Babol University of Medical Sciences

Patients with inborn errors of immunity (IEI) are susceptible to developing cancer due to defects in the immune system. The prevalence of cancer is higher in IEI patients compared to the immunocompetent population and cancers are considered as an important and common cause of death in IEI patients.

To systematically review demographic, genetic and cancer-related data of IEI patients with a history of malignancy. Moreover, we performed a meta-analysis aiming to determine the frequency of cancer in patients with different types of IEI.

We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (until September 2023) introducing terms related to IEI and cancer. Studies with human subjects with confirmed IEI who had developed at least one malignancy during their lifetime were included.

A total number of 4607 IEI patients with a cancer history were included in the present study. Common variable immunodeficiency (CVID) had the highest number of reported cases (1284 cases), mainly due to a higher relative proportion of patients with predominantly antibody deficiencies (PAD) and their increased life expectancy contributing to the higher detection and reporting of cancers among these patients. The most common malignancy was hematologic/blood cancers (3026 cases, mainly diffuse large B cell lymphoma). A total number of 1173 cases (55.6%) succumbed to cancer, with the highest rate of bone marrow failure (64.9%). Among the patients with monogenic defects in IEI-associated genes, the majority of cases had ATM deficiency (926 cases), but the highest cancer frequency rate belonged to NBS1 deficiency (50.5%). 1928 cases out of total 4607 eligible cases had detailed data to allow further statistical analysis that revealed BRCA2 deficiency had the earliest cancer development (~ 38 months), lowest cure frequency, and highest fatality rate (85%), while ATM deficiency had the lowest cure frequency and highest fatality rate (72%) among total cases reviewed with exclusion of Fanconi anemia.

The overall reported cancer frequency in the cases reviewed with and without exclusion of Fanconi anemia was 11.1% (95% confidence interval: 9.8-12.5%) and 12.0% (95% confidence interval: 10.6-13.5%), respectively. Our study revealed that the incidence of cancer is significantly dependent on the molecular and pathway defects in IEI patients, and individualized early screening and appropriate treatment, might improve the prognosis of these patients.

Certain types of non-Hodgkin lymphoma, such as Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL), often necessitate multiple treatment approaches. One promising avenue is immune checkpoint inhibition, specifically targeting the programmed cell death protein 1 (PD-1). Pembrolizumab, an immunotherapy medication, acts by inhibiting the PD-1 pathway and has gained approval from the United States Food and Drug Administration (FDA) for treating various cancers, including melanoma, Hodgkin lymphoma, lung cancer, and endometrial cancer. This meta-analysis aims to assess the impact of pembrolizumab on patient outcomes and survival in the context of B-cell lymphoma.

This study adhered to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two independent reviewers conducted a thorough search of electronic databases up to September 28, 2023. We included studies that investigated the effects of pembrolizumab treatment on patient outcomes and survival in individuals diagnosed with B-cell lymphoma. All statistical analysis was performed by STATA V.17.

Our meta-analysis encompassed 13 eligible clinical trials involving 426 B-cell lymphoma patients. The study findings revealed a Disease Control Rate (DCR) of 63%, Overall Response Rate (ORR) of 42%, Complete Response Rate (CRR) of 23%, and 1-year Overall Survival Rate (OSR) of 64%. Notably, 65% of patients experienced Treatment-Related Adverse Events (TRAEs) of any grade, with 39% encountering grade ≥ 3 TRAEs. The most prevalent grade ≥ 3 TRAEs included anemia, neutropenia, thrombocytopenia, and lymphopenia.

The utilization of pembrolizumab, both as a monotherapy and in combination with other drugs, presented encouraging outcomes in patients with B-cell lymphoma.

The hepatocyte growth factor (HGF)/MET signaling pathway plays a pivotal role in cancer progression, metastasis, and therapeutic resistance, making it an attractive target for anticancer therapies. HGF, a multifunctional cytokine, binds to the MET receptor, triggering downstream pathways such as PI3K/AKT, MAPK/ERK, and STAT3, which regulate cell proliferation, survival, and epithelial-mesenchymal transition (EMT). Dysregulation of this pathway-through mutations, amplifications, or overexpression-contributes to tumorigenesis, drug resistance, and poor prognosis in various cancers, including lung, breast, gastric, and hepatocellular carcinomas. This review explores the molecular mechanisms of HGF/MET in cancer, highlights the therapeutic potential of natural compounds, and discusses ongoing clinical trials targeting this pathway. Despite advances in targeted therapies, resistance to MET inhibitors remains a clinical challenge, necessitating alternative strategies. Natural compounds, including flavonoids, curcumin, ginger derivatives, epigallocatechin-3-gallate (EGCG), honokiol, metformin, and resveratrol, exhibit potent inhibitory effects on the HGF/MET axis. These phytochemicals modulate MET expression, disrupt downstream signaling, and reverse chemoresistance by targeting key oncogenic mechanisms such as EMT, cancer stem cell (CSC) maintenance, and tumor microenvironment interactions. For instance, flavonoids like apigenin and quercetin suppress MET-mediated invasion, while curcumin inhibits PI3K/AKT/mTOR signaling. EGCG and honokiol demonstrate synergistic effects with conventional therapies, overcoming resistance in non-small cell lung cancer (NSCLC) and renal cell carcinoma. By synthesizing preclinical and clinical findings, this work highlights the therapeutic potential of phytochemicals as adjunctive or alternative agents, offering innovative approaches to enhance the efficacy and outcomes of cancer treatments.