Exploiting tertiary lymphoid structures gene signature to evaluate tumor microenvironment infiltration and immunotherapy response in colorectal cancer.

Background: Tertiary lymphoid structures (TLS) is a particular component of tumor microenvironment (TME). However, its biological mechanisms in colorectal cancer (CRC) have not yet been understood. We desired to reveal the TLS gene signature in CRC and evaluate its role in prognosis and immunotherapy response. Methods: The data was sourced from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Based on TLS-related genes (TRGs), the TLS related subclusters were identified through unsupervised clustering. The TME between subclusters were evaluated by CIBERSORT and xCell. Subsequently, developing a risk model and conducting external validation. Integrating risk score and clinical characteristics to create a comprehensive nomogram. Further analyses were conducted to screen TLS-related hub genes and explore the relationship between hub genes, TME, and biological processes, using random forest analysis, enrichment and variation analysis, and competing endogenous RNA (ceRNA) network analysis. Multiple immunofluorescence (mIF) and immunohistochemistry (IHC) were employed to characterize the existence of TLS and the expression of hub gene. Results: Two subclusters that enriched or depleted in TLS were identified. The two subclusters had distinct prognoses, clinical characteristics, and tumor immune infiltration. We established a TLS-related prognostic risk model including 14 genes and validated its predictive power in two external datasets. The model's AUC values for 1-, 3-, and 5-year overall survival (OS) were 0.704, 0.737, and 0.746. The low-risk group had a superior survival rate, more abundant infiltration of immune cells, lower tumor immune dysfunction and exclusion (TIDE) score, and exhibited better immunotherapy efficacy. In addition, we selected the top important features within the model: VSIG4, SELL and PRRX1. Enrichment analysis showed that the hub genes significantly affected signaling pathways related to TLS and tumor progression. The ceRNA network: PRRX1-miRNA (hsa-miR-20a-5p, hsa-miR-485-5p) -lncRNA has been discovered. Finally, IHC and mIF results confirmed that the expression level of PRRX1 was markedly elevated in the TLS- CRC group. Conclusion: We conducted a study to thoroughly describe TLS gene signature in CRC. The TLS-related risk model was applicable for prognostic prediction and assessment of immunotherapy efficacy. The TLS-hub gene PRRX1, which had the potential to function as an immunomodulatory factor of TLS, could be a therapeutic target for CRC.

Sunitinib for adenocarcinoma of the rete testis: a case report.

Background: Adenocarcinoma of the rete testis (AORT) is an extremely rare and aggressive tumor with a poor prognosis. Its etiology and pathological characteristics have not been extensively studied, making accurate diagnosis and appropriate management challenging. AORT, an invasive testicular tumor with a mortality rate of 46%, treatment typically involves radical orchiectomy, retroperitoneal pelvic lymph node dissection (RPLND), adjuvant chemotherapy, and/or ongoing monitoring, but the response to conventional radiation and chemotherapy is limited. At present, no effective targeted therapy for AORT has been found. Case description: In this case report, we present the clinical scenario of a 50-year-old male patient initially diagnosed with a right testicular hydrocele, who subsequently underwent eversion of the parietal tunica vaginalis. Postoperative pathological analysis revealed metastatic clear cell renal cell carcinoma (ccRCC). PET/CT demonstrated findings suggestive of left renal upper pole carcinoma with involvement of the right scrotum, para-aortic region, bilateral iliac vessels, bilateral inguinal region, and multiple metastases. Sunitinib, a tyrosine kinase inhibitor, is commonly employed in the treatment of ccRCC. The patient underwent treatment with sunitinib for a duration of 20 months, resulting in the inactivation of multiple metastases. Following this, a radical orchiectomy was performed, and the postoperative pathology confirmed the presence of AORT. This article provides a comprehensive account of the patient's medical history, diagnostic process, treatment modalities, and subsequent follow-up observations. Conclusions: This case report highlights the successful use of targeted therapy with sunitinib in a patient with AORT. The patient showed a positive response to targeted therapy. This study not only provides a novel foundation for the treatment of AORT, but also offers valuable insights for future treatment strategies in managing this particular form of testicular cancer.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Enhancing Oocyte Quality in Aging Mice: Insights from Mesenchymal Stem Cell Therapy and FOXO3a Signaling Pathway Activation.

Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings.

The remodeling of ovarian function: targeted delivery strategies for mesenchymal stem cells and their derived extracellular vesicles.

Premature ovarian insufficiency (POI) is an essential cause of reduced fertility and quality of life in young women. Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have the ability to migrate to damaged tissues and are considered as promising therapeutic approaches for POI. However, the homing ability and therapeutic efficacy of MSCs administered in vivo are still insufficient, and their potential tumorigenicity and multi-differentiation potential also bring many doubts about their safety. The targeting ability and migration efficiency of MSCs can be improved by genetic engineering and surface modification, thereby maximizing their therapeutic efficacy. However, the use of viral vectors also has increased safety concerns. In addition, EVs, which seem to be the current therapeutic alternative to MSCs, are still poorly targeted for distribution, although they have improved in terms of safety. This paper reviews the comparative therapeutic effects of MSCs and their derived EVs on POI, their biodistribution after in vivo administration, and the most important possible ovarian targeting strategies. Difficulties such as homogeneity and yield before clinical application are also discussed. This article will provide new insights into precision therapy and targeted drug delivery for female ovarian diseases.

Preliminary exploration of the potential biological functions and prognosis values of RAB4B in pan-cancer combing with experimental validation in BLCA.

Background: Ras-related protein Rab-4B (RAB4B), a small GTPase in the RAS superfamily, is involved in glucose homeostasis, synaptic homeostasis, adaptive immunity, and other processes. RAB4B has also been implicated in tumorigenesis, and its dysregulation has been linked to cancer in multiple organs. However, the potential role of RAB4B in human pan-cancers remains unknown, and whether RAB4B is a predictive biomarker for cancer immunotherapy is yet to be explored. Methods: In order to investigate the potential for RAB4B as a therapeutic agent in human pan-cancers and its predictive properties, firstly, relevant data were downloaded from pan-cancers databases. Using the RAB4B expression as a parameter, an analysis was performed. The next step was to investigate how RAB4B relates to overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Moreover, we performed an analysis of the relationship between RAB4B and tumor mutational burden (TMB), microsatellite instability (MSI), and tumor microenvironment (TME). Besides, the tumor immune dysfunction and exclusion (TIDE) algorithm was applied to evaluate the efficacy of RAB4B as a potential biomarker for cancer immunotherapy. A final analysis was performed on RAB4B in relation to immune-related genes and pathways. Results: Results reflected that RAB4B expression was different between tumors and normal tissues. RAB4B not only positively or negatively correlated with survival indicators, but also with clinical characteristics. In addition, RAB4B positively or negatively correlated with TMB, MSI, and TME. The TIDE algorithm revealed that RAB4B was positively or negatively associated with immune checkpoint blockade. The outcome of gene set enrichment analysis (GSEA) suggested that RAB4B positively regulated biological processes and immune cell-related pathways in most cancers. Conclusions: According to the research results, we come to the conclusion that RAB4B as a biomarker for tumor immunotherapy, RAB4B facilitates the prediction of pan-cancers prognosis.

Topological Structure Realized in Cove-Edged Graphene Nanoribbons via Incorporation of Periodic Pentagon Rings.

Cove-edged zigzag graphene nanoribbons are predicted to show metallic, topological, or trivial semiconducting band structures, which are precisely determined by their cove offset positions at both edges as well as the ribbon width. However, due to the challenge of introducing coves into zigzag-edged graphene nanoribbons, only a few cove-edged graphene nanoribbons with trivial semiconducting bandgaps have been realized experimentally. Here, we report that the topological band structure can be realized in cove-edged graphene nanoribbons by embedding periodic pentagon rings on the cove edges through on-surface synthesis. Upon noncontact atomic force microscopy and scanning tunneling spectroscopy measurements, the chemical and electronic structures of cove-edged graphene nanoribbons with periodic pentagon rings have been characterized for different lengths. Combined with theoretical calculations, we find that upon inducing periodic pentagon rings the cove-edged graphene nanoribbons exhibit nontrivial topological structures. Our results provide insights for the design and understanding of the topological character in cove-edged graphene nanoribbons.

Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer.

Background: Immunotherapy favors patients with tumors; however, only 3-26.3% of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors. Combined immunotherapy and chemotherapy has been explored against tumor; however, the combination remains controversial. This study aimed to investigate the tumor immune microenvironment (TIME) and the effects of platinum-based neoadjuvant chemotherapy (NACT) in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy. Methods: Multiplex immunohistochemistry (IHC) with 11 markers (cluster of differentiation [CD]3, CD8, CD4, CD11c, CD68, forkhead box P3 [Foxp3], programmed cell death 1 [PD-1], programmed cell death 1 ligand 1 [PD-L1], indoleamine 2,3-dioxygenase [IDO], cyclin-dependent kinase inhibitor 2A [p16], and cytokeratin [CK]) was performed to evaluate TIME from 108 matched pre- and post-NACT cervical cancer samples. The mechanism of antitumor immunity triggered by NACT was explored using RNA sequencing (RNA-seq) from four paired samples and subsequently verified in 41 samples using IHC. Results: The infiltration rate of the CD8+ T cells in treatment-naive cervical cancer was 0.73%, and those of Foxp3+ regulatory T cells (Tregs) and IDO+ cells were 0.87% and 17.15%, respectively. Moreover, immunoreactive T cells, dendritic cells, and macrophages were more in the stromal than the intratumor region. NACT increased dendritic, CD3+ T, CD8+ T, and CD4+ T cells and decreased Tregs. The aforementioned alterations occurred predominantly in the stromal region and were primarily in responders. Non-responders primarily showed decreased Tregs and no increase in CD8+ T or dendritic cell infiltration. Furthermore, dendritic cells interacted more closely with CD3+ T cells after NACT, an effect primarily observed in responders. RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex (MHC) I and MHC II after chemotherapy, validated using IHC. Conclusions: NACT can reduce Tregs, and when tumor cells are effectively killed, antigen presentation is enhanced, subsequently activating antitumor immunity finitely. Our study provides the molecular characteristics and theoretical basis for the simultaneous or sequential combination of platinum-based NACT and immunotherapy for cervical cancer.

Machine learning-based overall and cancer-specific survival prediction of M0 penile squamous cell carcinoma：A population-based retrospective study.

Background: Penile cancer is a rare tumor and few studies have focused on the prognosis of M0 penile squamous cell carcinoma (PSCC). This retrospective study aimed to identify independent prognostic factors and construct predictive models for the overall survival (OS) and cancer-specific survival (CSS) of patients with M0 PSCC. Methods: Data was extracted from the Surveillance, Epidemiology, and End Results database for patients diagnosed with malignant penile cancer. Eligible patients with M0 PSCC were selected according to predetermined inclusion and exclusion criteria. These patients were then divided into a training set, a validation set, and a test set. Univariate and multivariate COX regression analyses were initially performed to identify independent prognostic factors for OS and CSS in M0 PSCC patients. Subsequently, traditional and machine learning prognostic models, including random survival forest (RSF), COX, gradient boosting, and component-wise gradient boosting modelling, were constructed using the scikit-survival framework. The performance of each model was assessed by calculating time-dependent area under curve (AUC), C-index, and integrated Brier score (IBS), ultimately identifying the model with the highest performance. Finally, the Shapley additive explanation (SHAP) value, feature importance, and cumulative rates analyses were used to further estimate the selected model. Results: A total of 2, 446 patients were included in our study. Cox regression analyses demonstrated that age, N stage, and tumor size were predictors of OS, while the N stage, tumor size, surgery, and residential area were predictors of CSS. The RSF and COX models had a higher time-independent AUC and C-index, and lower IBS value than other models in OS and CSS prediction. Feature importance analysis revealed the N stage as a common significant feature for predicting M0 PSCC patients' survival. The SHAP and cumulative rate analyses demonstrated that the selected models can effectively evaluate the prognosis of M0 PSCC patients. Conclusion: In M0 PSCC patients, age, N stage, and tumor size were predictors of OS. In addition, the N stage, tumor size, surgery, and residential area were predictors of CSS. The machine learning-based RSF and COX models effectively predicted the prognosis of M0 PSCC patients.

Mitochondria in Mesenchymal Stem Cells: Key to Fate Determination and Therapeutic Potential.

Mesenchymal stem cells (MSCs) have become popular tool cells in the field of transformation and regenerative medicine due to their function of cell rescue and cell replacement. The dynamically changing mitochondria serve as an energy metabolism factory and signal transduction platform, adapting to different cell states and maintaining normal cell activities. Therefore, a clear understanding of the regulatory mechanism of mitochondria in MSCs is profit for more efficient clinical transformation of stem cells. This review highlights the cutting-edge knowledge regarding mitochondrial biology from the following aspects: mitochondrial morphological dynamics, energy metabolism and signal transduction. The manuscript mainly focuses on mitochondrial mechanistic insights in the whole life course of MSCs, as well as the potential roles played by mitochondria in MSCs treatment of transplantation, for seeking pivotal targets of stem cell fate regulation and stem cell therapy.

The Dominant Mechanism of Cyclophosphamide-Induced Damage to Ovarian Reserve: Premature Activation or Apoptosis of Primordial Follicles?

Cyclophosphamide (CPM), a part of most cancer treatment regimens, has demonstrated high gonadal toxicity in females. Initially, CPM is believed to damage the ovarian reserve by premature activation of primordial follicles, for the fact that facing CPM damage, primordial oocytes show the activation of PTEN/PI3K/AKT pathways, accompanied by accelerated activation of follicle developmental waves. Meanwhile, primordial follicles are dormant and not considered the target of CPM. However, many researchers have found DNA DSBs and apoptosis within primordial oocytes under CPM-induced ovarian damage instead of premature accelerated activation. A stricter surveillance system of DNA damage is also thought to be in primordial oocytes. So far, the apoptotic death mechanism is considered well-proved, but the premature activation theory is controversial and unacceptable. The connection between the upregulation of PTEN/PI3K/AKT pathways and DNA DSBs and apoptosis within primordial oocytes is also unclear. This review aims to highlight the flaw and/or support of the disputed premature activation theory and the apoptosis mechanism to identify the underlying mechanism of CPM's injury on ovarian reserve, which is crucial to facilitate the discovery and development of effective ovarian protectants. Ultimately, this review finds no good evidence for follicle activation and strong consistent evidence for apoptosis.

Analysis of the Correlation and Prognostic Significance of Tertiary Lymphoid Structures in Breast Cancer: A Radiomics-Clinical Integration Approach.

BACKGROUND: Tertiary lymphoid structures (TLSs) are potential prognostic indicators. Radiomics may help reduce unnecessary invasive operations. PURPOSE: To analyze the association between TLSs and prognosis, and to establish a nomogram model to evaluate the expression of TLSs in breast cancer (BC) patients. STUDY TYPE: Retrospective. POPULATION: Two hundred forty-two patients with localized primary BC (confirmed by surgery) were divided into BC + TLS group (N = 122) and BC - TLS group (N = 120). FIELD STRENGTH/SEQUENCE: 3.0T; Caipirinha-Dixon-TWIST-volume interpolated breath-hold sequence for dynamic contrast-enhanced (DCE) MRI and inversion-recovery turbo spin echo sequence for T2-weighted imaging (T2WI). ASSESSMENT: Three models for differentiating BC + TLS and BC - TLS were developed: 1) a clinical model, 2) a radiomics signature model, and 3) a combined clinical and radiomics (nomogram) model. The overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were compared to evaluate the prognostic value of TLSs. STATISTICAL TESTS: LASSO algorithm and ANOVA were used to select highly correlated features. Clinical relevant variables were identified by multivariable logistic regression. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and through decision curve analysis (DCA). The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The radiomics signature model (training: AUC 0.766; test: AUC 0.749) and the nomogram model (training: AUC 0.820; test: AUC 0.749) showed better validation performance than the clinical model. DCA showed that the nomogram model had a higher net benefit than the other models. The median follow-up time was 52 months. While there was no significant difference in 3-year OS (P = 0.22) between BC + TLS and BC - TLS patients, there were significant differences in 3-year DFS and 3-year DMFS between the two groups. DATA CONCLUSION: The nomogram model performs well in distinguishing the presence or absence of TLS. BC + TLS patients had higher long-term disease control rates and better prognoses than those without TLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.

Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance.

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor ß pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.

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Tumor-associated tertiary lymphoid structures (TLSs) are ectopic lymphoid formations within tumor tissue, with mainly B and T cell populations forming the organic aggregates. The presence of TLSs in tumors has been strongly associated with patient responsiveness to immunotherapy regimens and improving tumor prognosis. Researchers have been motivated to actively explore TLSs due to their bright clinical application prospects. Various studies have attempted to decipher TLSs regarding their formation mechanism, structural composition, induction generation, predictive markers, and clinical utilization. Meanwhile, the scientific approaches to qualitative and quantitative descriptions are crucial for TLS studies. In terms of detection, hematoxylin and eosin (H&E), multiplex immunohistochemistry (mIHC), multiplex immunofluorescence (mIF), and 12-chemokine gene signature have been the top approved methods. However, no standard methods exist for the quantitative analysis of TLSs, such as absolute TLS count, analysis of TLS constituent cells, structural features, TLS spatial location, density, and maturity. This study reviews the latest research progress on TLS detection and quantification, proposes new directions for TLS assessment, and addresses issues for the quantitative application of TLSs in the clinic.

Cancer-associated fibroblasts: Just on the opposite side of antitumour immunity?

The tumour microenvironment (TME) is critical for the initiation, progression, and metastasis of tumours, and cancer-associated fibroblasts (CAFs) are the most dominant cells and have attracted interest as targets for cancer therapy among the stromal components within the TME. Currently, most of the identified CAF subpopulations are believed to exhibit suppressive effects on antitumour immunity. However, accumulating evidence indicates the presence of immunostimulatory CAF subpopulations, which play an important role in the maintenance and amplification of antitumour immunity, in the TME. Undoubtedly, these findings provide novel insights into CAF heterogeneity. Herein, we focus on summarizing CAF subpopulations that promote antitumour immunity, the surface markers of these populations, and possible immunostimulatory mechanisms in the context of recent advances in research on CAF subpopulations. In addition, we discuss the possibility of new therapies targeting CAF subpopulations and conclude with a brief description of some prospective avenues for CAF research.

The potential of high-order features of routine blood test in predicting the prognosis of non-small cell lung cancer.

BACKGROUND: Numerous studies have demonstrated that the high-order features (HOFs) of blood test data can be used to predict the prognosis of patients with different types of cancer. Although the majority of blood HOFs can be divided into inflammatory or nutritional markers, there are still numerous that have not been classified correctly, with the same feature being named differently. It is an urgent need to reclassify the blood HOFs and comprehensively assess their potential for cancer prognosis. METHODS: Initially, a review of existing literature was conducted to identify the high-order features (HOFs) and classify them based on their calculation method. Subsequently, a cohort of patients diagnosed with non-small cell lung cancer (NSCLC) was established, and their clinical information prior to treatment was collected, including low-order features (LOFs) obtained from routine blood tests. The HOFs were then computed and their associations with clinical features were examined. Using the LOF and HOF data sets, a deep learning algorithm called DeepSurv was utilized to predict the prognostic risk values. The effectiveness of each data set's prediction was evaluated using the decision curve analysis (DCA). Finally, a prognostic model in the form of a nomogram was developed, and its accuracy was assessed using the calibration curve. RESULTS: From 1210 documents, over 160 blood HOFs were obtained, arranged into 110, and divided into three distinct categories: 76 proportional features, 6 composition features, and 28 scoring features. Correlation analysis did not reveal a strong association between blood features and clinical features; however, the risk value predicted by the DeepSurv LOF- and HOF-models is significantly linked to the stage. Results from DCA showed that the HOF model was superior to the LOF model in terms of prediction, and that the risk value predicted by the blood data model could be employed as a complementary factor to enhance the prognosis of patients. A nomograph was created with a C-index value of 0.74, which is capable of providing a reasonably accurate prediction of 1-year and 3-year overall survival for patients. CONCLUSIONS: This research initially explored the categorization and nomenclature of blood HOF, and proved its potential in lung cancer prognosis.

Neoadjuvant camrelizumab plus chemotherapy for locally advanced cervical cancer (NACI Study): a study protocol of a prospective, single-arm, phase II trial.

INTRODUCTION: Neoadjuvant chemotherapy (NACT) is an emerging approach for locally advanced cervical cancer (LACC). However, the clinical response and postoperative adjuvant radiation or chemoradiation trimodality treatment resulted in controversy. PD-1 inhibitors have shown promising role in recurrent or metastatic cervical cancer, and there is preclinical evidence of the activation and synergistic effects of NACT on PD-1 inhibitors. This study aims to evaluate the efficacy and safety of the preoperative PD-1 inhibitor camrelizumab combined with NACT for LACC. METHODS AND ANALYSIS: The study is designed as a multicentre, open-label, single-arm, prospective phase II study. A total of 82 patients will receive neoadjuvant chemo-immunotherapy, defined as one cycle of cisplatin (75-80 mg/m2, intravenously) plus nab-paclitaxel (260 mg/m2, intravenously) NACT and subsequent two cycles of camrelizumab (200 mg, intravenously) combined with NACT. After neoadjuvant chemo-immunotherapy, patients exhibiting complete response and partial response will undergo radical surgery and subsequent adjuvant therapy. In contrast, patients with stable disease and progressive disease will transfer to concurrent chemoradiotherapy (CCRT). Following surgery, patients will receive adjuvant CCRT or radiotherapy. The primary endpoint is the objective response rate. The secondary endpoints are the pathological complete response, patients requiring postoperative adjuvant therapy, safety of neoadjuvant chemo-immunotherapy, surgical complication, event-free survival, and overall survival. An additional aim is to dynamically evaluate peripheral immune responses and local immunological microenvironments and their association with neoadjuvant immunotherapy. ETHICS AND DISSEMINATION: This trial was approved by the Medical Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (S2020-112). This study is among the first to evaluate the efficacy and safety of neoadjuvant chemo-immunotherapy in LACC. The findings of this research will promote neoadjuvant anti-PD-1 immunotherapy with radical surgery as a new therapeutic strategy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04516616).

Ovarian hyperstimulation syndrome and pregnancy luteoma mimicking malignant ascites: a rare case report.

BACKGROUND: During pregnancy, both ovarian hyperstimulation syndrome (OHSS) and pregnancy luteoma could manifest as massive ascites, enlarged ovaries, or elevated serum levels of cancer antigen 125 (CA125), and atypical cells may be found in the ascitic fluid of OHSS patients. Whether this should be treated aggressively as peritoneal carcinomatosis is controversial. CASE PRESENTATION: A 35-year-old G2P1A1 woman with secondary infertility had a successful pregnancy after one cycle of assisted reproductive technology. The patient complained of lower abdominal distension, oliguria, and poor appetite 19 days after embryo transplantation. She was diagnosed with late-onset OHSS. Although the size of the ovaries decreased bilaterally to the normal range at 12 weeks of gestation after prompt medical care, the ascites increased again after an initial decreasing trend. Elevated serum levels of CA125 (191.1 IU/mL), and suspected adenocarcinoma cells were observed in the ascitic fluid. Although further magnetic resonance imaging examination or diagnostic laparoscopy was recommended, the patient was provided with supportive treatment and closely monitored upon her request. Surprisingly, her ascites diminished, and serum level of CA125 started to decline at 19 weeks of gestation. During cesarean section, pathological examination of the solid mass in the right ovary revealed pregnancy luteoma, which was presumably the other cause of the intractable ascites. CONCLUSIONS: Caution should be exercised in cases of suspicious malignant ascites during pregnancy. This may due to OHSS or pregnancy luteoma, in which abnormalities usually regress spontaneously.

Fertility and prognosis assessment between bleomycin/etoposide/cisplatin and paclitaxel/carboplatin chemotherapy regimens in the conservative treatment of malignant ovarian germ cell tumors: a multicenter and retrospective study.

OBJECTIVE: To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). METHODS: A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. RESULTS: We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. CONCLUSION: The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.