Anticancer research最新文献

Background/aim: The combination of chemotherapy and nivolumab has become the standard first-line therapy for advanced gastric cancer (AGC) following the results of the CheckMate 649 and ATTRACTION-4 trials. Claudin18.2 (CLDN18.2) and trophoblast cell surface antigen 2 (TROP2) have recently emerged as potential therapeutic targets in AGC. However, their association with the efficacy of nivolumab is not known. The aim of this study was to clarify the efficacy of nivolumab according to CLDN18.2 and TROP2 expression in AGC.

Patients and methods: This retrospective study included patients with AGC who had received systemic chemotherapy, with the primary objective of evaluating clinical outcomes in patients treated with nivolumab monotherapy after third-line therapy, by CLDN18.2 and TROP2 expression. The endpoints were overall survival after starting systemic chemotherapy and progression-free survival and overall survival after starting nivolumab monotherapy after third line treatment (Nivo-PFS and Nivo-OS, respectively).

Results: The primary analysis included 69 patients treated with nivolumab monotherapy out of the 121 patients selected from the database. No significant difference in Nivo-PFS or Nivo-OS was found between the CLDN18.2-positive and CLDN18.2-negative populations or between the TROP2-positive and TROP2-negative populations. In the CLDN18.2-positive population, multivariable analysis showed that combined positive score (CPS) ≥1 was associated with significantly longer OS, Nivo-PFS, and Nivo-OS (p=0.03, p=0.03, p<0.01, respectively). In the TROP2-positive population, CPS ≥1 showed a tendency toward better prognosis for Nivo-OS (p=0.31) in the multivariable analysis.

Conclusion: Among patients undergoing nivolumab treatment, CPS ≥1 was significantly associated with longer survival outcomes in CLDN18.2-positive patients, and a tendency toward improved Nivo-OS in TROP2-positive patients.

Background/aim: Recent investigations have highlighted the prognostic significance of the C-reactive protein-albumin-lymphocyte (CALLY) index across various malignancies. However, its prognostic relevance in patients with intrahepatic cholangiocarcinoma (ICC) treated with surgical resection remains to be fully clarified. This study aimed to evaluate whether the prognostic significance of preoperative CALLY index for long-term outcomes in patients with intrahepatic cholangiocarcinoma undergoing surgical resection.

Patients and methods: We retrospectively examined 131 patients who underwent curative-intent hepatectomy for ICC between January 2007 and June 2022. The optimal cutoff value of the CALLY index for predicting overall survival (OS) was identified using the minimum p-value method. Clinicopathological features and survival outcomes were then compared between patient groups with high and low CALLY index, and multivariate statistical analyses were subsequently performed to determine independent prognostic indicators.

Results: The median preoperative CALLY index was 3.5 (interquartile range=1.1-10.1). A cutoff value of 3.0 best stratified OS, classifying 73 patients into the high CALLY group and 58 into the low CALLY group. Patients with CALLY ≤3.0 had significantly poorer disease-free survival (DFS) and OS compared with those with CALLY >3.0 (5-year DFS: 27.1% vs. 49.7%, p<0.001; 5-year OS: 31.2% vs. 62.2%, p=0.003). Multivariate analysis, using pre/intra-operative variables, confirmed a low CALLY index as an independent predictor of both DFS (hazard ratio=2.05, p=0.004) and OS (hazard ratio=1.79, p=0.046).

Conclusion: A preoperative CALLY index threshold of 3.0 provides significant prognostic discrimination in patients undergoing resection for ICC. This easily measurable biomarker may serve as a valuable tool for prediction of long-term outcomes in clinical practice.

Background/aim: Temozolomide (TMZ) is the first-line drug for the treatment of glioblastoma multiforme (GBM). Unfortunately, most patients with GBM eventually develop drug resistance. Camptothecin (CPT) and honokiol (HNK) are bioactive ingredients of Camptotheca acuminata and Magnolia officinalis, respectively. Our previous studies showed the benefits of CPT and CPT-containing nanoparticles on suppressing GBM tumorigenesis. However, CPT can have side effects. This study evaluated the synergistic effects of HNK and CPT at low and non-toxic concentrations on the killing of TMZ-resistant glioblastoma cells, as well as the underlying mechanisms.

Materials and methods: Cytotoxicity of HNK and CPT toward normal human astrocytes and mouse cerebral endothelial cells (CECs) was assessed using colorimetric and flow cytometric assays. Synergistic apoptotic effects in human and mouse TMZ-resistant GBM cells were evaluated by viability assays, trypan blue exclusion, DNA fragmentation, flow cytometry, and caspase activity analyses. CDK1 involvement was examined using siRNA knockdown. The roles of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase-9 activation were investigated using fluorogenic assays and antioxidant pretreatment.

Results: Under low and non-toxic concentrations, HNK enhanced CPT-triggered apoptosis of human TMZ-resistant glioblastomas cells. Cotreatment of TMZ-resistant glioblastoma cells with HNK and CPT stimulated production of CDK1 and subsequent G₂/M arrest. CDK1 knockdown alleviated these effects. Moreover, HNK sequentially enhanced CPT-triggered production of intracellular ROS, reduced the mitochondrial membrane potential, and activated caspase-9 and cell apoptosis. Suppressing the levels of intracellular ROS attenuated the HNK-induced enhanced effects. The effects of HNK on CPT-induced apoptotic insults were further confirmed in mouse TMZ-resistant glioblastoma cells.

Conclusion: HNK synergistically enhances CPT-induced apoptosis in TMZ-resistant glioblastoma cells through CDK1-mediated G₂/M arrest and ROS-dependent mitochondrial activation of caspases-9, -3, and -6. Co-administration of HNK may enable effective CPT-based therapy at reduced doses, potentially minimizing CPT-related toxicity and offering a promising strategy for treating drug-resistant GBM.

Background/aim: This review surveys scientific literature published mainly during the past five years to compile information on the anti-glioma activities of various flavonoid groups, with particular attention to structural modifications in flavonoids, isoflavonoids, and neoflavonoids.

Materials and methods: This review is based on selective literature searches in scientific databases, mainly PubMed and Scopus.

Results: Optimal lipophilicity is probably important for flavonoid action in lipidic tissues of the brain. Many studies on flavonoids have shown that their biological activity and pharmacophore depend on the presence of three rings, one of which is heterocyclic with an oxygen atom. This ring is formed by the connection between rings A and B and is essential for the pharmacophore structure. Its shortening in iso- and neo-flavonoids results in a decreased concentration of these compounds in natural sources and possibly a decreased biological activity. Various hydroxyl groups and other substituents do not alter the basic pharmacophore structure but contribute to changes in biological activities, resulting in the inhibition of many enzymes or signaling pathways by individual flavonoids.

Conclusion: In general, because of the variation in the structure, flavonoids are capable of interacting with a high number of biological targets. As a result, a compound or compounds with high anti-glioma activity may be discovered.

Background/aim: In Japan, contemporary real-world data that simultaneously assess effectiveness, safety, conversion feasibility, and long-term outcomes of first-line FOLFOXIRI-based chemotherapy for unresectable metastatic colorectal cancer (mCRC) remain limited. Here, we aimed to evaluate the real-world efficacy, safety, and long-term outcomes of this treatment as well as to identify factors associated with conversion surgery.

Patients and methods: We conducted a retrospective single-center cohort study of consecutive patients with first-line FOLFOXIRI (±targeted agent). Progression-free survival (PFS) encompassed the entire first-line treatment period. Survival outcomes were analyzed using Kaplan-Meier and log-rank tests, with hazard ratios (HRs) estimated by Cox models. Adverse events (AEs) were graded according to CTCAE v5.0.

Results: Of 59 patients (median FOLFOXIRI cycles: 7), bevacizumab was administered to 74.6%. The objective response rate was 66.1% and the disease control rate was 88.1%. Conversion surgery was achieved in 27.1% of patients, with R0 resection in 23.7% of the cohort. Patients undergoing conversion surgery had longer PFS and overall survival (OS) than those who did not. Conversion was associated with rectal primaries and the absence of peritoneal metastasis. In RAS-stratified analyses, PFS was similar, whereas OS was shorter in RAS-mutant tumors. Grade ≥3 neutropenia and febrile neutropenia occurred in 72.9% and 25.4% of patients, respectively; severe non-hematological AEs were rare, and no treatment-related deaths occurred.

Conclusion: In Japanese practice, first-line FOLFOXIRI achieved substantial disease control and clinically meaningful survival with manageable toxicity. R0 conversion was achieved in the subset with longer survival. A conversion-oriented triplet induction strategy may be considered for rectal cancer without peritoneal metastasis, irrespective of RAS status.

Background/aim: Extrapancreatic invasion (EPI) is a well-known adverse prognostic factor in pancreatic cancer; however, whether the absence of EPI defines a distinct clinical entity remains unclear. This study aimed to clarify the clinicopathological features and prognosis of pancreatic ductal adenocarcinoma (PDAC) confined within the pancreas.

Patients and methods: A total of 199 patients who underwent curative-intent pancreatectomy for PDAC between 2012 and 2022 were retrospectively analyzed. Patients were classified into EPI-negative (n=19) and EPI-positive (n=180) groups. Clinicopathological characteristics, recurrence-free survival (RFS), and overall survival (OS) were compared between the two groups.

Results: EPI-positive tumors were significantly associated with higher CA19-9 levels, larger tumor size, lymph node metastasis, and lymphovascular/perineural invasion. None of the EPI-negative patients experienced recurrence within 3 years or disease-specific death within 5 years. Multivariate analysis identified the absence of EPI as an independent favorable prognostic factor for both RFS and OS.

Conclusion: PDAC confined within the pancreas, without EPI, represents a biologically distinct subset with remarkably favorable outcomes. Assessing EPI status may aid in tailoring perioperative treatment strategies and preventing overtreatment in selected patients.

Background/aim: This study aimed to investigate prognostic factors in pulmonary metastasectomy for colorectal cancer (CRC), considering the location of the primary tumor.

Patients and methods: We collected information from patients who underwent pulmonary resection for CRC at two high-volume centers from January 2010 to December 2023. Using a multivariate Cox proportional hazards model, patient background factors that affected the prognosis after pulmonary metastasectomy were identified.

Results: A total of 289 patients were included in the study. The multivariate analysis revealed the primary tumor site [hazard ratio (HR)=1.89, p=0.016], the maximum diameter of the pulmonary nodule (HR=1.76, p=0.016), and multiple metastases (HR=2.10, p<0.001) had significant prognostic impact on overall survival (OS). The multivariate analysis of disease-free survival (DFS) revealed smoking history (HR=1.58, p=0.039) and multiple metastases (HR=2.08, p<0.001) as significant prognostic factors. After 1:1 propensity score matching (PSM) of patients based on the number of metastatic tumors, two populations revealed a consistent trend with 5-year survival rates of 73.4% and 48.0% for single pulmonary and multiple metastases.

Conclusion: Multiple metastases significantly worsened both OS and DFS after pulmonary metastasectomy, and the similar trend was observed after PSM.

Background/aim: This study aimed to clarify the lymphatic network around the anorectum using cadavers and consider a treatment strategy for locally advanced lower rectal cancer (LARC).

Materials and methods: We performed microscopic observations of three female cadavers using India ink into the submucosa at the dentate line (DL) of the cadaver. We examined the clinical outcomes of 74 patients with LARC who underwent total mesorectal excision after preoperative treatment, classifying them as anterior (A), lateral (L), or posterior (P) based on the deepest part of the tumor.

Results: Two of the three anterior walls contained the Denonvilliers' fascia (DVF), and the DVF became indistinct at the height of DL, where India ink extended to the vagina via the perivascular space and was absorbed into the vaginal lymph vessels. One case did not have DVF, and lymph vessels in the rectum distributed in close proximity to vagina. On the lateral posterior wall, the ink spread extensively from DL and the front of the levator ani muscle, whereas on the posterior wall, lymph vessels containing absorbed ink were observed from the hiatal ligament to the front of the sacrum. In the survival analysis, the 3-year disease-free survival rates were 71.9%, 100%, and 69.7% for A, L, and P groups, respectively, with a higher recurrence rate in the anterior and posterior walls.

Conclusion: Lymphatic network beyond fascia around anorectum was spread to a specific route by location. The anatomical diversity of this network was thought to be involved in the poor outcome for LARC.

Background/aim: Hand-foot syndrome (HFS) is a common adverse event associated with capecitabine. While the fibroblast growth factor receptor (FGFR) signaling pathway is involved in skin wound healing, its essential role in capecitabine-induced HFS remains unclear. We examined the association between polymorphisms in FGFR signaling pathway-related genes and capecitabine-induced HFS in patients with colorectal cancer (CRC).

Patients and methods: This retrospective study included patients with CRC who received capecitabine and oxaliplatin. HFS was evaluated using CTCAE v5.0, up to 2 cycles. Polymorphisms were identified using whole-exome sequencing and confirmed using direct sequencing. The association between HFS and polymorphisms was analyzed using Fisher's exact test. The Bonferroni correction for multiple testing was performed to calculate the corrected p-value (Pc).

Results: Overall, 937 polymorphisms were identified in 71 genes. Intronic FGFR2 rs2981460 C/C, and rs2981461 T/T genotypes, and haplotype II/II comprising the C and T alleles were associated with a lower HFS incidence (p=0.0161, Pc=0.113; p=0.0163, Pc=0.114; and p=0.0161, Pc=0.113, respectively). Synonymous FGFBP2 rs2286459 A/A was associated with a lower HFS frequency (p=0.0469, Pc=0.328). 3'-Untranslated region and nonsynonymous variants SPRY2 rs11911 T/G or G/G and rs504122 G/A or A/A, and homozygotes or heterozygotes of haplotype 2 comprising respective G and A alleles, were significantly associated with higher HFS incidence (p=0.0000803, Pc=0.000562; p=0.0000803, Pc=0.000562; and p=0.0000803, Pc=0.000562, respectively). A significantly higher HFS incidence was observed in patients with a combined risk genotype and diplotypes of FGFR2 any/II or any/any, FGFBP2 rs2286459 G/G or G/A, and SPRY2 2/2 or any/2 (p=0.0000314).

Conclusion: Variants in FGFR signaling pathway-related factors were significantly associated with capecitabine-induced HFS.

Background/aim: Ovarian yolk sac tumors (YSTs) are highly uncommon in postmenopausal women and may show unusual morphological patterns, including neuroendocrine differentiation. Such presentations are exceptionally rare and poorly characterized.

Case report: We report the case of a 75-year-old woman presenting with a pelvic mass and diffuse peritoneal and hepatic involvement. Histopathological evaluation revealed a yolk sac tumor with mixed architectural features and focal chromogranin A expression, consistent with neuroendocrine differentiation. The disease was classified as FIGO stage IVB. The patient started first-line chemotherapy with a dose-adjusted combination of bleomycin, etoposide, and cisplatin, tailored to her age and overall condition.

Conclusion: This case illustrates a particularly rare and aggressive presentation of ovarian YST in a postmenopausal patient. Early recognition, accurate pathological characterization, and individualized treatment are essential, although prognosis remains poor in this setting. Reporting such cases is crucial to improve understanding and management of these exceptional tumors.