Trophoblast cell surface antigen 2 (Trop2) is a glycoprotein that is barely expressed in normal tissues but highly expressed in malignant tumors; it is remarkably associated with poor prognosis. Various targeted therapeutics against Trop2, such as anti-Trop2 antibodies and antibody-drug conjugate drugs targeting Trop2, have been developed, and some therapeutics have been approved or are in clinical trials for cancer treatment. In this review, we comprehensively discuss the gene structure, mechanism of action, clinical research, drug development, and other aspects of Trop2 to provide references for the clinical development of effective and safe Trop2-targeting drugs.

Ovulatory dysfunction (OD) is one of the main causes of infertility in women of childbearing age, which not only affects their reproductive ability, but also physical and mental health. Traditional treatment strategies have limited efficacies, and the emergence of biomedicines provides a promising alternative solution via the strategies of combining engineered design with modern advanced technology. This review explores the pathophysiological characteristics and related induction mechanisms of OD, and evaluates the current cutting-edge advances in its treatments. It emphasizes the potentials of biomedicines strategies such as hydrogels, nanoparticles and extracellular vesicles in improving therapeutic precision and efficacy. By mimicking natural physiological processes, and achieving controlled drug release, these advanced drug carriers are expected to address the challenges in ovarian microenvironment reprogramming, tissue repair, and metabolic and immune regulation. Despite the promising progress, there are still challenges in terms of biomedical complexity, differences between animal models and human physiology, and the demand for intelligent drug carriers in the therapy of OD. Future researches are mainly dedicated to developing precise personalized biomedicines in OD therapy through interdisciplinary collaboration, promoting the development of reproductive regenerative medicine.

BACKGROUND: Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. METHODS: In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC). RESULTS: A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. CONCLUSIONS A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.
Humans ; Female ; Breast Neoplasms/genetics* ; East Asian People ; Neoplasm Recurrence, Local/genetics* ; Breast ; Algorithms ; Chronic Disease ; Prognosis ; Tumor Microenvironment

Objective:To describe a prospective study of pre-operative tumor-bed boost performed at the 1.5 T MR-Linac in combination with adjuvant whole breast irradiation, and a first case, with an accentuation on clinical feasibility and safety.Methods:A phase II, single arm study recruiting early stage patients follows a paradigm that first boosts the tumor bed and then undergoes breast conservative surgery in 2 weeks, and last irradiates the whole breast in 6 weeks. The primary endpoint is ≥ grade 2 acute breast toxicity. A 43 years old patient affected by a breast carcinoma, not special type of the right-sided lateral quadrant, staged cT 2N 0M 0, was planned and treated. The dose, 8 Gy for one time, was calculated by Monaco on CT simulation images. Both the air electron stream effect (ESE) and the electron return effect (ERE) at the presence of 1.5 T magnetic field were evaluated. During the pre-treatment evaluation, we carried out adaptation-to-position adjustment. Results:The normal organ dosimetry is within toleration. The Dmax to the skin, the chin and the right upper arm was 8.44 Gy, 28.5 cGy and 17.8 cGy, respectively. There was no increased toxicity from ERE and ESE, and the treatment was well tolerated without > grade 1 acute toxicity. The patient received breast conservative surgery on day 7 without delayed wound healing.Conclusions:This is the first case successfully treated within a clinical trial by pre-operative tumor-bed boost under 1.5 T MR-Linac in our institution. More participants are needed to validate and optimize the paradigm.

Objective:To compare the outcomes of watch&wait (W&W) strategy in patients with locally advanced rectal cancer who achieved complete clinical response (cCR) after neoadjuvant therapy, with those who obtained pathological complete response (pCR) after total mesorectal excision (TME).Methods:This is a retrospective cohort analysis study. Patients histologically proven with locally advanced rectal adenocarcinoma (stage Ⅱ-Ⅲ) who had received neoadjuvant chemotherapy were eligible between January 2014 and December 2019. In whom we included patients who had cCR offered management with W&W strategy after completing neoadjuvant therapy and follow-up ≥1 year (W&W group), and patients who did not have cCR but pCR after TME (pCR group). The primary endpoints were 3-year and 5-year overall survival (OS), colostomy-free survival (CFS), disease-free survival (DFS), non-local regrowth disease-free survival (NR-DFS), and organ preservation rate. Kaplan-Meier analysis was used for survival analysis and log-rank test was performed. For comparative analysis, we also derived one-to-one paired cohorts of W&W versus pCR using propensity-score matching (PSM).Results:A total of 118 patients were enrolled, 49 of whom had cCR and managed by W&W, 69 had pCR, with a median follow-up period of 49.5 months (12.1-79.9 months). No difference was observed in the 3-year OS (97.1% vs. 96.7%) and 5-year OS (93.8% vs. 90.9%, P=0.696) between the W&W and pCR groups. Patients managed by W&W had significantly better 3-year and 5-year CFS (89.1% vs. 43.5%, P<0.001), better 3-year DFS (83.6% vs. 97.0%) and 5-year DFS (83.6% vs. 91.2%, P=0.047) compared with those achieving pCR. The 3-year NR-DFS (95.9% vs. 97.0%) and 5-year NR-DFS (92.8% vs. 97.0%, P=0.407) did not significantly differ between the W&W and pCR groups. Local regeneration occurred in six cases, and 87.7% of patients had successful rectum preservation in the W&W group. In the PSM analysis (34 patients in each group), absolutely better CFS (90.1% vs. 26.5%, P<0.001) was noted in the W&W group. A median interval of 17.5 weeks was observed for achieving cCR, while only 23.9% of patients achieved cCR within 5 to 12 weeks from radiation completion. Patients with short-course sequential chemoradiotherapy achieved cCR significantly later when compared with those with long-course concurrent chemoradiotherapy (19.0 vs. 9.8 weeks, P<0.001). Conclusions:The oncological outcomes of W&W strategy in patients with locally advanced rectal cancer are safe and effective, significantly improving the quality of life. Longer interval for cCR evaluation may improve rectal organ preservation rate.

Objective:To explore the motion and influencing factors of implanted gold markers in guiding liver stereotactic body radiation therapy (SBRT) using abdominal compression.Methods:Twenty patients with oligometastatic colorectal cancer or primary hepatocellular carcinoma from January 2016 to December 2019 were included. All patients were treated with SBRT under abdominal compression, with 1-3 gold markers were implanted within 2 cm from the lesion before positioning. Four-dimensional computed tomography (4DCT) scan was used for treatment planning. The respiratory cycle was divided into 0-90% respiratory phase images based on the respiratory signal, which were reconstructed by the system (Pinnacle 3 version 9.1; Philips Medical System, Madison, WI, USA), and cone beam CT validation images before radiation exposure were obtained. The liver volume was divided into 3 parts: within 2 cm from the main hepatic portal vein, 2-5 cm from the main hepatic portal vein, and>5 cm from the main hepatic portal vein. The motion of different tumor locations was evaluated. Results:The average intrafractional motion amplitude was (2.63±2.81) mm in the cranial-caudal (CC) direction, (1.35±1.23) mm in the anterior-posterior (AP) direction, and (0.76±0.88) mm in the left-right (LR) direction, respectively. The average interfractional motion amplitude was (3.45±3.06) mm, (2.64±2.60) mm, and (2.23±2.07) mm, respectively. Both the intra-or inter-fractional motion amplitudes in the CC direction were the highest, followed by those in the AP and LR direction (all P<0.001). The motion varied at different tumor locations. The longer distance from the main hepatic portal vein, the larger the intrafractional motion (all P<0.05). To cover the 95% population-based confidence interval, the internal target volume (ITV) was suggested to include the expansion of 3.9 mm, 5.2 mm and 7.9 mm in the LR, AP and CC direction. The expansion of 4.3 mm, 4.4 mm and 6.1 mm was delivered within 2 cm from the main hepatic portal vein, and 3.5 mm, 7.3 mm and 9.7 mm>5 cm from the main hepatic portal vein, respectively. The expansion varied significantly depending on the tumor location, whereas the motion in the CC direction was the largest regardless of the tumor location. The longer distance of the tumor from the main portal vein, the larger expansion in the CC direction. The expansion of tumor > 5 cm from the main portal vein in the AP direction was larger than that of inner parts. Conclusion:Liver tumors at different locations require individual external expansion of ITV.

Objective: To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy. Methods: This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer′s protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS. Results: There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109). Conclusion There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

PURPOSE: Mismatch repair (MMR) deficiency plays a critical role in rectal cancer. This study aimed to explore the associations between genetic variations in seven MMR genes and adverse events (AEs) and survival of patients with rectal cancer treated with postoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Fifty single nucleotide polymorphisms in seven MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) genes were genotyped by Sequenom MassARRAY method in 365 patients with locally advanced rectal cancer receiving postoperative CRT. The associations between genotypes and AEs were measured by odds ratios and 95% confidence intervals (CIs) by unconditional logistic regression model. The associations between genetic variations and survival were computed by the hazard ratios and 95% CIs by Cox proportional regression model. RESULTS: The most common grade ≥ 2 AEs in those 365 patients, in decreasing order, were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). Except 38 cases missing, 61 patients (18.7%) died during the follow-up period. We found MSH3 rs12513549, rs33013 and rs6151627 significantly associated with the risk of grade ≥ 2 diarrhea. PMS1 rs1233255 had an impact on the occurrence of grade ≥2 dermatitis. Meanwhile, PMS1 rs4920657, rs5743030, and rs5743100 were associated with overall survival (OS) time of rectal cancer. CONCLUSION: These results suggest that MSH3 and PMS1 polymorphisms may play important roles in AEs prediction and prognosis of rectal cancer patients receiving postoperative CRT, which can be potential genetic biomarkers for rectal cancer personalized treatment.
Biomarkers ; Chemoradiotherapy ; Dermatitis ; Diarrhea ; DNA Mismatch Repair ; Follow-Up Studies ; Genetic Variation ; Genotype ; Humans ; Leukopenia ; Logistic Models ; Methods ; Odds Ratio ; Polymorphism, Single Nucleotide ; Prognosis ; Rectal Neoplasms

Objective: This study aimed to reveal the potential clinical and biological functions of frizzled related protein (FRZB) mRNA expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Methods: We used the keyword “lung cancer” to search the data through Gene Expression Omnibus (GEO) database attached to NCBI(National Center of Biotechnology) and download the data of LUAD and LUSC from TCGA (The Cancer Genome Atlas) Database. A total of eight LUAD and six LUSC datasets were incorporated in this analysis. We defined cutoff value of FRZB using Cutoff Finder into the two groups to calculate hazard ratio (HR). Results: We found that high expression level of FRZB mRNA in tumor tissues was a positive prognostic factor for overall survival in LUAD [pooled HR（95%CI）=0.54（0.46-0.64）,P＜0.05 in univariate analysis; pooled HR（95%CI）=0.66（0.54-0.79）,P＜0.05 in multivariate analysis]. Interestingly, there was no similar results in LUSC [pooled HR（95%CI）=1.11（0.67-1.84）,P＞0.05 in univariate analysis; pooled HR（95%CI）=1.13（0.71-1.78）,P＞0.05 in multivariate analysis]. We also found that FRZB may inhibit WNT signal pathway by t-SNE and correlation analysis. By enrichment analysis, FRZB and its most correlated genes were involved in multiple immune-related pathways, such as complement and coagulation cascades, humoral immune response, etc. Conclusion High expression of FRZB mRNA in LUAD was associated with better prognosis of lung adenocarcinoma. These results suggest that FRZB may be used as a potential marker for favorable prognosis of lung adenocarcinoma.

Objective: To analyze the expression of programmed death ligand 1 (PD-L1) in patients with advanced lung adenocarcinoma and the consistency of four PD-L1 immunohistochemical detection platforms, with an aim of establishing baseline information to predict and select patients for programmed death 1 (PD-1)/PD-L1 immune inhibitor therapy. Methods: This was a multi-center retrospective study, collecting totally 57 advanced lung adenocarcinoma biopsy specimens from four centers from August 2017 to December 2017.The mean age of 57 patients was 59 (range 34-81) years, and 29 cases were male, 28 cases were female. Four PD-L1 immunohistochemical stains were done for each case, including 22C3 (Dako), 28-8 (Abcam), SP263 (Ventana), and SP142 (Ventana). Among them, 22C3 staining was done using Dako autostainer, and for the other three antibodies, Ventana Ultraview detection system and autostainer was used. The immunohistochemical slides were read by two trained histopathologists in a double-blinded way, and the percentage of PD-L1 positive tumor cells was assessed as <1%, 1%-24%, 25%-49% and more than 50%. Results: The Dako 22C3 was used as the standard. There were eight cases in which the PD-L1 staining was more than 50% (14.0%, 8/57). The staining consistency of tumor cells was higher in 22C3, 28-8 and SP263 (ρ=0.729-0.809). The two scoring doctors had a high degree of concordance in PD-L1 positive tumor cells (ρ=0.707-0.896), and this was most noticeable in 22C3 and SP263. Conclusions 22C3, 28-8 and SP263 show high consistency in tumor cell staining. The study can provide an effective basis for screening for potential patient population that may benefit from immunotherapy.