Anticancer research最新文献

Background/aim: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype, posing numerous challenges in clinical decision-making. Biomarkers are essential to personalize management of TNBC patients. While tumor infiltrating lymphocytes (TILs) are validated prognostic biomarkers, the requirement for tumor biopsy limits their routine use. Therefore, more accessible and reliable quantitative biomarkers are needed. Given the significant role of systemic inflammatory response in tumor onset and progression, assessing inflammatory cells via liquid biopsies emerges as a promising alternative.

Patients and methods: The PERCEPTION study, conducted at Centre Jean Perrin in France, aims to determine the correlation between TILs and peripheral blood components at diagnosis. An interim analysis was conducted after enrolling 50% of the estimated population, to evaluate study feasibility and preliminary correlations between blood cell counts and TILs.

Results: Sixty-one patients were enrolled over 4.5 years, demonstrating a good inclusion rate with minimal missing data. Preliminary results for 36 analyzable patients showed no correlation between the neutrophil-to-lymphocyte ratio (NLR) and TILs (r_s=-0.19, 95%CI=-0.49-0.16, p=0.3). However, a moderate, positive, statistically significant correlation was found between NLR and the CD8/FoxP3 TILs ratio (r_s=0.36, 95%CI=0.03-0.64, p=0.043). The probabilistic index of 0.7 (p=0.06) between NLR-high and NLR-low groups for this ratio supports the correlation.

Conclusion: The interim analysis of the PERCEPTION study confirms the feasibility of correlating blood cell counts with TILs in TNBC. Although no significant correlation was observed between NLR and TILs, the moderate positive correlation between the CD8/FoxP3 ratio and TILs suggests a potential link between systemic inflammation and local immune response. These findings underscore the potential of blood-based markers as non-invasive surrogates for TILs, encouraging further research to enhance prognosis and guide treatment strategies in TNBC.

Background/aim: During low anterior rectal resection for rectal cancer, a protective ileostomy (PI) is routinely created to reduce the severity of anastomotic complications. The aim of this study was to investigate the side-effects of PI during adjuvant chemotherapy.

Patients and methods: A retrospective cohort of patients was operated on for non-metastatic rectal cancer with a PI during 2005-2022. Patients treated with adjuvant chemotherapy (AC) were compared with those not receiving AC. A subgroup analysis compared patients with early PI closure (<10 weeks) and those with a PI in place during chemotherapy.

Results: A total of 242 patients were included: 178 (73.6%) without adjuvant chemotherapy and 64 (26.4%) with. History, tumour location, neoadjuvant treatment and postoperative follow-up were similar for both groups. Patients treated with AC had a greater risk of renal failure (37.5% vs. 14.6%, p=0.0002), ionic disorders (45.3% vs. 26.9% p=0.008), malnutrition (23.4% vs. 5.6%, p=0.0002) and rehospitalization (35.9% vs. 18.5% p=0.007). Patients treated with AC needed significant dose adjustments of oxaliplatin in 40.6% of cases, this adjustment being higher in patients with a PI compared to patients with early closure (47.1 vs. 9.1%, p=0.021).

Conclusion: Presence of a PI during chemotherapy predisposes to increased episodes of renal failure, and requires major adaptation of chemotherapy doses, especially of oxaliplatin.

Background/aim: Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related deaths worldwide. Adavosertib (AZD1775), a small molecule inhibitor of WEE1 kinase, abrogates G₂/M cell cycle arrest and induces double-stranded DNA breaks. According to previous findings, adavosertib, in combination with other DNA-damaging agents, causes premature mitosis and cell death in p53-mutated cancer cells mainly via abrogation of the G₂/M cell cycle checkpoint. This study aims to evaluate the inhibition of WEE1 kinase by adavosertib as monotherapy in the TP53-wildtype human CRC cell line HCT116.

Materials and methods: In this study, HCT116 cells were treated with different concentrations of adavosertib for 24 to 72 hours. Cell viability was assessed by Water-Soluble Tetrazolium 1 (WST-1) assay and crystal violet assays. Cell migration was evaluated by the wound healing assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry.

Results: The IC₅₀ value of adavosertib for the HCT116 cell line was 0.1310 μM. Adavosertib monotherapy (both 0.125 and 0.250 μM) significantly reduced cell viability, inhibited cell migration and abrogated intra-S phase cell cycle arrest. In addition, 0.250 μM of adavosertib significantly induced apoptosis in HCT116 cells.

Conclusion: Adavosertib effectively inhibits the TP53-wildtype HCT116 cells via the abrogation of intra-S phase cell cycle arrest. Our findings suggest that adavosertib monotherapy may be a potential targeted therapy for CRC.

Background/aim: Cancer-associated systemic inflammatory response is a pivotal indicator of tumor progression and prognosis in various cancers. "Lymphocyte × albumin (LA)" is a prognostic inflammatory marker in rectal cancer. This study examined the correlation between LA, complete adjuvant chemotherapy (ACT), and prognosis in patients with gastric cancer (GC) who underwent radical gastrectomy.

Patients and methods: We retrospectively evaluated 108 patients with stage II/III GC who underwent radical gastrectomy at our institute between January 2015 and December 2021. Survival was assessed using Kaplan-Meier and Cox regression analyses. Factors associated with complete ACT were identified using logistic regression analysis.

Results: Of the 108 patients with GC, 60 (55.6%) and 41 (38.0%) initiated and completed ACT, respectively. In multivariate analysis, the pre-operative LA was an independent factor for complete ACT [hazard ratio (HR)=0.35, 95% confidence interval (CI)=0.121-0.995; p=0.049]. In addition, age, pre-operative creatinine clearance, neutrophil-to-lymphocyte ratio, modified Glasgow prognostic score, and poor overall survival were significantly associated with low LA (<7,474). LA was an independent prognostic factor for overall survival in univariate analysis (HR=2.29, 95%CI=1.020-5.145; p=0.045) but not in multivariate analysis (HR=2.00, 95%CI=0.882-4.552; p=0.097).

Conclusion: Pre-operative LA is a useful marker for predicting complete ACT and prognosis of patients with GC following radical gastrectomy.

Background/aim: Peritoneal dissemination (PD) is a frequent cause of death in gastric cancer (GC), and there is evidence of an association between protease-activated receptor-1 (PAR1) and the development of PD. This study hypothesized that PD in GC might be influenced by PAR1.

Materials and methods: The cytotoxic effect of paclitaxel (PTX) on PAR1-transfected MKN45 (MKN45/PAR1) cells was analyzed using the MTT assay, and IC₅₀ values were determined. In female athymic nude mice, MKN45/PAR1 cells were suspended in 0.05 ml phosphate-buffered saline (PBS) medium and inoculated into the stomach mid-wall. In each group, intraperitoneal injections of PBS, PTX, SCH79797 (PAR1-antagonist), or PTX plus SCH79797 were administered on days 8, 15, and 22 following tumor inoculation. At 56 days after tumor inoculation, mice were examined for both abdominal tumor nodule status and size and weight of the tumors.

Results: The IC₅₀ of PTX for MKN45/PAR1 cells was 0.0697 μM and that of SCH79797 was 0.0145 μM. Mean survival of the MKN45/PAR1 mice in the PBS group was 28.75 days, whereas survival times for the mice treated with SCH79797, PTX, or a combination of PTX and SCH79797 were 31.2, 49.2, and 48.5 days, respectively. Tumor weight was smaller in the group receiving PTX and SCH79797 intraperitoneally compared with that in the PBS group (1,086±127.2 mg vs. 33.2±19.9 mg; p<0.001).

Conclusion: The PAR1 antagonist was found to inhibit PD in a PAR1-expressing GC cell line. PAR1 may serve as a promising therapeutic target for managing PD in gastric cancer, as it plays a crucial role in its progression.

Background/aim: Ferroptosis is a nonapoptotic type of cell death that is dependent on iron and involves the accumulation of reactive oxygen species. Ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) are ferroptosis regulators that inhibit ferroptosis through independent pathways. This study assessed the prognostic value of GPX4 and FSP1 expression in colorectal cancer (CRC). We also examined the effects of FSP1 and GPX4 inhibition on cell survival of CRC cells.

Materials and methods: This study included 206 surgical specimens from Stage II or III CRC patients. FSP1 and GPX4 expression was analyzed immunohistochemically, and the association of their expression levels with clinical outcome was evaluated. We also examined the effects of FSP1 and GPX4 inhibitors on the cell proliferative capacity of CRC cell lines.

Results: Overall survival and recurrence-free survival were reduced in patients with high expression of FSP1 or GPX4, and those with both GPX4 and FSP1 expression showed worse prognosis. Positivity of both FSP1 and GPX4 was an independent poor prognostic factor for CRC patients. In CRC cells, the combination of GPX4 and FSP1 inhibitors led to more effective cell death than either inhibitor alone.

Conclusion: High expression of both GPX4 and FSP1 is a significant poor prognostic factor for CRC. Simultaneous inhibition of GPX4 and FSP1 to induce ferroptosis may be a novel therapeutic strategy in CRC.

Background/aim: The randomized phase II COMPASS trial revealed that neither the regimen nor the number of courses of preoperative neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) significantly influence overall survival (OS). However, the impact of NAC regimens on OS may vary from patient to patient. The aim of this study was to identify biomarkers that can predict more appropriate individualized NAC regimens for improved prognosis using biopsy specimens from the COMPASS trial.

Patients and methods: RNA was extracted from endoscopic biopsy specimens of primary tumors obtained prior to NAC and real-time PCR analysis of 127 genes was conducted to identify those significantly affecting survival in the context of specific NAC regimens.

Results: THBS1, MSI1, and IGF2BP3 were identified as significant factors for stratifying survival among different NAC regimens, with statistically significantly interaction p values. Immunohistochemical analysis confirmed that the protein levels of THBS1, MSI1, and IGF2BP3 strongly correlated with their gene expression levels, validating these proteins as reliable biomarkers.

Conclusion: This study effectively identified THBS1, MSI1, and IGF2BP3 as promising biomarkers for personalizing NAC regimens in patients with locally advanced GC. By tailoring NAC based on these biomarkers, it is possible to enhance survival outcomes and advance personalized treatment strategies. The findings underscore the potential for incorporating biomarker-guided approaches into clinical trials, aiming to refine and optimize NAC regimens for improved patient-specific treatment efficacy.

Background/aim: The trend in today's surgical gynecological oncology is to provide equal oncological safety with less radical surgery. The SHAPE trial demonstrated the non-inferiority of a simple hysterectomy compared to a radical hysterectomy in low-risk cervical cancer. As a result, the accuracy of preoperative diagnostics has become increasingly important to avoid both under- and overtreatment. The aim of the study was to investigate the accuracy of MRI-based T-stage.

Patients and methods: Forty-five patients who were surgically treated for an initial diagnosis of a primary cervical carcinoma at the University Hospital Cologne in the Department of Gynecology and Obstetrics between 2015 and 2021 were included in the study. All patients underwent MRI prior to their surgical treatment.

Results: In 44.4% of cases, the pathological tumor size in the surgical specimen was consistent with the preoperative tumor size determined by MRI. In 28.9% of the cases, MRI overestimated the final pathologic T-stage while in 26.7% of cases, MRI underestimated it. Furthermore, we were able to show that overall survival was significantly poorer (p<0.05) in patients whose preoperative MRI had underestimated the final T-stage in our study cohort.

Conclusion: Preoperative MRI diagnostics alone are not reliable enough for accurate T-stage estimation. Multimodal diagnostic approaches are essential for accurate preoperative staging. Prospective trials are needed to evaluate preoperative staging strategies to optimize sizing accuracy.

Background/aim: Presurgical tumor volume progression in glioblastoma (GBM) may be a predictor of survival. This study aims to evaluate the potential impact of preoperative tumor growth and other clinical as well as laboratory parameters on overall survival (OS) of GBM patients.

Patients and methods: We retrospectively analyzed 98 adult patients with GBM who received two magnetic resonance imaging (MRI) scans between 2013 and 2023, before primary surgery and concurrent Stupp chemoradiotherapy. Tumor growth rates were calculated to classify GBM into slower and faster growing categories. Statistical analyses, including Kaplan-Meier and multivariable Cox regression survival analyses, were performed to evaluate the impact of various clinical and treatment-related factors on OS and progression-free survival (PFS).

Results: Slower growing tumors had a significantly longer doubling time than faster growing lesions. Univariable analysis showed no significant differences in OS (p=0.12) or PFS (p=0.4) when analyzed according to tumor growth. When stratified by O6-methylguanin-DNA-methyltransferase (MGMT) status, there were still no differences in OS (p=0.14), but in PFS (p=0.009). In the multivariable Cox regression analysis, radiation dose (p=0.02) and the number of adjuvant cycles of temozolomide (TMZ) (p=0.002) were significantly associated with OS. MGMT status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with prolonged PFS. Specific volume growth rate (SVGR), patient age, baseline tumor volume, Karnofsky performance status, extent of resection, and total radiation dose were not significantly associated with PFS.

Conclusion: SVGR was not significantly associated with OS or PFS. In contrast, MGMT status, radiation dose, and number of adjuvant TMZ cycles were identified as predictors of treatment outcomes. These factors can guide physicians when designing personalized treatment concepts for patients with GBM.

Background/aim: High-risk/refractory neuro-blastoma (NBL) treatments include anti-GD2-monoclonal antibodies (mAbs). Several immunoliposomes (ILs) covered with anti-GD2-mAbs (GD2-ILs) have been tested pre-clinically. We aimed to review literature on GD2-IL for characteristics of nanoparticles/payloads, conjugation of mAb/fragments and preclinical data, as well as to explore the feasibility of a recently proposed GD2-IL loaded with the antimetabolite oxamate.

Materials and methods: Initial PubMed search was generalized for immunoliposomes in cancer. Further search was focused on papers for GD2-IL [keywords: "Immunoliposomes and cancer (or neuroblastoma)"].

Results: There were 811 results on "immunoliposomes"; >50% were on "immunoliposomes, cancer" (n=439, June 2024). Seventeen items resulted from "immunoliposomes, neuroblastoma" (one was "publishers' correction"). Sixteen GD2-IL references were reviewed (1993-current). The mean±SD GD2-ILs size was 124.8±31 nm (range=86-171). Six papers described GD2-ILs with DNA-damaging agents [doxorubicin (n=4), etoposide (n=1), irinotecan+HDAC inhibitor (n=1)]. Other payloads included: fenretinide (n=4 papers), C-myb antisense (n=2), survivin inhibitor (n=1), tyrosine kinase inhibitor (n=1), IL15 (n=1), and oxamate (n=1). These 9 drug-loads included both hydrophilic and hydrophobic molecules. Except for IL15 and C-myb antisense with high molecular weights (MWs), and oxamate with low MW, the remaining compounds had comparable MWs (496±100 g/mol, range=349-588.6). The overall encapsulation efficiency was 66.2±25.6%. There were 17-30 mAb molecules attached to an IL with PEGylation. Experiments with GD2-positive/GD2-negative cells demonstrated selective efficacy/tropism of GD2-ILs. Mouse models confirmed efficacy, GD2-specific tumor accumulation, decreased toxicity, and improved pharmacokinetic-pharmacodynamics.

Conclusion: PEGylated anti-GD2-IL may allow NBL tropism. A size of approximately 100 nm could allow vascular permeability and packaging of oxamate in amounts needed for profound/selective lactate dehydrogenase-A inhibition. Thus, oxamate-loaded GD2-ILs may allow exploring the great translational potential of Warburg effect inhibition in GD2-positive cancers.