BACKGROUND:To evaluate the dissemination and real-world implementation of recommendations from the 5th Edition of the Japanese Esophageal Cancer Practice Guidelines and to inform development of the upcoming 6th Edition, the Guideline Committee of the Japanese Esophageal Society conducted a nationwide Quality Indicator (QI) survey in Japan. METHODS:A nationwide, cross-sectional, web-based questionnaire survey was distributed to 381 certified institutions participating in the 2023 National Registry of Esophageal Cancer in Japan. Conducted in November 2024, the survey covered six domains-epidemiology, surgery, endoscopy, chemotherapy, radiation therapy, and pathology-reflecting key recommendations of the 5th Edition. Responses were summarized descriptively at the institutional level. RESULTS:Valid responses were obtained from 190 institutions (49.9%). Smoking cessation guidance was implemented in more than 90% of institutions, and over 90% also provided guidance on alcohol abstinence or moderation, although complete alcohol abstinence was less uniformly recommended. Minimally invasive, including robot-assisted, esophagectomy was adopted by over 90% of institutions. The proportion of institutions performing prophylactic cervical lymph node dissection varied by tumor location and stage, reflecting contemporary staging concepts. The DCF regimen was the predominant neoadjuvant therapy for stage II/III disease (94.7%), and immune checkpoint inhibitor-based chemotherapy was widely used for unresectable or recurrent disease. Advanced endoscopic diagnostic modalities, including magnifying and image-enhanced endoscopy, were widely adopted. CONCLUSIONS:This nationwide QI survey demonstrates broad adherence to guideline-based multidisciplinary management of esophageal cancer in Japan and provides an evidence base for refining recommendations in the 6th Edition of the Japanese Esophageal Cancer Practice Guidelines.
BACKGROUND:Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with pulmonary involvement is a rare, indolent lymphoma with no standard treatment approaches. METHODS:To clarify patient characteristics, treatment, and prognosis of pulmonary MALT lymphoma in the modern era, a multi-institutional observational study of patients diagnosed between 2013 and 2022 was conducted. A modified Ann Arbor system was used for the analysis. RESULTS:Among 186 eligible patients, 131 (70%) had stage IE/IIE disease, whereas 55 (30%) had stage IV disease. No patient had stage III disease. With a median follow-up of 57 months, the 4-year overall survival (OS) rates for the stage IE, IIE, and IV groups were 96%, 92%, and 90%, respectively. The stage IIE and IV groups had similar progression-free survival (PFS) that was significantly worse than that of the stage IE group (p < .001). In stage IE/IIE patients, no differences were found in OS (p = .89) or PFS (p = .90) among the first-line treatment groups. In stage IV patients, the stomach was the most common synchronous extranodal site of involvement (36%). There were no differences in OS among the first-line treatment groups (p = .64). CONCLUSIONS:The OS of patients with MALT lymphoma with pulmonary involvement was favorable regardless of first-line treatment modality, including watchful waiting. The short PFS in the stage IIE and IV groups indicates that these groups are candidates for therapeutic development.
Immune checkpoint inhibitors (ICIs) have greatly improved advanced melanoma prognosis. However, the efficacy of ICIs in Japanese patients has been found to be lower than that in their white counterparts. We aimed to elucidate the genomic and transcriptomic features associated with response to ICIs in Japanese patients with melanoma. A total of 129 tumor samples were collected from 78 patients with melanoma who received therapeutic regimens with or without ICI treatment. We performed exome and RNA sequencing and investigated the association between genomic and transcriptomic factors and the clinical efficacy of ICI. The number of somatic SNVs in Japanese patients with melanoma is lower than that in the TCGA white data owing to the biased distribution of WHO subtypes. The driver subtypes BRAF, NRAS, and NF1 are less prevalent, but the triple wildtype predominantly exists in this cohort. An exome-wide survey reveals no significant association of mutated genes with ICI response; however, transcriptomic analysis reveals inflammation-associated genes, including several chemokines and cytokines, that are highly expressed in clinically benefited patients. Follicular helper T cells, measured by immune cell composition analysis, are significantly enriched in clinically benefited patients (p = 0.0373). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes, MARCO on tumor-associated macrophages is found to be induced by ICI treatment in clinically benefited patients (p = 0.0040). Protein expression of these genes is confirmed by immunohistochemical and multiplex immunofluorescence analyses. To our knowledge, this is the first and largest genomic cohort study in Japanese patients with melanoma in which tumor samples were prospectively analyzed. Genomic and transcriptomic analyses reveal candidate biomarkers for ICI in Japan. Melanoma treatment has been improved by the introduction of drugs called Immune checkpoint inhibitors (ICIs). However, Japanese people often show lower response rates than white people. To understand why, we collected tumor and blood samples from Japanese people with melanoma and analyzed their DNA and RNA. DNA is a component of cells that is changed (mutated) compared to normal cells. We found that DNA from Japanese people tends to have fewer mutations that are associated with favorable responses to ICIs compared with DNA from white people. In contrast, certain features of the immune system could be used to predict which people would benefit from ICI treatment. Among them, we hypothesize that cells called “follicular helper T cells” and “MARCO-positive macrophages” may play particularly beneficial roles in Japanese patients. Kimura, Tanaka et al. perform exome and RNA sequencing in Japanese melanoma patients to investigate genomic and transcriptomic factors associated with clinical efficacy of immune checkpoint inhibitors. Findings reveal the characteristic genomic features and potential biomarkers of melanoma in Japanese patients.
Abstract Purpose: The phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway is frequently activated in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, with loss of phosphatase and tensin homolog (PTEN) activity contributing to this activation. Capivasertib is a potent pan-AKT inhibitor, approved in combination with fulvestrant for the treatment of HR-positive/HER2-negative locally advanced/metastatic breast cancer with one or more PIK3CA/AKT1/PTEN tumor alterations. Next-generation sequencing (NGS) is commonly used to identify patients with PIK3CA/AKT1/PTEN tumor alterations. However, the utility of immunohistochemistry (IHC) to identify patients with PTEN-deficient tumors has not been explored in this context. Experimental Design: This exploratory analysis was based on tumor samples collected from patients in the global phase III CAPItello-291 study. Results: PTEN IHC results were obtained for 367 tumor samples, with 70 (19.1%) identified as PTEN deficient by IHC. A total of 346 (94.3%) samples with a PTEN IHC test result also had NGS test results available for PIK3CA/AKT1/PTEN alteration status. When comparing PTEN deficiency by IHC with PTEN alteration status by NGS, the overall, positive, and negative percent agreements were 87.0% (301/346), 71.9% (23/32), and 88.5% (278/314), respectively. Exploratory analysis in patients with PTEN-deficient tumors by IHC (n = 70) showed improved progression-free survival in the capivasertib plus fulvestrant versus placebo plus fulvestrant treatment arm (median 9.3 vs. 3.7 months; hazard ratio: 0.52, 95% confidence interval, 0.28–0.90). Conclusions: These results suggest potential utility for IHC in determining tumor PTEN status in breast cancer and raise the possibility of IHC identifying additional patients who could benefit from treatment with capivasertib and fulvestrant.
BACKGROUND:Squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA) are routinely monitored after definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC) in Japan, but their clinical significance remains unclear. METHODS:We analyzed data from patients with resectable ESCC treated with dCRT in the JCOG0502 and JCOG0909 trials, who underwent intensive protocolized surveillance with computed tomography (CT), esophagogastroduodenoscopy (EGD), SCC-Ag, and CEA. Tumor marker positivity was defined as exceeding the cut-off value at least once, at two consecutive measurements, or at three consecutive measurements during follow-up. Sensitivity and specificity were calculated for SCC-Ag and CEA at 0.1-ng/mL increments to determine whether any cut-off met the predefined performance criteria (sensitivity ≥60% and specificity ≥70%). RESULTS:This study included 239 patients (stage I/II/III = 147/58/34 [UICC 6th edition]), among whom 38% (91/239) experienced disease progression or recurrence. The median baseline SCC-Ag and CEA levels were 1.0 ng/mL (interquartile range [IQR], 0.8-1.5) and 2.3 ng/mL (IQR, 1.6-3.6), respectively, with a median of 16 measurements each (IQR, 8-19 for SCC-Ag; 8-20 for CEA). The highest specificities with sensitivity ≥60% were 19.6% for SCC-Ag (cut-off, 1.5 ng/mL) and 20.3% for CEA (cut-off, 2.2 ng/mL), but neither met the predefined criteria. CONCLUSIONS:In this pooled cohort of patients with resectable ESCC who underwent dCRT and intensive protocolized CT and EGD surveillance, routine SCC-Ag and CEA monitoring showed limited incremental diagnostic value. The relevance of these findings to higher-risk cohorts and less intensive surveillance settings warrants further study.
