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The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.

BackgroundThere is growing interest in the clinical significance of intratumoral HER2 heterogeneity. Its prognostic and predictive impacts on trastuzumab efficacy were demonstrated in breast cancer. However, its clinical significance in gastric cancer is still unclear.MethodsTwenty-eight HER2-positive gastric cancer patients who had gastrectomy prior to trastuzumab-based chemotherapy were consecutively enrolled. Intratumoral HER heterogeneity was evaluated using whole-tissue sections by immunohistochemistry. When all tumor cells overexpressed HER2 protein, the tumor was defined as homogeneously HER2 (Homo-HER2)-positive group. The others were defined as heterogeneously HER2 (Hetero-HER2)-positive group.ResultsThere was no significant difference in clinicopathological features between the two groups. The median progression-free survival (PFS) and overall survival (OS) in the Homo-HER2-positive group were significantly longer than those in the Hetero-HER2-positive group (PFS; 20.0 months [95% CI 17.8–22.2] vs. 6.0 months [95% CI 2.3–9.7]; HR 0.11; 95% CI 0.03–0.41; p < 0.001, OS; not reached vs. 14.0 months [95% CI 11.9–16.1]; HR 0.18; 95% CI 0.06–0.61; p = 0.003). In the multivariate analysis, these associations remained significant both in PFS (HR 0.12; 95% CI 0.03–0.46, p = 0.002) and OS (HR 0.21; 95% CI 0.06–0.72, p = 0.013). With respect to response rate, no statistical difference was found between two groups. However, deeper tumor shrinkage was obtained in the Homo-HER2-positive group compared with the Hetero-HER2-positive group (p = 0.046).ConclusionsIntratumoral HER2 heterogeneity may have robust clinical impact on trastuzumab efficacy in patients with HER2-positive gastric cancer. These findings should be validated by larger independent cohorts and further molecular correlative analyses are warranted.

PurposeIn the ATTRACTION-2 trial, nivolumab significantly improved the survival of advanced gastric cancer patients. The pretreatment neutrophil-to-lymphocyte ratio (NLR) is prognostic in patients receiving immune checkpoint inhibitors (ICIs) to treat various cancers. However, a few reports have explored the relationships between NLR changes during ICI treatment and patient survival. Here, we evaluated factors (including NLR changes in patients on nivolumab monotherapy) prognostic for gastric cancer patients.MethodsWe retrospectively analyzed 98 gastric cancer patients who received nivolumab (3 mg/kg or 240 mg/body bi-weekly) at our institution between December 2014 and September 2018. We evaluated pretreatment data, and those obtained 30 and 60 days after treatment commenced. We explored the prognostic utility of relative NLR changes in terms of the overall survival (OS) of patients on nivolumab monotherapy.ResultsOver a median of 4.9 months of follow-up, 98 gastric cancer patients received a median of four treatment courses. The overall response and disease-control rates were 25% and 52%, respectively. The median OS was 6.4 months (95% confidence interval [CI] 4.6–9.1). On multivariate analysis, factors poorly prognostic in terms of OS were an ECOG performance status of 0–1, a pretreatment NLR > 3, and an NLR difference ≧ 2 over the 60 days before and after nivolumab administration (∆NLR60). Patients with ∆NLR60 values < 2 survived significantly longer than did those with ∆NLR60 values ≧ 2 (median OS 9.2 months [95% CI 6.4–11.6] vs. 4.0 months [2.1–4.9]; P = 0.0002).ConclusionsNivolumab monotherapy was efficacious in gastric cancer patients. NLR changes during such therapy may be predictive of outcomes.

BackgroundWe recently reported the clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using surgical specimens; patients with homogeneously HER2 positive gastric cancer benefitted more from trastuzumab. However, the majority of patients are diagnosed by endoscopic biopsy, and surgical specimens are not available in these patients. The aim of this study is to verify clinical significance of HER2 heterogeneity on trastuzumab efficacy using biopsy specimens.MethodsEighty-seven patients, who received trastuzumab-based chemotherapy and whose endoscopic biopsy specimens were available for HER2 assessment, were consecutively enrolled. When all tumor cells in all biopsy specimens overexpressed HER2 protein, it was defined as homogeneously HER2 (homo-HER2) positive group, and the others were defined as heterogeneously HER2 (hetero-HER2) positive group. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were evaluated.ResultsThirty-four patients (39%) were diagnosed as the homo-HER2 group and 53 patients (61%) were the hetero-HER2 group. After the median follow-up period of 17.8 months, the median PFS and OS were 7.6 and 17.8 months, respectively. Significant survival differences were shown between the two groups; the homo-HER2 group showed significantly longer PFS (10.8 vs. 6.1 months, HR 0.469 95% CI 0.29–0.77, p = 0.003) and OS (29.3 vs. 14.4 months, HR 0.352 95% CI 0.20–0.61, p < 0.001). ORR was 68.6% in this cohort. Higher response rate (85.2% vs 58.1%, p = 0.020) and deeper response (− 49.0% vs − 40.0%, p = 0.018) were also found in the homo-HER2 group.ConclusionsSimilar to surgical specimens, we verified clinical significance of HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens.

Follistatin-like 1 (FSTL1) has been demonstrated to be a key molecule in cancer intractability associated with immune exhaustion and dysfunction, and increased expression of FSTL1 and its receptor DIP2A in tumor tissues has also been reported as a significant poor prognostic factor in various types of cancer, including gastric cancer (GC). However, the relationship between FSTL1/DIP2A levels, especially those in the peripheral circulation, and clinical outcomes in anti-PD1/PDL1 therapy remains to be elucidated in clinical practice. We collected peripheral blood collected from patients with advanced GC before and after nivolumab monotherapy, and analyzed for FSTL1 by ELISA, and for DIP2A + cells by flow cytometry, followed by statistical analysis of association with patient prognosis. High FSTL1 levels at baseline were significantly associated with shorter progression-free survival (PFS) and overall survival (OS). Patients with high levels of DIP2A + subsets in CD11b + myeloid cells, CD3 + T cells, and CD56 + NK cells both before and after treatment showed significantly shorter PFS and OS as compared to patients with low levels. Combination of low baseline levels of both FSTL1 and DIP2A + cells identified patients with long-term survival, known as durable responders. These data suggest that high baseline levels of both FSTL1 and DIP2A + cells in peripheral blood are significant poor prognostic factors for nivolumab therapy for advanced GC. Targeting the FSTL1-DIP2A axis may be a promising strategy to improve clinical outcomes in GC as a biomarker to predict anti-PD1/PDL1 therapeutic efficacy more accurately.

Background Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. Methods The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. Results In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. Conclusions Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. Trail registration ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.

Background: The combination of anti–programmed cell death-1 antibody with human epidermal growth factor receptor 2 (HER2)–targeted therapy and chemotherapy is widely used in the United States and Europe for HER2-positive advanced gastric cancer (AGC). Molecular profiles that predict the efficacy of this dual-target therapy are unclear. Objectives: To explore the clinical utility of circulating tumor DNA (ctDNA) as a predictive marker of the efficacy of standard chemotherapy plus HER2 and programmed death-ligand 1 dual-targeted therapy in patients with HER2-positive AGC. Design: Collaborative study of the Ni-High phase Ib clinical trial. Methods: A total of 21 patients with tissue-confirmed HER2-positive AGC who received chemotherapy with dual-targeted therapy (capecitabine/S-1, oxaliplatin, trastuzumab, and nivolumab) in a phase Ib clinical trial (UMIN000034222) were enrolled. The association of genomic profiles in plasma ctDNA with tissue HER2 amplification status and their correlation with clinical outcomes was investigated. Results: Among the 21 patients studied, 20 (95.2%) showed somatic alterations in ctDNA. ERBB2 amplifications and single-nucleotide variants (SNVs)/indels were found in 12 (57.1%) and 3 (14.3%) patients, respectively. Significant associations between maximum mutant allele frequency (mMAF) and tumor size and between ctDNA and tissue ERBB2 copy numbers were found. Patients without ERBB2 SNV/indels showed longer median progression-free survival (PFS) and overall survival (OS) than those with these alterations. Patients with focal ERBB2 amplification in ctDNA showed better outcomes than those with aneuploidy (median PFS: 20.8 vs 8.4 months, hazard ratio (HR) = 0.08; median OS: NA vs 14.8 months, HR = 0.077). Lower mMAF at cycle 2 was associated with a better response to chemotherapy with dual-targeted therapy. Conclusion: ERBB2 genetic status and mMAF changes in ctDNA may, respectively, predict and reflect the efficacy of chemotherapy with dual-targeted therapy in HER2-positive AGC. Trial registration: UMIN000034222

Coronavirus disease 2019 (COVID-19) was declared to be a global pandemic by the World Health Organization on March 11, 2020. On April 7, 2020, a state of emergency was declared in Japan, as had been by other nations worldwide. This unprecedented crisis has profound implications for patients undergoing chemotherapy and for practicing healthcare professionals. Various reports have shown data indicating that cancer patients with COVID-19 have high morbidity and mortality rates. In order to reduce the use of medical resources to avoid the risk of COVID-19 infections in both cancer patients and health care providers, oncologists now have to draw the line for cancer treatments by maintaining their efficacy while avoiding severe adverse events. In this article, we outlined the decisions made regarding the practice of gastrointestinal oncology in our institution during the COVID pandemic.

Background Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (DCF) has become the new standard of care for locally advanced esophageal squamous cell carcinoma (ESCC). In a real-world setting, the efficacy, recurrence, and adverse events (AEs) remain unclear. Methods This retrospective cohort study included 86 patients who received neoadjuvant DCF followed by esophagectomy for resectable ESCC. Results Following neoadjuvant DCF treatment, 75 patients underwent R0 curative resection. At the median follow-up of 19.2 months, the median disease-free survival (DFS)/recurrence-free survival (RFS) was not yet reached, with estimated 3-year DFS/RFS rates of 65.2%, respectively. The incidence of primary tumor regression grading (TRG) grade 1a and pathological complete response (pCR) were 21.3% (16/75) and 14.7% (11/75), respectively. The estimated 1-year DFS/RFS rates were 93.8% for primary TRG grade 1a and 100% for pCR. Baseline elevated serum SCC-antigen levels were inversely associated with achieving primary TRG grade 1a or pCR. In 64 patients who did not achieve pCR, residual tumor cells in the lymph nodes (ypN; HR, 16.96; 95% CI, 2.11-136.12; P  < 0.01) and Glasgow prognostic score (GPS; HR, 8.34; 95% CI, 1.73–40.31; P  < 0.01) were independent predictors of shorter DFS/RFS. The most common grade  ≥  3 AEs were neutropenia (61.6%) and febrile neutropenia (26.7%), which were not associated with clinicopathological factors. The most common non-hematological AEs were appetite loss (9.3%), pulmonary embolism (8.1%), diarrhea (7.0%), and nausea (2.3%). Nine patients discontinued neoadjuvant DCF due to toxicities. Conclusions Neoadjuvant DCF was effective and well-tolerated in real-world ESCC patients. Primary TRG grade 1a or pCR showed a favorable DFS/RFS, while positive ypN and GPS were independent risk factors for worse DFS/RFS.

Background: Trastuzumab deruxtecan (T-DXd) has been approved for a third- or later-line treatment of HER2-positive advanced gastric cancer (AGC) in Japan. However, clinical data on the use of T-DXd in real-world practice remain insufficient. Although early tumor shrinkage (ETS) serves as an early on-treatment indicator of high treatment sensitivity, the use of ETS in predicting T-DXd efficacy remains unclear. Objectives: This study aimed to evaluate the clinical efficacy and safety of T-DXd and investigate the clinical utility of ETS as a predictor of long-term efficacy and survival. Design: Single-center retrospective cohort study Methods: This study consecutively enrolled patients with HER2-positive AGC who received T-DXd as a third- or later-line treatment between March 2018 and December 2023. Data on patient characteristics, adverse events (AEs), and clinical outcomes were obtained from electronic medical records. Clinical efficacy was assessed using progression-free survival (PFS) and overall survival (OS). In patients with measurable lesions, the overall response rate (ORR), ETS, and depth of response (DpR) were evaluated. Prognostic outcomes were assessed using the log-rank test and the Cox proportional hazards model. Results: A total of 65 patients received T-DXd, with a median age of 66 years (range, 31–82 years); 77% had HER2 immunohistochemistry score of 3+, 71% received T-DXd as a third-line treatment, and 32% required initial dose reduction. At a median follow-up of 33.6 months, the median PFS and OS were 4.5 months and 7.7 months, respectively. Among the 47 patients with measurable lesions, the ORR was 36%. A median DpR of 15.8% was observed, with higher DpR correlating with longer OS. ETS was achieved in 38% of the patients and was an independent predictor of favorable PFS (hazard ratio (HR), 0.21; 95% confidence interval (CI), 0.09–0.49; p < 0.01) and OS (HR, 0.23; 95% CI, 0.10–0.52; p < 0.01). Longer second-line treatment duration was independently associated with improved OS. Overall, grade ⩾ 3 AEs occurred in 37% of the patients. Initial dose reduction reduced AE-induced discontinuation of treatment without compromising efficacy. Conclusion: T-DXd demonstrated notable efficacy and a manageable safety profile in patients with HER2-positive AGC. Rapid and deep tumor shrinkage may have a significant impact on survival. Plain language summary Early tumor shrinkage as a predictor of survival in HER2-positive advanced gastric cancer patients treated with trastuzumab deruxtecan This study investigated the impact of early tumor shrinkage on survival outcomes in patients with HER2- positive advanced gastric cancer (AGC) treated with trastuzumab deruxtecan (T-DXd). T-DXd, a targeted therapy, has shown promising results in treating HER2-positive AGC. In this retrospective study, 65 patients with HER2-positive AGC received T-DXd as a third- or later-line treatment in the real-world setting. The study found that early tumor shrinkage (ETS), defined as a significant reduction in tumor size early in treatment, was linked to better survival outcomes. Patients who experienced ETS had a significantly longer progression-free survival (PFS) and overall survival (OS) compared to those who did not. The study also showed that patients who achieved a deeper tumor response (DpR), indicating a greater reduction in tumor size, had better survival outcomes. Additionally, longer duration of secondline treatment was associated with improved survival. The safety of T-DXd was manageable, with common side effects being nausea, neutropenia, and fatigue. Importantly, starting T-DXd at a lower dose reduced the risk of treatment-related discontinuations without compromising effectiveness. These findings suggest that T-DXd demonstrated notable efficacy and a manageable safety profile in patients with HER2-positive AGC. ETS can serve as an important predictor of treatment success, helping to guide clinical decisions and improve patient outcomes in clinical practice