TYRO Protein Tyrosine Kinase-binding Protein Predicts Favorable Overall Survival in Osteosarcoma and Correlates With Antitumor Immunity

Objective: To explore the prognostic significance and underlying mechanism of TYRO protein tyrosine kinase-binding protein (TYROBP) in osteosarcoma. Methods: Firstly, the expression of TYROBP was analyzed using the t-test. The Kaplan-Meier plotter analysis and a receiver operating characteristic (ROC) curve were performed to evaluate the influence of TYROBP on overall survival (OS). Further, Cox regression analysis was conducted to predict the independent prognostic factors for OS of osteosarcoma patients, and a nomogram was constructed. Then, the relationship between TYROBP and clinicopathological characteristics was determined using statistical methods. Enrichment analyses were conducted to evaluate the biological functions of TYROBP. Finally, ESTIMATE algorithm was used to assess the association of TYROBP with immune cell infiltration. Results: TYROBP was significantly increased in osteosarcoma (all P <0.001). However, the high expression of TYROBP was related to better OS of osteosarcoma patients. Cox regression analysis showed that TYROBP was an independent prognostic factor for predicting OS (P =0.005), especially in patients with male sex, age <18 years, metastasis, and tumor site leg/foot (all P <0.05). Besides, TYROBP mRNA expression was significantly associated with tumor site (P <0.01) but had no remarkable relationship with age, gender, and metastasis status (all P>0.05). Functional annotation and GSEA revealed that TYROBP was mainly involved in immune-related pathways. Importantly, TYROBP positively correlated with immune scores (P <0.001, r=0.87). Conclusions: TYROBP served as an independent prognostic biomarker for OS in osteosarcoma. High TYROBP expression might prolong the survival of osteosarcoma patients mainly through promoting antitumor immunity.

Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.

Enhanced Photothermal Heating and Combination Therapy of NIR Dye via Conversion to Self-Assembled Ionic Nanomaterials

Combination nanodrugs are promising therapeutic agents for cancer treatment. However, they often require the use of complex nanovehicles for transportation into the tumor site. Herein, a new class of carrier-free...

Mathematical modeling of therapeutic neural stem cell migration in mouse brain with and without brain tumors

<abstract><p>Neural stem cells (NSCs) offer a potential solution to treating brain tumors. This is because NSCs can circumvent the blood-brain barrier and migrate to areas of damage in the central nervous system, including tumors, stroke, and wound injuries. However, for successful clinical application of NSC treatment, a sufficient number of viable cells must reach the diseased or damaged area(s) in the brain, and evidence suggests that it may be affected by the paths the NSCs take through the brain, as well as the locations of tumors. To study the NSC migration in brain, we develop a mathematical model of therapeutic NSC migration towards brain tumor, that provides a low cost platform to investigate NSC treatment efficacy. Our model is an extension of the model developed in Rockne et al. (PLoS ONE 13, e0199967, 2018) that considers NSC migration in non-tumor bearing naive mouse brain. Here we modify the model in Rockne et al. in three ways: (i) we consider three-dimensional mouse brain geometry, (ii) we add chemotaxis to model the tumor-tropic nature of NSCs into tumor sites, and (iii) we model stochasticity of migration speed and chemosensitivity. The proposed model is used to study migration patterns of NSCs to sites of tumors for different injection strategies, in particular, intranasal and intracerebral delivery. We observe that intracerebral injection results in more NSCs arriving at the tumor site(s), but the relative fraction of NSCs depends on the location of injection relative to the target site(s). On the other hand, intranasal injection results in fewer NSCs at the tumor site, but yields a more even distribution of NSCs within and around the target tumor site(s).</p></abstract>

Retrospective Analysis of INRG Clinical and Genomic Factors for 605 Neuroblastomas in Japan: A Report from the Japan Children’s Cancer Group Neuroblastoma Committee (JCCG-JNBSG)

Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic and genomic markers in a Japanese NB cohort using a retrospective analysis. Follow-up data based on 30 common INRG queries in 605 NB cases diagnosed in Japan between 1990 and 2014 were collected and the genome signature of each tumor sample was integrated. As previously indicated, age, tumor stage, MYCN, DNA ploidy, the adrenals as the primary tumor site, serum ferritin and lactate dehydrogenase (LDH) levels, segmental chromosome aberrations, and the number of chromosome breakpoints (BP) correlated with lower survival rates, while the thorax as the primary tumor site and numerical chromosome aberrations correlated with a favorable prognosis. In the patient group with stage 4, MYCN non-amplified tumors (n = 225), one of the challenging subsets for risk stratification, age ≥ 18 months, LDH ≥ 1400 U/L, and BP ≥ 7 correlated with lower overall and event-free survival rates (p < 0.05). The genome subgroup GG-P2s (partial chromosome gain/loss type with 1p/11q losses and 17q gain, n = 30) was strongly associated with a lower overall survival rate (5-year survival rate: 34%, p < 0.05). Therefore, the combination of the tumor genomic pattern (GG-P2s and BP ≥ 7) with age at diagnosis and LDH will be a promising predictor for MYCN-non-amplified high-risk NBs in patient subsets, in accordance with previous findings from the INRG project.

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

Long-term analysis of bilateral versus unilateral neck dissection in the treatment of early-stage supraglottic laryngeal cancer

OBJECTIVE: This study aimed to investigate the effect of routine bilateral neck dissection on the survival outcomes of supraglottic laryngeal cancer patients with lateralized tumors and clinically negative necks. METHODS: The data of 234 patients surgically treated for supraglottic squamous cell carcinoma between January 2000 and September 2014 were retrospectively collected. Patients treated previously for head and neck cancer, patients who could not be contacted, and those with missing data were excluded. Of the remaining 187 patients, 124 patients with early-stage primaries (T1-T2) (116 males, 8 females; mean age: 55.5±9.5 years; range, 33 to 82 years) were included. Age and sex of the patients, site of the primary tumor, TNM stage, type of the neck dissection, length of follow-up, and survival rates were evaluated. The tumors were classified into three groups according to their relationship with the median line of the larynx, and the neck dissections were recorded as unilateral or bilateral. Recurrences and survival outcomes were evaluated. RESULTS: There was no statistically significant difference in the recurrences according to tumor site groups (p=0.39). Similarly, there was no statistically significant difference in 10-year overall survival rates in patient groups according to the tumor site (p=0.072). We found no statistically significant difference in 10-year overall survival rates between the patients who underwent unilateral and bilateral neck dissection (p=0.580). CONCLUSION: Long-term survival analysis of 124 patients with supraglottic carcinoma did not show a survival benefit of elective contralateral neck dissection in lateralized supraglottic cancer with contralateral clinically negative neck.

Metastasis and Tumor Cell Migration of Solid Tumors

The developmental process of local and distant metastases represents the major and defining trait of malignant tumors, whereby tumor cells sustain the capability to migrate from the initial tumor site, seed, and grow at a location other than that of the initial tumor [...]