The emerging roles and therapeutic implications of immunosenescence-mediated inflammaging in age-related hearing loss.

Age-related hearing loss (ARHL) represents one of the most prevalent chronic sensory deficits experienced by the elderly, significantly diminishing their quality of life and correlating with various medical and psychological morbidities. This condition arises from the cumulative effects of aging on the auditory system, implicating intricate interactions between genetic predispositions and environmental factors. Aging entails a progressive decline in immune system functionality, termed immunosenescence, leading to a chronic low-grade inflammation known as inflammaging. This phenomenon potentially serves as a common mechanism underlying ARHL and other age-related pathologies. Recent research suggests that rejuvenating immunosenescence could mitigate inflammaging and ameliorate age-related functional declines, offering promising insights into anti-aging therapies. Consequently, this review endeavors to elucidate the role of immunosenescence-mediated inflammaging in ARHL progression and discuss its therapeutic implications.

The diversity of inhibitory receptor co-expression patterns of exhausted CD8+ T cells in oropharyngeal carcinoma.

Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Prognostic effects of previous cancer history on patients with major salivary gland cancer.

OBJECTIVES: To explore the prognostic effects of previous cancer history on patients with major salivary gland cancer (SGC). SUBJECTS AND METHODS: SGC patients with (sec-SGC) and without (one-SGC) a previous cancer from the SEER database were identified. Cox proportional hazards regression (CoxPH) models were used to compare the prognosis between sec-SGC and one-SGC patients. Subgroup analyses for sec-SGC patients by gender, previous cancer types, previous cancer histology, and cancer diagnosis interval (CDI) were performed. Two CoxPH models were constructed to distinguish sec-SGC patients with different prognostic risks. RESULTS: 9098 SGC patients were enrolled. Overall, sec-SGC patients (adjusted HR [aHR] = 1.26, p < 0.001), especially those with a CDI ≤ 5 years (aHR = 1.47, p < 0.001), had worse overall survival (OS) than one-SGC patients. In subgroup analysis, only sec-SGC patients with a previous head and neck cancer who were female (aHR = 2.38, p = 0.005), with a CDI ≤ 5 years (aHR = 1.65, p = 0.007) or with a previous squamous cell carcinoma (aHR = 6.52, p < 0.001) had worse OS. Our models successfully differentiated all sec-SGC patients into high-, intermediate- and low-risk groups with different prognosis. CONCLUSIONS: Sec-SGC patients with different previous cancer types, gender, CDI and previous cancer histology had varied prognosis. The models we constructed could help differentiate the prognosis of sec-SGC patients with different risks.

Low Bone Mineral Density and the Risk of Benign Paroxysmal Positional Vertigo.

OBJECTIVE: This study aimed to comprehensively analyze the relationship between low bone mineral density (BMD) and the risk of benign paroxysmal positional vertigo (BPPV) based on the large prospective population-based UK Biobank (UKB) cohort. STUDY DESIGN: Prospective population-based cohort study. SETTING: The UKB. METHODS: This prospective cohort study included UKB participants recruited between 2006 and 2010 who had information on BMD and did not have BPPV before being diagnosed with low BMD. Univariable and multivariable logistic regression models were constructed to assess the association between low BMD (overall low BMD, osteopenia, and osteoporosis) and BPPV. We further conducted sex and age subgroup analysis, respectively. Finally, the effects of antiosteoporosis and female sex hormone medications on BPPV in participants with osteoporosis were evaluated. RESULTS: In total, 484,303 participants were included in the final analysis, and 985 developed BPPV after a maximum follow-up period of 15 years. Osteoporosis was associated with a higher risk of BPPV (odds ratio [OR] = 1.37, P = .0094), whereas osteopenia was not. Subgroup analyses suggested that the association between osteoporosis and BPPV was significant only in elderly females (≥60 years, OR = 1.51, P = .0007). However, no association was observed between antiosteoporosis or female sex hormone medications and BPPV in the participants with osteoporosis. CONCLUSION: Osteoporosis was associated with a higher risk of developing general BPPV, especially in females aged ≥ 60 years old, whereas osteopenia was not associated with BPPV.

A Population-Based Outcome-Wide Association Study of the Comorbidities and Sequelae Following COVID-19 Infection.

BACKGROUND: Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection. METHODS: In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%). CONCLUSION: In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period.

mRNA-LNP vaccination-based immunotherapy augments CD8+ T cell responses against HPV-positive oropharyngeal cancer.

Although mRNA vaccines are known as potent activators of antigen-specific immune responses against infectious diseases, limited understanding of how they drive the functional commitment of CD8+ T cells in tumor microenvironment (TME) and secondary lymphoid organs hinders their broader application in cancer immunotherapy. Here, we systematically evaluated the immunological effects of a lipid nanoparticle (LNP)-encapsulated mRNA vaccine that encodes human papillomavirus E7 protein (HPV mRNA-LNP), a tumor-specific antigen of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). HPV mRNA-LNP vaccination activated overall and HPV-specific CD8+ T cells, as well as differentially drove the functional commitment of CD8+ T cells through distinct IFN-response and exhaustion trajectories in the spleen and TME, respectively. Combination therapies of HPV mRNA-LNP vaccination with immune checkpoint blockades boosted HPV-specific CD8+ T cells while maintaining their anti-tumor function, thus further promoting tumor regression. Our results showed that the HPV mRNA-LNP vaccination combined with immune checkpoint blockade is a promising approach for immunotherapy of HPV-positive OPSCC.

Associations between immune-mediated diseases (IMDs) and the risk of HPV-associated diseases: a UK Biobank cohort analysis.

OBJECTIVES: To systematically assess the associations between various immune-mediated diseases (IMDs) and human papillomavirus (HPV)-associated diseases. DESIGN: Retrospective cohort study. SETTING: UK Biobank. PARTICIPANTS: A total of 500 371 subjects aged 40-69 years were eligible for the analysis, after excluding those with prevalent HPV-associated diseases at baseline and those who had withdrawn their informed consent or lacked information on sex. EXPOSURE: Eighty IMDs (involving allergic/atopic diseases, autoimmune diseases, immunodeficiency diseases, etc) were identified in the UK Biobank. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome was the incidence of HPV-associated diseases (including warts and malignancies of the cervix, oropharynx, anus, penis, vulva and vagina). Cox proportional hazards model was used to estimate HRs and 95% CIs with particular adjustment for sexual behaviours. We also conducted subgroup analyses based on benign and malignant status, and anatomical sites of HPV-associated diseases, respectively. RESULTS: During a median of 12.0 years of follow-up, 2244 cases out of 500 371 subjects developed HPV-associated diseases. Overall, participants with IMDs had a higher risk of HPV-associated diseases than their controls after adjustment for sexual behaviours and other potential confounders (female: HR=1.90, 95% CI=1.66 to 2.17, p<0.001; male: HR=1.66, 95% CI=1.41 to 1.97, p<0.001). Additionally, eight individual IMDs in women (eg, asthma: HR=1.76, 95% CI=1.47 to 2.11, p<0.001) and three in men (eg, chronic nephritic syndrome: HR=6.05, 95% CI=3.32 to 11.04, p<0.001) were associated with increased risk of HPV-associated diseases. Subgroup analyses revealed significant IMD differences between benign and malignant subgroups as well as between oropharyngeal and anogenital subgroups. CONCLUSION: In this large retrospective cohort study, IMDs were significantly associated with an elevated risk of HPV-associated diseases. Besides, gender-specific and region-specific associations were also observed between individual IMDs and HPV-associated diseases.

Associations Between Body Composition and Sensorineural Hearing Loss Among Adults Based on the UK Biobank.

OBJECTIVE: To explore the association between body composition and sensorineural hearing loss (SNHL). STUDY DESIGN: Cross-sectional study, prospective study and Mendelian randomization (MR) analyses. SETTING: UK Biobank. METHODS: This cross-sectional study included 147,296 adult participants with complete data on body composition and the speech-reception-threshold (SRT) test. We further conducted a prospective study with 129,905 participants without SNHL at baseline and followed up to 15 years to explore the association between body composition and new-onset SNHL. Multivariable logistic regression and Cox regression models were used. Subgroup analyses stratified by age and sex were performed. We further assessed the causal association between body composition and SNHL using two-sample MR analyses. RESULTS: Our cross-sectional study revealed that fat percentage, especially leg (odds ratio [OR] 1.46, p = .029) and arm (OR 1.43, p = .004), were significant risk factors for SNHL. However, fat-free mass, especially in the arm (OR 0.27, p < .001) and leg (OR 0.58, p < .001) showed significant protective effects against SNHL, which was substantially consistent with the results of the prospective study. In addition, we found that young women with SNHL were more susceptible to body composition indicators. However, MR analyses revealed no evidence of significant causal association. CONCLUSION: Fat percentage, especially in the leg and arm, was a significant risk factor for SNHL, whereas fat-free mass, especially in the leg and arm, had significant protective effects against SNHL, however, these associations may not be causal.

Comparison of Primary B/NKT Non-Hodgkin Lymphomas in Nasopharynx, Nasal Cavity, and Paranasal Sinuses.

OBJECTIVE: We aimed to compare clinical and survival differences between B-cell (B-NHL) and NKT-cell non-Hodgkin lymphomas (NKT-NHL) located in the nasal cavity (NC), nasopharynx, and paranasal sinuses, which are always categorized as one sinonasal type. STUDY DESIGN: Patients diagnosed with primary B-NHL and NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses from Surveillance, Epidemiology, and End Results (SEER) database were included (1975-2017). SETTING: Population-based cohort study. METHODS: We conducted univariate and multivariate Cox regressions and Kaplan-Meier analysis to examine survival outcomes of B/NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses, respectively. RESULTS: Overall, most B-NHL cases originated from the nasopharynx, while the majority of NKT-NHL cases occurred in the nasal cavity. Notably, the cancer-special survival (CSS) outcomes improved significantly in all sinonasal B-NHL cases over time, whereas no such improvement trend was observed in each sinonasal NKT-NHL type. Additionally, increasing age was linked with an elevated risk of death in B-NHL, particularly in the nasal cavity (Hazard ratio [HR]: 3.37), rather than in NKT-NHL. Compared with B-NHL, the adverse effect of a higher stage on CSS was more evident in NKT-NHL, particularly in its nasopharynx site (HR: 5.12). Furthermore, radiotherapy was beneficial for survival in patients with sinonasal B-NHL and NKT-NHL, except in the nasopharynx NKT-NHL. However, chemotherapy has only been beneficial for CSS in patients with paranasal sinuses B-NHL (HR: 0.42) since 2010, rather than in other types of B/NKT-NHL. CONCLUSION: Although B-NHL and NKT-NHL in the nasal cavity, nasopharynx and paranasal sinuses have similar anatomical locations, their clinicodemographics and prognoses are largely different and should be treated and studied as distinct diseases.

Proliferative exhausted CD8+ T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8+ T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen-presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects.

Clinical outcomes of temporal bone squamous cell carcinoma: A single-institution experience.

OBJECTIVES: This study aimed to investigate the survival outcomes and potential prognostic factors of patients with temporal bone squamous cell carcinoma (TBSCC) treated at our institution. METHODS: We retrospectively included patients who were diagnosed with TBSCC between 2008 and 2019. The Kaplan-Meier (KM) method was used to describe overall survival (OS), and the association between baseline characteristics and prognoses was examined using Cox proportional hazards models. RESULTS: Fifty consecutive patients with TBSCC were included in this study. The results showed that patients with advanced modified Pittsburgh (MPB)- T classifications had a poorer prognosis (T3 vs. T1-2: HR: 2.81, 95% CI: 0.34-23.43; T4 vs. T1-2: HR: 7.25, 95% CI: 0.95-55.41; p = 0.041). Meanwhile, middle ear squamous cell carcinoma (MESCC) showed a significantly worse prognosis than external auditory canal squamous cell carcinoma (EACSCC, HR: 2.65, 95% CI: 1.04-6.76, p = 0.04). CONCLUSIONS: MESCC and advanced MPB-T classifications might be considered predictors of unfavorable outcomes in patients with TBSCC, indicating that special attention should be paid to the original tumor subsite and tumor extension in the management of patients with TBSCC.

The role of HPV status in patients with overlapping grey zone cancer in oral cavity and oropharynx.

PURPOSE: We aimed to explore the clinicodemographic characteristics and prognosis of grey zone squamous cell cancer (GZSCC) located in the overlapping or ambiguous area of oral cavity and oropharynx and to identify valuable factors that would improve its differential diagnosis and prognosis. METHODS: Information of GZSCC patients in the Surveillance, Epidemiology, and End Results (SEER) database were compared to patients with oral cavity (OCSCC) and oropharyngeal (OPSCC) squamous cell carcinomas with corresponding HPV status, respectively. Kaplan-Meier method with log-rank test and multivariate Cox regression analysis were applied to assess associations between clinical characteristics and overall survival (OS). A predictive model integrating age, gender, marital status, HPV status and staging variables was conducted to classify GZSCC patients into three risk groups and verified internally by tenfold cross validation. RESULTS: A total of 3318 GZSCC, 10792 OPSCC and 6656 OCSCC patients were identified. HPV-positive GZSCC patients had the best 5-year OS as HPV-positive OPSCC (81% vs. 82%). However, the 5-year OS of HPV-negative/unknown GZSCC (43%/42%) were the worst among all groups, indicating that HPV status and the overlapping nature of tumors were valuable prognostic predictors in GZSCC patients. Compared with the strategy of dividing GZSCC into two groups by HPV status, the predictive model integrating more variables could additionally identify a unique high-risk GZSCC group with the lowest OS rate. CONCLUSIONS: GZSCC patients had distinct clinical characteristics and prognosis compared with OPSCC and OCSCC, integrating HPV status and other clinical factors could help distinguish GZSCC and predict their prognosis.

Dynamic changes of hematological indices in oropharyngeal cancer patients treated with radiotherapy.

BACKGROUND: Hematological indices assist in predicting clinical outcomes. OBJECTIVES: To explore changes of hematological indices on oropharynx squamous cell carcinoma (OPSCC) patients received radiotherapy and their association with survival. MATERIAL AND METHODS: The white blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), hemoglobin (Hb), platelet (Plt), albumin (Alb), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline, 1-, 3-, 6- and 12-months follow-up were retrospectively collected. The trajectory of indices was described. A linear model with random effects was to describe indices' changing rate and trend. Univariable Cox analysis was to assess the correlation between indices and survival. RESULTS: Of the 85 patients, WBC and ALC dropped during acute phase and gradually recovered, while NLR and PLR increased during acute phase and subsequently declined (all p < .01). Higher absolute value of nutritional indices (Alb and Hb) was associated with better prognosis (p < .05). In contrast, patients with higher absolute value or upward trend of inflammatory indices (ANC, Plt, NLR and PLR) had worse survival (p < .05). CONCLUSIONS AND SIGNIFICANCE: The short- and long-term changes of indices differed in OPSCC patients received radiotherapy, and absolute values and dynamic changes of indices had the potential to be prognostic factors.

The Prognostic Prediction Value of Positive Lymph Nodes Numbers for the Hypopharyngeal Squamous Cell Carcinoma.

Background: The current American Joint Committee on Cancer (AJCC) system only considered the importance of the size and laterality of lymph nodes while not the positive lymph node number (PLNN) for hypopharyngeal squamous cell carcinoma (HPSCC). Methods: A total of 973 patients with HPSCC from the Surveillance, Epidemiology, and End Results database (2004-2015) were identified. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic effects. We applied six Cox regression models to compare the survival prognostic values of PLNN and AJCC systems. Results: Positive lymph node number showed a significant association with overall survival (OS) and cancer-specific survival (CSS) (P < 0.001) in univariate and multivariable analyses. The increased PLNN of HPSCC gave rise to poor OS and CSS. The survival model incorporating a composite of PLNN and TNM classification (C-index for OS:0.682, C-index for CSS:0.702) performed better than other models. Conclusions: A positive lymph node number could serve as a survival predictor for patients with HPSCC and a complement to enhance the prognostic assessment effects of TNM cancer staging systems.

Is postauricular injection a systemic or a topical route for inner ear drug delivery?

The challenges associated with the blood-labyrinth barrier and unwanted systemic adverse effects severely impede the development of systemic drug administration for inner ear therapy. Previous studies have demonstrated that postauricular injection might be an alternative route for the systemic administration for inner ear therapy because it is minimally invasive and can achieve a high drug concentration in the inner ear. However, the in vivo effects remain unclear. This study aimed to compare differences in cisplatin-induced ototoxicity and systemic adverse effects between postauricular and systemic administration. Here, we compared the differences in hair cell loss, body weight change, and renal dysfunction (indicated by serum levels of blood urea nitrogen and creatinine) between these two routes of administration. The results showed that although postauricular injection of cisplatin might induce greater hair cell damage in the ipsilateral cochleae than that after intraperitoneal injection, significant hair cell damage in the contralateral cochleae as well as systemic adverse effects were also observed. Our results indicated that: (1) topical administration effects might occur in the ipsilateral inner ear following postauricular injection, and (2) systemic circulation might also be an underestimated route of drug delivery to the inner ear following postauricular injection. Overall, postauricular injection is a hybrid administration route, which simultaneously shares the features of topical and systemic administration for inner ear drug delivery.

Gender-specific association between obstructive sleep apnea and cognitive impairment among adults.

OBJECTIVES: This study aims to explore the gender-specific association between obstructive sleep apnea (OSA) and cognitive impairment. METHODS: Participants from UK biobank who have completed at least one of the five baseline cognitive tests (visuospatial memory, prospective memory, fluid intelligence, short numeric memory and reaction time) were included, which were initially divided into two groups based on gender and were further categorized into three subgroups: (1) OSA, (2) self-reported snoring but without OSA, and (3) healthy controls (without OSA or snoring). Multivariable regression analysis was performed to examine the associations among snoring, OSA and performance of each of the five cognitive domains. RESULTS: A total of 267,889 participants (47% male, mean age: 57 years old) were included in our study. In the multivariable regression analysis, female participants in the OSA group had a higher risk of having poor prospective memory (OR: 1.24, 95% CI: 1.02～1.50, p = 0.03). Meanwhile, among female participants, OSA were inversely associated with the performances of fluid intelligence (ß: 0.29, 95% CI: 0.46～-0.13, p < 0.001) and short-numeric memory (ß: 0.14, 95% CI: 0.35～0.08, p = 0.02). Besides, age-related subgroup analyses showed that these associations were largely reserved in younger (＜65 years old) female participants rather than older (≥65 years old) female participants. In contrast, among male participants, no significant association was observed between OSA and impairment of the five cognitive domains. CONCLUSIONS: OSA was significantly associated with cognitive impairment at certain dimensions in female participants rather than in male participants, indicating that more special attention and timely interventions should be given to younger female OSA patients to prevent further cognitive impairment.

Single-Cell Transcriptome Profiling Identifies Phagocytosis-Related Dual-Feature Cells in A Model of Acute Otitis Media in Rats.

Background: The molecular mechanisms of acute otitis media (AOM) development, and the intercellular crosstalk within the multicellular ecosystem of AOM, are not clear. Methods: We established a model of AOM in rats (with normal rats as controls) and undertook single-cell RNA sequencing (scRNA-seq) for the middle-ear mucosa (MEM). Cell clustering and trajectory analyses were undertaken using Seurat and Monocle 2 packages in R software. Pathway analyses were done by gene set enrichment analysis (GSEA). Cell-cell interactions were inferred by CellChat. Cell scores were calculated to identify cells with dual-feature. Results: A total of 7023 cells from three samples of inflamed MEM and 5258 cells from three samples of healthy MEM underwent scRNA-seq, which identified 20 cell clusters belonging to eight major cell types. After exposure to lipopolysaccharide, the MEM underwent significant conversion of cell types characterized by rapid infiltration of macrophages and neutrophils. M2 macrophages seemed to play a key part in inflammatory intercellular crosstalk, which facilitated the maintenance and proliferation of macrophages, cell chemotaxis, and regulation of the proinflammatory activities of cytokines. Three rare cell clusters with phagocytosis-related dual-feature were also identified. They coexisted with professional phagocytes in the MEM, and displayed distinct immunoregulatory functions by maintaining a normal immune microenvironment or influencing inflammation progression. Conclusions: Macrophages might be the "master" initiators and regulators of the inflammatory response of the MEM to external stimuli. And their functions are fulfilled by a specific polarization status (M2) and sophisticated intercellular crosstalk via certain signaling pathways. Besides, the coexistence of professional phagocytes and non-professional phagocytes as well as their interplay in the MEM provides new clues for deciphering the underlying pathogenic mechanisms of AOM.

Evaluating the prognostic contributions of TNM classifications and building novel staging schemes for middle ear squamous cell carcinoma.

BACKGROUND: A universally acknowledged cancer staging system considering all aspects of the T-, N-, and M-classifications for middle ear squamous cell carcinoma (MESCC) remains absent, limiting the clinical management of MESCC patients. MATERIALS AND METHODS: A total of 214 MESCC patients were extracted from the SEER (the Surveillance, Epidemiology, and End Results) database between 1973 and 2016. The relationships between patient's characteristics and prognoses were analyzed by Kaplan-Meier and Cox proportional hazards regression models. Novel staging schemes for MESCC were designed by adjusted hazard ratio (AHR) modeling method according to the combinations of Stell's T-classification and the eighth AJCC N- and M-classifications, of which performances were evaluated based on five criteria: hazard consistency, hazard discrimination, explained variation, likelihood difference, and balance. RESULTS: T-classification was the most significant prognostic factor for MESCC patients in multivariable analysis (p = 0.021). The N- and M-classifications also had obvious prognostic effect but were not statistically significant by multivariate analysis due to the limited metastasis events. Three novel staging schemes (AHR-Ⅰ-Ⅲ models, different combination of T- and N-classifications) and ST (solely derived from Stell's T-classification) were developed, among which the AHR-Ⅰ staging scheme performed best. CONCLUSIONS: Tumor extension, quantified by Stell's T-classification, is the most significant prognostic factor for MESCC patients. However, our AHR-Ⅰ staging scheme, a comprehensive staging scheme that integrating T-, N-, and M-classifications, might be an optimal option for clinical practitioners to predict MESCC patients' prognosis and make proper clinical decisions.