Five-year progression-free survival and overall survival based on CD73 and CD155 expression in resected epithelial malignant pleural mesothelioma: a retrospective single-centre study

Five-year progression-free survival and overall survival based on CD73 and CD155 expression in resected epithelial malignant pleural mesothelioma: a retrospective single-centre study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Five-year progression-free survival and overall survival based on CD73 and CD155 expression in resected epithelial malignant pleural mesothelioma: a retrospective single-centre study Yusuke Nabe, Yasuhiro Fujita, Teppei Hashimoto, Kanji Tanaka, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6538045/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour requiring multidisciplinary treatment. Identifying prognostic biomarkers could improve treatment planning and patient outcomes. CD73 and CD155 are immunomodulatory molecules involved in immune evasion and tumour progression in various cancers; however, their roles in MPM remain unclear. Therefore, this study aimed to investigate the association between CD73 and CD155 expression in resected epithelial MPM specimens and their impact on 5-year progression-free survival (PFS) and 5-year overall survival (OS). Methods: This single-centre retrospective study included 43 consecutive patients with epithelial MPM who underwent curative-intent surgery, with or without chemotherapy and immune checkpoint inhibitor (ICI) treatment, at our institution between January 1, 2013 and December 31, 2020. Immunohistochemical staining for CD73 and CD155 was performed on surgical specimens, and HALO-AI pathology software was used for quantitative analysis. Receiver operating characteristic (ROC) curve analysis determined cutoff values for CD73/CD155 positivity. Patients were categorised into CD73+/CD155+ and non-CD73+/CD155+ groups and survival outcomes (5-year PFS and 5-year OS) were analysed using Kaplan–Meier curves. Cox proportional hazards regression was used for univariate and multivariate analyses to identify independent prognostic factors. Results: Among 35 evaluable cases, patients with CD73+/CD155+ tumours had significantly improved 5-year PFS compared with those with non-CD73+/CD155+ tumours (64.8% vs. 10.8%, p=0.017), though OS differences were not significant (p=0.376). Among CD73+/CD155+ patients, those who underwent postoperative pleurodesis with OK432 demonstrated significantly higher PFS (83.3% vs. 33.3%, p=0.043), suggesting a potential therapeutic benefit. In contrast, in non-CD73+/CD155+ cases, postoperative chemotherapy significantly improved PFS (p=0.03). Multivariate analysis revealed non-CD73+/CD155+ expression and lack of postoperative chemotherapy as independent predictors of disease progression (HR 6.555, p=0.008) and mortality (HR 5.835, p=0.006). Among recurrent cases, patients treated with ICIs had significantly improved OS (p=0.001), highlighting the potential role of immunotherapy in this subgroup. Conclusions: CD73 and CD155 expression patterns may serve as prognostic biomarkers in epithelial MPM. CD73+/CD155+ tumours appear to benefit from pleurodesis with OK432, while non-CD73+/CD155+ tumours may be more responsive to postoperative chemotherapy. These findings suggest that CD73/CD155 status could guide personalised treatment strategies in MPM, warranting further validation in larger cohorts. Surgery CD155 antigen CD73 antigen chemotherapy adjuvant disease progression immunotherapy malignant pleural mesothelioma pleurodesis prognostic biomarkers survival analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Background Malignant pleural mesothelioma (MPM) accounts for 94.5% of all malignant mesothelioma cases, with 87% of patients having a history of asbestos exposure, highlighting a strong association between asbestos and tumour development [ 1 ]. The United States introduced its first asbestos regulations in 1973, while many European countries implemented partial or complete bans in the 1980s and 1990s. However, some non-European countries, such as Albania, Andorra, and Armenia, have yet to enforce such restrictions [ 2 ]. Although malignant mesothelioma is classified as a rare cancer, it has a long latency period, with the condition developing even 40 years or more after asbestos exposure [ 3 ]. Consequently, the incidence of malignant mesothelioma is expected to rise in the future. The prognosis for MPM remains poor, with a median survival of approximately 12 months after diagnosis [ 4 ] and a 5-year survival of only 5% [ 5 ]. Treatment of MPM typically involves a multidisciplinary approach, including surgery, chemotherapy, and radiation therapy. For resectable tumours, the standard surgical approach aims for macroscopic complete resection, typically performed via either pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). P/D, which preserves lung parenchyma, is associated with lower perioperative mortality than EPP [ 6 ]. Factors such as sarcomatoid histology, contralateral mediastinal or supraclavicular lymph node metastases, extrathoracic disease, multilevel chest wall involvement, or inadequate cardiopulmonary reserve may preclude the benefits from surgery [ 7 ]. A recent randomised controlled trial found that extended P/D was associated with lower 2-year survival and a higher incidence of serious adverse events than chemotherapy alone [ 8 ], reinforcing the critical role of chemotherapy in the treatment of MPM. Among chemotherapy regimens, pemetrexed (PEM) combined with cisplatin and vitamin supplementation has demonstrated superior outcomes in survival, time to progression, and response rate to cisplatin monotherapy [ 9 ]. More recently, immune checkpoint inhibitor (ICI) therapy with nivolumab and ipilimumab has shown significant improvements in overall survival (OS) compared with standard chemotherapy [ 10 ]. Additionally, studies have reported promising results with combination therapies involving chemotherapy, ICIs, or angiogenesis inhibitors [ 11 – 13 ]. Furthermore, pleurodesis has been shown to improve survival in patients with malignant pleural effusion, including those with MPM [ 14 ]. Although several biomarkers for MPM have been reported [ 15 , 16 ], there are no widely generalised biomarkers that can be used to guide optimal treatment strategies. These findings indicate the need to develop additional biomarkers for improving treatment planning. Cluster of differentiation 73 (CD73), an enzyme expressed on the surface of cancer and immune cells, plays a key role in converting adenosine monophosphate to extracellular adenosine, thereby contributing to an immunosuppressive tumour microenvironment [ 17 ]. Targeting CD73 may help reverse this immunosuppression by enhancing CD8 + effector cell activity, activating macrophages, and reducing the presence of myeloid-derived suppressor cells and regulatory T lymphocytes [ 18 , 19 ]. Moreover, targeting cancer cell CD73 directly inhibits tumour cell migration and metastasis [ 20 ]. CD155, also known as the poliovirus receptor (PVR), was initially identified as a poliovirus receptor [ 21 ]. CD155 is involved in immune regulation through interactions with the costimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. CD155 has been reported to influence tumour-infiltrating lymphocyte function [ 22 ] and facilitate tumour cell invasion and migration [ 23 ]. According to the 2015 World Health Organization’s histological classification, malignant mesothelioma is primarily classified into epithelioid, sarcomatoid, and biphasic subtypes. Among these, the epithelioid subtype is associated with a more favourable prognosis [ 24 ]. To the best of our knowledge, no studies to date have investigated the relationship between CD73 and CD155 expression and prognosis in patients with MPM. MPM is characterised by relentless local progression, with hematogenous metastasis being rare in the advanced stages. Despite aggressive local control measures, most patients experience locoregional recurrence [ 25 ]. Improvement in local invasion control by combining conventional chemotherapy with ICI and molecular targeted drugs could increase the number of patients who could be cured by surgery. These findings supported the importance of identifying biomarkers for considering new treatment strategies. We hypothesised that high CD73/CD155 expression is associated with poorer prognosis in epithelial MPM. Therefore, this study aimed to investigate the relationship between CD73 and CD155 expression in resected specimens of epithelial MPM and their impact on 5-year progression-free survival (PFS) and 5-year OS. Herein, we investigated the expression of CD73 and CD155 in resected specimens of MPM, focusing on the migration, metastasis, and invasion ability of cancer cells. Methods Patients This single-centre retrospective study included 43 cases of epithelial MPM in consecutive patients who underwent surgery at our hospital between January 1, 2013, and December 31, 2020. Patients who did not provide consent and cases with unknown progression dates due to transfer to other hospitals were excluded. A flowchart outlining case selection is provided in Fig. 1 . Treatment decisions were made at the discretion of the attending physician, with the primary treatment plan determined through a multidisciplinary conference involving multiple thoracic surgeons. Postoperative follow-up included blood tests, chest X-rays, and computed tomography (CT) scans at least every 6 months. In cases where recurrence was suspected, PET/CT scans were performed at the discretion of the treating physician. Immunohistochemical examination was performed on surgically resected specimens for all cases. Serial sections were obtained from each formalin-fixed, paraffin-embedded primary tumour specimen. Ethics declaration Ethics declaration The authors have completed the STROBE reporting checklist. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of the University of Occupational and Environmental Health (Japan; No.: UOEHCRB21-065). Patients who were unable to provide informed consent were excluded; thus, written informed consent was obtained for all specimen sections included in the study. CD73 immunohistochemistry The primary antibodies used were NT5E/CD73 (D7F9A) Rabbit monoclonal antibody (mAb) (Cell Signalling Technology, Danvers, MA, USA; #13160; 1:200 dilution) and Rabbit (DA1E) mAb IgG XP Isotype Control (Cell Signalling Technology; #3900S; 1:200 dilution). Primary antibodies were incubated for 1 h at room temperature. Signal Stain Boost (Cell Signalling Technology; #8114) was used as the secondary antibody and Signal Stain Diluent (Cell Signalling Technology; #8112) was used for antibody dilution. An isotype control (diluted 1:200) was used as a negative control. Additional reagents included citrate buffer (pH 9), blocking buffer (Agilent Technologies, Santa Clara, CA, USA; X090930), the DAKO Envision + Kit/HRP (DAB) (Agilent Technologies; K3458), the DAB + substrate kit (Agilent Technologies; K3468), and phosphate-buffered saline (PBS). Immunohistochemistry was performed according to the manufacturers’ protocols. CD155 immunohistochemistry A549 cells were used as a positive control. The primary antibody used was PVR/CD155 (D8A5G) Rabbit mAb #81254 (diluted 1:200). Primary antibodies were incubated for 1 hour at room temperature. An isotype control (diluted 1:200) was used as a negative control. Both the primary antibody and isotype control were diluted using Signal Stain Diluent (Cell Signalling Technology; #8112), while the secondary antibody was diluted using Signal Stain Boost (#8114). Other reagents used included citrate buffer solution (LSI Medience Corporation, Tokyo, Japan; RM102-C), blocking buffer (a non-specific reaction blocking reagent containing casein, Agilent Technologies Japan, Ltd., X090930), the DAKO Envision + Kit/HRP (DAB) DAB + Substrate Kit (Code: K3458), and PBS. Immunohistochemistry was performed according to the manufacturers’ protocols. HALO-AI In immunohistochemical evaluations, the tumour proportion score (TPS) used for PD-L1 assessment can vary depending on the experience of the evaluating pathologist, leading to potential subjectivity. HALO-AI, an artificial intelligence-based pathological analysis tool, offers the potential for more objective and standardised evaluations. Reports on its applications have been increasing in recent years [ 26 – 31 ]. All slides stained with haematoxylin and eosin, CD73, and CD155 were digitised at 20× magnification using NDP.view2 (Hamamatsu Electronic Press Co., Iwata, Japan). Analysis was conducted using the Halo Image Analysis Platform v3.6 (IndicaLabs) with the Membrane v1.7 module. The AI system calculated the percentage of CD73- and CD155-positive tumour cells by segmenting the tissue into tumour cell, stromal, and background categories. A pathologist manually annotated malignant and non-malignant areas on each slide, carefully excluding ambiguous regions and areas with artefacts. Pleurodesis Following local anaesthesia of the pleural cavity with xylocaine, OK432 dissolved in saline was injected into the pleural cavity via a chest drain. OK432 is composed of heat-treated, penicillin-killed, freeze-dried Streptococcus pyogenes group A2 (Picibanil, Chugai Pharmaceutical Ltd., Japan). Statistical analysis We analysed whether the percentage of CD73- and CD155-positive cells in resected specimens of epithelial MPM followed a normal or non-normal distribution using normal Q-Q plots. We calculated the mean and standard deviation of 5-year PFS for the CD73+/CD155 + group, non-CD73+/CD155 + group, and overall and performed sample size adequacy and power analyses. Power analysis was based on the difference in the mean values ​​between the CD73+/CD155 + group and non-CD73+/CD155 + group and the overall standard deviation. The required sample size was calculated with an alpha error of 0.05, a statistical power of 0.8, and a sample ratio of 1:2.5. The number of samples required was 17 for the CD73+/CD155 + group and 42.5 for the non-CD73+/CD155 + group. Categorical data were compared using a two-sided Fisher's exact test, while continuous data were analysed using the nonparametric Mann–Whitney U test. To determine the optimal cutoff values for the percentage of CD73- and CD155-positive cells, receiver operating characteristic (ROC) curves were constructed by plotting the model’s false positive rate against its true positive rate for predicting tumour recurrence and the area under the curve (AUC) was calculated. The Kaplan–Meier method was used to estimate 5-year PFS and 5-year OS, with differences in survival between the CD73+/CD155 + group and non-CD73+/CD155 + group analysed using the log-rank test. Univariate and multivariate analyses were conducted using Cox proportional hazards regression models to identify independent prognostic factors. Significant prognostic factors from the univariate analysis, along with potential poor prognostic factors, were included as covariates in the multivariate analysis. EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R (The R Foundation for Statistical Computing), was used for sample size adequacy and power analyses. Other statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY, USA). Statistical significance was defined as p < 0.05 ( q < 0.05 in multivariate analysis). Results Patient demographics are summarised in Table 1 . The majority of patients were male, comprising 85.7% (30/35) of the cohort. P/D was the predominant surgical procedure, performed in 82.9% (29/35) of cases. Pathological staging was standardised according to the UICC-TNM Classification (8th edition), with stage IB representing 45.7% (16/35) of patients. Preoperative pleurodesis was performed in 42.9% (15/35) of cases and postoperative pleurodesis in 51.4% (18/35). Talc was used in 20% (3/15) of preoperative pleurodesis cases, while OK432 was used in the remaining 80% (12/15). OK432 was exclusively used for postoperative pleurodesis. Preoperative chemotherapy was administered to 22.9% (8/35) of patients, while postoperative chemotherapy was administered to 77.1% (27/35), with 92.6% (25/27) receiving a regimen containing PEM. Disease progression within 5 years post-surgery was observed in 68.6% (24/35) of cases. Among the 19 deaths recorded, 89.5% (17/19) were attributed to MPM, while the remaining two deaths resulted from acute exacerbation of interstitial pneumonia (one case) and an unknown cause (one case). The median PFS and OS within 5 years post-surgery were 13 months and 28 months, respectively. Table 1 Demographic characteristics of the study patients Patient characteristics (n = 35) Age (median), years 69 (47–79) Sex Male 30 Female 5 Surgical procedure P/D 29 EPP 1 Debulking Surgery 2 Partial resection 2 Pleurectomy 1 p-stage (UICC-TNM Classification Ver.8) IA 4 IB 16 II 1 IIIA 5 IIIB 9 Pleurodesis Preoperative 15 Postoperative 18 Chemotherapy Preoperative 8 Postoperative 27 Pemetrexed-containing regimens 25 Progression (within 5 years) 24 Cause of death (within 5 years) Death from underlying disease 17 Death from other illnesses 1 Details unknown 1 Progression-free survival within 5 years (median) 13 months Overall survival within 5 years (median) 28 months The results of the analysis of the mean and standard deviation of 5-year PFS for the CD73+/CD155 + group, non-CD73+/CD155 + group, and overall cohort are shown in Table 2 . Table 2 Results of the analysis of the mean and standard deviation of 5-year PFS n Mean Standard deviation Non-CD73་/CD155་ 25 16.88 14.698 CD73་/CD155་ 10 33.5 27.228 Total 35 21.63 20.169 PFS: progression-free survival Examples of immunostaining results for CD73 and CD155 are shown in Fig. 2 . The percentage of MPM tumour cells immunostained for CD73 and CD155 was analysed using HALO-AI. Analysis of normal Q-Q plots showed that the percentage of cells positive for CD73 and CD155 immunostaining in the resected specimens of epithelial MPM was non-normally distributed (Fig. 3 ). The analysis results from HALO-AI are provided in Additional file 1. Cutoff values for CD73 and CD155 positivity were determined using ROC curve analysis, with positivity defined as ≥ 8.63% for CD73 and ≥ 3.75% for CD155 (Fig. 4 ). Patient characteristics based on tumour CD73 and CD155 status are summarised in Table 3 . No significant differences were observed in 5-year PFS and 5-year OS across different CD73 and CD155 expression groups (Additional files 2 and 3). The 5-year PFS was 64.8% in the CD73+/CD155 + group compared with the 10.8% in the other groups (CD73-/CD155-, CD73-/CD155+, CD73+/CD155-), indicating a significantly worse prognosis for groups other than CD73+/CD155+ (p = 0.017) (Fig. 5 a). However, no significant difference was observed in the 5-year OS between the CD73+/CD155 + group and other groups (p = 0.376) (Fig. 5 b). Table 3 Patient characteristics according to tumour CD73 and CD155 status Variables Total % Positive cells (MPM/CD73) % Positive cells (MPM/CD155) All patients, n (%) Positive Negative P-value Positive Negative P-value 35 13 (37.1) 22 (62.9) 16 (45.7) 19 (54.3) Age (years) 0.180 0.230 Median 69 73 68.5 72 68 Range 47–79 61–79 47–77 56–79 47–77 Sex 0.630 0.347 Male 30 12 18 15 15 Female 5 1 4 1 4 Surgical procedure 0.648 0.379 P/D 29 10 19 12 17 other 6 3 3 4 2 Pathological stage 0.999 0.739 I/II 21 8 13 9 12 III 14 5 9 7 7 Postoperative pleurodesis 0.489 0.315 Yes 18 8 10 10 8 No 17 5 12 6 11 Postoperative chemotherapy 0.433 0.105 Yes 27 9 18 10 17 No 8 4 4 6 2 The impact of postoperative pleurodesis on 5-year PFS was examined by comparing the CD73+/CD155 + group with the other groups (Fig. 6 ). Among patients in the CD73+/CD155 + group, those who underwent postoperative pleurodesis had a significantly higher 5-year PFS (83.3%) than those who did not (33.3%, p = 0.043). In contrast, in the non-CD73+/CD155 + group, the 5-year PFS for patients who underwent postoperative pleurodesis was 18.2%. The association between postoperative chemotherapy and 5-year PFS was compared between the CD73+/CD155 + group and other groups (Fig. 7 ). In the non-CD73+/CD155 + group, patients who received postoperative chemotherapy had a significantly higher 5-year PFS (12.9%) than those who did not (0%, p = 0.003). However, in the CD73+/CD155 + group, the 5-year PFS remained at 66.7% regardless of whether postoperative chemotherapy was administered, indicating no significant difference in outcome. In the CD73+/CD155 + group, the proportion of patients who underwent postoperative pleurodesis was 60% (6/10) in those who received postoperative chemotherapy and 50% (2/4) in those who did not. In the non-CD73+/CD155 + group, the proportion was 42.9% (9/21) in the chemotherapy group and 50% (2/4) in the non-chemotherapy group. Survival analysis was conducted using a Cox proportional hazards regression model, incorporating age, sex, surgical technique, stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155 + expression status as covariates. The results of the univariate and multivariate analyses for 5-year PFS are presented in Table 4 . In the univariate analysis, a significant difference was observed for CD73+/CD155 + expression status, with the non-CD73+/CD155 + group demonstrating a higher risk of disease progression (HR 3.927, p = 0.029). In the multivariate analysis, which included stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155 + expression status as covariates, significant associations were found for both postoperative chemotherapy and CD73+/CD155 + expression. Table 4 Hazard ratio for progression-free survival Covariates Univariate Multivariate Hazard ratio 95% confidence interval p value Hazard ratio 95% confidence interval p value Age 0.975 0.919–1.033 0.389 − − − Sex (male vs. female) 0.46 0.164–1.294 0.141 − − − Surgical procedure (P/D vs others) 1.566 0.532–4.608 0.416 − − − Pathological stage (I/II vs. III) 0.477 0.212–1.074 0.074 0.486 0.206–1.145 0.099 Postoperative pleurodesis (yes vs no) 2.264 0.985–5.204 0.054 1.703 0.723–4.009 0.223 Postoperative chemotherapy (yes vs no) 2.354 0.859–6.447 0.096 5.593 1.596–19.603 0.007 CD73+/CD155+ (yes vs no) 3.927 1.147–13.441 0.029 6.555 1.630–26.356 0.008 Patients who did not receive postoperative chemotherapy had a significantly higher risk of recurrence than those who did (HR 5.593, p = 0.007). Additionally, among the other groups, patients in the non-CD73+/CD155 + group had a significantly higher risk of postoperative progression (HR 6.555, p = 0.008). Table 5 presents the results of the univariate and multivariate analyses of 5-year OS. In the univariate analysis, significant differences were observed for postoperative pleurodesis (p = 0.012) and postoperative chemotherapy (p = 0.012). The absence of postoperative pleurodesis (HR 3.539) and the absence of postoperative chemotherapy (HR 3.5) were associated with an increased risk of mortality. In the multivariate analysis, which included disease stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155 + expression status as covariates, postoperative chemotherapy remained a significant factor (p = 0.006). Patients who did not receive postoperative chemotherapy had a significantly higher risk of death than those who did (HR 5.835). Table 5 Hazard ratio for overall survival Covariates Univariate Multivariate Hazard ratio 95% confidence interval p value Hazard ratio 95% confidence interval p value Age 1.033 0.965–1.106 0.35 − − − Sex (male vs. female) 1.327 0.305–5.779 0.706 − − − Surgical procedure (P/D vs others) 1.412 0.410–4.870 0.585 − − − Pathological stage (I/II vs. III) 0.532 0.215–1.315 0.172 0.532 0.172–1.642 0.272 Postoperative pleurodesis (yes vs no) 3.539 1.327–9.438 0.012 2.755 0.969–7.828 0.057 Postoperative chemotherapy (yes vs no) 3.500 1.311–9.344 0.012 5.853 1.664–20.586 0.006 CD73+/CD155+ (yes vs no) 1.639 0.537–5.001 0.385 2.597 0.704–9.576 0.152 Among the 24 patients who experienced disease recurrence, the 5-year OS was compared among those who did not receive chemotherapy, those who received chemotherapy without a history of ICI use, and those who received chemotherapy with a history of ICI use (Fig. 8 ). The chemotherapy group with a history of ICI treatment showed a significantly improved prognosis (p = 0.001). A cross-tabulation of each treatment group and the CD73+/CD155 + status of recurrent cases is shown in Table 6 . Table 6 Cross-tabulation of CD73/CD155 expression and treatment groups in patients with relapsed epithelial malignant pleural mesothelioma CD73/CD155 status Non-chemotherapy group Chemotherapy group (without a history of ICI use) Chemotherapy group (history of ICI use) CD73+/CD155+ 2 0 1 Others 6 3 12 Discussion This study investigated the prognostic significance of CD73 and CD155 expression in epithelial MPM and explored the impact of postoperative pleurodesis and chemotherapy on survival outcomes. The CD73+/CD155 + group had significantly better 5-year PFS, particularly after postoperative pleurodesis, while showing potential resistance to chemotherapy. These findings suggest that CD73 and CD155 may serve as biomarkers for predicting treatment response, highlighting the need for further research on targeted therapies. Initially, we hypothesised that cases with high CD73 and CD155 expression would have poorer PFS and OS. However, the CD73-positive/CD155-positive group demonstrated a significantly better 5-year PFS than the non-CD73-positive/CD155-positive group. Cabioglu et al. reported that patients with triple-negative breast cancer with high CD73 expression had significantly improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) compared with those with low CD73 expression (10-year DFS: 77.9% vs. 34.8%, p = 0.021; 10-year DSS: 90.9% vs. 37.3%, p = 0.015) [ 32 ]. These findings suggest that CD73 expression may have contributed to the improved PFS observed in the CD73-positive/CD155-positive group. In contrast, the expression of CD73 and CD155 genes has been reported to be a negative prognostic factor [ 33 ]. One possible reason why the results of this study were contrary to our expectations is that multidisciplinary treatments, such as pleurodesis and chemotherapy, performed after surgery for MPM may have affected CD73-positive/CD155-positive patients. In the study by Cabioglu et al., all patients received anthracycline-containing NAC followed by a taxane before surgery [ 32 ], which may have affected the outcomes of CD73-positive patients. We believe that exploring treatments that affect the prognosis of CD73-positive/CD155-positive patients will lead to the development of personalised treatments. In the CD73-positive/CD155-positive group, patients who underwent postoperative pleurodesis with OK432 had a significantly better PFS than those who did not (83.3% vs. 33.3%, p = 0.043). This suggests that postoperative pleurodesis using OK432 may be effective in CD73-positive/CD155-positive cases. In Japan, the use of sterilised modified talc for preventing the re-accumulation of malignant pleural effusion was approved by the Japanese Ministry of Health, Labor, and Welfare in December 2013 [ 34 ]. Therefore, our institution has limited experience using talc in pleurodesis for MPM. Instead, OK432, which has been widely used in Japan, was utilised for all cases of postoperative pleurodesis. OK432 (Picibanil®), a streptococcal preparation, enhances dendritic cell maturation and induces antigen-specific cytotoxic T cells in colon cancer cell lines [ 35 ]. A recent study has shown that OK432 treatment activates the cyclic GMP–AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, increasing the expression of cGAS and STING proteins while promoting TBK1 and IRF3 phosphorylation in dendritic cells [ 36 ]. As a Toll-like receptor activator, OK432 induces dendritic cell activation and cytokine production, effectively bridging innate and adaptive immunity [ 37 – 40 ]. Among the CD73/CD155-positive cases that underwent postoperative pleurodesis, 60% (6/10) received adjuvant chemotherapy, with all chemotherapy regimens including PEM. Yoshida et al. reported that PEM enhances the immunogenicity of EGFR-mutated lung cancer by activating the STING pathway and that CD73 suppresses PEM-induced immunogenicity [ 41 ]. MPM exhibits high levels of STING expression [ 42 ], with reported expression rates of 88.5–95.7% [ 43 ]. In this study, CD73 expression may have contributed to the suppression of the therapeutic effect of PEM in CD73-positive cases. However, in CD73-positive/CD155-positive cases, the 5-year PFS was significantly higher in patients who underwent postoperative pleurodesis (60% of whom also received adjuvant chemotherapy) than in those who did not undergo pleurodesis (84% of whom received adjuvant chemotherapy) (83.3% vs. 33.3%). This suggests that postoperative pleurodesis with OK432 may have played a role in improving PFS. We propose that CD73-positive/CD155-positive status in epithelial MPM may serve as a biomarker for predicting the therapeutic effectiveness of pleurodesis using OK432. CD155 (PVR/Necl5/Tage4), a member of the nectin-like adhesion molecule family, is highly upregulated in tumour cells across various cancer types, where it is associated with poor patient outcomes [ 22 ]. CD155 is believed to exert an extracellular pro-metastatic effect by interacting with immunoregulatory receptors such as CD96, CD226, or TIGIT on the surface of NK cells and T cells [ 44 ]. In CD73-positive/CD155-positive epithelial MPM, there was no difference in the 5-year PFS between patients who underwent postoperative chemotherapy and those who did not, with both groups showing a PFS of 66.7%. In contrast, in non-CD73-positive/CD155-positive cases, the 5-year PFS was 12.9% in patients who underwent postoperative chemotherapy, demonstrating an improvement compared with those who did not receive chemotherapy. The difference in PFS between the CD73-positive/CD155-positive group and non-CD73-positive/CD155-positive group may be influenced by the effect of postoperative pleurodesis, suggesting that the CD73-positive/CD155-positive group included cases in which pleurodesis contributed to improved prognosis. In the non-CD73+/CD155 + group, although the proportion of patients who underwent postoperative pleurodesis was lower in the chemotherapy group than in the non-chemotherapy group, the 5-year PFS showed improvement. This suggests that postoperative chemotherapy is effective in certain cases within the non-CD73+/CD155 + group. Conversely, in the CD73+/CD155 + group, postoperative chemotherapy may not be as effective. In recent years, therapeutic agents targeting TIGIT have been developed. Tiragolumab, a fully human monoclonal antibody, binds to TIGIT and inhibits its interaction with its ligand, the PVR [ 45 ]. The combination of tiragolumab and atezolizumab has shown objective responses in non-small-cell lung cancer and head and neck squamous cell carcinoma [ 46 ]. In epithelial MPM, the CD73+/CD155 + group may be resistant to chemotherapy, indicating the need for combination therapy with agents targeting CD73 or CD155, although further research and validation are necessary to confirm these findings. Multivariate analysis of 5-year OS using Cox proportional hazards regression showed that non-CD73+/CD155 + was not a poor prognostic factor. In MPM, the prognostic improvement effect of ICI has been reported [ 10 ]. As most patients who underwent ICI treatment for recurrent cases were non-CD73+/CD155 + patients, ICIs may have affected the results of Cox proportional hazards regression for 5-year OS. In the CD73+/CD155 + group, the Kaplan-Meier curve showed an improvement in PFS after postoperative pleurodesis. However, multivariate analysis of 5-year PFS and OS using Cox proportional hazards regression showed no significant difference in the risk of death between patients who did and did not undergo postoperative pleurodesis. This is thought to be because this study did not take into account CD73/CD155 expression status. Owing to the small number of cases in this study, this analysis was not performed; however, we believe that if we accumulate more cases and analyse the CD73+/CD155 + group in the future, our results may show that postoperative pleurodesis improves PFS and OS. This study has some limitations. Firstly, as this study was conducted retrospectively, some patients were followed up at other hospitals after surgery, resulting in missing data, which may have influenced the results. Secondly, the study was conducted at a single institution with a limited sample size of 35 cases, which may have affected the statistical analysis. Although we assessed the adequacy of the sample size, the number of cases did not meet the required sample size, resulting in power analysis result of 59.6%. Given the rarity of MPM and the study’s focus on the epithelial subtype, obtaining a larger sample size at a single institution remains challenging. Thirdly, the use of multidisciplinary treatment introduces potential bias in PFS. However, preoperative and postoperative chemotherapy regimens were largely standardised, with most cases receiving platinum-based agents for patients in good general condition undergoing PEM treatment. Although cisplatin was administered intrapleurally in one case, the overall bias is considered minimal. To address these three limitations, a prospective multicentre study is needed, which will minimise loss to follow-up and missing data and maximise the sample size. Additionally, by defining enrolment criteria, a prospective study will reduce bias due to patient background and treatment. Fourthly, AI-based learning programs, such as HALO-AI, inherently function as a ‘black box’, meaning certain aspects of the analysis may remain unclear. In AI-based analysis, non-mesothelioma cells could be misidentified as tumour cells, but a pathologist reviews the results to minimise the risk of misdiagnosis. Finally, the evaluation of TPS via immunohistochemistry can vary significantly between pathologists, making it a subjective assessment. Despite these limitations, the study has valuable strengths. HALO-AI provides an objective evaluation by using a trained AI system, which generates quantifiable results. CD73 and CD155 are generally considered markers of poor prognosis in malignant tumours. However, as of February 5, 2025, no reports have been published on the expression and prognostic significance of CD73 and CD155 in MPM, based on a PubMed search (search keywords: ‘malignant mesothelioma’ AND ‘CD73’ AND ‘CD155’). Perioperative treatment options for MPM remain limited. However, as observed in other cancers such as lung cancer, perioperative chemotherapy using ICIs or molecular targeted drugs may provide beneficial in some cases. These study findings indicate the importance of investigating the expression status of CD73 and CD155 to help develop new treatment strategies. Thus, this study is particularly significant as the first report to explore the relationship between CD73 and CD155 and prognosis in epithelial MPM cases. Conclusions This study highlights the potential role of CD73 and CD155 as prognostic biomarkers in epithelial MPM, particularly in predicting response to postoperative pleurodesis. Although the findings suggest that CD73/CD155 expression affects treatment outcomes, further large-scale, multicentre studies are needed to validate these results and explore targeted therapeutic strategies. Understanding the interplay between these biomarkers and treatment response could facilitate the development of more personalised and effective management of MPM. Abbreviations AI, artificial intelligence AUC, area under the curve CD155, Cluster of differentiation 155 CD73, Cluster of differentiation 73 CT, computed tomography HR, hazard ratio ICI, immune checkpoint inhibitor mAB, monoclonal antibody OS, overall survival P/D, pleurectomy and decortication PBS, phosphate-buffered saline PFS, progression-free survival PVR, poliovirus receptor ROC, receiver operating characteristic TPS, tumour proportion score Declarations Ethics approval and consent to participate The authors are accountable for all aspects of the work and for ensuring that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of the University of Occupational and Environmental Health (Japan; No.: UOEHCRB21-065). Patients who were unable to provide informed consent were excluded; thus, written informed consent was obtained for all specimen sections included in the study. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests Fumihiro Tanaka has received grants from Ono Pharmaceutical, Taiho Pharmaceutical, Illy Lilly Japan, and Chugai Pharmaceutical; consulting fees from Astra Zeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Meyers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Bristol-Meyers Squibb, Boehringer Ingelheim Japan, Ono Pharmaceutical, Johnson & Johnson, Covidien Japan, Taiho Pharmaceutical, Illy Lilly Japan, Astra Zeneca, Chugai Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Pfizer, Olympus, Stryker, and Intuitive Japan. Masaru Takenaka has received compensation or honoraria from AstraZeneka for speaking engagements, presentations, speaker roles, manuscript writing, or educational events. The other authors declare that they have no competing interests. Funding This work was supported by the UOEH Grant-in-Aid for Promotion of Research in the Field of Occupational Medicine (2024-8). Amount: 143,750 yen. The funder had no specific role in the conception, design, data collection, analysis, decision to publish, or preparation of the manuscript. Authors' contributions RO, HM, YN, and FT conceived and designed the study and made substantial contributions to writing the manuscript. YF, TH, KT, and TM provided administrative support for writing the manuscript. KY, YN, NN, and YH provided study materials and recruited patients. YN, HM, MK, AT, MT, and KK collected and assembled the data. YN, SS, and FT analysed and interpreted the data and contributed substantially to the paper. All authors read and approved the final manuscript. Acknowledgements We would like to thank Editage for English language editing. We would also like to thank research staff member Kawashima Eri for helping with immunostaining. 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Cancer Res 80:CT302 Additional Declarations The authors declare potential competing interests as follows: Fumihiro Tanaka has received grants from Ono Pharmaceutical, Taiho Pharmaceutical, Illy Lilly Japan, and Chugai Pharmaceutical; consulting fees from Astra Zeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Meyers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Bristol-Meyers Squibb, Boehringer Ingelheim Japan, Ono Pharmaceutical, Johnson & Johnson, Covidien Japan, Taiho Pharmaceutical, Illy Lilly Japan, Astra Zeneca, Chugai Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Pfizer, Olympus, Stryker, and Intuitive Japan. Masaru Takenaka has received compensation or honoraria from AstraZeneka for speaking engagements, presentations, speaker roles, manuscript writing, or educational events. The other authors declare that they have no competing interests. Supplementary Files Additionalfile1.docx File name: Additional file 1 File format: .DOCX Title of data: Analysis results from HALO-AI Description of data: The percentages of CD73- and CD155-positive cells in MPM tumour cells are shown. Additionalfile2.jpg File name: Additional file 2 File format: .TIFF Title of data: Five-year progression-free survival according to CD73/CD155 expression status (Kaplan–Meier curve) Description of data: There was no significant difference in 5-year progression-free survival between CD73/CD155 expression statuses (p=0.076). Additionalfile3.jpg File name: Additional file 3 File format: .TIFF Title of data: Five-year overall survival according to CD73/CD155 expression status (Kaplan–Meier curve) Description of data: There was no significant difference in 5-year overall survival between CD73/CD155 expression statuses (p=0.453). 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6538045","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":448518951,"identity":"7e00a15b-ec7d-4660-a12d-5d4862b94839","order_by":0,"name":"Yusuke 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05:00:02","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6538045/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6538045/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81955194,"identity":"955e94d3-a174-40b1-b8a8-343a93bbe91b","added_by":"auto","created_at":"2025-05-05 09:48:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1544662,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of patient inclusion in this study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/a1725fbbc8a26b548fd001fa.jpg"},{"id":81956547,"identity":"aafcd5a0-138f-4d63-b65a-29aac4d1cbd2","added_by":"auto","created_at":"2025-05-05 09:56:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6540477,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExamples of immunostaining results for CD73 and CD155 (magnification: 20×)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Case 25: positive CD73 immunostaining in the resected specimen.\u003c/p\u003e\n\u003cp\u003e(b) Case 25: positive CD155 immunostaining in the resected specimen.\u003c/p\u003e\n\u003cp\u003e(c) Case 32: negative CD73 immunostaining in the resected specimen.\u003c/p\u003e\n\u003cp\u003e(d) Case 32: negative CD155 immunostaining in the resected specimen.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/9d182f6b5460db325af9a208.jpg"},{"id":81953954,"identity":"b83c3ce2-87c8-43a4-8833-31c8362f166a","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":418380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNormal Q-Q plots showing the percentage of CD73- and CD155-positive cells in malignant pleural mesothelioma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe percentage of cells positive for (a) CD73 and (b) CD155 immunostaining in the resected specimens of epithelial malignant pleural mesothelioma was non-normally distributed.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/c06dc298250cf17863681d78.jpg"},{"id":81953959,"identity":"506dba64-9e38-45b8-9afc-ef8f354502d7","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":563340,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver operating characteristic (ROC) curves for predicting tumour progression in malignant pleural mesothelioma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) ROC curve of the percentage of CD73+ cells for predicting tumour progression in malignant pleural mesothelioma. CD73 positivity was defined as ≥8.63%.\u003c/p\u003e\n\u003cp\u003e(b) ROC curve of the percentage of CD155+ cells for predicting tumour progression in malignant pleural mesothelioma.\u003cstrong\u003e \u003c/strong\u003eCD155 positivity was defined as ≥3.75%.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/8c7f8d7adb7142884ae35489.jpg"},{"id":81953958,"identity":"36e22146-e84e-4910-b5a2-e5bc2eac5c0f","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":438395,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFive-year progression-free survival and overall survival according to CD73+/CD155+ expression status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Five-year progression-free survival (PFS) according to CD73+/CD155+ expression status (Kaplan–Meier curves). The 5-year PFS was 64.8% in the CD73+/CD155+ group compared with the 10.8% in the non-CD73+/CD155+ group, indicating a significantly worse prognosis for the non-CD73+/CD155+ group (p=0.017).\u003c/p\u003e\n\u003cp\u003e(b) Five-year overall survival (os) according to CD73+/CD155+ expression status (Kaplan–Meier curve). The 5-year OS between the CD73+/CD155+ group and non-CD73+/CD155+ group was 55.6% and 27.9%, respectively, although the difference was not significant (p=0.376).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/90922af5b690c0043e8d6238.jpg"},{"id":81953961,"identity":"d784244d-b11e-4f03-b8cd-24425b7682e0","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":490848,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFive-year PFS in patients with/without postoperative pleurodesis in CD73+/CD155+ and non-CD73+/CD155+ tumours (Kaplan–Meier curves)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong patients in the CD73+/CD155+ group, those who underwent postoperative pleurodesis had a significantly higher 5-year PFS (83.3%) than those who did not (33.3%). PFS: progression-free survival.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/b61fc462546ac642dd8360d0.jpg"},{"id":81955198,"identity":"f9914ee6-0e3b-4add-ad6b-725d3474def2","added_by":"auto","created_at":"2025-05-05 09:48:56","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":493250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFive-year PFS in patients with/without postoperative chemotherapy in CD73+/CD155+ and non-CD73+/CD155+ tumours (Kaplan–Meier curves)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the CD73+/CD155+ group, the 5-year PFS remained at 66.7% regardless of whether postoperative chemotherapy was administered, indicating no significant difference in outcome. PFS: progression-free survival.\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/9ed112d5385cffc2a90a9998.jpg"},{"id":81953965,"identity":"9c9a603e-4a5a-42c3-8af8-5fda9ac3e7b4","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":517808,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFive-year overall survival for each treatment group in recurrent cases (Kaplan–Meier curves)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe chemotherapy group with a history of ICI treatment showed a significantly improved prognosis (p=0.001).\u003c/p\u003e","description":"","filename":"Figure8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/dd6be9d50a977206af403448.jpg"},{"id":81956914,"identity":"76c03cdd-cf0d-4c6c-bcee-bc4835980af8","added_by":"auto","created_at":"2025-05-05 10:04:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":12388203,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/2e7e2430-3c01-4db1-a313-70b13a001b5a.pdf"},{"id":81953952,"identity":"1975a350-2745-4685-84bb-05592c7d8325","added_by":"auto","created_at":"2025-05-05 09:40:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33745,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFile name:\u003c/strong\u003e Additional file 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFile format: \u003c/strong\u003e.DOCX\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTitle of data: \u003c/strong\u003eAnalysis results from HALO-AI\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription of data:\u003c/strong\u003e The percentages of CD73- and CD155-positive cells in MPM tumour cells are shown.\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/0a76d437d5a57a67aef03967.docx"},{"id":81955196,"identity":"0a13f99f-c648-4787-872f-f124cc55d5f0","added_by":"auto","created_at":"2025-05-05 09:48:56","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":651212,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFile name:\u003c/strong\u003e Additional file 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFile format:\u003c/strong\u003e .TIFF\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTitle of data:\u003c/strong\u003e Five-year progression-free survival according to CD73/CD155 expression status (Kaplan–Meier curve)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription of data: \u003c/strong\u003eThere was no significant difference in 5-year progression-free survival between CD73/CD155 expression statuses (p=0.076).\u003c/p\u003e","description":"","filename":"Additionalfile2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/d2bec3eb6cc0ac2e7f02f437.jpg"},{"id":81955197,"identity":"056ffc5d-6c03-448c-9883-3b271d41095d","added_by":"auto","created_at":"2025-05-05 09:48:56","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":507548,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFile name:\u003c/strong\u003e Additional file 3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFile format:\u003c/strong\u003e .TIFF\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTitle of data\u003c/strong\u003e: Five-year overall survival according to CD73/CD155 expression status (Kaplan–Meier curve)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription of data: \u003c/strong\u003eThere was no significant difference in 5-year overall survival between CD73/CD155 expression statuses (p=0.453).\u003c/p\u003e","description":"","filename":"Additionalfile3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6538045/v1/7f2e93b150fd44ebcb62d0be.jpg"}],"financialInterests":"The authors declare potential competing interests as follows: Fumihiro Tanaka has received grants from Ono Pharmaceutical, Taiho Pharmaceutical, Illy Lilly Japan, and Chugai Pharmaceutical; consulting fees from Astra Zeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Meyers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Bristol-Meyers Squibb, Boehringer Ingelheim Japan, Ono Pharmaceutical, Johnson \u0026 Johnson, Covidien Japan, Taiho Pharmaceutical, Illy Lilly Japan, Astra Zeneca, Chugai Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Pfizer, Olympus, Stryker, and Intuitive Japan. Masaru Takenaka has received compensation or honoraria from AstraZeneka for speaking engagements, presentations, speaker roles, manuscript writing, or educational events. The other authors declare that they have no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eFive-year progression-free survival and overall survival based on CD73 and CD155 expression in resected epithelial malignant pleural mesothelioma: a retrospective single-centre study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eMalignant pleural mesothelioma (MPM) accounts for 94.5% of all malignant mesothelioma cases, with 87% of patients having a history of asbestos exposure, highlighting a strong association between asbestos and tumour development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The United States introduced its first asbestos regulations in 1973, while many European countries implemented partial or complete bans in the 1980s and 1990s. However, some non-European countries, such as Albania, Andorra, and Armenia, have yet to enforce such restrictions [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although malignant mesothelioma is classified as a rare cancer, it has a long latency period, with the condition developing even 40 years or more after asbestos exposure [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Consequently, the incidence of malignant mesothelioma is expected to rise in the future.\u003c/p\u003e \u003cp\u003eThe prognosis for MPM remains poor, with a median survival of approximately 12 months after diagnosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and a 5-year survival of only 5% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Treatment of MPM typically involves a multidisciplinary approach, including surgery, chemotherapy, and radiation therapy. For resectable tumours, the standard surgical approach aims for macroscopic complete resection, typically performed via either pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). P/D, which preserves lung parenchyma, is associated with lower perioperative mortality than EPP [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Factors such as sarcomatoid histology, contralateral mediastinal or supraclavicular lymph node metastases, extrathoracic disease, multilevel chest wall involvement, or inadequate cardiopulmonary reserve may preclude the benefits from surgery [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A recent randomised controlled trial found that extended P/D was associated with lower 2-year survival and a higher incidence of serious adverse events than chemotherapy alone [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], reinforcing the critical role of chemotherapy in the treatment of MPM.\u003c/p\u003e \u003cp\u003eAmong chemotherapy regimens, pemetrexed (PEM) combined with cisplatin and vitamin supplementation has demonstrated superior outcomes in survival, time to progression, and response rate to cisplatin monotherapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. More recently, immune checkpoint inhibitor (ICI) therapy with nivolumab and ipilimumab has shown significant improvements in overall survival (OS) compared with standard chemotherapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, studies have reported promising results with combination therapies involving chemotherapy, ICIs, or angiogenesis inhibitors [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, pleurodesis has been shown to improve survival in patients with malignant pleural effusion, including those with MPM [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough several biomarkers for MPM have been reported [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], there are no widely generalised biomarkers that can be used to guide optimal treatment strategies. These findings indicate the need to develop additional biomarkers for improving treatment planning. Cluster of differentiation 73 (CD73), an enzyme expressed on the surface of cancer and immune cells, plays a key role in converting adenosine monophosphate to extracellular adenosine, thereby contributing to an immunosuppressive tumour microenvironment [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Targeting CD73 may help reverse this immunosuppression by enhancing CD8\u0026thinsp;+\u0026thinsp;effector cell activity, activating macrophages, and reducing the presence of myeloid-derived suppressor cells and regulatory T lymphocytes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Moreover, targeting cancer cell CD73 directly inhibits tumour cell migration and metastasis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCD155, also known as the poliovirus receptor (PVR), was initially identified as a poliovirus receptor [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. CD155 is involved in immune regulation through interactions with the costimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. CD155 has been reported to influence tumour-infiltrating lymphocyte function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and facilitate tumour cell invasion and migration [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. According to the 2015 World Health Organization\u0026rsquo;s histological classification, malignant mesothelioma is primarily classified into epithelioid, sarcomatoid, and biphasic subtypes. Among these, the epithelioid subtype is associated with a more favourable prognosis [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, no studies to date have investigated the relationship between CD73 and CD155 expression and prognosis in patients with MPM. MPM is characterised by relentless local progression, with hematogenous metastasis being rare in the advanced stages. Despite aggressive local control measures, most patients experience locoregional recurrence [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Improvement in local invasion control by combining conventional chemotherapy with ICI and molecular targeted drugs could increase the number of patients who could be cured by surgery. These findings supported the importance of identifying biomarkers for considering new treatment strategies. We hypothesised that high CD73/CD155 expression is associated with poorer prognosis in epithelial MPM. Therefore, this study aimed to investigate the relationship between CD73 and CD155 expression in resected specimens of epithelial MPM and their impact on 5-year progression-free survival (PFS) and 5-year OS. Herein, we investigated the expression of CD73 and CD155 in resected specimens of MPM, focusing on the migration, metastasis, and invasion ability of cancer cells.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis single-centre retrospective study included 43 cases of epithelial MPM in consecutive patients who underwent surgery at our hospital between January 1, 2013, and December 31, 2020. Patients who did not provide consent and cases with unknown progression dates due to transfer to other hospitals were excluded. A flowchart outlining case selection is provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Treatment decisions were made at the discretion of the attending physician, with the primary treatment plan determined through a multidisciplinary conference involving multiple thoracic surgeons. Postoperative follow-up included blood tests, chest X-rays, and computed tomography (CT) scans at least every 6 months. In cases where recurrence was suspected, PET/CT scans were performed at the discretion of the treating physician. Immunohistochemical examination was performed on surgically resected specimens for all cases. Serial sections were obtained from each formalin-fixed, paraffin-embedded primary tumour specimen.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics declaration\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eEthics declaration\u003c/div\u003e \u003cp\u003eThe authors have completed the STROBE reporting checklist. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of the University of Occupational and Environmental Health (Japan; No.: UOEHCRB21-065). Patients who were unable to provide informed consent were excluded; thus, written informed consent was obtained for all specimen sections included in the study.\u003c/p\u003e\n\u003ch3\u003eCD73 immunohistochemistry\u003c/h3\u003e\n\u003cp\u003eThe primary antibodies used were NT5E/CD73 (D7F9A) Rabbit monoclonal antibody (mAb) (Cell Signalling Technology, Danvers, MA, USA; #13160; 1:200 dilution) and Rabbit (DA1E) mAb IgG XP Isotype Control (Cell Signalling Technology; #3900S; 1:200 dilution). Primary antibodies were incubated for 1 h at room temperature. Signal Stain Boost (Cell Signalling Technology; #8114) was used as the secondary antibody and Signal Stain Diluent (Cell Signalling Technology; #8112) was used for antibody dilution. An isotype control (diluted 1:200) was used as a negative control. Additional reagents included citrate buffer (pH 9), blocking buffer (Agilent Technologies, Santa Clara, CA, USA; X090930), the DAKO Envision\u0026thinsp;+\u0026thinsp;Kit/HRP (DAB) (Agilent Technologies; K3458), the DAB\u0026thinsp;+\u0026thinsp;substrate kit (Agilent Technologies; K3468), and phosphate-buffered saline (PBS). Immunohistochemistry was performed according to the manufacturers\u0026rsquo; protocols.\u003c/p\u003e\n\u003ch3\u003eCD155 immunohistochemistry\u003c/h3\u003e\n\u003cp\u003eA549 cells were used as a positive control. The primary antibody used was PVR/CD155 (D8A5G) Rabbit mAb #81254 (diluted 1:200). Primary antibodies were incubated for 1 hour at room temperature. An isotype control (diluted 1:200) was used as a negative control. Both the primary antibody and isotype control were diluted using Signal Stain Diluent (Cell Signalling Technology; #8112), while the secondary antibody was diluted using Signal Stain Boost (#8114). Other reagents used included citrate buffer solution (LSI Medience Corporation, Tokyo, Japan; RM102-C), blocking buffer (a non-specific reaction blocking reagent containing casein, Agilent Technologies Japan, Ltd., X090930), the DAKO Envision\u0026thinsp;+\u0026thinsp;Kit/HRP (DAB) DAB\u0026thinsp;+\u0026thinsp;Substrate Kit (Code: K3458), and PBS. Immunohistochemistry was performed according to the manufacturers\u0026rsquo; protocols.\u003c/p\u003e\n\u003ch3\u003eHALO-AI\u003c/h3\u003e\n\u003cp\u003eIn immunohistochemical evaluations, the tumour proportion score (TPS) used for PD-L1 assessment can vary depending on the experience of the evaluating pathologist, leading to potential subjectivity. HALO-AI, an artificial intelligence-based pathological analysis tool, offers the potential for more objective and standardised evaluations. Reports on its applications have been increasing in recent years [\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. All slides stained with haematoxylin and eosin, CD73, and CD155 were digitised at 20\u0026times; magnification using NDP.view2 (Hamamatsu Electronic Press Co., Iwata, Japan). Analysis was conducted using the Halo Image Analysis Platform v3.6 (IndicaLabs) with the Membrane v1.7 module. The AI system calculated the percentage of CD73- and CD155-positive tumour cells by segmenting the tissue into tumour cell, stromal, and background categories. A pathologist manually annotated malignant and non-malignant areas on each slide, carefully excluding ambiguous regions and areas with artefacts.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePleurodesis\u003c/h2\u003e \u003cp\u003eFollowing local anaesthesia of the pleural cavity with xylocaine, OK432 dissolved in saline was injected into the pleural cavity via a chest drain. OK432 is composed of heat-treated, penicillin-killed, freeze-dried \u003cem\u003eStreptococcus pyogenes\u003c/em\u003e group A2 (Picibanil, Chugai Pharmaceutical Ltd., Japan).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eWe analysed whether the percentage of CD73- and CD155-positive cells in resected specimens of epithelial MPM followed a normal or non-normal distribution using normal Q-Q plots. We calculated the mean and standard deviation of 5-year PFS for the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, and overall and performed sample size adequacy and power analyses. Power analysis was based on the difference in the mean values ​​between the CD73+/CD155\u0026thinsp;+\u0026thinsp;group and non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group and the overall standard deviation. The required sample size was calculated with an alpha error of 0.05, a statistical power of 0.8, and a sample ratio of 1:2.5. The number of samples required was 17 for the CD73+/CD155\u0026thinsp;+\u0026thinsp;group and 42.5 for the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group.\u003c/p\u003e \u003cp\u003eCategorical data were compared using a two-sided Fisher's exact test, while continuous data were analysed using the nonparametric Mann\u0026ndash;Whitney U test. To determine the optimal cutoff values for the percentage of CD73- and CD155-positive cells, receiver operating characteristic (ROC) curves were constructed by plotting the model\u0026rsquo;s false positive rate against its true positive rate for predicting tumour recurrence and the area under the curve (AUC) was calculated. The Kaplan\u0026ndash;Meier method was used to estimate 5-year PFS and 5-year OS, with differences in survival between the CD73+/CD155\u0026thinsp;+\u0026thinsp;group and non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group analysed using the log-rank test.\u003c/p\u003e \u003cp\u003eUnivariate and multivariate analyses were conducted using Cox proportional hazards regression models to identify independent prognostic factors. Significant prognostic factors from the univariate analysis, along with potential poor prognostic factors, were included as covariates in the multivariate analysis. EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R (The R Foundation for Statistical Computing), was used for sample size adequacy and power analyses. Other statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY, USA). Statistical significance was defined as \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (\u003cem\u003eq\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in multivariate analysis).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient demographics are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The majority of patients were male, comprising 85.7% (30/35) of the cohort. P/D was the predominant surgical procedure, performed in 82.9% (29/35) of cases. Pathological staging was standardised according to the UICC-TNM Classification (8th edition), with stage IB representing 45.7% (16/35) of patients. Preoperative pleurodesis was performed in 42.9% (15/35) of cases and postoperative pleurodesis in 51.4% (18/35). Talc was used in 20% (3/15) of preoperative pleurodesis cases, while OK432 was used in the remaining 80% (12/15). OK432 was exclusively used for postoperative pleurodesis. Preoperative chemotherapy was administered to 22.9% (8/35) of patients, while postoperative chemotherapy was administered to 77.1% (27/35), with 92.6% (25/27) receiving a regimen containing PEM. Disease progression within 5 years post-surgery was observed in 68.6% (24/35) of cases. Among the 19 deaths recorded, 89.5% (17/19) were attributed to MPM, while the remaining two deaths resulted from acute exacerbation of interstitial pneumonia (one case) and an unknown cause (one case). The median PFS and OS within 5 years post-surgery were 13 months and 28 months, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of the study patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (median), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (47\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical procedure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP/D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEPP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDebulking Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePartial resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePleurectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep-stage (UICC-TNM Classification Ver.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleurodesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePemetrexed-containing regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression (within 5 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCause of death (within 5 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeath from underlying disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeath from other illnesses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDetails unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression-free survival within 5 years (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival within 5 years (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of the analysis of the mean and standard deviation of 5-year PFS for the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, and overall cohort are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of the analysis of the mean and standard deviation of 5-year PFS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStandard deviation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-CD73་/CD155་\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.698\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD73་/CD155་\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePFS: progression-free survival\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eExamples of immunostaining results for CD73 and CD155 are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The percentage of MPM tumour cells immunostained for CD73 and CD155 was analysed using HALO-AI. Analysis of normal Q-Q plots showed that the percentage of cells positive for CD73 and CD155 immunostaining in the resected specimens of epithelial MPM was non-normally distributed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The analysis results from HALO-AI are provided in Additional file 1. Cutoff values for CD73 and CD155 positivity were determined using ROC curve analysis, with positivity defined as \u0026ge;\u0026thinsp;8.63% for CD73 and \u0026ge;\u0026thinsp;3.75% for CD155 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatient characteristics based on tumour CD73 and CD155 status are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. No significant differences were observed in 5-year PFS and 5-year OS across different CD73 and CD155 expression groups (Additional files 2 and 3). The 5-year PFS was 64.8% in the CD73+/CD155\u0026thinsp;+\u0026thinsp;group compared with the 10.8% in the other groups (CD73-/CD155-, CD73-/CD155+, CD73+/CD155-), indicating a significantly worse prognosis for groups other than CD73+/CD155+ (p\u0026thinsp;=\u0026thinsp;0.017) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). However, no significant difference was observed in the 5-year OS between the CD73+/CD155\u0026thinsp;+\u0026thinsp;group and other groups (p\u0026thinsp;=\u0026thinsp;0.376) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics according to tumour CD73 and CD155 status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e% Positive cells (MPM/CD73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e% Positive cells (MPM/CD155)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll patients, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 (62.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16 (45.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e19 (54.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47\u0026ndash;77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e56\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e47\u0026ndash;77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.347\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical procedure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.648\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.379\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP/D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eother\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.739\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI/II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative pleurodesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe impact of postoperative pleurodesis on 5-year PFS was examined by comparing the CD73+/CD155\u0026thinsp;+\u0026thinsp;group with the other groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Among patients in the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, those who underwent postoperative pleurodesis had a significantly higher 5-year PFS (83.3%) than those who did not (33.3%, p\u0026thinsp;=\u0026thinsp;0.043). In contrast, in the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, the 5-year PFS for patients who underwent postoperative pleurodesis was 18.2%. The association between postoperative chemotherapy and 5-year PFS was compared between the CD73+/CD155\u0026thinsp;+\u0026thinsp;group and other groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). In the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, patients who received postoperative chemotherapy had a significantly higher 5-year PFS (12.9%) than those who did not (0%, p\u0026thinsp;=\u0026thinsp;0.003). However, in the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, the 5-year PFS remained at 66.7% regardless of whether postoperative chemotherapy was administered, indicating no significant difference in outcome. In the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, the proportion of patients who underwent postoperative pleurodesis was 60% (6/10) in those who received postoperative chemotherapy and 50% (2/4) in those who did not. In the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, the proportion was 42.9% (9/21) in the chemotherapy group and 50% (2/4) in the non-chemotherapy group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSurvival analysis was conducted using a Cox proportional hazards regression model, incorporating age, sex, surgical technique, stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155\u0026thinsp;+\u0026thinsp;expression status as covariates. The results of the univariate and multivariate analyses for 5-year PFS are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In the univariate analysis, a significant difference was observed for CD73+/CD155\u0026thinsp;+\u0026thinsp;expression status, with the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group demonstrating a higher risk of disease progression (HR 3.927, p\u0026thinsp;=\u0026thinsp;0.029). In the multivariate analysis, which included stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155\u0026thinsp;+\u0026thinsp;expression status as covariates, significant associations were found for both postoperative chemotherapy and CD73+/CD155\u0026thinsp;+\u0026thinsp;expression.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHazard ratio for progression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% confidence interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% confidence interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.919\u0026ndash;1.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male vs. female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.164\u0026ndash;1.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical procedure (P/D vs others)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.532\u0026ndash;4.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological stage (I/II vs. III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.212\u0026ndash;1.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.206\u0026ndash;1.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative pleurodesis (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.985\u0026ndash;5.204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.723\u0026ndash;4.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative chemotherapy (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.859\u0026ndash;6.447\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.596\u0026ndash;19.603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD73+/CD155+ (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.927\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.147\u0026ndash;13.441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.630\u0026ndash;26.356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients who did not receive postoperative chemotherapy had a significantly higher risk of recurrence than those who did (HR 5.593, p\u0026thinsp;=\u0026thinsp;0.007). Additionally, among the other groups, patients in the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group had a significantly higher risk of postoperative progression (HR 6.555, p\u0026thinsp;=\u0026thinsp;0.008).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e presents the results of the univariate and multivariate analyses of 5-year OS. In the univariate analysis, significant differences were observed for postoperative pleurodesis (p\u0026thinsp;=\u0026thinsp;0.012) and postoperative chemotherapy (p\u0026thinsp;=\u0026thinsp;0.012). The absence of postoperative pleurodesis (HR 3.539) and the absence of postoperative chemotherapy (HR 3.5) were associated with an increased risk of mortality. In the multivariate analysis, which included disease stage, postoperative pleurodesis, postoperative chemotherapy, and CD73+/CD155\u0026thinsp;+\u0026thinsp;expression status as covariates, postoperative chemotherapy remained a significant factor (p\u0026thinsp;=\u0026thinsp;0.006). Patients who did not receive postoperative chemotherapy had a significantly higher risk of death than those who did (HR 5.835).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHazard ratio for overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% confidence interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% confidence interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.965\u0026ndash;1.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male vs. female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.305\u0026ndash;5.779\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.706\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical procedure (P/D vs others)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.412\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.410\u0026ndash;4.870\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological stage (I/II vs. III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.532\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.215\u0026ndash;1.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.532\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.172\u0026ndash;1.642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative pleurodesis (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.539\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.327\u0026ndash;9.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.755\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.969\u0026ndash;7.828\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative chemotherapy (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.311\u0026ndash;9.344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.664\u0026ndash;20.586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD73+/CD155+ (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.537\u0026ndash;5.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.704\u0026ndash;9.576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 24 patients who experienced disease recurrence, the 5-year OS was compared among those who did not receive chemotherapy, those who received chemotherapy without a history of ICI use, and those who received chemotherapy with a history of ICI use (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). The chemotherapy group with a history of ICI treatment showed a significantly improved prognosis (p\u0026thinsp;=\u0026thinsp;0.001). A cross-tabulation of each treatment group and the CD73+/CD155\u0026thinsp;+\u0026thinsp;status of recurrent cases is shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCross-tabulation of CD73/CD155 expression and treatment groups in patients with relapsed epithelial malignant pleural mesothelioma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD73/CD155\u003c/p\u003e \u003cp\u003estatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-chemotherapy group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChemotherapy group\u003c/p\u003e \u003cp\u003e(without a history of ICI use)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChemotherapy group\u003c/p\u003e \u003cp\u003e(history of ICI use)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD73+/CD155+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated the prognostic significance of CD73 and CD155 expression in epithelial MPM and explored the impact of postoperative pleurodesis and chemotherapy on survival outcomes. The CD73+/CD155\u0026thinsp;+\u0026thinsp;group had significantly better 5-year PFS, particularly after postoperative pleurodesis, while showing potential resistance to chemotherapy. These findings suggest that CD73 and CD155 may serve as biomarkers for predicting treatment response, highlighting the need for further research on targeted therapies.\u003c/p\u003e \u003cp\u003eInitially, we hypothesised that cases with high CD73 and CD155 expression would have poorer PFS and OS. However, the CD73-positive/CD155-positive group demonstrated a significantly better 5-year PFS than the non-CD73-positive/CD155-positive group. Cabioglu et al. reported that patients with triple-negative breast cancer with high CD73 expression had significantly improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) compared with those with low CD73 expression (10-year DFS: 77.9% vs. 34.8%, p\u0026thinsp;=\u0026thinsp;0.021; 10-year DSS: 90.9% vs. 37.3%, p\u0026thinsp;=\u0026thinsp;0.015) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. These findings suggest that CD73 expression may have contributed to the improved PFS observed in the CD73-positive/CD155-positive group. In contrast, the expression of CD73 and CD155 genes has been reported to be a negative prognostic factor [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. One possible reason why the results of this study were contrary to our expectations is that multidisciplinary treatments, such as pleurodesis and chemotherapy, performed after surgery for MPM may have affected CD73-positive/CD155-positive patients. In the study by Cabioglu et al., all patients received anthracycline-containing NAC followed by a taxane before surgery [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], which may have affected the outcomes of CD73-positive patients. We believe that exploring treatments that affect the prognosis of CD73-positive/CD155-positive patients will lead to the development of personalised treatments.\u003c/p\u003e \u003cp\u003eIn the CD73-positive/CD155-positive group, patients who underwent postoperative pleurodesis with OK432 had a significantly better PFS than those who did not (83.3% vs. 33.3%, p\u0026thinsp;=\u0026thinsp;0.043). This suggests that postoperative pleurodesis using OK432 may be effective in CD73-positive/CD155-positive cases. In Japan, the use of sterilised modified talc for preventing the re-accumulation of malignant pleural effusion was approved by the Japanese Ministry of Health, Labor, and Welfare in December 2013 [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Therefore, our institution has limited experience using talc in pleurodesis for MPM. Instead, OK432, which has been widely used in Japan, was utilised for all cases of postoperative pleurodesis. OK432 (Picibanil\u0026reg;), a streptococcal preparation, enhances dendritic cell maturation and induces antigen-specific cytotoxic T cells in colon cancer cell lines [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. A recent study has shown that OK432 treatment activates the cyclic GMP\u0026ndash;AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, increasing the expression of cGAS and STING proteins while promoting TBK1 and IRF3 phosphorylation in dendritic cells [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs a Toll-like receptor activator, OK432 induces dendritic cell activation and cytokine production, effectively bridging innate and adaptive immunity [\u003cspan additionalcitationids=\"CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Among the CD73/CD155-positive cases that underwent postoperative pleurodesis, 60% (6/10) received adjuvant chemotherapy, with all chemotherapy regimens including PEM. Yoshida et al. reported that PEM enhances the immunogenicity of EGFR-mutated lung cancer by activating the STING pathway and that CD73 suppresses PEM-induced immunogenicity [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. MPM exhibits high levels of STING expression [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], with reported expression rates of 88.5\u0026ndash;95.7% [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In this study, CD73 expression may have contributed to the suppression of the therapeutic effect of PEM in CD73-positive cases. However, in CD73-positive/CD155-positive cases, the 5-year PFS was significantly higher in patients who underwent postoperative pleurodesis (60% of whom also received adjuvant chemotherapy) than in those who did not undergo pleurodesis (84% of whom received adjuvant chemotherapy) (83.3% vs. 33.3%). This suggests that postoperative pleurodesis with OK432 may have played a role in improving PFS.\u003c/p\u003e \u003cp\u003eWe propose that CD73-positive/CD155-positive status in epithelial MPM may serve as a biomarker for predicting the therapeutic effectiveness of pleurodesis using OK432. CD155 (PVR/Necl5/Tage4), a member of the nectin-like adhesion molecule family, is highly upregulated in tumour cells across various cancer types, where it is associated with poor patient outcomes [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. CD155 is believed to exert an extracellular pro-metastatic effect by interacting with immunoregulatory receptors such as CD96, CD226, or TIGIT on the surface of NK cells and T cells [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In CD73-positive/CD155-positive epithelial MPM, there was no difference in the 5-year PFS between patients who underwent postoperative chemotherapy and those who did not, with both groups showing a PFS of 66.7%. In contrast, in non-CD73-positive/CD155-positive cases, the 5-year PFS was 12.9% in patients who underwent postoperative chemotherapy, demonstrating an improvement compared with those who did not receive chemotherapy. The difference in PFS between the CD73-positive/CD155-positive group and non-CD73-positive/CD155-positive group may be influenced by the effect of postoperative pleurodesis, suggesting that the CD73-positive/CD155-positive group included cases in which pleurodesis contributed to improved prognosis.\u003c/p\u003e \u003cp\u003eIn the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group, although the proportion of patients who underwent postoperative pleurodesis was lower in the chemotherapy group than in the non-chemotherapy group, the 5-year PFS showed improvement. This suggests that postoperative chemotherapy is effective in certain cases within the non-CD73+/CD155\u0026thinsp;+\u0026thinsp;group. Conversely, in the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, postoperative chemotherapy may not be as effective. In recent years, therapeutic agents targeting TIGIT have been developed. Tiragolumab, a fully human monoclonal antibody, binds to TIGIT and inhibits its interaction with its ligand, the PVR [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The combination of tiragolumab and atezolizumab has shown objective responses in non-small-cell lung cancer and head and neck squamous cell carcinoma [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. In epithelial MPM, the CD73+/CD155\u0026thinsp;+\u0026thinsp;group may be resistant to chemotherapy, indicating the need for combination therapy with agents targeting CD73 or CD155, although further research and validation are necessary to confirm these findings.\u003c/p\u003e \u003cp\u003eMultivariate analysis of 5-year OS using Cox proportional hazards regression showed that non-CD73+/CD155\u0026thinsp;+\u0026thinsp;was not a poor prognostic factor. In MPM, the prognostic improvement effect of ICI has been reported [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. As most patients who underwent ICI treatment for recurrent cases were non-CD73+/CD155\u0026thinsp;+\u0026thinsp;patients, ICIs may have affected the results of Cox proportional hazards regression for 5-year OS. In the CD73+/CD155\u0026thinsp;+\u0026thinsp;group, the Kaplan-Meier curve showed an improvement in PFS after postoperative pleurodesis. However, multivariate analysis of 5-year PFS and OS using Cox proportional hazards regression showed no significant difference in the risk of death between patients who did and did not undergo postoperative pleurodesis. This is thought to be because this study did not take into account CD73/CD155 expression status. Owing to the small number of cases in this study, this analysis was not performed; however, we believe that if we accumulate more cases and analyse the CD73+/CD155\u0026thinsp;+\u0026thinsp;group in the future, our results may show that postoperative pleurodesis improves PFS and OS.\u003c/p\u003e \u003cp\u003eThis study has some limitations. Firstly, as this study was conducted retrospectively, some patients were followed up at other hospitals after surgery, resulting in missing data, which may have influenced the results. Secondly, the study was conducted at a single institution with a limited sample size of 35 cases, which may have affected the statistical analysis. Although we assessed the adequacy of the sample size, the number of cases did not meet the required sample size, resulting in power analysis result of 59.6%. Given the rarity of MPM and the study\u0026rsquo;s focus on the epithelial subtype, obtaining a larger sample size at a single institution remains challenging. Thirdly, the use of multidisciplinary treatment introduces potential bias in PFS. However, preoperative and postoperative chemotherapy regimens were largely standardised, with most cases receiving platinum-based agents for patients in good general condition undergoing PEM treatment. Although cisplatin was administered intrapleurally in one case, the overall bias is considered minimal. To address these three limitations, a prospective multicentre study is needed, which will minimise loss to follow-up and missing data and maximise the sample size. Additionally, by defining enrolment criteria, a prospective study will reduce bias due to patient background and treatment. Fourthly, AI-based learning programs, such as HALO-AI, inherently function as a \u0026lsquo;black box\u0026rsquo;, meaning certain aspects of the analysis may remain unclear. In AI-based analysis, non-mesothelioma cells could be misidentified as tumour cells, but a pathologist reviews the results to minimise the risk of misdiagnosis. Finally, the evaluation of TPS via immunohistochemistry can vary significantly between pathologists, making it a subjective assessment.\u003c/p\u003e \u003cp\u003eDespite these limitations, the study has valuable strengths. HALO-AI provides an objective evaluation by using a trained AI system, which generates quantifiable results. CD73 and CD155 are generally considered markers of poor prognosis in malignant tumours. However, as of February 5, 2025, no reports have been published on the expression and prognostic significance of CD73 and CD155 in MPM, based on a PubMed search (search keywords: \u0026lsquo;malignant mesothelioma\u0026rsquo; AND \u0026lsquo;CD73\u0026rsquo; AND \u0026lsquo;CD155\u0026rsquo;).\u003c/p\u003e \u003cp\u003ePerioperative treatment options for MPM remain limited. However, as observed in other cancers such as lung cancer, perioperative chemotherapy using ICIs or molecular targeted drugs may provide beneficial in some cases. These study findings indicate the importance of investigating the expression status of CD73 and CD155 to help develop new treatment strategies. Thus, this study is particularly significant as the first report to explore the relationship between CD73 and CD155 and prognosis in epithelial MPM cases.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study highlights the potential role of CD73 and CD155 as prognostic biomarkers in epithelial MPM, particularly in predicting response to postoperative pleurodesis. Although the findings suggest that CD73/CD155 expression affects treatment outcomes, further large-scale, multicentre studies are needed to validate these results and explore targeted therapeutic strategies. Understanding the interplay between these biomarkers and treatment response could facilitate the development of more personalised and effective management of MPM.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAI, artificial intelligence\u003c/p\u003e\n\u003cp\u003eAUC, area under the curve\u003c/p\u003e\n\u003cp\u003eCD155, Cluster of differentiation 155\u003c/p\u003e\n\u003cp\u003eCD73, Cluster of differentiation 73\u003c/p\u003e\n\u003cp\u003eCT, computed tomography\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio\u003c/p\u003e\n\u003cp\u003eICI, immune checkpoint inhibitor\u003c/p\u003e\n\u003cp\u003emAB, monoclonal antibody\u003c/p\u003e\n\u003cp\u003eOS, overall survival\u003c/p\u003e\n\u003cp\u003eP/D, pleurectomy and decortication\u003c/p\u003e\n\u003cp\u003ePBS, phosphate-buffered saline\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival\u003c/p\u003e\n\u003cp\u003ePVR, poliovirus receptor\u003c/p\u003e\n\u003cp\u003eROC, receiver operating characteristic\u003c/p\u003e\n\u003cp\u003eTPS, tumour proportion score\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are accountable for all aspects of the work and for ensuring that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of the University of Occupational and Environmental Health (Japan; No.: UOEHCRB21-065). Patients who were unable to provide informed consent were excluded; thus, written informed consent was obtained for all specimen sections included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFumihiro Tanaka has received grants from Ono Pharmaceutical, Taiho Pharmaceutical, Illy Lilly Japan, and Chugai Pharmaceutical; consulting fees from Astra Zeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Meyers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Bristol-Meyers Squibb, Boehringer Ingelheim Japan, Ono Pharmaceutical, Johnson \u0026amp; Johnson, Covidien Japan, Taiho Pharmaceutical, Illy Lilly Japan, Astra Zeneca, Chugai Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Pfizer, Olympus, Stryker, and Intuitive Japan. Masaru Takenaka has received compensation or honoraria from AstraZeneka for speaking engagements, presentations, speaker roles, manuscript writing, or educational events. The other authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the UOEH Grant-in-Aid for Promotion of Research in the Field of Occupational Medicine (2024-8). Amount: 143,750 yen. The funder had no specific role in the conception, design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRO, HM, YN, and FT conceived and designed the study and made substantial contributions to writing the manuscript. YF, TH, KT, and TM provided administrative support for writing the manuscript. KY, YN, NN, and YH provided study materials and recruited patients. YN, HM, MK, AT, MT, and KK collected and assembled the data. YN, SS, and FT analysed and interpreted the data and contributed substantially to the paper. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage for English language editing. We would also like to thank research staff member Kawashima Eri for helping with immunostaining.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYates DH, Corrin B, Stidolph PN, Browne K (1997) Malignant mesothelioma in south east England: clinicopathological experience of 272 cases [published correction appears in Thorax 1997. 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Cancer Res 80:CT302\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Occupational and Environmental Health Japan","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"CD155 antigen, CD73 antigen, chemotherapy, adjuvant, disease progression, immunotherapy, malignant pleural mesothelioma, pleurodesis, prognostic biomarkers, survival analysis","lastPublishedDoi":"10.21203/rs.3.rs-6538045/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6538045/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMalignant pleural mesothelioma (MPM) is a rare and aggressive tumour requiring multidisciplinary treatment. Identifying prognostic biomarkers could improve treatment planning and patient outcomes. CD73 and CD155 are immunomodulatory molecules involved in immune evasion and tumour progression in various cancers; however, their roles in MPM remain unclear. Therefore, this study aimed to investigate the association between CD73 and CD155 expression in resected epithelial MPM specimens and their impact on 5-year progression-free survival (PFS) and 5-year overall survival (OS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis single-centre retrospective study included 43 consecutive patients with epithelial MPM who underwent curative-intent surgery, with or without chemotherapy and immune checkpoint inhibitor (ICI) treatment, at our institution between January 1, 2013 and December 31, 2020. Immunohistochemical staining for CD73 and CD155 was performed on surgical specimens, and HALO-AI pathology software was used for quantitative analysis. Receiver operating characteristic (ROC) curve analysis determined cutoff values for CD73/CD155 positivity. Patients were categorised into CD73+/CD155+ and non-CD73+/CD155+ groups and survival outcomes (5-year PFS and 5-year OS) were analysed using Kaplan–Meier curves. Cox proportional hazards regression was used for univariate and multivariate analyses to identify independent prognostic factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 35 evaluable cases, patients with CD73+/CD155+ tumours had significantly improved 5-year PFS compared with those with non-CD73+/CD155+ tumours (64.8% vs. 10.8%, p=0.017), though OS differences were not significant (p=0.376). Among CD73+/CD155+ patients, those who underwent postoperative pleurodesis with OK432 demonstrated significantly higher PFS (83.3% vs. 33.3%, p=0.043), suggesting a potential therapeutic benefit. In contrast, in non-CD73+/CD155+ cases, postoperative chemotherapy significantly improved PFS (p=0.03). Multivariate analysis revealed non-CD73+/CD155+ expression and lack of postoperative chemotherapy as independent predictors of disease progression (HR 6.555, p=0.008) and mortality (HR 5.835, p=0.006). Among recurrent cases, patients treated with ICIs had significantly improved OS (p=0.001), highlighting the potential role of immunotherapy in this subgroup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eCD73 and CD155 expression patterns may serve as prognostic biomarkers in epithelial MPM. CD73+/CD155+ tumours appear to benefit from pleurodesis with OK432, while non-CD73+/CD155+ tumours may be more responsive to postoperative chemotherapy. These findings suggest that CD73/CD155 status could guide personalised treatment strategies in MPM, warranting further validation in larger cohorts.\u003c/p\u003e","manuscriptTitle":"Five-year progression-free survival and overall survival based on CD73 and CD155 expression in resected epithelial malignant pleural mesothelioma: a retrospective single-centre study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-05 09:40:51","doi":"10.21203/rs.3.rs-6538045/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"10823693-76d5-4c5b-8a9f-44baa2a1c3b0","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47733060,"name":"Surgery"}],"tags":[],"updatedAt":"2025-05-05T09:40:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-05 09:40:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6538045","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6538045","identity":"rs-6538045","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}