Tumor Infiltration Research Articles

Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma

Adoptive cell therapy (ACT) using invitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and Tcell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon invitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.

Facteurs pronostiques : degré d’invasion de la sous-séreuse, distance tumeur-séreuse et invasion de la limitante élastique de la sous-séreuse dans l’adénocarcinome colique

The aim was to study the prognostic impact of tumor infiltration of the subserosa in colonic adenocarcinoma, by evaluating the degree of tumor infiltration in the subserosa (DISS), tumor-serosa distance (DTS), and invasion of the elastic boundary of the subserosa (ILE) after elastic fiber staining.Material and methods: All patients operated on for colonic adenocarcinoma classified as pT3 without lymph node or visceral metastasis operated on at CHU-Amiens between 2004 and 2017 were included. All slides were reviewed by 2 pathologists. Bivariate and subgroup analyses were performed according to the presence of a DISS ≤5 mm or >5mm, a DTS ≤1mm or >1mm and the presence or absence of an ILE. These statistical analyses were then correlated with 5-year survival.Results: 101 patients were included in the study. We performed elastic fiber staining on an average of 2 tumor blocks per case, and 39.6% of patients had invasion of the elastic boundary. However, bivariate and subgroup analyses showed no statistically significant association between DISS, DTS or ILE and 5-year survival.Conclusion: None of these three histological criteria proved to have prognostic value in our series, contrary to some results in the literature. However, as these data are subject to a number of confounding factors, we do not recommend that pathologists specify these different criteria in their reports.

Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report

BackgroundAcute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs.Case presentationThis is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made.ConclusionsRenal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed.

CD25+FOXP3+CD45RA− regulatory T-cell infiltration as a prognostic biomarker for endometrial carcinoma

BackgroundRegulatory T (Treg) cells reportedly play crucial roles in tumor angiogenesis as well as antitumor immunity. In order to explore their therapeutic potential, we investigated the precise prognostic impact of Treg markers in endometrial carcinoma.MethodsWe performed multiplexed immunofluorescence and quantitative image analyses of CD25, FOXP3, CTLA4, and CD45RA in tumor specimens from 176 consecutive patients treated at our institution for primary endometrial carcinomas. Bioinformatics analyses were further conducted to corroborate the findings.ResultsHigh CD25+, FOXP3+, and CD25+FOXP3+CD45RA− stromal cell counts correlated with better overall survival (OS) (p = 0.00019, 0.028 and 0.0012) and MSI-high (p = 0.015, 0.016 and 0.047). High CD45RA+ stromal cell count was associated with superficial myometrial invasion (p = 0.0038). Bioinformatics survival analysis by Kaplan-Meier plotter showed that high CD25, FOXP3, CTLA4, and CD45RA mRNA expressions correlated with better OS (p = 0.046, 0.00042, 0.000044, and 0.0022). Univariate and multivariate analyses with various clinicopathologic prognostic factors indicated that high CD25+ or CD25+FOXP3+CD45RA− stromal cell count was significant and independent for favorable OS (p = 0.0053 and 0.0015). We subsequently analyzed the correlations between the multiplexed immunofluorescence results and treatment-free interval (TFI) after primary chemotherapy in recurrent cases, finding no significant associations. Further analysis revealed that high ratio of CD25+ : CD8+ cell count or CD25+FOXP3+CD45RA− : CD8+ cell count correlated with longer TFI (p = 0.021 and 0.021).ConclusionThe current observations suggest that the balance between CD25+ or CD25+FOXP3+CD45RA− cells and CD8+ cells, corresponding to promoting or inhibiting effect on tumor angiogenesis, affect tumor chemosensitivity leading to prognostic significance. CD25+FOXP3+CD45RA− effector Treg tumor infiltration may serve as a useful prognostic biomarker and a potential target for immunotherapeutic manipulation of tumor chemosensitivity by novel management for advanced/recurrent endometrial carcinomas.

Lymphedema of the Head and Neck-Where Do We Stand and Where We Are Headed.

Great advancements have been made in the management of lymphedema of the extremities with lymphatic surgery. However, lymphedema of other regions, including head and neck, has remained neglected. Recent discovery of lymphatic system in the brain and the communication between intracranial and paracranial lymphatic systems has drawn attention to the head and neck lymphatics. Lymphedema of the head and neck region can result from inherent abnormality of the lymphatic system (primary) or be caused by accidental or iatrogenic injury to lymphatics (secondary). The head and neck contain a large network of lymphatic tissue. They may be affected by direct tumor infiltration, surgical resection of tumors and surrounding cancer tissue, and/or radiotherapy. Proper screening and counseling of patients before facial aesthetic procedures may avoid managing the distress of lymphedema postprocedure. Progression of head and neck lymphedema (HNL) can lead to chronic inflammatory, fibrosclerotic, and fibrofatty deposition, resulting in permanent deformity and disability. Patients may experience functional impairment, including skin changes, pain, range of motion limitations, contracture, dysphagia, dysarthria, dyspnea, and trismus, all leading to reduced quality of life. Despite these known disabilities, HNL is underdiagnosed due to a lack of awareness about this entity and of tools available for measuring internal or external swelling. The authors' article comprehensively reviews the current diagnostic methods and management strategies and what lies ahead.

Dynamic changes in immune cells in humanized liver metastasis and subcutaneous xenograft mouse models

Preclinical drug efficacy and tumor microenvironment (TME) investigations often utilize humanized xenograft mouse models, yet these models typically fall short in replicating the intricate TME. We developed a humanized liver metastasis (LM) model by transplanting human peripheral blood mononuclear cells (PBMCs) and assessed it against the conventional subcutaneous (SC) xenograft model, focusing on immune cell dynamics post-transplantation and immunotherapy response. NOD-scid IL2Rgammanull(NSG) were inoculated with PBMCs to create humanized models. We induced SC and LM models using HCT116 cells, to investigate and compare the distributions and transformations of immune cell subsets, respectively. Both models were subjected to anti-PD-L1 therapy, followed by an analysis the TME analysis. The LM model demonstrated enhanced central tumor infiltration by tumor-infiltrating lymphocytes (TILs) compared to the peripheral pattern of SC model. TIL subpopulations in the LM model showed a progressive increase, contrasting with an initial rise and subsequent decline in the SC model. Post-anti-PD-L1 therapy, the LM model exhibited a significant rise in central and effector memory T cells, a response absents in the SC model. Our study highlights differential TME responses between SC and LM models and introduces a robust humanized LM model that swiftly indicates the potential efficacy of immunotherapies. These insights could streamline the preclinical evaluation of TME-targeting immunotherapeutic agents.

CT-based radiomics nomogram to predict proliferative hepatocellular carcinoma and explore the tumor microenvironment

BackgroundProliferative hepatocellular carcinomas (HCCs) is a class of aggressive tumors with poor prognosis. We aimed to construct a computed tomography (CT)-based radiomics nomogram to predict proliferative HCC, stratify clinical outcomes and explore the tumor microenvironment.MethodsPatients with pathologically diagnosed HCC following a hepatectomy were retrospectively collected from two medical centers. A CT-based radiomics nomogram incorporating radiomics model and clinicoradiological features to predict proliferative HCC was constructed using the training cohort (n = 184), and validated using an internal test cohort (n = 80) and an external test cohort (n = 89). The predictive performance of the nomogram for clinical outcomes was evaluated for HCC patients who underwent surgery (n = 201) or received transarterial chemoembolization (TACE, n = 104). RNA sequencing data and histological tissue slides from The Cancer Imaging Archive database were used to perform transcriptomics and pathomics analysis.ResultsThe areas under the receiver operating characteristic curve of the radiomics nomogram to predict proliferative HCC were 0.84, 0.87, and 0.85 in the training, internal test, and external test cohorts, respectively. The radiomics nomogram could stratify early recurrence-free survivals in the surgery outcome cohort (hazard ratio [HR] = 2.25; P < 0.001) and progression-free survivals in the TACE outcome cohort (HR = 2.21; P = 0.03). Transcriptomics and pathomics analysis indicated that the radiomics nomogram was associated with carbon metabolism, immune cells infiltration, TP53 mutation, and heterogeneity of tumor cells.ConclusionThe CT-based radiomics nomogram could predict proliferative HCC, stratify clinical outcomes, and measure a pro-tumor microenvironment.

540. INFILTRATION OF RESECTED OESOPHAGEAL ADENOCARCINOMA WITH ANTIGEN-EXPERIENCED PD-1 AND CD39 POSITIVE CD8+ TISSUE RESIDENT MEMORY CELLS CORRELATE WITH IMPROVED SURVIVAL

Abstract Background The development of novel treatments for oesophageal adenocarcinoma (OAC) represents an area of significant unmet need. Despite the application of immune checkpoint blockade alongside chemotherapy as standard of care for some patients with metastatic OAC, responses to immunotherapies are modest and 5-year survival is 17%. The reasons for this remains unclear and while tumour infiltration with CD8+ T lymphocytes (TILs) at the time of resection is associated with improved outcomes, this heterogeneous population remains incompletely characterised in OAC. Tissue resident memory cells (TRM) are increasingly understood as key mediators of immunotherapy response but their role in OAC is poorly understood. Methods Tumour samples were accessed by punch biopsy from the central portion of cancers resected from 44 patients undergoing curative surgery for OAC. Samples were assessed by multi-parametric flow cytometry for the presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of antigen-experienced PD-1 and CD39 positive CD8+ OAC TILs were sorted, and bulk RNA sequencing (RNAseq) undertaken using a modified SmartSeq2 protocol allowing differential gene expression analysis and gene set enrichment analysis. Flow cytometric assessment of functionality was completed. Results Resected OAC are often highly infiltrated with antigen experienced CD8+ TILs expressing high levels of PD-1 and CD39 and an abundance of this population correlates with improved survival (%PD-1/CD39+ &amp;gt;Median, OS HR 0.12). RNAseq of sorted TILs identified this PD-1+ and CD39+ lymphocyte population as enriched for precursor exhausted-like CD8+ TRM (NES 2.01 p=0.00). This is correlated by their CD103+ and TIM3- predominance on flow cytometry in keeping with TRMsassociated with immunotherapy response in other cancers. This population demonstrated a maintained proliferative potential, an ability to degranulate and produce the key effector molecules IFN-γ, TNF-α and Granzyme B. Conclusions An abundance of a PD-1 and CD39 positive CD8+ TIL population, consistent with a precursor exhausted-like TRM population with maintained proliferative and functional capacity, is observed to correlate with improved outcomes following curative surgery for OAC. This TRM population is consistent with analogous populations observed to be responsible for immunotherapy response in other cancers and their identification may predict benefit from such approaches in OAC and allow better patient selection for treatment with immune checkpoint inhibitors.

Intraoperative confocal laser endomicroscopy during 5-aminolevulinic acid-guided glioma surgery: significant considerations for resection at the tumor margin.

Because gliomas have poorly defined tumor margins, the ability to achieve maximal resection is limited. To better discern these margins, fluorescence-guided surgery has been used to aid maximal safe resection. The authors describe their experience with the simultaneous use of intraoperative fluorescein sodium (FNa) confocal laser endomicroscopy (CLE) and operating microscope 5-aminolevulinic acid (5-ALA) fluorescence imaging for glioma resection to improve CLE use for better margin discrimination. FNa CLE and 5-ALA wide-field imaging were used in 33 patients with gliomas. CLE imaging was enhanced with the use of a telesurgical pathology software platform that enables real-time conversation between the operating neurosurgeons and the pathologists located remotely. CLE was used for imaging tumor regions that were subjectively regarded as tumor margins under normal visualization with the operative microscope. After FNa CLE imaging, 5-ALA wide-field imaging was performed in the same regions. Tissue was biopsied at imaging locations, and interpretations of FNa CLE and 5-ALA wide-field imaging were compared to those of permanent histological sections. Eighty-eight deep- and superficial-margin regions of interest (ROIs) were imaged with FNa CLE and 5-ALA imaging. Most of the ROIs interpreted by the neuropathologist as infiltrative glioma based on FNa CLE imaging lacked 5-ALA-induced fluorescence. Permanent histological sections from the corresponding regions were concordant with the interpretation of FNa CLE images in 57 of 88 (65%) ROIs and with the interpretation of 5-ALA imaging in 43 of 88 (49%) ROIs. The sensitivity and specificity of FNa CLE for the interpretation of tumor margins were 73% and 41%, respectively, and those of 5-ALA were 38% and 82%, respectively. Positive and negative predictive values for CLE were 79% and 33%, respectively, and those for 5-ALA were 86% and 31%, respectively. Conventional intraoperative evaluation of tumor margins, based on MRI and wide-field fluorescence imaging, can underestimate the invasiveness of gliomas. FNa CLE showed higher accuracy in detecting regions with infiltrating tumors than intraoperative 5-ALA imaging. Future considerations should include more rigorous comparisons of FNa CLE imaging and 5-ALA-guided resections on a larger cohort of patients.

Deep Learning Segmentation of Infiltrative and Enhancing Cellular Tumor at Pre- and Posttreatment Multishell Diffusion MRI of Glioblastoma.

Purpose To develop and validate a deep learning (DL) method to detect and segment enhancing and nonenhancing cellular tumor on pre- and posttreatment MRI scans in patients with glioblastoma and to predict overall survival (OS) and progression-free survival (PFS). Materials and Methods This retrospective study included 1397 MRI scans in 1297 patients with glioblastoma, including an internal set of 243 MRI scans (January 2010 to June 2022) for model training and cross-validation and four external test cohorts. Cellular tumor maps were segmented by two radiologists on the basis of imaging, clinical history, and pathologic findings. Multimodal MRI data with perfusion and multishell diffusion imaging were inputted into a nnU-Net DL model to segment cellular tumor. Segmentation performance (Dice score) and performance in distinguishing recurrent tumor from posttreatment changes (area under the receiver operating characteristic curve [AUC]) were quantified. Model performance in predicting OS and PFS was assessed using Cox multivariable analysis. Results A cohort of 178 patients (mean age, 56 years ± 13 [SD]; 116 male, 62 female) with 243 MRI timepoints, as well as four external datasets with 55, 70, 610, and 419 MRI timepoints, respectively, were evaluated. The median Dice score was 0.79 (IQR, 0.53-0.89), and the AUC for detecting residual or recurrent tumor was 0.84 (95% CI: 0.79, 0.89). In the internal test set, estimated cellular tumor volume was significantly associated with OS (hazard ratio [HR] = 1.04 per milliliter; P < .001) and PFS (HR = 1.04 per milliliter; P < .001) after adjustment for age, sex, and gross total resection (GTR) status. In the external test sets, estimated cellular tumor volume was significantly associated with OS (HR = 1.01 per milliliter; P < .001) after adjustment for age, sex, and GTR status. Conclusion A DL model incorporating advanced imaging could accurately segment enhancing and nonenhancing cellular tumor, distinguish recurrent or residual tumor from posttreatment changes, and predict OS and PFS in patients with glioblastoma. Keywords: Segmentation, Glioblastoma, Multishell Diffusion MRI Supplemental material is available for this article. © RSNA, 2024.

802. TECHNICAL DETAILS: FREE JEJUNAL GRAFT AND REVERSE SAPHENOUS VEIN GRAFT FOR RECONSTRUCTION AFTER TOTAL PHARYNGO-LARYNGECTOMY AND PROXIMAL ESOPHAGECTOMY

Abstract Background We would like to show our tips for free jejunal graft and vascular reconstruction after pharyngo-laryngectomy and proximal esophagectomy. Methods 65 years-old man with history of hypopharynx squamous cell carcinoma cT3 cN0 cM0 who underwent radical Qt/Rt with initially complete response. After 2 years follow-up, he presented dysphagia and recurrence of squamous cell carcinoma proven by histology. Upper endoscopy shows cervical esophageal stenosis due to tumor infiltration. Rescue surgery was decided after systemic dissemination was ruled out with PET-CT. Results Pharyngo-laryngectomy, total thyroidectomy and proximal esophagectomy was performed. Free margin tumor was confirmed by frozen section. Jejunal segment with adequate vascular supply is selected, preferable with a single artery and vein. Peristaltic direction of the jejunum is marked to avoid mistakes during graft transposition. Division of mesenteric branches to prevent postoperative bleeding. Before jejunal section we recommend administration of hyoscine butilbromide 20 mg iv to avoid jejunal spams. Measuring the length graft needed before dividing the jejunum to avoid redundant or short graft is recommended. We must carefully isolate the pedicle avoiding damaging blood supply. To reduce time of ischemia, jejunal graft pedicle should not be ligated until cervical dissection is completed and we have ruled out if venous graft may be needed. After cervical artery and vein dissection, we ensure adequate blood flow and heparinize vessels before clipping. When dividing the pedicle, artery should be divided before the vein to avoid venous congestion, posteriorly we must heparinize the vessels. Povidone-iodine intraluminal washing is recommended. Jejuno-jejunal anastomosis for GI tract restoration. GI reconstruction first is recommended to avoid unnecessary traction on the vascular anastomosis. After ensuring adequate direction of the jejunal graft jejuno-esophageal anastomosis is performed with interrupted suture. Pharyngo-jejunal anastomosis is performed with barbed 3-0 running suture for anterior and posterior layer. Methylene blue test is performed for check the anastomosis. Vascular reconstruction technique depends on the vascular anatomical variations and availability. In this case, superior thyroid artery and sublingual vein were available. Saphenous vein graft might be needed, this graft must be used in reverse way to avoid the vein valves and length must be adjusted. Venous anastomosis should be performed before than arterial reconstruction after heparinize solution in both vessels to avoid thrombosis. Conclusion Free jejunal graft is a highly complex procedure that must be extremely coordinated and protocolized to avoid longer time of ischemia and risk of thrombosis that might compromise the graft viability. https://1drv.ms/v/s!AmFrct07P6MP1Fbyh_7Ce_OK5bB8?e=OMSjsK

Colon-specific controlled release of oral liposomes for enhanced chemo-immunotherapy against colorectal cancer

A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer. However, the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location, and intratumoral accumulation remains unsatisfactory. Here, an oral colon-specific drug delivery system (CBS-CS@Lipo/Oxp/MTZ) was constructed by covalently conjugating Clostridium butyricum spores (CBS) with drugs loaded chitosan (CS)-coated liposomes, where the model chemotherapy drug oxaliplatin (Oxp) and anti-anaerobic bacteria agent metronidazole (MTZ) were loaded. Following oral administration, CBS germinated into Clostridium butyricum (CB) and colonized in the colon. Combined with colonic specifically β-glucosidase responsive degrading of CS, dual colon-specific release of liposomes was achieved. And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold. Simultaneously, the released liposomes penetrated deep tumor tissue via the permeation enhancement effect of CS to kill localized intratumoral bacteria. Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB, the intratumoral pathogenic bacteria were eliminated fundamentally, blocking their recruitment to immunosuppressive cells. Furtherly, synchronized with lipopolysaccharide (LPS) released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells, they jointly enhanced tumor infiltration of CD8+ T cells and reactivated robust antitumor immunity.

Tumor cell membrane biomimetic liposomes-coated oncolytic viruses to target the homotypic tumor and augment the antitumor efficacy

Though oncolytic viruses (OVs) hold significant potential for comprehensive treatment of malignant tumors, their systemic administration faces substantial challenges such as insufficient circulation time, inadequate tumor targeting, and spontaneous antiviral immune response of the body, which seriously limits the clinical application of OVs. Herein, we proposed a tumor targeting strategy of tumor cell membrane biomimetic liposomes to encapsulate OVs for intravenous delivery, which enables OVs to target the homotypic tumor lesions and exert their oncolytic effect. On the one hand, this cell membrane biomimetic carrier enhanced the encapsulation of OVs by the hybrid lipid membranes, concealed the viral capsid proteins, and diminished the neutralization and clearance of the virions from the bloodstream. On the other hand, enhanced tumor targeted delivery can be achieved through the utilization of homologous adhesion molecules on the surface of tumor cell membrane. In addition, this strategy also promoted the tumor infiltration of CD4+, CD8+ T cells mediated by the oncolytic effect of OVs and increased the levels of inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the tumor, thereby effectively enhancing the anti-tumor effect of intravenous administration of OVs. The findings of our study demonstrate that T-L@Ad11 offers a handy and efficient approach for targeting tumors, thereby enhancing the antitumor efficacy of intravenous administration of OVs.

794. RETROSPECTIVE ANALYSIS OF CLINICAL CHARACTERISTICS AND PROGNOSIS OF SYNCHRONOUS MULTIPLE PRIMARY ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Multiple primary esophageal squamous cell carcinoma (MPESCC) is a rare and complex type of esophageal cancer, categorized into synchronous multiple primary esophageal squamous cell carcinoma (S-MPESCC) and metachronous multiple primary esophageal squamous cell carcinoma (M-MPESCC). Compared to solitary esophageal squamous cell carcinoma (SESCC), multiple primary esophageal squamous cell carcinoma (MPESCC) generally has a poorer prognosis, with significant differences in treatment strategies and survival outcomes. This study aims to explore the clinical characteristics and prognosis of S-MPESCC through a retrospective analysis of a large patient cohort. Methods This study retrospectively analyzed clinical data from 758 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgical resection at two medical centers in China from January 2012 to December 2021. The S-MPESCC group included 68 patients, and the SESCC group included 690 patients. All patients underwent radical esophagectomy with systematic lymph node dissection. Preoperative and postoperative data were collected, including gender, age, family history, tumor staging, and lymph node metastasis. Results There were no significant differences in baseline characteristics, such as gender, age, and family history, between the S-MPESCC and SESCC groups. The lymph node metastasis rate was significantly higher in the S-MPESCC group compared to the SESCC group, especially in the upper mediastinal and abdominal regions (P&amp;lt;0.05). Survival status was monitored through outpatient visits and telephone calls until December 2022. The results showed that the 3-year and 5-year survival rates of the S-MPESCC group were significantly lower than those of the SESCC group (P&amp;lt; 0.05). Patients with a greater depth of primary tumor infiltration had poorer survival outcomes in the S-MPESCC group. Conclusion This study clarified the clinical characteristics and prognosis of S-MPESCC through a retrospective analysis of 758 ESCC patients. S-MPESCC patients had a significantly higher rate of lymph node metastasis and a poorer prognosis compared to SESCC patients. Future efforts should focus on optimizing treatment strategies to improve the prognosis and survival rates of patients with S-MPESCC.

Biomimetic copper-containing nanogels for imaging-guided tumor chemo-chemodynamic-immunotherapy

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T1-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. Statement of significanceDeveloping multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T1-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Polypyrrole/iron-glycol chitosan nanozymes mediate M1 macrophages to enhance the X-ray-triggered photodynamic therapy for bladder cancer by promoting antitumor immunity

X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive iron-glycol chitosan-polypyrrole nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with potentially high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers.

Potential Impact of Omega 6/3 Ratio and CD68+ Macrophage Infiltration on Survival in NSCLC Patients Undergoing Pulmonary Resection.

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide with non-small cell lung cancer (NSCLC) accounting for the majority of cases. The stage of detection significantly influences survival rates with early-stage diagnosis offering the best prognosis. This study investigates the prognostic impact of the omega-6/omega-3 ratio and tumor infiltration by CD8+ lymphocytes and CD68+ macrophages on overall survival (OS) and disease-free survival (DFS) in NSCLC patients undergoing pulmonary resection. Methods: We conducted a retrospective analysis of 53 patients with early-stage NSCLC who underwent pulmonary resection between September 2017 and January 2020. The omega-6/omega-3 ratio was quantified using gas chromatography and spectrometry. Tumor infiltration by CD8 and CD68 was assessed through immunohistochemistry. Survival outcomes were evaluated using Kaplan-Meier and Cox regression analyses. Results: An increased omega-6/omega-3 ratio and higher CD68+ macrophage infiltration were associated with a trend towards worse OS and DFS in NSCLC patients, though these results did not reach statistical significance. CD8+ T-cell infiltration was associated with improved survival outcomes, confirming its role as a favorable prognostic marker. Comparative analysis with existing datasets revealed similar demographic and clinical characteristics, reinforcing the generalizability of our findings. Conclusions: The omega-6/omega-3 ratio and CD68+ macrophage infiltration serve as important factors potentially influencing prognosis in NSCLC patients undergoing pulmonary resection. These findings highlight the need for further research to refine the prognostic utility of these biomarkers and to explore therapeutic strategies targeting inflammation and immune cell infiltration.

Predicting peritumoral glioblastoma infiltration and subsequent recurrence using deep-learning-based analysis of multi-parametric magnetic resonance imaging.

Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

A pan-cancer analysis of the association of METRN with prognosis and immune infiltration in human tumors

BackgroundMeteorin (METRN) is expressed predominantly in the central nervous system (CNS), where it functions by regulating glial cell differentiation and promoting axonal elongation. Nonetheless, its function within tumors is still not well understood. In this study, we focused on investigating its expression across various cancers and delving deeper into how METRN expression correlates with prognosis and immune infiltration. MethodsWe explored METRN expression patterns in pan-cancers utilizing data obtained from the UCSC Xena and TCGA. In addition, analyses of survival and clinical association were conducted for tumors where METRN could affect the prognosis. Subsequently, nomogram models were constructed for sarcoma (SARC) and prostate adenocarcinoma (PRAD) to verify METRN's prognostic value in tumors. Furthermore, we also discussed the link between METRN and immune infiltration. As far as mechanisms are concerned, functional enrichment analysis was conducted to analyze the functional components and signaling pathways involved in METRN. ResultsThis study found that METRN was abnormally expressed in various tumors, closely connected with the prognosis and clinical characteristics of several tumors, and had good prognostic value. Moreover, analysis of immune infiltration revealed that METRN interacts with multiple immune cells, with alterations in the immune microenvironment potentially influencing tumor prognosis. Enrichment analysis indicates that METRN may influence tumorigenesis and progression through immune-related pathways. ConclusionTo sum up, our study demonstrates that METRN can be a prospective predictive biomarker in diverse cancer types and a promising target for cancer immunotherapy for pan-cancer.

Tumor budding and complete epithelial mesenchymal transition correlate with late nodal metastasis in early-stage tongue squamous cell carcinoma

BackgroundLate nodal metastasis is a poor prognostic factor for early-stage tongue squamous cell carcinoma. However, for most early-stage patients, there is a low risk for late nodal metastasis, which currently lacks a diagnostic marker. Tumor budding is a nodal metastasis risk factor in other human cancers. Here, we evaluated tumor budding by partial or complete epithelial-mesenchymal transition and Ovol2 expression, a transcription factor that directly suppresses epithelial-mesenchymal transition. MethodsSixty-six T1–2N0 patients were enrolled in this retrospective study. Tumor expressions of E-cadherin and vimentin (epithelial-mesenchymal transition markers) and Ovol2 were assessed by immunohistochemistry. Tumor histopathological and immunohistochemical features, mode of invasion, and tumor budding were assessed. Correlations between these potential predictive factors and late nodal metastasis were determined statistically. ResultsUnivariate analysis demonstrated lymphoid infiltrate, perineural invasion, infiltrative growth pattern, tumor budding, vimentin positive, and complete epithelial-mesenchymal transition were significant factors of late nodal metastasis (all P < 0.05), observed in 25.8 % of patients. Multivariate analysis identified tumor budding and vimentin positive were independent prognostic factors (both P < 0.025). Ovol2 expression was significantly decreased in partial and complete epithelial-mesenchymal transition cells (both P < 0.01) compared with normal epithelia. Univariate analysis, but not multivariate analysis, showed Ovol2 correlated with depth of invasion and tumor budding (both P < 0.05). ConclusionTumor budding and vimentin expression are risk factors for late nodal metastasis in T1–2N0 tongue squamous cell carcinoma. Ovol2 might be involved in the early stages of epithelial-mesenchymal transition. Evaluation of these factors might identify patients susceptible to late nodal metastasis who require elective neck dissection.