Association of peripheral basophils with tumor M2 macrophage infiltration and outcomes of the anti-PD-1 inhibitor plus chemotherapy combination in advanced gastric cancer.

BACKGROUND: Although the anti-programmed death-1 (PD-1) inhibitor plus chemotherapy combination has been approved as the standard first-line treatment for advanced gastric cancer, a proportion of patients do not significantly benefit from this therapy. Who would respond poorly to this treatment and the underlying mechanisms of treatment failure are far from clear. METHODS: We retrospectively analyzed the associations between the peripheral basophils at baseline and clinical outcomes in 63 advanced gastric cancer patients treated with anti-PD-1 plus chemotherapy and 54 patients treated with chemotherapy alone. Immunohistochemistry and immunofluorescence staining in gastric cancer samples were utilized to investigate the basophil-related immunophenotype. RESULTS: The optimal cutoff of basophil count to distinguish responders to anti-PD-1 plus chemotherapy from non-responders was 20.0/µL. Compared with the low basophil group (≤ 20.0/µL, n = 40), the high basophil group (> 20.0/µL, n = 23) had a significantly lower objective response rate (ORR 17.4% vs. 67.5%, p = 0.0001), worse progression-free survival (median PFS 4.0 vs. 15.0 months, p = 0.0003), and worse overall survival (median OS not reached, p = 0.027). Multivariate analyses identified a basophil count of > 20.0/µL as an independent risk factor for a worse ORR (OR 0.040, 95% CI 0.007-0.241, p = 0.0004), worse PFS (HR 3.720, 95% CI 1.823-7.594, p = 0.0003) and worse OS (HR 3.427, 95% CI 1.698-6.917, p = 0.001). In contrast, there was no significant association between peripheral basophil counts and tumor response or survival in the chemotherapy-alone group (p > 0.05). In primary gastric cancer samples, we observed a correlation between higher peripheral basophil counts and the accumulation of tumor-infiltrating basophils (r = 0.6833, p = 0.005). Tumor-infiltrating basophils were found to be spatially proximate to M2 macrophages within TME and positively correlated with tumor M2 macrophage infiltration (r = 0.7234, p = 0.0023). The peripheral basophil counts also had a significant positive correlation with tumor-infiltrating M2 macrophage counts (r = 0.6584, p = 0.003). Further validation in tumor samples treated with the neoadjuvant anti-PD-1 inhibitor plus chemotherapy combination suggests that the peripheral basophils, tumor infiltration of basophils, and M2 macrophages were significantly more abundant in non-responders than in responders (p = 0.0333, p = 0.0007, and p = 0.0066, respectively). CONCLUSIONS: The peripheral basophil count was observed to be a potential biomarker of anti-PD-1 efficacy for advanced gastric cancer. Moreover, basophils may induce an immune-evasive tumor microenvironment by increasing M2 macrophage infiltration, which could be a potential immunotherapeutic target for advanced gastric cancer.

Development and validation of a novel competing risk model for predicting survival of esophagogastric junction adenocarcinoma: a SEER population-based study and external validation.

BACKGROUND: Adenocarcinoma in Esophagogastric Junction (AEG) is a severe gastrointestinal malignancy with a unique clinicopathological feature. Hence, we aimed to develop a competing risk nomogram for predicting survival for AEG patients and compared it with new 8th traditional tumor-node-metastasis (TNM) staging system. METHODS: Based on data from the Surveillance, Epidemiology, and End Results (SEER) database of AEG patients between 2004 and 2010, we used univariate and multivariate analysis to filter clinical factors and then built a competing risk nomogram to predict AEG cause-specific survival. We then measured the clinical accuracy by comparing them to the 8th TNM stage with a Receiver Operating Characteristic (ROC) curve, Brier score, and Decision Curve Analysis (DCA). External validation was performed in 273 patients from China National Cancer Center. RESULTS: A total of 1755 patients were included in this study. The nomogram was based on five variables: Number of examined lymph nodes, grade, invasion, metastatic LNs, and age. The results of the nomogram was greater than traditional TNM staging with ROC curve (1-year AUC: 0.747 vs. 0.641, 3-year AUC: 0.761 vs. 0.679, 5-year AUC: 0.759 vs. 0.682, 7-year AUC: 0.749 vs. 0.673, P < 0.001), Brier score (3-year: 0.198 vs. 0.217, P = 0.012; 5-year: 0.198 vs. 0.216, P = 0.008; 7-year: 0.199 vs. 0.215, P = 0.014) and DCA. In external validation, the nomogram also showed better diagnostic value than traditional TNM staging and great prediction accuracy. CONCLUSION: We developed and validated a novel nomogram and risk stratification system integrating clinicopathological characteristics for AEG patients. The model showed superior prediction ability for AEG patients than traditional TNM classification.

N4-Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF-1α Positive Feedback Loop.

Anti-angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti-angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4-acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF-1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP-sequencing, Ribosome profiling sequencing, RNA-sequencing, and functional studies confirm that NAT10 in turn activates the HIF-1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF-1α positive feedback loop leads to excessive activation of the HIF-1 pathway and induces glycolysis addiction. Combined anti-angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti-angiogenic therapy by combining apatinib with ac4C inhibition.

Fibroblast-derived LPP as a biomarker for treatment response and therapeutic target in gastric cancer.

Association of tumor microenvironment and immune checkpoint (e.g., PD-L1) is important for immune escape, impacting chemotherapy and immunotherapy efficacy. We aimed to investigate biomarkers and therapeutic targets against treatment resistance in gastric cancer. Abundances of tumor-infiltrating immune cells were estimated in multiple datasets. Three patient subgroups (A, B, and C) were identified based on seven types of PD-L1- and IFN-γ-associated immune cells. Patients yielded increased prognosis from subgroup A to C (p = 0.027). Subgroup A was characterized by high activated CD4+ memory T cell infiltration, while more resting CD4+ memory T cells were in subgroup C. Further, a risk score was developed for prognostication. Lipoma preferred partner (LPP), as the hub gene in subgroup-related regulatory network, was upregulated (p < 0.01) and was associated with high risk score (p < 0.001) and poor survival (p < 0.05). Bioinformatics analyses and experiments found that LPP expressed restrictively in fibroblasts and associated with activated CD4+ memory T cell infiltration and tumor growth. High-LPP patients yielded fewer benefits from chemotherapy or immunotherapy, compared with the low-LPP group. We finally identified 28 compounds as sensitive drugs for high-LPP patients. Our findings suggested LPP might be a biomarker for treatment response and therapeutic target in gastric cancer.

Prognostic characteristics and clinical response to immunotherapy targeting programmed cell death 1 for patients with advanced gastric cancer with liver metastases.

Background: The specific efficacy of immunotherapy for patients with liver metastases of gastric cancer is unclear. This study set out to explore the treatment response and related prognostic factors for patients with liver metastases of gastric cancer treated with immunotherapy. Patients and methods: This retrospective cohort study included 135 patients with unresectable advanced gastric cancer. According to the presence of liver metastases and/or first-line treatment with immunotherapy, patients were divided into the following three groups: I-LM(-) group(patients without liver metastases treated with immunotherapy, n=66), I-LM(+) group(patients with liver metastases treated with immunotherapy, n=36), C-LM(+) group(patients with liver metastases treated with chemotherapy and/or target therapy, n=33). Cox regression analyses were used to identify factors associated with survival in all patients and the three groups, respectively. Results: For the patients with liver metastases treated with immunotherapy, multivariate analysis showed that only the presence of peritoneal metastases was significantly associated with shorter PFS [hazard ratios (HR), 3.23; 95% CI, 1.12-9.32; P=0.030] and the patients with peritoneal metastases had shorter median PFS than patients without peritoneal metastases(3.1 vs 18.4 months; P=0.004), while the objective response rate was 100% in patients with HER2-positive (2 complete radiographic responses and 2 partial responses; 3 of 4 patients were still ongoing benefits [median follow-up time, 15.3 months ; interquartile range(IQR), 6.3-17.9 months]). Conclusions: The findings suggest that patients with various types of gastric cancer liver metastases respond differently to immune checkpoint inhibitors, HER2-positive patients may derive clinical benefits from immune checkpoint inhibitors, while the presence of peritoneal metastases is associated with resistance.

The Effect of Neoadjuvant Therapies for Patients with Locally Advanced Gastric Cancer: A Propensity Score Matching Study.

Background: The aim of this study was to evaluate the effect of neoadjuvant therapies (NAT) on patients with locally advanced gastric cancer (LAGC). Methods: This study retrospectively analyzed LAGC patients treated at the China National Cancer Center between October 2006 and December 2018. All patients included were divided into two groups, NAT followed by surgery (NAT-Surgery) and adjuvant chemotherapy following surgery (Surgery-ACT). Subgroup analysis compared between patients underwent either neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiation (nCRT) was conducted. Propensity score matching (PSM) was implemented to reduce selection bias. Results: In total, 2779 patients were included in this study (494 of NAT-Surgery group and 2285 of Surgery-ACT group). After PSM, the patients in NAT-Surgery group had a significantly longer overall survival (OS) than patients in Surgery-ACT group (P<0.001). Subgroup analysis revealed that grade 3 or 4 adverse events were more frequently observed in nCRT group during neoadjuvant treatment (52.0% in nCRT group vs. 34.0% in nCT group, P=0.010). Pathological complete response (pCR) being achieved in 17.0% after nCRT versus 4.0% after nCT (P<0.001). Patients of the nCRT group obtained better disease-free survival (DFS, P=0.024) and local-recurrence-free survival (LRFS, P=0.014) than patients in nCT group, while there was no significant difference in OS between the two groups. Conclusions: In conclusion, NAT improved survival outcomes among LAGC patients over surgery followed by adjuvant chemotherapy. In comparison with nCT, nCRT resulted in higher pCR rate, better DFS and LRFS, without significantly affecting OS.

Development and validation of a novel nomogram for predicting the prognosis of patients with resected pancreatic adenocarcinoma.

The survival prediction for patients with resected pancreatic adenocarcinoma by using the Tumor-Node-Metastasis (TNM) staging system remains limited. A nomogram is a efficient tool that can be used to predict the outcome of patients with various types of malignancy. The present study aimed to develop and validate a nomogram for patients with resected pancreatic adenocarcinoma. A total of 368 patients (258 in the training set and 110 in the validation set) who underwent pancreatic adenocarcinoma resection at the China National Cancer Center between January 2008 and October 2018 were included in the present study. The nomogram was established according to the results from Cox multivariate analysis, which was validated by discrimination and calibration. The area under the receiver operating characteristic curve (AUC) was determined to assess the accuracy of survival predictions. The results from multivariate analysis in the training set demonstrated that blood transfusion, T-stage, N-stage, tumor grade, capsule invasion, carbohydrate antigen 199, neutrophil percentage and adjuvant therapy were independent prognostic factors for overall survival (OS; all P<0.05). Subsequently, a nomogram predicting the 1-year, 3-year and 5-year OS rates, with favorable calibration, was established based on the independent prognostic factors. The concordance indices of the nomogram were higher compared with the TNM staging system in both training and validation sets. Furthermore, a clear risk stratification system based on the nomogram was used to classify patients into the three following groups: Low-risk group (≤168), moderate-risk group (168-255) and high-risk group (>255). The risk stratification system demonstrated an improved ability in predicting the 1-year, 3-year and 5-year OS rates compared with the TNM system (AUC, 0.758, 0.709 and 0.672 vs. AUC, 0.614, 0.604 and 0.568; all P<0.05). The present study developed and validated a nomogram for patients with resected pancreatic adenocarcinoma by including additional independent prognostic factors, including tumor marker, immune index, surgical information, pathological data and adjuvant therapy. Taken together, the results from the present study indicated an improved performance of the nomogram in predicting the prognosis of patients with resected pancreatic adenocarcinoma compared with the TNM staging system.

Neoadjuvant chemotherapy-induced severe neutropenia is associated with histopathological response and survival in locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been shown to improve the prognosis for patients with locally advanced gastric cancer (LAGC). Neutropenia, a predominant chemotherapy-related adverse event, affects the therapeutic course for NAC. METHODS: Data for 233 patients with LAGC treated with NAC and curative gastrectomy at our center were retrospectively analysed in terms of the relationship between neutropenia and clinicopathological features or outcomes. RESULTS: NAC-induced neutropenia, NAC-induced severe (grade 3/4) neutropenia (NISN), and a favorable histopathological response (HPR) were observed in 102 (43.8%), 35 (15.0%), and 103 (44.2%) patients, respectively. Together with tumor differentiation, clinical response, and lymphovascular invasion (LVI), and NISN independently predicted a favorable HPR [odds ratio (OR) =4.158, 95% confidence interval (CI): 1.762-9.812, P=0.001). Among patients treated with postoperative chemotherapy, NISN independently predicted poor compliance with postoperative chemotherapy (OR 0.364, 95% CI: 0.148-0.894, P=0.028) and thus poor overall survival (OS) and disease-free survival (DFS). Among patients treated with preoperative chemotherapy alone, NISN was associated with a tendency towards a better DFS (P=0.116) and independently predicted superior OS (hazard ratio =0.253, 95% CI: 0.077-0.830, P=0.023). CONCLUSIONS: In conclusion, our study revealed a link between NISN, HPR, treatment compliance, and survival. NISN is useful for guiding treatment strategies and predicting prognosis for LAGC patients.

Primary tumor resection and lymph node dissection improve survival in de novo metastatic pancreatic ductal adenocarcinoma: an inverse probability of treatment weighting analysis.

BACKGROUND: Primary tumor resection (PTR) and lymph node dissection (LND) may be performed occasionally in patients with de novo metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the role of PTR and LND in such cases remains unclear. Thus, we aimed to test the effect of PTR and LND on overall survival (OS) and cancer-specific survival (CSS) in mPDAC patients. METHODS: Patients with de novo mPDAC were identified from the Surveillance Epidemiology and End Results (SEER) database (2010-2015). The inverse probability of treatment weighting (IPTW) method was used to minimize the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS and CSS in different treatment groups. RESULTS: A total of 10,036 patients met the inclusion criteria. Of these patients, 275 (2.7%) underwent PTR, while 217 (2.2%) also underwent LND with a median of 16 nodes removed. In the IPTW-adjusted Kaplan-Meier analysis, the median OS was 13 versus 6 months (P<0.001) for the PTR and non-PTR groups, respectively, and 15 versus 5 months (P=0.007) for the LND and non-LND groups, respectively. In the IPTW-adjusted Cox regression analysis, PTR was independently associated with better OS [hazard ratio (HR) 0.483, 95% confidence interval (CI): 0.468-0.498, P<0.001], as was LND (HR 0.286, 95% CI: 0.228-0.358, P<0.001). Similar results were observed in the analysis of CSS. In the LND group, the extent of LND was not associated with either OS or CSS. CONCLUSIONS: PTR and LND were independent prognostic factors that prolonged OS and CSS in de novo mPDAC patients. These findings must be validated in prospective randomized studies.

Effects of Neoadjuvant Chemotherapy Toxicity and Postoperative Complications on Short-term and Long-term Outcomes After Curative Resection of Gastric Cancer.

BACKGROUND: Whether neoadjuvant chemotherapy (NAC) increased the risk of postoperative morbidities for patients with locally advanced gastric cancer (GC) is unknown. Whether neoadjuvant chemotherapy toxicity (NCT) and postoperative complications (POCs) correlate with short-term and long-term outcomes also remains unclear. We aimed to evaluate the role of NAC on the development of POCs, as well as the impact of NCT and POCs on postoperative and oncologic outcomes in curatively resected GC treated with NAC. METHODS: This study retrospectively reviewed 230 patients who underwent curative gastrectomy for locally advanced GC (clinically T3/4 or N+) after NAC between 2006 and 2016. Five hundred patients undergoing upfront and curative surgery were selected as a control group. After matching, the incidence of POCs was compared between two groups. In the NAC group, clinicopathological characteristics of patients who experienced POCs were compared to those who did not. Logistic and Cox multivariate regression analyses were used to examine factors associated with POCs, disease-free survival (DFS), and overall survival (OS). RESULTS: Following matching, 230 and 230 patients treated with surgery plus NAC and upfront surgery remained, respectively. The incidence of POCs was 28.7% and 24.3%, respectively (p = 0.290). In the NAC group, NCT (OR [odds ratio] 22.968, 95% CI [confidence interval] 2.948-> 99, p = 0.003) and operation time (OR 1.006, 95% CI 1.001-1.011, p = 0.021) were independent predictive factors of POCs. NCT did not affect oncologic outcomes. The Cox regression model demonstrated that POCs were independently associated with worse DFS (HR [hazard ratio] 2.128, 95% CI 1.240-3.653, p = 0.006) but not OS for patients treated with NAC. CONCLUSIONS: The administration of NAC is not associated with an elevated risk of POCs. For patients treated with NAC, NCT is an independent predictor of POCs, but does not affect oncologic outcomes. POCs is independently associated with worse DFS but not OS. NAC should be considered a safe approach in patients who have locally advanced GC. Strategies to minimize chemotherapy toxicity and postoperative morbidities associated with NAC are warranted.

Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal Adenocarcinoma with Tumor Grade: A Novel Staging System.

BACKGROUND: The 8th American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC) outperforms its previous version in reproducibility but not in survival discrimination. Tumor grade, an indicator of the aggressive biology of PDAC, has been suggested as a reliable prognostic factor. This study aimed to construct a novel staging system with greater prognostication for resectable PDAC by incorporating tumor grade into the 8th AJCC system. METHODS: A total of 9966 patients with resectable PDAC from the Surveillance Epidemiology and End Results (SEER) database were randomly separated into training and interval validation sets. Another 324 patients from our center were included as an external validation set. We proposed a novel staging system by sorting the substages yielded by a combination of T, N, and tumor grade based on their overall survival (OS) and grouping them into several stages. Prognostic homogeneity and discrimination were determined using the likelihood ratio χ 2 and the linear trend χ 2 test, respectively. Prognostic accuracies were evaluated by the area under the receiver operating characteristics curve (AUC). RESULTS: Using the 8th AJCC system, the prognosis of patients within the same stage was quite heterogeneous among different substages. The multivariate Cox model identified the tumor grade (hazard ratio 1.333, 95% confidence interval 1.250-1.423, p < 0.001) was an independent prognostic factor of the OS. In the training set, the AUC, homogeneity, and discriminatory ability were superior for the novel staging system than for the 8th AJCC system (0.642 vs. 0.615, 403.4 vs. 248.6, and 335.1 vs. 218.0, respectively). Similar results were observed in the internal and external validation sets. CONCLUSIONS: The novel staging system incorporating tumor grade into the 8th AJCC system was associated with better prognostic accuracy, homogeneity, and discriminatory ability among resectable PDAC patients. Moreover, the novel staging system also allowed possibly adjuvant chemotherapy decisions.

Neo-adjuvant Chemotherapy-Induced Neutropenia Is Associated with Histological Responses and Outcomes after the Resection of Colorectal Liver Metastases.

BACKGROUND: Neutropenia, the major adverse event in chemotherapy, is associated with favourable clinical outcome in several solid tumours. We aimed to investigate the predictive value of neo-adjuvant chemotherapy (NAC)-induced neutropenia for the pathological response and prognosis in colorectal liver metastases (CRLM) patients. METHODS: A retrospective review was performed in 141 CRLM patients receiving NAC followed by liver resection. A logistic regression was applied to analyse potential predictors. A Cox proportional hazards analysis was used to analyse survival. RESULTS: Neutropenia due to NAC was observed in 42.6% (60/141) of all patients, and grade 3/4 neutropenia was noted in 31.7% (19/60). A pathological response (tumour regression grade (TRG) 1-3) was reported in 46.1% (65/141) of patients. Multivariate analysis showed that neutropenia significantly predicted the favourable pathological response (OR = 3.718, 95% CI 1.716-8.329, P = 0.001), as well as targeted therapy, good differentiation and preoperative CEA < 10 ng/ml as independent predictors of favourable histological response. Of the patients, 54.6% (77/141) had postoperative complications, including 28 major complications (28/77, 36.4%). Severe neutropenia significantly predicted postoperative major complications in multivariate analysis (OR = 4.077, 95% CI 1.184-14.038, P = 0.026). Compared to patients without neutropenia, patients with neutropenia had significantly better progression-free survival (PFS) (P = 0.007; mPFS, 10.2 months vs. 6.7 months). Patients with histological response had significantly better PFS than patients with no histological response (P = 0.001; mPFS, 10.0 months vs. 5.5 months). According to multivariate analyses, neutropenia was a significant predictor for better PFS (HR = 0.613, 95% CI 0.406-0.925, P = 0.020) but not OS. CONCLUSIONS: For CRLM patients receiving NAC followed by liver resection, NAC-induced neutropenia was a significant predictor of favourable pathological response, postoperative major complications and better prognosis, which makes it useful for CRLM patients in guiding treatment approaches and prognosis assessments.

Development and validation of a nomogram to individually predict survival of young patients with nonmetastatic gastric cancer: A retrospective cohort study.

BACKGROUND/AIMS: Evidence regarding gastric cancer (GC) patients <40 years old is limited. The aim of the study was to identify risk factors affecting overall survival (OS) of young patients with nonmetastatic GC and to establish a nomogram for prognostic prediction using data from the Surveillance, Epidemiology and End Results (SEER) database. Furthermore, this study sought to externally validate this nomogram in an independent patient cohort. PATIENTS AND METHODS: In this retrospective cohort study, the records of patients aged <40 years with nonmetastatic GC (n = 559), from the SEER database, between 2006 and 2015, were examined. The nomogram was established based on the Cox proportional hazards regression model using the SEER dataset. Patients with nonmetastatic GC (n = 201) in our department between 2009 and 2015 were selected as an external validation set. Discrimination and calibration were performed in both cohorts. RESULTS: The multivariate Cox model identified race, tumor subsites, tumor size, depth of invasion, lymph node metastasis, number of examined lymph nodes, and surgery as independent covariates associated with OS. The nomogram exhibited superior discriminative power than the eighth tumor, node, metastasis (TNM) staging system in both the training set [Harrell's concordance index (C index): 0.762 vs. 0.635,P < 0.001] and validation set (C index: 0.805 vs. 0.712,P= 0.176). Calibration of the nomogram was good in both cohorts. CONCLUSIONS: We developed a nomogram predicting 3- and 5-year OS rates in young patients with nonmetastatic GC. Both the training set and validation set showed good discrimination and calibration, suggesting good clinical applicability.

Impact of the time from the completion of neoadjuvant chemotherapy to surgery on the outcomes of patients with gastric cancer.

BACKGROUND: Gastrectomy is usually recommended within 5 to 6 weeks after the completion of neoadjuvant chemotherapy (NCT). However, the optimal timing of surgery is not clearly defined. METHODS: This study retrospectively reviewed the clinical records of 229 patients with locally advanced gastric cancer (GC) who underwent curative gastrectomy after NCT between 2006 and 2016. The effect of the time to surgery (TTS), defined as ≤4, 5-6, and >6 weeks, on patient outcomes was examined. Descriptive statistics and Cox proportional hazards models were used. RESULTS: Seventy of 229 patients (30.6%) had surgery within 4 weeks after their last dose of NCT, 103 (45.0%) within 5-6 weeks, and 56 (24.5%) after 6 weeks. The median age was 56.0 [interquartile range (IQR), 47.0-63.0] years, and the median TTS was 34.0 (IQR, 26.0-42.0) days. The three groups did not significantly differ regarding most surgical and histopathological characteristics except for the NCT regimen (P=0.010), number of cycles of NCT (P=0.017) and pathological stage (P=0.015). The NCT regimen was the only independent factor associated with TTS >6 weeks (P=0.015). The 3-year progression-free survival (PFS) estimates were 41.9%, 42.8% and 61.7% in patients who underwent surgery in ≤4, 5-6, and >6 weeks after NCT, respectively (P=0.044). The 3-year overall survival (OS) estimates were 57.7%, 58.0% and 68.2% in the three groups, respectively (P=0.202). According to multivariable analysis, compared with the interval of ≤4 weeks, patients who underwent surgery at 5-6 or >6 weeks had equivalent PFS and OS. CONCLUSIONS: The NCT-surgery interval time has no impact on patient outcomes.

[RESEARCH PROGRESS OF OSTEOCLASTS FUNCTION BEYOND BONE RESORPTION].

OBJECTIVE: To review the osteoclasts (OC) function beyond bone resorption. METHODS: The related literature on OC function beyond bone resorption was reviewed, analyzed, and summarized. RESULTS: OC control the bone formation through releasing of matrix-derived growth factors, bidirectional cell-to-cell signals, and secreting OC-coupling factors, and play an important role in the niche formation, hematopoietic stem cells mobilization, and maintenance of its quantity and function; besides, OCs also regulate angiogenesis. CONCLUSION: These discoveries greatly enrich the current knowledge of OC function and open up an all-new research domain. However, the exact regulatory mechanism of OC affecting the hematopoiesis is still lack in-depth understood. Additionally, it remains to be elucidated how OC-coupling factors act on osteoblast lineage differentiation and how OC-induced angiogenesis participates in physiological and pathological processes. Unclosing the underlying mechanisms will facilitate providing scientific therapeutic strategies for treatment of many OC-related diseases.