International Journal of Cancer最新文献

This single-center, open-label, single-arm phase II trial (NCT05165407) aimed to evaluate the efficacy and safety of surufatinib (250 mg orally once daily) combined with sintilimab (200 mg intravenously every 3 weeks) and IBI310 (1 mg/kg intravenously every 6 weeks) in patients with advanced high-grade neuroendocrine neoplasms (HG-NENs). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of March 28, 2025, 24 patients with measurable baseline lesions and at least one post-treatment tumor assessment were included in the efficacy-evaluable analysis set. The ORR was 37.5% (95% confidence interval [CI]: 18.8-59.4); DCR, 79.2% (95% CI: 57.8-92.9); and median DoR, 14.8 months. Among 31 treated patients in the full analysis set population, the median PFS was 3.81 months (95% CI: 2.79-4.50), and the median OS was 13.44 months (95% CI: 10.28-not estimable). Subgroup analyses showed improved response in patients with the following characteristics: female sex, age <55 years, ECOG performance status of 1, received ≤1 prior treatment line, without liver metastases, and <2 metastatic sites. Treatment-related adverse events (TRAEs) occurred in 96.8% of patients; 45.2% experienced grade ≥3 TRAEs. Among them, 71.0% experienced TRAEs attributed to sintilimab/IBI310, and 87.1% to surufatinib. Serious adverse events occurred in 45.2% of patients. These findings suggest that surufatinib, IBI310, and sintilimab may offer clinical benefit with manageable toxicity in patients with advanced HG-NENs.

This descriptive analysis evaluates design strategies, regulatory outcomes, and temporal trends in oncology accelerated approvals (AAs) over three decades, comparing solid tumors with hematologic malignancies. We retrospectively reviewed publicly available U.S. Food and Drug Administration (FDA) data on oncology drugs granted AA between December 1992 and January 2025, focusing on those with completed post-approval assessments. Key measures included trial design, endpoints, conversion and withdrawal rates, and time to regulatory resolution. Of 204 AAs representing 204 drug-indication pairs (across 133 drugs), 138 had completed post-approval assessments; 77.5% converted to regular approval, 22.5% were withdrawn. Solid tumors accounted for 63% (87/138) of AAs, and had higher conversion rates to regular approvals compared to hematologic malignancies (82% vs. 71%, respectively). Withdrawals were more frequent in hematologic malignancies compared to solid tumors (29% vs. 18%, respectively). Orphan drug designation and post-approval label modifications were more common in hematologic malignancies than solid tumors (76% vs. 45%, and 18% vs. 11%, respectively). Randomized controlled trials (RCTs) drove most successful conversions (63%). Among 105 AA trials for solid tumors, overall response rate (ORR) was the primary endpoint in 74%, with progression-free survival (PFS) and overall survival (OS) in 13% and 9% AAs, respectively. Hematologic trials favored ORR (33%) and disease-specific endpoints. The most common AA → confirmatory pathway was ORR → PFS (46%). OS as a confirmatory endpoint after surrogate-based AA was linked to higher withdrawal rates, whereas consistent endpoints (e.g., OS → OS) had none. RCTs and aligned endpoints drive successful oncology AA conversions, while surrogate-confirmed OS often precedes withdrawal.

Despite advances in cancer immunotherapy, low response rates remain a critical clinical challenge. Myeloid-derived suppressor cells (MDSCs) drive tumor immune evasion by directly suppressing antitumor immunity, positioning them as prime therapeutic targets to improve immunotherapy efficacy. While dysregulated ionic microenvironments, particularly elevated potassium, are emerging as broad-spectrum immunomodulators, the role of high potassium in regulating MDSC function remains poorly understood. Here, we demonstrate that elevated extracellular potassium reprograms MDSC differentiation toward an immunosuppressive phenotype via the activation of the inwardly rectifying potassium channel Kir4.1. Mechanistically, Kir4.1 triggers metabolic rewiring by upregulating fatty acid-binding protein 3, thereby enhancing fatty acid uptake and oxidation to fuel the production of immunosuppressive molecules. In preclinical models, pharmacological inhibition of Kir4.1 with VU0134992 reversed MDSC-mediated T cell suppression, remodeled the tumor microenvironment, and synergized with anti-PD-1 therapy to achieve superior antitumor responses. Clinically, elevated Kir4.1 expression in tumor-infiltrating MDSCs correlates with an adverse prognosis in patients with lung and gastric cancer. Our study establishes Kir4.1 as a critical metabolic regulator governing MDSC functionality and proposes targeting potassium signaling as a strategy to overcome resistance to cancer immunotherapies.

The impact of prior immune checkpoint inhibitor (ICI) therapy on subsequent antiangiogenic treatment efficacy in advanced gastric cancer remains unclear. We retrospectively analyzed 134 patients with advanced gastric cancer who received apatinib as third-line treatment between January 2018 and October 2023, comparing outcomes between those with (n = 66) and without (n = 68) prior ICI exposure. The ICI-pretreated group demonstrated significantly improved survival outcomes, with longer median progression-free survival (7.1 vs. 4.2 months; HR = 0.42, 95% CI: 0.24-0.75, p = .003) and overall survival (9.0 vs. 5.1 months; HR = 0.53, 95% CI: 0.31-0.91, p = .023) compared to the ICI-naive group. Disease control rate was also higher in ICI-pretreated patients (72.7% vs. 61.8%). Subgroup analyses revealed particularly pronounced survival benefits among male patients (HR = 0.30, 95% CI: 0.14-0.65), HER2-negative patients (HR = 0.35, 95% CI: 0.18-0.69), and those with liver metastases (HR = 0.33, 95% CI: 0.15-0.76, p = .009). Prior ICI therapy emerged as an independent favorable prognostic factor for survival in multivariate analysis. These findings suggest that prior ICI therapy may enhance the efficacy of subsequent third-line apatinib treatment in patients with advanced gastric cancer, providing important insights for optimizing treatment sequencing strategies in this setting.

Self-sampling for human papillomavirus (HPV) is an established strategy to increase participation in cervical screening. We previously reported a randomized trial targeting women who had not attended screening after >10 invitations, where sending of self-sampling kits resulted in a 19% attendance and a positive predictive value (PPV) for high grade lesions (HSIL+) of 40%, despite no triaging after the HPV test. Because of the striking results, the intervention was extended to all women resident in Stockholm County, Sweden, in the years 2019/20, who had not attended screening >10 years (N = 42,409). Participation was 35.6% and 11.6% of the participating women were HPV-positive. Among these, there were 43 cases of invasive cervical cancer and 319 cases of high-grade lesions. The PPV was particularly high for HPV16/18 positive women (12% for invasive cancer and 59% for HSIL). In summary, participation with HPV self-sampling among long-term non-attenders in the real-life program was considerably higher than in the research setting and the high yield of HSIL+ implied high effectiveness.

Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumor types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The MSI-H/dMMR phenotype may arise from an inherited pathogenic variant in the context of Lynch syndrome and is most frequently observed in endometrial, colorectal, and gastric cancers. MSI-H/dMMR is a major predictive biomarker for the efficacy of immune-checkpoint inhibitors (ICIs). Following the approval of ICIs for metastatic disease, these drugs are now being evaluated in localized disease settings. In this review, we provide an overview of current knowledge regarding the use of ICIs as neoadjuvant therapy and as a part of immuno-ablative, surgery-sparing strategies, with a focus on Lynch-related cancers. Finally, we address the diagnosis, monitoring, and prevention challenges raised by these de-escalation strategies.

Although the prevalence of waterpipe smoking is increasing worldwide, evidence on its health hazards, including cancer, is limited. We examined the association between waterpipe smoking and head and neck squamous cell carcinoma (HNSCC) and its subsites. We analyzed data of 918 cases and 3477 controls from the IROPICAN study. Multiple logistic regression models estimated the odds ratios (OR) and 95% confidence intervals (CI). We additionally excluded cigarette smokers, opium users, and nass users to study the association between exclusive waterpipe smoking and HNSCC. The crude OR for ever waterpipe smoking was 1.0 (95% CI: 0.8, 1.3), which decreased to 0.8 (95% CI: 0.6, 1.1) after adjusting for confounding variables. However, we observed statistically non-significant elevated odds of HNSCC (OR: 1.3, 95% CI: 0.9, 1.9), while a significant excess odds of laryngeal cancer (OR: 2.5, 95% CI: 1.0, 5.7) in exclusive waterpipe smokers compared to never tobacco users. Additionally, an especially high OR was observed for laryngeal cancer in exclusive waterpipe smokers with more than 20 years of use (OR: 4.9, 95% CI: 1.7, 14.7). Initiating exclusive waterpipe smoking before the age of 20 was also significantly associated with increased odds of HNSCC (OR: 2.9, 95% CI: 1.3, 6.7) and laryngeal cancer (OR: 9.0, 95% CI: 2.1, 38.2). In conclusion, although no association was found between waterpipe smoking and HNSCC, exclusive waterpipe smoking, particularly at high doses and long duration, seems to lead to an increased risk of HNSCC, especially laryngeal cancer. Larger studies with sufficient power are warranted.

Current epidemiological thinking is that classic Hodgkin lymphoma (cHL) comprises multiple aetiologically distinct disease entities that may in part be defined by either histological subtype or the presence of Epstein-Barr virus (EBV) in the malignant cells, or by both. This study aimed to advance our understanding of epidemiological differences between cHL subtypes, in particular EBV-positive and EBV-negative cHL. We retrospectively collected and EBV-typed 1992 cHL primary tumour tissues from among all 2811 patients diagnosed with incident HL in Denmark in the period 1990 through 2010 'Hodgkin lymphoma in Denmark' [HOLYDAN] project. Based on characteristics of retrieved samples combined with additional information from national registers, we projected nationwide age-, sex-, histology- and EBV-specific cHL incidence rates. The analyses demonstrated age- and sex-dependent variation in histology- and EBV-tumour status-specific cHL incidence rates, details of which yielded new aetiological clues. cHL incidence increased markedly around the age of puberty, irrespective of histological subtype and EBV status. The incidence of all subtypes of cHL increased with age after age 50 years, with the exception of EBV-negative nodular sclerosis cHL in females, which therefore showed a single peak in incidence and was higher than in males among young adults. These results were obtained in a small homogeneous population and might, therefore, only apply to rich, industrialised, Western populations. Nevertheless, we propose that puberty creates an immunological host environment conducive to cHL development irrespective of EBV status and histology, and that age-related decline in immune function facilitates the development of both EBV-positive and EBV-negative cHL.

This study (TACTIC GC-01) aimed to evaluate the efficacy and safety of fruquintinib combined with albumin-bound paclitaxel as a second-line treatment for advanced gastric cancer (GC) following progression on programmed cell death protein 1 (PD-1) inhibitor-based therapy. In this single-center, single-arm, prospective trial, patients with metastatic gastric adenocarcinoma who failed first-line anti-PD-1 combined with chemotherapy treatment received six cycles of albumin-bound paclitaxel combined with fruquintinib, followed by fruquintinib maintenance monotherapy. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse event (AE) incidence. Between February 24, 2022, and March 26, 2024, 41 patients were enrolled, with three receiving only one treatment cycle. The safety analysis included all 41 patients, while the full analysis set comprised 38 patients. Median PFS and OS were 5 months and 14 months, respectively, with corresponding 6- and 12-month PFS rates of 31.7% and 17.3%, and OS rates of 87.8% and 51.7%, respectively. Log-rank analysis identified frontline immunotherapy duration (≥3 cycles) as a key risk factor for PFS, while metastasis to ≥2 organs significantly impacted OS. The ORR and DCR were 44.7% and 94.7%, respectively. Treatment-related AEs occurred in 90.2% of patients, with grade 3-4 AEs (notably neutropenia and thrombocytopenia) observed in 41.5% of them. These findings suggest that fruquintinib plus albumin-bound paclitaxel exhibits promising efficacy and manageable toxicity in anti-PD-1-refractory GC, warranting further exploration in combination strategies targeting alternative pathways.

Although phase II trials have shown that adding docetaxel to S-1/oxaliplatin (DOS) improves pathological response in HER2-negative locally advanced gastric cancer (LAGC), robust real-world evidence comparing DOS with the standard S-1/oxaliplatin (SOX) regimen is lacking. We retrospectively reviewed 1283 consecutive patients with cT2N⁺ or cT3-4NanyM0, HER2-negative gastric adenocarcinoma treated with ≥2 cycles of DOS (n = 461) or SOX (n = 822) at four high-volume Chinese centers between 2010 and 2024. To address confounding, we applied propensity-score matching (PSM, 1:1) and inverse probability-of-treatment weighting (IPTW). Major pathological response (MPR) was the primary endpoint; secondary endpoints included disease-free survival (DFS), overall survival (OS), and perioperative safety. DOS yielded a higher MPR rate than SOX (25.7% vs. 17.8%; OR 1.59, 95% CI 1.14-2.23; E-value =1.83 in PSM cohort) without increasing severe postoperative complications (2.2% each). In multivariable Cox models, DOS reduced progression risk (HR 0.74, 95% CI 0.59-0.93 in IPTW cohort), while OS was similar after a median 34.8-month follow-up. The DFS advantage was consistent across prespecified subgroups, particularly in patients aged ≥65 years, those with cT2-3 or cN0-1 disease, and proximal tumors. These findings indicate that neoadjuvant DOS induces deeper pathological regression and longer DFS than SOX without compromising surgical safety, supporting taxane-based triplets as a preferred perioperative option for HER2-negative LAGC; longer follow-up will clarify any impact on OS.