Anticancer research最新文献

Background/aim: Although trastuzumab-based chemotherapy improves survival in HER2-positive advanced gastric cancer, some patients demonstrate suboptimal efficacy and limited response durations. We examined the relationship between clinical outcomes and genomic features, including co-mutations and the length of the ERBB2-amplified segment.

Patients and methods: We retrospectively analyzed 151 patients who had received first-line trastuzumab-based chemotherapy. Targeted next-generation sequencing was employed to assess genomic alterations. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression or death.

Results: The median patient age was 62 years, and 73.5% of patients were male. The median follow-up period was 45.8 months, and the median PFS was 8.2 months [95% confidence interval (CI)=6.5-9.4]. Patients with a focal amplification of ERBB2 (≤879 Kb) had significantly longer PFS compared to those with non-focal amplifications (>879 Kb) (10.1 vs. 6.1 months; log-rank p=0.007). NOTCH3 alterations were associated with shorter PFS (log-rank p=0.003). Multivariate analysis confirmed that ERBB2 focal amplification is an independent prognostic factor associated with improved prognosis, whereas NOTCH3 alterations serve as an independent prognostic factor for poorer outcomes.

Conclusion: ERBB2 focal amplification is associated with improved outcomes in trastuzumab-treated patients with HER2-positive gastric cancer, whereas NOTCH3 alterations predict a poor prognosis. These genomic features may support risk stratification and therapeutic decisions.

Background/aim: Lung cancer bone metastasis significantly reduces the quality of life of advanced-stage patients, leading to cancer-related pain and pathological fractures. Currently, there is a lack of drugs simultaneously inhibiting the growth of metastatic lesions and reducing pain. Ibrutinib, a selective inhibitor of EGFR-mutated non-small cell lung cancer, has been shown to inhibit the proliferation and migration of lung cancer cells. This study aimed to investigate the effects of ibrutinib on tumor progression, pain, and bone protection.

Materials and methods: Cell viability and migration of the murine Lewis lung carcinoma (LLC, FH0325) and human NSCLC (NCI-H1975, FH0086) cell lines were assessed using CCK-8, wound healing, and transwell assays after treatment with ibrutinib. Behavior tests, mechanical allodynia, flinches and pain scoring, micro-computed tomography and histological analysis were evaluated on the tumor-bearing C57BL/6 mice.

Results: CCK-8, wound healing, and transwell assays demonstrated that ibrutinib significantly suppressed the proliferation and migration of lung cancer cell lines. The efficacy of ibrutinib treatment was evaluated in a mouse model of lung cancer bone metastasis. Behavioral analysis validated the reduction in mechanical and spontaneous pain and the delay in the loss of motor function. Micro-CT revealed greater bone volume and density and less bone trabecular separation. Moreover, TRAP staining indicated a decrease in osteoclast numbers following ibrutinib treatment. Histopathological examination revealed fewer lung metastatic lesions, while TUNEL staining indicated more severe tumor cell apoptosis induced by ibrutinib.

Conclusion: Ibrutinib effectively inhibited the proliferation and migration of lung cancer cells, and in a lung cancer bone metastasis model, this drug inhibited tumor growth, alleviated pain, and protected the tibial bone.

Background/aim: Patients with metastatic urothelial carcinoma (mUC) often experience impaired renal function because of tumor invasion, nephroureterectomy, and chemotherapy. Enfortumab vedotin (EV) has been approved in Japan as a third-line treatment for advanced UC. This study aimed to assess renal function changes in patients with mUC receiving EV therapy.

Patients and methods: We retrospectively analyzed renal function changes and clinical outcomes in 63 patients with mUC who received EV following platinum-based chemotherapy and immune checkpoint inhibitors. Data were collected from five Institutions in Japan from September 2021 to September 2024.

Results: The median baseline estimated glomerular filtration rate (eGFR) was 44.1 ml/min/1.73 m². Chronic kidney disease stage remained unchanged in 54% of patients, upstaging in 17%, and downstaging in 29%. The median change rate in eGFR was 2.6%. The median overall survival was 12.0 months in the eGFR ≥45 ml/min/1.73 m² group and 15.4 months in the eGFR <45 ml/min/1.73 m² group. The objective response rate was 45% in the eGFR ≥45 ml/min/1.73 m² group and 34% in the eGFR <45 ml/min/1.73 m² group. Adverse events (AEs) of any grade occurred in 84% of patients with eGFR ≥45 and 69% of those with eGFR <45, with grade ≥3 AEs reported in 7% and 13% patients, respectively.

Conclusion: EV did not significantly impair renal function in patients with mUC. Comparable efficacy and safety were observed regardless of baseline eGFR, supporting the feasibility of EV in patients with impaired renal function.

Background/aim: Leucine-rich repeat-containing 15 (LRRC15) is a recently identified cancer-associated fibroblast (CAF) marker found in various types of cancer. However, its functional role and clinical significance in cervical cancer (CC) remain unclear.

Materials and methods: We analyzed LRRC15 expression in 20 normal cervical (NC) tissue samples and 87 CC tissue samples using RT-qPCR. Correlations between LRRC15 expression and clinicopathological parameters and prognosis in CC patients were evaluated. The biological functions of LRRC15 and its effects were investigated in CC cell lines with and without human papillomavirus (HPV) infection.

Results: LRRC15 expression was significantly associated with lympho-vascular space (LVS) involvement in patients with CC (p<0.001). Patients with high LRRC15 expression had significantly poorer progression-free survival outcomes than those with low LRRC15 expression (p=0.014). LRRC15 knockdown suppressed WNT and focal adhesion kinase (FAK) signaling, leading to increased Caspase3/7 expression and, consequently, enhanced apoptosis in CC cells, regardless of HPV infection.

Conclusion: LRRC15 expression is a marker of poorer prognosis in patients with CC, suggesting that LRRC15 represents a potential therapeutic strategy for CC.

Background/aim: Previous studies demonstrated the safety of laparoscopic gastrectomy in patients with locally advanced gastric cancer. However, the feasibility of minimally invasive surgery (MIS) following neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer remains unclear. To our knowledge, no previous study has conducted a comprehensive analysis that evaluated NAC and surgical approach simultaneously. This study aimed to assess the feasibility of MIS for locally advanced gastric cancer after NAC using a four-arm comparison.

Patients and methods: This study retrospectively analyzed 174 patients who underwent gastrectomy at Kobe University Hospital between January 2011 and July 2024. The patients were categorized into four groups based on NAC and surgical approaches: No NAC/open surgery (n=63), no NAC/MIS (n=49), NAC/open surgery (n=20), and NAC/MIS (n=42). We compared surgical and survival outcomes among the four groups.

Results: Patients in the group treated with NAC/MIS experienced less blood loss, fewer transfusions, and a shorter hospital stay. Additionally, compared with the NAC/open (20%) and no NAC/MIS (6.1%) groups, the rate of severe postoperative complications (grade ≥III) was lowest in the group treated with NAC/MIS, with no incidence of pancreatic fistula. The R0 resection rate was highest (97.6%) in the group treated with NAC/MIS. Although 5-year relapse-free survival and overall survival were higher in the group treated with NAC/MIS, the differences were not statistically significant.

Conclusion: This four-arm study suggests that minimally invasive surgery after NAC for locally advanced gastric cancer may be technically and oncologically safe.

Background/aim: Lung adenocarcinoma (LUAD), a predominant subtype of non-small cell lung cancer (NSCLC), is characterized by a complex tumor microenvironment (TME) that drives immune evasion and contributes to variable clinical outcomes. This study investigates the role of tumor-derived macrophage migration inhibitory factor (MIF) on immune modulation and prognosis in LUAD.

Materials and methods: Single-cell RNA sequencing (scRNA-seq) data from three LUAD tumors (E-MTAB-6149; 29,936 cells) were analyzed with Seurat to identify cell types and marker genes. Cell-cell communication was assessed using CellChat, and prognostic significance was evaluated in the TCGA-LUAD cohort with GEPIA2.

Results: Malignant cells showed the highest expression of MIF, which may interact with CD74 ⁺ CXCR4 ⁺ and CD74 ⁺ CD44 ⁺ receptor complexes on B cells, T cells, and myeloid cells, consistent with known MIF-mediated signaling pathways. A predominant B cell subset (59%) expressing CD74 or CXCR4 (termed as MIFR⁺ B cells) showed elevated expression of MHC class II genes (such as HLA-DRA and HLA-DPB1) and co-stimulatory genes (such as CD40 and CD83), indicating antigen-presenting cell (APC)-like functions. High MIF expression was associated with a poor prognosis in TRU-subtype LUAD [hazard ratio (HR)=2.5, p-value=0.029], while MIFR⁺ B cell signatures was correlated with improved survival.

Conclusion: Tumor-derived MIF is associated with poor prognosis, likely by suppressing the immune system, but it also promotes the induction of APC-like B cells, which are associated with improved outcomes, highlighting its dual role in LUAD. These findings position MIF as a potential therapeutic target and suggest that MIFR⁺ B cells could serve as important prognostic markers.

Background/aim: The study aimed to analyze the Dunning-Kruger effect (DKE) in oncologists' self-perceived and accurate knowledge of scientific data, prescribing indications, and clinical results of the new radioligand therapy (RLT) for metastatic castration-resistant prostate carcinoma (mCRPC).

Patients and methods: Clinical oncologists, including urologists, medical and radiation oncologists, were asked to voluntarily participate in a web-based nine-question test to explore the DKE in the clinical setting of 177-lutetium RLT for mCRPC. Before the test, participants were asked to estimate their performance percentage on a scale from 1 (poor performance, lack of knowledge) to 100 (efficient, entirely accurate performance, expert). A board of six experts evaluated knowledge performance, reporting results as a percentage on a 0-100% scale.

Results: A total of 128 physicians agreed to participate and completed the questionnaire. Participants were divided into four quartile groups based on their ranked test scores. The observed difference between self-estimation and actual knowledge performance was statistically significant, indicating that less skilled participants often overestimate their abilities. Specialty, work environment, scientific production, participation in a multidisciplinary board, and expertise were all strongly correlated with quartile level (p<0.001).

Conclusion: Clinical oncologists display significant DKE when assessed in the developing therapeutic area of RLT in mCRPC. These results underscore the need to transition toward multidisciplinary training programs, which are essential for effective education in RLT.

Background/aim: Methionine addiction is a metabolic hallmark of cancer. Recombinant methioninase (rMETase) targets methionine addiction and effectively depletes methionine. rMETase has shown synergy with chemotherapeutic agents on numerous types of cancer cells. Chloroquine (CQ), an anti-autophagy agent, has demonstrated anti-cancer efficacy in pre-clinical studies. The present study aimed to evaluate the cancer selectivity and synergistic efficacy of rMETase and CQ in a co-culture model of colon-cancer cells and normal fibroblasts.

Materials and methods: HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts were co-cultured in Dulbecco's Modified Eagle's Medium (DMEM) and treated with rMETase (0.1-0.5 U/ml) alone, CQ (10-60 μM) alone, or rMETase at various concentrations in combination with CQ (20 μM). Cell morphology and viability were monitored for six days using phase-contrast microscopy (Olympus IX71). The effects of each treatment on the cancer cells and normal fibroblasts were compared.

Results: rMETase treatment selectively reduced HCT116 viability in a dose-dependent manner while sparing normal fibroblasts. In contrast, high-concentrations of CQ decreased the viability of both cell types, with strong cytotoxicity at ≥40 μM. Combination treatment with rMETase and low-dose CQ (20 μM) produced greater selective efficacy against the cancer cells than rMETase alone, eliminating the cancer cells and without significant inhibition of fibroblast viability.

Conclusion: rMETase has selective efficacy against cancer cells in the presence of normal cells, and its efficacy is significantly enhanced selectively on the cancer cells by CQ. The results of the present study suggest the potential for future clinical application of the combination of rMETase and CQ for cancer treatment.

Background/aim: The use of serological biomarker testing for diagnosing upper abdominal symptoms and screening for gastric cancer (GC) risk conditions is increasing worldwide, raising questions about its diagnostic accuracy. This study evaluated the diagnostic concordance between a serological biomarker panel, gastroscopy (EGD), and biopsy histology in patients referred for gastroscopy.

Patients and methods: A total of 522 patients referred from primary care to Oulu University Hospital (Finland) underwent GastroPanel^® (GP) testing, EGD, and gastric biopsies classified using the Updated Sydney System (USS). Three gastroenterology experts independently assessed cases with discrepant results to determine preferred management. Agreement between diagnostic methods was measured using kappa statistics.

Results: Of the GP test-negatives (n=447), 60% had normal findings on EGD, 36% (n=161) were diagnosed as inflammatory lesions and 4% (n=19) were classified as having possible or definite atrophic gastritis (AG). Biopsies revealed moderate AG in only three GP-negative patients (0.007%). GP and USS showed excellent agreement (weighted k=0.861) while agreement between GP/EGD and EGD/USS was moderate (weighted k=0.458 and k=0.480, respectively). Of the 175 discrepant diagnoses, over 90% were ranked by all gastroenterologists as benign conditions with no need for therapy or EGD follow-up.

Conclusion: GP, EGD, and USS do not always provide uniform diagnoses; however, after a negative GP test, the probability of detecting moderate/severe AG using EGD is extremely low (3/447; 0.007%). In the first-line diagnosis of upper abdominal symptoms, substantial cost savings (90%) could be achieved by preserving EGD only for those (<10%) patients whose GP test indicates AG.

Background/aim: Treatment strategies for metastatic castration-sensitive prostate cancer (mCSPC) have become complex. This study aimed to investigate the role of androgen receptor signaling inhibitors (ARSI) as upfront therapy for Japanese patients with mCSPC.

Patients and methods: This retrospective study was conducted using the MAHOROBA database. A total of 418 patients who received ARSI as first-line treatment (group A, n=143) or vintage hormonal therapy as first-line and ARSI as second-line treatment (group B, n=275) were extracted. Propensity score matching (PSM) was conducted to minimize differences between the groups. In group B, secondary progression was defined as progression with ARSI as the second-line treatment after progression to castration-resistant prostate cancer (CRPC). We compared adverse events, first progression-free survival (PFS) rate, second PFS rate, and overall survival (OS) rates.

Results: Grade 2 or higher adverse events after first-line treatment were observed in 22.4% of patients in Group A and 7.6% of patients in Group B. A total of 234 patients (117 in each group) were identified after PSM. The median follow-up periods for groups A and B were 23 and 47 months, respectively. There was no significant difference in OS between the two groups (p=0.46). The first PFS rate was significantly higher in group A than in group B (p<0.001). However, when comparing the first PFS rate in group A group with the second PFS in group B, there was no significant difference (p=0.35).

Conclusion: Upfront ARSI therapy for Japanese patients with mCSPC significantly extended the time to CRPC but did not demonstrate a benefit in OS compared to vintage hormonal therapy.