Systemic and local immunosuppression in glioblastoma and its prognostic significance.

The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity of the host immune cells. However, various local and systemic mechanisms of immunosuppression operate in cancer patients. Tumor-associated immunosuppression involves deregulation of many components of immunity, including a decrease in the number of T lymphocytes (lymphopenia), an increase in the levels or ratios of circulating and tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)], as well as defective functions of subsets of antigen-presenting, helper and effector immune cell due to altered expression of various soluble and membrane proteins (receptors, costimulatory molecules, and cytokines). In this review, we specifically focus on data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related immunosuppression at baseline and the prognostic significance of different subsets of circulating and tumor-infiltrating immune cells (lymphocytes, CD4+ and CD8+ T cells, Tregs, natural killer (NK) cells, neutrophils, macrophages, MDSCs, and dendritic cells), including neutrophil-to-lymphocyte ratio (NLR), focus on the immune landscape and prognostic significance of isocitrate dehydrogenase (IDH)-mutant gliomas, proneural, classical and mesenchymal molecular subtypes, and highlight the features of immune surveillance in the brain. All attempts to identify a reliable prognostic immune marker in glioblastoma tissue have led to contradictory results, which can be explained, among other things, by the unprecedented level of spatial heterogeneity of the immune infiltrate and the significant phenotypic diversity and (dys)functional states of immune subpopulations. High NLR is one of the most repeatedly confirmed independent prognostic factors for shorter overall survival in patients with glioblastoma and carcinoma, and its combination with other markers of the immune response or systemic inflammation significantly improves the accuracy of prediction; however, more prospective studies are needed to confirm the prognostic/predictive power of NLR. We call for the inclusion of dynamic assessment of NLR and other blood inflammatory markers (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, and systemic immune response index) in all neuro-oncology studies for rigorous evaluation and comparison of their individual and combinatorial prognostic/predictive significance and relative superiority.

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy.

Despite significant advances in our knowledge regarding the genetics and molecular biology of gliomas over the past two decades and hundreds of clinical trials, no effective therapeutic approach has been identified for adult patients with newly diagnosed glioblastoma, and overall survival remains dismal. Great hopes are now placed on combination immunotherapy. In clinical trials, immunotherapeutics are generally tested after standard therapy (radiation, temozolomide, and steroid dexamethasone) or concurrently with temozolomide and/or steroids. Only a minor subset of patients with progressive/recurrent glioblastoma have benefited from immunotherapies. In this review, we comprehensively discuss standard therapy-related systemic immunosuppression and lymphopenia, their prognostic significance, and the implications for immunotherapy/oncolytic virotherapy. The effectiveness of immunotherapy and oncolytic virotherapy (viro-immunotherapy) critically depends on the activity of the host immune cells. The absolute counts, ratios, and functional states of different circulating and tumor-infiltrating immune cell subsets determine the net immune fitness of patients with cancer and may have various effects on tumor progression, therapeutic response, and survival outcomes. Although different immunosuppressive mechanisms operate in patients with glioblastoma/gliomas at presentation, the immunological competence of patients may be significantly compromised by standard therapy, exacerbating tumor-related systemic immunosuppression. Standard therapy affects diverse immune cell subsets, including dendritic, CD4+, CD8+, natural killer (NK), NKT, macrophage, neutrophil, and myeloid-derived suppressor cell (MDSC). Systemic immunosuppression and lymphopenia limit the immune system's ability to target glioblastoma. Changes in the standard therapy are required to increase the success of immunotherapies. Steroid use, high neutrophil-to-lymphocyte ratio (NLR), and low post-treatment total lymphocyte count (TLC) are significant prognostic factors for shorter survival in patients with glioblastoma in retrospective studies; however, these clinically relevant variables are rarely reported and correlated with response and survival in immunotherapy studies (e.g., immune checkpoint inhibitors, vaccines, and oncolytic viruses). Our analysis should help in the development of a more rational clinical trial design and decision-making regarding the treatment to potentially improve the efficacy of immunotherapy or oncolytic virotherapy.

Age-related Disparities in Pan-Cancer Mortality and Causes of Death: Analysis of Surveillance, Epidemiology, and End Results (SEER) Data.

Comprehensive analysis of mortality and causes of death (COD) in cancers was of importance to conduct intervention strategies. The current study aimed to investigate the mortality rate and COD among cancers, and to explore the disparities between age. Initially, cancer patients diagnosed between 2010 and 2019 from the surveillance, epidemiology, and end results (SEER) database were extracted. Then, frequencies and percentage of deaths, and mortality rate in different age groups were calculated. Meanwhile, age distribution of different COD across tumor types was illustrated while the standardized mortality ratios (SMR) stratified by age were calculated and visualized. A total of 2,670,403 death records were included and digestive system cancer (688,953 death cases) was the most common primary cancer type. The mortality rate increased by 5.6% annually in total death, 4.0% in cancer-specific death and 10.9% in non-cancer cause. As for cancer-specific death, the age distribution varied among different primary tumor types due to prone age and prognosis of cancer. The top five non-cancer causes in patients older than 50 were cardiovascular and cerebrovascular disease, other causes, COPD and associated conditions, diabetes as well as Alzheimer. The SMRs of these causes were higher among younger patients and gradually dropped in older age groups. Mortality and COD of cancer patients were heterogeneous in age group due to primary tumor types, prone age and prognosis of cancer. Our study conducted that non-cancer COD was a critical part in clinical practice as well as cancer-specific death. Individualized treatment and clinical intervention should be made after fully considering of the risk factor for death in different diagnosis ages and tumor types.

Extracellular vesicles of human glial cells exert neuroprotective effects via brain miRNA modulation in a rat model of traumatic brain injury.

Stem cell-based therapeutic approaches for neurological disorders are widely studied. Paracrine factors secreted by stem cells in vitro and delivered intranasally might allow bypassing the disadvantages associated with a surgical cell delivery procedure with likely immune rejection of a transplant. In this study, we investigated the therapeutic effect of the extracellular vesicles secreted by glial progenitor cells (GPC-EV) derived from human induced pluripotent stem cell in a traumatic brain injury model. Intranasal administration of GPC-EV to Wistar rats for 6 days improved sensorimotor functions assessed over a 14-day observation period. Beside, deep sequencing of microRNA transcriptome of GPC-EV was estimate, and was revealed 203 microRNA species that might be implicated in prevention of various brain pathologies. Modulation of microRNA pools might contribute to the observed decrease in the number of astrocytes that inhibit neurorecovery processes while enhancing neuroplasticity by decreasing phosphorylated Tau forms, preventing inflammation and apoptosis associated with secondary damage to brain tissue. The course of GPC-EV administration was promoted the increasing protein levels of NF-κB in studied areas of the rat brain, indicating NF-κB dependent mechanisms as a plausible route of neuroprotection within the damaged area. This investigation showed that GPC-EV may be representing a therapeutic approach in traumatic brain injury, though its translation into the clinic would require an additional research and development.

Improving Efficiency of Direct Pro-Neural Reprogramming: Much-Needed Aid for Neuroregeneration in Spinal Cord Injury.

Spinal cord injury (SCI) is a medical condition affecting ~2.5-4 million people worldwide. The conventional therapy for SCI fails to restore the lost spinal cord functions; thus, novel therapies are needed. Recent breakthroughs in stem cell biology and cell reprogramming revolutionized the field. Of them, the use of neural progenitor cells (NPCs) directly reprogrammed from non-neuronal somatic cells without transitioning through a pluripotent state is a particularly attractive strategy. This allows to "scale up" NPCs in vitro and, via their transplantation to the lesion area, partially compensate for the limited regenerative plasticity of the adult spinal cord in humans. As recently demonstrated in non-human primates, implanted NPCs contribute to the functional improvement of the spinal cord after injury, and works in other animal models of SCI also confirm their therapeutic value. However, direct reprogramming still remains a challenge in many aspects; one of them is low efficiency, which prevents it from finding its place in clinics yet. In this review, we describe new insights that recent works brought to the field, such as novel targets (mitochondria, nucleoli, G-quadruplexes, and others), tools, and approaches (mechanotransduction and electrical stimulation) for direct pro-neural reprogramming, including potential ones yet to be tested.

Unveiling the Role of the Properties of Magnetic Nanoparticles for Highly Efficient Low-Frequency Magneto-Mechanical Actuation of Biomolecules.

The role of the properties of magnetic nanoparticles in the remote magneto-mechanical actuation of biomolecules under the influence of external magnetic fields is still of particular interest. Here, a specially designed strategy based on the mechanical destruction of short oligonucleotide duplexes is used to demonstrate the effect of magnetic nanoparticles with different sizes (5-99 nm) on the magnitude of the magneto-mechanical actuations in a low-frequency alternating magnetic field. The results show that the mechanical destruction of complementary chains of duplexes, caused by the rotational-vibrational movements of nanoparticles upon exposure to a magnetic field, has a nonmonotonic dependence on the nanoparticle core size. The main hypothesis of this phenomenon is associated with a key role of magneto-dipole interactions between individual nanoparticles, which blocks the movements of nanoparticles in dense clusters. This result will allow fine-tuning of the magnetic nanoparticle properties for addressing specific magneto-mechanical tasks.

Ten-year retrospect of the investigation of proximal limbs metastasis in cancer: a multi-center study on survival outcome, limb function status and surgical procedures analysis.

BACKGROUND: The aim of study was to evaluate survival outcome and limb function in cancer patients with proximal limbs metastasis. Associated factors on survival outcome and limb function were identified. The comparative analysis between intramedullary nailing and prosthesis surgery in cancer patients with proximal limb metastasis was performed. METHODS: In this five-center retrospective study, patients diagnosed with limbs metastasis were collected. Descriptive statistics was used and log-rank test was performed to analyze the survival in subgroups. The Cox proportional hazards regression analysis was performed to identify the independent prognostic factors. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate limb function after surgery, and t test or analysis of variance (ANOVA) was utilized in subgroup analysis. RESULTS: A total of 316 patients with limb metastasis were included with mean age at 61.0 years. The most common primary tumor was breast, followed by renal cancer and lung cancer. The median overall survival was 24.0 months and the 1-, 3- and 5-year survival rates were 86.9%, 34.7% and 6.8%, respectively. Primary tumor type, visceral metastasis and chemotherapy were proved to be the independent prognostic factors. The mean Musculoskeletal Tumor Society (MSTS) score was 20.5, significant difference was observed in subgroup of solitary/multiple bone metastasis, with/without pathological fracture, and type of surgery. CONCLUSION: The present study concluded that primary tumor type, visceral metastasis and chemotherapy were three factors affecting the survival of patients. Compared with intramedullary nailing, the patients underwent prosthesis surgery showed better limb function, this procedure should be encouraged in patients with indication.

Therapeutic Efficiency of Proteins Secreted by Glial Progenitor Cells in a Rat Model of Traumatic Brain Injury.

Traumatic brain injuries account for 30-50% of all physical traumas and are the most common pathological diseases of the brain. Mechanical damage of brain tissue leads to the disruption of the blood-brain barrier and the massive death of neuronal, glial, and endothelial cells. These events trigger a neuroinflammatory response and neurodegenerative processes locally and in distant parts of the brain and promote cognitive impairment. Effective instruments to restore neural tissue in traumatic brain injury are lacking. Glial cells are the main auxiliary cells of the nervous system, supporting homeostasis and ensuring the protection of neurons through contact and paracrine mechanisms. The glial cells' secretome may be considered as a means to support the regeneration of nervous tissue. Consequently, this study focused on the therapeutic efficiency of composite proteins with a molecular weight of 5-100 kDa secreted by glial progenitor cells in a rat model of traumatic brain injury. The characterization of proteins below 100 kDa secreted by glial progenitor cells was evaluated by proteomic analysis. Therapeutic effects were assessed by neurological outcomes, measurement of the damage volume by MRI, and an evaluation of the neurodegenerative, apoptotic, and inflammation markers in different areas of the brain. Intranasal infusions of the composite protein product facilitated the functional recovery of the experimental animals by decreasing the inflammation and apoptotic processes, preventing neurodegenerative processes by reducing the amounts of phosphorylated Tau isoforms Ser396 and Thr205. Consistently, our findings support the further consideration of glial secretomes for clinical use in TBI, notably in such aspects as dose-dependent effects and standardization.

Clinicomics-guided distant metastasis prediction in breast cancer via artificial intelligence.

BACKGROUND: Breast cancer has become the most common malignant tumour worldwide. Distant metastasis is one of the leading causes of breast cancer-related death. To verify the performance of clinicomics-guided distant metastasis risk prediction for breast cancer via artificial intelligence and to investigate the accuracy of the created prediction models for metachronous distant metastasis, bone metastasis and visceral metastasis. METHODS: We retrospectively enrolled 6703 breast cancer patients from 2011 to 2016 in our hospital. The figures of magnetic resonance imaging scanning and ultrasound were collected, and the figures features of distant metastasis in breast cancer were detected. Clinicomics-guided nomogram was proven to be with significant better ability on distant metastasis prediction than the nomogram constructed by only clinical or radiographic data. RESULTS: Three clinicomics-guided prediction nomograms on distant metastasis, bone metastasis and visceral metastasis were created and validated. These models can potentially guide metachronous distant metastasis screening and lead to the implementation of individualized prophylactic therapy for breast cancer patients. CONCLUSION: Our study is the first study to make cliniomics a reality. Such cliniomics strategy possesses the development potential in artificial intelligence medicine.

Dynamic MRI of the Mesenchymal Stem Cells Distribution during Intravenous Transplantation in a Rat Model of Ischemic Stroke.

Systemic transplantation of mesenchymal stem cells (MSCs) is a promising approach for the treatment of ischemia-associated disorders, including stroke. However, exact mechanisms underlying its beneficial effects are still debated. In this respect, studies of the transplanted cells distribution and homing are indispensable. We proposed an MRI protocol which allowed us to estimate the dynamic distribution of single superparamagnetic iron oxide labeled MSCs in live ischemic rat brain during intravenous transplantation after the transient middle cerebral artery occlusion. Additionally, we evaluated therapeutic efficacy of cell therapy in this rat stroke model. According to the dynamic MRI data, limited numbers of MSCs accumulated diffusely in the brain vessels starting at the 7th minute from the onset of infusion, reached its maximum by 29 min, and gradually eliminated from cerebral circulation during 24 h. Despite low numbers of cells entering brain blood flow and their short-term engraftment, MSCs transplantation induced long lasting improvement of the neurological deficit, but without acceleration of the stroke volume reduction compared to the control animals during 14 post-transplantation days. Taken together, these findings indicate that MSCs convey their positive action by triggering certain paracrine mechanisms or cell-cell interactions or invoking direct long-lasting effects on brain vessels.

Analysis of Single Biomacromolecules and Viruses: Is It a Myth or Reality?

The beginning of the twenty-first century witnessed novel breakthrough research directions in the life sciences, such as genomics, transcriptomics, translatomics, proteomics, metabolomics, and bioinformatics. A newly developed single-molecule approach addresses the physical and chemical properties and the functional activity of single (individual) biomacromolecules and viral particles. Within the alternative approach, the combination of "single-molecule approaches" is opposed to "omics approaches". This new approach is fundamentally unique in terms of its research object (a single biomacromolecule). Most studies are currently performed using postgenomic technologies that allow the properties of several hundreds of millions or even billions of biomacromolecules to be analyzed. This paper discusses the relevance and theoretical, methodological, and practical issues related to the development potential of a single-molecule approach using methods based on molecular detectors.

Repeated dosing improves oncolytic rhabdovirus therapy in mice via interactions with intravascular monocytes.

There is debate in the field of oncolytic virus (OV) therapy, whether a single viral dose, or multiple administrations, is better for tumor control. Using intravital microscopy, we describe the fate of vesicular stomatitis virus (VSV) delivered systemically as a first or a second dose. Following primary administration, VSV binds to the endothelium, initiates tumor infection and activates a proinflammatory response. This initial OV dose induces neutrophil migration into the tumor and limits viral replication. OV administered as a second dose fails to infect the tumor and is captured by intravascular monocytes. Despite a lack of direct infection, this second viral dose, in a monocyte-dependent fashion, enhances and sustains infection by the first viral dose, promotes CD8 T cell recruitment, delays tumor growth and improves survival in multi-dosing OV therapy. Thus, repeated VSV dosing engages monocytes to post-condition the tumor microenvironment for improved infection and anticancer T cell responses. Understanding the complex interactions between the subsequent viral doses is crucial for improving the efficiency of OV therapy and virus-based vaccines.

Association between malnutrition and leucopenia in patients with osteosarcoma.

Background and aim: Leucopenia (LP) greatly limits the efficacy of chemotherapy in osteosarcoma patients. This study aimed to evaluate the nutritional status of osteosarcoma patients before chemotherapy, assess the risk of LP during the perichemotherapy period, and explore the association between malnutrition and LP. Materials and methods: This study retrospectively analyzed osteosarcoma patients treated in the Tianjin Medical University Cancer Institute and Hospital, China, between January 2009 and December 2020 according to the inclusion and exclusion criteria. Malnutrition in adolescents (5 to 19 years old) and adults (≥20 years old) was diagnosed using WHO AnthroPlus software (version 1.0.4) and Global Leadership initiative on Malnutrition (GLIM), respectively. According to the diagnostic criteria of LP in CTCAE 5.0, patients were divided into the LP group and the non-LP group. Results: A total of 245 osteosarcoma patients were included. The incidence of malnutrition was 49.0%, and the incidence of LP was 51.8%. The incidence of malnutrition in adolescent patients was 53.1%, and their incidence of LP was 55.2%; the incidence of malnutrition in adult patients was 43.1%, and their incidence of LP was 47.1%. Logistic regression analysis showed that malnutrition before chemotherapy was an independent risk factor for the occurrence of LP after chemotherapy (OR = 6.85, 95% CI = 2.16-25.43; and OR = 35.03, 95% CI = 6.98-238.46 in mildly and severely malnourished young patients; OR = 6.06; 95% CI = 1.43-30.16; and OR = 38.09, 95% CI = 7.23-285.78 in mildly and severely malnourished adult patients, respectively). The results showed that age and nutritional status had a joint effect on the occurrence of LP. Conclusion: The nutrition status of osteosarcoma patients before chemotherapy is significantly correlated with the occurrence and severity of LP during peri-chemotherapy period. During osteosarcoma chemotherapy, necessary nutritional support should be given to patients of different ages to correct their malnutrition status in a timely manner, ultimately improving the efficacy of chemotherapy and the prognosis of patients.

In Vivo Tracking for Oncolytic Adenovirus Interactions with Liver Cells.

Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, the complex interplay between Ad and liver cells is not fully understood. Here, by using intravital microscopy, we aimed to follow the infection and immune response in mouse liver from the first minutes up to 72 h post intravenous injection of three Ads carrying delta-24 modification (Ad5-RGD, Ad5/3, and Ad5/35). At 15-30 min following the infusion of Ad5-RGD and Ad5/3 (but not Ad5/35), the virus-bound macrophages demonstrated signs of zeiosis: the formation of long-extended protrusions and dynamic membrane blebbing with the virus release into the blood in the membrane-associated vesicles. Although real-time imaging revealed interactions between the neutrophils and virus-bound KCs within minutes after treatment, and long-term contacts of CD8+ T cells with transduced hepatocytes at 24-72 h, depletion of neutrophils and CD8+ T cells affected neither rate nor dynamics of liver infection. Ad5-RGD failed to complete replicative cycle in hepatocytes, and transduced cells remained impermeable for propidium iodide, with a small fraction undergoing spontaneous apoptosis. In Ad5-RGD-immune mice, the virus neither killed KCs nor transduced hepatocytes, while in the setting of hepatic regeneration, Ad5-RGD enhanced liver transduction. The clinical and biochemical signs of hepatotoxicity correlated well with KC death, but not hepatocyte transduction. Real-time in vivo tracking for dynamic interactions between virus and host cells provides a better understanding of mechanisms underlying Ad-related hepatotoxicity.

The 100 most cited papers on bone metastasis: A bibliometric analysis.

Background: Over the past few decades, a vast number of articles focused on bone metastasis have been published. Bibliometric analysis is helpful to determine the qualities and characteristics and to reveal the influential articles in this field. Methods: All the databases in Web of Science were utilized to identify articles published from 1961 to 2020. The top 100 most cited articles on bone metastases were involved for degree centrality analysis and analyses on publication time and citations, journals, authors, geographical distribution, research institutions, and research keywords. Results: The selected articles were published mainly from 1986 to 2015. The 100 most cited articles were selected from a total of 67,451 citations out of 90,502 publications with a density of 50.239 citations/year. Citations per article ranged from 357 to 2167. The leading country was USA, followed by Canada and United Kingdom. The most frequently studied themes were clinical management of bone metastasis from different malignancy origins. A co-authorship analysis revealed an intense collaborative activity between countries and institutions. Conclusions: This study identified the top 100 most cited articles on bone metastasis. Publication time, area, and theme distribution were thoroughly analyzed. The present study highlighted some of the most influential contributions to the field. Clinical and academic communities have shown a sustained interest in the management of bone metastasis.

Survival Estimation, Prognostic Factors Evaluation, and Prognostic Prediction Nomogram Construction of Breast Cancer Patients with Bone Metastasis in the Department of Bone and Soft Tissue Tumor: A Single Center Experience of 8 Years in Tianjin, China.

Purpose: Bone metastasis in breast cancer remains globally concerned. Accurate survival estimation would be beneficial for clinical decision-making, especially for the patients with potential indications of surgery. Based on a retrospective cohort from China, the study aimed to construct a prognostic prediction nomogram for breast cancer patients with bone metastasis. Methods: Breast cancer patients with bone metastasis diagnosed between 2009 and 2017 in our department were retrospectively selected. The total cohort was divided into construction and validation cohorts (ratio 7 : 3). A nomogram was constructed to predict the probability of survival, and the performance of model was validated. Results: A total of 343 patients were enrolled with 243 and 100 patients in construction and validation cohorts, respectively. The median overall survival for the total cohort was 63.2 (95% CI: 52.4-74.0) months. Elevated ALP (HR = 1.71, 95% CI: 1.16-2.51; P=0.006), no surgery for breast cancer (HR = 2.19, 95% CI: 1.30-3.70; P=0.003), synchronous bone metastasis (HR = 1.98, 95% CI: 1.22-3.22; P=0.006), and liver metastasis (HR = 1.68, 95% CI: 1.20-2.37; P=0.003) were independent prognostic factors for worse survival. The independent predictors and other five factors (including age at diagnosis, ER status, PR status, Her-2 status, and the performance of bisphosphonate) were incorporated to construct the nomogram. The C-index was 0.714 (95% CI: 0.636-0.792) and 0.705 (95% CI: 0.705) in the construction cohort and validation cohort, respectively. All the calibration curves were close to the 45-degree line, which indicated satisfactory calibration. Conclusion: A retrospective study aiming at prognostic estimation of breast cancer patients with bone metastasis was designed. Four independent prognostic factors were identified and a prognostic nomogram was constructed with satisfactory discrimination and calibration. The model could be used in survival estimation and individualized treatment planning.

Non-cancer Causes of Death Following Initial Synchronous Bone Metastasis in Cancer Patients.

Purpose: To investigate the non-cancer causes of death (COD) in cancer patients with synchronous bone metastasis (BM) that is based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The retrospective cohort study included malignant cancer patients with synchronous BM diagnosed from 2010 to 2018 in the SEER database. The frequencies and proportion of non-cancer COD were calculated and analyzed in different genders, ages, and races subgroups. Results: A total of 97,997 patients were deceased and included into the current study and 6,782 patients were died of non-cancer causes with a male predominance (N = 4,515, 66.6%). Around half of deaths (N = 3,254, 48.0%) occurred within 6 months after diagnosis while 721 patients were deceased after 3 years. Lung and bronchus cancer, prostate cancer, breast cancer, kidney and renal pelvis cancer, and liver cancer were proved to be the top five cancer types resulting in non-cancer caused death. Cardiovascular and cerebrovascular diseases were the leading non-cancer cause of death (N = 2,618), followed by COPD and associated conditions (N = 553) and septicemia, infectious and parasitic diseases (N = 544). Sub-analyses stratified by gender, age and race were performed and the similar results with slightly difference were observed. Conclusions: Cardiovascular and cerebrovascular diseases were the main non-cancer cause of death in cancer patients with synchronous BM. Other non-cancer causes included COPD, septicemia, infectious and parasitic diseases, and so on. These findings should be considered by physicians. Physicians can counsel cancer patients with BM regarding survivorship with death causes screening and focus on prevention of non-cancer deaths.

Nomogram predicting leukopenia in osteosarcoma after high-dose methotrexate chemotherapy.

PURPOSE: To explore the trends of plasma drug concentration changes after high-dose methotrexate (MTX) treatment of osteosarcoma (OS), analyse the risk factors for leukopenia (LP) after MTX treatment, and establish a LP prediction nomogram. METHODS: A total of 35 OS patients at Tianjin Medical University Cancer Institute and Hospital between 2017 and 2021 were collected (the construction cohort). Another 12 OS patients between 2019 and 2021 in P.A. Hertsen Moscow Oncology Research Center were involved (the external validation cohort). Peripheral venous blood MTX concentration (CMTX) was monitored at 0h, 6h, 24h, 48h and 72h after MTX administration. The characteristics were collected: age, sex, body surface area, lesion site, pathological subtype, pathological fractures, American Joint Committee on Cancer (AJCC) clinical stage, MTX dose, tumour necrosis, Ki-67 index, erythrocyte count, haemoglobin count, white blood cell count, platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin concentration, creatinine, alkaline phosphatase, and lactate dehydrogenase. Logistic regression analysis was used to determine the risk factors for LP occurrence. Significant factors were used to construct the prediction nomogram. RESULTS: A total of 128 MTX chemotherapy cycles from 35 OS patients were included. Female, Ki-67>20%, CMTX>112µmol/L at 6h, PLT, and AST were risk factors for post-chemotherapy LP occurrence. The LP prediction nomogram was created and validated. CONCLUSIONS: Female, CMTX at 6h, Ki-67 index, AST and PLT before MTX treatment were risk factors for LP in OS patients who received MTX treatment. The established nomogram can guide personalized LP prediction in OS patients receiving MTX chemotherapy.

Infection of non-cancer cells: A barrier or support for oncolytic virotherapy?

Oncolytic viruses are designed to specifically target cancer cells, sparing normal cells. Although numerous studies demonstrate the ability of oncolytic viruses to infect a wide range of non-tumor cells, the significance of this phenomenon for cancer virotherapy is poorly understood. To fill the gap, we summarize the data on infection of non-cancer targets by oncolytic viruses with a special focus on tumor microenvironment and secondary lymphoid tissues. The review aims to address two major questions: how do attenuated viruses manage to infect normal cells, and whether it is of importance for oncolytic virotherapy.

A Predictive Nomogram for Early Death in Pheochromocytoma and Paraganglioma.

Background: Pheochromocytoma (PHEO) and paraganglioma (PGL) are relatively rare neuroendocrine tumors. The factors affecting patients with early death remain poorly defined. We aimed to study the demographic and clinicopathologic pattern and to develop and validate a prediction model for PHEO/PGL patients with early death. Methods: Data of 800 participants were collected from the Surveillance Epidemiology and End Results (SEER) database as a construction cohort, while data of 340 participants were selected as a validation cohort. Risk factors considered included the year of diagnosis, age at diagnosis, gender, marital status, race, insurance status, tumor type, primary location, laterality, the presence of distant metastasis. Univariate and multivariate logistic regressions were performed to determine the risk factors. R software was used to generate the nomogram. Calibration ability, discrimination ability, and decision curve analysis were analyzed in both construction and validation cohorts. Results: PHEO and PGL patients accounted for 54.3% (N=434) and 45.7% (N=366), respectively. More than half of tumors (N=401, 50.1%) occurred in the adrenal gland, while 16.9% (N=135) were in aortic/carotid bodies. For the entire cohort, the median overall survival (OS) was 116.0 (95% CI: 101.5-130.5) months. The multivariate analysis revealed that older age (versus age younger than 31; age between 31 and 60: OR=2.03, 95% CI: 1.03-4.03, P=0.042; age older than 60: OR=5.46, 95% CI: 2.68-11.12, P<0.001), female gender (versus male gender; OR=0.59, 95% CI: 0.41-0.87, P=0.007), tumor located in aortic/carotid bodies (versus tumor located in adrenal gland; OR=0.49, 95% CI: 0.27-0.87, P=0.015) and the presence of distant metastasis (versus without distant metastasis; OR=4.80, 95% CI: 3.18-7.23, P<0.001) were independent risk factors of early death. The predictive nomogram included variables: age at diagnosis, gender, primary tumor location, and distant metastasis. The model had satisfactory discrimination and calibration performance: Harrell's C statistics of the prediction model were 0.733 in the construction cohort and 0.716 in the validation cohort. The calibration analysis showed acceptable coherence between predicted probabilities and observed probabilities. Conclusions: We developed and validated a predictive nomogram utilizing data from the SEER database with satisfactory discrimination and calibration capability which can be used for early death prediction for PHEO/PGL patients.