Primary intraosseous papillary intralymphatic angioendothelioma of the distal femoral epiphysis: a case report with literature review.

INTRODUCTION: Papillary intralymphatic angioendothelioma (PILA) is an exceptionally rare metastasizing soft tissue tumor. It tends to arise in the subcutaneous tissues of distal extremities in children. Only four intraosseous PILA cases have been reported until now in English language literature. CASE REPORT: We present a case of PILA arising in the distal femoral epiphysis of a 50-year-old female patient. It started as a relentless pain in her left knee. A plain radiography revealed a radiolucent area in the left internal femoral condyle. Computerized tomography revealed a 1-cm lytic lesion with a sclerotic rim. Magnetic resonance images showed a significant bone marrow edema signal focused on a 1-cm subchondral lesion suggestive of an intraarticular osteoid osteoma. Histologically, the tumor contained vascular channels covered by a single endothelial layer with intraluminal papillary endothelial structures lined with hobnail cells. Immunohistochemically, the cells were positive for ERG, CD31, and D2-40. The tumor underwent cryoablation and 6 months later, after local recurrence or tumor persistence, a wide tumor resection was referred. After 7 years of follow-up, the patient displayed neither local recurrence nor distant metastases. CONCLUSION: Primary intraosseous PILAs are exceedingly rare tumors that should be considered in the differential diagnosis of vascular bone tumors.

Detection and Characterization of Clonal Hematopoiesis.

Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cell clones resulting from the acquisition of somatic point mutations or mosaic chromosomal alterations (mCAs). It is linked to adverse systemic effects, including hematologic malignancies, cardiovascular diseases, metabolic disorders, as well as liver and kidney ailments, ultimately contributing to elevated overall mortality.Given its diverse biological and clinical implications, the identification of clonal hematopoiesis holds significance in various contexts. While traditionally centered on mutations associated with myeloid malignancies, stem/progenitor cell involvement has been documented for various lymphoid malignancies, including T-cell lymphoma, chronic lymphocytic leukemia (CLL), and follicular lymphoma (FL). Lymphoid CH (L-CH) involves a broader spectrum of genes and occurs at a lower prevalence, resulting in reduced mutation prevalences per gene. This characteristic poses challenges for efficient CH detection.The major strategies to identify CH are whole exome sequencing (WES), whole genome sequencing (WGS), or targeted sequencing. Targeted sequencing allows for much higher sequencing depth compared to WES and WGS because of the focus on genes known to be associated with CH and therefore allows detecting potential variants at low frequencies with high precision. Here, we describe an error-corrected targeted sequencing approach for detection of CH in bone marrow (BM) or peripheral blood (PB) samples, which we have successfully established and used in various cohorts. This protocol includes the process of DNA isolation from PB and BM samples, library preparation with molecular tags including quality control steps and computational analysis including variant filtering.

Two-color fluorescence-guided surgery for head and neck cancer resections.

Significance: Head and neck squamous cell carcinoma (HNSCC) has the sixth highest incidence worldwide, with > 650,000 cases annually. Surgery is the primary treatment option for HNSCC, during which surgeons balance two main goals: (1) complete cancer resection and (2) preservation of normal tissues to ensure post-surgical quality of life. Unfortunately, these goals are not synergistic, where complete cancer resection is often limited by efforts to preserve normal tissues, particularly nerves, and reduce life-altering comorbidities. Aim: Currently, no clinically validated technology exists to enhance intraoperative cancer and nerve recognition. Fluorescence-guided surgery (FGS) has successfully integrated into clinical medicine, providing surgeons with real-time visualization of important tissues and complex anatomy, where FGS imaging systems operate almost exclusively in the near-infrared (NIR, 650 to 900 nm). Notably, this spectral range permits the detection of two NIR imaging channels for spectrally distinct detection. Approach: Herein, we evaluated the utility of spectrally distinct NIR nerve- and tumor-specific fluorophores for two-color FGS to guide HNSCC surgery. Using a human HNSCC xenograft murine model, we demonstrated that facial nerves and tumors could be readily differentiated using these nerve- and tumor-specific NIR fluorophores. Results: The selected nerve-specific fluorophore showed no significant difference in nerve specificity and off-target tissue fluorescence in the presence of xenograft head and neck tumors. Co-administration of two NIR fluorophores demonstrated successful tissue-specific labeling of nerves and tumors in spectrally distinct NIR imaging channels. Conclusions: We demonstrate a comprehensive FGS tool for cancer resection and nerve sparing during HNSCC procedures for future clinical translation.

Abdominal MR Multitasking for radiotherapy treatment planning: A motion-resolved and multicontrast 3D imaging approach.

PURPOSE: Radiotherapy treatment planning (RTP) using MR has been used increasingly for the abdominal site. Multiple contrast weightings and motion-resolved imaging are desired for accurate delineation of the target and various organs-at-risk and patient-tailored planning. Current MR protocols achieve these through multiple scans with distinct contrast and variable respiratory motion management strategies and acquisition parameters, leading to a complex and inaccurate planning process. This study presents a standalone MR Multitasking (MT)-based technique to produce volumetric, motion-resolved, multicontrast images for abdominal radiotherapy treatment planning. METHODS: The MT technique resolves motion and provides a wide range of contrast weightings by repeating a magnetization-prepared (saturation recovery and T2 preparations) spoiled gradient-echo readout series and adopting the MT image reconstruction framework. The performance of the technique was assessed through digital phantom simulations and in vivo studies of both healthy volunteers and patients with liver tumors. RESULTS: In the digital phantom study, the MT technique presented structural details and motion in excellent agreement with the digital ground truth. The in vivo studies showed that the motion range was highly correlated (R2 = 0.82) between MT and 2D cine imaging. MT allowed for a flexible contrast-weighting selection for better visualization. Initial clinical testing with interobserver analysis demonstrated acceptable target delineation quality (Dice coefficient = 0.85 ± 0.05, Hausdorff distance = 3.3 ± 0.72 mm). CONCLUSION: The developed MT-based, abdomen-dedicated technique is capable of providing motion-resolved, multicontrast volumetric images in a single scan, which may facilitate abdominal radiotherapy treatment planning.

Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy.

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

A pancreatic cancer organoid incorporating macrophages reveals the correlation between the diversity of tumor-associated macrophages and cancer cell survival.

Pancreatic ductal adenocarcinoma (PDAC) is a progressive cancer with a poor prognosis. It contains a complex tumor microenvironment (TME) that includes various stromal cell types. Comprehending cellular communications within the TME is difficult due to a lack of research models that can recapitulate human PDAC-TME. Previously, we recapitulated, in part, the PDAC-TME containing a diversity of cancer-associated fibroblasts (CAFs) in vitro. This was done by establishing a PDAC organoid by co-culturing patient-derived cancer cells with human induced pluripotent stem cell (hiPSC)-derived mesenchymal and endothelial cells, which was designated the fused pancreatic cancer organoid (FPCO). We further incorporated macrophages derived from the THP-1 cell line, which are the source of tumor-associated macrophages (TAMs), a major TME component, into FPCO, which was designated M0-FPCO. Bulk RNA sequencing (RNAseq) analysis revealed that macrophages in M0-FPCO (FPCO-Mac) lost their pro-inflammatory features but acquired pro-angiogenic features. Consistently, the formation of an endothelial cell network was enhanced in M0-FPCO. Single-cell RNA-seq (scRNA-seq) analysis revealed that M0-FPCO contained five TAM subpopulations similar to the corresponding TAM in human PDAC tissue in the integrated analysis, including SPP1+-TAM, which has been correlated with tumor angiogenesis and cell proliferation. Focusing on PDAC cells, we found that they could survive longer within the organoid in the presence of TAM. Consistent with the prolonged proliferation and survival of PDAC cells, PDAC subclusters were characterized by proliferative features, such as increased M0-FPCO. Therefore, by establishing a PDAC organoid with macrophages, we recapitulated the diversity of TAMs and identified the role of TAM in endothelial network formation as well as in the modulation of PDAC cell properties. SIGNIFICANCE: PDAC organoids, including macrophages using hiPSC, showed that PDAC-TAM has angiogenic features and contributes to PDAC cell survival.

Folic acid modified silver nanoparticles promote endothelialization and inhibit calcification of decellularized heart valves by immunomodulation with anti-bacteria property.

Xenogeneic decellularized heart valves (DHVs) have become one of the most commonly used scaffolds for tissue engineered heart valves (TEHVs) due to extensive resources and possessing the distinct three-layer structure similar to native heart valves. However, DHVs as scaffolds face the shortages such as poor mechanical properties, proneness to thrombosis and calcification, difficulty in endothelialization and chronic inflammatory responses etc., which limit their applications in clinic. In this work, we constructed a novel TEHV with immunomodulatory functions by loading folic acid modified silver nanoparticles (FS NPs) on DHVs to overcome these issues. The FS NPs preferentially targeted M1 macrophages and reduced their intracellular H2O2 level, resulting in polarizing them into M2 phenotype. The increased M2 macrophages facilitated to eliminate inflammation, recruit endothelial cells, and promote their proliferation and endothelialization by secreting relative factors. We founded that FS NPs with the size of 80 nm modified DHVs (FSD-80) performed optimally on cytocompatibility and regulating macrophage phenotype ability in vitro. In addition, the FSD-80 had excellent mechanical properties, hemocompatibility and anti-bacteria property. The results of the subcutaneous implantation in rats revealed that the FSD-80 also had good performance in regulating macrophage phenotype, promoting endothelialization, remolding the extracellular matrix and anti-calcification in vivo. Therefore, FS NPs-loaded DHVs possess immunomodulatory functions, which is a feasible and promising strategy for constructing TEHVs with excellent comprehensive performance.

Engineered bacterium-metal-organic framework biohybrids for boosting radiotherapy with multiple effects.

Hypoxia and lactate-overexpressed tumor microenvironment always lead to poor therapeutic effect of radiotherapy. Here, platinum nanoparticles-embellished hafnium metal-organic framework (Hf-MOF-Pt NPs) were elaborately integrated with Shewanella oneidensis MR-1 (SO) to construct an engineered biohybrid platform (SO@Hf-MOF-Pt) for enhancing radiotherapy. Benefiting from the tumor-targeting and metabolic respiration characteristics of SO, SO@Hf-MOF-Pt could enrich in tumor sites and continuously metabolize the overexpressed lactate, which specifically downregulated the expression of hypoxia-inducible factor (HIF-1α), thereby relieving the radiosuppressive tumor microenvironment to some extent. Moreover, SO@Hf-MOF-Pt would react with tumor-overexpressed hydrogen peroxide (H2O2) to generate oxygen (O2) and further inhibit the expression of HIF-1α, resulting in the downregulation of lactate dehydrogenase (LDHA) and subsequently reducing the lactate production. Under these multiple cascaded effects, the radiosuppressive tumor microenvironment was significantly reshaped, thus potentiating the radiosentization of SO@Hf-MOF-Pt and remarkably amplifying the therapeutic outcomes of radiotherapy. The designed biohybrid SO@Hf-MOF-Pt represented promising prospects in sensitizing radiotherapy via bacterium-based metabolic regulation.

Cisplatin intra-arterial chemotherapy for recurrent maxillary gingival cancer and metastatic lymph nodes without radiation or surgery: A case report.

Most patients with head and neck cancers struggle with their treatment, particularly those with recurrent cancer. However, there is no consensus on effective treatments for recurrent head and neck cancer. Recurrent cases are often challenging to treat because performing both reirradiation and surgical intervention can occasionally be difficult. This report describes the effective cisplatin intra-arterial chemotherapy with oral S-1 for a recurrent case of maxillary gingival cancer (rT4bN1M0, rStage ⅣB). The patient who had undergone chemoradiotherapy 13 years ago and achieved complete response (CR) was referred to us due to recurrence. His recurrent lesions were located on the left maxillary bone, and a metastatic cervical lymph node was detected. We approached the feeder of the locoregional recurrence site using Seldinger's technique and repeated the cisplatin intra-arterial chemotherapy 5 times. As a result, we achieved a complete response, including the regional metastatic lymph node, without radiation or surgery. Notably, although we infused the anticancer drug into the feeder of the locoregional metastatic area, we noticed its effect on the metastatic cervical lymph node. Initially, neck dissection following intra-arterial chemotherapy had been planned; however, owing to the high effectiveness of the treatment, the subsequent surgery was deemed unnecessary. No evidence of recurrence has been observed during the 2.5-year follow-up period. In the future, intra-arterial chemotherapy can be an alternative option for patients with recurrent head and neck cancers, and our result seems to be enough to indicate that possibility.

Clinical implementation of RTT-only CBCT-guided online adaptive focal radiotherapy for bladder cancer.

Purpose: The study assesses the clinical implementation of radiation therapist (RTT)-only Conebeam CT (CBCT)-guided online adaptive focal radiotherapy (oART) for bladder cancer, by describing the training program, analyzing the workflow and monitoring patient experience. Materials and methods: Bladder cancer patients underwent treatment (20 sessions) on a ring-based linac (Ethos, Varian, a Siemens Healthineers Company, USA). Commencing April 2021, 14 patients were treated by RTTs supervised by the Radiation Oncologist (RO) and Medical Physics Expert (MPE) in a multidisciplinary workflow. From March 2022, 14 patients were treated solely by RTTs. RTT training included target delineation lessons and practicing oART in a simulation environment. We analyzed the efficiency of the RTT-only workflow regarding session time, adjustments by RTTs, attendance of the RO and MPE at the linac, and qualitative assessment of gross tumor volume (GTV) delineation. Patient experience was monitored through questionnaires. Results: A training program resulted in a skilled team of RTTs, ROs and MPEs.The RTT-only workflow demonstrated shorter session times compared to the multidisciplinary approach. Among 14 patients treated using the RTT-only workflow, RTTs adjusted 99% of bladder volumes and 44% of GTV. 79% of the sessions proceeded without MPEs and ROs. All GTV delineations were RO-approved, thus considered clinically acceptable, and 87% required minor or no adjustments. Patient satisfaction was reported in 18 of 21 cases. Conclusions: The RTT-only oART workflow for bladder cancer, complemented by a training program and on-call support from ROs and MPEs, demonstrated success. Patient experience is positive. It is currently introduced as standard in our clinic.

Carotid Complications in Skull Base Surgery.

Carotid artery rupture is a worrisome complication that sometimes occurs during microsurgical or endoscopic skull base procedures. Many identifiable aspects are related to prevention, intraoperative management, and immediate postoperative endovascular treatment. This article deals with microsurgical and endoscopic cases in which the carotid artery or its branches have been damaged in the context of a resection of skull base lesions. Factors related to the anatomy of the skull base and the arteries and their variations are considered, along with intraoperative measures to control the bleeding. Finally, depending on the case, recommendations for immediate postoperative endovascular management are made.

Features of late local failure of early­stage non­small cell lung cancer treated with stereotactic body radiotherapy.

Local failure of non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) often occurs within 2 years and delayed local failure is uncommon. In the present study, features of late local failure (LLF; >2 years after SBRT) after SBRT were investigated and compared with those of early local failure (ELF; ≤2 years after SBRT) to explore whether these two local recurrence features have different prognostic implications. Patients who underwent SBRT for stage I-IIA NSCLC between July 2006 and March 2014 were retrospectively reviewed. Overall, 173 patients underwent SBRT for NSCLC. The median follow-up times after SBRT were 50 and 31 months for survival and computed tomography (CT) follow-up, respectively. LLF and ELF occurred in 7 and 13 patients, respectively. The median times to LLF and ELF were 42 months (range, 31-61 months) and 13 months (range, 4-16 months), respectively. Local-only failure occurred in 14% (1/7) of LLF cases and 77% (10/13) of ELF cases, which was significantly different (Fisher's exact test, P=0.02). Curative-intent salvage treatment was impossible in all of the LLF cases and 69% (9/13) of the ELF cases, which was significantly different (Fisher's exact test, P<0.01). The median survival times after local failure were 9 and 25 months for patients with LLF and ELF, respectively. Additionally, the 1-year overall survival rates after local failure were 29 and 83% in the LLF and ELF groups, respectively, which was significantly different (log-rank test, P<0.01 at 1-year). In summary, the prognosis after LLF was significantly unfavorable compared with after ELF. Curative-intent salvage treatment is often difficult for LLF due to metastases. Therefore, it seems reasonable to decrease the frequency of follow-up CT for detecting tumor recurrence after the first 2 years post-SBRT.

Optimizing treatment sequence for inoperable locally advanced breast cancer: Long-term outcomes of surgery first versus neoadjuvant chemotherapy in a real-world setting.

Locally advanced breast cancer (LABC) is challenging with limited treatment options. This study investigates the feasibility and long-term outcomes of upfront surgery compared to neoadjuvant chemotherapy (NAC) in a real-world cohort. This retrospective study analyzed 243 inoperable LABC patients (excluding T3N1M0) that underwent upfront surgery (n = 187) or NAC (n = 56) in matched groups. Disease-free survival (DFS) and overall survival (OS) are primary outcomes. Secondary outcomes included NAC response rate and subgroup analyses based on age, tumor stage, and treatment response. Survival was estimated using Kaplan-Meier methods with log-rank tests for comparisons. Cox proportional hazards models were used for subgroup analyses. With a median follow-up of 60.9 months, no significant difference emerged in 5-year OS (upfront surgery: 89.6%, NAC: 81.9%, p = .12) or 5-year DFS rates (73.0% vs. 67.1%, p = .24). Subgroup analyses revealed upfront surgery offered significantly better OS for patients under 60 (HR = 0.32; 95% CI: 0.10-0.96; p = .0429) and stage IIIA disease (HR = 0.22; CI: 0.06-0.86; p = .03). Upfront surgery showed a trend towards improved OS for tumors under 5 cm (HR = 0.37; 95% CI: 0.13-1.03; p = .056). Patients with progressive disease (PD) or stable disease (SD) after NAC had significantly worse DFS (HR = 0.27; 95% CI: 0.09-0.79; p = .017) and OS (HR = 0.09; 95% CI: 0.02-0.48; p = .004) compared to responders. Upfront surgery may be viable for LABC patients, particularly younger patients, those with stage IIIA disease, or smaller tumors. NAC response can inform treatment decisions. These findings highlight the need for personalized LABC treatment considering patient characteristics and NAC response.

Increased inflammation in older high-pressure glaucoma mice.

Besides an elevated intraocular pressure (IOP), advanced age is one of the most crucial risk factors for developing glaucoma. ßB1-Connective Tissue Growth Factor (ßB1-CTGF) high-pressure glaucoma mice were used in this study to assess whether glaucoma mice display more inflammatory and aging processes than age-matched controls. Therefore, 20-month-old ßB1-CTGF and corresponding wildtype (WT) controls were examined. After IOP measurements, retinas were processed for (immuno-)histological and quantitative real-time PCR analyses. A significantly higher IOP and diminished retinal ganglion cell numbers were noted in ßB1-CTGF mice compared to WT. An enhanced macrogliosis as well as an increased number of microglia/macrophages and microglia was detected in retinas of old glaucoma mice. Interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and transforming growth factor-ß2 were upregulated, suggesting an ongoing inflammation. Moreover, ßB1-CTGF retinas displayed an increased senescence-associated ß-galactosidase staining accompanied by a downregulation of Lmnb1 (laminin-B1) mRNA levels. Our results provide a deeper insight into the association between inflammation and high-pressure glaucoma and thus might help to develop new therapy strategies.

Sinonasal Outcomes after Endoscopic Pituitary Surgery in Patients With Cushing's Disease.

PURPOSE: The endoscopic endonasal approach (EEA) has become the preferred treatment for pituitary tumors, with minimal sinonasal morbidity. However, patients with Cushing's disease (CD) may represent a subgroup with prolonged impairment of sinonasal quality of life (QOL). METHODS: We retrospectively identified patients with CD who underwent EEA at our institution. Control patients with non-functional tumors were matched by age, gender, and extent of EEA. The primary outcome was post-operative 22-item Sino-Nasal Outcome Test (SNOT-22) scores. RESULTS: Ten patients with CD met the selection criteria and 20 controls were selected for comparison. Nine of the CD patients achieved persistent endocrinologic remission post-operatively. Comparing the CD and control groups, there was no difference in post-operative SNOT-22 score at 1 or 3 months. At 6 months, SNOT-22 scores were significantly worse in the CD group (27.4 ± 21.6 vs. 2.8 ± 2.3, P = .039). SNOT-22 scores improved to normal from 1 to 6 months in the control cohort (P = .007), but not in the Cushing's group (P = .726). Morbidity was present across all SNOT-22 domains, but was highest in the sleep domain (P = .023). Only morbidity in the facial domain improved over time (P = .032). CONCLUSIONS: Patients with CD have significantly prolonged postoperative sinonasal QOL impairment following EEA compared to patients with non-functioning tumors, who normalize within 6 months. In CD patients, only morbidity in the facial domain, likely related to post-operative pain and nasal packing, improved over time, while the sleep domain was the most affected.

Cell membrane-camouflaged nanoarchitectonics of photosensitizer nanoparticles for enhanced phototherapy in surgery.

Surgical risk and wound area can be reduced by diminishing tumor volume before surgery. The chemotherapy and radiotherapy currently used that can reduce the tumor volume generally cause severe systemic side effects. Phototherapy has recently emerged as an effective treatment modality for superficial cancers. However, phototherapy is limited by the low utilization of photosensitizer, the tumor hypoxia, and the low photothermal conversion efficiency. Herein, we report the cancer membrane biomimetic nanoparticles assembled by Chlorin e6 (Ce6) and chlorambucil (CRB). Ce6@CRB nanoparticles (CCNPs) show excellent photothermal conversion efficiency, which is 2 times higher than free Ce6. Meanwhile, CCNPs can produce singlet oxygen stably compared to free Ce6 thereby reducing the dependence on oxygen. Furthermore, the coating of 4 T1 cancer membrane on the surface of CCNPs endows them with the ability of homologous targeting, not only improving the utilization of Ce6, but also effectively activating the immune system in vivo when combined photodynamic therapy (PDT) and photothermal therapy (PTT). Intriguingly, surgical resection is performed after phototherapy in this treatment regimen, which can effectively reduce the wound area. Together, this work provided a feasible and creative method for tumor clinical therapy for its patient-centric and humanitarian focus.

Enhanced expression of galectin-9 in triple negative breast cancer cells following radiotherapy: Implications for targeted therapy.

Optimizations are expected in the development of immunotherapy for the treatment of Triple-negative breast cancer (TNBC). We studied the expression of galectin-9 (Gal-9) after irradiation and assessed the differential impacts of its targeting with or without radiotherapy. Tumor resections from TNBC patients who received neoadjuvant radiotherapy revealed higher levels of Gal-9 in comparison to their baseline level, only in non-responder patients. Gal-9 expression was also found to be increased in TNBC tumor biopsies and cell lines after irradiation. We investigated the therapeutic advantage of targeting Gal-9 after radiotherapy in mice. Irradiated 4T1 cells or control non-irradiated 4T1 cells were injected into BALB/c mice. Anti-Gal-9 antibody treatment decreased tumor progression only in mice injected with irradiated 4T1 cells. This proof-of-concept study demonstrates that Gal-9 could be considered as a dynamic biomarker after radiotherapy for TNBC and suggests that Gal-9 induced-overexpression could represent an opportunity to develop new therapeutic strategies for TNBC patients.

The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis.

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.