Postoperative radiotherapy versus surgery alone in pN1 oral cavity cancer patients: A meta-analysis.

Objectives: The aim of this meta-analysis is to evaluate the potential benefits of postoperative radiotherapy (PORT) in patients with pN1 oral cavity squamous cell carcinoma. Methods: A literature search through major databases was conducted until January 2023. The adjusted hazard ratio (aHR) or risk ratio (RR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. Results: Ten studies published between 2005 and 2022, with a pooled patient population of 2888, were included in this meta-analysis. Due to differences in study design and reported outcomes, the studies were categorized into distinct groups. In pN1 patients without extranodal extension (ENE), PORT was associated with a significant improvement in overall survival (OS) (aHR 0.76, 95% CI: 0.61-0.94). In pN1 patients without ENE and positive margins, PORT improved OS (aHR 0.71, 95% CI: 0.56-0.89) and was associated with a lower regional recurrence rate (RR 0.35, 95% CI: 0.15-0.83). However, in pN1 patients without ENE, positive margins, perineural invasion, and lymphovascular invasion, there were no significant differences observed between the PORT and observation groups in either 5-year OS (RR 0.48, 95% CI: 0.07-3.41) or 5-year disease-free survival (RR 0.37, 95% CI: 0.07-2.06). Conclusions: The current study demonstrated that PORT has the potential to improve OS in pN1 disease. However, the decision of whether to administer PORT still hinges on diverse clinical scenarios, and additional research is necessary to furnish a more conclusive resolution. Level of Evidence: 2.

New-Onset Atrial Fibrillation Is a Red Flag to Microvascular Free Tissue Transfer Failure in Head and Neck Cancer Patients.

BACKGROUND: Postoperative new-onset atrial fibrillation (AF) has been shown to be associated with increased surgical morbidity and mortality following cancer ablation surgery. However, evidence of new-onset AF's impact on surgical outcomes in head and neck cancer patients undergoing tumor ablation and microvascular free tissue transfer remains scarce. This study aims to evaluate the association between AF and surgical outcomes in these patients. METHODS: We enrolled head and neck cancer patients who underwent tumor ablation reconstructed with microvascular free tissue transfer from the National Health Insurance Research Database (NHIRD). Patients were grouped into the following: (1) without AF, (2) new-onset AF, and (3) preexisting AF. The groups were matched by propensity score based on age, gender, cancer stage, and comorbidities. The primary outcome was postoperative complications, whereas all-cause mortality was the secondary outcome. RESULTS: In total, 26,817 patients were included in this study. After matching, we identified 2,176 (79.24%) patients without AF, 285 (10.37%) with preexisting AF, and 285 (10.37%) with new-onset AF. Our results demonstrated that the free flap failure rate was twofold escalated in patients with new-onset AF (9.8%) compared to those without AF (5.4%) or preexisting AF (5.3%; p = 0.01). However, we did not identify significant differences among other postoperative complications across groups. Additionally, we found that the risk of all-cause mortality was significantly elevated in patients with preexisting AF (p < 0.001) compared to those without AF or new-onset AF. CONCLUSION: Our study demonstrated that new-onset AF is associated with an increased risk of flap failure and could serve as a predictor. On the other hand, all-cause mortality in patients with preexisting AF was significantly elevated. Close postoperative monitoring in patients with new-onset and preexisting AF is crucial to identify any potential adverse effects.

Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair.

The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration.

Risk factors for postoperative adverse airway events in patients with primary oral cancer undergoing reconstruction without prophylactic tracheostomy.

OBJECTIVE: To identify risk factors associated with adverse airway events (AAEs) in primary oral cancer patients undergoing tumor ablation followed by free tissue transfer without prophylactic tracheostomy. METHODS: We retrospectively collected primary oral cancer patients who underwent tumor ablation surgery following free-tissue transfer without prophylactic tracheostomy during February 2017 to June 2019 in Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan. 379 patients were included. Data were analysed from 2020 to 2021. Demographics, comorbidities, intraoperative variables and postoperative respiration profile were obtained from the medical record. Main outcome was postoperative AAEs, including requirement of endotracheal intubation after extubation and tracheostomy after prolonged intubation. RESULTS: Of the 379 patients, postoperative AAEs happened in 29 patients (7.6 %). In reintubation group, patients were older with more diabetes mellitus, hypertension and cerebrovascular disease. These patients had lower preoperative hemoglobin, creatinine, and albumin level with more intraoperative blood transfusion. In postoperative respiration profile, rapid shallow breathing index (RSBI) and PaO2/FiO2 (PF) ratio were poorer. On multivariate analysis, patient's age, tumor location, and cross-midline segmental mandibulectomy and a lower PF ratio were independent risk factors for postoperative AAEs. CONCLUSIONS: In head and neck cancer patients that underwent tumor ablation followed by free tissue transfer without prophylactic tracheostomy, patient's age, tumor location, cross-midline segmental mandibulectomy and P/F ratio are associated with postoperative AAEs.

The Transplantation of 3-Dimensional Spheroids of Adipose-Derived Stem Cells Promotes Achilles Tendon Healing in Rabbits by Enhancing the Proliferation of Tenocytes and Suppressing M1 Macrophages.

BACKGROUND: Tendons have limited regenerative potential, so healing of ruptured tendon tissue requires a prolonged period, and the prognosis is suboptimal. Although stem cell transplantation-based approaches show promise for accelerating tendon repair, the resultant therapeutic efficacy remains unsatisfactory. HYPOTHESIS: The transplantation of stem cells preassembled as 3-dimensional spheroids achieves a superior therapeutic outcome compared with the transplantation of single-cell suspensions. STUDY DESIGN: Controlled laboratory study. METHODS: Adipose-derived stem cells (ADSCs) were assembled as spheroids using a methylcellulose hydrogel system. The secretome of ADSC suspensions or spheroids was collected and utilized to treat tenocytes and macrophages to evaluate their therapeutic potential and investigate the mechanisms underlying their effects. RNA sequencing was performed to investigate the global difference in gene expression between ADSC suspensions and spheroids in an in vitro inflammatory microenvironment. For the in vivo experiment, rabbits that underwent Achilles tendon transection, followed by stump suturing, were randomly assigned to 1 of 3 groups: intratendinous injection of saline, rabbit ADSCs as conventional single-cell suspensions, or preassembled ADSC spheroids. The tendons were harvested for biomechanical testing and histological analysis at 4 weeks postoperatively. RESULTS: Our in vitro results demonstrated that the secretome of ADSCs assembled as spheroids exhibited enhanced modulatory activity in (1) tenocyte proliferation (P = .015) and migration (P = .001) by activating extracellular signal-regulated kinase (ERK) signaling and (2) the suppression of the secretion of interleukin-6 (P = .005) and interleukin-1α (P = .042) by M1 macrophages via the COX-2/PGE2/EP4 signaling axis. Gene expression profiling of cells exposed to an inflammatory milieu revealed significantly enriched terms that were associated with the immune response, cytokines, and tissue remodeling in preassembled ADSC spheroids. Ex vivo fluorescence imaging revealed that the engraftment efficiency of ADSCs in the form of spheroids was higher than that of ADSCs in single-cell suspensions (P = .003). Furthermore, the transplantation of ADSC spheroids showed superior therapeutic effects in promoting the healing of sutured stumps, as evidenced by improvements in the tensile strength (P = .019) and fiber alignment (P < .001) of the repaired tendons. CONCLUSION: The assembly of ADSCs as spheroids significantly advanced their potential to harness tenocytes and macrophages. As a proof of concept, this study clearly demonstrates the effectiveness of using ADSC spheroids to promote tendon regeneration. CLINICAL RELEVANCE: The present study lays a foundation for future clinical applications of stem cell spheroid-based therapy for the management of tendon injuries.

Comparison between a novel salivary marker and several clinical prognosticators in oral cavity cancer.

Objectives: This study aimed to investigate the association between salivary matrix metalloproteinase-1 (MMP-1) and clinicopathological parameters of oral cavity squamous cell carcinoma (OSCC) and compare the prognostic efficacy of salivary MMP-1 and other established circulating markers for OSCC. Methods: Saliva specimens from 479 OSCC subjects were examined using an enzyme-linked immunosorbent assay. The area under the curve (AUC) values of salivary MMP-1 and other markers were calculated, and survival analyses were conducted using Kaplan-Meier and multivariate regression methods. Results: Salivary MMP-1 showed good discrimination in predicting overall survival, with an AUC of 0.638, which was significantly higher than that of albumin (0.530, p = .021) and Charlson comorbidity index (0.568, p = .048) and comparable with neutrophil-to-lymphocyte ratio (0.620, p = .987), platelet-to-lymphocyte ratio (0.575, p = .125), and squamous cell carcinoma antigen (0.609, p = .605). Elevated levels of salivary MMP-1 were significantly associated with higher pT classification, pN classification, overall pathological stage, positive extranodal extension, tumor differentiation, positive lymphovascular invasion, positive perineural invasion, and tumor depth (p all <.05). Multivariate analyses indicated that a higher level of salivary MMP-1 (≥2060.0 pg/mL) was an independent predictive factor of poorer overall survival (adjusted hazard ratio: 1.421 [95% confidential interval: 1.014-1.989], p = .041). Conclusion: The study found that the salivary MMP-1 level was significantly associated with many adverse clinicopathological parameters of OSCC. In OSCC, it was found to have superior efficacy in predicting prognosis and was an independent prognostic factor of post-treatment outcome. Level of evidence: 3.

A 10-year experience in microsurgical reconstruction of the nose with a lower extremity flap.

BACKGROUND: Traditionally, radial forearm free flaps are utilized for nasal lining reconstruction when local flaps cannot provide adequate coverage. However, according to our clinical observation, the skin of the forearm flap is relatively thin and prone to collapse. We present a series of nasal reconstructions using free flaps harvested from the lower extremities to determine if the thick flap could provide more support and decrease the tendency of airway collapse. METHODS: From March 2011 to July 2021, we identified 15 patients who underwent total or subtotal nasal reconstruction with free flap from the lower extremities (10 anterolateral thigh flap, 4 medial sural artery perforator flap, and 1 profunda artery perforator flap). We included 15 patients who underwent free forearm flap reconstruction as controls. The Nasal Obstruction Symptoms Evaluation (NOSE) score was utilized to subjectively evaluate the degree of nasal obstruction symptoms. RESULTS: The lower extremity group had a lower NOSE score than the forearm group (25.4 vs. 40). It took more time (6.5 vs. 4.2 months) and more surgeries (4.6 vs. 2.6) from the first free flap reconstruction till forehead flap reconstruction in the lower extremity group than in the forearm group, although the total number of surgeries was comparable between the 2 groups (7.2 vs. 8.1). CONCLUSIONS: Utilizing free flaps from the lower extremities in total or subtotal reconstruction of the nasal lining may decrease the tendency of flap collapse and alleviate airway obstruction symptoms and may also allow reconstruction of surrounding defects simultaneously compared with using forearm flaps.

Aligned core-shell fibrous nerve wrap containing Bletilla striata polysaccharide improves functional outcomes of peripheral nerve repair.

Peripheral nerve injuries are commonly encountered in extremity traumas. Their motor and sensory recovery following microsurgical repair is limited by slow regeneration speed (<1 mm/d) and subsequent muscle atrophy, which are consequently correlated with the activity of local Schwann cells and efficacy of axon outgrowth. To promote post-surgical nerve regeneration, we synthesized a nerve wrap consisting of an aligned polycaprolactone (PCL) fiber shell with a Bletilla striata polysaccharide (BSP) core (APB). Cell experiments demonstrated that the APB nerve wrap markedly promoted neurite outgrowth and Schwann cell migration and proliferation. Animal experiments applying a rat sciatic nerve repair model indicated that the APB nerve wrap restored conduction efficacy of the repaired nerve and the compound action potential as well as contraction force of the related leg muscles. Histology of the downstream nerves disclosed significantly higher fascicle diameter and myelin thickness with the APB nerve wrap compared to those without BSP. Thus, the BSP-loaded nerve wrap is potentially beneficial for the functional recovery after peripheral nerve repair and offers sustained targeted release of a natural polysaccharide with good bioactivity.

Quantization of extraoral free flap monitoring for venous congestion with deep learning integrated iOS applications on smartphones: a diagnostic study.

BACKGROUND: Free flap monitoring is essential for postmicrosurgical management and outcomes but traditionally relies on human observers; the process is subjective and qualitative and imposes a heavy burden on staffing. To scientifically monitor and quantify the condition of free flaps in a clinical scenario, we developed and validated a successful clinical transitional deep learning (DL) model integrated application. MATERIAL AND METHODS: Patients from a single microsurgical intensive care unit between 1 April 2021 and 31 March 2022, were retrospectively analyzed for DL model development, validation, clinical transition, and quantification of free flap monitoring. An iOS application that predicted the probability of flap congestion based on computer vision was developed. The application calculated probability distribution that indicates the flap congestion risks. Accuracy, discrimination, and calibration tests were assessed for model performance evaluations. RESULTS: From a total of 1761 photographs of 642 patients, 122 patients were included during the clinical application period. Development (photographs =328), external validation (photographs =512), and clinical application (photographs =921) cohorts were assigned to corresponding time periods. The performance measurements of the DL model indicate a 92.2% training and a 92.3% validation accuracy. The discrimination (area under the receiver operating characteristic curve) was 0.99 (95% CI: 0.98-1.0) during internal validation and 0.98 (95% CI: 0.97-0.99) under external validation. Among clinical application periods, the application demonstrates 95.3% accuracy, 95.2% sensitivity, and 95.3% specificity. The probabilities of flap congestion were significantly higher in the congested group than in the normal group (78.3 (17.1)% versus 13.2 (18.1)%; 0.8%; 95% CI, P <0.001). CONCLUSION: The DL integrated smartphone application can accurately reflect and quantify flap condition; it is a convenient, accurate, and economical device that can improve patient safety and management and assist in monitoring flap physiology.

Reliability of Postoperative Free Flap Monitoring with a Novel Prediction Model Based on Supervised Machine Learning.

BACKGROUND: Postoperative free flap monitoring is a critical part of reconstructive microsurgery. Postoperative clinical assessments rely heavily on specialty-trained staff. Therefore, in regions with limited specialist availability, the feasibility of performing microsurgery is restricted. This study aimed to apply artificial intelligence in postoperative free flap monitoring and validate the ability of machine learning in predicting and differentiating types of postoperative free flap circulation. METHODS: Postoperative data from 176 patients who received free flap surgery were prospectively collected, including free flap photographs and clinical evaluation measures. Flap circulation outcome variables included normal, arterial insufficiency, and venous insufficiency. The Synthetic Minority Oversampling Technique plus Tomek Links (SMOTE-Tomek) was applied for data balance. Data were divided into 80%:20% for model training and validation. Shapley Additive Explanations were used for prediction interpretations of the model. RESULTS: Of 805 total included flaps, 555 (69%) were normal, 97 (12%) had arterial insufficiency, and 153 (19%) had venous insufficiency. The most effective prediction model was developed based on random forest, with an accuracy of 98.4%. Temperature and color differences between the flap and the surrounding skin were the most significant contributing factors to predict a vascular compromised flap. CONCLUSIONS: This study demonstrated the reliability of a machine-learning model in differentiating various types of postoperative flap circulation. This novel technique may reduce the burden of free flap monitoring and encourage the broader use of reconstructive microsurgery in regions with a limited number of staff specialists.

Simultaneous free flap and forehead flap for nasal reconstruction.

BACKGROUND: Reconstruction of total or near-total nasal defects is challenging and requires the re-creation of three nasal layers. Fasciocutaneous free flaps have been used effectively for restoring the vascularized nasal lining and staged forehead flap for nasal skin replacement, which is a long process. The aim of this study is to share our experience of combination of preliminary free tissue transfer with paramedian forehead flap reconstruction in the same stage of complex nasal reconstruction. METHODS: From December 2015 to July 2021, 10 patients underwent nasal reconstruction with free flaps including 4 medial sural artery perforator (MSAP) flaps, 5 anterolateral thigh (ALT) flaps and 1 radial forearm flap for lining and forehead flaps for skin coverage simultaneously for total or subtotal nasal defects. Nasal obstruction symptoms evaluation (NOSE) score was utilized to evaluate the functional outcome and the aesthetic results were evaluated with the last follow-up photos with score 1-5 by 5 plastic surgeon and 5 laypersons. RESULTS: The size of the free flaps ranged from 3 cm x 6 cm to 6 cm x 13 cm. After excluding one patient who expired before forehead flap division due to comorbidities, the average duration between combination surgery and the division of the forehead flap pedicle of the remaining patients was 5.7 months (range, 2-12). For patients without any postoperative events, the duration was 2.2 months (range, 2-3). One free flap had partial necrosis due to infection. The average follow-up duration was 29.6 months (range, 12-64). The NOSE score was 5.9 (range, 0-10) and the aesthetic score is 4.1 (range, 3-5) in average. CONCLUSIONS: The combination of preliminary free tissue transfer for nasal lining restoration with a paramedian forehead flap for nasal skin replacement in the same stage may shorten the long process and achieve satisfactory reconstruction in complex nasal reconstruction.

Discovering the Clinical and Prognostic Role of Pan-Immune-Inflammation Values on Oral Cavity Squamous Cell Carcinoma.

A newly introduced pan-immune-inflammation value (PIV) was not evaluated for its role in oral cavity squamous cell carcinoma (OSCC). In this study, the PIV was calculated with the following equation (neutrophil count × platelet count × monocyte count)/lymphocyte count from the results of the automated hematology analyzers in 853 OSCC patients from 2005 to 2017. The optimal cutoff for the preoperative PIV was 268, as determined by a receiver operating characteristic curve. Significant differences were observed for alcohol consumption, smoking, pT status, pN status, overall pathological status, extranodal extension, cell differentiation, depth of invasion, and perineural invasion between higher and lower PIV patients (all p values < 0.05). Kaplan-Meier and univariate regression analyses indicated that higher PIV was associated with worse overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival (all p values < 0.001). Multivariate analyses adjusted by various factors further demonstrated that PIV was an independent prognostic factor for overall and distant metastasis-free survival (p = 0.027, HR: 1.281 and p = 0.031, HR: 1.274, respectively). In conclusion, a higher PIV level was associated with poor clinicopathological factors in OSCC patients and could be used to predict poor posttreatment outcomes, especially for overall and distant metastasis-free survival.

Plasma Matrix Metalloproteinase-1 as a Prognostic Biomarker in Oral Cavity Squamous Cell Carcinoma.

Purpose: Plasma matrix metalloproteinase-1 (MMP-1) is a collagenase encoded by the MMP-1 gene. However, the prognostic value of plasma MMP-1 levels in oral cavity squamous cell carcinoma (OSCC) has yet to be elucidated. The study is the first to use a cohort of OSCC patients to assess the association of plasma MMP-1 levels with clinicopathological factors/survival outcomes in OSCC patients. Patients and Methods: A total of 677 patients were retrospectively enrolled, including 276 oral potentially malignant disease (OPMD) and 401 OSCC patients from 2013 to 2021. Pretreatment plasma MMP-1 levels were measured with an enzyme-linked immunosorbent assay, and the values were compared between OPMD and OSCC patients. Furthermore, the association of plasma MMP-1 levels and clinicopathological characteristics/survival outcomes in OSCC patients was investigated. Results: Plasma MMP-1 levels were significantly higher in OSCC patients than in OPMD patients (p = 0.04). In the OSCC group, plasma MMP-1 levels were significantly higher in females, tumor depth ≥10 mm, advanced pT classification and advanced overall stage (p = 0.04, <0.001, <0.001, 0.002, respectively). Higher plasma MMP-1 levels were significantly associated with poorer overall, disease-specific, disease-free, locoregional recurrence-free and distant metastasis-free survival (p = 0.003, 0.02, 0.005, 0.01, 0.001, respectively). Multivariate analysis revealed that plasma MMP-1 levels were a significant predictor for overall, disease-free, and distant metastasis-free survival (p = 0.03, 0.02, and 0.010, respectively). Conclusion: Plasma MMP-1 levels are associated with more severe clinicopathological manifestations and can also be regarded as a significant prognostic factor for OSCC posttreatment outcomes.

Thermosensitive hydrogel carrying extracellular vesicles from adipose-derived stem cells promotes peripheral nerve regeneration after microsurgical repair.

Peripheral nerve injuries are commonly occurring traumas of the extremities; functional recovery is hindered by slow nerve regeneration (<1 mm/day) following microsurgical repair and subsequent muscle atrophy. Functional recovery after peripheral nerve repair is highly dependent on local Schwann cell activity and axon regeneration speed. Herein, to promote nerve regeneration, paracrine signals of adipose-derived stem cells were applied in the form of extracellular vesicles (EVs) loaded in a thermosensitive hydrogel (PALDE) that could solidify rapidly and sustain high EV concentration around a repaired nerve during surgery. Cell experiments revealed that PALDE hydrogel markedly promotes Schwann-cell migration and proliferation and axon outgrowth. In a rat sciatic nerve repair model, the PALDE hydrogel increased repaired-nerve conduction efficacy; contraction force of leg muscles innervated by the repaired nerve also recovered. Electromicroscopic examination of downstream nerves indicated that fascicle diameter and myeline thickness in the PALDE group (1.91 ± 0.61 and 1.06 ± 0.40 µm, respectively) were significantly higher than those in PALD and control groups. Thus, this EV-loaded thermosensitive hydrogel is a potential cell-free therapeutic modality to improve peripheral-nerve regeneration, offering sustained and focused EV release around the nerve-injury site to overcome rapid clearance and maintain EV bioactivity in vivo.

The impact of depression on survival of head and neck cancer patients: A population-based cohort study.

Background: Depression is common among patients with head and neck cancer, thereby affecting their survival rate. However, whether close monitoring of depression affects the survival outcomes of these patients is unknown. Therefore, this study aimed to determine whether depression treatment continuity after the diagnosis of cancer affects the survival of these patients. Methods: A total of 55,069 patients diagnosed with head and neck cancer in the Cancer Registration System database in Taiwan were enrolled. This cohort was followed from January 1, 2007 to December 31, 2017. Furthermore, the patients were divided into four groups, namely, "no depression," "pre-cancer only," "post-cancer only," and "both before and after cancer," on the basis of the diagnosis of depression and the duration of the follow-up period in the psychiatric clinic. Further, the Cox proportional hazard model was applied to estimate the hazard of death for the four groups. Results: A total of 6,345 (11.52%) patients were diagnosed with depression in this cohort. The "pre-cancer only" group had a lower overall survival (HR = 1.18; 95% CI = 1.11-1.25) compared with the "no depression" group. Moreover, the "post-cancer only" group had better overall survival (HR = 0.88; 95% CI = 0.83-0.94) compared with the "no depression" group, especially in advanced-stage patients. Patients who were diagnosed with depression before cancer and had continuous depression treatments after the cancer diagnosis had better overall survival (HR = 0.78; 95% CI = 0.71-0.86) compared with patients who had treatment interruptions. Conclusion: Patients with pre-cancer depression had poorer survival outcomes, especially those who did not receive psychiatric clinic visits after their cancer diagnosis. Nonetheless, in patients with advanced-stage cancer, depression treatment may improve overall survival.

Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice.

(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-ß1 and activate the TGF-ß/Smad3 signaling pathway. Fibroblasts activated by TGF-ß1containing exosomes from ASCs initiate the production of TGF-ß1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-ß1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.

In Vivo Evaluation of Mechanically Processed Stromal Vascular Fraction in a Chamber Vascularized by an Arteriovenous Shunt.

Mechanically processed stromal vascular fraction (mSVF) is a promising source for regenerative purposes. To study the in vivo fate of the mSVF, we herein used a vascularized tissue engineering chamber that insulates the target mSVF from the surrounding environment. In contrast to previous models, we propose an arteriovenous (AV) shunt between saphenous vessels in rats without a venous graft. Mechanical SVF was processed from the fat pads of male Sprague Dawley rats, mixed with a fibrin hydrogel and implanted into an inguinal tissue engineering chamber. An arteriovenous shunt was established between saphenous artery and vein. On the contralateral side, an mSVF-fibrin hydrogel mix without vascular axis served as a non-vascularized control. After two and six weeks, rats were sacrificed for further analysis. Mechanical SVF showed significant numbers of mesenchymal stromal cells. Vascularized mSVF explants gained weight over time. Perilipin and CD31 expression were significantly higher in the mSVF explants after six weeks while no difference in DAPI positive cells, collagen deposition and FABP4 expression was observed. Morphologically, no differentiated adipocytes but a dense cell-rich tissue with perilipin-positive cells was found after six weeks. The phosphorylation of ERK1/2 was significantly enhanced after six weeks while Akt activation remained unaltered. Finally, mSVF explants stably expressed and released VEGF, bFGF and TGFb. Vascularized mSVF is able to proliferate and express adipocyte-specific markers. The AV shunt model is a valuable refinement of currently existing AV loop models in the rat which contributes to the fundamental 3R principles of animal research.

Risk Factors of Carpal Tunnel Syndrome in Taiwan: A Population-Based Cohort Study.

BACKGROUND: Carpal tunnel syndrome (CTS), 1 of the most common peripheral neuropathies of the upper extremity, has been studied for decades regarding its epidemiology and associated medical conditions. We conducted a large-scale, age- and gender-matched study from an Asian population database to investigate the relationship between the incidence and the demographic characteristics. METHODS: A retrospective cohort study using data of National Health Insurance Research Database was conducted. One million enrollees in Taiwan was used to identify 9442 patients with CTS and 37,768 randomly selected controls, in a control-case ratio of 4:1. Diagnoses of CTS were ascertained from January 1, 2003, to December 31, 2012. Sociodemographic and medical characteristics were evaluated to assess the correlation with CTS. RESULTS: Annual incidence of CTS was approximately 0.4% during the 10-year-period in Taiwan, with higher incidence rate in female sex and middle age of group (50-59 years). Among the medical conditions, previous wrist injuries, obesity, gout, and rheumatoid arthritis were associated with CTS most significantly. CONCLUSIONS: Carpal tunnel syndrome has presented a relatively constant incidence in Taiwan. Female gender with middle age seemed to have the highest incident rate during a 10-year period from 2003 to 2012. Among the risk factors of CTS, previous wrist injuries, obesity, gout, and rheumatoid arthritis were demonstrated to be the most significantly correlated comorbidities.

The Prognostic Value of Lymph Node Burden in Oral Cavity Cancer: Systematic Review and Meta-Analysis.

OBJECTIVES: Lymph node burden has been proposed to estimate the cumulative adverse effect of nodal metastasis. In this study, a meta-analysis was conducted to evaluate the prognostic value of lymph node burden in oral cavity squamous cell carcinoma. STUDY DESIGNS: Systemic review and meta-analysis. METHODS: PubMed, EMBASE and the Cochrane Library as well as manual searches were performed until April 2020. The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival, disease-specific survival, and disease-free survival were extracted and pooled. RESULTS: Eleven included studies were published between 2009 and 2019. The cumulative number of patients was 20,607 (range 35-14,554). Extranodal extension was adjusted or evaluated in all of the studies. The meta-analysis indicated that a higher lymph node burden was significantly related to worse overall survival (HR 2.62, 95% CI 2.12-3.25), worse disease-specific survival (HR 3.14, 95% CI 1.85-5.33) and worse disease-free survival (HR 2.30, 95% CI 1.62-3.26). The highest hazard ratio was observed when the cutoff value was 3 for overall survival, 3 for disease-specific survival, and 4 for disease-free survival. The hazard ratio showed an upward trend before the cutoff value of 3 but no significant incremental change when the cutoff exceeded 3. CONCLUSIONS: In oral squamous cell carcinoma, lymph node burden is an independent prognosticator for survival outcomes. However, more prospective or high-quality studies are required to determine the optimal cutoff. LEVEL OF EVIDENCE: NA Laryngoscope, 132:88-95, 2022.