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Penile cancer is a rare malignant tumor of the male urinary system. The treatment benefit of standard first-line chemotherapy is not ideal for patients with locally advanced or metastatic lymph nodes. Immunotherapy has brought new treatment strategies and opportunities for patients with penile cancer. At present, clinical studies on immunotherapy for penile cancer have been reported, and the results show that it is effective but not conclusive. With the development of immunotherapy and the progress of molecular research technology, we can better screen the immunotherapy response population and explore new combination treatment regimens to evaluate the best combination regimen and obtain the optimal treatment options, which is also an important research direction for the immunotherapy of penile cancer in the future.

Abstract Background Supraclavicular nodal (SCL) irradiation is commonly used for patients with high-risk breast cancer after breast surgery. The Radiation Therapy Oncology Group (RTOG) and European Society for Radiotherapy and Oncology (ESTRO) breast contouring atlases delineate the medial part of the SCL region, while excluding the posterolateral part. However, recent studies have found that a substantial proportion of SCL failures are located in the posterolateral SCL region, outside of the RTOG/ESTRO-defined SCL target volumes. Consequently, many radiation oncologists advocate for enlarging the SCL irradiation target volume to include both the medial and posterolateral SCL regions. Nevertheless, it remains uncertain whether adding the posterolateral SCL irradiation improves survival outcomes for high-risk breast cancer patients. Methods The SUCLANODE trial is an open-label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) and medial plus posterolateral SCL irradiation (entire SCL irradiation, E-SCLI group) in high-risk breast cancer patients who underwent breast conserving-surgery or mastectomy. Patients with pathological N2-3b disease following initial surgery, or clinical stage III or pathological N1-3b if receiving neoadjuvant systemic therapy, are eligible and randomly assigned (1:1) to M-SCLI group and E-SCLI group. Stratification is by chemotherapy sequence (neoadjuvant vs. adjuvant), T stage (T3-4 vs. T1-2), N stage (N1-2 vs. N3), and ER status (positive vs. negative). Other radiation volumes are identical in the two arms, including breast/chest wall, undissected axillary lymph node, and internal mammary node. Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended. Both hypofractionated and conventional fractionation schedules are permitted. The primary end point is invasive disease-free survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes. The target sample size is 1650 participants. Discussion The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer. Trial registration ClinicalTrials.gov Identifier: NCT05059379. Registered 28 September 2021, https://www.clinicaltrials.gov/ct2/show/NCT05059379 .

Summary: Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control. Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046). Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3–35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%–90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT. Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment. Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program.

Abstract Background Breast cancer brain metastases (BCBM) are highly heterogenous with widely differing survival. The prognosis of the oligometastatic breast cancer (BC) patients with brain metastases (BM) has not been well studied. We aimed to investigate the prognosis of BCBM patients with limited intracranial and extracranial metastatic lesions. Methods Four hundred and forty-five BCBM patients treated between 1st January 2008 and 31st December 2018 at our institute were included. Clinical characteristics and treatment information were obtained from patient’s medical records. The updated breast Graded Prognostic Assessment (Breast GPA) was calculated. Results The median OS after diagnosis of BM were 15.9 months. Median OS for patients with GPA 0–1.0, 1.5–2, 2.5–3 and 3.5–4 were 6.9, 14.2, 21.8, 42.6 months respectively. The total number of intracranial and extracranial metastatic lesions, in addition to the Breast GPA, salvage local therapy and systemic therapy (anti-HER2 therapy, chemotherapy and endocrine therapy) were demonstrated to be associated with prognosis. One hundred and thirteen patients (25.4%) had 1–5 total metastatic lesions at BM diagnosis. Patients with 1–5 total metastatic lesions had a significantly longer median OS of 24.3 months compared to those with greater than 5 total metastatic lesions with a median OS of 12.2 months (P

Background: Contralateral axillary lymph node metastasis (CAM) is rare. It remains controversial whether CAM should be regarded as a regional or distant metastatic disease. Our study aims to investigate the accurate clinical orientation and management of CAM. Methods: Two hundred and ninety-nine female patients diagnosed with breast cancer from 2000 to 2014 and confirmed to develop CAM, oligometastasis (OM) or locoregional recurrence (LRR) at Fudan University Shanghai Cancer Center (FUSCC) were included in this study. Baseline information and survival outcomes were analyzed and compared among the three groups. Results: Patients with CAM exhibited similar overall survival (OS) and progression-free survival (PFS) to those with OM, but worse than those with LRR (HR: 0.47 [95 % CI: 0.27–0.85], p = 0.0097; HR:0.39 [95 % CI: 0.24–0.63], p

Abstract Background Esophageal cancer (EC) is a global health problem. Asia represents a huge burden of EC globally, and incidence and mortality vary considerably across different Asian regions. Methods Data on incidence, mortality, and preference were extracted from GLOBOCAN 2020. Age‐standardized incidence and mortality rates were calculated overall by sex, age, country, region, and continent. The predicted burden of incidence and mortality in 2040 was calculated based on global demographic projections. Results It was estimated there were 481 552 new cases of and 434 363 deaths from EC in Asia in 2020, accounting for 79.7% and 79.8% of world EC cases and deaths, respectively. EC incidence and mortality in Asia ranked the highest among all continents. Eastern Asia represents the highest age‐standardized world incidence rate (ASWIR) of 12.3 per 100 000 for all Asian regions. Western Asia represents the lowest ASWIR of 1.7 per 100 000, accounting for 0.7% of the globe. There exist obvious differences in epidemiological features in Asian countries, including incidence, mortality, prevalence, and mortality incidence ratio. There is forecast to be up to 781 000 new cases of EC in Asia by 2040, with increasing rates of 63% for incidence and 72% for mortality from 2020. Conclusions Asia has an increasing number of EC cases and deaths. Strategies for targeting in high‐incidence areas, the elderly, and survival should be prioritized to reduce the global EC burden, especially in low‐ and middle‐income countries in Asia.

Abstract Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi‐omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8+ T cell recruitment by decreasing pro‐inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8+ T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti‐PD‐1 treatment by enhancing infiltration and cytotoxicity of CD8+ T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5+ tumor cells and CD8+ T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real‐world and several public immunotherapy cohorts. In summary, S100A5 shapes a non‐inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro‐inflammatory chemokines and the recruitment and cytotoxicity of CD8+ T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.

Nasopharyngeal carcinoma (NPC) is a highly metastatic and invasive malignant tumor that originates in the nasopharynx. The DNA‐binding protein WD repeat and HMG‐box DNA‐binding protein 1 (WDHD1) are highly expressed in a variety of tumours, but its expression and mechanism of action in NPC have not been reported to date. To investigate the involvement of WDHD1 in NPC, we first mined databases for the gene expression profile of NPC. Immunohistochemistry (IHC) was performed on 338 cases of NPC and 112 non‐NPC samples to verify the results. We report that the expression of WDHD1 is significantly elevated in NPC. ChIP‐seq was used to show that integrin alpha V (ITGAV) and WDHD1 exhibit a significant binding peak in the promoter region of the ITGAV gene. The expression levels of ITGAV and WDHD1 exhibit a significant positive correlation, and IHC was performed to show that ITGAV is highly expressed in NPC. Expression of ITGAV increased after overexpression of WDHD1, suggesting that ITGAV may be a potential target gene of WDHD1. Pathway analysis showed that both genes were closely related to the cell cycle, and flow cytometry was used to further confirm that decreased expression of WDHD1 significantly increased the number of apoptotic cells. In conclusion, our results suggest that expression of WDHD1 is increased in NPC and is likely to be associated with the NPC cell cycle; thus, we propose that WDHD1 may have the potential as a target gene for primary screening and treatment of NPC.

Purpose: Changes in biological features and functional status make management decisions in older women with primary breast cancer complicated. We aimed to provide an overview of the clinicopathological characteristics and survival outcomes of older breast cancer patients based on the current treatment strategies. Methods: Female patients diagnosed with primary invasive breast cancer at Fudan University Shanghai Cancer Centre from 2008 to 2016 were included. Patients were divided into a younger group (

BackgroundThe cancer screening rate in the working population is very low in China. Information-motivation-behavioral skills (IMB) model has been applied to elucidate screening behavior for various chronic diseases but has not been investigated in analyzing cancer screening behavior. This study aimed to examine factors influencing cancer screening behavior and their linkages based on the IMB model.MethodsA cross-sectional study was conducted in Shanghai, China from August to October 2021. Data were obtained through an anonymous questionnaire. Predictive relationships between variables in the IMB model and cancer screening behavior were evaluated. Structural equation modeling (SEM) was constructed to demonstrate the utility of the IMB model.ResultsAmong the 556 participants included in the analysis, 34.4% of participants had ever done a cancer screening. The construct validation analysis supported that the measure items included were acceptable. SEM found that knowledge of cancer warning signs and symptoms (β = 0.563, p

Abstract Introduction Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50–50.4 Gy has been established decades ago and been confirmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have encouraged clinicians for dose escalation investigation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation. Methods and analysis The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concurrent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radiotherapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/CT non-responders (SUVmax > 4.0) and overall survival in total population. Patients will be stratified by standardized uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/CT non-responder reached 132 and the total population reached 646 for randomization. Ethics and dissemination This trial has been approved by the Fudan University Shanghai Cancer Center Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553.

Abstract Background Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC. Methods Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy. Discussion The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety. Trial registration ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.

Breast cancer is the most common malignant tumor in Chinese women, and its incidence is increasing. Regular screening is an effective method for early tumor detection and improving patient prognosis. In this review, we analyze the epidemiological changes and risk factors associated with breast cancer in China and describe the establishment of a screening strategy suitable for Chinese women. Chinese patients with breast cancer tend to be younger than Western patients and to have denser breasts. Therefore, the age of initial screening in Chinese women should be earlier, and the importance of screening with a combination of ultrasound and mammography is stressed. Moreover, Chinese patients with breast cancers have several ancestry-specific genetic features, and aiding in the determination of genetic screening strategies for identifying high-risk populations. On the basis of current studies, we summarize the development of risk-stratified breast cancer screening guidelines for Chinese women and describe the significant improvement in the prognosis of patients with breast cancer in China.

Abstract Background Little is known about the prognostic advantage of sex for pulmonary adenocarcinoma among Chinese patients. In this study, we aimed to investigate the true sex differences in prognosis by adjusting for confounders and to explore whether the differences were time‐varying. Methods We identified 4438 lung adenocarcinoma patients who underwent surgery at a regional Cancer Center of China from 2008 to 2016, retrospectively. Sex, age group, smoking history, year of diagnosis and pathological stage were collected. Time‐dependent Cox regression models with inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of sex and account for confounders. Landmark analyses were conducted to assess survival before, and after, five years. Results Of these patients, 1761 (39.7%) were men and 2677 (60.3%) were women. Median follow‐up time was 52.6 months. After IPTW adjustment, women were found to have significantly better survival than men varying with time in both crude and IPTW models (hazard ratio [HR] [t] = 0.453*1.015t, where t is the length of time from treatment and its unit is month, p

BackgroundOver the recent years, machine learning methods have been increasingly explored in cancer prognosis because of the appearance of improved machine learning algorithms. These algorithms can use censored data for modeling, such as support vector machines for survival analysis and random survival forest (RSF). However, it is still debated whether traditional (Cox proportional hazard regression) or machine learning-based prognostic models have better predictive performance. ObjectiveThis study aimed to compare the performance of breast cancer prognostic prediction models based on machine learning and Cox regression. MethodsThis retrospective cohort study included all patients diagnosed with breast cancer and subsequently hospitalized in Fudan University Shanghai Cancer Center between January 1, 2008, and December 31, 2016. After all exclusions, a total of 22,176 cases with 21 features were eligible for model development. The data set was randomly split into a training set (15,523 cases, 70%) and a test set (6653 cases, 30%) for developing 4 models and predicting the overall survival of patients diagnosed with breast cancer. The discriminative ability of models was evaluated by the concordance index (C-index), the time-dependent area under the curve, and D-index; the calibration ability of models was evaluated by the Brier score. ResultsThe RSF model revealed the best discriminative performance among the 4 models with 3-year, 5-year, and 10-year time-dependent area under the curve of 0.857, 0.838, and 0.781, a D-index of 7.643 (95% CI 6.542, 8.930) and a C-index of 0.827 (95% CI 0.809, 0.845). The statistical difference of the C-index was tested, and the RSF model significantly outperformed the Cox-EN (elastic net) model (C-index 0.816, 95% CI 0.796, 0.836; P=.01), the Cox model (C-index 0.814, 95% CI 0.794, 0.835; P=.003), and the support vector machine model (C-index 0.812, 95% CI 0.793, 0.832; P

Conventional tumor-targeted drug delivery systems (DDSs) face challenges, such as unsatisfied systemic circulation, low targeting efficiency, poor tumoral penetration, and uncontrolled drug release. Recently, tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas. With the introduction of several additional functionalities, the properties of these smart DDSs including size, surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting, and eventually achieve desired drug release for an optimized therapeutic efficiency. This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery. Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli, including pH, glutathione, adenosine-triphosphate, reactive oxygen species, enzyme and inflammatory factors are summarized. Special emphasis of this review is placed on their responsive mechanisms, drug loading models, drawbacks and merits. Several typical multi-stimuli responsive DDSs are listed. And the main challenges and potential future development are discussed.

Abstract Background A high prevalence of osteoblastic bone metastases is characteristic of prostate cancer. Prostate‐specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serological marker for prostate cancer. However, whether PSA modulates the osteogenic process remains largely unknown. In this study, we explored the effect of PSA on modulating the osteoblastic differentiation of mesenchymal stem cells (MSCs). In this study, we used flow cytometry, CCK‐8 assay, Alizarin red S (ARS) staining and quantification, alkaline phosphatase (ALP) activity and staining, Western blotting, and quantitative real‐time PCR (qRT‐PCR) to explore the effect of PSA on osteogenic differentiation of MSCs. Results We first demonstrated that although PSA did not affect the proliferation, morphology, or phenotype of MSCs, it significantly promoted the osteogenic differentiation of MSCs in a concentration‐dependent manner. Furthermore, we demonstrated that PSA promoted the osteogenic differentiation of MSCs by elevating the expression of Cadherin 11 in MSCs and, thus, activating the Akt signaling pathway. Conclusions In conclusion, we demonstrated that PSA could promote the osteogenesis of MSCs through Akt signaling pathway activation by elevating the expression of cadherin‐11 in MSCs. These findings imply a possible role of PSA in osteoblastic bone metastases in prostate cancer.

Evidence of the risk factors associated with early-onset colorectal neoplasm from prospective population-based studies is limited. We enrolled 17,293 participants younger than 50 years from the Shanghai colorectal cancer (CRC) screening program cohort. Face-to-face interviews were performed by trained primary care physicians using a standardized questionnaire to collect the information on potential risk factors at baseline entry. Furthermore, 124 cases of early-onset colorectal neoplasm, including six CRC cases and 118 colorectal adenoma (CRA) cases, were detected between 2012 and 2016. Multivariable logistic regression models and restricted cubic spline (RCS) were used to evaluate the risk factors associated with early-onset colorectal neoplasm. We found that sex, body mass index (BMI), and family history of CRC were associated with the early onset of colorectal neoplasm. The RCS model showed a positive dose–response and linear association between BMI and risk of early-onset colorectal neoplasm among young participants (p-overall = 0.19, p-nonlinear = 0.97). The findings indicated that it was beneficial for normal people younger than 50 years to start opportunistic CRC screening. As for those at high risk, increased surveillance is strongly recommended. Further close follow-up is required for research on the underlying causes of early-onset CRC.

Ferroptosis induced by lipid peroxidation is closely related to cancer biology. Prostate cancer (PCa) is not only a malignant tumor but also a lipid metabolic disease. Previous studies have identified ferroptosis as an important pathophysiological pathway in PCa development and treatment, but its role in the prognosis of PCa is less well known. In this study, we constructed a nine-ferroptosis-related gene risk model that demonstrated strong prognostic and therapeutic predictive power. The higher risk score calculated by the model was significantly associated with a higher ferroptosis potential index, higher Ki67 expression, higher immune infiltration, higher probability of biochemical recurrence, worse clinicopathological characteristics, and worse response to chemotherapy and antiandrogen therapy in PCa. The mechanisms identified by the gene set enrichment analysis suggested that this signature can accurately distinguish high- and low-risk populations, which is possibly closely related to variations in steroid hormone secretion, regulation of endocrine processes, positive regulation of humoral immune response, and androgen response. Results of this study were confirmed in two independent PCa cohorts, namely, The Cancer Genome Atlas cohort and the MSK-IMPACT Clinical Sequencing Cohort, which contributed to the body of scientific evidence for the prediction of biochemical recurrence in patients with PCa. In addition, as the main components of this signature, the effects of the AIFM2 and NFS1 genes on ferroptosis were evaluated and verified by in vivo and in vitro experiments, respectively. The above findings provided new insights and presented potential clinical applications of ferroptosis in PCa.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

BackgroundTaxane, carboplatin and trastuzumab (TCH) is an effective neoadjuvant regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer with high pathologic complete response (pCR) rate. The KATHERINE trial changes the outlook for high-risk HER2-positive breast cancer, which suggests that escalation treatment for patients with residual disease after neoadjuvant anti-HER2 therapy may improve survival. The major objective of this study was to investigate the fewest cycles of neoadjuvant TCH therapy needed to screen out non-pCR patients.MethodsThis retrospective study included patients with HER2-positive breast cancer who received either four or six cycles of TCH preoperatively at Fudan University Shanghai Cancer Center between 2008 and 2019. The pCR status was evaluated, and relevant factors associated with pCR were identified using univariate and multivariable analyses. The pathological results of core needle biopsy (CNB) in the breast tumor after two cycles of neoadjuvant chemotherapy were also collected. Kaplan-Meier curve was used to estimate the event-free survival (EFS).ResultsOf 758 eligible patients, 303 were included and analyzed in the four-cycle group and 455 in the six-cycle group. There was no significant difference between the two groups in terms of the pCR rate (46.5% [95% CI 40.9% - 52.2%] in the four-cycle group and 49.9% [95% CI 45.3% - 54.5%] in the six-cycle group, p = 0.365) or the four-year EFS (90.8% in four-cycle group and 93.8% in six-cycle group; p = 0.264). Multivariable analysis indicated that a negative hormone receptor status and the weekly paclitaxel were independent factors for predicting pCR. After adjusting for factors in the multivariable analysis, there was still no significant difference between four and six cycles of neoadjuvant TCH (OR = 1.252, 95% CI 0.904 - 1.733, p = 0.176). Furthermore, 17.9% patients with invasive carcinoma on CNB after two cycles of TCH ultimately achieved pCR in the breast after the completion of neoadjuvant treatment.ConclusionFour cycles of taxane/carboplatin-based neoadjuvant anti-HER2 therapy may be applied as an optimal treatment duration for screening high-risk HER2-positive breast cancer patients for escalation treatment. Further prospective study is warranted.

BackgroundAccumulating evidences indicate significant alterations in the aerobic glycolysis in clear cell renal cell carcinoma (ccRCC). We aim to develop and validate a glycolysis-related genes signature for predicting the clinical outcomes of patients with ccRCC.MethodsmRNA expression profiling of ccRCC was obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and lasso Cox regression model were performed to identify and construct the prognostic gene signature. The protein expression levels of the core genes were obtained from the Human Protein Atlas database. We used four external independent data sets to verify the predictive power of the model for prognosis, tyrosine kinase inhibitor (TKI) therapy, and immunotherapy responses, respectively. Finally, we explored the potential mechanism of this signature through gene set enrichment analysis (GSEA).ResultsThrough the GSEA, glycolysis-related gene sets were significantly different between ccRCC tissues and normal tissues. Next, we identified and constructed a seven-mRNA signature (GALM, TGFA, RBCK1, CD44, HK3, KIF20A, and IDUA), which was significantly correlated with worse survival outcome and was an independent prognostic indicator for ccRCC patients. Furthermore, the expression levels of hub genes were validated based on the Human Protein Atlas databases. More importantly, the model can predict patients’ response to TKI therapy and immunotherapy. These findings were successfully validated in the external independent ccRCC cohorts. The mechanism exploration showed that the model may influence the prognosis by influencing tumor proliferation, base mismatch repair system and immune status of patients.ConclusionsOur study has built up a robust glycolysis-based molecular signature that predicts the prognosis and TKI therapy and immunotherapy responses of patients with ccRCC with high accuracy, which might provide important guidance for clinical assessment. Also, clinical investigations in large ccRCC cohorts are greatly needed to validate our findings.

Background: As a transcription factor, Zinc finger protein ZIC2 can interact with various DNAs and proteins. Current studies have shown that ZIC2 plays an oncogene role in various cancers. In this study, we systematically characterize the prevalence and predictive value of ZIC2 expression across multiple cancer types.Methods: We mined several public databases, including Oncomine, the Cancer Genome Atlas (TCGA), cBioPortal, Kaplan-Meier Plotter and PrognoScan to evaluated the differentially expressed ZIC2 between tumor samples and normal control samples in pan-cancner, and then explored the association between ZIC2 expression and patient survival, prognosis and clinicopathologic stage. We also analyzed the relationship between tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment, tumor- and immune-related genes and ZIC2 expression. Finally, we explored the potential signaling pathway mechanism through gene set enrichment analysis (GSEA).Results: ZIC2 expression was higher in most cancer tissues compared with adjacent normal tissues. High ZIC2 expression was associated with worse prognosis and a higher clinicopathologic stage. ZIC2 expression was strongly associated with the TMB, MSI, tumor microenvironment and tumor- and immune-related genes. The GSEA revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype.Conclusion: ZIC2 expression may be a potential prognostic molecular biomarker of poor survival in pan-cancer and may act as an oncogene with a strong effect in the processes of tumorigenesis and progression.

Background and AimA healthy body composition can improve the prognosis of breast cancer survivors. The study aimed to describe the body composition profile of breast cancer survivors and find out whether a short-term (3 months) wearable device-based lifestyle intervention had an effect on patients’ body weight and body composition.MethodsA before-and-after study was conducted on patients with stage I–III postoperative breast cancer, aged 18–70 years. Body composition was analyzed at baseline, and then patients went for a health education program. A wearable activity tracker and a goal of calorie consumption based on each individual’s weight were provided to each participant, and they were required to be equipped for 90 days. After 3 months, body composition was analyzed again.ResultsOf 113 patients who completed the study, 65.49% showed a normal body mass index (BMI) at baseline assessment, 71.68% had a body fat percentage of more than 30%, and 41.59% had less skeleton muscle mass. During the intervention, the daily step count was 8,851.28 ± 2,399.31, and 59.21% reached the set goal calorie consumption. After a 3-month intervention, the patients had a significant reduction in body weight, fat mass, BMI, body fat percentage, and visceral fat area, but not in protein mass and skeleton muscle mass. Patients of different age, molecular classification, and therapy benefited from the intervention.ConclusionWearable technology with body composition analysis and health education for breast cancer survivors may help reduce weight and improve body composition even in a short time.Clinical Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=40672, identifier ChiCTR1900024258.

Activations of Akt or ERK pathway induced by clinical drugs promote therapeutic failure due to decrease of drug response, and no available strategies have been developed to solve these problems. In this study, we found that pirarubicin (THP), one important chemotherapeutic drug for treating bladder cancer intravesically, dramatically elevated phosphorylations of both Akt and Erk1/2 in addition to inducing DNA damage. MK2206 or AZD6244, representative Akt and Erk1/2 inhibitors, respectively, profoundly sensitized bladder cancer cells to THP treatment. Interestingly, we found that inhibition of a single arm of either Akt or Erk1/2 pathway would induce the increase of another arm, indicating the existence of the crosstalk between these two pathways. Thus, simultaneous suppression of both signals may be needed for increasing the sensitivity of THP. On the other hand, we revealed that phenformin efficiently inhibited both Akt and Erk1/2 phosphorylation in a dose-dependent manner. Furthermore, we demonstrated that phenformin, mimicking dual inhibitors, plays dramatically synergistic action with THP both in vitro and in vivo. Our findings suggest that combination therapy of THP with dual inhibitors may constitute a successful strategy for improving chemotherapy response.

OBJECTIVES:The current study aims to summarize breast anthropomorphic measurement features in Chinese patients with breast diseases and to investigate their potential correlations with demographic factors. MATERIALS AND METHODS:Fifteen breast anthropomorphic parameters of 605 Chinese female patients were collected prospectively. Breast ptosis status was scaled by two methods and breast volume was calculated according to a modified formula of BREAST-V. RESULTS:Among 1210 breasts, the average breast volume was 340.0±109.1 ml (91.8-919.2 ml). The distance from the nipple to the inframammary fold was 7.5±1.6 cm in the standing position. The width of the breast base was 14.3±1.4 cm (8.5-23.5 cm). The incidence of breast ptosis was 22.8% (274/1204), of which 37 (23.5%) and 79 (31.7%) women had severe ptosis assessed by different criteria. Increased height (OR[odds ratio] = 1.500, P

To investigate the effects of CCL21/CCR7 on the proliferation, migration, and invasion of T24 cells and the possible associated mechanisms: expression of MMP-2 and MMP-9, and regulation of BCL-2 and BAX proteins.T24 cells received corresponding treatments including vehicle control, antibody (20 ng/mL CCR7 antibody and 50 ng/ml CCL21), and 50, 100, and 200 ng/ml CCL21. Proliferation was evaluated by MTT assay; cell migration and invasion were assayed using a transwell chamber. Cell apoptosis was induced by Adriamycin (ADM). The rate of cell apoptosis was examined by flow cytometry using annexin V-FITC/PI staining. Western-blot was used to analyze MMP-2 and MMP-9 and BCL-2 and BAX proteins.CCL21 promoted T24 cell proliferation in concentration-dependent manner with that 200 ng/mL induced the largest amount of proliferation. Significant differences of cell migration were found between CCL21treatment groups and the control group in both the migration and invasion studies (P < 0.001 for all). The expressions of MMP-2 and MMP-9 proteins were significantly increased after CCL21 treatment (p < 0.05 for all). Protein expression of Bcl-21 follows an ascending trend while the expression of Bax follows a descending trend as the concentration of CCL21 increases. No difference was found between the control group and antibody group for all assessments.CCL21/CCR7 promoted T24 cell proliferation and enhanced its migration and invasion via the increased expression of MMP-2 and MMP-9. CCL21/CCR7 had antiapoptotic activities on T24 cells via regulation of Bcl-2 and Bax proteins. CCL21/CCR7 may promote bladder cancer development and metastasis.

The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer.Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4-6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection.Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection.ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary evaluation after effective downstaging by neoadjuvant chemo-trastuzumab therapy.