The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features-the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-κB, cGAS-STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment. Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment-particularly SASP-holds great potential for advancing future anti-tumor therapies.

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

Objective:To analyze the prognostic factors of breast cancer patients with isolated chest wall recurrence (ICWR) after mastectomy, and investigate the optimal treatment.Methods:A total of 201 breast cancer patients with ICWR after mastectomy who were treated in Cancer Hospital, Chinese Academy of Medical Sciences and the Fifth Medical Center Chinese PLA General Hospital from October 1998 to April 2018 were retrospectively analyzed. The median follow-up was 92.8 months and survival data were obtained.Results:Among 201 patients with ICWR, 103 patients developed subsequent locoregional recurrence (sLRR) and 5-year cumulative sLRR rate was 49.1%; 134 patients developed distant metastasis (DM) and 5-year DM rate was 64.4%; 103 patients died, the median progression-free survival (PFS) was 17.4 months and the 5-year PFS rate was 23.2%; the median overall survival (OS) was 62.5 months and the 5-year OS rate was 52.1%. Multivariate analysis showed that the recurrence interval ( HR=2.17, 95% CI: 1.26-3.73) and the locoregional treatment ( HR=1.59, 95% CI: 1.05-2.40) were the independent prognostic factors for sLRR. The initial HER2 status ( HR=1.60, 95% CI: 1.03-2.48) was the independent prognostic factor for DM. The recurrence interval ( HR=1.99, 95% CI: 1.30-3.04), the locoregional treatment ( HR=1.99, 95% CI: 1.43-2.76) and the treatment modalities after recurrence ( HR=1.70, 95% CI: 1.18-2.46) were the independent prognostic factors for PFS. The initial HER2 status ( HR=1.69, 95% CI: 1.02-2.81), the recurrence interval ( HR=1.85, 95% CI: 1.15-2.98) and the treatment modalities after recurrence ( HR=2.48, 95% CI: 1.56-3.96) were the independent prognostic factors for OS. Conclusions:Breast cancer patients after ICWR have an optimistic OS until now, but the risk of sLRR and DM is high. Comprehensive treatment modalities including surgery, radiotherapy and systemic therapy improve the outcome of breast cancer patients with ICWR after mastectomy.

Objective:To analyze the prognostic factors of breast cancer patients with isolated chest wall recurrence (ICWR) after mastectomy, and investigate the optimal treatment.Methods:A total of 201 breast cancer patients with ICWR after mastectomy who were treated in Cancer Hospital, Chinese Academy of Medical Sciences and the Fifth Medical Center Chinese PLA General Hospital from October 1998 to April 2018 were retrospectively analyzed. The median follow-up was 92.8 months and survival data were obtained.Results:Among 201 patients with ICWR, 103 patients developed subsequent locoregional recurrence (sLRR) and 5-year cumulative sLRR rate was 49.1%; 134 patients developed distant metastasis (DM) and 5-year DM rate was 64.4%; 103 patients died, the median progression-free survival (PFS) was 17.4 months and the 5-year PFS rate was 23.2%; the median overall survival (OS) was 62.5 months and the 5-year OS rate was 52.1%. Multivariate analysis showed that the recurrence interval ( HR=2.17, 95% CI: 1.26-3.73) and the locoregional treatment ( HR=1.59, 95% CI: 1.05-2.40) were the independent prognostic factors for sLRR. The initial HER2 status ( HR=1.60, 95% CI: 1.03-2.48) was the independent prognostic factor for DM. The recurrence interval ( HR=1.99, 95% CI: 1.30-3.04), the locoregional treatment ( HR=1.99, 95% CI: 1.43-2.76) and the treatment modalities after recurrence ( HR=1.70, 95% CI: 1.18-2.46) were the independent prognostic factors for PFS. The initial HER2 status ( HR=1.69, 95% CI: 1.02-2.81), the recurrence interval ( HR=1.85, 95% CI: 1.15-2.98) and the treatment modalities after recurrence ( HR=2.48, 95% CI: 1.56-3.96) were the independent prognostic factors for OS. Conclusions:Breast cancer patients after ICWR have an optimistic OS until now, but the risk of sLRR and DM is high. Comprehensive treatment modalities including surgery, radiotherapy and systemic therapy improve the outcome of breast cancer patients with ICWR after mastectomy.

Objective:To investigate the radiation field and dose selection of patients with isolated chest wall recurrence (ICWR) after modified radical mastectomy, and analyze the prognostic factors related to subsequent chest wall recurrence.Methods:Clinical data of 201 patients with ICWR after mastectomy admitted to the Fifth Medical Center, Chinese PLA General Hospital from 1998 to 2018 were retrospectively analyzed. None of the patients received postoperative adjuvant radiotherapy. After ICWR, 48 patients (73.6%) underwent surgery and 155 patients (77.1%) received radiotherapy. Kaplan-Meier method was used to calculate the post-recurrence progression-free survival (PFS) rates and the difference was compared by log-rank test. Multivariate analysis was performed using Cox regression model. Competing risk model was adopted to estimate the subsequent local recurrence (sLR) rates after ICWR and the difference was compared with Gray test. Multivariate analysis was conducted using F&G analysis. Results:With a median follow up of 92.8 months after ICWR, the 5-year PFS rate was 23.2%, and the 5-year sLR rate was 35.7%. Multivariate analysis showed that patients with surgery plus radiotherapy and recurrence interval o F>12 months had a lower sLR rate. Patients with recurrence interval o F>48 months, local plus systemic treatment and surgery plus radiotherapy had a higher PFS rate. Among the 155 patients who received chest wall radiotherapy after ICWR, total chest wall irradiation plus local boost could improve the 5-year PFS rate compared with total chest wall irradiation alone (34.0% vs. 15.4%, P=0.004). Chest wall radiation dose (≤60 Gy vs.>60 Gy) exerted no significant effect upon the sLR and PFS rates (both P>0.05). In the 53 patients without surgery, the 5-year PFS rates were 9.1% and 20.5%( P=0.061) with tumor bed dose ≤60 Gy and>60 Gy, respectively. Conclusions:Local radiotherapy is recommended for patients with ICWR after modified radical mastectomy of breast cancer, including total chest wall radiation plus local boost. The radiation dose for recurrence should be increased to 60 Gy, and it should be above 60 Gy for those who have not undergone surgical resection. In addition, patients with ICWR still have a high risk of sLR, and more effective treatments need to be explored.

Objective:To analyze the prognosis of patients with isolated regional recurrence (RR) after mastectomy, and evaluate the efficacy of radiotherapy and identify the optimal radiation target volumes.Methods:Clinical data of 144 patients with first isolated RR after mastectomy between 2001 and 2018 were retrospectively analyzed. All patients had not received post-mastectomy radiotherapy. The primary endpoints consisted of the subsequent locoregional recurrence (sLRR), distant metastasis (DM), progression-free survival (PFS) and overall survival (OS).Results:With a median follow-up of 82.5 months after RR, the 5-year sLRR, DM, PFS and OS rates for the entire group were 42.1%, 71.9%, 22.9% and 62.6%, respectively. Local plus systemic therapy was an independent favorable prognostic factor for sLRR ( P<0.001) and PFS ( P=0.013). The sLRR rate in the surgery plus radiotherapy group was the lowest ( P<0.001). Surgery plus radiotherapy significantly reduced the 5-year risk of recurrence within the initially involved nodal regions ( P<0.001). Patients with chest wall irradiation obtained the 5-year subsequent chest wall recurrence rate of 12.1% compared to 14.8%( P=0.873) for those without chest wall irradiation. The subsequent supraclavicular recurrence rate was lower in patients with prophylactic supraclavicular irradiation than that without prophylactic supraclavicular irradiation (9.9% vs. 23.8%, P=0.206). The incidence rates of initially uninvolved axillary and internal mammary nodal recurrence were below 10% regardless of prophylactic irradiation or not. Conclusions:Patients with RR alone have an optimistic 5-year OS in the contemporary era. Comprehensive locoregional treatment including surgery and radiotherapy combined with systemic therapy is recommended. The chest wall, axillary and internal mammary nodal prophylactic irradiation should not be routinely performed for all patients with RR. The value of supraclavicular prophylactic irradiation remains to be evaluated.

BACKGROUND: Despite improvements in disease diagnosis, treatment, and prognosis, breast cancer is still a leading cause of cancer death for women. Compelling evidence suggests that targeting cancer stem cells (CSCs) have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy. In the present study, we aimed to study the effects of T cells and a critical anti-tumor cytokine, interferon-gamma (IFN-γ), on breast cancer stem cells. METHODS: BALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells. Tumor growth and pulmonary metastasis were assessed. ALDEFLOUR™ assays were performed to identify aldehyde dehydrogenasebright (ALDHbr) tumor cells. ALDHbr cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry. The effects of CD8+ T cells on ALDHbr tumor cells were assessed in vitro and in vivo. The expression profiles of ALDHbr and ALDHdim 4T1 tumor cells were determined. The levels of plasma IFN-γ were measured by enzyme-linked immunosorbent assay, and their associations with the percentages of ALDHbr tumor cells were evaluated. The effects of IFN-γ on ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro. RESULTS: There were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice (25.40 vs. 54.67, P < 0.050). CD8+ T cells decreased the percentages of ALDHbr 4T1 tumor cells in vitro (control vs. effector to target ratio of 1:1, 10.15% vs. 5.76%, P < 0.050) and in vivo (control vs. CD8+ T cell depletion, 10.15% vs. 21.75%, P < 0.001). The functions of upregulated genes in ALDHbr 4T1 tumor cells were enriched in the pathway of response to IFN-γ. The levels of plasma IFN-γ decreased gradually in tumor-bearing BALB/c mice, while the percentages of ALDHbr tumor cells in primary tumors increased. IFN-γ at a concentration of 26.68 ng/mL decreased the percentages of ALDHbr 4T1 tumor cells (22.88% vs. 9.88%, P < 0.050) and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells (0.86 vs. 0.49, P < 0.050) and inhibited the abilities of sphere formation (sphere diameter <200 μm, 159.50 vs. 72.0; ≥200 μm, 127.0 vs. 59.0; both P < 0.050) and invasion (89.67 vs. 67.67, P < 0.001) of 4T1 tumor cells. CONCLUSION CD8+ T cells and IFN-γ decreased CSC numbers in a 4T1 mouse model of breast cancer. The application of IFN-γ may be a potential strategy for reducing CSCs in breast cancer.
Aldehydes ; Animals ; Breast Neoplasms ; Cell Line, Tumor ; Female ; Humans ; Interferon-gamma ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplastic Stem Cells

Objective: To analyze the clinical efficacy and pregnancy outcomes of fertility- preserving re-treatment in patients with recurrent atypical endometrial hyperplasia (AEH) and early stage endometrial carcinoma (EEC) after achieved complete remission (CR) of primary fertility-preserving therapy. Methods: There were 104 cases of AEH and EEC collected from 9 hospitals in the multi-center research network platform of fertility-preserving therapy of endometrial carcinoma in China from January 2005 to May 2019. Thirth-one cases of them relapsed from four hospitals mentioned above,who achieved CR after primary fertility-preserving therapy,was analyzed retrospectively. Of the 31 cases, 27 cases chose fertility-preserving re-treatment. The demographic characteristics, re-treatment effect, clinical factors and pregnancy outcomes were observed. Results: (1) There were 16 AEH cases and 11 ECC cases among 27 recurrent patients who chose fertility-preserving therapy again. After re-treatment, CR was found in 13 out of 16 cases of AEH and 9 out of 11 cases of EEC. The overall CR rate was 81% (22/27). (2) After CR of recurrence, 5 cases (23%, 5/22) of re-recurrence were found after with a median time of 33 months (range 21-80 months). There were 4 cases underwent comprehensive surgical staging, and 1 patient chose the third round of fertility preservation therapy with fully informed consent, and CR was reached after 15 months. (3) There were 16 cases with pregnancy intention, with a total of 12 pregnancies, including 5 cases were natural pregnancy and 7 cases were assisted reproductive technology pregnancy. There were 5 live births. The follow-up time was up to May 2019, and the median follow-up time was 73 months (range 0-123 months). All 27 patients had disease free survival. Conclusions Recurrent patients with AEH and EEC after achieving successful fertility-preserving therapy could choose fertility-preserving therapy again with comprehensive assessment and fully informed consent. After re-treatment, there is a certain tumor CR rate and pregnancy rate, while the close follow-up is required during treatment.

Objective: To introduce the application of free-style perforator flap based on aesthetic units to repair facial defect after tumor resection. Methods: By following the concept of free-style perforator flap and the principle of facial aesthetic unit, the design of a free-style perforator flap allowed over any nearby cutaneous vessel chosen purely on the characteristics of its Doppler signal. Conventional knowledge of anatomical landmarks and possible vascular variations were less relevant. A greater freedom in flap selection was gained to recover defect in different forms such as rotation flap, advanced flap and propeller flap, which were all based on free-style perforators. The flap size ranged from 1.5 cm×1.0 cm to 12.0 cm×6.0 cm with the perforator diameter of 0.3-3.0 mm in pedicle, and some of the pedicles are "perforator clusters" . Results: A total of 72 cases underwent surgery, and 68 cases survived completely with satisfactory appearance. 1 case healed two weeks later through dressing due to undesired healing, which result ed from high tension secondary postoperative blooding. 3 cases healed in a delay due to congestion and gained acupuncture treat. Conclusions The free-style perforator flap, which depended on Doppler-discerned perforator and facial aesthetic unit, represents safe, reliable and versatile for repairing facial defect after extended resection, and it not only offers a greater freedom in flap selection but also provides good aesthetic result.

Objective To explore the effect of prognosis of consolidation radiotherapy for patients after R0 resection of local recurrence after radical mastectomy. Methods Totally 110 breast cancer patients with local recurrence receiving R0 resection were admitted and treated in our hospital from January 1st, 2003 to November 30th, 2015 were retrospectively analyzed. Results The median local progression time of 74 patients receiving consolidation radiotherapy ( 67.3％) was remarkably better than that of those without radiotherapy(36 patients, 32.7％), and the difference was statistically significant (χ2 =8. 526, P<0.05). Meanwhile, there was no statistically significant difference (P>0.05) of distance disease-free survival and overall survival between the radiotherapy group and the non-radiotherapy group. Multifactor analysis indicated that pseudo-adjuvant endocrine therapy (χ2 =7.541,95％CI:27.1％ -80.4％, P <0.05), DDFS(≥2 years vs. <2 years,χ2 =4.068,95％CI:101.4％ -267％,P<0. 05) and pseudo-adjuvant radiotherapy(χ2 =14.126, 95％CI:21.7％ -80.4％, P <0. 05 ) were the independent risk factors affecting the OS of patients with local recurrence after R0 resection. Conclusions For the patients with local recurrence after R0 resection of local recurrence, it is recommended that consolidation radiotherapy should be done and the radiation field should include the same side of the chest wall and clavicle area lymphatic drainage area.