Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer

doi:10.21203/rs.3.rs-4192847/v1

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Research Article

Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer

https://doi.org/10.21203/rs.3.rs-4192847/v1

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published 11 Sep, 2024

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Objective: This study aimed to investigate the impact of vasculogenic mimicry (VM) and postoperative adjuvant therapy on the prognosis and survival of patients with esophageal squamous cell carcinoma (ESCC), as well as to assess whether VM affects the clinical benefit of postoperative adjuvant therapy.

Methods: A single-center retrospective analysis was conducted on patients who underwent radical surgery for squamous esophageal cancer, documented in the medical record system. The presence or absence of VM in surgical specimens was determined using double staining with PAS/CD31. Stratification was applied based on adjuvant therapy and VM status. Survival curves and COX modelling were used to analyze the impact of the presence or absence of VM on the benefit of adjuvant therapy and survival prognosis of patients.

Results: VM-positive patients were more prone to postoperative recurrence and metastasis. VM was identified as an independent risk factor for progression-free survival (p<0.001, 95% CI:1.809-3.852) and overall survival (p<0.001, 95% CI:1.603-2.786) in postoperative squamous esophageal cancer. Postoperative adjuvant therapy significantly prolonged progression-free survival (p=0.008) and overall survival time (p<0.001) in patients with stage II and III esophageal cancer, with concurrent chemoradiotherapy being the most effective. However, the presence of VM significantly reduced the benefit of postoperative adjuvant therapy (p＝0.152).

Conclusion: VM negatively impacts the prognosis of postoperative ESCC patients and reduces the efficacy of postoperative adjuvant therapy.

esophageal squamous cell carcinoma

postoperative adjuvant therapy

vascular mimicry

Esophageal squamous carcinoma is a prevalent upper gastrointestinal malignancy in many economically underdeveloped countries and regions, including China. Surgical resection stands as the standard treatment, excluding cervical esophageal cancer[1]. Despite postoperative adjuvant therapy’s advancement, which complements surgical resection and enhances prognosis beyond the T1N0 stage, a considerable proportion of patients still encounter regional lymph node recurrence and distant organ metastasis. This indicates that the current adjuvant treatment strategy may overlook undefined prognostic risk factors. Therefore, further clarification of such factors is crucial to refining adjuvant treatment strategies and postoperative survival in esophageal cancer.

Vascular mimicry (VM) represents a new model of blood supply within tumors, wherein highly invasive tumor cells remodel into vascular-like channels to self-nourish[2]. VM typically thrives in hypoxic regions, intimately tied to tumor cell heterogeneity and microenvironment remodeling [3]. VM fosters the exchange of substances between the local microenvironment, including tumor cells, and the external milieu, fostering systemic symptoms and distant metastasis of the tumor. While some previous studies [4]have indicated VM’s adverse impact on postoperative survival of esophageal cancer, none have scrutinized the relationship between VM and postoperative adjuvant therapy, or delineated its intrinsic link with clinical recurrence and progression manifestations post-adjuvant therapy. Thus, the influence of adjuvant therapy on the postoperative survival benefit of VM-positive patients remains unclear.

Presently, prophylactic radiotherapy with local tumor bed + regional draining lymph nodes and systemic therapy are standard postoperative adjuvant therapies for esophageal cancer[5, 6]. Recurrence progression under these conditions, characterized by lymph nodes and metastasis to distant organs and tissues, is closely related to early escape of tumor cells from the primary lesion and adjuvant therapy resistance. Further deterioration of the tumor cell's own phenotype (stem cell-like differentiation, epithelial mesenchymal transition, and epithelial endothelial-like transition) gives it the ability to form haemangiomas, often closely linked with the acquisition of adjuvant therapy resistance at the primary site. At the same time, primary lesion hemangiomas formation provides a direct pathway for metastasis of tumor cells[7]. Intervening in VM thus emerges as a potential strategy to mitigate postoperative recurrence and progression risk in esophageal cancer patients with such pathologies.

The mechanism of VM formation is complex, involving abnormal activation of multiple signaling pathways and signaling attenuation. Similarly, postoperative adjuvant therapy mechanisms are complex, all geared towards improving prognosis, quality of life, and prolonging survival time. Currently, scant studies explore the relationship between VM and postoperative adjuvant therapy. Thus, our focus lies in elucidating whether VM affects the prognosis of postoperative esophageal cancer and the efficacy of postoperative adjuvant therapy, and if current postoperative adjuvant therapy suppresses VM, aiming to establish a foundation for developing a comprehensive therapeutic strategy for patients with VM-positive esophageal cancer.

1.1 Patient Information and Tissue Sample Sources

The study employed a single-center retrospective design, adhering to the Declaration of Helsinki and relevant Chinese laws, and received approval from the Ethics Committee (Project Ethics No. NO.TZEYLL20170401). The study subjects comprised patients with esophageal cancer who underwent surgical treatment at the Second People's Hospital of Taizhou City between 2010 and 2015. Inclusion criteria encompassed: 1) patients undergoing surgical treatment at the Second People's Hospital of Taizhou City with the same surgical style and operator; 2) postoperative pathological confirmation of squamous carcinoma; 3) availability of comprehensive patient information, including preoperative, hospitalization, follow-up adjuvant treatment, and survival of all patients at the end of follow-up. Exclusion criteria were: 1) patients diagnosed with pathologic types other than squamous carcinoma; 2) patients with revised diagnosis; 3) patients receiving neoadjuvant therapy prior to surgery; 4) patients experiencing severe treatment complications interrupting or resulting in postoperative death.

The patient's prognosis was recorded through outpatient review and telephone follow-up. The variables collected were common clinical risk indicators: gender, age, lesion site, grade of differentiation, cancer embolism, T-stage, N-stage, clinical stage, vascular mimicry, lesion length, adjunctive treatment, overall survival time and progression-free survival time.Overall survival (OS) was defined as the duration from surgery to death or last follow-up date. Progression-free survival (PFS) was defined as the period from the day after surgery to the date of disease recurrence, metastasis, or last follow-up.

1.2 CD31/PAS duble staining and analysis of VM

CD31-PAS double staining was used to identify VMs and EDVs. Paraffin-embedded tissues were serially sectioned at 4 μm, followed by dewaxing and hydration. Immunohistochemically[8, 9] staining with PAS/CD31 (primary and secondary antibodies was purchased from Shanghai Long Island Antibody Diagnostic Reagent Co.). Briefly, the procedure was as follows: after antigen repair, the sections were incubated overnight at 4°C with primary antibody (CD31 antibody reagent, JC/70A/rabbit polyantibody, product no. 0114, 1:200), and then incubated with biotinylated secondary antibody for CD31 staining, and then stained with PAS staining (Beijing Ruigen Bio-Reagent Co.), as per literature guidelines[10]. Staining results were observed under a light microscope(Olympus).

1.3 Hematoxylin-Eosin staining（HE）

HE staining was used to characterize cancer tissues and their pathological properties. Paraffin sections underwent sequential staining with hematoxylin for 5 min and eosin for 3 min after dewaxing, dehydrating, and repairing. Stained sections were dehydrated with anhydrous ethanol, permeabilized with xylene, and finally sealed with neutral resin. Observations were made using an optical microscope (Olympus).

All statistical analyses were performed using SPSS Statistics 25.0 (IBM, Armonk, NY, USA). Categorical variables were numerically expressed and comparatively analyzed using the chi-square test; grade variables were analyzed using the Mann-Whitney U test; grouping was done using binary logistic; survival analysis and comparison of survival time were done using the Kaplan-Meier and Log-rank tests; Cox regression modeling was used to analyze the relationship between each factor and postoperative recurrence metastasis. A two-sided P < 0.05 indicated that the results were statistically significant.

3.1 Demographic and clinical characteristics of patients

A total of 301 patients underwent surgery for esophageal cancer in this study. 12 cases of esophageal adenocarcinoma and 1 case of spindle cell carcinoma were excluded, leaving 288 cases of esophageal squamous carcinoma meeting the study criteria. Among these, 230 cases (79.9%) were males and 58 cases (20.1%) were females; the oldest was 82 years old, the youngest was 39 years old, with a median age of 67 years old. 160 cases (55.6%) were 67 years old or younger, while 128 cases (44.4%) were older than 67 years old. Regarding histological differentiation, there were 37 cases (12.8%) of high-differentiated squamous carcinoma, 173 cases (60.1%) of moderately-differentiated carcinoma, and 78 cases (27.1%) of poorly-differentiated carcinoma (27.1%). 75 patients (26.0%) were classified as stage I, 94 patients (32.6%) as stage II, and 119 patients (41.3%) as stage III. And 182 cases (63.2%) with a lesion length of less than 5 CM, and 106 cases (36.8%) with a lesion length of more than 5 cm (Table 1).

3.2 Morphologic structure and detection rate of VM in ESCC

Pathological specimens were analyzed by HE staining and CD31/PAS staining comparison. Endothelial dependent vessel (EDV), mosaic vessel (MV), and vasculogenic mimicry (VM) were found respectively. CD31-negative/PAS-positive vascular structures were classified as VM, CD31-positive/PAS-negative vascular structures as EDV, and CD31/PAS double-positive vascular structures as MV. 94 cases (32.6%，Fig 2c) of ESCC tissues exhibited VM structures, characterized by tubular structures away from the EDV region, PAS-positive/CD31-negative, with visible circulating erythrocytes within (Fig 1B-G). Statistically, VM-positive patients had a lower differentiation grade (p=0.044), a higher probability of presenting VTT (p<0.001), and a late N stage and clinical stage (p<0.001, p<0.001), while no statistical difference were observed in gender, age, lesion site, and T stage (p>0.05). The presence or absence of VM structures showed near variability in the length of primary lesions (p=0.054), with no statistical difference based on Fisher's exact examination (p=0.068, Table 1).

3.3 Effect of VM on recurrent metastasis and survival after ESCC surgery

The median PFS in VM-positive cases was 1 year (0.25-5.2), significantly shorter than VM-negative cases, which was 2.5 years (0.25-4.7). A significant difference was observed between the two groups (Log-rank test, p < 0.001, Figure 2a). The median OS was 1.6 years (0.5-6.4) in VM-positive cases, significantly shorter than that of 3 years (0.6-6.3) in VM-negative cases, with a statistically significant difference in the comparison between the two groups (Log-rank test,p<0.001, Figure 2b). According to COX model analysis, VM was found to be an independent risk factor affecting PFS (HR: 2.387, 95% CI: 1.809-3.152) and OS (HR: 0.531 and 95% CI: 0.384-0.734) after esophageal cancer surgery (Tables 2 and 3).

Among the 288 esophageal cancer cases, 213 (74%, 213/288) showed recurrent progression, with 85 (40%, 85/213) exhibiting local recurrence and 128 (60%, 128/213, Figure 2c) distant metastases. Common sites of metastasis included the lungs in 74 cases (34.7%, 74/213), liver in 41 cases (18.8%, 41/213), lymph nodes outside the local drainage area in 22 cases (10.3%, 22/213), and bone metastases in 30 cases (14.1%, 30/213, Figure 2d). 85 patients (90.4%, 85/94) in the VM group developed recurrent metastases compared to 128 patients (66%, 128/194) in the no-VM group, suggesting a higher likelihood of recurrent metastases in the VM group, predominantly in distant metastases.

3.4 Impact of VM on postoperative adjuvant therapy for ESCC

Among the 288 cases, 213 (74.0%) were stage II-III patients, with 155 (72.8%) receiving postoperative adjuvant therapy (Fig 3a). The median PFS was about 2.5 years (0.3-5.2) in the postoperative adjuvant therapy group and about 1.6 years (0.3-3.5) in the no postoperative adjuvant therapy group, showing a significant difference between the two groups (p=0.008, Fig 3b, left). The median OS was about 2.5 years (0.5-6.4) in the postoperative adjuvant therapy group and about 1.6 years (0.5-3.7) in the no postoperative adjuvant therapy group, with a statistical significant difference (p < 0.001, Fig 3b, right). Stage II and III postoperative patients receiving adjuvant therapy exhibited longer progression-free survival and overall survival compared to those without adjuvant therapy.

The median PFS in the postoperative adjuvant therapy group was 1.1 years (0.8-1.4) for chemotherapy-only, 1.5 years (1.3-1.7) in the group receiving radiotherapy alone, and 2.2 years (1.8-2.6) in the synchronous radiotherapy group, showing statistical differences among the three groups (p=0.001, Fig 3c,left), and the synchronous radiotherapy yielded the longest PFS among the three adjuvant therapies. This trend was also reflected in OS (p=0.004, Fig 3c,right). Postoperative adjuvant therapy was able to reduce the risk of postoperative recurrent progression by 46.2% in stage II and III patients by Cox model analysis (HR: 0.649 95% CI: 0.469-0.898, Fig 3d).

The median PFS for patients with VM in stages II and III who did not receive postoperative adjuvant therapy was approximately 0.7 years (0.4-3.2). The median PFS was 0.9 years (0.4-1.5) for those receiving radiotherapy alone, 0.9 years (0.3-3.6) for chemotherapy, and 1.6 years (0.2-5.2) for concurrent radiotherapy and chemotherapy, with no significant difference among the four groups (Log-rank p=0.056, Fig 4c, left). Respectively，the median OS was 0.9 years (0.5-3.7), 1.4 years (0.5-5.1), 1.4 years (0.5-5.4), and 2.4 years (0.8-6.4), with no significant difference among the four groups (Log-rank p=0.152, Fig 4c, right).These results showed no significant prolongation of PFS and OS by adjuvant therapy in VM-positive patients, and no significant differences were observed between adjuvant treatments.

Among patients without VM in stages II and III, the median PFS was 1.2 years (0.3-3.5) for patients without postoperative adjuvant therapy, 2.1 years (0.2-3.3) for radiotherapy alone, 1.7 years (0.3-4.7) for chemotherapy alone, and 3.3 years (0.7-3.7) for simultaneous radiotherapy and chemotherapy, with a significant difference among the four groups (Log-rank p < 0.001, Fig 4g). The median OS was 1.8 years (2-3.6) for no adjuvant therapy, 2.7 years (0.7-3.6) for radiotherapy alone, 2.4 years (1.2-5) for chemotherapy alone, and 3.7 years (1.2-4.8) for concurrent radiotherapy and chemotherapy, with a significant difference between the three groups (Log-rank p<0.001, Fig 4h). T The results showed that postoperative adjuvant therapy was effective in prolonging PFS and OS and effectively improving prognosis in stages II and III, with concurrent radiotherapy and chemotherapy being particularly effective.

Survival analyses of patients in the VM(+) and VM(-) groups in stages II and III showed that patients in the VM-negative group had a median survival and OS approximately twice that of the VM group in the absence of adjuvant therapy. The three different adjuvant treatment modalities presented a more favorable therapeutic effect in the group without VM compared to the group with VM, resulting in prolonged PFS and OS by more than one year. The analysis showed that VM reduced the clinical benefit of postoperative adjuvant therapy in patients with ESCC.

Several previous studies have demonstrated the association between vascular mimicry and tumor invasion, recurrence, metastasis, and poor prognosis, making VM a potential target for antitumor therapy in recent years [11-13]. In this study, we found a VM incidence in resectable esophageal cancer was 32.6% (94/288，Fig 2c), and patients with VM structures had a postoperative recurrence progression rate of 90.4% (85/94，Fig 2c). In addition, our findings show that VM compromises the effectiveness of postoperative adjuvant therapy, with conventional adjuvant therapy failing to significant prolong disease-free survival or overall survival in VM-positive patients based on relevant survival analyses. These results indicate that the formation of VM in esophageal cancer not only accelerates postoperative recurrence and metastasis but also contributes to the resistance of tumors to conventional treatment. Thus, further studies into the mechanisms underlying VM formation are needed to mitigate its adverse effects on adjuvant therapy by intervening in its formation, ultimately reducing the risk of postoperative recurrence and metastasis in esophageal cancer.

Since Maniotins et al. discovered and named the phenomenon of vascular mimicry in melanoma in 1999, more and more studies have shown its pivotal role in tumor invasion and metastasis, with research on the mechanism of VM gradually deepening. However, the mechanism of VM remains to be fully elucidated due to the complexity of VM itself. Hypoxia has emerged as a central factor in the formation of VM, as indicated by numerous studies [14, 15]. In this study, it was found (Fig.1D) that the areas where the three vascular morphologies (VM, MV and EDV) were present in the surgical specimens of esophageal cancer had some regional differences. VM tended to appear in an area farther away from EDV, typically in a hypoxic area distant away from the center of the tumor. In order to obtain nutrients and oxygen for their own growth, tumors form VM that do not depend on endothelial cells but have endothelial-like vascular structure and function, so VM is predominantly located in the center of the tumor; endothelium-dependent blood vessels are found in oxygen-rich areas, mostly at the margins away from the center of the tumor; and mosaic blood vessels are found at the junction of these regions. As oxygen concentration decreased, the sequential distribution of EDV, MV and VM is observed.

Currently, conventional postoperative adjuvant therapy for esophageal cancer includes radiotherapy, chemotherapy, and concurrent chemoradiotherapy. In this study, we found that the order of efficacy of the three modalities was simultaneous radiotherapy > radiotherapy > chemotherapy. However, none of these conventional adjuvant therapies were effective in VM-positive patients. Previous studies on postoperative adjuvant therapy for esophageal squamous carcinoma have shown its clinical value [5, 16], with studies indicating that POCT[17] improves the survival rate of lymph node-positive and -negative patients, and PORT[18] reduces the risk of tumor recurrence and prolongs survival time[19]. While conventional adjuvant therapy can temporarily impede the growth of tumors with VM, it lacks significant inhibitory effects on metastasis and malignancy in the distant future. The stemness and differentiation of tumor stem cells can drive VM formation, endowing it with the ability to establish blood transport pipelines and providing a pathway for tumor escape [20, 21]. Most current anti-angiogenic treatments are based on the theory of VM to develop drugs that inhibit tumor angiogenesis by targeting endothelial growth factors, aiming to correct tumor vascular system disorders and sever the tumor-donor connection [22, 23]. However, existing anti-angiogenic treatments may not effectively target VM, as it represents another mode of tumor microcirculation angiogenesis, and their hypoxia-causing side effects may accelerate VM formation [14, 24-27]. The strategy of the comprehensive treatment of oesophageal cancer is still in urgent need of updating.

This study confirms that angiomas and postoperative adjuvant therapy are opposing factors in esophageal cancer, highlighting a subtle relationship between these factors. Specifically, VM significantly reduces the efficacy of postoperative adjuvant therapy, while conventional adjuvant therapy’s inability to effectively suppress angiogenesis leads to a lack of clinical benefit in adjuvant therapy in angioma-positive patients, contradicting the original therapeutic intent and posing a significant challenge to clinicians and patients alike. Breaking the unilateral influence of VM on the effectiveness of postoperative adjuvant therapy for ESCC is essential to offer more comprehensive treatment options for ESCC patients. Therefore, in-depth studies into the relevant signaling pathways and key genes involved in VM formation and its mechanisms are warranted to provide a solid theoretical basis for subsequent drug development and the expansion of therapeutic modalities. Due to the fact that this study is a retrospective study, the sample size collected is small, and there is bias in variables such as age and gender, the above may affect the results to some extent. In the follow-up study, we will try to expand the sample size and conduct related studies in different hospitals and districts to test the accuracy of this study.

Our findings suggest that VM is an important risk factor affecting the prognosis of ESCC, and that VM may exert its efficacy by interfering with postoperative adjuvant therapy, thereby accelerating disease progression. Therefore, we further pondered whether the clinical efficacy of adjuvant therapy could be improved by intervening in the formation of vascular stimulating hormones to better improve the prognosis of ESCC.

VM:Vascular mimicry; ESCC:Esophageal squamous cell carcinoma; PFS: Progression-free survival; OS:Overall survival; POCT:Postoperative chemotherapy; PORT:Postoperative radiotherapy; POCRT:Postoperative radiochemotherapy; EDV:Endothelium-dependent vasodilation; MV:Mosaic vessel.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

Not applicable.

Contributions

JC: Project administration, Conceptualization, Writing-review & editing, Funding acquisition, Supervision; YW: Writing-Original draft, Data curation; MKW: Formal analysis, Writing-embellishment; KKY: Formal analysis, Experiment, Data curation; JCL: Investigation, Documentation management; JYC: Validation, Documentation management. All authors reviewed the manuscript.

Funding

This research received no external funding.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the institutional review board of the second People’s hospital of Taizhou city (TZEYLL20170401) and conducted according to the Declaration of Helsinki and Chinese laws. The need for individual consent was waived by the committee because of the retrospective nature of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Table 1 Demographic and clinical characteristics of the patients

Characteristics	Category	All(n=288，%)	Without VM(n=194，%)	With VM(n=94，%)	P value
Gender	Male	230（79.9）	154（79.4）	76(80.9)	0.771
	Female	58（20.1）	40(20.6)	18(19.1)
Age(years)	≤67	160（55.6）	108(55.7)	52（55.3）	0.955
	＞67	128(44.4)	86(44.3)	42（44.7）
Location	Upper	22(7.6)	15（7.7）	7（7.4）	0.932
	Middle	192(66.7)	134（69.1）	58（61.7）
	Lower	74(25.7)	45（23.2）	29（30.9）
Differentiation	Well	37（12.8）	27（13.9）	10（10.6）	0.044
Differentiation	Moderate	173(60.1)	122(62.9)	51(54.3)
	Poor	78(27.1)	45(23.2)	33(35.1)
VTT	With	49(17)	22（11.3）	27（28.7）	＜0.001
	Without	239(83)	172（88.7）	67（71.3）
T stage	T1	51(17.7)	38（19.6）	13（13.8）	0.231
	T2	68(23.6)	42（21.6）	26（27.7）
	T3	150(52.1)	104（53.6）	46（48.9）
	T4	19(6.6)	10（5.2）	9（9.6）
N stage	N0	140(48.6)	125（64.4）	15（16.0）	＜0.001
	N1	118(41.0)	57（29.4）	61（64.9）
	N2	24(8.3)	11（5.7）	13（13.8）
	N3	6(2.1)	1（0.5）	5（5.3）
Clinical stage	Ⅰ	75(26.0)	66（34.0）	9（9.6）	＜0.001
	Ⅱ	94(32.6)	67（34.5）	27（28.7）
	Ⅲ	119(41.3)	61（31.4）	58（61.7）
Focal length(cm)	＜5（cm）	182(63.2)	130（67)	52(55.3)	0.054
	≥5（cm）	106(36.8)	64(33)	42(44.7)	Fisher 0.068

All are shouwn as n(%); VM vasculogenic mimicry, VTT vascular tumor thrombus

Table 2 Univariate and multivariate analyses of progression-free survival among patients with ESCC

Univariable analysis					Multivariable analysis
Variable	HR	95%CI		p	HR	95%CI		p
Gender (male/female)	0.95	0.677	1.332	0.766
Age （≤67/＞67）	1.043	0.794	1.369	0.765
Location（Upper/Middle-Lower）	1.104	0.653	1.868	0.711
Differentiation（Poor/Well-Moderate）	0.686	0.511	0.921	0.012	0.723	0.529	0.988	0.042
T stage （T1/2-4）	1.989	1.494	2.889	＜0.001	1.934	1.249	2.996	0.003
N stage （N0/1-3）	3.009	2.273	3.984	＜0.001	2.112	1.467	3.04	＜0.001
Clinical stage （1/2-3）	3.073	2.141	4.41	＜0.001	1.689	1.085	2.628	0.02
VTT（with/without）	2.157	1.548	3.006	＜0.001	1.593	1.122	2.261	0.009
VM（with/without）	2.387	1.809	3.152	＜0.001	1.785	1.301	2.45	＜0.001
Adjuvant treatment （with/without）	1.193	0.895	1.591	0.229	0.593	0.434	0.812	0.001

HR hazard ratio, CI confidence interval, vascular tumor thrombus

Table 3 Univariate and multivariate analyses of overall survival among patients with ESCC

Univariable analysis					Multivariable analysis
Variable	HR	95%CI		p	HR	95%CI		p
Gender	0.946	0.675	1.327	0.748
(male/female)
Age	1.115	0.849	1.464	0.434
（≤67/＞67）
Location	1.006	0.595	1.703	0.981
（Upper/Middle-Lower）
Differentiation	0.616	0.458	0.828	0.001	0.695	0.503	0.961	0.028
（Poor/Well-Moderate）
T stage （T1/2-4）	2.062	1.546	2.75	＜0.001	1.665	1.082	2.563	0.021
N stage （N0/1-3）	2.763	2.088	3.657	＜0.001	1.817	1.27	2.599	0.001
Clinical stage （1/2-3）	3.117	2.169	4.479	＜0.001	2.104	1.322	3.351	0.002
VTT (with/without）	2.372	1.699	3.311	＜0.001	1.79	1.244	2.577	0.002
VM (with/without)	2.113	1.603	2.786	＜0.001	1.659	1.214	2.268	0.001
Adjuvant treatment (with/without)	1.141	0.857	1.519	0.367	0.531	0.384	0.734	＜0.001

HR hazard ratio,CI confidence interval, vascular tumor thrombus

No competing interests reported.

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published 11 Sep, 2024

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Vasculogenic mimicry triggers early recidivation and resistance to adjuvant therapy in esophageal cancer

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