Pharyngeal flap in velopharyngeal insufficiency: Proposal of an algorithm in a series of 31 patients.

This study evaluated the results of a reproductible protocol indicating the need for a pharyngeal flap in children with cleft palate and velopharyngeal insufficiency (VPI). A retrospective review of all patients operated for a pharyngeal flap between 2010 and 2019 in our center was conducted. After exclusion of patients with primary VPI or residual fistulas, 31 patients' data were analyzed. Our main outcome measure was the improvement of the Borel Maisonny Classification (BMC) by at least 1 rank. Further analysis was made to evaluate the impact of age, type of cleft, and BMC before surgery on the gain in the velopharyngeal function. Of the 31 patients, success was achieved in 29 (93.5%, p<0.005). There was no significant correlation between age and gain in the velopharyngeal function (p = 0.137). There was no significant correlation between type of cleft and gain in the velopharyngeal function (p = 0.148). There was a significant correlation observed between the starting classification and gain in velopharyngeal function. The gain observed was greater as the initial velopharyngeal function was worse (p = 0.035). The use of an algorithm combining clinical assessment with a standardized classification of the velopharyngeal function proved to be a reliable tool for the indication of surgery in patients with VPI. A close follow up is essential in a multidisciplinary team.

TAp73 loss favors Smad-independent TGF-ß signaling that drives EMT in pancreatic ductal adenocarcinoma.

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-ß (TGF-ß) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-ß pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-ß signaling through a SMAD-independent pathway, favoring oncogenic TGF-ß effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-ß signaling. By suggesting TAp73 as a predictive marker for response to TGF-ß inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-ß inhibitors.

[Annular lipoatrophy of the ankles treated by fat grafting: Case report and review of the literature]. / Lipoatrophie annulaire des chevilles traitée par autogreffe de tissu graisseux : à propos d'un cas et revue de la littérature.

INTRODUCTION: Annular lipoatrophy of the ankles is a rare disease. Eleven cases are described in the literature. CASE REPORT: We report the case of a 10-year-old girl having an annular lipoatrophy of the ankles. The clinical history begins with the appearance of inflammatory infiltrated nodules at the two legs, which have evolved in a few months to a circumferential lipoatrophy of the ankles. Laboratory studies showed a very high antistreptolysin O titer, concluding streptococcal origin of this hypodermitis. After two years of stable lesions, the patient received two sessions of fat injection. RESULT/DISCUSSION: A satisfactory outcome of the adipocyte graft was observed with reconstitution of shapely legs, stable over time. Eleven cases described in the literature are found. It is a pediatric pathology seen predominantly in female children. The evolution towards lipoatrophy is systematic with or without treatment initiated at the inflammatory phase. We first discuss the management of aesthetic sequelae of this disease. CONCLUSION: Fat grafting appears to be a good indication for the treatment of the cosmetic sequelae seen in annular lipoatrophy of the ankles.

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

Collective decision-making in white-faced capuchin monkeys.

In group-living animals, collective movements are a widespread phenomenon and occur through consensus decision. When one animal proposes a direction for group movement, the others decide to follow or not and hence take part in the decision-making process. This paper examines the temporal spread of individual responses after the departure of a first individual (the initiator) in a semi-free ranging group of white-faced capuchins (Cebus capucinus). We analysed 294 start attempts, 111 succeeding and 183 failing. Using a modelling approach, we have demonstrated that consensus decision-making for group movements is based on two complementary phenomena in this species: firstly, the joining together of group members thanks to a mimetic process; and secondly, a modulation of this phenomenon through the propensity of the initiator to give up (i.e. cancellation rate). This cancellation rate seems to be directly dependent upon the number of followers: the greater this number is, the lower the cancellation rate is seen to be. The coupling between joining and cancellation rates leads to a quorum: when three individuals join the initiator, the group collectively moves. If the initiator abandons the movement, this influences the joining behaviour of the other group members, which in return influences the initiator's behaviour. This study demonstrates the synergy between the initiator's behaviour and the self-organized mechanisms underlying group movements.

[Non vascularized toe phalangeal transfers for symbrachydactyly. Active range of motion without joint reconstruction]. / Transferts non vascularisés de phalanges d'orteils pour symbrachydactylie. Mobilités articulaires actives sans reconstruction articulaire.

Symbrachydactyly is a rare congenital malformation of the hand and its treatment is controversial. Non vascularized toe phalangeal transfers have been used for management of short digits for three children. Six phalanges have been harvested complete with their periosteum. No joint reconstruction has been performed and all children have undergone surgery at a young age. Four of six digits involved have an active range of motion (range 30 to 105 degrees ). All authors who have reported active range of motion of toe phalangeal transfers have performed joint reconstruction. Here, we report obtaining active range of motion of phalangeal transfers without necessity of joint reconstruction.

Immunohistochemical profiles of 30 monoclonal antibodies against cytokeratins 8, 18 and 19. Second report of the TD5 workshop.

In the first report of the TD5 workshop (TD5-1), the epitope specificities of 30 different monoclonal antibodies against cytokeratins 8, 18 and 19 were determined. This second report presents the immunohistochemical profiles of these antibodies using human appendix and normal skin for evaluation. Each antibody was tested by one or two different laboratories recruited from the Dutch Working Group on Immunohistochemistry and Cytochemistry. Eight different laboratories participated. The histological specimens were pretreated by the participants in three different ways for immunohistochemistry: microwave antigen retrieval in citrate buffer, enzymatic digestion to restore epitope exposure, no specific treatment (untreated paraffin-embedded samples), and tested blindly without knowledge of cytokeratin or epitope specificity of the antibodies at three different concentrations of 50, 10 and 1 microg/ml. Most of the tested antibodies (29/30) were useful in at least one pretreatment method, with microwave antigen retrieval being the most sensitive approach. For some antibodies, very high backgrounds were observed. Furthermore, it can be concluded that 11 MAbs performed well using all three staining protocols, including untreated paraffin-embedded sections. Interestingly, all the antibodies with documented selected specificity towards cytokeratin 8 (i.e. 178, 191, 199, 202 and 206) are reactive with an immunodominant region corresponding to amino acids 340-365 on cytokeratin 8, which evidently is well-suited as target for immunohistochemical interactions. Similarly, three antibodies with the same capacity to react with untreated samples had specificity against cytokeratin 19 (i.e. 179, 197 and 204) in the corresponding region in this filament, i.e. amino acids 311-335, or the KS 19.1 epitope. None of the six antibodies against the other major cytokeratin 19 epitope (BM 19.21) were found useful for immunohistochemistry on untreated samples. The overall conclusions from the present investigation are that all cytokeratin-8-specific antibodies with defined epitope specificities were very useful. Only one of the major two epitopes on cytokeratin 19 seems to be available for efficient immunohistochemistry. Cytokeratin 18 exposes some epitopes outside the immunodominant region reactive with the antibodies 190, 203 and 205 which can be used for untreated samples. The implications of these findings are of significance both for diagnostic histopathology and for the biology of tumor marker epitope expression in tissues.

Epitope specificity of 30 monoclonal antibodies against cytokeratin antigens: the ISOBM TD5-1 Workshop.

The epitope specificities of 30 monoclonal antibodies (MAbs) against the most common human cytokeratins. i.e., Nos. 8, 18, and 19, in epithelial cells were investigated in the ISOBM TD-5 Workshop. Seven research groups from universities or companies participated independently in the evaluation of the antibody specificities. The complex assembly of cytokeratins in vivo, with obligatory heterologous dimeric combinations of different cytokeratins from each of the two major groups, comprising together more than 20 different individual cytokeratins, made analysis of the antibody reactivity patterns with isolated single cytokeratins necessary. The concordance of the evaluations was striking and independent of the technologies used. As antigens purified individual cytokeratins, chemically degraded purified cytokeratins, recombinant intact and truncated cytokeratins, as well as specific synthesized shorter peptides were used. In order to elucidate the epitope specificity, reactivity patterns in ELISA assays and immunoblots with partial enzymatic degradation of the antigens were performed. Competitive cross-inhibition experiments between antibodies using antigens and antibodies in all possible combinations were performed with radioimmunometric assays, BIAcore, and ELISA technology. All 30 antibodies could convincingly be classified with regard to target cytokeratin. One MAb (192) had to be deleted due to dual specificities in both isotype and epitope specificity against its target. Six antibodies bound selectively to cytokeratin 8, 14 to cytokeratin 18, and 10 to cytokeratin 19, as demonstrated by using native, recombinant, and synthesized antigens. The immunodominant part of the molecule for all three types of cytokeratins was located in the region of amino acid (aa) 270-400. Out of the six MAbs reactive with cytokeratin 8, four MAbs, i.e., 178, 199, 202, and 206, were reactive with a sequence in the interval aa 340-365, and MAb 191 reacted with a closely related epitope. The remaining antibody, 192, presented dual specificities. At least two closely related major immunogenic epitopes could be identified in cytokeratin 8. In cytokeratin 18 four distinct epitopes could be documented, again with the dominating sequence region 270-429 as target for 10 (181, 184, 186, 188, 189, 190, 193, 196, 198, and 200) out of 14 antibodies. Since MAb 193 is known to react with the M3 epitope, aa 322-342 in cytokeratin 18, this entire group is reactive in the region close to the charge shift, in the middle of the rod 2B region, as shown by competitive binding. The remaining four anticytokeratin 18 antibodies (180, 185, 203, and 205) displayed unique, noncompetitive binding to this filament. Cytokeratin 19, reactive with altogether ten antibodies, displayed two major epitopes, all of them also within the large immunodominant region. MAbs 179, 195, 197, and 204 were reactive with the peptides aa 311-335 also known as the KS 19.1 epitope, and MAbs 182, 183, 187, 194, and 201 bound to peptide aa 346-367, known as the BM 19.21 epitope. One antibody, 231, was selectively reactive with aa 356-370 in cytokeratin 19. A complex pattern of binding specificities comprising at least ten different, noncompetitive epitopes, mainly situated in the rod portion, 2A and 2B, situated close to the charge shift in the rod of all three cytokeratins was documented. Out of the 29 classifiable antibodies, altogether 22 were reactive in this very short region, i.e., from aa 311 to 370 in all cytokeratin filaments. The remaining seven antibodies displayed unique binding properties. The implications of the findings are of significance both for immunohistochemistry and for assaying circulating heterodimeric, partially degraded complexes in patients' blood for tumor marker evaluation.