh human cadaver heads were used for the validation study. To evaluate impact resistance, we developed a pendulum Charpy impact testing machine. The impact force was gradually increased until failure (fracture) of the defined parietal bone area. According to the protocol, we measured the maximum absorbable energy or impact force to failure. With our test setup, measurement of the impact resistance of parietal bone was accurate to within 0.025 J. We defined a range of values and particularly a threshold value. The initial maximal impact must not to exceed 4 J. For more accuracy, we compared 5 nondestructive measurement methods using a surgical navigation system with optoelectronic tracking. We achieved an algorithm based on 2 methods that ensured a measurement resolution of 0.1 mm. Validation of this protocol will allow us to evaluate the loss of strength resulting from bone removal and the correlation between strength and thickness of the parietal bone.

Facial resurfacing with split-thickness skin grafts in xeroderma pigmentosum variant.

Xeroderma Pigmentosum (XP) is a rare systemic disease which is transmitted through an incomplete sex-linked recessive gene. As a result of this, exposure to the ultraviolet (UV) rays of the sun causes malignant skin lesions. One of the most effective treatment options for the malignant lesions is full-face resurfacing with skin grafts. These grafts should be harvested from areas that have not been affected by UV exposure or have at least been minimally affected. The authors present a patient with XP whose face was resurfaced by split-thickness skin grafts taken from the buttocks.

Launois-Bensaude syndrome involving the orbits.

BACKGROUND: We report the first description of a Launois-Bensaude syndrome involving the orbit. CASE REPORT: Launois-Bensaude syndrome was diagnosed in a 70-year-old-man who presented with severe bilateral proptosis (Hertel value 26mm). We performed a bilateral transpalpebral orbital decompression by resection of intraorbital fat without bone removal. The surgery was uneventful. The volume of resected orbital fat was 16cc in both sides. Proptosis reduction was 7mm. Postoperative Hertel values were 19mm in both eyes. CONCLUSION: The proptosis was managed successfully. Orbital lipectomy lead to minimal sequelae and, may be repeated if necessary in this case.