Adcitmer® , a new CD56-targeting monomethyl auristatin E-conjugated antibody, is a potential therapeutic approach in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. OBJECTIVES: To produce and evaluate the therapeutic performance of a new antibody-drug conjugate (Adcitmer® ) targeting CD56 in preclinical models of MCC. METHODS: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56-targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56-targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. RESULTS: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56-targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56-mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. CONCLUSIONS: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors.

Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a survey of 407 children.

INTRODUCTION: Pyloromyotomy is the standard care for hypertrophic pyloric stenosis. The traditional approach for this procedure is a right upper quadrant transverse incision, although other "open" approaches, such as circumumbilical or periumbilical incision have been described. The more recent approach used is laparoscopic pyloromyotomy (LP), but experience feedback is still debated and its benefits remain unproven. The aim of this study was to make a review of all our LP procedures with an objective evaluation according to the literature. METHODS: A retrospective analysis of all the LPs performed in one University Children's Hospital between 1 January 1996, and 30 December 2015 was realized. Information regarding the patient's status, intraoperative and postoperative data was analyzed. RESULTS: 407 patients were included in this study. The mean operative time of the overall procedure was 24 ± 13 min, which significantly increased with the length of the pyloric muscle (p = 0.004) and significantly impacted the full feeding time (p = 0.006). 3.4% required conversion to an open procedure during the LP. We observed a significant correlation between conversion for mucosal perforation and weight loss (p = 0.04) and between conversion for mucosal perforation and preoperative weight (p = 0.002). A redo procedure was indicated in 3.7%, for incomplete pyloromyotomy each time. The mean postoperative hospital length of stay for all procedures was 1.6 ± 0.8 days. There were no inflammatory scars. None had incisional hernias or wound dehiscence. DISCUSSION: LP procedure appeared to be as quick as the open procedure. Our results were similar to others series for intraoperative complications. According to operative time, this technique does not have an impact on operative room utilization. Vomiting duration at presentation in HPS does not seem to have a significant impact on postoperative outcomes. LP procedure causes little pain during the postoperative period. No wound complications were registered.

Pretransplantation Donor-Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation.

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV-associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor-recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high-BKPyV-seroreactive donors with low-seroreactive recipients resulted in a 10-fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5-29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.

[Tissue expansion in children: Indications and management of complications. A 10-year experience]. / L'expansion cutanée chez l'enfant : indications et gestion des complications. Notre expérience sur 10 ans.

INTRODUCTION: Tissue expansion is a plastic surgery technique which enables optimal quality and skin surface reconstruction in case of soft tissue defect. Despite the good results obtained, both from a functional and aesthetic point of view, there is a high rate of complications whose management seems to be essential to ensure satisfactory results. PATIENTS AND METHODS: We retrospectively reviewed the medical files of 45 children treated in our department between 2002 and 2012: 73 expanders were placed during 51 protocols. RESULTS: The studied protocols gathered a large variety of situations. Varied pathologies were treated: burn sequelae (39 %), giant congenital naevus (GCN) (27 %), scars (20 %), hamartoms (8 %), cutis aplasia (6 %), as well as diverse sites: scalp (45 %), trunk (35 %), head and neck (8 %), lower extremity (8 %), upper extremity (4 %). Complications occurred in 17 protocols representing 26 % of total expanders. GCN is a pathology with a significantly lower complication rate (P=0.013) whereas trunk is an anatomical location with a significantly higher complication rate (P=0.026). Overall, 84 % of reconstructions were evaluated as having a good result. This rate reached 76 % for complicated protocols. CONCLUSION: Tissue expansion in paediatric patients remains an efficient therapy in order to achieve a satisfactory reconstruction. Despite a high complication rate, good results can be obtained even in those complicated cases as long as they are well managed and anticipated. We also think that specific paediatric material would help to reduce supervention of some complications.

[Tissue expansion in management of giant omphalocele parietal sequelae]. / Place de l'expansion cutanée dans le traitement des séquelles pariétales des omphalocèles géantes.

OBJECTIVE: According to major difficulty for the giant omphalocele management in the visceral reintegration and the parietal closure, many teams use currently conservative treatment by topical application. These techniques are suppliers of a covered eventration and a scar sequela requiring a complementary treatment. We report the place of the tissue expansion as complementary treatment. PATIENTS AND METHODS: Two patients with a giant omphalocele benefited from a protocol of cutaneous expansion for the correction of their abdominal scar±of their residual eventration. RESULTS: An eventration closure was possible thanks to this protocol. The skin expansion allowed the complete excision of the abdominal scar and the defect cover. An additional skin graft was necessary in the first case. CONCLUSION: The cutaneous expansion in the parietal sequela management of the giant omphaloceles seems to be an interesting alternative. This technique should be realized remotely and except any septic context.

Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.

Trichodysplasia spinulosa (TS) is a rare skin disease, caused by a specific polyomavirus, occurring in immunocompromised patients. The pathophysiological mechanisms of TS are not yet fully understood. By using polymerase chain reaction and skin biopsy immunostaining we report evidence, in a paediatric case, of follicular keratinocytes being the primary target of trichodysplasia spinulosa-associated polyomavirus.

Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell polyomavirus (MCPyV) is the main aetiological agent of Merkel cell carcinoma (MCC). Serum antibodies against the major MCPyV capsid protein (VP1) are detected in the general population, whereas antibodies against MCPyV oncoproteins (T antigens) have been reported specifically in patients with MCC. OBJECTIVES: The primary aim was to assess whether detection of serum antibodies against MCPyV proteins at baseline was associated with disease outcome in patients with MCC. The secondary aim was to establish whether evolution of these antibodies during follow-up was associated with the course of the disease. METHODS: Serum T-antigen and VP1 antibodies were assessed by enzyme-linked immunosorbent assay using recombinant proteins in a cohort of 143 patients with MCC, including 84 patients with serum samples available at baseline. RESULTS: Low titres of VP1 antibodies at baseline (< 10 000) were significantly and independently associated with increased risk of recurrence [hazard ratio (HR) 2·71, 95% confidence interval (CI) 1·13-6·53, P = 0·026] and death (HR 3·74, 95% CI 1·53-9·18, P = 0·004), whereas T-antigen antibodies were not found to be associated with outcome. VP1 antibodies did not differ between patients in remission and those with recurrence or progression during follow-up. However, T-antigen antibodies were more frequently detected in patients with recurrence or progression at 12 months (P = 0·020) and 24 months (P = 0·016) after diagnosis. CONCLUSIONS: VP1 antibodies constitute a prognostic marker at baseline, whereas T-antigen antibodies constitute a marker of disease recurrence or progression if detected > 12 months after diagnosis.

Screening of human papillomavirus infection in women with systemic sclerosis.

OBJECTIVES: High risk human papilloma-viruses (HR HPV) are associated with risk of cervical dysplasia and carcinoma. The risk is increased in patients with immune deficiency or auto-immune disease as systemic lupus erythematosus. Currently, no data are available about the human papillomavirus status in women with systemic sclerosis (SSc). METHODS: Thirty-one women with SSc were evaluated for cervical HPV infection and dysplasia, and compared to fifty age-matched control. Cervical swabs were tested by the INNO-LiPA assay®. Serum antibodies against HPV 16 and 18 were assessed using enzyme-linked immunosorbent assay in the SSc group. RESULTS: The overall HPV frequency was comparable between SSc and controls (32% vs. 38%), as well as the HR HPV frequency (28% vs. 34%), but infection by ≥2 HPV was two times more frequent in the SSc group (50% vs. 26% of the HPV positive samples). The most prevalent genotype was 52 in the SSc group (12%), and 52/53 in the control group (8% for both). Pap smears were within the normal range. Seropositivity for HPV 16 and 18 was 13% and 6.5%, respectively. A diffuse systemic sclerosis and a younger age at first intercourse were more frequent in cases of overall HPV positivity. Current smoking and a higher number of sexual partners were only observed in cases of seropositivity. CONCLUSIONS: This is the first study to evaluate HPV status in women with SSc. HR HPV52 was the most common genotype with a greater multi-HPV infection rate. This result needs to be confirmed in a larger study.

Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients.

BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC.

Simultaneous enucleation of the tonsils in "Pickwickian patients".

Tonsillar surgery was, from the 19th century, the reference treatment for apneic patients. Adapting to the technical limitations of the time, surgeons devised ingenious procedures. The purpose of this historical note is to travel back to that time and rediscover one of the techniques favored by Chassaignac: "simultaneous enucleation" of the tonsils.

Throat cancer surgery training in France.

This article reviews the development of practical and theoretical teaching of surgical management of throat cancer, from the dialectic of the Middle Ages to computer simulation of the 21st century. This work is essentially based on original historical publications, analysed from secondary references relevant to the interpretation of the original texts. The literature search was essentially conducted in the "bibliothèque universitaire de médecine de Tours", the "bibliothèque inter-universitaire de médecine de Paris", the "Assistance publique-Hôpitaux de Paris archives" and the "bibliothèque nationale de France". PubMed was used for the most recent references. The search terms focused on surgical training, the history of otorhinolaryngology and throat cancer. Up until the 19th century, throat cancer surgery training was provided by general surgeons. The otorhinolaryngology specialty was created at the turn of the 20th century: throat cancer surgery became a subspecialty, but certain university obstacles prevented the creation of formal throat cancer surgery training. In the 20th and 21st century, throat cancer surgery training was enhanced by technical innovations as well as ethical imperatives. The principle of mentoring, essential in surgical training, has remained a constant feature throughout the ages, regardless of the scientific progress described in this historical review.

Weight-for-height Z-score improves in half of undernourished children hospitalized in surgical wards.

BACKGROUND: Overall, 10-15% of hospitalized children are undernourished. The present study focuses on pediatric surgical wards. We assessed the impact of undernutrition upon admission on the weight-for-height Z-score (Z-WFH) during hospitalization for surgery. Secondary aims were to investigate the influence of associated factors and to report on the use of nutritional support. METHODS: All children hospitalized for a surgical procedure between July 2015 and March 2016 were included in this monocentric, prospective study. Children were divided into two groups: whether the Z-WFH upon admission was below -2 standard deviations (undernourished) or not (not undernourished). RESULTS: A total of 161 of 278 eligible children were included; 27 were undernourished (17%). The change in Z-WFH during hospitalization was greater in undernourished children (0.31±0.11 vs. -0.05±0.05, P=0.005). Of undernourished children, 49% recovered a Z-WFH above -2 SD during hospitalization. There was no difference between undernourished children and not undernourished children regarding age, length of hospital stay, pre- and post-operative duration of nil per os, duration of surgical procedure, ASA score, emergency level of the surgical procedure, and enteral/parenteral nutrition. CONCLUSION: Our data suggest that the Z-WFH of undernourished children upon admission improved during hospitalization.

Unilateral vagus nerve lesion revealing clival meningocele.

INTRODUCTION: Cranial nerve lesions can be secondary to a space-occupying lesion of the skull base compressing adjacent nerves. CASE REPORT: We report the case of an 84-year-old man, who presented with rapid and concomitant onset of dysphagia and ipsilateral recurrent laryngeal nerve paralysis, suggesting an isolated lesion of the vagus nerve. MRI revealed a diagnosis of previously unknown clival meningocele. DISCUSSION: Unilateral vagus nerve paralysis constitutes an exceptional mode of presentation of meningocele. Only a few isolated cases of clival meningocele have been reported to date, with no cranial nerve repercussions. The symptomatic management adopted in this case allowed rapid improvement of the patient's disorders.

Hormonal receptors in cutaneous vascular malformations: 51 cases.

Vascular malformations (VMs) are rare congenital anomalies that develop during embryogenesis in different types of vessels. Several triggering factors of cutaneous VMs include trauma, infections, or hormonal changes. We investigated the expression of hormonal receptors (androgen, estrogen, progesterone) in tissue samples of well-characterized VMs. A secondary objective was to identify self-reported triggering factors for these VMs, including hormonal changes, in the cohort of patients. We included patients with VM samples obtained in the tertiary center for vascular anomalies of the University Hospital Center of Tours, France, from January 1, 2007, to August 1, 2018. Immunohistochemistry was used to detect the expression of hormonal receptors (estrogen, progesterone, androgens). We obtained 51 samples from 51 patients: 13 cystic lymphatic malformations (CLMs), 16 venous malformations (VeMs), 11 arteriovenous malformations (AVMs), 4 combined VMs, 4 PIK3CA-related overgrowth spectrum, 1 Parkes-Weber syndrome, 1 Gorham syndrome, and 1 multiple lymphangioendotheliomatosis with thrombopenia. In total, 38 (74.5%) samples were positive for androgen receptor: 11 (84.6%) CLMs, 12 (75.0%) VeMs, 8 (72.2%) AVMs, and 7/11 (63.5%) other samples. All samples were negative for estrogen and progesterone receptors. Triggering factors were self-reported in 7 cases and were most frequently hormonal changes (n = 6, 18.2%). Hormonal triggers were frequent in AVMs (n = 4). Among patients with identified hormonal triggers, VM samples were positive for androgen receptor in 3 and negative in 3. Three-quarters of our VM samples expressed androgen receptor, and most CLM, VeM, and AVM samples were positive. Hormonal triggers were identified in 6/33 patients, mostly with AVMs.

Correction to: Hormonal receptors in cutaneous vascular malformations: 51 cases.

The original version of this article contained error. Table 2 was shown in the wrong version, thus corrected table is shown in this article.

Compressive chylothorax after lumbar spine fracture.

A 14-year-old boy was admitted to the hospital after an episode of blunt trauma to the thorax, resulting in a Chance fracture of L1 and a compressive chylothorax 72h after admission. After initial drainage in the operating room, conservative management was successful. This case study documents one of the rare complications of spinal fractures in the context of high-energy blunt trauma. It is the first detailing a noniatrogenic post-traumatic compressive chylothorax in pediatrics responding positively to conservative management. Drainage should be considered the first-line procedure for both therapeutic and diagnostic purposes. Surgery is required if the leakage is still present after parenteral feeding and the implementation of a fat-free diet for 5-7 days.

BK polyomavirus in the urine for follow-up of kidney transplant recipients.

OBJECTIVES: After kidney transplantation, human BK polyomavirus (BKPyV) can induce a progressive disease, in three stages: viruria, viraemia, and then nephropathy after a few months of viral replication. Therapeutic intervention is recommended when BKPyV is detected in the plasma. The objective of our study was to assess urinary BKPyV nucleic acid test as a predictor for developing viraemia. METHODS: We first defined a viruria threshold based on 393 time-matched urine and plasma samples collected after kidney transplantation; to validate this threshold, we followed-up a cohort of 236 kidney transplant patients. RESULTS: A BKPyV viruria threshold of 6.71 log10 copies/mL best discriminated between plasma-positive and plasma-negative patients (sensitivity 90.9% (95% CI 86.5-95); specificity 90.3% (95% CI 86.3-94.3); area under the curve 0.953 (95% CI 0.933-0.974). In the validation cohort, the risk of developing BKPyV viraemia at 1 year was 16.5% (39/236) and rose to 90.7% (39/43) if BKPyV viruria remained above the threshold of 6.71 for more than 1 month. CONCLUSIONS: Sustained BKPyV viruria is a reliable, early marker of patients at high risk of developing BKPyV viraemia. This marker should alert the clinician early, and thus allow timely therapeutic intervention.