Anticancer research最新文献

Background/aim: In recent years, blood flow assessment using indocyanine green (ICG) fluorescence imaging has been widely used in gastrointestinal surgeries. Several studies have reported the superiority of distal gastrectomy with preservation of a very small remnant stomach (subtotal gastrectomy; STG) over total gastrectomy (TG), which has become an increasingly interesting topic. However, in such cases, inadequate blood supply to the remnant stomach can become a critical issue. Herein, we report a case of laparoscopic STG for gastric cancer in which intraoperative evaluation of blood flow using ICG led to conversion to TG to avoid the risk of postoperative complications and present a review of the literature.

Case report: A 73-year-old man was diagnosed with early gastric cancer in the lower gastric body and underwent endoscopic submucosal dissection (ESD). Histopathological examination revealed submucosal invasion with lymphatic and venous involvement, which required additional resection. During ESD, two more early gastric cancers were identified in the upper and middle gastric body. Although preoperative computed tomography yielded poor visualization of the left inferior phrenic artery, raising concerns regarding insufficient perfusion, laparoscopic STG with Roux-en-Y reconstruction, rather than TG, was planned with priority given to functional preservation. Intraoperatively, the short gastric and posterior gastric arteries were ligated because of the tumor location. While the remnant stomach appeared viable after STG, blood flow was assessed using ICG fluorescence imaging, and blood flow insufficiency was diagnosed. The preservation of a small remnant stomach was abandoned, and TG was performed. The patient was discharged without any postoperative complications.

Conclusion: In distal gastrectomy, particularly in cases of STG or when compromised perfusion is anticipated, intraoperative blood flow assessment using ICG can be effective in preventing complications.

Background/aim: Although, the number of pancreatoduodenectomy for elderly patients is increasing, the significance of pancreatoduodenectomy for long-term prognosis in elderly patients remains unclear. To clarify the validity of pancreatoduodenectomy in elderly patients with ampullary carcinoma, particularly in terms of nutritional status at recurrence.

Patients and methods: We compared 21 patients aged ≥75 years and 40 patients aged <75 years, who underwent pancreatoduodenectomy for ampullary carcinoma and evaluated the relationship among age, nutritional status, and prognosis.

Results: The 5-year recurrence-free, disease-specific, and overall survival rates were similar ≥75 years: 42.9, 57.1, and 57.1%, respectively; and <75 years: 44.0, 69.9, and 62.1%; p=0.99, 0.41, and 0.48, respectively. The median time from recurrence to death was significantly shorter in elderly patients than in younger patients (1.3 vs. 1.8 years, p=0.0063). At recurrence, serum albumin levels, prognostic nutritional index, Glasgow prognostic score, controlling nutritional status score, and treatment rate were lower in elderly patients. Moreover, among elderly patients, these four nutritional indices were poorer in recurrent cases than in non-recurrent cases, whereas they were comparable in younger patients. Even in non-recurrent cases, these nutritional indices were similar between elderly and younger patients. In multivariate analysis, age ≥75 years was an independent risk factor for both a short time from recurrence to death and the likelihood of treatment implementation after recurrence (hazard ratio=3.3, odds ratio=0.019).

Conclusion: In elderly patients, some nutritional status and treatment rates at the time of recurrence were poorer, which resulted in shorter survival times after recurrence. Information on nutritional status changes based on age and recurrence may be important when considering treatment strategies for elderly patients.

Background/aim: Upper-tract urothelial carcinomas (UTUCs) are highly aggressive malignancies with a poor prognosis, necessitating the development of new therapeutic targets and biomarkers. Paternally expressed gene 10 (PEG10) functions as a transcription factor and plays an important role in the development and progression of cancer. However, no studies have examined the role of PEG10 in UTUC.

Patients and methods: We retrospectively analyzed 103 patients with UTUC who underwent radical nephroureterectomy. We evaluated PEG10 expression using immunohistochemistry and performed in silico analyses using the UTUC public database.

Results: Immunohistochemistry showed the PEG10 over-expression was associated with lower cancer-specific survival (p=0.018). In the UTUC public database, the high PEG10 expression group had a higher T-category (p<0.001), tumor grade (p=0.016), and non-papillary tumors were more frequent in the high PEG10 expression group (p=0.015). The high PEG10 expression group was significantly correlated with lower disease-specific survival (p=0.004) and progression-free survival (p<0.001). Furthermore, the high PEG10 expression group was observed in both TP53 and RB1 mutated types (p=0.002) and related to the neuroendocrine subtype (p<0.001). Gene Set Enrichment Analysis showed that the high PEG10 expression group is connected to epithelial-mesenchymal transition, G2M checkpoint, E2F targets, mitotic spindle, and myogenesis.

Conclusion: Over-expression of PEG10 is associated with a poor prognosis in UTUC and may be linked to epithelial-mesenchymal transition. Furthermore, the over-expression of PEG10 may be related to the neuroendocrine subtype. PEG10 may be a biomarker of cancer progression in UTUC and represents a potential therapeutic target.

Background: Patients with colorectal cancer (CRC) and malignant melanoma (MM) are at a significant risk of developing liver metastases. Despite surgical resection and systemic therapies, disease recurrence is common and long-term survival after relapse remains limited. Autologous tumor vaccines represent a promising immunotherapeutic approach by harnessing the immune system's capacity to elicit durable antitumor responses.

Case report: A previously established melanoma immunotherapy protocol was used, combining low-dose cyclophosphamide with repeated intradermal injections of dinitrophenyl-modified autologous tumor cells admixed with Bacillus Calmette-Guérin as an immune adjuvant. Vaccine-induced delayed-type hypersensitivity (DTH) responses were prospectively monitored as a clinical marker of antitumor immune activation and treatment efficacy. This approach was adapted for use in non-melanoma solid tumors. Two patients with advanced disease - one with metastatic melanoma and one with metastatic CRC - experienced recurrent liver metastases following standard treatments and underwent vaccination using tumor cells derived from resected liver lesions. Initial vaccination failed to prevent disease recurrence in both patients. Treatment was subsequently individualized: a modified vaccine was generated for the patient with melanoma, whereas the patient with CRC was successfully treated with vaccine re-challenge. In both cases, the emergence of a positive DTH response was associated with complete clinical remission and durable disease control, with follow-up exceeding 20 years.

Conclusion: Autologous tumor cell vaccines derived from liver metastases may represent a feasible therapeutic strategy capable of achieving durable remission and improved long-term outcomes in selected high-risk patients with metastatic disease.

Background/aim: This study investigated the effectiveness of a protocol-based pharmacotherapy management (PBPM) system in preventing hepatitis B virus (HBV) reactivation induced by chemotherapy.

Patients and methods: This protocol requires pharmacists to verify orders for hepatitis B (HB) surface antigen (HBsAg), anti-HB core antibody (HBcAb), anti-HBs antibody (HBsAb), and HBV-deoxyribonucleic acid (DNA) tests before the start of chemotherapy. Pharmacists are also required to enter any missing test orders after confirming them with physicians. We retrospectively compared the implementation rates of HBsAg, HBcAb, HBsAb, and HBV-DNA tests using the chi-squared test across the following three periods: the pre-PBPM system implementation (pre-PBPM) period (July to September 2021; n=203), the ≤6 month post-PBPM system implementation (≤6M post-PBPM) period (November 2021 to April 2022; n=453), and the >6 month post-implementation (>6M post-PBPM) period (May to July 2022; n=245).

Results: The implementation rate of HBsAg tests remained at 100% throughout the entire study period. The overall HBsAg positivity rate was 2.0% (18/901). The implementation rates of HBcAb/HBsAb tests increased significantly, from 59.6% (121/203; pre-PBPM period) to 91.2% (413/453; ≤6M post-PBPM period, p<0.001) and to 98.0% (240/245; >6M post-PBPM period, p<0.001). The HBcAb/HBsAb positivity rates and HBV-DNA implementation rates in the respective periods were 33.1% (40/121), 26.9% (111/413), and 23.8% (57/240), and 90.0% (36/40), 89.2% (99/111), and 91.2% (52/57), with no statistically significant differences observed. No cases of HBV reactivation were observed during the study period.

Conclusion: Introduction of the PBPM system significantly contributed to the improvement in the implementation rates of HBsAb/HBcAb testing.

Background/aim: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis. Although multiple treatment modalities are available, reliable biomarkers to stratify tumor immune status and guide prognosis remain limited. Increasing evidence suggests that tumors with an inflamed immune microenvironment exhibit improved therapeutic responsiveness; however, the molecular determinants underlying immune activation and their prognostic implications in HCC are not fully defined.

Materials and methods: Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to classify TCGA-LIHC tumors into immune-hot and immune-cold subtypes based on immune infiltration profiles. Differentially expressed genes (DEGs) were further screened by integrating an HCC TACE-treated cohort with multiple immunotherapy and targeted-therapy cohorts to assess broader immune relevance. The immune associations of specific biomarkers were validated through bulk RNA-seq correlation analyses, single-cell RNA-seq profiling, and in vitro functional assays.

Results: PSMB9 was identified as a key immune-related biomarker associated with the immune-hot phenotype in HCC, characterized by elevated immune scores, enriched antigen presentation and interferon signaling pathways, and increased expression of immune checkpoints. Its expression was associated with enhanced responsiveness to TACE and potentially to immunotherapy and targeted therapies. Despite its immune-activating role, high PSMB9 expression predicted poorer overall survival, reflecting a paradoxical phenotype combining immune stimulation with malignant adaptation. Single-cell analysis revealed PSMB9 expression in both malignant and immune compartments, while in vitro assays confirmed that PSMB9 overexpression enhanced proliferation, migration, and resistance to apoptosis in HepG2 cells.

Conclusion: PSMB9 links immune activation with tumor progression in HCC and delineates a patient subgroup with unfavorable prognosis but increased therapeutic responsiveness. These findings suggest that high PSMB9 expression is associated with benefit from TACE and may serve as a prognostic biomarker to inform combined locoregional and systemic treatment strategies in HCC.

Background/aim: Deficient mismatch repair (dMMR) colorectal cancer (CRC) arises from either sporadic epigenetic changes or hereditary Lynch syndrome. This retrospective multicenter cohort study is the first to evaluate the differences in risk for dMMR non-colorectal malignancy between patients with sporadic CRC and those with Lynch syndrome-associated CRC.

Patients and methods: A cohort of 1,753 patients treated between 1996 and 2019 in Sweden, Finland, and the Czech Republic was evaluated for MMR status by immunohistochemistry and classified as either proficient (pMMR) or dMMR. The last one underwent BRAF V600E and MLH1 methylation testing to classify sporadic versus Lynch-associated cases. Non-CRC malignancies occurring within ±20 years of CRC diagnosis were identified via national cancer registries and medical records. Incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age, sex, tumor site, and stage.

Results: Among 277 dMMR cases (186 sporadic, 91 Lynch), 101 patients (36%) developed at least one non-CRC malignancy. Sporadic dMMR was associated with significantly lower risk compared to Lynch-associated dMMR [multivariable IRR=0.82; 95% confidence interval (CI)=0.51-0.91; p=0.014]. The reduced risk was consistent for malignancies occurring both before (IRR=0.48; p=0.047) and after CRC diagnosis (IRR=0.37; p=0.026). Age was an independent predictor of risk.

Conclusion: Sporadic dMMR CRC confers a substantially lower risk of non-colorectal malignancy than Lynch syndrome-associated CRC. These findings underscore the importance of incorporating MMR etiology into personalized surveillance strategies.

Background/aim: Tertiary lymphoid structures (TLSs) have prognostic relevance in various cancers; however, the relationship is complex and depends on TLS properties. In this study, we evaluated the prognostic significance of TLS spatial distribution and maturation in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant chemotherapy (NAC).

Patients and methods: We retrospectively analyzed data for 131 patients with PDAC, including 64 who underwent upfront surgery (UpS) and 67 who underwent NAC followed by surgery. TLSs were evaluated using hematoxylin-eosin staining and immunohistochemistry. TLSs were categorized as intratumoral or peritumoral (periTLS) and by maturation status using immunohistochemical markers. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards models.

Results: TLSs were identified in 81.3% of patients in the UpS group and 83.6% in the NAC group. The prevalence of periTLS was significantly lower in the NAC group than in the UpS group (50.7% vs. 73.4%, p<0.05). Among NAC-treated patients, those with immature periTLS showed significantly higher rates of early distant recurrence within 12 months after surgery (53.8% vs. 14.3%, p<0.05). In a multivariate analysis, the presence of immature periTLS was the only independent poor prognostic factor for recurrence-free survival [hazard ratio (HR)=2.89, 95% confidence interval (CI)=1.20-6.91, p<0.05], only in the NAC group. Serum CA19-9 levels decreased following NAC treatment in 47.4% of PDACs with mature periTLS and 10% of those with immature periTLS (p<0.05). Among 22 patients with post-NAC CA19-9 <100 U/ml, immature periTLS remained the only factor significantly associated with shorter recurrence-free survival (RFS) (HR=2.97, 95%CI=1.05-8.36, p<0.05).

Conclusion: Immature periTLS could serve as a novel histological biomarker for poor RFS in patients with PDAC treated with NAC.

Background/aim: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis owing to chemoresistance to neoadjuvant chemotherapy (NAC). Ferroptosis, regulated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), is a potential therapeutic target. This study investigated the significance of GPX4 and FSP1 in NAC-treated ESCC.

Patients and methods: We analyzed 97 patients with ESCC who underwent NAC and esophagectomy. GPX4 and FSP1 expressions were assessed in relation to clinicopathological factors and survival. Three ESCC cell lines were exposed to cisplatin or 5-fluorouracil with or without the ferroptosis inhibitor liproxstatin-1, GPX4 inhibitor RSL3, or FSP1 inhibitor iFSP1. Cell viability, mRNA expression, and drug interactions were evaluated.

Results: Post-NAC GPX4-positivity (44.3%) was associated with aggressive clinicopathological features, poor histopathological effect, and worse overall and relapse-free survival. Post-NAC FSP1-positivity (28.9%) was associated with poor histopathological effects. Persistent GPX4-positivity from pre- to post-NAC was an independent prognostic factor for poor relapse-free survival (hazard ratio=2.098; 95% confidence interval=1.013-4.345). Cisplatin up-regulated GPX4 mRNA expression, particularly in KYSE70 cells. Liproxstatin-1 partially attenuated chemotherapy-induced cytotoxicity without altering the half-maximal inhibitory concentration. RSL3 enhanced cisplatin and 5-fluorouracil effects in a cell line-dependent manner.

Conclusion: GPX4 mediates tumor aggressiveness and chemoresistance in NAC-treated ESCC. Persistent GPX4-positivity may serve as a prognostic biomarker, and targeting the GPX4-mediated ferroptosis pathway with standard chemotherapy may overcome resistance in advanced ESCC.

Background: Small cell neuroendocrine carcinoma of the cervix (SCNEC) has an extremely poor prognosis. We report a case of recurrent SCNEC with CD274 [Programmed Death-Ligand 1 (PD-L1)] gene amplification and HPV18 positivity, which showed a favorable response to the immune checkpoint inhibitor (ICI) nivolumab.

Case report: A 42-year-old woman presented with a lower abdominal mass and was referred to our department. Imaging revealed a uterine cervical tumor with multiple enlarged pelvic lymph nodes. Biopsy confirmed HPV18-positive SCNEC. After one cycle of neoadjuvant chemotherapy, surgery was performed, revealing stage IIIC2p (ypT1b1, ypN1, M0) SCNEC with regional lymph-node invasion, followed by adjuvant chemotherapy. Two months later, enlargement of the para-aortic and left pelvic lymph nodes was detected. Concurrent chemoradiotherapy (CCRT) was administered, resulting in a reduction of lymphadenopathy. Seven months later, an enlarged right supraclavicular lymph node was detected. Nivolumab therapy was initiated because CD274 (PD-L1) gene amplification was detected in tumor tissue. The lymph node decreased in size, and no signs of relapse had been observed for more than three years.

Conclusion: Comprehensive multimodal therapy, including standard surgery, neoadjuvant and adjuvant chemotherapy, chemoradiation for recurrent lymph nodes, and immune checkpoint inhibition, can achieve a remarkable response in advanced SCNEC harboring CD274 (PD-L1) amplification and HPV18 infection.