Influence of AFP On Surgical Outcomes in Non-B Non-C Patients With Curative Resection For Hepatocellular Carcinoma

Objective: To study the clinical and prognostic features of non-B non-C alpha-fetoprotein (AFP) (-)-hepatocellular carcinoma (HCC) (NBNC-AFP(-)-HCC), and the relationship between the prognostic features of HCC and hepatitis B virus surface antigen (HBsAg) status and AFP. Methods: We enrolled 227 patients underwent hepatic resection for HCC between January 1998 and December 2007 in Sun Yat-Sen University Cancer Center, all of them were diagnosed with HCC by pathology. All patients were stratified into one of four groups (B-AFP(+)-HCC, B-AFP(-)-HCC, NBNC-AFP(+)-HCC, and NBNC-AFP(-)-HCC) according to AFP levels and HBsAg status. The clinicopathologic and survival characteristics of NBNC-AFP(-)-HCC patients were compared with all other three groups. Results: Out of the 105 NBNC-HCC patients, 43 patients (40.9%) were AFP-negative HCC. There were some differences in factors between the B-AFP(+) and NBNC-AFP(-) patients, such as age, body mass index (BMI), diabetes, and ALT (P<0.05). On univariate analysis, tumor size, secondary tumor, and portal invasion were prognostic factors for overall survival (OS) and disease-free survival (DFS) (P<0.05). Cox multivariate regression analysis suggested that tumor size and tumor number (P<0.05) were independent predictors. In addition, compared with that in the B-AFP(+)-HCC, B-AFP(-)-HCC, and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had the best DFS (P<0.05). Compared with that in the B-AFP(+)-HCC and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had better OS(P<0.05), and survival rates were similar to those of B-AFP(-)-HCC patients. Conclusion: NBNC-AFP(-)-HCC patients had a relatively favorable prognosis. It can serve as a useful marker in predicting the risk of tumor recurrence in the early stages.

The Role of Extracellular Vesicles in the Progression of Tumors towards Metastasis

Extracellular vesicles (EVs) are cell-derived lipid membrane bound vesicles that serve as mediators of intercellular communication. EVs have been found to regulate a wide range of cellular processes through the transference of genetic, protein and lipid messages from the host cell to the recipient cell. Unsurprisingly, this major mode of intracellular communication would be abrogated in cancer. Ever increasing evidence points towards a key role of EVs in promoting tumor development and in contributing to the various stages of metastasis. Tumor released EVs have been shown to facilitate the transference of oncogenic proteins and nucleic acids to other tumor cells and to the surrounding stromal cells, thereby setting up a tumor permissive microenvironment. EVs released from tumor cells have been shown to promote extracellular matrix (ECM) remodeling through the modulation of neighboring tumor cells and stromal cells. EVs released from disseminated tumor cells have been reported to attract circulating tumor cells (CTCs) via chemotaxis and induce the production of specific extracellular matrix components from neighboring stromal cells so as to support the growth of metastatic cells at the secondary tumor site. Circulating levels of tumor derived EVs of patients have been correlated with incidence of metastasis and disease relapse.

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

Background Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer. Methods Mice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter. Results NBTXR3 + HDXRT + LDXRT + ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3 + HDXRT + LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice. Conclusions NBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response. Graphical Abstract

Analysis of influencing factors and prognosis of early postoperative recurrence, secondary tumor and metastasis of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world and it accounts for more than 90% of oral cancers. In this study, we tried to estimate the risk of early postoperative recurrence, secondary tumor and metastasis of OSCC to predict the patient's prognosis according to its clinical condition to help increase their survival by screening high-risk patients. 153 patients with OSCC who were over 40 years of age were studied during 1985-2020. The influencing factors included gender, race, stage of tumor progression, treatment method, histological grade and tumor location, date of diagnosis and death, which were analyzed by the Markov multi-state model. Also, their saliva was sampled to determine the amount of Matrix Metalloproteinase13 (MMP13). Following-up of patients for 60 months showed that one year after the end of treatment, the probability of death was almost the same for patients with early postoperative recurrence or secondary tumor, but after 5 years, patients with early postoperative recurrence are at higher risk of death. Also, the MMP13 amount in the saliva of patients showed that high levels of MMP13 belonged to metastasis of OSCC than early postoperative recurrence and secondary tumor. Therefore, patients with more amount of MMP13 are more involved in metastasis than early postoperative recurrence and secondary tumor. Approximate knowledge of OSCC patients' next state and time according to their clinical condition can be one of the ways of timely diagnosis and treatment and thus reduce their mortality rate.

Clinical Characteristics, Treatment Outcomes, And Genetic Alterations of Radiation-Induced Gliomas

Purpose: We aimed to elucidate the clinical characteristics, treatment outcomes, and genetic alterations in patients with radiation-induced glioma (RIG).Methods: Patients with high-grade glioma who satisfied the Cahan’s criteria for RIG in our database during 2001–2021 were included. Isocitrate dehydrogenase (IDH) 1 and 2, telomerase reverse transcriptase (TERT) promoter, B-Raf (BRAF), and histone H3.3 (H3F3A) and methylation status of the O-6-methylguanine DNA methyltransferase (MGMT) promoter were analyzed. Methods: We identified 11 patients with RIG, including 7 glioblastoma (GBM), IDH1/2-wildtype; 2 GBM, not otherwise specified (NOS); 1 anaplastic astrocytoma (AA), IDH1/2-wildtype; and 1 AA, NOS. The median latency period was 17 years (range: 9–30 years). The median progression-free survival (PFS) and median survival time (MST) were 11.3 months and 28.3 months, respectively. The median PFS in patients treated with initial reirradiation (N = 5) tended to be longer than that in patients without initial reirradiation (N = 6) (17.0 vs 8.1 months; p = 0.51), but not MST (29.6 vs 27.4 months; p = 0.28). There were no alterations in IDH1/2, TERT promoter, BRAF and H3F3A mutations. Two tumors had a hypermethylated MGMT promoter. In one case, different IDH2 mutation status between primary and secondary tumor was useful to diagnose the secondary tumor as RIG. Conclusions: RIG may occur more than 20 years after the treatment for primary disease; therefore, long-term follow-up is needed. Reirradiation could be a therapeutic option for RIG. Identifying IDH1/2 mutation status has a diagnostic impact on establishing RIG in cases of recurrent glioma.

Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication

BackgroundClinical success of therapeutic cancer vaccines depends on the ability to mount strong and durable antitumor T cell responses. To achieve this, potent cellular adjuvants are highly needed. Interleukin-1β (IL-1β) acts on CD8+ T cells and promotes their expansion and effector differentiation, but toxicity and undesired tumor-promoting side effects hamper efficient clinical application of this cytokine.MethodsThis ‘cytokine problem’ can be solved by use of AcTakines (Activity-on-Target cytokines), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to a priori selected cell types and as such evade toxicity and unwanted off-target side effects. Here, we employ subcutaneous melanoma and lung carcinoma models to evaluate the antitumor effects of AcTakines.ResultsIn this work, we use an IL-1β-based AcTakine to drive proliferation and effector functionality of antitumor CD8+ T cells without inducing measurable toxicity. AcTakine treatment enhances diversity of the T cell receptor repertoire and empowers adoptive T cell transfer. Combination treatment with a neovasculature-targeted tumor necrosis factor (TNF) AcTakine mediates full tumor eradication and establishes immunological memory that protects against secondary tumor challenge. Interferon-γ was found to empower this AcTakine synergy by sensitizing the tumor microenvironment to TNF.ConclusionsOur data illustrate that anticancer cellular immunity can be safely promoted with an IL-1β-based AcTakine, which synergizes with other immunotherapies for efficient tumor destruction.

Experience in the treatment of primary malignant tumors (retinoblastoma and osteosarcoma): analysis of the clinical case

Background. Retinoblastoma is a malignant intraocular tumor developing from the retinal neuroectoderm and diagnosed primarily in young children. This type of cancer is associated with a high risk of multiple primary tumors emerging after treatment completion. Multiple primary tumors are two or more independent tumors developing in one patient. Treatment of this disease is challenging.Objective – to evaluate the impact of risk factors on the efficacy of therapy for multiple primary tumors and to analyze treatment outcomes.Materials and methods. A 2-year-old boy was diagnosed with bilateral retinoblastoma (OD – stage T3bN0M0 and OS – stage T3cN0M0). He received special treatment from September 2005 to November 2006. In 2012, the patient underwent cataract surgery: the lens was removed, then an intraocular lens was installed, and laser dissection of the posterior capsule of the lens was performed. Six years later, in August 2018, the patient was diagnosed with osteosarcoma. The boy received combination organ-sparing therapy according to the EURAMOS-1 treatment protocol for osteosarcoma. During therapy, he developed a secondary tumor, namely osteoblastic osteosarcoma. Both the boy and his father were found to have a mutation in the RB1 gene.Results. Currently, patient’s condition is satisfactory; he has no complains. The boy is in remission for 2 years.Conclusion. The development of secondary tumors depends on the genetic factors, type of treatment for primary tumor, and environmental factors. Therefore, it is extremely important to assess risk factors for multiple primary tumors at the moment of primary retinoblastoma detection. The results of such assessment will help to choose an optimal treatment strategy.

Synovial Sarcoma of the Extremities: A Literature Review

Synovial sarcoma (SS) is a rare and highly malignant tumor and a type of soft tissue sarcoma (STS), for which survival has not improved significantly in recent years. Synovial sarcomas occur mostly in adolescents and young adults (15–35 years old), usually affecting the deep soft tissues near the large joints of the extremities, with males being at a slightly higher risk. Despite its name, synovial sarcoma is neither related to the synovial tissues that are a part of the joints, i.e., the synovium, nor does it express synovial markers; however, the periarticular synovial sarcomas can spread as a secondary tumor to the joint capsule. SS was initially described as a biphasic neoplasm comprising of both epithelial and uniform spindle cell components. Synovial sarcoma is characterized by the presence of the pathognomonic t (X; 18) (p11.2; q11.2) translocation, involving a fusion of the SS18 (formerly SYT) gene on chromosome 18 to one of the synovial sarcoma X (SSX) genes on chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SSs and results in the formation of SS18-SSX fusion oncogenes.