Surgical treatment of painful neuroma in amputated and non-amputated patients: does the level of neurotomy affect clinical outcomes?

PURPOSE: To compare the outcomes of distal neurotomy (DN) versus proximal neurotomy (PN) for the surgical management of painful neuromas in amputees and non-amputees, whether used in passive or active treatment. METHODS: A retrospective study was conducted on patients who underwent surgery for painful traumatic neuromas between 2019 and 2022. DN with neuroma excision was performed at the level of the injury or amputation. PN was performed using a separate proximal approach without neuroma excision. Outcomes included a Numerical Rating Scale (NRS) score and Patient-Reported Outcomes Measurement Information System (PROMIS) scores, as well as patients' subjective assessments. RESULTS: A total of 33 patients were included: 17 amputees and 16 non-amputees. They totalized 43 neuromas treated by DN in 21 cases and PN in 22 cases. At the median follow-up time of 13 months, there were significant decreases in all NRS and PROMIS scores in the whole series. The decrease in limb pain scores was not significantly different between groups, except for the decrease in pain interference and patient satisfaction which were higher in the DN group. Sub-group analyses found the same significant differences in amputees. Targeted muscle reinnervation (TMR) was associated with a higher decrease in PROMIS scores. CONCLUSION: DN seemed to give better results in amputees but there were confusing factors related to associated lesions. In other situations, the non-inferiority of PN was demonstrated. PN could be of interest for treating neuromas of superficial sensory nerves, for avoiding direct revision of a well-fitted stump and in conjunction with TMR.

T Cells Expressing a Modified FcγRI Exert Antibody-Dependent Cytotoxicity and Overcome the Limitations of CAR T-cell Therapy against Solid Tumors.

The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.

Does the choice of the optic portal influence the radiographic and early functional results in acute acromioclavicular disjunctions?

Exposure of the coracoid process during arthroscopic stabilization of acute acromioclavicular disjunctions (ACDs) can be achieved either by passing an extra- articular optical portal through the subacromial space or by an intra-articular optical route through the glenohumeral joint with opening of the rotator interval. The objective of our study was to compare the impact on the functional results of these two optical routes. This was a retrospective, multicentre study that included patients operated on for an acute acromioclavicular disjunction arthroscopically. The treatment consisted of surgical stabilization under arthroscopy. The surgical indication was retained for an acromioclavicular disjunction of grade 3, 4 or 5, according to the Rockwood classification. Group 1, which consisted of 10 patients, was operated on with an extra-articular subacromial optical route, and group 2, which consisted of 12 patients, was operated on with an intra-articular optical route with opening of the rotator interval according to the habits of the surgeon. A follow-up of 3 months was performed. The functional results were evaluated for each patient using the Constant score, Quick DASH, and SSV. The delays in returning to professional and sports activities were also noted. A precise postoperative radiological analysis made it possible to analyse the quality of the radiological reduction. No significant difference between the two groups was found between the Constant score (88 vs. 90; p = 0.56), Quick DASH (7 vs. 7; p = 0.58), or SSV (88 vs. 93; p = 0.36). The times to return to work (6.8 weeks vs. 7.0 weeks; p = 0.54) and sports activities (15.6 weeks vs. 19.5 weeks; p = 0.53) were also comparable. The quality of the radiological reduction was satisfactory in the two groups and did not depend on the approach. No clinically or radiologically significant differences between the extra-articular and intra-articular optical portals in the surgical treatment of acute ACDs were found. The optical route can be chosen according to the habits of the surgeon.

Pain management during a bromelain-based selective enzymatic debridement in paediatric and adult burn patients.

BACKGROUND: Pain associated with surgical or enzymatic burn wound debridement prevents many burn centres from working outside an operating theatre, creating a burden. Alternatives for general anaesthesia to manage pain in burn patients treated with enzymatic debridements, such as regional anaesthesia, have not been studied in detail. This study explores the different possibilities for pain management during a bedside NexoBrid™ procedure. MATERIAL AND METHODS: We performed a single-centre retrospective study that included 82 paediatric, adolescent, and adult patients with deep dermal and full-thickness burns treated bedside with NexoBrid™ under regional or general anaesthesia. Outcome measures were pain during the NexoBrid™ procedure, the safety of the anaesthesia and the NexoBrid™ procedure, logistics of the bedside NexoBrid™ procedure, and time to wound closure. RESULTS: Forty-three patients in the adult group (43/67, 64%) only presented with burn wounds on one upper or the one or two lower extremities. In 29 of them (29/43, 67%), a NexoBrid™ procedure was performed under regional anaesthesia, which resulted in low pain levels without any adverse events. All seven patients in the paediatric group, where only one upper or one or two lower limbs were involved (7/15, 47%), underwent a NexoBrid™ procedure performed under regional anaesthesia where no adverse events were reported. In these children, the use of regional anaesthesia was associated with a significant decrease in time to wound closure (average treatment effect on the treated = -22.5 days, p = 0.021). CONCLUSION: This study highlights that regional anaesthesia administered at the bedside should be the method of choice for pain management during NexoBrid™ procedures because often, it can be adequately and safely performed in all age groups. This approach will reduce the burden on operating theatres. A flow chart has been developed to guide pain management during a NexoBrid™ procedure.

Classification of node-positive melanomas into prognostic subgroups using keratin, immune, and melanogenesis expression patterns.

Cutaneous melanoma tumors are heterogeneous and show diverse responses to treatment. Identification of robust molecular biomarkers for classifying melanoma tumors into clinically distinct and homogenous subtypes is crucial for improving the diagnosis and treatment of the disease. In this study, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates with worse survival, suggesting the involvement of melanosomes in melanoma aggression. We experimentally validated the secretion of melanosomes into surrounding tissues by melanoma tumors, which potentially affects the lethality of metastasis. We propose a simple molecular decision tree classifier for predicting a tumor's subtype based on representative genes from the three identified signatures. Key predictor genes were experimentally validated on melanoma samples taken from patients with varying survival outcomes. Our three-pattern approach for classifying melanoma tumors can contribute to advancing the understanding of melanoma variability and promote accurate diagnosis, prognostication, and treatment.

Bisphenol S Impaired Human Granulosa Cell Steroidogenesis in Vitro.

Bisphenol S (BPS) is a structural analog of the endocrine disruptor bisphenol A (BPA); it is the main BPA replacement in the plastics industry. Previous studies have shown that BPA and BPS exhibit similar effects on reproduction in fish and rodent species. BPS reportedly alters steroidogenesis in bovine granulosa cells. Luteinised granulosa cells collected from 59 women who were undergoing an in vitro fertilization procedure were cultured for 48 h in the presence or absence of BPS (10 nM, 100 nM, 1 µM, 10 µM or 50 µM). BPS exposure was investigated by assessing follicular fluids from these 59 women for their BPS content. Culture medium, cells, total messenger RNA (mRNA) and total protein extracted from the luteinised granulosa cells were examined for oestradiol and progesterone secretion, cellular proliferation, viability, gene expression, steroidogenic enzyme expression and cell signaling. BPS was measured in follicular fluids using mass spectrometry. Exposure of granulosa cells to 10 or 50 µM BPS for 48 h induced a 16% (p = 0.0059) and 64% (p < 0.0001) decrease, respectively, in progesterone secretion; 50 µM BPS decreased oestradiol secretion by 46% (p < 0.0001). Ten µM BPS also tended to reduce CYP11A1 protein expression by 37% (p = 0.0947) without affecting HSD3B1 and CYP19A1 expression. Fifty µM BPS increased ERRγ expression. Environmental levels of BPS (nanomolar range) did not induce changes in steroidogenesis in human granulosa cells. The effects of BPS were observed after only 48 h of BPS exposure. These acute effects might be similar to chronic effects of physiological BPS levels.

Adipocytes sensitize melanoma cells to environmental TGF-ß cues by repressing the expression of miR-211.

Transforming growth factor-ß (TGF-ß) superfamily members are critical signals in tissue homeostasis and pathogenesis. Melanoma grows in the epidermis and invades the dermis before metastasizing. This disease progression is accompanied by increased sensitivity to microenvironmental TGF-ß. Here, we found that skin fat cells (adipocytes) promoted metastatic initiation by sensitizing melanoma cells to TGF-ß. Analysis of melanoma clinical samples revealed that adipocytes, usually located in the deeper hypodermis layer, were present in the upper dermis layer within proximity to in situ melanoma cells, an observation that correlated with disease aggressiveness. In a coculture system, adipocytes secreted the cytokines IL-6 and TNF-α, which induced a proliferative-to-invasive phenotypic switch in melanoma cells by repressing the expression of the microRNA miR-211. In a xenograft model, miR-211 exhibited a dual role in melanoma progression, promoting cell proliferation while inhibiting metastatic spread. Bioinformatics and molecular analyses indicated that miR-211 directly targeted and repressed the translation of TGFBR1 mRNA, which encodes the type I TGF-ß receptor. Hence, through this axis of cytokine-mediated repression of miR-211, adipocytes increased the abundance of the TGF-ß receptor in melanoma cells, thereby enhancing cellular responsiveness to TGF-ß ligands. The induction of TGF-ß signaling, in turn, resulted in a proliferative-to-invasive phenotypic switch in cultured melanoma cells. Pharmacological inhibition of TGF-ß prevented these effects. Our findings further reveal a molecular link between fat cells and metastatic progression in melanoma that might be therapeutically targeted in patients.

Robot-Assisted Laparoscopic Fundoplications in Pediatric Surgery: Experience Review.

INTRODUCTION: Laparoscopic fundoplicature for gastroesophageal reflux disease has become the gold standard because of the improvement of postoperative rehabilitation compared with the open procedure. The robot-assisted surgery has brought new advantages for the patient and the surgeon compared with laparoscopy. We studied this new approach and the learning curve. MATERIALS AND METHODS: Sixty robot-assisted fundoplicatures were performed in two university pediatric surgery centers. Data of the patients were recorded, including peroperative data (operation length and complications), postoperative recoveries, and clinical evolution. The learning curve was evaluated retrospectively and each variable was compared along this learning curve. RESULTS: We observed a flattening of the learning curve after the 20th case for one surgeon. The mean operative time decreased significantly to 80 ± 10 minutes after 20 cases. There were no conversions to an open procedure. A revision surgery was indicated for 4.7% of the patients by a surgical robot-assisted laparoscopic approach. CONCLUSION: The robotic system appears to add many advantages for surgical ergonomic procedures. There is a potential benefit in operating time with a short technical apprenticeship period. The setting up system is easy with a short docking time.

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Laparoscopic one port appendectomy: Evaluation in pediatric surgery.

BACKGROUND: Appendectomy is a well-established surgical procedure in pediatric surgery used in the management of acute appendicitis. With the continuous advancement in the field of minimal invasive surgery, the recent focus is on single incision laparoscopic (SIL) surgery. SILA also goes further in order to decrease pain, improve recovery and enhance patient satisfaction. However, this approach is still not a well-established technique and not widely practiced, especially in pediatric surgery. METHODS: We prospectively recorded the data in our pediatric universitary hospital center since January, 01 2017 to July, 01 2017. Patients included in this study were randomized in two groups: SILA group (managed by one-port laparoscopy, n=40) and LA group (conventional laparoscopy using three trocars, n=40). RESULTS: The mean operative time for SILA was significantly lower. There were no postoperative complications in SILA group. If peritonitis was associated with appendicitis, the operative duration was not significantly different between each group. The duration in recovery room after surgery was significantly lower in SILA group. The morphine consumption was significantly lower for SILA group according to patient weight. SILA is less painful significantly than CLA for the first postoperative 6 h. After, even if SILA appears less painful, difference is not significant. The hospital length of stay was significantly higher in LA than SILA group CONCLUSIONS: SILA procedure for appendectomy appears to be safe and efficient for appendicitis management in children. This technique could be applied in routine as in emergency tome. TYPE OF STUDY: Prospective comparative study LEVEL OF EVIDENCE: II.

Dendritic Cells in the Context of Human Tumors: Biology and Experimental Tools.

Dendritic cells (DC) are the most potent and versatile antigen-presenting cells (APC) in the immune system. DC have an exceptional ability to comprehend the immune context of a captured antigen based on molecular signals identified from its vicinity. The analyzed information is then conveyed to other immune effector cells. Such capability enables DC to play a pivotal role in mediating either an immunogenic response or immune tolerance towards an acquired antigen. This review summarizes current knowledge on DC in the context of human tumors. It covers the basics of human DC biology, elaborating on the different markers, morphology and function of the different subsets of human DC. Human blood-borne DC are comprised of at least three subsets consisting of one plasmacytoid DC (pDC) and two to three myeloid DC (mDC) subsets. Some tissues have unique DC. Each subset has a different phenotype and function and may induce pro-tumoral or anti-tumoral effects. The review also discusses two methods fundamental to the research of DC on the single-cell level: multicolor flow cytometry (FCM) and image-based cytometry (IC). These methods, along with new genomics and proteomics tools, can provide high-resolution information on specific DC subsets and on immune and tumor cells with which they interact. The different layers of collected biological data may then be integrated using Immune-Cytomics modeling approaches. Such novel integrated approaches may help unravel the complex network of cellular interactions that DC carry out within tumors, and may help harness this complex immunological information into the development of more effective treatments for cancer.