Anticancer research最新文献

Background/aim: The local immune response in colorectal cancer is closely related to prognosis and therapeutic efficacy. In this study, histological analyses were performed to determine the phenotype of tumor-infiltrating lymphocytes (TILs) and their infiltration in the stromal and intratumoral regions, aiming to elucidate their interactions and prognostic effects.

Patients and methods: Multiplex fluorescent labeling was performed using surgically resected colorectal cancer specimens to investigate the infiltration of CD45RO (+) TILs, which exhibit cytotoxicity, and subsets of CD4 (+) TILs, identified by their characteristic transcription factor expression.

Results: The degree of CD45RO (+) TIL infiltration in the entire observation field or stromal area was not associated with prognosis. However, a high degree of infiltration in the tumor nest (intratumoral area) was significantly associated with a favorable prognosis. CD4 (+) TILs and their subsets were not associated with prognosis. However, stratified analyses revealed that a high degree of infiltration of stromal CD4 (+) TILs and the subsets T helper (Th)1, Th2, Th17, and regulatory T cells is necessary for the association between high intratumoral CD45RO (+) TIL infiltration and favorable prognosis.

Conclusion: A sufficient degree of infiltration of stromal CD4 (+) TIL subsets is required for intratumoral CD45RO (+) TILs to exert toxicity against cancer cells. This highlights the significance of stromal immune reactions in achieving effective cytotoxic immune responses in the intratumoral area and demonstrates the critical role of the spatial distribution pattern of TILs in exerting their functions.

Background/aim: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer.

Case report: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects.

Conclusion: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Background/aim: The tumor suppressor CDKN2C (also designed as p18^INK4C or p18) is deleted in approximately 7% to 40% of multiple myeloma (MM) patients, indicative of its potential association with myeloma pathogenesis.

Materials and methods: A quantitative real-time PCR-based assay was developed to determine p18 deletion in DNA from peripheral blood mononuclear cells (PBMCs) in a cohort of 108 multiple myeloma patients after autologous stem cell transplant (ASCT). Additionally, the p18 mRNA expression level in PBMCs was quantitatively assessed using Taqman^® gene expression assays.

Results: p18 was homozygously and hemizygously deleted in PBMCs from 3 (2.8%) and 5 (4.6%) patients, respectively. Neither the p18 deletion nor the p18 mRNA levels in PBMCs were associated with progression-free survival (PFS), 90-day response, and the occurrence of severe mucositis in these patients (all p-values >0.20).

Conclusion: Neither p18 deletion nor p18 mRNA expression in PBMCs can be used as a prognostic biomarker in MM patients.

Background/aim: Recent studies suggest that PD-L1 expression in immune cells, rather than tumor cells, plays a key role in tumor immunity. Trefoil factor family 1 (TFF1) is a secreted protein expressed mainly by the gastrointestinal epithelium and is related to the development of malignant disease. This study investigated the effects of TFF1 on tumor immunity in a xenograft mouse model of colorectal cancer (CRC).

Materials and methods: MC38 cells were implanted in wild-type (WT) and TFF1KO mice, and the tumor micro-environment was investigated using immunohistochemistry. The circulating immune cells were analyzed using flow cytometry.

Results: Tumor growth was suppressed in TFF1KO mice. In the tumor microenvironment, CD8- and CD4-positive T cells and CD11c-positive dendritic cells (DCs) were frequently found in TFF1KO mice. When an immune checkpoint inhibitor was administered to these mice, almost half of the tumors in TFF1KO mice showed a complete response. The number of circulating PD-L1/DCs was markedly associated with tumor volume, with TFF1 deletion accelerating this effect and its injection decreasing it. These findings indicate that loss of TFF1 activates tumor immunity via frequent T-cell priming by DCs, and eventually suppresses tumor growth in CRC. In addition, the number of circulating PD-L1/DCs was identified as a predictive marker of checkpoint-inhibiting therapy efficacy.

Conclusion: Loss of TFF1 resulted in accelerated immune response to colorectal cancer. Further studies are needed to investigate the precise mechanisms of TFF1 in immunotolerance and develop a novel TFF1-inhibiting immunotherapeutic strategy for CRC.

Cancer immunotherapy activates the host immune system against tumor cells and has the potential to lead to the development of innovative strategies for cancer treatment. Neoantigens are non-self-antigens produced by genetic mutations in tumor cells that induce a strong immune response against tumor cells without central immune tolerance. Along with advances in neoantigen analysis technology, the development of vaccines focusing on neoantigens is being accelerated. Whereas there are various platforms for neoantigen vaccines, combined immuno-therapies are being developed simultaneously with the clinical application of synthetic long peptides and mRNA and dendritic-cell (DC)-based vaccines. Personalized DC-based vaccines not only can load various antigens including neoantigens, but also have the potential to elicit a strong immune response in T cells as antigen-presenting cells. In this review, we describe the properties of neoantigens and the basic characteristics of DCs. We also discuss the clinical applications of neoantigen vaccines, focusing on personalized DC-based vaccines, as well as future research and development directions and challenges.

Background/aim: TP53 mutation in breast cancer (BC) is associated with chemoresistance, endocrine therapy resistance, and late recurrence, resulting in poor prognosis. Nuclear accumulation of p53 in immunohistochemistry (IHC) is a surrogate marker of TP53 mutation. This study analyzed the frequency, type, and distribution of TP53 mutations in BCs and assessed the efficacy of p53 IHC as a surrogate marker of TP53 mutation.

Patients and methods: We collected data from 112 BC cases, including the results of p53 IHC and next-generation sequencing (NGS).

Results: Over-expression of p53 IHC was observed in 36 patients (32.1%), complete absence in 19 patients (17.0%), aberrant cytoplasmic staining in 1 patient (0.9%), and wild-type in 56 (50.0%) patients. The concordance rate between TP53 mutation and p53 IHC was 88.4% in all BCs, 89.9% in luminal BCs, and 86.0% in triple-negative BCs (TNBC). TNBC, abnormal p53 IHC pattern, p53 IHC over-expression, neoadjuvant chemotherapy (NAC) history, TP53 mutation, and high pre-treatment ki-67 labeling index (≥50%) were significantly associated with worse distant metastasis-free survival (DMFS) and overall survival (OS) (p<0.05). Pre-NAC clinical stage III was associated with worse DMFS but not OS. Multivariate analysis showed that NAC history, TNBC, and p53 IHC over-expression were independent predictors of worse DMFS. An abnormal p53 IHC pattern and NAC history were independent predictors of worse OS.

Conclusion: P53 IHC is a valid surrogate marker of TP53 mutation in BC. Accumulation of abnormal p53 alone, regardless of TP53 mutation, was associated with worse DMFS and can be used as an easily accessible biomarker to predict chemoresistance.

Background/aim: In breast cancer (BC) patients who have received breast-conserving surgery, moderate hypofractionation is standard of care for whole-breast irradiation (HF-WBI). On the other hand, the fractionation schedule for the boost is less well defined. A previous prospective study of our group aimed at evaluating acute and late cutaneous and subcutaneous side effects related to a sequential hypofractionated boost (HB) in patients who had received HF-WBI. The present study aimed at evaluating late side effects at a longer follow-up.

Patients and methods: From 2014 to 2015, 219 BC patients received moderate HF-WBI (42.4 Gy in 16 fractions) at the Radiation Oncology Section of the University of Perugia. Patients with negative prognostic factors received a HB (2.65 Gy for 4 or 5 fractions). Late side effects were assessed using the Common Terminology Criteria for Adverse Events v5.0. Univariate and multivariate analyses estimated predictive factors for late toxicity.

Results: Median follow-up was 8.6 years (range=6.7-9.6). One hundred and sixty-five patients were evaluable in the present analysis; HB was administered to 47.3% of them. Late cutaneous and subcutaneous side effects occurred in 26/165 patients (15.8%); and all were G1. In univariate analysis ≥10 excised lymph nodes and HB administration emerged as risk factors for late side effects (p=0.003 and p=0.041, respectively). In multivariate analysis only ≥10 excised lymph nodes were confirmed as a risk factor for side effects (OR=3.431; 95%CI=1.209-9.737).

Conclusion: HB after HF-WBI was safe and well-tolerated, even at a long-term follow-up; consequently, it can be used in routine practice.

Background/aim: No clear treatment strategy for simultaneously detected liver and lung metastases (SLLM) of colorectal carcinoma has been established, to date. We aimed to identify the prognostic factors for SLLM and propose an appropriate treatment option.

Patients and methods: This retrospective study included 64 patients with SLLM: 32 underwent pulmonary resection after hepatectomy in 32, while the other 32 underwent hepatectomy alone in 32. Poor prognostic factors and a suitable strategy for SLLM were assessed.

Results: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) level ≥20 ng/ml (p=0.001) and unresected lung metastases (p=0.001) were independent prognostic factors for poor overall survival. Compared with the non-pulmonary resection group, the rate of R1 resection of liver tumors (46.8% vs. 15.6%; p=0.007), incidence of complications after hepatectomy (Clavien-Dindo grade ≥III: 21.8% vs. 0%; p=0.005) and having four or more metastatic lung nodules (40.6% vs. 3.2%; p=0.001) were significantly higher in the group that underwent hepatectomy only.

Conclusion: Preoperative CEA ≥20 ng/ml and unresectable pulmonary nodules were prognostic factors for poor survival of patients with SLLM. Furthermore, the presence of more than four pulmonary nodules was a preoperative predictive factor for unresectable pulmonary nodules. R1 resection and the occurrence of complications after hepatectomy should be avoided; a smooth transition from hepatectomy to pulmonary resection is important.

The transcription factor hypoxia inducible factor-1 (HIF-1) is one of the main factors in the cell's response to a lack of oxygen. Hypoxia is a typical feature of a growing cancerous tumor. Increased activity of HIF-1 is observed in many cancers, including endometrial cancer. HIF-1 functions as a heterodimer consisting of three subunits HIF-1α, HIF-2α, and HIF-3α and one subunit β. HIF-1α is a subunit that is sensitive to oxygen concentration and is constitutively expressed. The HIF-1α gene is highly polymorphic. Literature data suggest that single nucleotide polymorphisms (SNPs) of the HIF-1α gene may be risk factors for endometrial cancer. A better understanding of the molecular mechanisms of cancer development, progression and prognosis, including the role of SNPs, could lead to the development of new anti-cancer therapies.

Background/aim: How tumors regulate the genes of the coagulome is crucial for cancer-associated thrombosis and the occurrence of venous thromboembolic complications in patients with cancer. We have previously reported potent yet complex effects of glucocorticoids (GC) on the expression of three genes that play a key role in the regulation of thrombin/plasmin activation (F3, PLAU, and SERPINE1). This study aimed to extend the investigation of GC effects to the whole tumor coagulome and assess the resulting impact on the ability of cancer cells to activate thrombin and plasmin.

Materials and methods: Cancer RNA expression data were retrieved from various sources. Additionally, oral squamous cell carcinoma (OSCC) cells exposed to GC in vitro were analyzed using QPCR, enzymatic assays measuring thrombin and urokinase-type Plasminogen Activator (uPA) activity, and D-dimer concentrations.

Results: Our findings highlight the potent and specific stimulatory effect of GC on SERPINE1 expression across different types of cancer. Consistently, GC were found to inhibit uPA proteolytic activity and reduce the concentrations of D-dimers in OSCC in vitro.

Conclusion: Fibrinolysis inhibition is a key consequence of cancer cell exposure to GC, possibly leading to the stabilization of the fibrin clot in cancer.