Anticancer research最新文献

Background/aim: Gastric cancer (GACA) is a major global health burden, ranking fifth in incidence and third in cancer-related mortality worldwide. Despite growing knowledge of environmental risk factors such as Helicobacter pylori infection, smoking, and alcohol consumption, the role of genetic susceptibility, particularly polymorphisms in matrix metalloproteinase-11 (MMP-11), in GACA pathogenesis remains unclear.

Materials and methods: We conducted a hospital-based case-control study involving 161 patients with GACA and 483 age- and sex-matched cancer-free controls of Taiwanese ethnicity. Four MMP-11 single nucleotide polymorphisms (SNPs), rs738791, rs2267029, rs738792, and rs28382575, were genotyped using PCR-RFLP and direct sequencing. Logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with a significance threshold of p<0.05.

Results: Overall, no significant associations were observed between MMP-11 SNPs and GACA susceptibility. However, the rs28382575 C allele was associated with increased risk (p=0.0377). Stratified analysis revealed that rs738791 CT/TT genotypes were significantly associated with metastasis (p=0.0129). Among smokers and drinkers, rs28382575 CT/CC genotypes conferred elevated risk (smokers: p=0.0027; drinkers: p=0.0153), while rs738792 variant genotypes appeared protective (smokers: p=0.0124; drinkers: p=0.0022).

Conclusion: While MMP-11 polymorphisms are not suitable as population-level screening markers for GACA risk, rs738791 and rs28382575 may serve as predictors for metastasis, and rs28382575 and rs738792 as modifiers of gene-environment interaction. Functional validation is warranted to elucidate the biological relevance of these findings in GACA progression.

Background/aim: Pancreatic cancer (PC) has a poor prognosis and limited treatment options. The development of resistance to anticancer agents poses a significant challenge in the treatment of PC. Our previous study indicated that basic helix-loop-helix family member e41 (BHLHE41) is associated with the prognosis of lung cancer. Additionally, BHLHE41 affects the prognosis and response to anticancer drugs in several cancers. However, the functional role of BHLHE41 in cancer remains unclear. In PC, its expression has been reported to influence tumor malignancy; however, its impact on chemosensitivity has not yet been elucidated. Therefore, this study aimed to investigate the effects of BHLHE41 on PC chemosensitivity.

Materials and methods: Genetic modification and MTT assays were performed to evaluate the effect of BHLHE41 on anticancer agents. RNA sequencing (RNA-seq) was conducted to analyze the downstream pathways of BHLHE41. Furthermore, anticancer agent sensitivity tests were performed for the candidate genes identified through RNA-seq.

Results: BHLHE41 enhanced the sensitivity of PC cells to gemcitabine (GEM) while suppressing the expression of insulin-like growth factor binding protein 4 (IGFBP4). Additionally, IGFBP4 affected sensitivity to GEM independently of BHLHE41, suggesting that IGFBP4 contributes to resistance to this agent in PC cells.

Conclusion: These findings provide novel insights that may help identify potential targets for patients with PC undergoing chemotherapy and open new avenues for research and therapeutic strategies.

Background/aim: In carbon-ion radiotherapy (CIRT), a low dose-averaged linear energy transfer (LET_d) within the tumor has been suggested as a potential unfavorable prognostic factor for local recurrence. However, inter-fractional variations in LET_d during daily CIRT sessions remain unelucidated. This study aimed to investigate inter-fractional variations in LET_d profiles during CIRT for pancreatic cancer.

Patients and methods: Seven patients with locally advanced pancreatic cancer treated with CIRT were retrospectively analyzed. Treatment plans delivering 55.2 Gy (relative biological effectiveness) in 12 fractions were generated based on computed tomography (CT) images (Plan-CT). For each CIRT session, in-room CT images were acquired immediately after irradiation and referred to as Daily-CT; all 12 series of images were deformably registered to the Plan-CT. LET_d parameters (L_98%, L_95%, L_50%, and L_2%) for target volumes were compared between Plan-CT and Daily-CT (L_X% was defined as the minimum LET_d delivered to X% of the target volume).

Results: The L_50% and L_2% values for the planning target volumes were significantly lower on Daily-CT than on Plan-CT, although the differences were modest. Meanwhile, no significant differences were observed for L_98% and L_95%. One patient exhibited a consistent decrease in LET_d on Daily-CT across all LET_d parameters and target volumes examined. For this patient, increased bowel gas within the beam path was observed during daily sessions, which caused a distal shift of the LET_d distribution, which then reduced LET_d coverage of the target volumes.

Conclusion: During CIRT for pancreatic cancer, inter-fractional variations in LET_d profiles may be more pronounced at larger target volumes and at lower L_X% values. Although the variations were modest in most cases, inter-fractional changes in bowel gas within the beam path are a potential risk factor for reduced LET_d coverage.

Background/aim: Many patients with prostate cancer receive moderately hypo-fractionated radiotherapy (mHF-RT). Inappropriate bladder filling during the mHF-RT course increases urinary toxicity. This study investigated the impact of pre-RT bladder volumes on the subsequent filling status.

Patients and methods: One-hundred-and-nineteen prostate cancer patients irradiated with mHF-RT (60 Gy in 20 fractions) were included in this retrospective study from three European countries. The impact of pre-RT bladder volumes on the number of fractions with a volume <200 ml was examined.

Results: In case of a pre-RT bladder volume <200, <250, and <300 ml, the corresponding mean number of fractions with a bladder volume <200 ml during mHF-RT was 16.6 (±5.0), 15.9 (±5.6), and 15.1 (±5.9), respectively. The impact of the pre-RT volume (<200 vs. ≥200 ml, <250 vs. ≥250, <300 vs. ≥300 ml) on the number of fractions with a volume <200 ml was always highly significant (p<0.0001).

Conclusion: Pre-RT bladder volumes <200 ml, <250 ml, and <300 ml were significantly associated with higher numbers of bladder volumes <200 ml during mHF-RT. These findings will lead to an amendment to a prospective trial.

Background/aim: Multiple myeloma (MM) remains incurable due to relapse and therapeutic resistance. This study evaluated the cancer-testis antigen NY-ESO-1 as a target for T-cell-based immunotherapy and assessed the potential of a self-differentiated monocyte-derived dendritic cell platform expressing NY-ESO-1 (SD-DC-NY) to activate T-lymphocytes against MM in vitro.

Materials and methods: NY-ESO-1 expression was assessed by immunohistochemistry (IHC) in 95 MM cases. A lentiviral tri-cistronic construct encoding GM-CSF, IL-4, and NY-ESO-1 was used to generate SD-DC-NY. Autologous T-lymphocytes were activated with SD-DC-NY and tested against NY-ESO-1-positive U266 and NY-ESO-1-negative JJN-3 cells. Cytotoxicity (annexin V/PI) and interferon-gamma (IFN-γ) secretion (ELISA) were measured. Statistical significance was set at α=0.05 using two-sided tests.

Results: NY-ESO-1 was detected in 17.9% (17/95) of MM samples. SD-DC-NY showed DC maturation comparable to conventional cytokine-generated DCs. SD-DC-NY-activated T-lymphocytes induced higher apoptosis of U266 cells versus controls (p<0.0001) and secreted more IFN-γ (p<0.05).

Conclusion: SD-DC-NY effectively primes cytotoxic T-lymphocytes and enhances antitumor activity against NY-ESO-1-positive MM cells, supporting NY-ESO-1 as an immunotherapeutic target and highlighting SD-DC-NY as a promising platform for MM immunotherapy.

Background/aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system in infancy. Despite advances in treatment, the prognosis remains poor for high-risk NB patients. Although immunotherapy using anti-GD2 antibodies is available for high-risk NB, the therapeutic efficacy is insufficient. Near-infrared photoimmunotherapy (NIR-PIT) is an antitumor strategy that induces tumor-specific cytotoxicity by combining an antibody-photoabsorber conjugate (APC) with NIR light irradiation. In this study, we investigated the therapeutic efficacy of GD2-targeted NIR-PIT against human NB cells.

Materials and methods: GD2 expression was analyzed on the surface of high-risk human NB cells (CHP-134, LA-N-5, IMR-32) and non-high-risk human NB cells (SK-N-SH) by flow cytometry. The APC was synthesized by incubating anti-GD2 antibody and IR700. The cytotoxic effect of GD2-targeted NIR-PIT was evaluated using the XTT assay. The distribution of dead cells within tumor spheres was evaluated using a live/dead assay. The in vivo antitumor effect of GD2-targeted NIR-PIT was assessed using a subcutaneous human NB xenograft tumor model.

Results: GD2 protein was expressed on the surface of CHP-134, LA-N-5, and IMR-32 cells but not SK-N-SH cells. GD2-targeted NIR-PIT significantly suppressed the viability of GD2-positive NB cells but not GD2-negative NB cells, compared to the control and monotherapy groups. GD2-targeted NIR-PIT significantly reduced the volume of GD2-positive CHP-134 tumor spheres by inducing the accumulation of dead cells. Subcutaneous CHP-134 xenograft tumor models demonstrated that GD2-targeted NIR-PIT significantly inhibited tumor growth compared with the control and monotherapy groups.

Conclusion: GD2-targeted NIR-PIT is a promising antitumor strategy for treating high-risk NB tumors expressing GD2.

Background/aim: This study investigated the efficacy and safety of olanzapine and aprepitant in preventing chemotherapy-induced nausea and vomiting in patients with hepatocellular carcinoma (HCC) undergoing cisplatin-based hepatic arterial infusion chemotherapy (HAIC).

Patients and methods: This single-center, non-randomized, prospective study included patients with HCC receiving cisplatin-HAIC between December 2020 and February 2023. In the first treatment session, patients without diabetes mellitus received granisetron and olanzapine (GRA+OLA), and those with diabetes received granisetron monotherapy (GRA). The primary endpoint was the complete response (CR, no vomiting or rescue medications) rate in the GRA+OLA group. In the second session, aprepitant was added if complete control (CC, CR plus no severe nausea) was not achieved during the first treatment. Secondary endpoints were rates of CC and total control (TC, CR plus no nausea), changes in liver function, and toxicity in each medication group.

Results: The CR rate in the GRA+OLA group (n=7) was 85.7% (90% confidence interval=47.9-99.3%), which is numerically but not statistically significantly higher than the rate in the GRA group (n=9, 66.7%; p=0.59). Aprepitant was added in two cases, both of which achieved TC. No grade ≥3 treatment-related adverse events were observed.

Conclusion: Olanzapine and/or aprepitant with granisetron may be effective and safe as an antiemetic therapy in cisplatin-HAIC.

Background/aim: Adrenal insufficiency is a recognized complication following adrenalectomy and, less commonly, nephrectomy due to the anatomical and functional relationship between the adrenal glands and kidneys. While unilateral adrenalectomy is typically well tolerated due to compensation by the contralateral adrenal gland, adrenal insufficiency may still occur, particularly in cases involving bilateral disease. Recognizing and managing this risk is critical in postoperative care to prevent life-threatening adrenal crises.

Case report: We present a case of left renal cell carcinoma (RCC) with tumor thrombus (TT) level IV (extending into the right atrium). The surgery was completed exclusively through an abdominal approach without cardiopulmonary bypass (CPB). The surgical approach involved a left radical nephrectomy, left adrenalectomy, and removal of a large TT, which included a segment of the inferior vena cava (IVC) and the right adrenal vein. As a result, the right adrenal vein was sacrificed, and adrenal insufficiency was expected due to ligation of the right adrenal vein and removal of the left adrenal gland. However, one year after the procedure, adrenal insufficiency was not seen, perhaps due to venous collaterals draining the right adrenal gland.

Conclusion: This case highlights that in the case of complete obstruction of the IVC by the TT of an RCC, the remaining adrenal vein can be sacrificed without causing adrenal insufficiency, perhaps due to the presence of multiple venous collaterals that developed from chronic obstruction of the IVC.

Background/aim: Esophageal squamous cell carcinoma (ESCC) is resistant to multidisciplinary treatments. Neoadjuvant chemotherapy (NAC) enhances outcomes but varies in effectiveness, highlighting the need for predictive markers. This study aimed to identify factors influencing the efficacy of NAC in treating ESCC and predict its efficacy.

Patients and methods: We included 66 ESCC patients who underwent esophageal surgery at the Chiba University Hospital after receiving NAC with 5-fluorouracil and cisplatin between 2008 and 2021. We pathologically evaluated the chemotherapy response and classified it into low (Grades 0, 1a) and high (Grades 1b, 2, 3) sensitivity groups. We statistically analyzed clinical factors, blood tests, and predictors such as BMI, neutrophil percentage, and total protein.

Results: Sixty-six ESCC patients, classified into low (54.5%) and high (45.5%) sensitivity groups based on their response to chemotherapy, were included. Higher BMI was linked to reduced sensitivity (p=0.033). Blood tests showed correlation between NAC sensitivity and eosinophils, total protein (TP), and prothrombin time international normalized ratio (PT-INR). Multivariate analysis identified BMI, neutrophil percentage, and TP as significant predictors. A scoring system (0-3) using BMI, TP, and neutrophil fraction correlated significantly with treatment response (p=0.002). Kaplan-Meier analysis indicated improved disease-specific survival (DSS) in responders, though not significantly (p=0.061).

Conclusion: Three factors -BMI, neutrophil fraction, and TP- were identified that significantly affect the efficacy of NAC in ESCC. These factors were used to develop a scoring system that correlates with treatment efficacy, offering potential utility in predicting the success of NAC in ESCC patients.

Background/aim: Although various therapeutic options are available for advanced or recurrent non-small cell lung cancer (NSCLC), the optimal criteria for selecting combination therapies involving anti-programmed death-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) antibodies with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies remain unclear. Clinical trials suggest potential benefits of the treatment with anti-CTLA-4 antibodies in NSCLC with PD-L1 <1%; however, concerns persist regarding the increased risk of immune-related adverse events (irAEs). Therefore, identifying reliable biomarkers to guide the use of anti-CTLA-4 antibodies is crucial.

Patients and methods: We performed immunohistochemical staining to assess intratumoral tumor-infiltrating lymphocytes (iTILs) and stromal tumor-infiltrating lymphocytes (sTILs) expressing CD8 or FOXP3 using surgically obtained specimens. The association between these cells and the clinical efficacy of the treatment with nivolumab plus ipilimumab was evaluated using univariate and multivariate analyses in NSCLC patients with PD-L1 <1%. Kaplan-Meier analysis was conducted to assess survival outcomes.

Results: Univariate analysis revealed a significant correlation between progression-free survival and sTIL infiltration, but not iTIL infiltration. Patients who responded to therapy exhibited significantly higher CD8+ and lower FOXP3+ iTIL infiltration, as reported previously. Notably, responders also demonstrated significantly higher infiltration of both CD8+ and FOXP3+ sTILs. Moreover, high stromal infiltration of CD8+ T cells was significantly associated with prolonged overall survival, while high FOXP3+ sTILs infiltration showed a trend toward improved overall survival.

Conclusion: Despite the increased risk of irAEs, patients with high stromal infiltration of CD8+ and FOXP3+ T cells may derive meaningful clinical benefit from anti-CTLA-4 antibody therapy. Assessing these immune parameters could aid in appropriate patient selection and contribute to optimizing therapeutic outcomes.