P. Guerreschi

Radiotherapy alone for Merkel cell carcinoma: A comparative and retrospective study of 25 patients

BACKGROUNDnMerkel cell carcinoma (MCC) is a rare skin cancer. Cumulative data from retrospective series support the notion that benefits are obtained by both wide excision and adjuvant radiation therapy. However, surgery may be difficult to perform with tumors located in the head and neck region and/or in elderly patients with comorbidities incompatible with general anesthesia.nnnOBJECTIVEnWe assessed the benefit of treating MCC exclusively with radiation when conventional treatment (surgery followed by radiotherapy) is not possible.nnnMETHODSnA total of 25 patients with primary MCC were treated at our institution exclusively with radiotherapy. Because there is no consensus about this specific approach, we compared the recurrence rate of the 25 patients receiving radiotherapy alone with that of 25 patients who received conventional treatment at our institution.nnnRESULTSnThe median follow-up periods were 3 years (range: 5 months-11 years) for the group receiving only radiotherapy (group 1) and 9 years (range: 12 months-16 years) for the conventional therapy group (group 2). No local relapses were observed, but two locoregional relapses were observed in group 1, and 4 in group 2. No statistical differences were found in overall and disease-free survival between the two groups of patients.nnnLIMITATIONSnThe limitation of this study is its retrospective nature.nnnCONCLUSIONSnThis study confirms the results of our previous research demonstrating that it is possible to treat inoperable MCC exclusively with radiotherapy to obtain an outcome similar to that which is achievable with conventional treatment.

Aplasia cutis congenita: review of 29 cases and proposal of a therapeutic strategy.

INTRODUCTIONnAplasia cutis congenita (ACC) is a rare congenital disorder, which most commonly involves the scalp, and can affect the galea, the pericranium, the bone, and the dura mater. ACC thus is at risk of infection and hemorrhage. There is no consensus over the ideal management and the role for plastic surgery.nnnMATERIALS AND METHODSnWe reviewed retrospectively our experience with 29 patients treated between 1976 and 2011.nnnRESULTSnThe patients were 17 male and 12 female, 25 being referred immediately at birth. The size of the defect ranged from 1 to 192 cm2. Thirteen patients had bone aplasia. Initial conservative treatment was decided in five cases; 15 patients underwent excision-sutures with or without local plasty, 8 underwent pedicled scalp flap, and 1 had skin graft followed by further reconstruction by a free flap. Four patients died in neonatal period because of infection or associated ailments. All others patients achieved complete healing.nnnDISCUSSIONnThe mortality rate of ACC remains high and increases with the size of bone defect. We propose a therapeutic strategy based on the size of the skin defect and the nature of underlying exposed structures. Cranioplasty is exceptionally necessary because of good spontaneous bone regeneration within few months or years. Cosmetic appearance can be improved later by skin expansion.nnnCONCLUSIONnAplasia cutis congenita is a rare malformation with sometimes a rapid fatal issue. A precise evaluation of surface and depth of the lesion is essential to decide if and how to operate, in order to provide rapid and efficient coverage.

Mitochondrial oxidative phosphorylation controls cancer cell’s life and death decisions upon exposure to MAPK inhibitors

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER–mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.

Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic “drivers” inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy.

Patient-derived tumor xenograft model to guide the use of BRAF inhibitors in metastatic melanoma.

Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([18F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [18F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides ‘real-time’ results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this ‘coclinical’ trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.

Masseter muscle termination over the deep surface of the temporal fascia: look out the wrong path

PurposeThe masticatory muscles have a common embryological origin. Despite numerous anatomical studies their close anatomical relationships are not always accurately described in anatomical treatises. An expansion of the masseter muscle inserted into the deep surface of the superficial temporal aponeurosis has been described. Despite the classical description of two transition bundles (Yoshikawa et al. in Kaibogaku Zasshi 37:206–217, 1962), the literature concerning these fibres has remained difficult to interpret. Given the clinical applications of the lengthening of the temporal muscle in myoplasty, it is important that we have accurate anatomical knowledge of it.MethodsWe dissected 14 embalmed or untreated anatomical cadaver heads with a sex ratio of 1 in order to analyse the aforementioned fibres and their variations. A radiologic study allowed us to understand the entanglement of the fibres. 10 craniofacial MRI were processed by 3D MPR reconstruction.ResultsThe fibres were identified as an expansion of the posterior head of the masseter muscle and distinct from the two classically described transition bundles. These were present in all subjects of both sexes. We can systematically describe their origin, trajectory and termination.ConclusionFibres belonging to masseter muscle pass up to the zygomatic arch and terminate on the deep surface of the temporal fascia. Awareness of the nature and trajectory of these muscular fibres allows us to avoid taking “wrong path” when approaching the temporal muscle tendon on the coronoid process via the temporal fossa.

Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1

Purpose:Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown.Methods:We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.Results:We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype–phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.Conclusion:Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway–related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017

Lengthening temporalis myoplasty: a surgical tool for dynamic labial commissure reanimation.

Lengthening temporalis myoplasty (LTM), first described by Labbé in 1997, ensures the transfers of the entire temporal muscle from the coronoid process to the upper half of the lip without interposition of aponeurotic tissue. The temporal muscle changes function because it is entirely mobilized toward another effector: the labial commissure. Thanks to brain plasticity, the muscle loses its chewing function, and after 6 months of speech rehabilitation it acquires its new smiling function. We describe technical points especially the coronoid process approaches both through an upper temporal fossa approach and a lower nasolabial fold approach. Rehabilitation starts 3 weeks after the surgery following a standardized protocol to move from a mandibular smile to a voluntary, then spontaneous, smile in three steps. The LTM is the main part of a one-stage global treatment of the paralyzed face. It constitutes a dynamic palliative treatment usually started at the sequelae stage, 18u2009month after the outcome of a peripheral facial paralysis. This one-stage procedure is a reproducible and relevant surgical technique in the difficult treatment of peripheral facial paralysis. It allows implementing an active muscle transfer to reanimate the labial commissure and re-create a mobile nasolabial fold.

Metabolic Features of Melanoma: A Gold Mine of New Therapeutic Targets?

In recent years, our knowledge regarding the metabolism of melanoma has greatly advanced and consequently new therapeutic strategies are being developed. This review is focused on metabolic pathways contributing to melanoma proliferation, the influence of BRAF inhibitors on those metabolic pathways and finally a presentation of potential therapeutic strategies aimed at blocking metabolic signaling pathways and therefore melanoma development.

Les craniosténoses non syndromiques

Craniosynostosis are rare congenital malformations of the skull resulting from the premature fusion of one or several cranial sutures. Prevalence is considered in approximately 1xa0on 2000xa0births. Non syndromic craniosynostosis (NSC) or isolated form are the most frequent forms (85xa0% of the cases). They are classified most of the time according to the synostotic suture(s) and the engendered cranial deformation: sagittal synostosis or scaphocephaly, metopic synostosis or trigonocephaly, bicoronal synostosis or brachycephaly, coronal synostosis or plagiocephaly and oxycephaly. Although the multifactorial origin is commonly admitted, the precise mechanisms which lead to the premature fusion of a suture, remain incompletely resolute. The main risks are the intracranial high blood pressure and its consequences on the psychomotor development, the visual or respiratory infringement which can require a surgery in emergency. The treatment is realized by multidisciplinary teams allowing to provide a strategy adapted to every situation. The decision-making process depends on patients age, on the type and severity of the craniosynostosis, and on the patients health. This surgery is ideally performed before the age of 1xa0year and indication only in morphological purpose is widely recognized to avoid any social damage to the child. The follow-up is essential and is made throughout the growth in particular to detect a recurrence or the evolution towards a complex form of craniosynostosis.