A core scientific problem in the treatment of central nervous system diseases: newborn neurons.

It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons. Yet over recent decades, numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system, including humans'. This has challenged the long-held scientific consensus that the number of adult neurons remains constant, and that new central nervous system neurons cannot be created or renewed. Herein, we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury, and describe novel treatment strategies that target endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury. Central nervous system injury frequently results in alterations of endogenous neurogenesis, encompassing the activation, proliferation, ectopic migration, differentiation, and functional integration of endogenous neural stem cells. Because of the unfavorable local microenvironment, most activated neural stem cells differentiate into glial cells rather than neurons. Consequently, the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function. Scientists have attempted to enhance endogenous neurogenesis using various strategies, including using neurotrophic factors, bioactive materials, and cell reprogramming techniques. Used alone or in combination, these therapeutic strategies can promote targeted migration of neural stem cells to an injured area, ensure their survival and differentiation into mature functional neurons, and facilitate their integration into the neural circuit. Thus can integration replenish lost neurons after central nervous system injury, by improving the local microenvironment. By regulating each phase of endogenous neurogenesis, endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons. This offers a novel approach for treating central nervous system injury.

Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer.

Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.

In Silico Insights into Micro-Mechanism Understanding of Extracts of Taxus Chinensis Fruits Against Alzheimer's Disease.

BACKGROUND: The taxus chinensis fruit (TCF) shows promises in treatment of aging-related diseases such as Alzheimer's disease (AD). However, its related constituents and targets against AD have not been deciphered. OBJECTIVE: This study was to uncover constituents and targets of TCF extracts against AD. METHODS: An integrated approach including ultrasound extractions and constituent identification of TCF by UPLC-QE-MS/MS, target identification of constituents and AD by R data-mining from Pubchem, Drugbank and GEO databases, network construction, molecular docking and the ROC curve analysis was carried out. RESULTS: We identified 250 compounds in TCF extracts, and obtained 3,231 known constituent targets and 5,326 differential expression genes of AD, and 988 intersection genes. Through the network construction and KEGG pathway analysis, 19 chemicals, 31 targets, and 11 biological pathways were obtained as core compounds, targets and pathways of TCF extracts against AD. Among these constituents, luteolin, oleic acid, gallic acid, baicalein, naringenin, lovastatin and rutin had obvious anti-AD effect. Molecular docking results further confirmed above results. The ROC AUC values of about 87% of these core targets of TCF extracts was greater than 0.5 in the two GEO chips of AD, especially 10 targets with ROC AUC values greater than 0.7, such as BCL2, CASP7, NFKBIA, HMOX1, CDK2, LDLR, RELA, and CCL2, which mainly referred to neuron apoptosis, response to oxidative stress and inflammation, fibroblast proliferation, etc.Conclusions:The TCF extracts have diverse active compounds that can act on the diagnostic genes of AD, which deserve further in-depth study.

MR radiomics predicts pathological complete response of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a multicenter study.

BACKGROUND: More than 40% of patients with resectable esophageal squamous cell cancer (ESCC) achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), who have favorable prognosis and may benefit from an organ-preservation strategy. Our study aims to develop and validate a machine learning model based on MR radiomics to accurately predict the pCR of ESCC patients after nCRT. METHODS: In this retrospective multicenter study, eligible patients with ESCC who underwent baseline MR (T2-weighted imaging) and nCRT plus surgery were enrolled between September 2014 and September 2022 at institution 1 (training set) and between December 2017 and August 2021 at institution 2 (testing set). Models were constructed using machine learning algorithms based on clinical factors and MR radiomics to predict pCR after nCRT. The area under the curve (AUC) and cutoff analysis were used to evaluate model performance. RESULTS: A total of 155 patients were enrolled in this study, 82 in the training set and 73 in the testing set. The radiomics model was constructed based on two radiomics features, achieving AUCs of 0.968 (95%CI 0.933-0.992) in the training set and 0.885 (95%CI 0.800-0.958) in the testing set. The cutoff analysis resulted in an accuracy of 82.2% (95%CI 72.6-90.4%), a sensitivity of 75.0% (95%CI 58.3-91.7%), and a specificity of 85.7% (95%CI 75.5-96.0%) in the testing set. CONCLUSION: A machine learning model based on MR radiomics was developed and validated to accurately predict pCR after nCRT in patients with ESCC.

Different macaque brain network remodeling after spinal cord injury and NT3 treatment.

Graph theory-based analysis describes the brain as a complex network. Only a few studies have examined modular composition and functional connectivity (FC) between modules in patients with spinal cord injury (SCI). Little is known about the longitudinal changes in hubs and topological properties at the modular level after SCI and treatment. We analyzed differences in FC and nodal metrics reflecting modular interaction to investigate brain reorganization after SCI-induced compensation and neurotrophin-3 (NT3)-chitosan-induced regeneration. Mean inter-modular FC and participation coefficient of areas related to motor coordination were significantly higher in the treatment animals than in the SCI-only ones at the late stage. The magnocellular part of the red nucleus may reflect the best difference in brain reorganization after SCI and therapy. Treatment can enhance information flows between regions and promote the integration of motor functions to return to normal. These findings may reveal the information processing of disrupted network modules.

Non-human primate models of focal cortical ischemia for neuronal replacement therapy.

Despite the high prevalence, stroke remains incurable due to the limited regeneration capacity in the central nervous system. Neuronal replacement strategies are highly diverse biomedical fields that attempt to replace lost neurons by utilizing exogenous stem cell transplants, biomaterials, and direct neuronal reprogramming. Although these approaches have achieved encouraging outcomes mostly in the rodent stroke model, further preclinical validation in non-human primates (NHP) is still needed prior to clinical trials. In this paper, we briefly review the recent progress of promising neuronal replacement therapy in NHP stroke studies. Moreover, we summarize the key characteristics of the NHP as highly valuable translational tools and discuss (1) NHP species and their advantages in terms of genetics, physiology, neuroanatomy, immunology, and behavior; (2) various methods for establishing NHP focal ischemic models to study the regenerative and plastic changes associated with motor functional recovery; and (3) a comprehensive analysis of experimentally and clinically accessible outcomes and a potential adaptive mechanism. Our review specifically aims to facilitate the selection of the appropriate NHP cortical ischemic models and efficient prognostic evaluation methods in preclinical stroke research design of neuronal replacement strategies.

[Progress in application of adult endogenous neurogenesis in brain injury repair].

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.

Neuronal differentiation and functional maturation of neurons from neural stem cells induced by bFGF-chitosan controlled release system.

Available methods for differentiating stem cells into neurons require a large number of cytokines and neurotrophic factors, with complex steps and slow processes, and are inefficient to produce functional neurons and form synaptic contacts, which is expensive and impractical in clinical application. Here, we demonstrated a bioactive material, basic fibroblast growth factor (bFGF)-chitosan controlled release system, for facilitating neuronal differentiation from NSCs and the functional maturation of the induced neurons with high efficiency. We illustrated by immunostaining that the neurons derived from NSCs expressed mature immunomarkers of interneurons and excitatory neurons. And we found by patch-clamp that the induced neurons exhibited diverse electrophysiological properties as well as formed functional synapses. In vivo, we implanted bFGF-chitosan into lesion area in traumatic brain injury (TBI) mice and similarly observed abundance of neuroblasts in SVZ and the presence of newborn functional neurons in injury area, which integrated into synaptic networks. Taken together, our efficient and rapid tissue engineering approach may be a potential method for the generation of functional neuronal lineage cells from stem cells and a therapy of brain injury and disease.

Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8+ T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China.

BACKGROUND: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8+ T cell in SCCE for the first time. MATERIALS AND METHODS: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. RESULTS: No patients had PD-L1 expressed in their tumor cells. PD-L1+ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68+ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (Ptrend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. CONCLUSION: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC.

BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.

Development and testing of a 2D offshore oil spill modeling tool (OSMT) supported by an effective calibration method.

An Oil Spill Modeling Tool (OSMT) has been developed in this study to predict the transport and fate of oil spills resulting from surface releases. Particularly, the Kullback-Leibler (KL) divergence method is adopted as a performance metric for the first time to formulate a calibration framework for spill trajectory prediction (STP) from the Lagrangian transport model (LTM). By finding the candidate with minimal KL divergences from modeling scenarios using designed parameter combinations, the prediction discrepancy between simulated trajectories of the LTM and oil slicks detected from satellite images is reduced. The developed approach has been evaluated through a comparison analysis between OSMT and Operational Oil Modeling Environment (GNOME) model. Subsequently, a real case study is conducted to examine the applicability and effectiveness of the OSMT. The study results indicate that OSMT can provide reliable spill trajectory simulations, and the KL divergence-based calibration method is effective in calibrating the oil spill LTM.

Breakdown of intention-based outcome evaluation after transient right temporoparietal junction deactivation.

People judge the nature of human behaviors based on underlying intentions and possible outcomes. Recent studies have demonstrated a causal role of the right temporoparietal junction (rTPJ) in modulating both intention and intention-based outcome evaluations during social judgments. However, these studies mainly used hypothetical scenarios with socially undesirable contexts (bad/neutral intentions and bad/neutral outcomes), leaving the role of rTPJ in judging good intentions and good outcomes unclear. In the current study, participants were instructed to make goodness judgments as a third party toward the monetary allocations from one proposer to another responder. Critically, in some cases, the initial allocation by the proposer could be reversed by the computer, yielding combinations of good/bad intentions (of the proposer) with good/bad outcomes (for the responder). Anodal (n = 20), cathodal (n = 21), and sham (n = 21) transcranial direct current stimulation (tDCS) over the rTPJ were randomly assigned to 62 subjects to further examine the effects of stimulation over the rTPJ in modulating intention-based outcome evaluation. Compared to the anodal and sham stimulations, cathodal tDCS over the rTPJ reduced the goodness ratings of good/bad outcomes when the intentions were good, whereas it showed no significant effect on outcome ratings under unknown and bad intentions. Our results provide the first evidence that deactivating the rTPJ modulates outcome evaluation in an intention-dependent fashion, mainly by reducing the goodness rating towards both good/bad outcomes when the intentions are good. Our findings argue for a causal role of the rTPJ in modulating intention-based social judgments and point to nuanced effects of rTPJ modulation.

Circuit reconstruction of newborn neurons after spinal cord injury in adult rats via an NT3-chitosan scaffold.

An implanted neurotrophin-3 (NT3)-chitosan scaffold can recruit endogenous neural stem cells to migrate to a lesion region and differentiate into mature neurons after adult spinal cord injury (SCI). However, the identities of these newborn neurons and whether they can form functional synapses and circuits to promote recovery after paraplegia remain unknown. By using combined advanced technologies, we revealed here that the newborn neurons of several subtypes received synaptic input from the corticospinal tract (CST), rubrospinal tract (RST), and supraspinal tracts. They formed a functional neural circuit at the injured spinal region, further driving the local circuits beneath the lesion. Our results showed that the NT3-chitosan scaffold facilitated the maturation of spinal neurons and the reestablishment of the spinal neural circuit in the lesion region 12 weeks after SCI. Transsynaptic virus experiments revealed that these newborn spinal neurons received synaptic connections from the CST and RST and drove the neural circuit beneath the lesion via newly formed synapses. These re-established circuits successfully recovered the formation and function of the neuromuscular junction (NMJ) beneath the lesion spinal segments. These findings suggest that the NT3-chitosan scaffold promotes the formation of relay neural circuits to accommodate various types of brain descending inputs and facilitate functional recovery after paraplegia.

Predicting pathological complete response of neoadjuvant radiotherapy and targeted therapy for soft tissue sarcoma by whole-tumor texture analysis of multisequence MRI imaging.

OBJECTIVES: To construct effective prediction models for neoadjuvant radiotherapy (RT) and targeted therapy based on whole-tumor texture analysis of multisequence MRI for soft tissue sarcoma (STS) patients. METHODS: Thirty patients with STS of the extremities or trunk from a prospective phase II trial were enrolled for this analysis. All patients underwent pre- and post-neoadjuvant RT MRI examinations from which whole-tumor texture features were extracted, including T1-weighted with fat saturation and contrast enhancement (T1FSGd), T2-weighted with fat saturation (T2FS), and diffusion-weighted imaging (DWI) sequences and their corresponding apparent diffusion coefficient (ADC) maps. According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) and non-pCR (N-pCR) groups. pCR was defined as less than 5% of residual tumor cells by postoperative pathology. Delta features were defined as the percentage change in a texture feature from pre- to post-neoadjuvant RT MRI. After data reduction and feature selection, logistic regression was used to build prediction models. ROC analysis was performed to assess the diagnostic performance. RESULTS: Five of 30 patients (16.7%) achieved pCR. The Delta_Model (AUC 0.92) had a better predictive ability than the Pre_Model (AUC 0.78) and Post_Model (AUC 0.76) and was better than AJCC staging (AUC 0.52) and RECIST 1.1 criteria (AUC 0.52). The Combined_Model (pre, post, and delta features) had the best predictive performance (AUC 0.95). CONCLUSION: Whole-tumor texture analysis of multisequence MRI can well predict pCR status after neoadjuvant RT and targeted therapy in STS patients, with better performance than RECIST 1.1 and AJCC staging. KEY POINTS: • MRI multisequence texture analysis could predict the efficacy of neoadjuvant RT and targeted therapy for STS patients. • Texture features showed incremental value beyond routine clinical factors. • The Combined_Model with features at multiple time points showed the best performance.

Proper wiring of newborn neurons to control bladder function after complete spinal cord injury.

Activation of endogenous neurogenesis by bioactive materials enables restoration of sensory/motor function after complete spinal cord injury (SCI) via formation of new relay neural circuits. The underlying wiring logic of newborn neurons in adult central nervous system (CNS) is unknown. Here, we report neurotrophin3-loaded chitosan biomaterial substantially recovered bladder function after SCI. Multiple neuro-circuitry tracing technologies using pseudorabies virus (PRV), rabies virus (RV), and anterograde adeno-associated virus (AAV), demonstrated that newborn neurons were integrated into the micturition neural circuits and reconnected higher brain centers and lower spinal cord centers to control voiding, and participated in the restoration of the lower urinary tract function, even in the absence of long-distance axonal regeneration. Opto- and chemo-genetic studies further supported the notion that the supraspinal control of the lower urinary tract function was partially recovered. Our data demonstrated that regenerated relay neurons could be properly integrated into disrupted long-range neural circuits to restore function of adult CNS.

Recognition of necrotic regions in MRI images of chronic spinal cord injury based on superpixel.

BACKGROUND AND OBJECTIVE: The cystic cavity and its surrounding dense glial scar formed in chronic spinal cord injury (SCI) hinder the regeneration of nerve axons. Accurate location of the necrotic regions formed by the scar and the cavity is conducive to eliminate the re-growth obstacles and promote SCI treatment. This work aims to realize the accurate and automatic location of necrotic regions in the chronic SCI magnetic resonance imaging (MRI). METHODS: In this study, a method based on superpixel is proposed to identify the necrotic regions of spinal cord in chronic SCI MRI. Superpixels were obtained by a simple linear iterative clustering algorithm, and feature sets were constructed from intensity statistical features, gray level co-occurrence matrix features, Gabor texture features, local binary pattern features and superpixel areas. Subsequently, the recognition effects of support vector machine (SVM) and random forest (RF) classification model on necrotic regions were compared from accuracy (ACC), positive predictive value (PPV), sensitivity (SE), specificity (SP), Dice coefficient and algorithm running time. RESULTS: The method is evaluated on T1- and T2-weighted MRI spinal cord images of 24 adult female Wistar rats. And an automatic recognition method for spinal cord necrosis regions was established based on the SVM classification model finally. The recognition results were 1.00±0.00 (ACC), 0.89±0.09 (PPV), 0.88±0.12 (SE), 1.00±0.00 (SP) and 0.88±0.07 (Dice), respectively. CONCLUSIONS: The proposed method can accurately and noninvasively identify the necrotic regions in MRI, which is helpful for the pre-intervention assessment and post-intervention evaluation of chronic SCI research and treatments, and promoting the clinical transformation of chronic SCI research.

Costimulatory molecule expression profile as a biomarker to predict prognosis and chemotherapy response for patients with small cell lung cancer.

Owing to the paucity of specimens, progress in identifying prognostic and therapeutic biomarkers for small cell lung cancer (SCLC) has been stagnant for decades. Considering that the costimulatory molecules are essential elements in modulating immune responses and determining therapeutic response, we systematically revealed the expression landscape and identified a costimulatory molecule-based signature (CMS) to predict prognosis and chemotherapy response for SCLCs for the first time. We found T cell activation was restrained in SCLCs, and costimulatory molecules exhibited widespread abnormal genetic alterations and expression. Using a LASSO Cox regression model, the CMS was built with a training cohort of 77 cases, which successfully divided patients into high- or low-risk groups with significantly different prognosis and chemotherapy benefit (both P < 0.001). The CMS was well validated in an independent cohort containing 131 samples with qPCR data. ROC and C-index analysis confirmed the superior predictive performance of the CMS in comparison with other clinicopathological parameters from different cohorts. Importantly, the CMS was confirmed as a significantly independent prognosticator for clinical outcomes and chemotherapy response in SCLCs through multivariate Cox analysis. Further analysis revealed that low-risk patients were characteristic by an activated immune phenotype with distinct expression of immune checkpoints. In summary, we firstly uncovered the expression heterogeneity of costimulatory molecules in SCLC and successfully constructed a novel predictive CMS. The identified signature contributed to more accurate patient stratification and provided robust prognostic value in estimating survival and the clinical response to chemotherapy, allowing optimization of treatment and prognosis management for patients with SCLC.

Comparison of the Clinicopathological Characteristics and Prognosis of Esophageal Squamous Cell Carcinoma with Intramural Metastases and Multiple Primary Carcinomas.

BACKGROUND: It is difficult to distinguish esophageal squamous cell carcinoma with intramural metastases (IM) from multiple primary oesophageal carcinoma (MPEC). Nevertheless, there are significant differences in their prognoses and treatments. Therefore, our study aims to clarify the clinicopathological and prognostic characteristics of these two entities and to provide clues for differential diagnosis. METHODS: We retrospectively analyzed 6304 patients who underwent esophagectomy without neoadjuvant therapy. The clinicopathological and prognostic features of patients with IM and MPEC were evaluated. P53 and Rb1 were detected by immunohistochemical (IHC) staining using a tissue microarray. RESULTS: Among the 6304 patients, 127 (2.0%) had IM, and 138 (2.2%) had MPEC. Patients with IM were more likely to have an advanced pT (p < 0.001), pN (p < 0.001), more lymphovascular invasion (p < 0.001) and neural invasion (p < 0.001). Additionally, patients with IM had an extremely poor prognosis compared to those with MPEC, with 5-year overall survival (OS) rates of 18.9% and 56.9%, respectively. Meanwhile, IM was found to be an independent poor prognostic indicator for OS and DFS. In the IM group, all patients showed consistent p53 expression in both primary and IM foci. Of note, Rb1 loss was found in 3 pairs of primary foci and metastases, along with p53 nonsense mutation. CONCLUSIONS: Patients with IM had more risk factors and extremely worse prognosis than those with MPEC. It is essential to discriminate IM from MPEC when managing multifocal carcinomas. IHC staining of p53 and Rb1 may aid in differential diagnosis.

Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.