Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

Human Not in the Loop: Objective Sample Difficulty Measures for Curriculum Learning.

Curriculum learning is a learning method that trains models in a meaningful order from easier to harder samples. A key here is to devise automatic and objective difficulty measures of samples. In the medical domain, previous work applied domain knowledge from human experts to qualitatively assess classification difficulty of medical images to guide curriculum learning, which requires extra annotation efforts, relies on subjective human experience, and may introduce bias. In this work, we propose a new automated curriculum learning technique using the variance of gradients (VoG) to compute an objective difficulty measure of samples and evaluated its effects on elbow fracture classification from X-ray images. Specifically, we used VoG as a metric to rank each sample in terms of the classification difficulty, where high VoG scores indicate more difficult cases for classification, to guide the curriculum training process We compared the proposed technique to a baseline (without curriculum learning), a previous method that used human annotations on classification difficulty, and anti-curriculum learning. Our experiment results showed comparable and higher performance for the binary and multi-class bone fracture classification tasks.

Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial.

Importance: Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need. Objective: To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. Design, Setting, and Participants: This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020. Interventions: Participants were randomly assigned (2:1) to receive either EGCG solution (660 µmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. Main Outcomes and Measures: The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. Results: A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). Conclusions and Relevance: In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02580279.

SHCBP1 Promotes the Progression of Esophageal Squamous Cell Carcinoma Via the TGFß Pathway.

Esophageal cancer (EC) is known as a type of common malignant tumor, with the incidence ranking eighth worldwide. Because of the high metastasis of advanced EC, the total survival rate has been quite low. Esophageal squamous cell carcinoma (ESCC) is a main type of EC. Targeted therapy for ESCC has become a new direction; however, newly therapeutic targets are also badly needed. Shc SH2 domain-binding protein (SHCBP1) is located on 16q11.2, which is a downstream protein of the Shc adaptor. SHCBP1 participates in the regulation of several physiological and pathologic processes, such as cytokinesis. Recent studies have found that SHCBP1 was abnormally upregulated in multiple types of tumors, such as breast cancer and liver cancer, and that it affects the proliferation and motility of cancer cells in vitro. However, it remains unclear whether SHCBP1 is related to the progression of EC. Herein, we found the upregulation of SHCBP1 in human EC tissues. Our findings further demonstrated that SHCBP1 expression was related to the clinical features of ESCC patients. We found that SHCBP1 depletion inhibited the proliferation and motility of ESCC cells via the transforming growth factor ß pathway and that it suppressed the growth of tumors in mice. We, therefore, concluded that SHCBP1 could serve as a promising EC molecular target.

A novel long noncoding RNA, TMEM92-AS1, promotes gastric cancer progression by binding to YBX1 to mediate CCL5.

Numerous studies have revealed that long noncoding RNAs (lncRNAs) with oncogene properties play vital roles in gastric cancer (GC). In this study, we aimed to elucidate the function of TMEM92-AS1 in GC progression and to investigate its underlying mechanisms. TMEM92-AS1 was filtered from the Gene Expression Omnibus database. GC tissues and adjacent normal tissues were used to detect the expression level of TMEM92-AS1. MTT, colony-formation assays, Edu, cell cycle, apoptosis and subcutaneous tumour formation assays were used to detect the role of TMEM92-AS1 in cell function. RNA transcriptome sequencing was used to seek downstream target genes. Reverse transcription (RT)-qPCR, western blot, RNA and chromatin immunoprecipitation assays were used to investigate the mechanisms involved. TMEM92-AS1 was significantly overexpressed in GC tissues and correlated with poor overall survival and disease-free survival. Furthermore, TMEM92-AS1 promoted GC cell proliferation and migration in vitro and tumorigenic ability in vivo. RNA transcriptome sequence analysis revealed a potential downstream target gene, C-C motif chemokine ligand 5 (CCL5), and a mechanistic study found that TMEM92-AS1 regulated CCL5 by binding to the transcription factor Y-box binding protein 1(YBX1), which has oncogene properties. In addition, TMEM92-AS1 was found to be associated with peripheral blood leukocyte counts, especially neutrophils. Further investigation found that TMEM92-AS1 may affect leukocytes via regulation of the expression of granulocyte colony-stimulating factor in GC tissues. Our data provide an in-depth insight into the mechanism behind the lncRNA TMEM92-AS1, how it promotes GC progression and the possible mechanism in affecting peripheral leukocyte counts. Therefore, TMEM92-AS1 is a potential target for GC individualized therapy and prognostic assessment.

Hsa_circ_002178 Promotes the Growth and Migration of Breast Cancer Cells and Maintains Cancer Stem-like Cell Properties Through Regulating miR-1258/KDM7A Axis.

Breast cancer (BrCa) is the most common malignancy in women. Accumulating evidence demonstrated that abnormal circRNA expression is associated with the occurrence and progression of tumors. We analyzed the GSE101123 data and found that the expression of hsa_circ_002178 (circ_002178) was significantly increased in BrCa tissues. However, the role and possible underlying mechanisms of circ_002178 in BrCa still remain unrevealed. In this investigation, the expression levels of circ_002178 in cancer tissues or BrCa cells were significantly upregulated compared with those in paracancer tissues or normal cells. High expression of circ_002178 was correlated with the low survival rate, clinical tumor size, lymph node metastasis, and tumor, nodes, and metastases grade. After microsphere culture, the expression of circ_002178 in SUM149PT and MDA-MB-231 cells was significantly increased. Further investigation exhibited that overexpression of circ_002178 contributed to the formation of microspheres, the elevated protein levels of stemness marker, and the increased activity of ALDH1 in SUM149PT cells. Besides, the overexpression of circ_002178 also significantly promoted the growth, invasion, and migration of BrCa cells. Correspondingly, the knockdown of circ_002178 showed the opposite result in MDA-MB-231 cells. Hsa_circ_002178 was further proved to downregulate the level of miR-1258 and reduce the inhibitory effect of miR-1258 on KDM7A, thus regulating the stem-like characteristics of BrCa cells and promoting the growth and migration of BrCa cells. Taken together, targeting the circ_002178/miR-1258/KDM7A axis may be a prospective strategy for the diagnosis and therapies of BrCa in the future.

Sentinel lymph node biopsy in patients with breast ductal carcinoma in situ: Chinese experiences.

The axillary treatment of patients with ductal carcinoma in situ (DCIS) remains controversial. The aim of the present study was to evaluate the roles of sentinel lymph node biopsy (SLNB) in patients with breast DCIS. A database containing the data from 262 patients diagnosed with breast DCIS and 100 patients diagnosed with DCIS with microinvasion (DCISM) who received SLNB between January 2002 and July 2014 was retrospectively analyzed. Of the 262 patients with DCIS, 9 presented with SLN metastases (3 macrometastases and 6 micrometastases). Patients with large tumors diagnosed by ultrasound or with tumors of high histological grade had a higher positive rate of SLNs than those without (P=0.037 and P<0.0001, respectively). Of the 100 patients with DCISM, 11 presented with metastases. Younger patients had a higher positive rate of SLNs (P=0.028). According to the results of this study and the systematic review of recent studies, the indications of SLNB for patients with DCIS are as follows: SLNB should be performed in all DCISM patients and in those DCIS patients who received mastectomy, and could be avoided in those who received breast-conserving surgery. However, SLNB should be recommended to patients who have high risks of harboring invasive components. The risk factors include a large, palpable tumor, a mammographic mass or a high histological grade.

Validation of the Memorial Sloan Kettering Cancer Center nomogram for predicting non-sentinel lymph node metastasis in sentinel lymph node-positive breast-cancer patients.

BACKGROUND: The main purpose of the study reported here was to validate the clinical value of the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram that predicts non-sentinel lymph node (SLN) metastasis in SLN-positive patients with breast cancer. METHODS: Data on 1,576 patients who received sentinel lymph node biopsy (SLNB) at the Shandong Cancer Hospital from December 2001 to March 2014 were collected in this study, and data on 509 patients with positive SLN were analyzed to evaluate the risk factors for non-SLN metastasis. The MSKCC nomogram was used to estimate the probability of non-SLN metastasis and was compared with actual probability after grouping into deciles. A receiver-operating characteristic (ROC) curve was drawn and predictive accuracy was assessed by calculating the area under the ROC curve. RESULTS: Tumor size, histological grade, lymphovascular invasion, multifocality, number of positive SLNs, and number of negative SLNs were correlated with non-SLN metastasis (P<0.05) by univariate analysis. However, multivariate analysis showed that tumor size (P=0.039), histological grade (P=0.043), lymphovascular invasion (P=0.001), number of positive SLNs (P=0.001), and number of negative SLNs (P=0.000) were identified as independent predictors for non-SLN metastasis. The trend of actual probability in various decile groups was comparable to the predicted probability. The area under the ROC curve was 0.722. Patients with predictive values lower than 10% (97/492, 19.7%) had a frequency of non-SLN metastasis of 17.5% (17/97). CONCLUSION: The MSKCC nomogram can provide an accurate prediction of the probability of non-SLN metastasis, and offers a reference basis about axillary lymph node dissection. Axillary lymph node dissection could be avoided in patients with predictive values lower than 10%.

Using intra-operative GeneSearchTM Breast Lymph Node Assay to detect breast cancer metastases in sentinel lymph nodes: results from a single institute in China.

BACKGROUND: Sentinel lymph node (SLN) biopsy has become a common procedure for early breast cancer patients. The GeneSearch(TM) Breast Lymph Node (BLN) Assay is a real-time RT-PCR assay for the detecting nodal metastases larger than 0.2 mm. China Breast Cancer Clinical Study Group (CBCSG)-001a is a prospective multi-center clinical trial that was conducted to validate the GeneSearch(TM) BLN Assay in China. METHODS: The SLNs from 90 consecutive patients were identified and dissected, and then sectioned along the short axis into multiple blocks. Intra-operatively, the odd blocks were tested by BLN assay and the even ones were used for frozen section, while all the blocks were evaluated by touch imprint cytology. Post-operatively, the remaining tissues were assessed by histological evaluation. RESULTS: A total of 189 SLNs was tested by BLN assay. The sensitivity, specificity, positive predictive value, and negative predictive value were 88.9%, 97.4%, 88.9% and 97.4%, respectively, for BLN assay, 75.0%, 100%, 100% and 94.4%, respectively, for frozen section, and 63.9%, 100%, 100% and 92.2%, respectively, for touch imprint cytology. The sensitivity of BLN assay was higher than that of touch imprint cytology (P = 0.01) and frozen section (P = 0.13). When assessing the nodes with micro-metastases, BLN assay had a significant higher sensitivity than frozen section (P = 0.023) and touch imprint cytology (P = 0.005). CONCLUSION: The GeneSearch(TM) BLN Assay is an accurate and rapid intra-operative assay for breast SLNs and it is suitable for application in general medical practice.

Roles of preoperative lymphoscintigraphy for sentinel lymph node biopsy in breast cancer patients.

OBJECTIVE: To evaluate roles of preoperative lymphoscintigraphy for sentinel lymph node biopsy in breast cancer patients. METHODS: Five hundred and sixty-five consecutive breast cancer patients were prospectively randomized into groups with or without preoperative lymphoscintigraphy. RESULTS: In a group with lymphoscintigraphy, 238 patients had sentinel lymph nodes spotted in lymphoscintigram. The visualization of sentinel lymph nodes in lymphoscintigram was not associated with patients' age, primary tumor size and location, histopathologic type and time interval from injection of radiocolloid to lymphoscintigraphy. However, patients with axillary metastasis had a lower identification rate of sentinel lymph nodes by lymphoscintigraphy than those without metastasis (P = 0.003). The identification rate of axillary sentinel lymph nodes was 99.3% in the group and the rate was similar whether there was sentinel lymph nodes spotted in axillary in lymphoscintigram or not (99.6% vs. 98.1%, P = 0.327). The false-negative rate in this group was 4.2%. While in a group without lymphoscintigraphy, the identification rate and the false-negative rate were 99.6% and 4.8%, respectively. There was no significant difference between the two groups in the identification rate of axillary sentinel lymph nodes (P = 0.594) and in the false-negative rate (P = 1.00). CONCLUSION: Preoperative lymphoscintigraphy could neither improve the identification rate nor reduce the false-negative rate of breast cancer sentinel lymph node biopsy, and it is not necessary for sentinel lymph node biopsy in breast cancer patients.

Preoperative lymphoscintigraphy predicts the successful identification but is not necessary in sentinel lymph nodes biopsy in breast cancer.

BACKGROUND: Although preoperative lymphoscintigraphy in sentinel lymph node biopsy (SLNB) for breast cancer patients is undergone commonly, its clinical significance remains controversial. METHODS: We retrospectively analyzed our database that contained 636 consecutive breast cancer patients who received preoperative lymphoscintigraphy before SLNB. RESULTS: The sentinel lymph nodes (SLNs) of 86.5% of patients were well imaged by lymphoscintigraphy, and SLN were located extra-axilla in 5.3% patients. The visualization of SLN in lymphoscintigraphy was not associated with histopathologic type, location, and stage of primary tumor, as well as the time interval from injection of radiocolloid to surgery. The negative lymphoscintigraphy results were associated with excision ;biopsy before injection of radiocolloid and positive axillary node statues. The SLN was successfully detected in 625 (98.3%) enrolled patients. Failure of surgical identification of axillary SLN was associated with whether hot spot was imaged by lymphoscintigraphy. However, we identified axillary SLN in 90 (90.9%) out of 99 patients with negative axillary findings in lymphoscintigram. The false negative rate of SLNB in our study was 16.0% (15 of 94) among patients of training group, and there was no significant difference in the false negative rate between patients who had axillary hot spot in lymphoscintigram and those who had not (P = .273). CONCLUSIONS: Visualization of SLN in preoperative lymphoscintigraphy predicted the successful SLN identification. However, it was less informative for the location of SLN during operation. Considering the complexity, time consumed, and cost, lymphoscintigraphy should at present be undergone for investigation purposes only.

[Flow cytometric quantitative analysis of multiple tumor suppressor gene 1 (MTS1) and cyclooxygenase-2 (COX-2) gene expressions in invasive breast cancers and their clinical significance].

OBJECTIVE: The purpose of the present study was to explore the expression and clinical significance of multiple tumor suppressor gene 1 (MTS1) and cyclooxygenase-2 (COX-2) gene in invasive breast cancers. METHODS: Flow cytometry was used to analyze the expression level of MTS1 and COX-2 in cancer tissues and corresponding para-cancer tissues from 66 cases of primary invasive breast cancers. RESULTS: In breast cancer tissues, the expression of MTS1 and COX-2 assessed by relative fluorescence intensity were 0.84 and 10.54, respectively, and were 1.61 and 4.00 in corresponding para-cancer tissues, respectively. There was a significant difference between MTS1 and COX-2 expressions in cancer and corresponding para-cancer tissues (P <0.05). The differences of MTS1 and COX-2 expression of different ages, pathological types, tumor sizes or clinical stages of the breast cancer patients were not significant (P > 0.05). The MTS1 and COX-2 expressions were 1.12 and 5.94, respectively, in lymph node metastasis positive patients, and 0.79 and 13.05, respectively, in lymph node metastasis negative patients. The differences were significant (P <0.05). CONCLUSION: The preliminary research results suggest that MTS1 and COX-2 gene expressions play fairly important role in tumorigenesis and progression of breast cancers. MTS1 and COX-2 protein expressions have correlation with lymph node metastasis. This study provides theoretical basis for use of COX-2 selective inhibitors in prevention and treatment for breast cancer patients.

[Inhibitory and apoptosis regulating effects of adriamycin on different human breast cancer cell lines].

OBJECTIVE: To investigate the inhibitory and apoptosis regulating effects of adriamycin (ADM) on different human breast cancer cell lines and to evaluate the value of apoptosis in breast cancer treatment. METHODS: Human breast cancer cells of the lines Bcap37 and MDA-MB-231 were cultured. ADM of different concentrations was added into the culture fluid. MTT method was used to detect the inhibition rate. Flow cytometry was used to detect the proliferation and apoptosis of the cells. To examine the expression of apoptosis-related molecules: Fas, mutant p53, and Bcl-2 proteins. RESULTS: ADM inhibited the proliferation of Bcap37 cells and MDA-MB-231 cells dose and time-dependently, however, the inhibitory effect of ADM was stronger on the Bcap37 cells than on the MDA-MB-231 cells. After being treated by ADM the expression of Fas was increased and the expression of Bcl-2 was decreased in the Bcap37 cells. However, after being treated by ADM the expressions of Fas, Bcl-2, and mutant p53 in the MDA-MB-231 cells remained almost unchanged. Treated by ADM for 24 hours the apoptotic rate of the Bcap37 cells was increased from 0% to 5.8% (P < 0.05), however, no apoptosis was detected in the MDA-MB-231 cells after treatment of ADM at any time pint. CONCLUSION: With different molecular and biological characteristics, different breast cancer lines are different in chemosensitivity and drug-resistance, which are related to their apoptotic abilities induced by chemotherapeutic drugs.