Anticancer research最新文献

Background/aim: The clinical benefits of durvalumab consolidation therapy following concurrent chemoradiotherapy (CCRT) with daily low-dose carboplatin in elderly patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) remain unclear.

Patients and methods: This was a single-institution retrospective cohort study. We analyzed the medical records of consecutive patients diagnosed with NSCLC who received CCRT with daily low-dose carboplatin from April 2014 to March 2021. Outcomes were compared between the overall group and two subgroups: those who received durvalumab consolidation therapy (CCRT-durvalumab group) and those who did not (CCRT-alone group). The primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results: A total of 38 patients (median age: 76 years) were enrolled in this study. The median PFS was 9.9 months in the overall group, 11.7 months in the CCRT-durvalumab group, and 10.2 months in the CCRT-alone group. The median OS was 39.4 months in the overall group, 32.0 months in the CCRT-durvalumab group, and 39.4 months in the CCRT-alone group. There were no significant differences between the two subgroups in terms of PFS [hazard ratio (HR)=0.88, p=0.97] or OS (HR=1.21, p=0.70).

Conclusion: In real-world settings, durvalumab consolidation therapy following CCRT with daily low-dose carboplatin does not appear to provide clinical benefits in terms of PFS or OS for elderly patients with unresectable, locally advanced NSCLC.

Background/aim: An inverse association exists between type 2 diabetes mellitus (T2DM) and both plasma vitamin D levels and sun exposure, but vitamin D supplementation does not reduce the incidence. We sought to assess whether there is a dose-dependency in the association between sun exposure and T2DM.

Patients and methods: The melanoma in Southern Sweden (MISS) cohort is comprised of one thousand women without cancer from age groups between 25 and 64, drawn from the Southern Swedish Population Registry of 1990 by random selection. At the inception of the study, 74% of those women responded in writing to an inquiry (n=29,518) and provided detailed information on their sun exposure habits, age, exercise, education, and age at menarche. At the 11-year follow-up, 24,098 responses were received. We analyzed the data using logistic regression analysis with T2DM as a dependent variable and other as independent.

Results: We found a dose-dependent inverse relationship between degree of sun exposure and incidence of T2DM. Compared to women with the greatest sun exposure habits, those with moderate and low sun exposure had an odds ratio (OR) of 1.47, [95% confidence interval (CI)=1.2-1.8] and 2.47, (95% CI=1.8-3.4) for T2DM, respectively. In addition, the OR for T2DM was higher in women with normal BMI than in overweight women [3.72 (95% CI=1.8-7.9) vs. 1.90, (95% CI=1.3-2.7)].

Conclusion: A strong inverse dose-dependent association between sun exposure and T2DM indicated that an inverse causal relationship may exist between sun exposure and the incidence of T2DM, possibly via nitric oxide.

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: 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: 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".