Emerging roles of tRNA-derived small RNAs in cancer biology.

Transfer RNAs (tRNAs) play an essential role in mRNA translation by delivering amino acids to growing polypeptide chains. Recent data demonstrate that tRNAs can be cleaved by ribonucleases, and the resultant cleavage products, tRNA-derived small RNAs (tsRNAs), have crucial roles in physiological and pathological conditions. They are classified into more than six types according to their size and cleavage positions. Since the initial discovery of the physiological functions of tsRNAs more than a decade ago, accumulating data have demonstrated that tsRNAs play critical roles in gene regulation and tumorigenesis. These tRNA-derived molecules have various regulatory functions at the transcriptional, post-transcriptional, and translational levels. More than a hundred types of modifications are found on tRNAs, affecting the biogenesis, stability, function, and biochemical properties of tsRNA. Both oncogenic and tumor suppressor functions have been reported for tsRNAs, which play important roles in the development and progression of various cancers. Abnormal expression patterns and modification of tsRNAs are associated with various diseases, including cancer and neurological disorders. In this review, we will describe the biogenesis, versatile gene regulation mechanisms, and modification-mediated regulation mechanisms of tsRNA as well as the expression patterns and potential therapeutic roles of tsRNAs in various cancers.

Single-cell RNA sequencing reveals heterogeneity of adipose tissue-derived mesenchymal stem cells under chondrogenic induction.

This study investigated how adipose tissue-derived mesenchymal stem cells (AT-MSCs) respond to chondrogenic induction using droplet-based single-cell RNA sequencing (scRNA-seq). We analyzed 37,219 high-quality transcripts from control cells and cells induced for 1 week (1W) and 2 weeks (2W). Four distinct cell clusters (0-3), undetectable by bulk analysis, exhibited varying proportions. Cluster 1 dominated in control and 1W cells, whereas cluster 3, 2, and 0 exclusively dominated in control, 1W, and 2W cells, respectively. Furthermore, heterogeneous chondrogenic markers expression within clusters emerged. Gene ontology (GO) enrichment analysis of differentially expressed genes unveiled cluster-specific variations in key biological processes (BP): (1) Cluster 1 exhibited upregulation of GO-BP terms related to ribosome biogenesis and translational control, crucial for maintaining stem cell properties and homeostasis; (2) Additionally, cluster 1 showed upregulation of GO-BP terms associated with mitochondrial oxidative metabolism; (3) Cluster 3 displayed upregulation of GO-BP terms related to cell proliferation; (4) Clusters 0 and 2 demonstrated similar upregulation of GO-BP terms linked to collagen fibril organization and supramolecular fiber organization. However, only cluster 0 showed a significant decrease in GO-BP terms related to ribosome production, implying a potential correlation between ribosome regulation and the differentiation stages of AT-MSCs. Overall, our findings highlight heterogeneous cell clusters with varying balances between proliferation and differentiation before and after chondrogenic stimulation. This provides enhanced insights into the single-cell dynamics of AT-MCSs during chondrogenic differentiation.

Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer.

BACKGROUND: The transition of human epidermal growth factor receptor 2 (HER2) status after neoadjuvant chemotherapy (NAC) in HER2-low breast cancer has not been thoroughly evaluated. Here, we evaluated the HER2 transition among HER2-zero and HER2-low breast cancer cases post-NAC and its impact on clinical outcomes. METHODS: We included 1288 patients with HER2-low or zero breast cancer who underwent NAC and surgery between 2014 and 2018 and had paired pre- and post-therapeutic HER2 status results. RESULTS: Among patients who were HER2-zero pre-NAC (n = 650), 68% and 29% were HER2-zero and HER2-low, respectively, post-NAC. Among patients who were HER2-low pre-NAC (n = 638), 32% of patients showed HER2 changes (low to zero), and 59% of patients had a constant HER2-low status post-NAC. Patients with constant HER2-low or transitions from HER2-low to zero had a higher proportion of hormone receptor positivity (84% and 79%) than those with changes from HER2-zero to low (77%) or with constant HER2-zero (56%), respectively. Multivariable logistic regression analysis revealed that patients with oestrogen receptor positivity had a higher probability of gaining HER2-low expression than those with oestrogen receptor negativity (odds ratio 2.48). No significant differences were observed in terms of overall survival or disease-free survival between patients with and without HER2-changes according to their hormone receptor status, except in the post-therapeutic HER2-low, hormone receptor-negativity subset. CONCLUSION: Temporal heterogeneity of HER2-low expression is observed in substantial numbers of post-NAC breast cancer patients. Clinical outcomes show no significant associations, except in the post-therapeutic HER2-low, hormone receptor negativity subset. The prognostic implications of HER2 transition in HER2-low breast cancer require further investigation.

Pathological complete response, long-term outcomes, and recurrence patterns in HER2-low versus HER2-zero breast cancer after neoadjuvant chemotherapy.

BACKGROUND: The interest in HER2-low breast cancer (BC) has increased in recent years with the development of novel anti-HER2 antibody-drug conjugates. Here, we investigated the clinical outcomes and relapse patterns of patients with HER2-low or -zero BCs in an Asian population. METHODS: We retrospectively identified HER2-low or -zero BC patients with stage I-III tumours who were treated with neoadjuvant chemotherapy and underwent curative surgery, between 2014 and 2018 at Asan Medical Center, Seoul, Korea. RESULTS: A total of 818 and 754 HER2-zero and HER2-low BC patients, respectively, were consecutively included in this analysis. The HER2-low group had more hormone receptor [HR]-positive patients (81% versus 56%, P < 0.001). The HER2-zero group had a higher proportion of patients who achieved pathological complete response (pCR) (14.7% versus 9.8%, P = 0.003); however, no significant differences of pCR rate by HER2 status were identified in the HR-positive (P = 0.4) and HR-negative groups (P = 0.3) when analysed separately. The HER2-low BC cases had higher 5-year overall survival (OS) and disease-free survival (DFS) rates (P < 0.001 for OS; P = 0.002 for DFS); however, no differences were observed in terms of OS and DFS by HER2 status in the HR-positive group (P = 0.21 for OS and P = 0.66 for DFS). CONCLUSIONS: Our current findings do not support that HER2-low BC had different biology and clinical features compared to HER2-zero BC in patients who treated with neoadjuvant chemotherapy. However, the prognostic impact of HER2-low status in BC remains controversial; thus warranting further research.

Impact of Local Breast Cancer Recurrence on Reconstructed Breast in Nipple-Sparing Mastectomy with Immediate Reconstruction.

The impact of locally recurrent breast cancer on reconstructed breasts remains largely unknown. Therefore, this study aimed to investigate the incidence of reconstruction loss due to local recurrence in patients who underwent nipple-sparing mastectomy with immediate reconstruction for breast cancer and to identify potential recurrence-associated risk factors for loss of index reconstruction. The records of 1,696 patients who underwent nipple-sparing mastectomy with immediate reconstruction between March 2003 and December 2016 at a single institution were reviewed. Among them, 128 patients with local breast cancer recurrence as the first event were analyzed. The primary outcome was loss of reconstruction due to local breast cancer recurrence. Reconstruction loss was classified as partial flap loss with breast distortion, complete flap loss, or implant loss during salvage treatment of local recurrence. Reconstruction loss occurred in 21 of the 128 patients (16%). Reconstruction loss rates were 20% for autologous and 9.5% for implant-based reconstruction (P = 0.204). Multivariate analysis showed that recurrent tumor size > 2.0 cm and multifocal recurrence were independent factors associated with an increased risk of reconstruction loss. Moreover, age ≥ 50 years at the time of recurrence diagnosis, recurrent tumor size > 2.0 cm, and multifocal recurrence were independently associated with complete flap/implant loss in the multivariate analysis. The incidence of reconstruction loss due to local breast cancer recurrence after nipple-sparing mastectomy with immediate reconstruction was low in this study. Age ≥ 50 years at recurrence diagnosis and the extent of local recurrence independently affected reconstruction loss. To detect recurrence early, careful follow-up through regular ultrasonography or magnetic resonance imaging at the reconstruction site is important.

Effectiveness of a 6-Month 22.5-mg Leuprolide Acetate Depot Formulation With Tamoxifen for Postoperative Premenopausal Estrogen Suppression in Hormone Receptor-Positive Breast Cancer.

BACKGROUND: In patients with hormone receptor-positive (HR+)/premenopausal breast cancer, luteinizing hormone-releasing hormone analogs (LHRHas) are used as standard endocrine treatment. Based on previous clinical studies, 1-month formulations are recommended in most breast cancer treatment guidelines, but long-acting formulations facilitate reductions in side effects and patient discomfort caused by frequent administration. However, few efficacy studies have been conducted on 6-month formulations. Therefore, this study aimed to evaluate the efficacy of 6-month formulations of LHRHas. METHODS: This retrospective study was conducted from January 2018 to December 2019 and involved premenopausal patients with HR+ breast cancer administered 6-month LHRHas as adjuvant treatment after surgery, and those previously administered chemotherapy or other LHRHa types were excluded. Patients' estradiol (E2) and follicle-stimulating hormone (FSH) levels were measured before surgery, and their E2 levels were also measured at 3, 6, 12, 18, and 24 months at periodic postsurgical examinations. RESULTS: A total of 228 patients were included, and the median patient age was 44 (range, 25-54) years. The mean serum E2 and FSH levels before surgery were 69.7 (range, 4-683) pg/mL and 7.3 (range, 0.4-88.9) mIU/mL, respectively, whereas the mean serum E2 level monitored at intervals during the 6-month LHRHa administration was 5.5 (range, 4.0-52) pg/mL. No women menstruated during the follow-up period after the LHRHas administration, and the E2 levels were less than 30 pg/mL in all patients except one. CONCLUSIONS: The 6-month LHRHa formulation adequately suppressed ovarian function in premenopausal patients with HR+ breast cancer. This indicates that long-acting LHRHas can be effectively used for patient convenience and that there is high compliance with long-term use.

Locoregional recurrence following nipple-sparing mastectomy with immediate breast reconstruction: Patterns and prognostic significance.

INTRODUCTION: There are limited available data on the prognostic implications of locoregional recurrence (LRR) after nipple-sparing mastectomy (NSM) and immediate reconstruction. In this study, we investigated the patterns and prognosis associated with LRR following this treatment approach for breast cancer. METHODS: A total of 1696 patients with primary breast cancer who underwent NSM with immediate reconstruction from March 2003 to December 2016 were retrospectively analyzed. Post-recurrence disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards model were performed to evaluate the prognostic factors associated with the DFS and DMFS. RESULTS: After a median follow-up period of 84 months, we identified 172 patients (10.1%) with an LRR as the first event. The 5-year post-recurrence DFS rates for the nipple-areola complex recurrence (NCR), skin or subcutaneous recurrence/chest wall recurrence (SCR/CWR), and regional recurrence (RR) groups were 89.1%, 73%, and 59.4%, respectively (P = 0.009), and the 5-year post-recurrence DMFS rates for the NCR, SCR/CWR, and RR groups were 96%, 82.8%, and 59.7%, respectively (P < 0.001). In multivariate analysis, a time to LRR ≤2 years (P = 0.016) and the site of LRR (P = 0.022) were significantly associated with the post-recurrence DFS. CONCLUSIONS: NCR is more likely to be detected as a non-invasive recurrence and is associated with more favorable overall outcomes than other LRR types. The interval to LRR and its site of onset seem to be associated with the prognostic outcomes.

Breast-conserving surgery with 3D-printed surgical guide: a single-center, prospective clinical study.

To facilitate precise tumor resection at the time of breast-conserving surgery (BCS), we developed and implemented a magnetic resonance imaging (MRI)-based three-dimensional-printed (3DP) breast surgical guide (BSG). This prospective cohort study was conducted at a single institution from July 2017 to February 2019 on women with breast cancer who underwent partial breast resection using patient-specific 3DP BSGs. Eighty-eight patients with invasive cancer were enrolled, of whom 1 patient had bilateral breast cancer. The mean size of the tumor long-axis on MRI before surgery was 2.8 ± 0.9 cm, and multiple tumors were observed in 34 patients. In 16 cases (18.0%), the resection margin was tumor-positive according to intraoperative frozen biopsy; all of these tumors were ductal carcinoma in situ and were re-excised intraoperatively. In 93.3% of the cases, the resection margin was tumor-free in the permanent pathology. The mean pathological tumor size was 1.7 ± 1.0 cm, and the mean distance from the tumor to the border was 1.5 ± 1.0 cm. This exploratory study showed that the tumor area on the MRI could be directly displayed on the breast when using a 3DP BSG for BCS, thereby allowing precise surgery and safe tumor removal.Trial Registration Clinical Research Information Service (CRIS) Identifier (No. KCT0002375, KCT0003043).

Data on distant metastasis and survival after locoregional recurrence following nipple-sparing mastectomy and immediate breast reconstruction.

Nipple-spring mastectomy (NSM) with immediate breast reconstruction is being increasingly used in the treatment of breast cancer [1]. However, there are limited available data on the prognostic implications of locoregional recurrence (LRR) following this surgical procedure. This article is a supplementary resource of the original research article by Wu ZY et al. entitled "Locoregional Recurrence Following Nipple-Sparing Mastectomy with Immediate Breast Reconstruction: Patterns and Prognostic Significance" [2] and presents data regarding the subsequent distant metastasis following the first LRR, as well as the prognoses for isolated local recurrences according to the site of recurrence after NSM and immediate breast reconstruction for primary breast cancer. Data from a total of 1,696 patients with primary breast cancer who underwent NSM with immediate reconstruction from March 2003 to December 2016 at the Asan Medical Center, Seoul, Korea, were retrospectively reviewed. An LRR as the first event was found to have developed in 172 patients. Among these, 117 cases (6.9%) involved isolated local recurrence, including 52 cases (3.1%) of nipple-areola complex recurrence, 41 cases (2.4%) of skin/subcutaneous recurrence, and 24 cases (1.4%) of chest wall recurrence. Kaplan-Meier survival analysis and the log-rank test were performed to compare the subgroups of local recurrence. In 172 patients with LRR, subsequent distant metastases were observed in 30 cases (17.4%). Our data may be helpful for conducting further in-depth investigations on salvage treatment options in patients with LRR following NSM and immediate breast reconstruction.