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To simultaneously compare the efficacy and safety of small-molecule Human Epidermal Growth Factor Receptor 2 (HER2)-targeting tyrosine kinase inhibitor (TKI)-containing regimens for metastatic HER2-positive breast neoplasm. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Web of Science, and Scopus databases were systematically searched to identify randomized clinical trials (RCT) that investigated the difference in overall survival (OS), progression-free survival (PFS), overall response (OR), recurrence in central nervous system/brain metastasis (RCNS), total and grade 3 or 4 adverse events (AE), diarrheal AEs, and cardiac AEs of small-molecule HER2-targeting TKI-containing regimens in women with metastatic HER2-positive breast carcinoma. The revised Cochrane risk-of-bias tool for randomized trials (RoB2) was used to evaluate the risk of bias in the included studies. When applicable, pooled network estimates were synthesized by frequentist random-effect network meta-analysis using Stata MP Software (version 14). Twenty-three studies comprising 7497 eligible patients were included. In all, 17 small-molecule anti-HER2 TKI (Lapatinib, Neratinib, Afatinib, Pyrotinib, and Tucatinib)-containing and 10 other regimens were compared. In terms of increasing OS, the Pyrotinib/Capecitabine combination ranked first best among small-molecule HER2-targeting TKI-containing regimens. In terms of PFS, the Pyrotinib/Capecitabine combination prolonged PFS in comparison with all other small-molecule anti-HER2 TKI-containing regimens in the network. In the corresponding network, Pyrotinib/Capecitabine and Tucatinib/Trastuzumab/Capecitabine combinations ranked first best and second best among small-molecule anti-HER2 TKI-containing regimens. In terms of AE, the Tucatinib/Trastuzumab/Capecitabine combination ranked the highest for AE occurrence. Pyrotinib/Capecitabine and Tucatinib/Trastuzumab/Capecitabine combinations seemed to be the most efficacious small-molecule HER2-targeting TKI-containing regimens in metastatic HER2-positive breast cancer.

Recently, immunotherapy has emerged as an innovative approach for the management of various cancers, particularly those in advanced stages. Among these novel interventions, immune checkpoint inhibitors have gained significant attention. Given the observed efficacy of these pharmaceutical agents in treating a range of solid tumors, such as metastatic melanoma, they present a promising therapeutic strategy for managing metastatic and advanced colorectal cancer (CRC). The high mortality and incidence rates associated with CRC, coupled with its substantial societal burden, underscore the critical need to assess the effectiveness and safety of this emerging treatment modality. The objective of this research is to evaluate the impact of diverse immune checkpoint inhibitors on the mortality and survival rates of patients with advanced CRC.

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the two common types of pediatric leukemia. Despite conventional therapy, treatment failure and poor survival are observed in children with leukemia. Adoptive cell therapy needs to get more advanced to overcome high-risk pediatric leukemia. Dendritic Cells and cytokines are two influential factors in natural killer (NK) cell therapy. However, no defined effect of killer-cell immunoglobulin-like receptor (KIR) on NK cells has been obtained. Moreover, a combination of checkpoint fusion protein with chimeric antigen receptor (CAR) T-cell therapy can highly improve the anti-tumor function of T cells. Biomarkers, namely serum cytokines, MicroRNAs (miRs), ADAM6, CD200 and CD123, sGRP78 and CXCR4, and Semaphorin 4D (Sema4D) are helpful in finding patients with a risk of relapse, and an appropriate treatment approach, or act as a potential targetable marker. In this review, the clinical and preclinical/animal studies with the purpose of diagnosis and treatment of relapsed or refractory pediatric leukemia are discussed. Preclinical/animal ACT studies have shown improvements in the treatment of children with high-risk leukemia. However, clinical studies are required to verify the efficacy of these approaches for the treatment of childhood leukemia.

Brain metastasis (BM) is a common form of cancer that affects the central nervous system and has a significant impact on the life expectancy and quality of patients. Despite conventional treatments like surgery, chemotherapy, and radiotherapy, managing BM is challenging, and success rates are low. Immune checkpoint inhibitors (ICIs) have emerged as promising new therapies for advanced cancers and work by reversing the immune-evasive characteristics of tumor cells. ICIs have shown efficacy in various malignancies, prompting researchers to evaluate their efficacy in BM. Previously, the exclusion of BM patients from clinical trials was common due to the brain's immune-privileged nature. However, recent studies have demonstrated immune cell trafficking in and out of the brain, leading to several studies investigating the ICIs' application in BM patients. This study aimed to provide further evidence supporting the beneficial effects of ICIs in treating BM, as evidenced by improved response duration and survival time.

Brain Metastasis; Immune Checkpoint Inhibitors (ICIs); Anti-PD-1/Anti-PD-L1; Anti-CTLA-4; Anti-LAG-3

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and the leading cause of childhood death in contrast to the 90% cure rate. ALL includes different subtypes described by interrupt collections of somatic chromosomal alterations and sequence mutations that disrupt normal body functions such as lymphoid maturation, cell-cycle regulation, and tumor suppression. Having a significant role in several cancers, the high mobility group box-1 (HMGB1) gene is considered an important gene in the development of tumors.

Methods: Herein, the genetic role of HMGB1 was studied in the 49 Iranian patients with newly diagnosed ALL using Sanger sequencing of HMGB1 coding regions (exons 2 to 5).

Results: The results showed that none of the subjects in the study had any promising variants in the coding sequences of the HMGB1.

Conclusion: These findings suggest that HMGB1 is not directly associated with ALL incidence and behavior. Further investigations using a large group of patients with different races and ethnicities are required to analyze the possible role of HMGB1 gene polymorphisms in ALL patients.

Background: Radiotherapy (RT) is vital in cancer treatment, inducing tumor cell death and anti-tumor immunity. However, it can also enhance immunosuppressive factors like CD47 and PD-L1. While RT-immunotherapy combinations show promise, optimal strategies remain unclear. This study examines the impact of different RT regimens on the tumor immune microenvironment (TME) to guide more effective treatment approaches.

Methods: We treated CT26 tumor-bearing mice with three distinct RT regimens under the same biological equivalent dose (BED).

Result: We observed that the frequency of both tumor-infiltrating CD4+ and CD8+ cells were increased after ablative and hypo RT, although single high dose exposure in an ablative scheme led to a greater extent of CD8+ cells infiltration and increased the expression of IFNγ in those cells. While conventional RT enhanced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, the Ablative and hypo schemes induced regulatory T cells (Tregs) enrichment. The two hypofractionated regimens enhanced the expression of CD47 as well as the PD-1/PD-L1 axis, although PD-1 and its ligand (PD-L1) expression were temporarily induced by conventional RT on tumor-infiltrating lymphocytes and tumor cells, respectively.

Conclusion:The results suggest targeting the recruitment of MDSC and Treg are, respectively, crucial for therapeutic efficacy of conventional and hypofractionated RT regimens. Furthermore, anti-PD-1/PD-L1 and anti-CD47 treatments are necessary to improve the anti-tumor response from the hypofractionated schemes.

Background: Cancer-associated fibroblasts (CAFs) play an important role in the initiation and progression of tumor cells. These cells can trigger signaling pathways involved in tumor progression. HOTAIR, an increased long non-coding RNA (lncRNA) in breast cancer, has a vital role in the tumorigenesis and development of breast cancer cells.

Methods: In this study, a fibroblast cell culture medium was used to investigate its possible role in inducing the HOTAIR expression and PI3K/Akt/mTOR pathway in breast cancer cells. CAFs and normal fibroblasts (NFs) were isolated from tumors of 6 patients with breast cancer and subjects with healthy breasts, respectively. The MCF-7 cells were cultured in a medium obtained from CAFs (CAF-CM) or NFs (NF-CM), and then the expression of HOTAIR and PI3K/Akt/mTOR in MCF-7 cells was assessed using Real-Time PCR. HOTAIR was silenced in MCF-7 cells using siRNAs and then cultured in CAF-CM or NF-CM. Subsequently, the phosphorylation status of PI3K/Akt/mTOR proteins was analyzed by western blotting.

Results: Fibroblast culture medium enhanced the expression of HOTAIR and activation of the PI3K/Akt/mTOR pathway in breast cancer cells. By HOTAIR silencing, reduced activity of the PI3K/Akt/mTOR pathway, as well as the lower effect of fibroblast culture medium in the induction of PI3K/Akt/mTOR pathway, was seen.

Conclusion: HOTAIR can play a role as a mediator in inducing the PI3K/Akt/mTOR pathway in breast cancer cells by the effect of cancer-associated fibroblast cells.