HEAP: a task adaptive-based explainable deep learning framework for enhancer activity prediction.

Enhancers are crucial cis-regulatory elements that control gene expression in a cell-type-specific manner. Despite extensive genetic and computational studies, accurately predicting enhancer activity in different cell types remains a challenge, and the grammar of enhancers is still poorly understood. Here, we present HEAP (high-resolution enhancer activity prediction), an explainable deep learning framework for predicting enhancers and exploring enhancer grammar. The framework includes three modules that use grammar-based reasoning for enhancer prediction. The algorithm can incorporate DNA sequences and epigenetic modifications to obtain better accuracy. We use a novel two-step multi-task learning method, task adaptive parameter sharing (TAPS), to efficiently predict enhancers in different cell types. We first train a shared model with all cell-type datasets. Then we adapt to specific tasks by adding several task-specific subset layers. Experiments demonstrate that HEAP outperforms published methods and showcases the effectiveness of the TAPS, especially for those with limited training samples. Notably, the explainable framework HEAP utilizes post-hoc interpretation to provide insights into the prediction mechanisms from three perspectives: data, model architecture and algorithm, leading to a better understanding of model decisions and enhancer grammar. To the best of our knowledge, HEAP will be a valuable tool for insight into the complex mechanisms of enhancer activity.

Diagnosis and Treatment of an Unusual Maxillary Gingiva Malignant Melanoma Arising Around Dental Implant.

BACKGROUND: Oral mucosal malignant melanoma (OMMM) arises from malignant melanocytes, and the most affected age, sex, and site are 20 to 83 years, male, and the mucosa of hard palate and maxillary gingiva, respectively. Despite several cases of OMMM have been published in the literature, cases of malignant melanoma arising around the dental implant are rarely reported. CASE SUMMARY: A 59-year-old male was admitted to our Department with the complain of gingival black pigmentations following dental implant treatment for 3 years. Intraoral examination revealed a painless black lobulated mass around maxillary gingiva and alveolar fossa of dental implant (first molar). CBCT revealed bone destruction around the implant. Positron emission tomography/computed tomography confirmed the presence of tumoral lesion, which was diagnosed as right maxillary gingiva malignant melanoma (T4aN0M0). Partial maxillectomy+buccal fat pad transfer+free tissue patch repair were carried out. Pathologic analyses confirmed the diagnosis of malignant melanoma. The postoperative course was uneventfully, the patient is undergoing follow-up without any evidence of recurrence. CONCLUSION: Our report showed that an ill-fitting dental implant may cause OMMM. Excisional biopsy with sufficient surgical margins allows complete removal and final diagnosis of OMMM. Early diagnosis and treatment are recommended.

Clinical outcomes of conventional HDR intracavitary brachytherapy combined with complementary applicator-guided intensity modulated radiotherapy boost in patients with bulky cervical tumour.

OBJECTIVE: To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). DESIGN: A retrospective cohort study. SETTING: Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre, China. POPULATION: Large high-risk clinical target volume (HR-CTV) volume (>40 ml) at the time of brachytherapy cervical cancer patients were recruited. METHODS: This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemoradiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) was adminstered with cisplatin chemotherapy treatment before IC/IMRT. The IMRT plan was optimised using the ICBT plan base dose plan by an inverse dose optimisation tool which allows the use of DVH constraints on the total dose of ICBT. A seven-field gantry angle IMRT plan was devised to avoid hotspots when optimising the boost plan. The prescription dose for HR-CTV and IR-CTV were 6 and 5 Gy per fraction for five fractions, respectively. RESULTS: Mean HR-CTV was 65.8 ± 23.6 ml at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7 ± 3.6 Gy and 78.1 ± 2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8 ± 3.8, 64.6 ± 4.9, 63.9 ± 5.3 and 56.7 ± 8.7 Gy, respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence-free survival rate, metastasis recurrence-free survival rate, disease-free survival rate and cancer-special survival rate were 87.6, 82.4, 70.9 and 76.3%, respectively. The grade 1 + 2 gastrointestinal and urinary late toxicities were 15.8 and 21.1%, and grade 3 late toxicities were 3.9 and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. CONCLUSIONS: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved excellent local control and overall survival with low toxicity for bulky residual cervical tumour.

CXCL1 promoted the migration and invasion abilities of oral cancer cells and might serve as a promising marker of prognosis in tongue cancer.

BACKGROUND: Oral tongue squamous cell carcinoma tends to metastasize to cervical lymphatic nodes early which leads to a 50% drop of survival rate. CXCL1 could be secreted by LNMTca8113 cell induced lymphatic endothelial cells and promoted LNMTca8113 cell migration. The current study aimed to further explore the effect of CXCL1 on the proliferation and migration abilities of tongue cancer cells and the prognostic value of serum CXCL1 in oral tongue squamous cell carcinoma. METHODS: Cell proliferation and migration ability were analysed by CCK8 assays and transwell migration assays. Immunofluorescence technique was used to show cytoskeleton. GST pull-down assay was applied to quantify the activation of GTPases. Blood samples of patients were collected and clinicopathological characteristics were analysed. RESULTS: CXCL1 could promote cancer cell proliferation in appropriate concentration by PI3K/AKT pathway. It also regulated the activation of Rho GTPases to mediate the rearrangements of cytoskeleton to promote tumour cell migration. Level of plasma CXCL1 could predict the possibility of early lymphatic metastasis and had a predictive value in progression-free survival and overall survival. CONCLUSIONS: CXCL1 could promote oral cancer cell proliferation, migration and invasion in vitro and contributed theoretical knowledge for the target selection in molecular targeted therapy. Level of plasma CXCL1 might serve as a biomarker for prognosis in oral tongue squamous cell carcinoma patients.

Outcome of primary intraosseous carcinoma: Case review of a single institution.

OBJECTIVE: The purpose of this study was to investigate the prognostic factors and treatment of primary intraosseous carcinoma (PIOC). METHODS: Patients diagnosed with POIC and received treatment in Sichuan Cancer Hospital from 2000 to 2019 were followed up and retrospectively reviewed. RESULTS: A total of 28 patients were included in the study, with a mean age of 60 years (60 ± 10.11). The 2-year and 5-year overall survival (OS) were 60.7% and 38.5%, respectively. In the univariate analysis, surgery combined with adjuvant therapy improved the OS compared with surgery or radiotherapy alone (p = 0.035), and patients who received postoperative adjuvant radiotherapy had a higher OS than those who received radical radiotherapy (p = 0.01). In addition, patients with well-differentiated tumors have increased progression-free survival (p = 0.01). Multivariate analyses showed that radiotherapy was an independent indicator for OS (p = 0.007). CONCLUSIONS: Surgery combined with adjuvant therapy is the superior treatment strategy for PIOC at present. This study is the first to confirm the positive role of radiotherapy in treating PIOC with data to back it up.

Reconstruction of Buccal-penetrating Defects Using the Double-folded Lateral Arm Free Flap.

The reconstruction of buccal-penetrating defects remains challenging. The present study aims to explore the application value of the lateral arm free flap (LAFF) on the reconstruction of buccal-penetrating defects with the hope of providing a better option for clinical practice. Nineteen patients with this kind of issue posed by either tumor resections or deformities in the craniofacial regions were recruited in this study, and LAFF was employed to reconstruct these defects by double folding and individually designing the flap. All the flaps prepared for these subjects in our study survived, and the postoperative assessment of these subjects receiving LAFF revealed that this approach to managing buccal-penetrating defects is able to achieve satisfactory results in terms of appearance and functional recovery. Therefore, our study suggests that LAFF is 1 of the promising flaps to reconstruct the buccal-penetrating defects.

Gasless Endoscopic Submandibular Gland Excision Through Hairline Approach.

BACKGROUND: The aim of this study was to evaluate the therapeutic effect of gasless endoscopic submandibular gland excision through hairline approach and the safety, feasibility and practicability of this technique. METHODS: Twenty-five patients with submandibular gland lesions who underwent gasless endoscopic submandibular gland excision through hairline approach at the Department of Head and Neck Oncology of the West China Hospital of Stomatology from May 1 st 2021 to May 31 st 2022 were included in this prospective study. The variables were analyzed statistically with SPSS software version 23.0 (IBM Corp, Armonk, New York, USA). RESULTS: There was a female predominance (72%), female to male ratio was 2.6. The mean age was 30.6±10.2 years (range: 11 to 52 year). All 25 cases of endoscopic submandibular gland excision through hairline approach were done without conversion to conventional approach. This approach was indicated in 14 cases (56%) for pleomorphic adenoma, 8 cases (32%) for chronic sialadenitis, 2 cases (8%) for adenoid cystic carcinoma, and 1 case (4%) for lymphadenitis. The incision length mean was 4.8±0.4 mm (range: 4 to 5 mm); the operation duration mean was 100.6±39.7 min (range: 51 to 197 min); the intraoperative bleeding mean was 13.2±5.7 ml (range: 5 to 20 ml); the hospital length of stay mean was 4.5±0.8 days (range: 3 to 6 days). The follow-up mean was 10±3.4 months (range: 5 to 16 months). The patients were very satisfied with postoperative cosmetic result (score mean: 9.2±1). No recurrence of disease and complications such as postoperative bleeding, hematoma, nerve damage, skin necrosis, infection, and hair loss occurred. CONCLUSIONS: Gasless endoscopic submandibular gland excision through hairline approach is safe, feasible and practicable, resulting in a very satisfied cosmetic result without significant complications; the intraoperative bleeding is less, the operative field is clear, the operation duration decreases with accumulation of experience.

Single nucleotide polymorphisms within NFKBIA are associated with nasopharyngeal carcinoma susceptibility in Chinese Han population.

Genes involved in latent membrane protein 1 (LMP1) signaling pathways have been suggested to play an important role in nasopharyngeal carcinogenesis. We investigated potentially functional genetic variants associated with the risk of nasopharyngeal carcinoma (NPC) in genes involved in the LMP1 signaling pathway. Altogether, 73 single nucleotide polymorphisms (SNPs) with MAF ≥ 10% were located within the regions of interest of the four genes TRAF3, NFKBIA, CHUK and MAP2K4. From these, 10 SNPs were selected for genotyping based on LD (r2 ≥ 0.80) in a hospital-based case-control study of 332 NPC cases and 585 healthy controls from the Chinese Han population. Minor allele carriers of the promoter SNP rs2233409 in NFKBIA, had an increased risk of NPC (AA vs GG: OR 7.14, 95%CI, 1.08-34.18, P = 0.04, dominant model). Based on the results, we concluded that rs2233409 polymorphism in NFKBIA may be moderately associated with the risk of NPC. Further studies with larger independent samples and functional analysis are needed to verify our results.

Resection of Second, Third, and Fourth Branchial Cleft Anomalies with Recurrent or Repeated Neck Infection Using the Selective Neck Dissection Technique.

PURPOSE: To explore the applied value of the selective neck dissection to treat second, third, and fourth branchial cleft anomalies with recurrent or repeated neck infections. METHOD: We made a retrospective study about 29 patients with the second, third, and fourth branchial cleft anomalies with recurrent or repeated neck infections who were treated by surgery from 2002 to 2018 in Sichuan Province Cancer Hospital. According to the characteristics of branchial cleft anomaly on embryology and anatomy, different types of selective neck dissection were chosen to remove pathological scar tissue or inflammatory tissue en bloc. RESULT: Of 29 cases, 28 had primary healing, and 1 had local infection, healing after dressing change for a long time. In 1 case, branchial cleft anomalies adhered to the internal jugular vein, which was ruptured and sutured. During the follow-up time of 12∼195 months with an average of 91.76 months, there were no recurrent cases. CONCLUSION: The selective neck dissection technique is safe and effective in the treatment of branchial cleft anomalies with recurrent or repeated neck infection.

[Prospects and challenges of exosomes as drug delivery systems].

Exosomes are nanoscale vectors with a diameter of 30~100 nm secreted by living cells, and they are important media for intercellular communication. Recent studies have demonstrated that exosomes can not only serve as biomarkers for diagnosis, but also have great potential as natural drug delivery vectors. Exosomes can be loaded with therapeutic cargos, including small molecules, proteins, and oligonucleotides. Meanwhile, the unique biological compatibility, high stability, and tumor targeting of exosomes make them attractive in future tumor therapy. Though exosomes can effectively deliver bioactive materials to receptor cells, there is a wide gap between our current understanding of exosomes and their application as ideal drug delivery systems. In this review, we will briefly introduce the function and composition of exosomes, and mainly summarize the potential advantages and challenges of exosomes as drug carriers. Finally, this review is expected to provide new ideas for the development of exosome-based drug delivery systems.

Exosome-orchestrated hypoxic tumor microenvironment.

Hypoxic tumor microenvironment is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. A continuous interference between cancer cells and stromal cells within the hypoxic microenvironment has been uncovered for its importance in cancer development and treatment responsiveness. Exosomes, initially considered as "garbage bins" for unwanted material from cells, are now elucidated to perform a variety of functions that involve interactions within the cellular microenvironment due to their ability to carry numerous cargoes, including lipids, proteins, nucleic acids, and metabolites. Exosome-mediated continuous interference between cancer cells and stroma are believed to regulate hypoxia-adaptation and to rebuild the microenvironment in return. In this review, we will discuss the knowledge in literature with respect to the exosome-mediated multi-directional and mutual signal transmission among the variety of cell types within hypoxic cancer microenvironment.

Long noncoding RNA HAS2-AS1 mediates hypoxia-induced invasiveness of oral squamous cell carcinoma.

A hypoxic microenvironment plays important roles in the progression of solid tumors, including oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. However, it is not clear whether lncRNAs can regulate hypoxia adaptation of OSCC or which lncRNAs participate in this process. Using a lncRNA microarray, we analyzed the aberrant lncRNA expression profiles in OSCC tissues compared with paired normal oral mucosa and in hypoxic OSCC cells compared with normoxic OSCC cells. The top 10 lncRNAs that had more than threefold increase with P-value <0.01 in both microarray data were validated by qRT-PCR. Among the top 10 lncRNAs, hyaluronan synthase 2 antisense 1 (HAS2-AS1) was the only one that has a hypoxia-responsive element (HRE) on its promoter region and has been validated to increase in OSCC tissues and in cells cultured under hypoxia. Tumor HAS2-AS1 levels were closely associated with lymph node metastasis and hypoxic tumor status in patients with OSCC. Moreover, the hypoxia-induced HAS2-AS1 expression is dependent on HIF-1α which directly binds to and activates the transcription of HAS2-AS1. In addition, HAS2-AS1 mediates hypoxia-induced epithelial mesenchymal transition of OSCC cells via stabilizing HAS2. In conclusion, our results suggest that hypoxia would induce an overexpression of HAS2-AS1 in an HIF-1α dependent manner. The increase of HAS2-AS1 plays important roles mediating the hypoxia-regulated EMT and invasiveness of OSCC.

Reconstruction of Hypopharyngeal and Esophageal Defects Using a Gastric Tube after Total Esophagectomy and Pharyngolaryngectomy.

AIM: This study investigated the value of gastric tube during surgery for advanced hypopharyngeal and cervical esophageal cancer. METHOD: From November 2007 to December 2012, 42 patients underwent total pharyngo-laryngo-esophagectomy because of advanced hypopharyngeal or cervical esophageal cancer and were reconstructed with a gastric tube. Clinical swallowing function, morbidity, overall survival, and progression-free survival were evaluated postoperatively. RESULT: There were no severe complications, including no gastric necrosis, surgery-related postoperative morbidity, hemothorax, thoracostomach, or severe reflux esophagitis. Anastomotic leakage occurred in 2 cases, and these patients healed spontaneously with conservative management. Pulmonary infection developed in 5 patients. Anastomotic stenosis occurred in 2 cases and was managed with endoscopic dilatation. Regurgitation during the night was observed in 5 cases and was controlled by medication. All the patients regained their swallowing ability and thereby increased their quality of life. All patients were followed for 30-60 months; 2 of them were lost 6 months after surgery. The 3-year overall and progression-free survival rates were 58.1 and 56.2% respectively, and the 5-year overall and progression-free survival rates were 27.6 and 21.8%, respectively. CONCLUSION: Reconstruction by gastric tube is a dependable one-stage procedure that restores gastrointestinal continuity after total pharyngo-laryngo-esophagectomy.

The Neutrophil-to-Lymphocyte Ratio Correlates with Age in Patients with Papillary Thyroid Carcinoma.

AIM: The aim of this study is to explore the relationship between the neutrophil-to-lymphocyte ratio (NLR) and clinicopathological features in patients with papillary thyroid carcinoma (PTC). METHODS: We performed an analysis of 843 patients, including 321 patients with PTC, 83 patients with thyroid adenoma and 439 patients with nodular goiter (NG). Thyroglobulin and thyrotropin were measured in each patient. Neutrophils, lymphocytes, and platelets were counted. Statistical analysis was used to correlate the NLR with demographic and histopathologic characteristics of the patients. RESULT: Age correlated with NLR and lymphocyte number in patients with PTC and NG. In patients aged >45 years, those with PTC had a higher NLR and a lower lymphocyte count than those with NG. Patients with PTC aged <45 years had a higher leukocyte count and a lower NLR than those aged ≥45 years. Patients with clinical stage I/II PTC had a lower NLR and a higher lymphocyte count than patients with stage III/IV. CONCLUSIONS: Younger patients with PTC had a higher lymphocyte count but a lower NLR than older patients with PTC. The NLR and lymphocyte counts were associated with the clinical stage. Thus, a higher NLR and a lower lymphocyte count may be prognostic for stratifying patients with thyroidal goiters and are risk factors of PTC for older patients.

Modified free latissimus dorsi musculocutaneous flap in the reconstruction of extensive postoncologic defects in the head and neck region.

Oncological resection of advanced carcinoma in the head and neck region results in vast defects. The free latissimus dorsi musculocutaneous flap (FLDMF) is one of the most commonly used flaps for the repair of complex head and neck defects. We tried to modify FLDMF to multiple segments or combine it with acellular dermis to fit through-and-through defects in the oral-facial region during the last decade. A retrospective review of patients with FLDMF reconstruction between 2004 and 2012 was undertaken. Demographics, histology, surgical management, disease control and overall survival, complications, radiotherapy, aesthetic outcome, as well as economic results were analyzed. The majority of the patients (66.7%) had recurrent tumors, and the rest of the patients had primary tumor with stage IV. Fourteen patients (38.9%) had a history of prior radiation therapy, whereas 27.8% of the patients had postoperative radiation therapy. The areas of the defects vary from 52 cm to 180 cm (mean, 86.4 cm). The flap failed in 1 of the 37 patients. The complications at the recipient site include hematoma (n = 6, 16.7%), venous insufficiency (n = 4, 11.1%), infection (n = 3, 8.3), and partial flap necrosis (n = 2, 5.5%). The donor-site complications include delayed healing, necrosis of skin graft, and limited shoulder function. The 5-year overall survival rate was 39.1%, and the 5-year disease-free survival rate was 22.1%. In conclusion, the FLDMF could be modified to fit vast defects where voluminous tissue is needed to be transferred in the head and neck region.

A 3†M Evaluation Protocol for Examining Lymph Nodes in Cancer Patients: Multi-Modal, Multi-Omics, Multi-Stage Approach.

Through meticulous examination of lymph nodes, the stage and severity of cancer can be determined. This information is invaluable for doctors to select the most appropriate treatment plan and predict patient prognosis; however, any oversight in the examination of lymph nodes may lead to cancer metastasis and poor prognosis. In this review, we summarize a significant number of articles supported by statistical data and clinical experience, proposing a standardized evaluation protocol for lymph nodes. This protocol begins with preoperative imaging to assess the presence of lymph node metastasis. Radiomics has replaced the single-modality approach, and deep learning models have been constructed to assist in image analysis with superior performance to that of the human eye. The focus of this review lies in intraoperative lymphadenectomy. Multiple international authorities have recommended specific numbers for lymphadenectomy in various cancers, providing surgeons with clear guidelines. These numbers are calculated by applying various statistical methods and real-world data. In the third chapter, we mention the growing concern about immune impairment caused by lymph node dissection, as the lack of CD8 memory T cells may have a negative impact on postoperative immunotherapy. Both excessive and less lymph node dissection have led to conflicting findings on postoperative immunotherapy. In conclusion, we propose a protocol that can be referenced by surgeons. With the systematic management of lymph nodes, we can control tumor progression with the greatest possible likelihood, optimize the preoperative examination process, reduce intraoperative risks, and improve postoperative quality of life.

Tumor-infiltrating immune cell score as an independent prognostic predictor for endometrial carcinoma: Insights from a comprehensive analysis of the immune landscape.

BACKGROUND: Immune cells are crucial components in the tumor microenvironment and have a significant impact on the outcomes of patients. AIMS: Here, we aimed to establish a prognostic score based on different types of tumor-infiltrating immune cells for Endometrial Carcinoma (EC). METHODS AND RESULTS: We enrolled and analyzed 516 EC patients from The Cancer Genome Atlas. The relative abundance of 22 immune cells were estimated by using the CIBERSORTx algorithm. Cox regression was performed to identify potential prognostic immune cells, which were used to develop a Tumor-infiltrating Immune Cell Score (TICS). The prognostic and incremental value of TICS for overall survival were compared with traditional prognostic factors using the C-index and decision curves. Clustering analysis using all immune cells identified three immune landscape subtypes, which had weak correlation with survival. A TICS was constructed using CD8T cells, resting memory CD4 T cells, activated NK and activated DCs, and classified patients as low-, moderate- and high-risk subgroups. The low-risk subgroup had higher tumor mutation burden and activation of IL2/STAT5, IL2/STAT3 and IFN-gamma response pathways. Conversely, the high-risk subgroup was associated with DNA copy number variation, hypoxia and EMT process. The TICS subgroups significantly predicted overall survival, which was independent of patient age, tumor stage, grade and molecular classification. Moreover, we developed a nomogram incorporating TICS and clinicopathologic factors, which significantly improved the predictive accuracy compared to the clinicopathologic model alone. CONCLUSION: The TICS is an effective and independent prognostic predictor for EC patients and may serve as a useful supplement to clinicopathological factors and molecular subtyping.

Innovative principle of implant-oriented fibula placement in mandibular reconstruction using double-barrel fibula and simultaneous implants: A technical note.

Simultaneous or secondary inserted implants with double-barrel fibula to reconstruct the mandible have become a common method. However, difficulties in later restoration caused by placement errors of fibula or incipiently placed implants have also been reported in some studies. This note describes a novel technique of implant-oriented guide plates helpful for mandible ablation, fibula segmentation and positioning, and implant placement. We design a series of guide plates especially an implant-fibula placing guide plate, and record and fix the relative spatial positions of the remaining teeth, the simultaneous implants and upper fibula. During surgery, the placement of upper fibula is oriented towards appropriate placement of implants. Therefore, the position of upper fibula can meet the requirements of simultaneous implant as much as possible. Within the limits of present observation, we believe that this technique may increase the manipuility while reducing the errors and the risk of complications.

Variant of internal jugular vein reconstruction in bilateral radical neck dissection.

BACKGROUND: The internal jugular vein (IJV) plays a major role in collecting venous blood from the cranium, face, and neck. Preserving or reconstructing at least one IJV during bilateral radical neck dissection (RND) allows preventing severe complications. The aim of this report was to present a variant of IJV reconstruction in bilateral radical neck dissection. CASE SUMMARY: A 55-year-old male complained for a gingival mass for about 2 months, which was approximately 4 × 2 cm in size with a surface ulceration, located in the anterior mandibular area. There were bilateral cervical adenopathy. The computed tomography (CT) scan revealed mandibular bone destruction with surrounding soft tissue masse, multiple enlarged lymph nodes around bilateral submandibular space and bilateral carotid sheath, with obvious necrosis in the center. The preoperative diagnosis was mandibular gingiva squamous cell carcinoma (SCC), staged T4aN2bM0. Under general anesthesia, the patient underwent bilateral RND with sacrifice of right IJV and reconstruction of left IJV by anastomosis of IJV to the ipsilateral EJV using the common facial vein as a communicating way, followed by an expanded resection of mandibular gingiva SCC via marginal mandibulectomy, left anterolateral thigh (ALT) free flap reconstruction of the resulting defects, and tracheotomy. The patient's post-operative course was uneventfully. CONCLUSION: In our case report, the immediate IJV reconstruction by the W method was performed without compromising oncologic principles and was found feasible, safe and effective to prevent the occurrence of severe postoperative complications related to bilateral RND with sacrifice of both IJV.

NAD+ Metabolism Reprogramming Mediates Irradiation-Induced Immunosuppressive Polarization of Macrophages.

PURPOSE: Radiation therapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiation therapy resistance, whose mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiation therapy and the associated underlying mechanisms. METHODS AND MATERIALS: Male C3H mice bearing syngeneic SCC-VII tumor received irradiation (2 × 8 Gy). The impact of irradiation on tumor-infiltrating macrophages was assessed. Bone marrow-derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium and irradiated tumor-derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, whereas key metabolites were investigated for their role in the mechanism of immunosuppression of macrophages in vitro and in vivo. RESULTS: Radiation therapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in the tumor microenvironment and drove infiltrated macrophages toward an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of niacinamide (NAM) to macrophages. NAM directly bound to the nuclear factor kappa-B transcriptional activity regulator USP7, through which NAM reduced translocation of nuclear factor kappa-B into the nucleus, thereby decreasing the release of cytokines interleukin 6 and interleukin 8. Increased enzyme activity of NAM phosphoribosyl transferase which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAM phosphoribosyl transferase decreased NAM levels in irTEVs and increased radiation therapy sensitivity by alleviating the immunosuppressive function of macrophages. CONCLUSIONS: Radiation therapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophages toward an immunosuppressive phenotype. Pharmacologic targeting of NAD+ metabolism might be a promising strategy for radiation therapy sensitization of HNSCC.