Ethnic disparities and temporal trends in health resource allocation: a retrospective decadal analysis in Sichuan, a multi-ethnic Province of Southwest China (2009-2019).

BACKGROUND: Research on health resource allocation trends in ethnic minority and impoverished areas in China is limited since the 2009 Medical Reform. This study aimed to investigate the variations and inequalities in health resource distribution among ethnic minority, poverty-stricken, and non-minority regions in Sichuan Province, a multi-ethnic province in Southwest China, from 2009 to 2019. METHODS: The numbers of beds, doctors and nurses were retrospectively sourced from the Sichuan Health Statistics Yearbook between 2009 and 2019. All the 181 counties in Sichuan Province were categorized into five groups: Yi, Zang, other ethnic minority, poverty-stricken, and non-minority county. The Theil index, adjusted for population size, was used to evaluate health resource allocation inequalities. RESULTS: From 2009 to 2019, the number of beds (Bedp1000), doctors (Docp1000), and nurses (Nurp1000) per 1000 individuals in ethnic minority and poverty-stricken counties consistently remained lower than non-minority counties. The growth rates of Bedp1000 in Yi (140%) and other ethnic minority counties (127%) were higher than in non-minority counties (121%), while the growth rates of Docp1000 in Yi (20%) and Zang (11%) counties were lower than non-minority counties (61%). Docp1000 in 33% and 50% of Yi and Zang ethnic counties decreased, respectively. Nurp1000 in Yi (240%) and other ethnic minority (316%) counties increased faster than non-minority counties (198%). The Theil index for beds and nurses declined, while the index for doctors increased. Key factors driving increases in bed allocation include preferential policies and economic development levels, while health practitioner income, economic development levels and geographical environment significantly influence doctor and nurse allocation. CONCLUSIONS: Preferential policies have been successful in increasing the number of beds in health facilities, but not healthcare workers, in ethnic minority regions. The ethnic disparities in doctor allocation increased in Sichuan Province. To increase the number of doctors and nurses in ethnic minority and poverty-stricken regions, particularly in Yi counties, more preferential policies and resources should be introduced.

Is repeat sentinel lymph node biopsy possible for surgical axillary staging among patients with ipsilateral breast tumor recurrence?

BACKGROUND: There is a lack of studies assessing the survival of repeat sentinel lymph node biopsy (rSLNB) versus axillary lymph node dissection (ALND) for surgical axillary staging among patients with ipsilateral breast tumor recurrence (IBTR). METHODS: We retrospectively identified patients with IBTR from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. The primary outcome was overall survival (OS) between the rSLNB and ALND groups. RESULTS: Of the 2141 women with IBTR after lumpectomy and SLNB, 524 did not receive surgical axillary staging (nonsurgery group) and 1617 patients who did undergo axilla surgery received either rSLNB or ALND as axillary staging (1268 with rSLNB and 349 with ALND). The 10-year OS rates were 61.9% for the nonsurgery and 73.8% for axilla surgery groups (p = .001). In the 1:1 matched cohorts, the 10-year OS rates were 61.4% for the nonsurgery and 69.1% for axilla surgery groups (p = .072). After adjusting for other factors, axillary surgery treatment of IBTR was an independent favorable factor for OS (hazard ratio [HR], 0.71; 95% CI, 0.56-0.90; p = .004). Within the axilla surgery group, rSLNB presented a comparable 10-year OS to the ALND cohort (log-rank test p = .054). Multivariate Cox analysis, as well as subgroup analysis, showed that rSLNB had a similar benefit to ALND (10-year OS; HR, 1.18; 95% CI, 0.88-1.58; p = .268). CONCLUSIONS: The results of this cohort study suggested that receiving surgical axillary staging was associated with better survival of IBTR patients, and rSLNB had a similar long-term survival outcome as ALND. rSLNB might be considered for surgical axillary staging among patients with IBTR after lumpectomy and initial SLNB.

A novel risk model based on immune response predicts clinical outcomes and characterizes immunophenotypes in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous in prognosis. The current TNM staging system shows its limitation in accurate risk evaluation. Immune response and immune cell abundances in the tumor immune microenvironment (TIME) are critical for cancer progression, clinical outcome and therapeutic response in TNBC. However, there is a lack of an effective risk model based on the overall transcriptional alterations relevant to different immune responses. In this study, multiple bioinformatics and statistical approaches were used to develop an immune-related risk (IRR) signature based on the differentially expressed genes between the immune-active and immune-inactive samples. The IRR model showed great performance in risk stratification, immune landscape evaluation and immunotherapy response prediction. Compared with the low-IRR group, the high-IRR group exhibited a poorer prognosis, less cytotoxic cell infiltration, higher M2/M1 ratio and upregulated glycolytic activity. Moreover, the high-IRR group showed more resistance to immunotherapy than the low-IRR group. Our study reveals that the IRR model may be a promising tool to help clinicians assess risk and optimize treatment for TNBC patients.

Trends in axillary surgery and clinical outcomes among breast cancer patients with sentinel node metastasis.

BACKGROUND: There is a lack of studies examining the long-term trend and survival of axillary surgery for breast cancer patients with sentinel node metastasis, especially for the patients with 3-5 node metastases. METHODS: Breast cancer patients with 1-5 sentinel node metastases from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2016. Our study presented the trend of axillary surgery and assessed the long-term survival of sentinel lymph node biopsy (SLNB) alone vs axillary lymph node dissection (ALND) for those patients. RESULTS: Of the 41,996 patients diagnosed with T1-2 breast cancer after lumpectomy and radiation included, 34,940 had 1-2 sentinel node metastases and 7056 had 3-5 sentinel node metastases. The percentage of patients undergoing SLNB alone increased from 22.4% in 2000 to 81.0% in 2016 for patients with 1-2 sentinel node metastases, and quadrupled from 5.2% in 2009 to 20.6% in 2016 for those with 3-5 sentinel node metastases. Completion of ALND did not benefit the long-term survival of 1-2 sentinel node metastasis patients (hazard ratio [HR] = 1.02, P = 0.539), but improved the long-term survival of 3-5 node metastasis patients (HR = 0.73, P < 0.001). Subgroup analysis demonstrated the inferiority of SLNB to ALND in all subgroups of 3-5 sentinel node metastases. CONCLUSION: For patients with T1-2 breast cancer after lumpectomy and radiation, SLNB alone was an efficient and safe surgical choice for 1-2 sentinel node metastases but not for 3-5 sentinel node metastases. It is worth noting that for patients with 3-5 node metastasis, the proportion of omitted ALND quadrupled after 2009.

Prognostic value and tumour microenvironment characteristics of the Glasgow Microenvironment Score in primary triple-negative breast cancer.

AIMS: The Glasgow Microenvironment Score (GMS) reflects the tumour microenvironment (TME) status by combining inflammatory cell infiltration and the tumour-stroma percentage. This study aimed to investigate the prognostic value and TME characteristics of the GMS for patients with triple-negative breast cancer (TNBC). METHODS: A total of 123 patients with stage I-III TNBC were enrolled in this study. The association between GMS and clinicopathological characteristics was examined using the Pearson's χ2 test or Fisher's exact test. Kaplan-Meier plots were used to compare survival among the three GMS groups. Cox regression analyses were conducted to test the HR. Microenvironment Cell Populations-counter algorithm was used to estimate the TME components of each case. RESULTS: We found that higher GMS score tended to exhibit the lower nuclear grade (p=0.016), more positive lymph nodes (p=0.014) and later tumour, node, metastases stage (p=0.012). GMS was an independent prognostic factor for disease-free survival in TNBC, and GMS 2 showed the worst prognosis (HR=6.42, p=0.028). GMS 0 was more infiltrated with cytotoxic lymphocytes, including CD8+ T cells (p=0.037) and natural killer cells (p=0.005), while GMS 2 was enriched in more endothelial cells (p=0.014) and fibroblasts (p=0.008). CONCLUSION: Our study suggested that the GMS is a prognostic indicator for patients with TNBC. As an accessible and effective index, the GMS may be a promising tool to help clinicians assess prognostic risk and TME for patients with TNBC.

Effects of postmastectomy radiotherapy on survival in different age groups for patients with T3N0M0 breast cancer.

BACKGROUND: Postmastectomy radiotherapy (PMRT), as an important regional treatment, improves the survival rate of patients with T3N0M0 breast cancers. However, the therapeutic effect of PMRT on T3N0M0 patients in different age groups is unclear. METHODS: Using Surveillance, Epidemiology, and End Results database, we identified 4840 T3N0M0 patients between 2000 and 2015. The primary and secondary outcomes were overall survival (OS) and breast cancer-specific survival (BCSS). Survival outcomes were compared using Kaplan-Meier survival test, COX regression analysis, propensity score matching and forest plot, which present the relationship between age and PMRT. RESULTS: Survival analysis demonstrated that for young patients (aged 18-45 and 46-55), there was no significant difference in OS between with and without PMRT. However, for patients older than 65 years, PMRT could significantly improve survival time (P < 0.001). Multivariate Cox analysis of OS showed older patients with PMRT had a lower hazard ratio (HR) than those without PMRT (aged 56-65: HR = 0.67, P = 0.014; aged >65: HR = 0.60, P < 0.001), and little benefit for young patients. The consistent results were also observed in 1:1 matched cohort. Subgroup analysis revealed the survival HRs of with versus without PMRT for patients older than 65 years were significant in most subgroups. CONCLUSION: The effect of PMRT in T3N0M0 patients is related to the age. PMRT is associated with improved survival in older patients with T3N0M0 breast cancer, especially those older than 65 years. While the benefit of PMRT is limited in T3N0M0 patients of young age. The observation suggests the importance of age for T3N0M0 patients when individualized treatment is made.

The Prognostic Impact of Age at Diagnosis Upon Breast Cancer of Different Immunohistochemical Subtypes: A Surveillance, Epidemiology, and End Results (SEER) Population-Based Analysis.

Background and Objectives: The influence of age at diagnosis of breast cancer upon the prognosis of patients with different immunohistochemical (IHC)-defined subtypes is still incompletely defined. Our study aimed at examining the association of age at diagnosis and risk of breast cancer-specific mortality (BCSM). Methods: 172,179 eligible breast cancer patients were obtained for our study cohort using the Surveillance, Epidemiology, and End Results database from 2010 to 2015. Patients were classified into four IHC-defined subtypes according to their ER, PgR, and HER2 status. Kaplan-Meier plots were used to describe BCSM among patients in different age groups. A Cox proportional hazards model was used for multivariate analysis. A multivariable fractional polynomial model within the Cox proportional hazards model was used to evaluate the relationship between age at diagnosis and the risk of BCSM. Results: For the whole cohort, the median follow-up time was 43 months. Patients younger than 40 years and those older than 79 years presented with the worst BCSM (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.03-1.23, and HR 3.52, 95% CI 3.23-3.83, respectively, p < 0.01, with age 40-49 years as the reference). The log hazard ratios of hormone receptor (HoR)(+)/HER2(-) patients formed a quadratic relationship between age at diagnosis and BCSM, but not in the other three subtypes of breast cancer. In the HoR(+)/HER2(-) subtype, patients younger than 40 years had worse BCSM than those aged at 40-49 years (HR 1.26, 95% CI 1.10-1.45, and p < 0.01). Conclusions: Women diagnosed with HoR(+)/HER2(-) breast cancer younger than 40 years or older than 79 years of age suffer higher rates of cancer-specific mortality. Young age at diagnosis may be particularly prognostic in HoR(+)/HER2(-) breast cancer.

SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer.

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.

Clinicopathological characteristics and treatment outcomes of occult breast cancer: a SEER population-based study.

BACKGROUND: Occult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial. PATIENTS AND METHODS: We identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population. RESULTS: OBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P<0.001). This result was confirmed in a 1:1 matched case-control analysis. Within the four OBC treatment groups, we observed no difference in survival among the mastectomy group, the breast-conserving surgery (BCS) group, and the axillary lymph node dissection (ALND)-only group. The multivariable analysis revealed that the sentinel lymph node dissection-only group had the worst prognosis (P<0.001). Conclusion: OBC has unique clinicopathological characteristics and a favorable prognosis compared with non-OBC. BCS plus ALND and radiotherapy showed a survival benefit that was similar to that of mastectomy for OBC patients.

Acetylation of lysine 182 inhibits the ability of Mycobacterium tuberculosis DosR to bind DNA and regulate gene expression during hypoxia.

The DosR regulon is believed to be a key factor in latency adaptation of Mycobacterium tuberculosis and is strongly induced by multiple stresses, including hypoxia. Previous studies have revealed reversible acetylation of the conserved core DNA-binding lysine residue 182 (K182) of DosR in M. tuberculosis. In this study, we demonstrated that acetylated K182 plays an important role in the DNA-binding ability of DosR and that acetylation of K182 completely abolished the affinity of DosR for DNA in vitro. Antibodies that specifically recognized acetyllysine at position 182 of DosR were used to monitor DosR acetylation. We found that in vitro acetylation of K182 could be removed by deacetylase Rv1151c and that either the deacetylase-deletion strain ∆npdA or treatment with a deacetylase inhibitor resulted in increased levels of K182 acetylation in vivo. The physiological significance of DosR acetylation was demonstrated by decreased levels of acetylated K182 in M. tuberculosis in response to hypoxia and by the effects of K182 acetylation on the transcript levels of DosR regulon genes. Since the DosR regulon plays a critical role during host infection by M. tuberculosis, our findings suggest that targeting DosR acetylation may be a viable strategy for antituberculosis drug development.

Decreased survival in patients with carcinoma of axillary tail versus upper outer quadrant breast cancers: a SEER population-based study.

BACKGROUND: Carcinoma of the axillary tail of Spence (CATS) is a poorly studied type of breast cancer. The clinicopathological characteristics and prognostic features of CATS are unclear. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified 149,026 patients diagnosed with upper outer quadrant breast cancer (UOBC) (n=146,343) or CATS (n=2,683). The median follow-up was 88 months. The primary and secondary outcomes were breast cancer-specific survival (BCSS) and overall survival. The survival outcomes of UOBC and CATS were compared using competing risks analysis, log-rank test, Cox proportional hazards regression model, and propensity score matching method. Multivariate logistic regression was utilized to present the relationship between CATS and lymph node (LN) metastasis. RESULTS: CATS presented a higher grade, higher negative hormone receptor rate, and more positive nodal metastasis. The 10-year BCSS rate was worse for CATS than for UOBC (85.1% vs 87.3%, P=0.001). The multivariate Cox analysis showed a higher hazard ratio (HR) for CATS over UOBC (BCSS: HR =1.20, P=0.001; overall survival: HR =1.11, P=0.019). The difference in the BCSS was also observed in a 1:1 matched cohort (BCSS P=0.019). A subgroup analysis revealed the inferior outcomes of CATS in the metastatic LN subgroup and the hormone receptor-negative subgroup. The multivariate logistic regression indicated that CATS is an independent contributing factor to LN metastasis. CONCLUSION: CATS had distinct clinicopathological characteristics and was more likely associated with LN metastasis. Compared to UOBC, CATS had adverse impacts on BCSS.