BACKGROUND:The anterolateral thigh (ALT) flap is the primary choice for healthy and vascularized soft-tissue coverage for appendicular and axial soft tissue reconstruction, especially in the head and neck regions. Nonetheless, there is substantial anatomic variation in ALT perforators that affect flap integrity, survival rates, and donor-site morbidity. Regardless of the ALT flap type, accurate location of perforators can greatly improve surgical success rates and reduce the risk of secondary surgeries. Therefore, we investigated a novel approach for locating perforators. METHOD:We utilized augmented reality (AR) technology in combination with a self-designed device, Finder, to locate the perforators of the anterolateral thigh (ALT) flap, and compared its accuracy to that of traditional ultrasound localization. RESULT:In this study, 24 patients underwent ALT flap reconstruction, with all flaps surviving except one case of partial necrosis. Comparing the two positioning methods, Ultrasonic color Doppler (UCD) showed a sensitivity of 81.1 % [95 % confidence interval (CI) 64.3 %-91.4 %] and an AUC of 0.70 (95 % CI 0.55-0.86). AR-Finder demonstrated a higher sensitivity of 97.5 % (95 % CI 85.3 %-99.9 %, p = 0.031) and an AUC of 0.90 (95 % CI 0.80-1.01, p = 0.035). The average distance difference from the actual perforator to virtually determined location was 3.54 ± 2.80 mm (95 % CI 2.58-4.50) for AR-Finder and 9.57 ± 5.84 mm (95 % CI 7.75-11.58) for UCD (p < 0.001). CONCLUSION:In this pilot study, AR-Finder demonstrated superior accuracy compared to the UCD method for locating perforators in ALT flaps, providing a new and reliable tool for the design and elevation of ALT flaps.

Recent advancements in cancer immunotherapy have improved patient outcomes, yet responses to immunotherapy remain moderate. Immunosenescence has been shown to contribute to the development and progression of various diseases; however, its specific role in solid tumors has not been fully delineated. Here we conducted a phase 2 clinical trial involving 51 patients with cancer undergoing neoadjuvant chemoimmunotherapy and applied single-cell RNA as well as TCR and BCR sequencing on tumor and blood samples to elucidate the immune cell perturbations. Our findings associate poor response with reduced levels of CCR7+ CD4+ naive T cells and CD27+ memory B cells, as well as higher expression of immunosenescence-related genes in T and B cell subsets. Using naturally aged mice and Ercc1-deficient mice (premature aging), we found that senolytics enhance the therapeutic efficacy of immunotherapy in multiple solid tumors by mitigating immunosenescence. Notably, we launched a phase 2 clinical trial (COIS-01) investigating the combination of senolytics with anti-PD-1 therapy. The results showed that the combination therapy achieved a 33.3% (95% confidence interval 16.6-54.7%) major pathological response rate with a low incidence of grade 3-4 adverse events (4.2%). These findings underscore the pivotal role of immunosenescence characteristics in influencing the effectiveness of immunotherapy and suggest a promising therapeutic efficacy along with a favorable safety for the combination of senolytics with anti-PD-1 therapy. ClinicalTrials.gov Identifier: OOC-001( NCT04718415 ) and COIS-01( NCT05724329 ).

BACKGROUND:The localization of perforators in the anterolateral thigh (ALT) flap is important for flap survival. This study aimed to provide surgeons with a more effective instrument, Finder-I, for the perforator locations of ALT flaps. METHODS:Eighty-two patients who underwent head and neck reconstruction were recruited from June 2023 to February 2024. All patients underwent preoperative computed tomography angiography (CTA) and Ultrasonic color Doppler (UCD) to detect and mark perforator locations. The CTA data were transformed into spatial coordinates using the Finder-I device, and the accuracy of perforator localization was compared between Finder-I and UCD. RESULTS:Finder-I demonstrated higher sensitivity (95.7% vs. 82.8%, p = 0.012) and accuracy [the area under the curve (AUC) 0.86 vs. 0.70, p = 0.001] in perforator localization compared to UCD. CONCLUSIONS:Using Finder-I to convert CTA data into spatial coordinates, accurately localizes the ALT flap perforators and demonstrating superiority over UCD in perforator localization.

Mature tertiary lymphoid structures (TLSs) are immune aggregates associated with immune checkpoint blockade (ICB) responses in various cancers, yet their role in chemoimmunotherapy response in head and neck squamous cell carcinoma (HNSCC) remains unclear. By analyzing TCGA-HNSC transcriptomic data and pathology slides, we identified an immune subtype enriched in TLSs, predominantly in HPV-positive tumors, which correlated with favorable immunotherapy response. Single-cell and spatial transcriptomics further revealed distinct TLS compositions, with mature TLSs enriched in germinal center B cells, follicular helper T cells, and resident memory CD8 T cells, while immature TLSs contained FCRL4+ B cells and peripheral helper T cells. Multispectral immunohistochemistry, flow cytometry, and ELISA validated these findings. Notably, neoadjuvant chemoimmunotherapy promoted mature TLS formation. These results suggest that TLS maturity correlates with HPV status and response to anti-PD-1-based chemoimmunotherapy, providing insights for potential therapeutic strategies in HNSCC.

OBJECTIVE:This research provides a comprehensive analysis of immunotherapy clinical trials for head and neck squamous cell carcinoma, aiming to enhance future trial designs. METHODS:We analyzed all clinical trials focused on head and neck squamous cell carcinoma immunotherapy registered on ClinicalTrials.gov from January 1st, 2013, to December 31st, 2023, examining general characteristics, methodological features, and types of immunotherapeutic drugs. RESULTS:The analysis included 727 trials, with 687 interventional (94.50%) and 40 observational (5.50%). Most trials were small-sized (64.37%), single-centered (56.67%), non-blinded (94.76%), and non-randomized (72.93%). Over half of the trials were conducted in North America (55.71%), but trials in Asia increased significantly in the past 5 years (9.88% vs. 32.38%, p < 0.001). Only 20.63% of completed trials updated outcomes, with most results published 6-12 months after primary completion (55.13%). Immune checkpoint inhibitors were the predominant focus, and neoadjuvant immunotherapy was the main regimen in trials with resectable head and neck squamous cell carcinoma (74.83%). CONCLUSIONS:There has been a gradual increase in clinical trials over the past decade, with most being interventional. Delays or absences in outcome submission were prevalent. Novel immunotherapeutic drugs and treatment regimens are a significant focus.

Recent advancements in cancer immunotherapy have improved patient outcomes, yet responses to immunotherapy remain moderate. We conducted a Phase II clinical trial ([NCT04718415][1]) involving 51 cancer patients undergoing neoadjuvant chemoimmunotherapy and applied single-cell RNA and T/BCR sequencing on tumor and blood samples to elucidate the immune cell perturbations. Our findings associate poor response with reduced levels of CCR7+CD4 Naive T cells and CD27+ Memory B cells, as well as higher expression of immunosenescence-related genes in T and B cell subsets. Using naturally aged and Ercc1+/- transgenic aging mouse models, we found that senolytics enhance the therapeutic efficacy of immunotherapy in multiple solid tumors by mitigating tumor immunosenescence. Notably, we launched a Phase II clinical trial, COIS-01 ([NCT05724329][2]), which pioneers the combination of senolytics with anti-PD-1 therapy. The clinical results demonstrate that this therapeutic strategy is associated with a favorable safety profile and therapeutic efficacy, significantly mitigating adverse effects and alleviating immunosenescence. These findings underscore the pivotal role of immunosenescence characteristics in influencing the effectiveness of immunotherapy and suggest a promising therapeutic efficacy along with a beneficial safety assessment for the combination of senolytics with anti-PD-1 therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05724329 ### Funding Statement This study was funded by the Joint Funds of the National Natural Science Foundation of China (U21A20381), the General Funds of the National Natural Science Foundation of China (82373452), the Guangdong Natural Science Funds for Distinguished Young Scholar (2022B1515020061), the Guangdong Basic and Applied Basic Research Foundation (2021A1515220138), the Guangzhou Basic Research Program Jointly Funded by Municipal Schools (Institutes) (202201020367), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (16ykpy10), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (19ykzd20), the General Funds of the National Natural Science Foundation of China (32071451), the Guangdong Provincial Pearl River Talents Program (2021QN02Y747), the Shenzhen Science and Technology Program (RCYX20210706092100003), and by the Shenzhen Medical Research Funds grant (A2303005). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04718415&atom=%2Fmedrxiv%2Fearly%2F2024%2F10%2F15%2F2024.10.14.24315428.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05724329&atom=%2Fmedrxiv%2Fearly%2F2024%2F10%2F15%2F2024.10.14.24315428.atom

Supplementary methods, tables and figures

目的 评估发际线切口内镜辅助下良性腮腺肿瘤切除术的临床结果、术后免疫反应和手术应激反应.方法 47名腮腺良性肿瘤患者随机分为内镜组(n=25)和接受开放式手术的常规组(n=22).比较两组术后并发症、引流量、疼痛评分及外观满意度,并检测术后12 h(T1),24 h(T2),72 h(T3)的IL-6、IL-8、IL-10、IL-1β、TNF-α、C反应蛋白、皮质醇、促肾上腺皮质激素和生长激素水平,评估手术方式对免疫反应和手术应激的影响.结果 内镜组切口长度显著短于常规组(P<0.001),内镜组术中出血量显著低于常规组(P=0.004),内镜组患者对术后美容效果的满意度高于常规组(P=0.027).内镜组术后引流量显著高于常规组(P=0.024),且内镜组术后疼痛评分明显高于常规组(P=0.039).内镜组IL-6和CRP在T1,T2,T3均平明显高于常规组(P<0.05),IL-10和皮质醇在T1,T2高于常规组(P<0.05).结论 发际线切口内镜辅助下切除腮腺良性肿瘤可改善术后美容效果.内镜手术导致更剧烈的术后疼痛和更大的引流量,免疫反应及手术应激反应也更强烈.

目的 本研究观察iRootSP单尖充填法用于治疗糖尿病合并慢性根尖炎的临床疗效.方法 选取糖尿病合并慢性根尖炎患者80例,根据根管充填方法分2组,观察组(n=40)采用iRootSP单尖充填法,对照组(n=40)采用AH Plus+热牙胶垂直加压技术.随访并比较两组根管充填后1周内急症反应以及术后3个月,1年的临床疗效.结果 术后1周内急症反应程度的差异有统计学意义(Z=2.806,P=0.037),观察组均低于对照组.两组术后3个月和1年的治疗有效率差异无统计学意义(χ2=0.000;P=1.000);两组术后3个月的临床疗效差异有统计学意义(Z=2.269,P=0.023),观察组的治愈率高于对照组.但术后1年两组的临床疗效差异无统计学意义(Z=0.612,P=0.54).结论 iRootSP单尖充填法和热牙胶垂直加压技术治疗糖尿病合并根尖周炎的疗效有效率相当,但iRoot SP单尖充填法有利于减少根充后急诊反应的发生,且治疗后根尖周组织愈合可能较热牙胶垂直加压充填更快.

Objective. Carotid body tumors (CBTs) are benign but challenging. This study compared outcomes of 3 techniques of the surgical treatment of CBTs. Study Design. This retrospective observational study was conducted from April 2013 to March 2019. The 38 patients enrolled in the study had primary tumors, including 1 with bilateral tumors and another with adrenal gland pheochromocytoma. We collected data on age, sex, size of tumor, Shamblin classification, treatment, blood loss, operative time, hospital stay, complications, and recurrence. Statistical analyses were performed using IBM SPSS Statistics version 20 software. Results. Twenty-four patients were male, and 12 were female, and they ranged in age from 11 to 71 years. Cases were assigned to Shamblin groups I (n = 6), II (n = 19), and III (n = 14). Tumor size ranged from 2.0 pound 2.0 cm to 5.0 pound 6.0 cm. Eleven CBTs underwent blunt dissection (BD), 20 underwent BD plus resection of external carotid artery division plus vessels of encapsulation with allograft dermal matrix (BD + RECA + VE), and 8 tumors underwent surgical resection of tumors plus common carotid artery-internalcarotid artery artificial vascular reconstruction (SR +C-IAVR). No perioperative death or stroke occurred. There was a significant difference between Shamblin groups I, II, and III in terms of the size of the tumor, type of treatment used, blood loss, operative time, hospital stay, and complications. Six patients had mandibular branch facial nerve transient paresis; 7 patients had hypoglossal nerve dysfunction; 3 patients had Horner syndrome; and dysphasia occurred in 2 patients. The patients were seen in follow-up for 16 to 45 months, and 1 recurrence was observed. Conclusions. Three surgical techniques-BD, BD + RECA + VE, and SR + C-IAVR-are safe and feasible for the treatment of CBTs according to Shamblin classifications. (Oral Surg Oral Med Oral Pathol Oral Radiol 2021;131:643-649)

Abstract Purpose: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types. Experimental Design: We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. Results: B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T-cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenograft and metastatic models treated with autologous CAR T-cell infusions. Conclusions: Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.

OBJECTIVE:Although a positive result of labial salivary gland biopsy (LSGB) is critical for the diagnosis of Sjögren's syndrome, rheumatologists prefer assessing the non-invasive objective items and hope to learn the predicted probability of positive LSGB before referring patients with suspected Sjögren's syndrome to receive biopsy. This study aimed to explore the predictive value of combined B-mode ultrasonography (US) and shear-wave elastography (SWE) examination on LSGB results.METHODS:A derivation cohort and later a validation cohort of patients with suspected Sjögren's syndrome were recruited. All participants received clinical assessments, B-mode US and SWE examination on bilateral parotid and submandibular glands before LSGB. Positive LSGB was defined by a focus score ⩾1 per 4 mm2 of glandular tissue.RESULTS:In the derivation cohort of 91 participants, either the total US scores or the total SWE values of four glands significantly distinguished patients with positive LSGB from those with negative results (area under the curve (AUC) = 0.956, 0.825, both p < 0.001). The positive predictive value (PPV) was 100% in patients with total US scores ⩾9 or with total SWE values ⩾33 kPa. The negative predictive value (NPV) was 100% in patients with total US scores <5, but 68% in patients with total SWE values <27 kPa. A matrix risk model was derived based on the combination of total US scores and total SWE values. Patients can be stratified into high, moderate, and low risk of positive LSGB. In the validation cohort of 52 participants, the PPV was 94% in the high-risk subpopulation and the NPV was 93% in the low-risk subpopulation.CONCLUSION:A novel matrix risk model based on the combined B-mode US and SWE examination can help rheumatologists to make a shared decision with suspected Sjögren's syndrome patients on whether the invasive procedure of LSGB should be performed.

目的:评估面-颏下动脉岛状肌皮瓣(facial-submental artery island flap,FSAIF)修复年轻与老年舌癌患者的效果.方法:选取2008年1月-2017年6月中山大学孙逸仙纪念医院口腔颌面外科收治的舌鳞状细胞癌(tongue squamous cell carcinoma,TSCC)患者96例,所有患者均采用FSAIF进行肿瘤切除后半舌缺损的同期整复;按年龄分为＜60岁(62例)及≥60岁(34例)2组;皮瓣大小分别为3 cm×6 cm～5 cm×12 cm(《60岁)和3 cm×9 cm～5 cm×15 cm(≥60岁).所有患者均未行术后放疗,术后对每例患者随访并观察吞咽、言语功能及美观效果.采用SPSS 20.0软件包对数据进行统计学分析.结果:3例患者皮瓣失败,皮瓣存活率为96.9％ (93/96),2组皮瓣存活率无显著差异;2组患者吞咽、言语、美学及后期生存状态无显著差异.结论:FSAIF适用于修复肿瘤切除后的半舌缺损,无论年轻还是年老患者.

Background Reconstruction of lower vermilion defects is surgically challenging. Aims This study evaluated whether lower vermilion defects can be repaired using tongue flaps, and the reconstructive outcomes. Materials and Methods We evaluated 11 patients with early-stage lower vermilion cancers who underwent lower vermilion reconstruction using anteriorly based ventral tongue flaps following cancer ablation. We treated eight males and three females aged 54-67 years (median, 59.8 years). The defect/tongue flap dimensions ranged from 1.8 x 3.5 to 2.0 x 4.5 cm (median, 1.87 x 3.81 cm). Results No major complication developed in any patient. The postoperative esthetic results, orbicularis oris functions, and speech functions were excellent in six, eight, and nine patients, and satisfactory in five, three, and two, respectively. The patients were followed up for 13-36 months (median, 21.7 months); two local recurrences developed, and these patients underwent salvage surgeries. Conclusions An anteriorly based ventral tongue flap is a safe and feasible option for reconstruction of lower vermilion defects.

Objective Endoscopically assisted extracapsular dissection through a single incision along the cephaloauricular furrow has been adapted as a method of access for operating on benign parotid gland tumors. However, no study has compared the immune and stress responses after surgery between the endoscopic procedure and conventional open surgery. Methods Through a randomized method, 50 patients with benign parotid gland tumors were assigned to undergo either endoscopically assisted extracapsular dissection or open parotidectomy. The postoperative inflammatory changes and hormonal response in the patients were analyzed at serum level during the preoperative period and at 12, 24, and 72 hr after either surgery. Results Twenty-three patients received an endoscopic procedure, while 27 underwent open surgery. The size of the incision, amount of intraoperative bleeding, volume of drainage, postoperative pain score, and satisfaction with appearance were all improved in the endoscopic procedure group. Additionally, the serum levels of C-reactive protein, interleukin (IL)-6, IL-10, and cortisol were significantly lower in the endoscopy group in comparison with those in the open surgery group. Conclusion Endoscopically assisted extracapsular dissection on patients with benign parotid gland tumors is associated with lower inflammatory changes and hormone responses than open surgery, thereby reducing perioperative pathophysiological disturbance and enhancing recovery after surgery.

Additive manufacture (AM) has been widely and rapidly applied in fabrication of 3D porous scaffolds for tissue engineering applications. For synthetic polymers of high melting temperature, the melting-extruding technique is the most applied AM method for such fabrication of polymer porous scaffolds. This results in a big challenge to directly process the scaffolds using the polymers and thermosensitive substances simultaneously because of deactivation under high temperature. In this article, the selective laser sintering (SLS) method was proposed to make a poly(l-lactic acid) (PLLA) porous scaffold containing dexamethasone (Dex) simultaneously. Dex was encapsulated in two groups of PLLA-bioactive glass (BG) composite microspheres with an average diameter of 115-120 μm and loading amounts of 0.68 ± 0.09 and 0.84 ± 0.10 μg/mg, respectively. The drug-loading composite microspheres were then fabricated into scaffolds under a laser fluence of 0.83-2.08 J/mm2. The average pore size and compressive modulus for the porous scaffold were 450-500 μm and 18-25 MPa, respectively. Drug release experiments showed that Dex was released from the scaffold in a controlled manner until about a month. The eluting time of HPLC tests before or after SLS processing both presented at 4 min indicated no chemical structure changes for the drug. Ex vivo cell experiments also testified the comparable effect of released Dex with commercial products, showing that the bioactivities were not affected after SLS. Implantation of the composite scaffolds in rat cranium defects demonstrated that new bone and blood vessel formation was faster in the Dex-releasing scaffolds than in the groups without drug loading.

BACKGROUND:When treating actinic cheilitis (AC), it is essential to minimize the risk of malignant transformation (MT) and maintain lip functionality and cosmesis. AIMS:We evaluated the outcomes of vermilionectomy followed by reconstruction of the vermilion mucosa using allograft dermal matrix (ADM) in patients with AC of the lower lip. MATERIALS AND METHODS:We evaluated eight patients with lower lip AC who underwent vermilion mucosa reconstruction using ADM after vermilionectomy. We enrolled five males and three females ranging in age from 55 to 70 years (mean, 62.1 years). The ADM ranged in area from 1.3 × 5.0 to 1.7 × 5.8 cm (median, 1.6 × 5.5 cm). All patients were followed up for at least 3 months postoperatively by a panel of three surgeons who assessed the esthetic results, and orbicularis oris and speech functions. RESULTS:All patients underwent successful reconstruction of the vermilion mucosa using ADM after vermilionectomy, without complications. The postoperative esthetic results, and the orbicularis oris and speech functions, were satisfactory to excellent in all patients. Patients were followed up for 18-38 months (median, 26.1 months). No MT or recurrence was noted. CONCLUSIONS:Vermilionectomy followed by reconstruction of the vermilion mucosa with ADM is safe and feasible for AC patients.

目的:使用“五点八线”技术(five-point eight-line segment,FIPELS)设计半舌缺损修复皮瓣,并比较“五点八线”技术与传统皮瓣移植方法的临床疗效.方法:80例半舌缺损修复重建患者随机分为2组,分别为FIPELS组(42例)和传统皮瓣移植组(38例),使用Likert量表比较2组患者的术后功能恢复及美观效果.采用SPSS 18.0软件包进行统计学分析.结果:FIPELS组的皮瓣与半舌缺损匹配度更高,术中无需修整皮瓣,手术时间较传统皮瓣移植组更短(P=0.02).FIPELS组的术后吞咽功能、语言清晰度和美观度优于传统皮瓣移植组(P＜0.05).结论:相比传统皮瓣移植方法,FIPELS设计的皮瓣用于半舌缺损修复具有更好的功能和美观效果.

目的:探讨应用折叠延长下斜方肌岛状皮瓣修复全喉切除术后巨大咽皮瘘的临床效果.方法:8例(男7例,女1例;年龄46～65岁,平均年龄57.6岁)全喉切除术后巨大咽皮瘘患者,咽皮瘘直径2.0 cm×1.8 cm～4.5 cm×3.0 cm,采用折叠延长下斜方肌岛状皮瓣修复.皮岛宽5～9 cm,长10～23 cm,折叠修复咽皮瘘,恢复咽腔内衬里及外侧皮肤.结果:8例皮瓣全部成活,患者无继发咽皮瘘与咽狭窄,吞咽功能满意.结论:折叠延长下斜方肌岛状肌皮瓣可作为修复全喉切除术后巨大咽皮瘘的首选皮瓣,其操作简便,安全可靠.