International Journal of Clinical Oncology最新文献

Colorectal cancer remains one of the leading causes of cancer-related mortality worldwide, and early detection is essential for improving outcomes. Advances in liquid biopsy technologies and microbiota research have shed new light on diagnostic and therapeutic strategies for colorectal cancer. Notably, circulating tumor DNA methylation has emerged as a sensitive and specific biomarker for early detection, recurrence surveillance, and treatment monitoring. Recent progress in methylation-based assays, including stool- and plasma-derived approaches, highlights their potential clinical utility; however, challenges remain in detecting minimal residual disease at the earliest stages. Parallel to these developments, the gut microbiota has been recognized as a critical modulator of colorectal carcinogenesis and treatment response. Specific bacterial species, such as Fusobacterium nucleatum, polyketide synthase-positive Escherichia coli, and enterotoxigenic Bacteroides fragilis, have been implicated in tumor initiation and progression through epigenetic reprogramming, including aberrant DNA methylation. Microbial metabolites, particularly short-chain fatty acids such as butyrate, influence DNA methyltransferase activity and histone modifications, linking microbial ecology to the host epigenome. Microbiota composition also affects responses to chemotherapy, radiotherapy, and immunotherapy, underscoring its potential as a predictive biomarker and therapeutic target. Integrating circulating tumor DNA methylation profiling with microbiota analysis provides a promising strategy for personalized colorectal cancer management, combining early detection with treatment outcome prediction. This review summarizes the current evidence and future directions at the interface of DNA methylation and the gut microbiota, emphasizing their synergistic role as composite biomarkers in precision oncology.

Background: Pulmonary metastasectomy (PM) is a treatment for lung metastases of bone and soft tissue sarcomas. However, the criteria for repeat PM after a second pulmonary recurrence remain unclear. We evaluated prognostic significance of the second disease-free interval (DFI-2; from initial PM to second pulmonary recurrence) and defined the criteria for repeat PM.

Methods: We retrospectively reviewed 60 patients who underwent PM for bone or soft tissue sarcomas (2000-2024), among whom 31 experienced a second pulmonary recurrence. Overall survival (OS) was analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards models were used to identify independent prognostic factors. OS was compared between patients with DFI-2 < 6 and ≥ 6 months. The DFI-2 cut-off was determined to maximize Harrell's concordance index for OS.

Results: The median patient age, metastasis number, and metastasis size were 55 years, two, and 1.4 cm. The 5-year OS rate was 41.3%. Multivariable analysis identified DFI-1 < 12 months, ≥ 3 metastases, and incomplete resection as independent adverse factors. Among the 31 patients who developed second pulmonary recurrence, 16 underwent repeat PM, achieving the 5-year OS of 39.5%. Patients with DFI-2 ≥ 6 months had significantly better OS (median, 56.6 vs. 14.4 months, p < 0.001) and were more likely to undergo repeat PM (73.3% vs. 31.3%). All patients with DFI-2 < 6 months who underwent repeat PM experienced recurrence within 6 months.

Conclusions: DFI-2 ≥ 6 months predicts a favorable prognosis and may be a practical criterion for selecting candidates for repeat PM in bone and soft tissue sarcomas.

Background: Immune checkpoint inhibitors (ICIs) are now the standard first-line treatment for metastatic renal cell carcinoma (mRCC), yet many risk factors identified during the tyrosine kinase inhibitor era remain unvalidated in current practice. This study aimed to evaluate the prognostic value of body composition, nutritional, and inflammatory indices in the era of ICI-based first-line therapy.

Methods: We retrospectively analyzed 136 mRCC patients who received systemic therapy. Body composition indices (skeletal muscle index [SMI], visceral adipose tissue index [VATI], subcutaneous adipose tissue index [SATI]), nutritional markers (prognostic nutritional index [PNI], geriatric nutritional risk index [GNRI]), and inflammatory markers (Glasgow Prognostic Score [GPS], systemic inflammatory index [SII], and other indices) were assessed for their association with overall survival (OS). We also compared their prognostic impact on patients treated with non-ICI-based and ICI-based regimens as first-line therapy.

Results: Low VATI (HR 1.64, P = 0.030), and low SATI (HR 2.22, P < 0.001) were associated with shorter survival. PNI (HR 1.70, P < 0.001) and GNRI (HR 1.57, P < 0.001) showed strong prognostic value, as did GPS (HR 2.43, P < 0.001) and SII (HR 2.11, P < 0.001) in the overall cohort. In the ICI-based regimen group, PNI, GNRI, and SATI demonstrated higher prognostic performance (C-indices 0.736, 0.730, and 0.690, respectively), with PNI and SATI providing clear OS stratification.

Conclusion: Several indices reflecting body composition, nutritional status, and systemic inflammation remain valuable prognostic markers in patients with mRCC receiving ICI-based first-line therapy.

Purpose: The JCOG1806 trial (jRCTs031190129) is underway to evaluate the omission of surgery in patients with human epidermal growth factor receptor (HER2)-positive early breast cancer who have a clinical complete response (cCR) after primary systemic therapy (PST). We aimed to assess the cCR rate in this trial and identify predictive factors.

Methods: HER2-positivity was defined as an immunohistochemistry (IHC) score of 3 + or in situ hybridization-positivity. A cCR was defined as the absence of detectable lesions upon palpation, contrast-enhanced magnetic resonance imaging, and ultrasonography; biopsy-based confirmation was optional in hormone receptor (HR)-negative cases and mandatory in HR-positive cases. Multivariate logistic regression analyses were used to identify predictors of a cCR.

Results: The cCR rate was 57.6% (196/340 patients; 95% confidence interval [CI]: 52.2-63.0%). Strongly estrogen-receptor (ER)-positive tumors (≥ 10%) were significantly less likely to have a cCR than ER-negative tumors (odds ratio [OR], 0.41; 95% CI: 0.20-0.81). IHC 3 + tumors had higher cCR rates than IHC 1 + or 2 + tumors (OR, 2.19; 95% CI: 1.01-4.74). Compared with histological grade I tumors, cCR odds were higher in grade II (OR: 2.92; 95% CI: 1.07-7.93) and III (OR: 4.90; 95% CI: 1.76-13.7) tumors. Among patients without a cCR patients undergoing surgery, 22.2% were diagnosed with ypT0 tumors upon analysis of surgical specimens.

Conclusion: ER-negativity, an IHC score of 3 + , and a higher histological grade were independent predictors of a cCR. Identifying these features may improve the feasibility and safety of surgery omission for patients with HER2-positive early breast cancer.

Background: Cervical cancer poses a significant global health burden, particularly in its metastatic and recurrent forms, for which treatment options are limited. Although immune checkpoint inhibitors (ICIs) such as pembrolizumab have improved outcomes, predictive markers for efficacy are still undefined. This retrospective study investigated changes in peripheral blood eosinophil and lymphocyte counts as potential prognostic indicators in patients with metastatic or recurrent cervical cancer undergoing pembrolizumab-based therapy.

Methods: Forty-one patients treated with pembrolizumab plus taxane-platinum chemotherapy (± bevacizumab) were analyzed. Peripheral blood eosinophil and lymphocyte counts were measured before and 3 weeks after treatment initiation. Statistical analyses included Kaplan-Meier curves, Cox regression, and log-rank tests.

Results: Immune-related adverse events ≥ grade 2 emerged as a significant independent factor associated with prolonged progression-free survival (PFS) in this cohort (p = 0.014). Patients with decreased eosinophil count ratios post-treatment demonstrated longer PFS, particularly among those with recurrence and those who had received prior radiotherapy (p = 0.0001). Conversely, increased lymphocyte count ratios correlated with improved PFS in patients undergoing primary treatment (p = 0.018).

Conclusion: Changes in peripheral eosinophil and lymphocyte counts following pembrolizumab initiation may serve as predictive indicators of treatment efficacy in specific cervical cancer subgroups. Incorporating these hematologic parameters could help optimize patient selection and therapeutic strategies. Further research is needed to clarify their role as predictive markers of pembrolizumab efficacy in cervical cancer.

Background: Comprehensive genomic profiling (CGP) tests were approved, and opportunities to consider tissue-agnostic targeted therapies based on molecular tumor profiling have increased even in the community-based medicine practice. However, low treatment success rates and regional disparities in access to investigational drugs remain significant challenges. This retrospective study aimed to evaluate the drug accessibility rate and prognostic impact of CGP testing for advanced or metastatic solid tumors at Hiroshima Prefectural Hospital, a facility located far from clinical trial sites.

Methods: We analyzed data from 378 patients who underwent CGP testing between June 2019 and June 2024. Patient characteristics, specimen details, molecular tumor board (MTB) assessments of CGP results, and clinical courses were collected. Overall survival (OS) after MTB assessment was evaluated using the Kaplan-Meier method and log-rank test.

Results: The median patient age was 69 (range: 10-92) years. Lung cancer was the most common cancer type, affecting 105 patients (27.8%). CGP testing identified one or more gene mutations in 356 patients (94.2%), of whom 248 (65.6%) harbored druggable genomic alterations, and 37 (9.8%) received genomically matched therapy. Among them, 27 (73%) received approved drugs. The OS advantage observed in patients who received genomically matched therapy was statistically significant. Among patients who did not receive genomically matched therapy, approximately 20% expressed willingness to participate in clinical trials.

Conclusions: These findings demonstrate the clinical utility of CGP testing in local medical facilities; however, the high proportion of approved drugs among genomically matched treatments highlights significant barriers to clinical trial participation.

Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk of lung cancer, with cumulative incidence rates of 3.3% and 15.4% at 1 and 5 years of follow-up, respectively. The prognosis for patients with lung cancer and IPF is worse than that for patients with IPF alone, primarily due to the progression of lung cancer and complications arising after treatment. Epidemiological and molecular studies indicate that IPF and lung cancer share several pathogenic mechanisms, including genetic and epigenetic alterations. Germline mutations may contribute to both conditions by disrupting the balance between oncogenes and tumor suppressor genes, thereby driving carcinogenesis in fibrotic lungs. Epigenetic dysregulation, such as DNA methylation changes, histone modifications, and deregulation of noncoding RNAs, serves as a common link between these diseases by activating key signaling pathways, including Wnt/β-catenin and PI3K/Akt. These pathways promote alveolar type II cell hyperproliferation and metaplasia, both of which are critical processes in disease progression. In addition, mesenchymal transitions represent a shared pathological feature of lung fibrosis and tumorigenesis. In this review, we summarize the current molecular insights into lung carcinogenesis in lung cancer with IPF. Furthermore, we present findings from our recent comprehensive genetic analysis, which identifies distinct gene profiles indicative of unique carcinogenic mechanisms in lung cancer with IPF. These insights may contribute to improved risk assessment, early detection strategies, and the development of targeted therapies for lung cancer patients with IPF.

Background: In the phase 3 EV-302 study, enfortumab vedotin-pembrolizumab (EV + P) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with untreated locally advanced/metastatic urothelial carcinoma (la/mUC). We present a post hoc analysis in a pan-Asian population.

Methods: Patients from China, Japan, Singapore, South Korea, Taiwan, and Thailand received 3-week cycles of EV (1.25 mg/kg; intravenously; Days 1 and 8) plus P (200 mg; intravenously; Day 1) or chemotherapy (gemcitabine [Days 1 and 8] plus cisplatin/carboplatin [Day 1]). Primary endpoints were PFS and OS. Secondary endpoints included objective response rate (ORR) and safety.

Results: Overall, 176 patients were included (EV + P, n = 94; chemotherapy, n = 82). Median follow-up was 28.9 months for EV + P recipients and 26.6 months for chemotherapy recipients. EV + P prolonged PFS and OS versus chemotherapy, reducing the risk of disease progression or death by 63% (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.24-0.57) and death by 67% (HR, 0.33; [95% CI, 0.20-0.54]), respectively. Confirmed ORR was 72.2% versus 35.0%. Grade ≥ 3 treatment-related adverse events occurred in 66.0% of EV + P recipients and 68.4% of chemotherapy recipients. Most commonly maculopapular rash (11.7%) and hyperglycemia (10.6%) for EV + P and neutropenia (25.0%), anemia (19.7%), and neutrophil count decreased (18.4%) for chemotherapy.

Conclusion: EV + P demonstrated a clinically meaningful survival benefit in Asian patients with untreated la/mUC, with no new safety signals observed, consistent with the global EV-302 study. Results support guideline recommendations for EV + P as preferred first-line therapy in la/mUC.

Clinical trial registration: NCT04223856 (registered January 8, 2020).

Despite advances in adjuvant therapy for colorectal cancer, tumor relapses, often driven by minimal residual disease, remain a formidable clinical challenge. The cancer stem cell hypothesis provides a key framework for understanding this problem, positing that a small, therapy-resistant subpopulation of cells drives recurrence. To elucidate the role of these cells, we developed LGR5-specific monoclonal antibodies and a high-sensitivity immunofluorescence method to visualize the stem cell marker LGR5 in clinical tumors. Furthermore, we established a unique colorectal cancer cell line, PLR123, which maintains robust stem cell properties, and developed an in vitro model to study tumor recurrence. Through analyses including single-cell RNA sequencing and small molecule screening, we identified the RNA Polymerase I inhibitor BMH-21 as a compound that effectively suppresses recurrence both in vitro and in vivo. This article comprehensively reviews our series of studies on understanding the mechanisms of cancer stem cell-driven resistance and offers insights supporting the development of novel therapies aimed at preventing tumor relapses.

Background: Currently, there are no reports on the subsequent treatment of patients with ovarian cancer who exhibited platinum-resistant recurrence during treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. This retrospective study was aimed at evaluating the efficacy and safety of single-agent chemotherapy combined with bevacizumab (BEV) in such patients.

Patients and methods: The efficacy and safety of the treatment were evaluated in 16 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed with platinum-resistant recurrence during PARP inhibitor treatment between April 2019 and June 2025. Chemotherapy was administered with paclitaxel alone or nogitecan alone in combination with BEV and generally continued until the disease progressed.

Results: The median number of single-agent chemotherapy cycles with BEV was 6 (range: 1-20). The objective response and disease control rates were 31.3% and 75.0%, respectively. The median progression-free survival 2 and post-progression survival were 5.5 months [95% confidence interval (CI) = 4.0-6.0] and 17 months (95%CI = 10.0-29.0), respectively. Grade 3 or higher hematological toxicities were observed, including leukopenia, neutropenia, anemia, and thrombocytopenia in 7, 9, 1, and 3 patients, respectively. Non-hematological toxicities included hypertension in three patients and nausea, vomiting, fatigue, proteinuria, thrombosis, ileus, and heart failure in one patient each. None of the patients discontinued chemotherapy because of adverse events or treatment-related deaths.

Conclusion: BEV-combined single-agent chemotherapy has potential efficacy even in the challenging setting of platinum-resistant recurrence during PARP inhibitor treatment of ovarian cancer.