An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses.

Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.

Immune checkpoint inhibitors-related endocrinopathies exhibit increased severity in breast cancer patients: a real-world study.

PURPOSE: This study aims to systematically evaluate the incidence of immune checkpoint inhibitors (ICIs)-related endocrinopathies and their onset time in patients with breast cancer (BC) in a real-world setting. METHODS: An analysis was conducted on the medical records of 122 BC patients who underwent ICIs therapy at the Department of Breast Surgery, Guangdong Provincial People's Hospital, from April 2019 to September 2021. Follow-up data continued until October 2022. RESULTS: The research indicated that 60.66% of BC patients experienced ICI-related endocrinopathies. The endocrinopathies included pituitary injury (7.38%), primary thyroid dysfunction (34.43%), supranormal fasting blood glucose or glycohemoglobin levels (16.39%), and adrenal injury (2.46%). Subgroup analyses were further performed based on clinical characteristics, demonstrated variability in the incidence of ICI-related endocrinopathies. Notably, subpopulations harboring genetic mutations exhibited a markedly higher prevalence of hypophysitis, as evidenced by a statistically significant association (P = 0.022). Similarly, individuals with HER2 positivity were found to have a significantly increased incidence of pancreatic islet injury (P = 0.023). Moreover, the study documented that the median onset times of ICIs-related endocrinopathies in pituitary, thyroid, pancreatic, and adrenal damage were 264, 184, 99 and 141 days, respectively, which were substantially longer compared to previous reports involving other tumors. Remarkably, even after 500 days of initiating ICI therapy, new cases of ICI-related endocrine disorders continue to emerge, suggesting a situation of delayed onset of ICI-related endocrinopathies in BC patients. CONCLUSION: The retrospective analysis confirmed a higher incidence and longer median onset time of ICI-related endocrinopathies in BC patients compared to other cancers. These outcomes underscore the critical need for regular and extended monitoring of endocrine functions in BC patients receiving ICI therapy, advocating for personalized monitoring approaches based on individual clinical profiles.

Prognosis of pediatric BCP-ALL with IKZF1 deletions and impact of intensive chemotherapy: Results of SCCLG-2016 study.

BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

Stratified Treatment in Pediatric Anaplastic Large Cell Lymphoma: Result of a Prospective Open-Label Multiple-Institution Study.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin-Frankfurt-Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% [95% Confidence Interval (CI), 69.0%-83.9%] and 92.3% (95% CI,86.1%-95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5%-95.5%, and 67.9% (95% CI, 55.4%-77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6%-19.0%), 65.7% (95% CI, 47.6%-78.9%), 55.7% (95% CI, 26.2%-77.5%), and 70.7% (95% CI, 48.6%-84.6%), respectively. At the end of follow-up, one of the 5 patients who received maintenance therapy with VBL relapsed, and seven patients receiving ALK inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+) ，high risk site and SC/LH ,but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

The RAS-signaling-pathway-mutation-related prognosis in B-cell acute lymphoblastic leukemia: A report from South China children's leukemia group.

The next-generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T-ALL and B-ALL. In B-ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co-occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3-year RFS rates for the RAS signaling pathway mutation-positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation-positive. RAS signaling pathway mutation is an important biomarker for poorer relapse-free survival in pediatric B-ALL patients despite good early MRD levels.

Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Single-cell and whole-transcriptome sequencing of lymph node metastasis-related gene signature: A large-scale pan-cancer cohort, machine learning and experimental study.

BACKGROUND: Lymph node metastasis (LNM) is an independent prognostic factor in numerous types of cancer. Therefore, a LNM-related gene-based nomogram may precisely predict survival and drug sensitivity, and reveal the mechanism underlying LNM. MATERIALS AND METHODS: Gene sequencing profiles of pan-cancer data (33 cancer types) were acquired from The Cancer Genome Atlas UCSC Xena database. Patients were classified into primary (N = 10,071) and testing (N = 5,036) cohorts. The lymph node score (LNscore) was established via single-cell RNA sequencing, whole-transcriptome sequencing, machine learning, and Cox regression analyses. A novel prognosis model, formulated by incorporating the LNscore and clinical characteristics, was evaluated using the concordance index, calibration curve, and decision curve analysis. Moreover, patients were assigned into high- and low-risk groups according to the median LNscore. We investigated these two groups for survival prognosis, functional enrichment, immune infiltration, and drug sensitivity. In addition, we silenced and overexpressed insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). We also analyzed the behavior of breast cancer (BRCA) cells regarding lymphatic metastasis and lymphangiogenesis in vitro. IGF2BP2 stimulated the proliferation of BRCA cells via 5-Ethynyl-2'-deoxyuridine and Cell Counting Kit-8 experiments. RESULTS: A LNM-related set of 12 genes was identified and utilized to determine the LNscore. The concordance-index of both cohorts in the LNscore-based model was >0.7. The immune landscape revealed that the sensitivity to immunotherapy might be better in the high-risk group versus the low-risk group. In addition, we discovered that IGF2BP2 was overexpressed in BRCA tissues and significantly associated with poor survival. Functional analysis indicated that IGF2BP2 promoted BRCA cell migration and proliferation. Additionally, IGF2BP2 accelerated lymphatic metastasis and lymphangiogenesis in vivo. CONCLUSIONS: A novel LNscore-based model was established via comprehensive analysis of LNM-related genes. This model can accurately predict patient survival and drug sensitivity, and reveal the mechanism of LNM in the pan-cancer setting.

Study on the spatiotemporal distribution of algal blooms and its influencing factors in young reservoirs based on remote sensing interpretation.

Algal blooms caused by excessive proliferation of phytoplankton in young reservoirs have been frequently reported, seriously threatening the unstable aquatic ecosystem, water quality safety and public health. Thus, there is an urgent need to investigate the dynamics of phytoplankton in these young reservoirs, and many current studies on phytoplankton in young reservoirs are based on point monitoring information. This study used remote sensing interpretation to invert the chlorophyll-a concentration in 131 images of Zipingpu Reservoir from 2013 to 2021, and analyzed the spatiotemporal characteristics of algal blooms. Partial least squares-structural equation modeling was used to identify the environmental influencing factors of algal blooms. The results showed that the average chlorophyll-a concentration in the reservoir was 4.49 mg/m3, and the frequency of algal blooms was 28%. The maximum area of algal blooms shows a significant increase trend in the interannual (increase by 0.05%/yr in the proportion of water surface area), and the average blooms area shows a weaker increase trend (0.01%/yr). The prone period of algal bloom is from April to August every year. The solar duration and wind speed had significant direct positive effects on the maximum and average algal bloom area, which was the similar effects in different years and months (path coefficient exceeds 0.44). TP also has a significant direct positive effect on the average algal bloom area between different years (path coefficient of 0.30). The suitable meteorological factors level making the bloom-prone period from April to August, the prevailing westerly and southerly winds provide transport for the aggregation of phytoplankton and algal blooms outbreak in the northeastern waters. This study expand the monitoring frequency and spatial information of algal blooms, which provided a reference for young reservoir management and prevention of blooms.

Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

A radiogenomic multimodal and whole-transcriptome sequencing for preoperative prediction of axillary lymph node metastasis and drug therapeutic response in breast cancer: a retrospective, machine learning and international multicohort study.

BACKGROUND: Axillary lymph nodes (ALN) status serves as a crucial prognostic indicator in breast cancer (BC). The aim of this study was to construct a radiogenomic multimodal model, based on machine learning and whole-transcriptome sequencing (WTS), to accurately evaluate the risk of ALN metastasis (ALNM), drug therapeutic response and avoid unnecessary axillary surgery in BC patients. METHODS: In this study, conducted a retrospective analysis of 1078 BC patients from The Cancer Genome Atlas (TCGA), The Cancer Imaging Archive (TCIA), and Foshan cohort. These patients were divided into the TCIA cohort ( N =103), TCIA validation cohort ( N =51), Duke cohort ( N =138), Foshan cohort ( N =106), and TCGA cohort ( N =680). Radiological features were extracted from BC radiological images and differentially expressed gene expression was calibrated using technology. A support vector machine model was employed to screen radiological and genetic features, and a multimodal model was established based on radiogenomic and clinical pathological features to predict ALNM. The accuracy of the model predictions was assessed using the area under the curve (AUC) and the clinical benefit was measured using decision curve analysis. Risk stratification analysis of BC patients was performed by gene set enrichment analysis, differential comparison of immune checkpoint gene expression, and drug sensitivity testing. RESULTS: For the prediction of ALNM, rad-score was able to significantly differentiate between ALN- and ALN+ patients in both the Duke and Foshan cohorts ( P <0.05). Similarly, the gene-score was able to significantly differentiate between ALN- and ALN+ patients in the TCGA cohort ( P <0.05). The radiogenomic multimodal nomogram demonstrated satisfactory performance in the TCIA cohort (AUC 0.82, 95% CI: 0.74-0.91) and the TCIA validation cohort (AUC 0.77, 95% CI: 0.63-0.91). In the risk sub-stratification analysis, there were significant differences in gene pathway enrichment between high and low-risk groups ( P <0.05). Additionally, different risk groups may exhibit varying treatment responses ( P <0.05). CONCLUSION: Overall, the radiogenomic multimodal model employs multimodal data, including radiological images, genetic, and clinicopathological typing. The radiogenomic multimodal nomogram can precisely predict ALNM and drug therapeutic response in BC patients.

The influence mechanism of water level operation on algal blooms in canyon reservoirs and bloom prevention.

The water level operation of reservoirs affects the spatiotemporal patterns of water quality, light-heat, hydrodynamics and phytoplankton, which have implications for algal bloom prevention. However, the theoretical analysis and practical applications of related research are limited. Based on prototype observations and numerical modeling, data on algae, water level operation and environmental factors in the Zipingpu Reservoir from April and September in 2015 to 2017 and 2020 to 2022 were collected. An in-depth analysis of the causal mechanisms between algal blooms and water level operation was performed, and prevention strategies with practical application assessments were developed. Water level operation control in the reservoir from April to September can be divided into five stages (falling-rising-oscillating-falling-rising), with algal blooms occurring only in the second stage. The rising water level with inflow into the middle layers shapes a closed-loop circulation in the surface waters. This distributes the nutrients that were trapped in the surface layer during the first stage, helping algae avoid to phosphorus limitation and thrive in the closed loop circulation, leading to algal blooms (chlorophyll-a exceeding 10 mg/m3). There is a significant positive correlation (p < 0.05) between algal blooms and the rapid rise in water levels in the second stage, occurring within a span of three days. To contain the algal bloom, a water level operation limit of rising waters on the third day after a two-day consecutive rise in water level was examined. This was found to be effective after its practical application to the case reservoir in 2022, with chlorophyll-a concentrations consistently below 10 mg/m3. This study unveils the mechanisms through which water level operation affects algal blooms and presents a successful case of bloom prevention. Furthermore, it serves as a valuable reference for the management of canyon reservoirs.