Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial.

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.

Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases: A Nonrandomized Phase 2 Trial.

Importance: The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear. Objective: To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases. Design, Setting, and Participants: This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023. Interventions: Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function. Results: A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points. Conclusions and Relevance: The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT04582968.

Adjuvant medial versus entire supraclavicular lymph node irradiation in high-risk early breast cancer (SUCLANODE): a protocol for a multicenter, randomized, open-label, phase 3 trial.

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 .

Contralateral axillary lymph node metastasis in breast cancer: An oligometastatic-like disease.

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 < 0.0001, respectively). Considering the patients presented with CAM or OM as a whole, we found that local treatment combined with systemic treatment did not provide a superior survival benefit over systemic treatment alone. CONCLUSION: CAM was similar to an oligometastatic-like disease, and patients with these diseases may benefit from systemic treatment. Adding local treatment failed to significantly improve OS.

Predictors of cancer screening behavior of the working population in China based on the information-motivation-behavioral skills model.

Background: The 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. Methods: A 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. Results: Among 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 (ß = 0.563, p < 0.001) and cancer screening behavioral skills (ß = 0.264, p = 0.003) were related to participation in cancer screening, whereas cancer screening motivation was not directly influenced the participation in cancer screening (ß = - 0.075, p = 0.372). Conclusion: The cancer screening rate was found to be lower than expected in the working population. The IMB model could be used to make decisions in implementing behavioral interventions to participate in cancer screening among the Chinese working population. Enhancing the knowledge of cancer warning signs and symptoms and strengthening behavioral skills should be focused on to improve participation in cancer screening.

Favorable prognosis of breast cancer brain metastases patients with limited intracranial and extracranial metastatic lesions.

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 < 0.001; multivariate HR 0.55, 95% CI, 0.43-0.72). Among the patients with 1-5 metastatic lesions, median OS for GPA 0-1.0 was 9.8 months, compared to 22.8, 28.8 and 71.0 for GPA 1.5-2.0, 2.5-3.0 and 3.5-4.0 respectively, which is much longer than the corresponding patients with greater than 5 total metastatic lesions, with medium OS of 6.8, 11.6, 18.6 and 42.6 months respectively for GPA 0-1.0, 1.5-2.0, 2.5-3.0 and 3.5-4.0. CONCLUSIONS: The patients with 1-5 total metastatic lesions demonstrated better OS. The prognostic value of the Breast GPA and the survival benefit of salvage local therapy and continuation of systemic therapy after BM were confirmed.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Vasculopathies and Angiogenesis: Therapeutic Applications and Optimization.

Extracellular vesicles (EVs), as part of the cellular secretome, have emerged as essential cell-cell communication regulators in multiple physiological and pathological processes. Previous studies have widely reported that mesenchymal stromal cell-derived EVs (MSC-EVs) have potential therapeutic applications in ischemic diseases or regenerative medicine by accelerating angiogenesis. MSC-EVs also exert beneficial effects on other vasculopathies, including atherosclerosis, aneurysm, vascular restenosis, vascular calcification, vascular leakage, pulmonary hypertension, and diabetic retinopathy. Consequently, the potential of MSC-EVs in regulating vascular homeostasis is attracting increasing interest. In addition to native or naked MSC-EVs, modified MSC-EVs and appropriate biomaterials for delivering MSC-EVs can be introduced to this area to further promote their therapeutic applications. Herein, we outline the functional roles of MSC-EVs in different vasculopathies and angiogenesis to elucidate how MSC-EVs contribute to maintaining vascular system homeostasis. We also discuss the current strategies to optimize their therapeutic effects, which depend on the superior bioactivity, high yield, efficient delivery, and controlled release of MSC-EVs to the desired regions, as well as the challenges that need to be overcome to allow their broad clinical translation.

MIR663AHG as a competitive endogenous RNA regulating TGF-ß-induced epithelial proliferation and epithelial-mesenchymal transition in benign prostate hyperplasia.

Benign prostate hyperplasia (BPH) is the most commonly seen disease among aging males. Transforming growth factor(TGF)-ß-mediated epithelial-mesenchymal transition (EMT) and epithelial overproliferation might be central events in BPH etiology and pathophysiology. In the present study, long noncoding RNA MIR663AHG, miR-765, and FOXK1 formed a competing endogenous RNAs network, modulating TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. miR-765 expression was downregulated in TGF-ß-stimulated BPH-1 cells; miR-765 overexpression ameliorated TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. MIR663AHG directly targeted miR-765 and negatively regulated miR-765; MIR663AHG knockdown also attenuated TGF-ß-induced EMT and epithelial overproliferation in BPH-1 cells, whereas miR-765 inhibition attenuated MIR663AHG knockdown effects on TGF-ß-stimulated BPH-1 cells. miR-765 directly targeted FOXK1 and negatively regulated FOXK1. FOXK1 knockdown attenuated TGF-ß-induced EMT and epithelial overproliferation and promoted autophagy in BPH-1 cells, and partially attenuated miR-765 inhibition effects on TGF-ß-stimulated BPH-1 cells. In conclusion, this study provides a MIR663AHG/miR-765/FOXK1 axis modulating TGF-ß-induced epithelial proliferation and EMT, which might exert an underlying effect on BPH development and act as therapeutic targets for BPH treatment regimens.

Prognostic nomograms for nasopharyngeal carcinoma with nodal features and potential indication for N staging system: Validation and comparison of seven N stage schemes.

PURPOSE: To identify the prognostic value of the nodal features, propose a nomogram-based N stage system and evaluate the performance of seven N stage schemes of nasopharyngeal carcinoma (NPC) patients. METHODS: Data from 1638 non-distant metastatic NPC patients were used to develop nomograms predicting 3-year and 5-year overall survival (OS) and distant metastasis-free survival (DMFS). Based on nomogram and multivariate analyses, a new N-stage scheme was proposed. The performance of the nomogram-based N staging system was assessed against five newly proposed N staging systems and the current 8th N staging system using a quantitative model to compare hazard consistency, discrimination, outcome prediction, and sample size balance. The Kaplan-Meier method with log-rank tests was used to compare survival differences. RESULTS: Nomograms to predict OS and DMFS were constructed using extranodal extension infiltrating the surrounding structures (ENEmax), maximal axial diameter (MAD), large retropharyngeal lymph nodes (RLN, minimal axial diameter > 1.5 cm), multiple central nodal necrosis (CNN), and total lymph node (LN) number and level. Multivariate analysis showed the independent prognostic value of ENEmax and MAD > 3 cm for all selected survival endpoints (p < 0.05). Large RLN and lower neck involvement were independently associated with OS (p < 0.05). We proposed using a large RLN and MAD > 3 cm as N2 factors, and ENEmax and lower neck involvement as N3 factors. Among the seven N-stage schemes, our nomogram-based N scheme and ENEmax to N3 scheme (ENE3) ranked in the top two in the overall comparison with the elevated outcome predicting value (highest c-index). However, between the N0, N1, N1, and N2 subgroups, the ENE3 scheme showed no difference in OS or DMFS (p > 0.05). CONCLUSION: The predictive model highlighted the independent prognostic value of ENEmax, cervical lymph node, MAD, and large RLN, which can be used as criteria for future N staging.

S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8+ T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma.

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.

Clinical feasibility and oncological safety of non-radioactive targeted axillary dissection after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: a prospective diagnostic and prognostic study.

BACKGROUND: Targeted axillary dissection (TAD) includes biopsy of clipped lymph node and sentinel lymph nodes. However, clinical evidence regarding clinical feasibility and oncological safety of non-radioactive TAD in a real-world cohort remains limited. METHODS: In this prospective registry study, patients routinely underwent clip insertion into biopsy-confirmed lymph node. Eligible patients received neoadjuvant chemotherapy followed by axillary surgery. Main endpoints included the false-negative rate (FNR) of TAD and nodal recurrence rate. RESULTS: Data from 353 eligible patients were analyzed. After completion of neoadjuvant chemotherapy, 85 patients directly proceeded to axillary lymph node dissection (ALND), furthermore, TAD with or without ALND was performed in 152 and 85 patients, respectively. Overall detection rate of clipped node was 94.9% (95% CI, 91.3-97.4%) and FNR of TAD was 12.2% (95% CI, 6.0-21.3%) in our study, with FNR decreasing to 6.0% (95% CI, 1.7-14.6%) in initially cN1 patients. During a median follow-up of 36.6 months, 3 nodal recurrences occurred (3/237 with ALND; 0/85 with TAD alone), with a 3-year freedom-from-nodal-recurrence rate of 100.0% among the TAD-only patients and 98.7% among the ALND patients with axillary pathologic complete response ( P =0.29). CONCLUSIONS: TAD is feasible in initially cN1 breast cancer patients with biopsy-confirmed nodal metastases. ALND can safely be foregone in patients with negativity or a low volume of nodal positivity on TAD, with a low nodal failure rate and no compromise of 3-year recurrence-free survival.

The comparison of efficacy and safety evaluation of vacuum-assisted Elite 10-G system and the traditional BARD 14-G core needle in breast diagnosis: an open-label, parallel, randomized controlled trial.

BACKGROUND: Vacuum-assisted biopsy (VAB) and core needle biopsy (CNB) are both widely used methods in diagnosing breast lesions. We aimed to determine whether the Elite 10-gauge VAB achieves higher accuracy than the BARD spring-actuated 14-gauge CNB. MATERIALS AND METHODS: This was a phase 3, open-label, parallel, randomized controlled trial (NCT04612439). In total, 1470 patients with ultrasound (US)-visible breast lesions requiring breast biopsy were enrolled from April to July 2021 and randomized at a 1 : 1 ratio to undergo VAB or CNB. All patients underwent surgical excision after needle biopsy. The primary outcome was accuracy, defined as the proportion of patients who had a consistent qualitative diagnosis between the biopsy and surgical pathology results. The underestimation rate, false-negative rate and safety evaluations were the secondary endpoints. RESULTS: A total of 730 and 732 patients were evaluable for endpoints in the VAB and CNB groups, respectively. The accuracy of VAB surpassed that of CNB in the whole population (94.8 vs. 91.1%, P =0.009). The overall malignant underestimation rate was significantly lower in the VAB group than in the CNB group (21.4 vs. 30.9%, P =0.035). Additionally, significantly more false-negative events were noted in the CNB group (4.9 vs. 7.8%, P =0.037). In patients who presented with accompanying calcification, the accuracy of VAB surpassed that of CNB (93.2 vs. 88.3%, P =0.022). The potential superiority of VAB was indicated in patients with heterogeneous echo on US. CONCLUSIONS: In general, the 10-G VAB procedure is a reasonable alternative to the 14-G CNB procedure with higher accuracy. We recommend the use of VAB for lesions with accompanying calcification or heterogeneous echo on US.

Epidemiological landscape of esophageal cancer in Asia: Results from GLOBOCAN 2020.

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.

Proton and Carbon Ion Radiation Therapy Decreased Severe Lymphopenia by Reducing Thoracic Vertebra and Aortic Doses in Non-Small Cell Lung Cancer Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphopenia is a common adverse effect of radiation therapy (RT). Little is known about the difference in lymphopenia between intensity modulated (photon) radiation therapy (IMRT) and proton and carbon ion radiation therapy (PCIRT). This study aimed to investigate lymphopenia differences between IMRT and PCIRT in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Clinical and dosimetric parameters were collected from 343 patients who received definitive IMRT or PCIRT for NSCLC. Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) ≤0.5 × 103 cells/µL. Overall survival (OS) was analyzed using the Kaplan-Meier method. Propensity score matching was performed between the IMRT and PCIRT groups. Least absolute shrinkage and selection operator analysis was used to select appropriate dosimetric parameters. Univariate and multivariate logistic regression analyses were conducted to identify the predictors of SRL. RESULTS: Compared with the IMRT group, the PCIRT group was less likely to develop SRL (P < .001). Compared with the non-SRL group, the SRL group showed significant association with poorer OS, with a median survival time of 29.2 versus 15.0 months (P = .046). IMRT was an independent risk factor of SRL (P = .004). A lower ALC before RT (P = .030) and larger planning target volume (PTV) (P = .002) were also significant independent risk factors for SRL. Moreover, the majority of dosimetric parameters of organs at risk in PCIRT were lower than those in IMRT (P < .001). Thoracic vertebra V5 (P = .002) and aorta V5 (P = .026) were identified as independent risk predictors of SRL after adding dosimetric parameters to the regression model. CONCLUSIONS: Compared with IMRT, PCIRT could reduce SRL incidence, possibly by limiting thoracic vertebra and aortic doses, and SRL was associated with poor outcomes in patients with NSCLC.

All HER2-negative breast cancer patients need gBRCA testing: cost-effectiveness and clinical benefits.

BACKGROUND: The OlympiA trial demonstrated the benefits of adjuvant usage of olaparib for high-risk patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) and germline BRCA (gBRCA) mutation. This provoked thoughts on the clinical criteria of gBRCA testing. This study aims to estimate the costs and benefits of gBRCA testing and adjuvant olaparib therapy for patients with triple-negative breast cancer (TNBC) and hormone-receptor (HR)-positive and HER2-negative BC in China and the United States of America (USA). METHODS: We used a Markov chain decision tree analytic model to compare three gBRCA screening policies in China and the USA: (1) no gBRCA testing; (2) selected gBRCA testing and (3) universal gBRCA testing for nonmetastatic TNBC and HR-positive HER2-negative BC patients. We modelled the benefit of systemic therapy and risk-reducing surgeries among patients identified with pathogenic or likely pathogenic variants (PVs) in BRCA1 and BRCA2. RESULTS: Changing from the selected gBRCA testing to the universal gBRCA testing in TNBC patients is cost-effective, with the incremental cost-effectiveness ratios (ICERs) being 10991.1 and 56518.2 USD/QALY in China and the USA, respectively. Expanding universal gBRCA testing to HR-positive HER2-negative BC and TNBC patients has ICERs of 2023.3 and 16611.1 USD/QALY in China and the USA, respectively. DISCUSSION: By performing gBRCA testing on all HER2-negative BC patients, adjuvant olaparib can be offered to high-risk patients with a PV in BRCA1 or BRCA2. These patients are also candidates for risk-reducing surgeries, an important aspect of their survivorship care, and these interventions can improve survival outcomes. With the willingness-to-pay thresholds being 31,500.0 and 100,000.0 USD per QALY gained in China and the USA, respectively, universal gBRCA testing is likely cost-effective for all HER2-negative BC patients. This simplified criterion of gBRCA testing for BC is recommended for adoption by current guidelines in China and the USA.

WDHD1 is over-expressed in nasopharyngeal carcinoma and may control the expression of ITGAV.

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.

Changes of serum metabolites levels during neoadjuvant chemoradiation and prediction of the pathological response in locally advanced rectal cancer.

INTRODUCTION: Previous studies have explored prediction value of serum metabolites in neoadjuvant chemoradiation therapy (NCRT) response for rectal cancer. To date, limited literature is available for serum metabolome changes dynamically through NCRT. OBJECTIVES: This study aimed to explore temporal change pattern of serum metabolites during NCRT, and potential metabolic biomarkers to predict the pathological response to NCRT in locally advanced rectal cancer (LARC) patients. METHODS: Based on dynamic UHPLC-QTOF-MS untargeted metabolomics design, this study included 106 LARC patients treated with NCRT. Biological samples of the enrolled patients were collected in five consecutive time-points. Untargeted metabolomics was used to profile serum metabolic signatures from LARC patients. Then, we used fuzzy C-means clustering (FCM) to explore temporal change patterns in metabolites cluster and identify monotonously changing metabolites during NCRT. Repeated measure analysis of variance (RM-ANOVA) and multilevel partial least-squares discriminant analysis (ML-PLS-DA) were performed to select metabolic biomarkers. Finally, a panel of dynamic differential metabolites was used to build logistic regression prediction models. RESULTS: Metabolite profiles showed a clearly tendency of separation between different follow-up panels. We identified two clusters of 155 serum metabolites with monotonously changing patterns during NCRT (74 decreased metabolites and 81 increased metabolites). Using RM-ANOVA and ML-PLS-DA, 8 metabolites (L-Norleucine, Betaine, Hypoxanthine, Acetylcholine, 1-Hexadecanoyl-sn-glycero-3-phosphocholine, Glycerophosphocholine, Alpha-ketoisovaleric acid, N-Acetyl-L-alanine) were further identified as dynamic differential biomarkers for predicting NCRT sensitivity. The area under the ROC curve (AUC) of prediction model combined with the baseline measurement was 0.54 (95%CI = 0.43 ~ 0.65). By incorporating the variability indexes of 8 dynamic differential metabolites, the prediction model showed better discrimination performance than baseline measurement, with AUC = 0.67 (95%CI 0.57 ~ 0.77), 0.64 (0.53 ~ 0.75), 0.60 (0.50 ~ 0.71), and 0.56 (0.45 ~ 0.67) for the variability index of difference, linear slope, ratio, and standard deviation, respectively. CONCLUSION: This study identified eight metabolites as dynamic differential biomarkers to discriminate NCRT-sensitive and resistant patients. The changes of metabolite level during NCRT show better performance in predicting NCRT sensitivity. These findings highlight the clinical significance of metabolites variabilities in metabolomics analysis.

Treatment and survival outcomes in older women with primary breast cancer: A retrospective propensity score-matched analysis.

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 (<65 years) and older group (≥65 years). Propensity score matching was utilised to generate balanced cohorts. RESULTS: A total of 13,707 patients met the study criteria. Compared with younger patients, older patients had a higher Charlson Comorbidity Index (p < 0.001), less lymph node metastasis (p = 0.009), more advanced tumour stage (p = 0.038), and a larger proportion of estrogen receptor-positive (p < 0.001) and epidermal growth factor receptor 2-negative (p < 0.001) tumours. Older patients were likely to receive mastectomy and axillary lymph node dissection in addition to a lower proportion of adjuvant chemotherapy. Adjuvant chemotherapy (HR [hazard ratio] 0.69, p = 0.039) was independently correlated with better overall survival in the older patients. This survival benefit (HR 0.58, p = 0.041) was confirmed in matched cohorts. Among the older patients with larger tumours (HR 0.48, p = 0.038) and more lymph node involvement (HR 0.44, p = 0.040), adjuvant chemotherapy was associated with a significant survival benefit. CONCLUSION: Older breast cancer patients showed less aggressive biological characteristics, intensive surgical and moderate medical preferences. The addition of adjuvant chemotherapy should be considered for older patients, especially for patients with large tumours and more lymph node involvement.