Anticancer research最新文献

Background/aim: No prospective study has evaluated salvage chemotherapy with capecitabine plus oxaliplatin (XELOX) in patients with gastric cancer who are resistant to or intolerant of cisplatin.

Patients and methods: This multicenter, open-label, single-arm, phase II study was conducted at six centers in Japan, enrolling patients with metastatic or advanced gastric cancer resistant to or intolerant of fluoropyrimidine, cisplatin, taxane, and irinotecan. Capecitabine 1,000 mg/m² was administered orally twice daily for 14 days, followed by a 7-day rest period. Oxaliplatin 130 mg/m² was administered intravenously on day one. The primary endpoint was disease control rate (DCR). Secondary endpoints included response rate (RR), progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and safety.

Results: The study was terminated prematurely due to poor accrual, with 12 patients enrolled. Eight patients demonstrated resistance to prior cisplatin, while four experienced unacceptable toxicity. The median age was 64 years, and eight were male. Four, six, and two patients had Eastern Cooperative Oncology Group performance status 0, 1, and 2, respectively. Among 10 evaluable patients, DCR was 90%, with an RR of 30%. Median PFS, TTF, and OS were 4.2 months [95% confidence interval (CI)=1.4-5.3], 4.1 months (95%CI=1.4-4.4), and 7.1 months (95%CI=2.3-10.1), respectively. The most frequently reported grade 3-4 adverse events were fatigue (20%) and hypokalemia (20%). No treatment-related deaths occurred.

Conclusion: Salvage chemotherapy with XELOX may offer clinical benefits for patients with metastatic or advanced gastric cancer resistant to or intolerant of cisplatin.

Background/aim: Ivermectin was initially utilized as a veterinary medication, demonstrating efficacy against various parasites. Pancreatic cancer is currently one of the most recalcitrant diseases. The aim of the present study was to demonstrate the synergy of the combination of recombinant methioninase (rMETase) and ivermectin to eradicate human pancreatic cancer cells in vitro.

Materials and methods: MiaPaCa-2 human pancreatic cancer cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with the addition of 10% fetal bovine serum and 1 IU/ml penicillin/streptomycin. Reduction of cell viability by rMETase alone and ivermectin alone and their combination on MiaPaCa-2 cells was determined with the WST-reagent. Four experimental groups were examined in vitro: control group without treatment; ivermectin alone; rMETase alone; ivermectin combined with rMETase.

Results: The IC₅₀ of ivermectin for MiaPaCa-2 cells was 5.9 μM. The IC₅₀ of rMETase on MiaPaCa-2 cells was 2.93 U/ml. Ivermectin (5.9 μM) plus rMETase (2.93 U/ml) synergistically greatly reduced the viability of MiaPaCa-2 cells, compared to ivermectin alone (80% reduction vs. 45% reduction, respectively p<0.05).

Conclusion: The combination of ivermectin and rMETase effectively eradicated MiaPaCa-2 pancreatic cancer cells. The present results indicate the future clinical potential of the combination of rMETase, currently administered orally to patients as a dietary supplement, and oral ivermectin on pancreatic cancer.

Background/aim: The present study aimed to assess the relationship between the maximum standardized uptake value (SUVmax) on ¹⁸F-fluorodeoxyglucose positron emission tomography computed tomography (¹⁸F-FDG-PET/CT) and the geriatric nutritional risk index (GNRI) in patients with soft-tissue sarcomas (STSs).

Patients and methods: The present single-center retrospective observational study included patients who underwent ¹⁸F-FDG-PET/CT and for whom serum albumin levels, height, and body weight were measured prior to therapeutic intervention.

Results: A total of 81 patients were included in the study. The mean SUVmax was 11.1±9.9. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 79.7% and 52.4%, respectively, for the higher SUVmax group (≥11.1) and 91.0% and 73.0%, respectively, for the lower SUVmax group (<11.1). For the GNRI, the 5-year OS and DFS rates were 89.6% and 64.3%, respectively, for the negative-risk group, and 73.3% and 77.1% for the positive-risk group, respectively, with no significant differences. The mean SUVmax was 9.7±8.1 and 19.1±14.9 for the negative- and positive-risk groups, respectively. The positive-risk group had a significantly higher SUVmax than the negative-risk group (p=0.03). Furthermore, there was a negative correlation between the SUVmax and GNRI (r=-0.48, p<0.05).

Conclusion: A higher SUVmax and lower GNRI in patients with STS may contribute to a poor prognosis. The deregulatory elevation of tumor glucose metabolic activity may affect serum albumin levels and weight loss in patients with STS, resulting in a decrease in the GNRI.

Background/aim: Metastatic patterns are the most convenient and common prediction models for the prognosis of patients with stage IV colorectal cancer. However, current prediction models do not include the severity of metastases in organs and exclude certain types of metastatic patterns. The aim of this study was to develop a prediction model that included several metastatic organs as well as the severity of liver and lung metastases, based on the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma: the 3^rd English Edition.

Patients and methods: We performed a state-wide cohort study and developed a prediction model using Cox proportional hazard regression analysis, utilizing data on patients with stage IV colorectal cancer in hospital-based cancer registries of all nine designated cancer hospitals across Fukushima Prefecture, Japan.

Results: The study included 1,230 patients with stage IV colorectal cancer. The prediction score consisted of the severity of liver and lung metastases, peritoneal dissemination, non-regional lymph node metastases, and other organ metastases (scale: 0-9 on a 10-point scale; divided into a 2-point scale, grade: I-V). The study found that the model had good discrimination properties, with a Harrell's concordance index of 0.64 (95% confidence interval: 0.62-0.66), and the grade was an independent prognostic factor [hazard ratio (HR)=1.83; 95% confidence interval=1.68-2.00; p<0.001].

Conclusion: We created a practical prediction model for stage IV colorectal cancer that can be applied at the time of diagnosis, using only metastatic patterns. Further external validation studies are required to ensure the accuracy of this model.

Background/aim: Preclinical studies were undertaken to investigate whether eribulin's known cytotoxic antimitotic effects are characterized by immunogenic cell death (ICD) as assessed by three established ICD biomarkers: extracellular released ATP, released HMGB1 and cell surface calreticulin.

Materials and methods: Using BT-549, Hs578T and MCF-7 breast cancer cell lines, antiproliferative IC₅₀'s of eribulin, five other microtubule targeting agents (MTAs; ER-076349, vinblastine, vinorelbine, paclitaxel, docetaxel) and three DNA damaging agents (DDAs; doxorubicin, cisplatin, oxaliplatin) were determined.

Results: Treatment of cells with 10×IC₅₀ concentrations of all drugs in serum-free media resulted in time-dependent induction of cytotoxicity over DMSO controls. Measurement of ATP and HMGB1 released into conditioned media and appearance of cell surface calreticulin support eribulin's ability to induce ICD. Compared to the other agents tested, eribulin's potency as an ICD inducer was mid-range and shared with vinblastine, paclitaxel, doxorubicin and oxaliplatin. Interestingly, MTAs as a group appeared to be more potent inducers of ATP release compared to DDAs, whereas DDAs appeared to be more potent inducers of cell surface calreticulin compared to MTAs. Overall, drug effects on ATP release and cell surface calreticulin showed early peaking followed by rapid decline, while effects on HMGB1 release were generally slower and more prolonged.

Conclusion: Our results support the concept that eribulin's cytotoxic effects are associated with ICD. These findings provide impetus for investigating how eribulin-induced ICD may contribute to the larger spectrum of phenotypic and immunological effects by which eribulin exerts antitumor therapeutic benefits.

Background/aim: Adult granulosa cell tumor (aGCT) is a rare and challenging ovarian tumor due to its unpredictable recurrence and its associated increased risk of breast and endometrial cancer. Identifying and describing molecular alterations in tumors has become common with the advent of high-throughput sequencing. However, DNA sequencing in rare tumors, such as aGCT, often lacks statistical power due to the limited number of cases in each study, thereby clinical implications of DNA alterations are difficult to interpretate. This scoping review aims to systematically describe somatic and germline DNA alterations identified in women with aGCT.

Materials and methods: Search terms (granulosa cell tumour AND molecular alterations) were searched in May 2024 in the following databases: MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection and Google Scholar. Screening, full-text review and data extraction were performed by two independent reviewers.

Results: Twenty-four publications were identified. Eighteen reported on somatic DNA alterations of patholgenic mutations identified in total 1,226 tissues being sequenced. FOXL2 (c.402C>G; p.C134W) was present in 97% of aGCTs. Other pathogenic mutations in the tissues investigated were TERT promoter mutation (41%), truncating KMT2D mutations (14%) and TP53 pathogenic variant (4%). TERT promoter mutation was reported more frequently in recurrent tumors (p<0.01), whereas comparing truncating KMT2D and TP53 mutations reported in primary and recurrent tumors revealed no difference (p=0.15 and p=0.26 respectively). Tumor mutational burden (TMB) was reported in five studies and all showed a low TMB. None of the somatic mutations were candidate targets for biological treatment. Six publications reported germline variants and no shared germline pathogenic variants were described in the published literature.

Conclusion: The FOXL2 missense mutation was the only common somatic DNA alteration in aGCT. TERT promoter mutations were reported more frequently in recurrent aGCT but their clinical relevance remains uncertain. In contrast to previous reports, truncating KMT2D mutations were not found to be associated with recurrent aGCT. Evidence on common germline variants in aGCT is sparse. The role of somatic and germline DNA alterations in the development of other malignancies in women with aGCT remains uncertain. Further research involving matched primary and recurrent tumors, as well as other primary malignancies, is essential to better understand the mutations that drive tumor development.

Background/aim: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic cancer which is difficult to diagnose and has a lot of overlapping features with other diseases, particularly acute myeloid leukemia (AML). BPDCN shares several immunophenotypic markers with AML, such as CD4, CD56, CD123, and HLA-DR, stating the importance of having extending panel of specific immunohistochemical (IHC) markers.

Case report: This report details a case of CLL who presented with worsening symptoms of recurrent infections and leukocytosis. A bone marrow biopsy showed immunoprofile of the blast-like population with CD4-, CD56-, and CD123- positive and CD34- and CD117- negative, based on which BPDCN was diagnosed and patient was started on first-line therapy for BPDCN. However, an extended panel of IHC stains showed positivity for lysozyme, and negativity for TCL1, MPO, and CD303. Thus, BPDCN was excluded according to the WHO 5th edition criteria, and a diagnosis of AML with monocytic differentiation was confirmed.

Conclusion: AML with monocytic differentiation can express CD4, CD56, and CD123, which are very often the only markers considered for diagnosis of BPDCN. An extended panel of IHC analysis is required before making a definitive diagnosis of BPDCN.

Background/aim: Methionine addiction, known as the Hoffman effect, makes cancer cells more sensitive to methionine restriction than normal cells. However, the long-term effects of methionine restriction on cancer and normal cells have not been thoroughly studied.

Materials and methods: HCT-116 human colorectal-cancer cells and Hs27 normal skin fibroblasts were treated with 0-8 U/ml of recombinant methioninase (rMETase) for 12 days. The cells were cultured in Dulbecco's modified Eagle's medium in 96-well tissue-culture plates.

Results: HCT-116 cells were sensitive to all concentrations of rMETase from 0.125 U/ml to 8 U/ml. After day-8 of treatment, HCT-116 cells were acutely sensitive to rMETase, especially at rMETase concentrations of 0.5 U/ml or higher. Normal Hs27 fibroblasts were much less sensitive to rMETase: In the range of 0.125 U/ml to 0.5 U/ml, rMETase had no effect on Hs27 cells. rMETase concentrations up to 2 U/ml had a slight initial effect on Hs27 cells, whereas at concentrations ranging from 4 U/ml to 8 U/ml, rMETase reduced Hs27 viability over the 12-day test period, with acute loss of viability observed after eight days of exposure.

Conclusion: Cancer cells were significantly more sensitive to rMETase than normal cells, with an acute loss of cell viability observed in cancer cells after eight days of treatment at concentrations of 0.5 U/ml or higher. These findings highlight the large difference in sensitivity between cancer and normal cells to rMETase and introduce the phenomenon of acute cell death in methionine restriction, which we term "methionine-depletion catastrophe".

Background/aim: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma worldwide. Patients can have a wide range of clinical features and behavior which does not necessarily correlate to histologic grade or Ki-67 proliferation index. We hypothesized that patients with low grade but high proliferative index (LG/HP) FL have a more aggressive disease course. The aim of this study was to determine the role of LG/HP on the outcomes of FL patients.

Patients and methods: A retrospective single center study of FL patients treated within the Allegheny Health Network was conducted from January 2011 to December 2021. Patients were divided into three groups: low grade/high proliferation index (PI) (LG/HP), low grade/low PI (LG/LP), and high grade (HG). Cox regression models looking at variables including age, sex, race, Ann Arbor staging, PET SUV_max, FLIPI score, and treatment details were used to analyze predictors of progression. Survival estimates were calculated using the Kaplan-Meier method and compared using the Log-rank test.

Results: A total of 145 patients were treated for FL during the study period. Most were males and fell into the LG/LP group. We determined that the median progression-free survival in the LG/HP group was numerically worse than the LG/LP group; however, this did not meet statistical significance.

Conclusion: Our data suggest that a different treatment approach may not be warranted for LG/HP FL patients.

Background/aim: Hederagenin (3β,4α-3,23-dihydroxyolean-12-en-28-oic acid) is a natural pentacyclic triterpene that is present in various medicinal plants and exhibits pharmacological activities against various diseases, including cancer. The aim of the study was to investigate the effect of Aq3639 (3β-[(O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl)oxy]olean-12-en-28-oic acid), a hederagenin glycoside comprising hederagenin and a disaccharide of L-rhamnose and L-arabinose, on breast cancer cells.

Materials and methods: Aq3639 was isolated from the pericarps of Akebia quinata fruits, and its effects on cells from the human breast cell line MCF-7 were examined.

Results: Aq3639 was found to markedly inhibit the proliferation of MCF-7 cells in a concentration-dependent manner (particularly at concentrations above 25 μmol/l). The inhibitory effect [half-maximal inhibitory concentration (IC₅₀)=13.10 μmol/l] was similar to that of tamoxifen, which is used as a therapeutic agent for estrogen receptor-positive breast cancer; the inhibitory effect was also approximately seven-times greater than that of hederagenin (IC₅₀=93.05 μmol/l). Interestingly, neither of the sugars present in Aq3639, L-rhamnose nor L-arabinose, affected cell inhibition. Additionally, Aq3639 increased the generation of reactive oxygen species and, consequently, induced apoptosis in the MCF-7 cells in a time-dependent manner.

Conclusion: Our results strongly suggest that Aq3639 may be useful in the prevention and treatment of breast cancer.