Okazawa-Sakai M, et al. J Gynecol Oncol. 2024 Oct;36:e38. https://doi.org/10.3802/jgo.2025.36.e38

PURPOSE: Continuous use of antiangiogenic agents has demonstrated survival benefits in various cancers. This trial aimed to compare the efficacy and safety of ramucirumab plus irinotecan with irinotecan monotherapy as a third- or later-line treatment for patients with advanced or recurrent gastric or gastroesophageal cancer (AGC) that has progressed on previous ramucirumab-based chemotherapy. METHODS: Patients age 20 years and older with AGC, who had experienced disease progression during ramucirumab-based chemotherapy, were randomly assigned to receive either ramucirumab plus irinotecan or irinotecan monotherapy. The primary end point was overall survival (OS) expecting a hazard ratio (HR) of 0.77 (a power of 80% and a significance level of one-sided 0.05). Secondary end points included progression-free survival (PFS), response rate, disease control rate (DCR), and safety. RESULTS: Between February 2017 and August 2022, 402 patients in Japan were randomly assigned to receive ramucirumab plus irinotecan (n = 202) or irinotecan monotherapy (n = 200). The median OS was 9.4 months in the combination arm and 8.5 months in the monotherapy arm, with an adjusted HR of 0.91 (95% CI, 0.74 to 1.12; P = .49). PFS was improved (median, 3.8 v 2.8 months; HR, 0.72 [95% CI, 0.59 to 0.89]; P = .002), while the DCR was significantly better (64.4% v 52.1%; P = .03) with the combination therapy. The adverse events of the combination therapy were manageable. CONCLUSION: Adding ramucirumab to irinotecan does not provide a significant advantage in OS over irinotecan alone in patients with AGC who have progressed during ramucirumab-containing chemotherapy.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)–targeted therapies have shown promise in treating HER2 -amplified metastatic colorectal cancer (mCRC). Identifying optimal biomarkers for treatment decisions remains challenging. This study explores the potential of artificial intelligence (AI) in predicting treatment responses to trastuzumab plus pertuzumab (TP) in patients with HER2 -amplified mCRC from the phase II TRIUMPH trial. MATERIALS AND METHODS: AI-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis were applied to the prescreening cohort (n = 143) and the TRIUMPH cohort (n = 30). AI analyzers determined the proportions of tumor cells (TCs) with HER2 staining intensity and the densities of various cells in TME, examining their associations with clinical outcomes of TP. RESULTS: The AI-powered HER2 QCS for HER2 immunohistochemistry (IHC) achieved an accuracy of 86.7% against pathologist evaluations, with a 100% accuracy for HER2 IHC 3+ patients. Patients with ≥50% of TCs showing HER2 3+ staining intensity (AI-H3-high) exhibited significantly prolonged progression-free survival (PFS; median PFS, 4.4 v 1.4 months; hazard ratio [HR], 0.12 [95% CI, 0.04 to 0.38]) and overall survival (OS; median OS, 16.5 v 4.1 months; HR, 0.13 [95% CI, 0.05 to 0.38]) compared with the AI-H3-low (<50% group). Stratification among patients with AI-H3-high included TME-high (all lymphocyte, fibroblast, and macrophage densities in the cancer stroma above the median) and TME-low (anything below the median), showing a median PFS of 1.3 and 5.6 months for TME-high and TME-low respectively, with an HR of 0.04 (95% CI, 0.01 to 0.19) for AI-H3-high with TME-low compared with AI-H3-low. CONCLUSION: AI-powered HER2 QCS and TME analysis demonstrated potential in enhancing treatment response predictions in patients with HER2 -amplified mCRC undergoing TP therapy.

The rat heart receives its blood supply not only from the coronary arteries but also from the accessory coronary arteries that supply mainly the atria. The distribution and chemical nature of nitric oxide synthase-containing nerve fibers in the conduction system as well as the coronary and accessory coronary arteries were investigated using immunohistochemistry and NADPH diaphorase (NADPH-d) histochemistry. A few NADPH-d-positive nerve fibers were observed mainly around the main trunk of the coronary arteries, while NADPH-d-positive fibers were found along the entire course of the accessory coronary arteries from their main branches to the arteriolar level. A double-staining method demonstrated that NADPH-d-positive fibers innervating both the coronary and accessory coronary arteries contained vasoactive intestinal polypeptide or neuropeptide Y. NADPH-d-positive fibers were relatively abundant in the sinus node and penetrating bundle but were very sparse in the atrioventricular node and right bundle branch. No NADPH-d-positive fibers were detected in the left bundle branch. Some of the NADPH-d-positive fibers innervating the penetrating bundle exhibited distinct immunoreactivity to calcitonin gene-related peptide. These results suggest that nitric oxide may play a role as a neurotransmitter and/or neuromodulator in the neural control of the cardiac blood flow and impulse conduction.

Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (n = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (n = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73–1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07–1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; P = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; P = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs. Significance: As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.

Introduction: Efficacy and safety of docetaxel (DTX) or weekly-paclitaxel (wPTX) had been reported in single-arm phase II studies, and DTX or wPTX is widely used in clinical practice as second-line chemotherapy for patients with unresectable or recurrent esophageal cancer. However, there was no randomized controlled trial comparing DTX and wPTX. We investigated retrospectively the efficacy and safety of DTX and wPTX as second-line chemotherapy for patients with esophageal cancer in our institution.