Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis.

Cytochrome P450 F3 (CYP4F3) is recognized as a disease-associated immune response initiator that is involved in the synthesis of cholesterol, steroids, and lipids. This study identified the upregulation of CYP4F3 expression in colorectal cancer (CRC) and its association with poor patient prognosis through a comparative analysis between CRC tumor tissues with normal tissues from public databases. The overexpression of CYP4F3 in CT26.wt and SW620, promoted cell proliferation and migration, a reduction of cellular oxidative stress, an up-regulation of the oxidative stress-related pathway NRF2, and an inhibition of cellular ferroptosis. Additionally, inhibition of NRF2 activity stimulated cellular ferroptosis when CYP4F3 was overexpressed. Ferroptosis, characterized by iron-dependent lipid peroxidation, is a non-apoptotic way of cell death with a critical role in cancer development. When given a ferroptosis agonist to CYP4F3-overexpression CRC cells, NRF2 was activated, and cell proliferation and migration were reduced. Furthermore, the mice subcutaneously injected with CYP4F3-overexpression CT26.wt cells formed significantly larger tumors compared to the CYP4F3-vector CT26.wt cell group. This study systematically identified an important role of CYP4F3 in CRC development as a regulator of CRC cells to escape ferroptosis via NRF2, highlighting the significance of CYP4F3 as a potential therapeutic target for CRC.

Assessing the suitability of video-assisted anal fistula treatment for obese patients compared to conventional surgery: a question worth investigating.

BACKGROUND AND AIMS: Video-assisted anal fistula treatment (VAAFT) is an innovative surgical approach enabling the direct visualization of the fistula tract structure. This study aims to assess the efficacy of VAAFT in comparison with that of traditional surgical methods and explore potential risk factors contributing to fistula recurrence to provide new recommendations for surgical selection. MATERIALS AND METHODS: Information was collected from 100 patients with complex anal fistula (CAF) in our hospital who underwent surgical treatment from January 2021 to January 2023. We compared the baseline information and surgical outcomes of two groups, analyzed the risk factors for fistula recurrence by using logistic regression analysis, and conducted further exploration by using the body mass index. RESULTS: Equal numbers of patients underwent VAAFT and traditional surgeries, and no significant differences in baseline information were observed. Patients who received VAAFT experienced less intraoperative bleeding (15.5 (14.0-20.0) vs. 32.0 (25.0-36.0)), shorter hospital stays (2.0 (2.0-2.5) vs. 3.0 (3.0-3.5)), reduced postoperative pain and wound discharge, but longer operative times (43.3 ± 6.9 vs. 35.0 (31.5-40.0)) compared with patients who underwent traditional surgeries. No significant differences in recurrence rates were found three and six months after operation (the p-values were 0.790 and 0.806, respectively). However, the Wexner scores of the VAAFT group were significantly low in the first follow-up (0 (0-1.0) vs. 2.0 (1.0-2.0)). Postoperative recurrence of fistulas may be associated with obesity (p-value = 0.040), especially in patients undergoing traditional surgeries (p-value = 0.036). CONCLUSION: VAAFT offers advantages, such as less pain, less trauma, and faster recovery, compared with traditional surgical treatment. Obese patients with CAF are prone to recurrence, and we recommend that they undergo VAAFT treatment rather than traditional surgeries.

Crosstalk between CD8+ T cells and mesenchymal stromal cells in intestine homeostasis and immunity.

The intestine represents the most complex cellular network in the whole body. It is constantly faced with multiple types of immunostimulatory agents encompassing from food antigen, gut microbiome, metabolic waste products, and dead cell debris. Within the intestine, most T cells are found in three primary compartments: the organized gut-associated lymphoid tissue, the lamina propria, and the epithelium. The well-orchestrated epithelial-immune-microbial interaction is critically important for the precise immune response. The main role of intestinal mesenchymal stromal cells is to support a structural framework within the gut wall. However, recent evidence from stromal cell studies indicates that they also possess significant immunomodulatory functions, such as maintaining intestinal tolerance via the expression of PDL1/2 and MHC-II molecules, and promoting the development of CD103+ dendritic cells, and IgA+ plasma cells, thereby enhancing intestinal homeostasis. In this review, we will summarize the current understanding of CD8+ T cells and stromal cells alongside the intestinal tract and discuss the reciprocal interactions between T subsets and mesenchymal stromal cell populations. We will focus on how the tissue residency, migration, and function of CD8+ T cells could be potentially regulated by mesenchymal stromal cell populations and explore the molecular mediators, such as TGF-ß, IL-33, and MHC-II molecules that might influence these processes. Finally, we discuss the potential pathophysiological impact of such interaction in intestine hemostasis as well as diseases of inflammation, infection, and malignancies.

Targeting nanoplatform synergistic glutathione depletion-enhanced chemodynamic, microwave dynamic, and selective-microwave thermal to treat lung cancer bone metastasis.

Once bone metastasis occurs in lung cancer, the efficiency of treatment can be greatly reduced. Current mainstream treatments are focused on inhibiting cancer cell growth and preventing bone destruction. Microwave ablation (MWA) has been used to treat bone tumors. However, MWA may damage the surrounding normal tissues. Therefore, it could be beneficial to develop a nanocarrier combined with microwave to treat bone metastasis. Herein, a microwave-responsive nanoplatform (MgFe2O4@ZOL) was constructed. MgFe2O4@ZOL NPs release the cargos of Fe3+, Mg2+ and zoledronic acid (ZOL) in the acidic tumor microenvironment (TME). Fe3+ can deplete intracellular glutathione (GSH) and catalyze H2O2 to generate •OH, resulting in chemodynamic therapy (CDT). In addition, the microwave can significantly enhance the production of reactive oxygen species (ROS), thereby enabling the effective implementation of microwave dynamic therapy (MDT). Moreover, Mg2+ and ZOL promote osteoblast differentiation. In addition, MgFe2O4@ZOL NPs could target and selectively heat tumor tissue and enhance the effect of microwave thermal therapy (MTT). Both in vitro and in vivo experiments revealed that synergistic targeting, GSH depletion-enhanced CDT, MDT, and selective MTT exhibited significant antitumor efficacy and bone repair. This multimodal combination therapy provides a promising strategy for the treatment of bone metastasis in lung cancer patients.

Establishment of a neutrophil extracellular trap-related prognostic signature for colorectal cancer liver metastasis and expression validation of CYP4F3.

Liver metastasis stands as the primary contributor to mortality among patients diagnosed with colorectal cancer (CRC). Neutrophil extracellular traps (NETs) emerge as pivotal players in the progression and metastasis of cancer, showcasing promise as prognostic biomarkers. Our objective is to formulate a predictive model grounded in genes associated with neutrophil extracellular traps and identify novel therapeutic targets for combating CRLM. We sourced gene expression profiles from the Gene Expression Omnibus (GEO) database. Neutrophil extracellular trap-related gene set was obtained from relevant literature and cross-referenced with the GEO datasets. Differentially expressed genes (DEGs) were identified through screening via the least absolute shrinkage and selection operator regression and random forest modeling, leading to the establishment of a nomogram and subtype analysis. Subsequently, a thorough analysis of the characteristic gene CYP4F3 was undertaken, and our findings were corroborated through immunohistochemical staining. We identified seven DEGs (ATG7, CTSG, CYP4F3, F3, IL1B, PDE4B, and TNF) and established nomograms for the occurrence and prognosis of CRLM. CYP4F3 is highly expressed in CRC and colorectal liver metastasis (CRLM), exhibiting a negative correlation with CRLM prognosis. It may serve as a potential therapeutic target for CRLM. A novel prognostic signature related to NETs has been developed, with CYP4F3 identified as a risk factor and potential target for CRLM.

Dual-loss of PBRM1 and RAD51 identifies hyper-sensitive subset patients to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Homologous recombination deficiency (HRD), though largely uncharacterized in clear cell renal cell carcinoma (ccRCC), was found associated with RAD51 loss of expression. PBRM1 is the second most common mutated genes in ccRCC. Here, we introduce a HRD function-based PBRM1-RAD51 ccRCC classification endowed with diverse immune checkpoint blockade (ICB) responses. METHODS: Totally 1542 patients from four independent cohorts were enrolled, including our localized Zhongshan hospital (ZSHS) cohort and Zhongshan hospital metastatic RCC (ZSHS-mRCC) cohort, The Cancer Genome Atlas (TCGA) cohort and CheckMate cohort. The genomic profile and immune microenvironment were depicted by genomic, transcriptome data and immunohistochemistry. RESULTS: We observed that PBRM1-loss ccRCC harbored enriched HRD-associated mutational signature 3 and loss of RAD51. Dual-loss of PBRM1 and RAD51 identified patients hyper-sensitive to immunotherapy. This dual-loss subtype was featured by M1 macrophage infiltration. Dual-loss was, albeit homologous recombination defective, with high chromosomal stability. CONCLUSIONS: PBRM1 and RAD51 dual-loss ccRCC indicates superior responses to immunotherapy. Dual-loss ccRCC harbors an immune-desert microenvironment but enriched with M1 macrophages. Dual-loss ccRCC is susceptible to defective homologous recombination but possesses high chromosomal stability.

NKG2A+CD8+ T cells infiltration determines immunosuppressive contexture and inferior response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Immunotherapy is gaining momentum, but current treatments have limitations in terms of beneficiaries. Clear cell renal cell carcinoma (ccRCC) harbors the highest expression of human leukocyte antigen E (HLA-E), ligand of NKG2A, among all solid tumors. In this study, we aim to investigate the role of NKG2A+CD8+ T cells in tumor microenvironment and its potential as a novel target in ccRCC. METHODS: This study included four independent cohorts, including 234 patients from Zhongshan cohort (ZSHC) who underwent partial or radical nephrectomy at Zhongshan Hospital, and 117 metastatic patients from metastatic Zhongshan cohort (ZSHC-metastatic renal cell carcinoma) who were treated with immune checkpoint inhibitor or tyrosine kinase inhibitor alone. We also incorporated a cohort of 530 patients diagnosed with ccRCC from The Cancer Genome Atlas (referred to as TCGA-kidney renal clear cell carcinoma) and 311 patients from CheckMate cohort for bioinformatics exploration and hypothesis validation. Fresh surgical specimens from 15 patients who underwent ccRCC surgery at Zhongshan Hospital were collected for flow cytometry analysis. Another 10 fresh surgical specimens were used to investigate the therapeutic potential of NKG2A blockade after in vitro intervention. The infiltration of NKG2A+CD8+ T cells was assessed using immunohistochemical staining, flow cytometry, and immunofluorescence staining in ZSHC cohort. RESULTS: Patients with higher infiltration of NKG2A+CD8+ T cells in ccRCC exhibited shorter overall survival and resistance to immunotherapy. NKG2A+CD8+ T cells expressed upregulated checkpoint molecules and displayed impaired effector functions, along with tissue-residency characteristics. Combination of programmed cell death protein-1 (PD-1) blockade and NKG2A blockade demonstrated an enhanced capability in reactivating CD8+ T cells effector functions. CONCLUSION: Intense infiltration of NKG2A+CD8+ T cells were associated with poorer prognosis and response to immunotherapy. NKG2A blockade combined with current immunotherapy exhibited a robust ability to reactivate CD8+ T cells effector functions.

Prognostic analysis and outcome of hilar cholangiocarcinoma after radical resection: a retrospective study.

OBJECTIVES: The predictive factors affecting the survival of hilar cholangiocarcinoma (HC) are ambiguous. This study aimed to identify the predictors and recurrence patterns of HC. METHODS: A retrospective analysis of the clinicopathological findings of 126 patients with HC from 2009 to 2019 was performed. RESULTS: The proportion of Bismuth I and II HC in the recurrence group was higher than that in the non-recurrence group (p < 0.01). The recurrence group had poorer tumor differentiation, a more advanced N stage, and a higher incidence of perineural invasion compared with the non-recurrence group. N stage and tumor differentiation were independently associated with disease-free and overall survival of patients (p < 0.01). Bile duct resection (BDR) combined with hepatectomy was more favorable to disease-free and overall survivals than BDR alone in Bismuth I and II HC, although p values were marginal (p = 0.072 and p = 0.045). A higher proportion of patients in the non-recurrence group underwent BDR combined with hepatectomy than that in the recurrence group (p < 0.01). CONCLUSIONS: N stage and tumor differentiation are the two independent predictors of patient survival. BDR combined with hepatectomy is recommended for patients with Bismuth I and II hilar cholangiocarcinoma.

OBJETIVOS: Los predictores que afectan a la supervivencia del colangiocarcinoma hiliar son ambiguos. Este estudio tiene como objetivo identificar los factores predictivos y los patrones de recurrencia del colangiocarcinoma hiliar. MÉTODOS: Se aplicó un análisis retrospectivo con126 pacientes con colangiocarcinoma hiliar desde 2009 hasta 2019. RESULTADOS: La proporción de colangiocarcinoma hiliar Bismuth I y II en el grupo de recurrencia fue mayor que en el grupo de no recurrencia (p < 0.01). El tumor del grupo de recidiva tenía un estadio N más avanzado que el del grupo de no recidiva. El estadio N se asocia de forma independiente con la supervivencia libre de enfermedad y global del paciente (p < 0.01). La resección de la vía biliar combinada con la hepatectomía benefició más a la supervivencia libre de enfermedad y global que la resección de la vía biliar sola en el colangiocarcinoma hiliar (p = 0.072 y p = 0.045). Una mayor proporción de pacientes se sometió a resección de la vía biliar combinada con hepatectomía en el grupo de no recidiva que en el de recidiva (p < 0.01). CONCLUSIONES: El estadio N fue el predictor independiente. Se recomienda la resección de la vía biliar combinada con hepatectomía para los pacientes con colangiocarcinoma hiliar Bismuth I y II.

Regulation of CD8+ T memory and exhaustion by the mTOR signals.

CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.

Expanding the Reach of Monoclonal Antibodies: A Review of Synthetic Nucleic Acid Delivery in Immunotherapy.

Harnessing the immune system to combat disease has revolutionized medical treatment. Monoclonal antibodies (mAbs), in particular, have emerged as important immunotherapeutic agents with clinical relevance in treating a wide range of diseases, including allergies, autoimmune diseases, neurodegenerative disorders, cancer, and infectious diseases. These mAbs are developed from naturally occurring antibodies and target specific epitopes of single molecules, minimizing off-target effects. Antibodies can also be designed to target particular pathogens or modulate immune function by activating or suppressing certain pathways. Despite their benefit for patients, the production and administration of monoclonal antibody therapeutics are laborious, costly, and time-consuming. Administration often requires inpatient stays and repeated dosing to maintain therapeutic levels, limiting their use in underserved populations and developing countries. Researchers are developing alternate methods to deliver monoclonal antibodies, including synthetic nucleic acid-based delivery, to overcome these limitations. These methods allow for in vivo production of monoclonal antibodies, which would significantly reduce costs and simplify administration logistics. This review explores new methods for monoclonal antibody delivery, including synthetic nucleic acids, and their potential to increase the accessibility and utility of life-saving treatments for several diseases.

Misdiagnosis and delayed diagnosis of atypical autoimmune pancreatitis: Experience from clinical cases.

Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease characterized by inflammation and fibrosis of the pancreas. It is a systemic disease that can affect multiple organs, including the bile ducts, kidneys, lungs, and other organs. However, due to its complex presentation, AIP is often challenging to diagnose, and misdiagnosis with pancreatic tumors can occur. In our study, we reviewed three cases of atypical AIP where patients had normal serum IgG4 levels, leading to initial misdiagnosis with pancreatic tumors. Delayed diagnosis resulted in irreversible pathologies such as retroperitoneal fibrosis. All three patients had bile duct involvement, and imaging findings were similar to those of tumors, further complicating the diagnosis. The correct diagnosis was confirmed only after diagnostic therapy. Our study aims to raise awareness of atypical AIP and improve diagnostic efficiency by analyzing the clinical characteristics of these patients.

Comparison of Effectiveness and Safety in Treating Acute Acromioclavicular Joint Dislocation with Five Different Surgical Procedures: A Systematic Review and Network Meta-Analysis.

This network meta-analysis aims to evaluate the comparative effectiveness and safety of suture anchors (SA), tendon grafts (TG), hook plates (HP), Tight-Rope (TR), and EndoButton (EB) in the treatment of acute acromioclavicular joint (ACJ) dislocation. The Embase, PubMed, and Web of Science databases were searched from their inception date to June 3, 2022. Studies included all eligible randomized controlled trials (RCTs) and cohort studies with the comparison of five different fixation systems among SA, TG, HP, TR, and EB were identified. All studies were reviewed, performed data extraction, and assessed the risk of bias independently by two reviewers. The primary outcomes are Constant-Murley score (CMS) improvement for assessing clinical efficacy, and complications. The second outcomes are visual analog scale (VAS) for assessing pain relief and the coracoclavicular distance (CCD) for assessing postoperative joint reduction. Version 2 of the revised Cochrane risk of bias tool for randomized trials (RoB 2) and the risk of bias in nonrandomized studies of interventions (ROBINS-I) were used to assess the RCTs and non-randomized trials, respectively. The continuous outcomes were presented as mean differences (MD), and risk ratios (OR) were used for dichotomous outcomes, both with 95% confidence intervals (CI). Surface under the cumulative ranking curves (SUCRA) results were calculated to offer a ranking of each intervention. We identified 31 eligible trials, including 1687 patients in total. HP showed less CMS improvement than TR and EB in both the Network Meta-analysis (NMA) and pairwise meta-analysis. HP also showed less CMS improvement than SA in NMA. For pain relief, HP performed worse than TR both in pairwise meta-analysis and NMA. No significant differences were found for the measured value of CCD. Both TR and EB showed a lower incidence of complications than HP in pairwise meta-analysis. The rank of SUCRA for CMS improvement was as follows: SA, TR, EB, TG, and HP; for pain relief: TR, EB, TG, SA, and HP; for CCD: HP, TR, SA, EB, and TG. For complications, HP showed the highest rank, followed by TG, EB, TR, and SA. SA shows better clinical effectiveness and reliable safety in the treatment of acute ACJ dislocation. Although HP is the most widely used surgical option currently, it should be carefully taken into consideration for its high incidence of complications.

mRNA melanoma vaccine revolution spurred by the COVID-19 pandemic.

The advent of mRNA vaccines represents a significant advance in the field of vaccinology. While several vaccine approaches (mRNA, DNA, recombinant protein, and viral-vectored vaccines) had been investigated at the start of the COVID-19 pandemic, mRNA vaccines quickly gained popularity due to superior immunogenicity at a low dose, strong safety/tolerability profiles, and the possibility of rapid vaccine mass manufacturing and deployment to rural regions. In addition to inducing protective neutralizing antibody responses, mRNA vaccines can also elicit high-magnitude cytotoxic T-cell responses comparable to natural viral infections; thereby, drawing significant interest from cancer immunotherapy experts. This mini-review will highlight key developmental milestones and lessons we have learned from mRNA vaccines during the COVID-19 pandemic, with a specific emphasis on clinical trial data gathered so far for mRNA vaccines against melanoma and other forms of cancer.

Engineered antibody cytokine chimera synergizes with DNA-launched nanoparticle vaccines to potentiate melanoma suppression in vivo.

Cancer immunotherapy has demonstrated great promise with several checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and new engineered cytokines such as Neo2/15 now being evaluated in many studies. In this work, we designed antibody-cytokine chimera (ACC) scaffolding cytokine mimetics on a full-length tumor-specific antibody. We characterized the pharmacokinetic (PK) and pharmacodynamic (PD) properties of first-generation ACC TA99-Neo2/15, which synergized with DLnano-vaccines to suppress in vivo melanoma proliferation and induced significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rß/γ binding and attenuated but preserved IL-2Rα binding, induced lower systemic cytokine activation with non-inferior protection in murine tumor studies. Transcriptomic analyses demonstrated an upregulation of Type I interferon responsive genes, particularly ISG15, in dendritic cells, macrophages and monocytes following TA99-HL2-KOA1 treatment. Characterization of additional ACCs in combination with cancer vaccines will likely be an important area of research for treating melanoma and other types of cancer.

Biodegradable photothermal thermosensitive hydrogels treat osteosarcoma by reprogramming macrophages.

Osteosarcoma is one of the most common malignant tumors in children and tends to occur around the knee. Problems such as recurrence and metastasis are the outcomes of traditional treatment methods. One of the reasons for these issues is the infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Photothermal immunotherapy has emerged as one of the most potent approaches for cancer treatment. In this study, we designed a biodegradable, injectable, and photothermal hydrogel that functions to reprogram TAMs into classically activated macrophages (M1) based on hydroxypropyl chitin (HPCH), tannic acid and ferric ions (HTA). We found that HTA had better photothermal efficiency than a pure hydrogel; its photothermal repeatability is good and it can be NIR (808 nm) irradiated as needed. In addition, the precooled hydrogel solution can be injected into the tumor and it can rapidly gel in situ. In vitro, HTA with NIR irradiation (HTA + NIR) induced the apoptosis of K7M2 cancer cells. In vivo, the local administration of HTA + NIR exerted photothermal killing of primary tumors and reprogramming of TAMs into M1-type macrophages in the TME. Therefore, the injectable photothermally active antitumor hydrogel has great potential for modulating the TME to treat bone tumors.

External validation of the SORG machine learning algorithms for predicting 90-day and 1-year survival of patients with lung cancer-derived spine metastases: a recent bi-center cohort from China.

BACKGROUND CONTEXT: The survival prediction of lung cancer-derived spinal metastases is often underestimated by several scores. The SORG machine learning (ML) algorithm is considered a promising tool to predict the risk of 90-day and 1-year mortality in patients with spinal metastases, but not been externally validated for lung cancer. PURPOSE: This study aimed to externally validate the SORG ML algorithms on lung cancer-derived spinal metastases patients from two large-volume, tertiary medical centers between 2018 and 2021. STUDY DESIGN/SETTING: Retrospective, cohort study. PATIENT SAMPLE: Patients aged 18 years or older at two tertiary medical centers in China are treated surgically for spinal metastasis. OUTCOME MEASURES: Mortality within 90 days of surgery, mortality within 1 year of surgery. METHODS: The baseline characteristics were compared between the development cohort and our validation cohort. Discrimination (receiver operating curve), calibration (calibration plot, intercept, and slope), the overall performance (Brier score), and decision curve analysis was used to assess the overall performance of the SORG ML algorithms. RESULTS: This study included 150 patients with lung cancer-derived spinal metastases from two medical centers in China. Ninety-day and 1-year mortality rates were 12.9% (19/147) and 51.3% (60/117), respectively. Lung Cancer with targeted therapies had the lowest Hazard Ratio (HR=0.490), showing an optimal protecting factor. The AUC of the SORG ML algorithm for 90-day mortality prediction in lung cancer-derived spinal metastases is 0.714. While the AUC for 1-year mortality prediction is 0.832 (95CI%, 0.758-0.906). The algorithm for 1-year mortality was well-calibrated with an intercept of 0.13 and a calibration slope of 1.00. However, the 90-day mortality prediction was underestimated with an intercept of 0.60 and a slope of 0.37. The SORG ML algorithms for 1-year mortality showed a greater net benefit than the "treats all or no patients" strategies. CONCLUSIONS: In the latest cohort of lung cancer-derived spinal metastases in China, the SORG algorithms for predicting 1-year mortality performed well on external validation. However, 90-day mortality was underestimated. The algorithm should be further validated by single primary tumor-derived metastasis treated with the latest comprehensive treatment in diverse populations.

Neoadjuvant androgen deprivation therapy combined with abiraterone acetate in patients with locally advanced or metastatic prostate cancer: When to perform radical prostatectomy?

The surgical timing after neoadjuvant androgen-deprivation therapy (ADT) plus abiraterone acetate (AA) for patients with locally advanced or metastatic prostate cancer (PCa) is unknown. We divided patients with locally advanced or metastatic PCa into three groups according to prostate-specific antigen (PSA) nadir after neoadjuvant ADT plus AA: group 1 (PSA ≤ 0.2 ng/ml), group 2 (0.2 < PSA ≤ 4.0 ng/ml), and group 3 (PSA > 4.0 ng/ml).The median PSA baseline levels in groups 1, 2, 3 were 118.42 (32.03-457.78), 143.48 (17.7-8100.16), and153.35 (46.44-423.31) ng/ml, respectively. The median times of progression to CRPC in groups 1, 2,and 3 were 30, 26, and 26 months, respectively. Compared to patients with PSA nadir >0.2 ng/ml, patients with PSA nadir <0.2 ng/ml presented with longer PFS (p = 0.048).Our results suggested that, in patients with locally advanced or metastatic PCa, the time to progression to CRPC was longer after radical prostatectomy when PSA decreased below 0.2 ng/ml using neoadjuvant ADT plus AA.

Dissecting cellular heterogeneity and intercellular communication in cholangiocarcinoma: implications for individualized therapeutic strategies.

Background: Cholangiocarcinoma is characterized by significant cellular heterogeneity and complex intercellular communication, which contribute to its progression and therapeutic resistance. Therefore, unraveling this complexity is essential for the development of effective treatments. Methods: We employed single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and intercellular communication in cholangiocarcinoma and adjacent normal tissues from two patients. Distinct cell types were identified, and gene ontology analyses were conducted to determine enriched pathways. Moreover, cell-cell communications were analyzed using CellChat, a computational framework. Additionally, we performed sub-clustering analysis of T cells and fibroblasts. Results: The scRNA-seq analysis revealed distinct cell clusters and diverse cellular compositions of cholangiocarcinoma. CellChat analysis underscored an amplified outgoing signal from fibroblasts within the tumor, suggesting their pivotal role in the tumor microenvironment. Furthermore, T cell sub-clustering analysis revealed an active immune response within the tumor and new tumor-specific T cell clonotypes, suggesting scope for targeted immunotherapies. Moreover, fibroblast sub-clustering analysis indicated distinct functional states and highlighted the role of activated fibroblasts in shaping intercellular communication, particularly via CD99 and FN1 signaling. Conclusion: Our findings reveal the intricate cellular heterogeneity and dynamic intercellular communication in cholangiocarcinoma, providing valuable insights into disease progression and potential therapeutic strategies.

Bacillus Calmette-Guerin for the Treatment of Non-muscle Invasive Bladder Cancer: History and Current Status.

In the past decades, the bacillus Calmette-Guerin (BCG) treatment for non-muscle invasive bladder cancer, especially for intermediate and high-risk groups, is increasingly accepted by multiple guidelines. Currently, the front-line setting for the high-risk group is still intravesical BCG instillation. However, the BCG mechanism, usage, adverse events, and the definition of BCG failure are not yet fully understood or defined. In addition, despite BCG being generally efficacious, a number of bladder cancer patients are unresponsive to the BCG immunotherapy. In this review, we summarize the history and current status of BCG immunotherapy, and highlight recent developments in designing novel strategies for the treatment of BCG-unresponsive patients.