Tumor immune microenvironment remodeling and prognosis of patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy with and without immunotherapy: a retrospective cohort study.

Background: Immunochemotherapy was an emerging neoadjuvant treatment mode that can potentially benefit patients with esophageal carcinoma, but its synergistic mechanism and impact on the tumor immune microenvironment were still unclear. The purpose of this study was to investigate the outcomes of neoadjuvant chemotherapy (nCT) and neoadjuvant immunochemotherapy (nICT) in tumor microenvironment (TME) remodeling among patients with esophageal squamous cell carcinoma (ESCC) and to evaluate the prognostic value of immune-related biomarkers and clinicopathological characteristics. Methods: Patients with locally advanced ESCC who underwent neoadjuvant therapy followed by esophagectomy at the Fourth Hospital of Hebei Medical University between December 2019 and March 2022 were enrolled in this retrospective study. We examined TME features and immune antigen-related biomarkers before and after neoadjuvant therapy. Logistic and Cox regression model were used to evaluate the correlation between these factors and other clinical features and outcomes. Results: A total of 50 eligible participants were analyzed, including 31 males (62%), 25 patients of ≥65 years old, 4/28/18 of upper/middle/lower thoracic cancer, 25/17/8 of poor/moderate/high tumor differentiation, 8/42 of cT1+2/T3+4 stages and 30/20 of cN0/N+ stages. In the entire cohort, the rates of pathological complete response (pCR) and major pathological response (MPR) were 18% and 30%, respectively. pCR rates were 7.1% and 22.2% (χ2=0.699; P=0.40) MPR rates were 7.1% and 38.9% (χ2=4.837; P=0.03) in the nCT and nICT groups, respectively. Compared with the non-pCR patients, the pCR patients had a higher baseline programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) positive expression rate (16.7% vs. 77.8%, χ2=13.089; P<0.001). Following neoadjuvant therapy, the expression rates of PD-L1, CD3+ T cells, and CD8+ T cells in the tumor tissue was higher in the nICT group compared to the nCT group (P<0.05). Deficient expression of mismatch repair (MMR) genes was only observed in one patient (2%). Among patient-related biomarkers, lymphocyte and neutrophil counts decreased after treatment, with no significant changes in the neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio (PLR). Cox regression analysis showed that pretreatment, well-differentiated tumors and positive PD-L1 status were positive predictors of MPR (P<0.05). MPR was an independent predictor of disease-free survival (DFS) (P=0.03). Conclusions: Compared to nCT, nICT could more significantly upregulates PD-L1 TPS, PD-L1 combined positive score (CPS), CD3+ T cells, and CD8+ T cells. Pretreatment tumor differentiation and PD-L1 TPS level could be predictive of MPR. Our findings suggested that the combination of chemotherapy and immunotherapy may be more beneficial for activating anti-tumor immunity in the TME.

Effects of returning peach branch waste to fields on soil carbon cycle mediated by soil microbial communities.

In recent years, the rise in greenhouse gas emissions from agriculture has worsened climate change. Efficiently utilizing agricultural waste can significantly mitigate these effects. This study investigated the ecological benefits of returning peach branch waste to fields (RPBF) through three innovative strategies: (1) application of peach branch organic fertilizer (OF), (2) mushroom cultivation using peach branches as a substrate (MC), and (3) surface mulching with peach branches (SM). Conducted within a peach orchard ecosystem, our research aimed to assess these resource utilization strategies' effects on soil properties, microbial community, and carbon cycle, thereby contributing to sustainable agricultural practices. Our findings indicated that all RPBF treatments enhance soil nutrient content, enriching beneficial microorganisms, such as Humicola, Rhizobiales, and Bacillus. Moreover, soil AP and AK were observed to regulate the soil carbon cycle by altering the compositions and functions of microbial communities. Notably, OF and MC treatments were found to boost autotrophic microorganism abundance, thereby augmenting the potential for soil carbon sequestration and emission reduction. Interestingly, in peach orchard soil, fungal communities were found to contribute more greatly to SOC content than bacterial communities. However, SM treatment resulted in an increase in the presence of bacterial communities, thereby enhancing carbon emissions. Overall, this study illustrated the fundamental pathways by which RPBF treatment affects the soil carbon cycle, providing novel insights into the rational resource utilization of peach branch waste and the advancement of ecological agriculture.

Comparing the diagnostic efficacy of optical coherence tomography and frozen section for margin assessment in breast-conserving surgery: a meta-analysis.

AIMS: This meta-analysis assessed the relative diagnostic accuracy of optical coherence tomography (OCT) versus frozen section (FS) in evaluating surgical margins during breast-conserving procedures. METHODS: PubMed and Embase were searched for relevant studies published up to October 2023. The inclusion criteria encompassed studies evaluating the diagnostic accuracy of OCT or FS in patients undergoing breast-conserving surgery. Sensitivity and specificity were analysed using the DerSimonian and Laird method and subsequently transformed through the Freeman-Tukey double inverse sine method. RESULTS: The meta-analysis encompassed 36 articles, comprising 16 studies on OCT and 20 on FS, involving 10 289 specimens from 8058 patients. The overall sensitivity of OCT was 0.93 (95% CI: 0.90 to 0.96), surpassing that of FS, which was 0.82 (95% CI: 0.71 to 0.92), indicating a significantly higher sensitivity for OCT (p=0.04). Conversely, the overall specificity of OCT was 0.89 (95% CI: 0.83 to 0.94), while FS exhibited a higher specificity at 0.97 (95% CI: 0.95 to 0.99), suggesting a superior specificity for FS (p＜0.01). CONCLUSIONS: Our meta-analysis reveals that OCT offers superior sensitivity but inferior specificity compared with FS in assessing surgical margins in breast-conserving surgery patients. Further larger well-designed prospective studies are needed, especially those employing a head-to-head comparison design. PROSPERO REGISTRATION NUMBER: CRD42023483751.

Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

Tumour mutation burden and infiltrating immune cell subtypes influenced the breast cancer prognosis.

Background: Most of its issues are still undecided on the relationship between tumour mutation burden (TMB) and immune-related genes in the breast cancer. This study explores their relationship based on gene mutation and transcription data in The Cancer Genome Atlas (TCGA) database, and the effects of immune cells in TMB and tumour microenvironments on prognosis of breast cancer patients. Methods: Cases were divided into low-TMB and high-TMB subgroups. Differentially expressed immune-related genes were identified in different TMB subgroups, and patient prognosis was predicted by gene function enrichment analysis, invasive immune cells and different clinical pathological features were compared among different TMB subgroups. Results: A total of 986 mutation data from breast cancer patients were obtained. Compared with low-TMB group, the survival period of high-TMB group was relatively longer. A total of 337 differential expression genes were identified in this study. Of these genes, seven differentially expressed immune-related genes were associated with prognosis. In the high-TMB group, activated CD4+ memory T cells and other cells had high expression, the expression ratio of memory B cells and other cells in low-TMB group was high. Conclusions: TMB-related immunological infiltration characteristics showed meaningful value for prognosis prediction for breast cancer patients. Differentially expressed immune-related genes in TMB subgroups provide important information on the survival prediction.

The benefits of an offline to online cognitive behavioral stress management regarding anxiety, depression, spiritual well-being, and quality of life in postoperative intrahepatic cholangiocarcinoma patients.

AIM: Cognitive behavioral stress management (CBSM) has been introduced for the postoperative cancer management, but its application in intrahepatic cholangiocarcinoma (ICC) is rare. This current study constructed an offline to online CBSM (OO-CBSM) program and applying multiple assessing scales, aiming at exploring the benefits of OO-CBSM regarding anxiety, depression, spiritual well-being, and quality of life (QoL) in postoperative ICC patients. METHODS: The study randomly assigned 68 postoperative ICC patients into OO-CBSM (N = 34) and normal care (NC) (N = 34) groups to undergo 10-week interventions. Hospital anxiety-and-depression scale (HADS), Zung's self-reporting anxiety scale (SAS), and depression scale (SDS), functional-assessment of chronic-illness therapy-spiritual well-being scale (FACIT-Sp), European quality-of-life-5 dimensions (EQ-5D), and quality-of-life questionnaire-core30 (QLQ-C30) were assessed within 6 months (M). RESULTS: HADS-anxiety scores at M3 (P = 0.049) and M6 (P = 0.009), SAS score at M6 (P = 0.028), HADS-depression score at M3 (P = 0.043), and SDS scores at M3 (P = 0.044) and M6 (P = 0.028), were lower in the OO-CBSM group versus the NC group. Meanwhile, FACIT-Sp scores at M1 (P = 0.042) and M6 (P = 0.003) were higher in the OO-CBSM group over the NC group. Besides, EQ-5D scores at M3 (P = 0.067) and M6 (P = 0.087) disclosed trends to be lower in the OO-CBSM group versus the NC group, but not statistically significant. QLQ-C30-global-health scores at M3 (P = 0.049) and M6 (P = 0.033), and QLQ-C30-function score at M6 (P = 0.046), were higher in OO-CBSM group over NC group; but QLQ-C30-symptom score was not significantly different at any timepoints between them. CONCLUSION: OO-CBSM attenuates anxiety and depression, and advances spiritual well-being and QoL in postoperative ICC patients, indicating its potency for the ICC postoperative management.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Artificial intelligence enhances whole-slide interpretation of PD-L1 CPS in triple-negative breast cancer: A multi-institutional ring study.

BACKGROUND AND AIMS: Evaluation of the programmed cell death ligand-1 (PD-L1) combined positive score (CPS) is vital to predict the efficacy of the immunotherapy in triple-negative breast cancer (TNBC), but pathologists show substantial variability in the consistency and accuracy of the interpretation. It is of great importance to establish an objective and effective method which is highly repeatable. METHODS: We proposed a model in a deep learning-based framework, which at the patch level incorporated cell analysis and tissue region analysis, followed by the whole-slide level fusion of patch results. Three rounds of ring studies (RSs) were conducted. Twenty-one pathologists of different levels from four institutions evaluated the PD-L1 CPS in TNBC specimens as continuous scores by visual assessment and our artificial intelligence (AI)-assisted method. RESULTS: In the visual assessment, the interpretation results of PD-L1 (Dako 22C3) CPS by different levels of pathologists have significant differences and showed weak consistency. Using AI-assisted interpretation, there were no significant differences between all pathologists (P = 0.43), and the intraclass correlation coefficient (ICC) value was increased from 0.618 [95% confidence interval (CI) = 0.524-0.719] to 0.931 (95% CI = 0.902-0.955). The accuracy of interpretation result is further improved to 0.919 (95% CI = 0.886-0.947). Acceptance of AI results by junior pathologists was the highest among all levels, and 80% of the AI results were accepted overall. CONCLUSION: With the help of the AI-assisted diagnostic method, different levels of pathologists achieved excellent consistency and repeatability in the interpretation of PD-L1 (Dako 22C3) CPS. Our AI-assisted diagnostic approach was proved to strengthen the consistency and repeatability in clinical practice.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Background: Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. Methods: (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. Results: The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. Conclusions: This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

Federated attention consistent learning models for prostate cancer diagnosis and Gleason grading.

Artificial intelligence (AI) holds significant promise in transforming medical imaging, enhancing diagnostics, and refining treatment strategies. However, the reliance on extensive multicenter datasets for training AI models poses challenges due to privacy concerns. Federated learning provides a solution by facilitating collaborative model training across multiple centers without sharing raw data. This study introduces a federated attention-consistent learning (FACL) framework to address challenges associated with large-scale pathological images and data heterogeneity. FACL enhances model generalization by maximizing attention consistency between local clients and the server model. To ensure privacy and validate robustness, we incorporated differential privacy by introducing noise during parameter transfer. We assessed the effectiveness of FACL in cancer diagnosis and Gleason grading tasks using 19,461 whole-slide images of prostate cancer from multiple centers. In the diagnosis task, FACL achieved an area under the curve (AUC) of 0.9718, outperforming seven centers with an average AUC of 0.9499 when categories are relatively balanced. For the Gleason grading task, FACL attained a Kappa score of 0.8463, surpassing the average Kappa score of 0.7379 from six centers. In conclusion, FACL offers a robust, accurate, and cost-effective AI training model for prostate cancer pathology while maintaining effective data safeguards.

Perineural invasion in cervical cancer: A multicenter retrospective study.

OBJECTIVE: The study aimed to evaluate the accuracy of perineural invasion (PNI) diagnosis in cervical cancer, and to analyze the impact of PNI on the prognosis and postoperative adjuvant treatment decisions for cervical cancer. METHODS: A retrospective pathological review of PNI in cervical cancer was conducted from 2004 to 2016 in 15 hospitals. RESULTS: This study included a total of 1208 cases, comprising 273 cases with PNI and 935 cases without. The false positive rate and false negative rate of PNI diagnosis were 5.35% (50/935) and 33.33% (91/273), respectively. Adenocarcinoma, deep stromal invasion, lymphovascular space invasion (LVSI) (+), and margin involvement were independent risk factors for PNI. Both 5-year overall survival rate (OS) and 5-year disease-free survival rate (DFS) of PNI group were worse than non-PNI group. PNI was an independent risk factor for 5-year OS and 5-year DFS. In cases receiving standard postoperative adjuvant treatment, among those with two intermediate-risk factors, both 5-year OS and DFS were worse in the PNI group. Among cases with three intermediate-risk factors or at least one high-risk factor, there was no difference in 5-year OS between the two groups, but 5-year DFS was worse in the PNI group. CONCLUSION: The diagnosis of PNI in cervical cancer was not accurate. Adenocarcinoma, deep stromal invasion, LVSI, and margin involvement were independent risk factors for PNI. PNI was an independent risk factor for 5-year OS and DFS. PNI has the potential to serve as a new high-risk factor, thus providing guidance for postoperative adjuvant therapy.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence.

Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.

Downstaging guided neoadjuvant strategy shift and bladder preservation in locally advanced bladder cancer: A case report.

Background: The study of bladder preservation for muscle-invasive bladder cancer (MIBC) mainly focuses on the T2 stage, which remains difficult in the T3 and T4 stage. Pembrolizumab has been applied as neoadjuvant therapy followed by radical cystectomy for MIBC, gaining encouraging results in the phase II study. Disitamab vedotin, an antibody-drug conjugate (ADC), also achieved promising efficacy for refractory bladder cancer. However, the neoadjuvant therapy strategy of these drugs for bladder sparing remains further exploration. Case presentation: A patient with locally advanced MIBC at our institute underwent a neoadjuvant therapeutic regimen followed by transurethral resection of bladder tumor (TURBT) and concurrent chemoradiotherapy. In light of limited initial efficacy, we enacted an adaptive shift in the neoadjuvant treatment strategy, transitioning from a combination of gemcitabine, cis-platinum, and pembrolizumab to disitamab vedotin with pembrolizumab. This approach ultimately achieved bladder preservation, complete response, and a remarkable 1-year disease-free survival (DFS). Conclusion: Proactive evaluation in the early stages of tumor downstaging can serve as a guiding principle for neoadjuvant strategies. This is the first successful case of neoadjuvant pembrolizumab combined with disitamab vedotin and chemotherapy in MIBC patients achieving complete response and bladder preservation.

Humoral and cellular immune responses induced by serogroup W135 meningococcal conjugate and polysaccharide vaccines.

Investigating the mechanisms by which W135 meningococcal conjugate (PSW135-TT) activates adaptive immune responses in mice can provide a comprehensive understanding of the immune mechanisms of bacterial polysaccharide conjugate vaccines. We compared B-cell and T-cell immune responses immunized with W135 meningococcal capsular polysaccharides (PSW135), tetanus toxoid (TT) and PSW135-TT in mice. The results showed that PSW135-TT could induce higher PSW135-specific and TT-specific IgG antibodies with a significant enhancement after two doses. All serum antibodies immunized with PSW135- TT had strong bactericidal activity, whereas none of the serum antibodies immunized with PSW135 had bactericidal activity. Besides, IgM and IgG antibodies immunized with PSW135-TT after two doses were positively correlated with the titer of bactericidal antibodies. We also found Th cells favored Th2 humoral immune responses in PSW135-TT, PSW135, and TT-immunized mice, especially peripheral blood lymphocytes. Furthermore, PSW135-TT and TT could effectively activate bone marrow derived dendritic cells (BMDCs) and promote BMDCs to highly express major histocompatibility complex Ⅱ (MHCⅡ), CD86 and CD40 molecules in mice, whereas PSW135 couldn't. These data verified the typical characteristics of PSW135-TT and TT as T cell dependent antigen (TD-Ag) and PSW135 as T cell independent antigen (TI-Ag), which will be very helpful for further exploration of the immune mechanism of polysaccharide-protein conjugate vaccines and improvement of the quality of bacterial polysaccharide conjugate vaccines in future.

Periplcymarin targets glycolysis and mitochondrial oxidative phosphorylation of esophageal squamous cell carcinoma: Implication in anti-cancer therapy.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer (EC) in China, and demonstrates varying levels of resistance to multiple chemotherapeutic agents. Our previous studies have proved that periplocin (CPP), derived from the extract of cortex periplocae, exhibiting the capacity to hinder proliferation and induce apoptosis in ESCC cells. Several studies have identified additional anti-cancer constituents in the extract of cortex periplocae, named periplcymarin (PPM), sharing similar compound structure with CPP. Nevertheless, the inhibitory effects of PPM on ESCC and their underlying mechanisms remain to be further elucidated. PURPOSE: The aim of this study was to investigate function of PPM inhibiting the growth of ESCC in vivo and in vitro and to explore its underlying mechanism, providing the potential anti-tumor drug for ESCC. METHODS: Initially, a comparative analysis was conducted on the inhibitory activity of three naturally compounds obtained from the extract of cortex periplocae on ESCC cells. Among these compounds, PPM was chosen for subsequent investigation owing to its comparatively structure and anti-tumor activity simultaneously. Subsequently, a series of biological functional experiments were carried out to assess the impact of PPM on the proliferation, apoptosis and cell cycle arrest of ESCC cells in vitro. In order to elucidate the molecular mechanism of PPM, various methodologies were employed, including bioinformatics analyses and mechanistic experiments such as high-performance liquid chromatography combined with mass spectrometry (HPLC-MS), cell glycolysis pressure and mitochondrial pressure test. Additionally, the anti-tumor effects of PPM on ESCC cells and potential toxic side effects were evaluated in vivo using the nude mice xenograft assay. RESULTS: Our study revealed that PPM possesses the ability to impede the proliferation of ESCC cells, induce apoptosis, and arrest the cell cycle of ESCC cells in the G2/M phase in vitro. Mechanistically, PPM exerted its effects by modulating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as confirmed by glycolysis pressure and mitochondrial pressure tests. Moreover, rescue assays demonstrated that PPM inhibits glycolysis and OXPHOS in ESCC cells through the PI3K/AKT and MAPK/ERK signaling pathways. Additionally, we substantiated that PPM effectively suppresses the growth of ESCC cells in vivo, with only modest potential toxic side effects. CONCLUSION: Our study provides novel evidence that PPM has the potential to simultaneously target glycolysis and mitochondrial OXPHOS in ESCC cells. This finding highlights the need for further investigation into PPM as a promising therapeutic agent that targets the tumor glucose metabolism pathway in ESCC.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac: Estimated delivered dose and early toxicity results.

Background: Magnetic resonance (MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation (UHF-WPRT) is a novel approach to radiotherapy for patients with high-risk (HR) and very high-risk (VHR) prostate cancer (PCa). However, the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time. We aimed to estimate the delivered dose, study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac. Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa, who consecutively received UHF-WPRT, were enrolled prospectively. The contours of the target and organ-at-risks on the position verification-MR (PV-MR), beam-on 3D-MR(Bn-MR), and post-MR (after radiotherapy delivery) were derived from the pre-MR data by deformable image registration. The physician then manually adjusted them, and dose recalculation was performed accordingly. GraphPad Prism 9 (GraphPad Prism Software Inc.) was utilized for conducting statistical analyses. Results: In total, we collected 188 MR scans (50 pre-MR, 50 PV-MR, 44 Bn-MR, and 44 post-MR scans). With median 59 min, the mean prostate clinical target volume (CTV)-V100% was 98.59% ± 2.74%, and the mean pelvic CTVp-V100% relative percentages of all scans was 99.60% ± 1.18%. The median V29 Gy change in the rectal wall was -2% (-18% to 20%). With a median follow-up of 9 months, no patient had acute Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or more severe genitourinary (GU) or gastrointestinal (GI) toxicities (0%). Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape (ATS) workflow was technically feasible for patients with HR and VHR PCa, presenting only mild GU and GI toxicities. The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis. Clinical trial registration: Chinese Clinical Trial Registry ChiCTR2000033382.

A prospective phase II clinical trial of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma.

To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.

Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.

Background: Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods: We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results: Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion: We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.