ヒストン ダツ メチルカ コウソ Jumonji Domain Containing 3/Lysine-Specific Demethylase 6B ノ ダイチョウガン ハツイク シンテン ヨゴ エ ノ エイキョウ ニ カンスル ケントウ

熊本大

Advanced Lung Cancer Inflammation Index: A Novel Comprehensive Biomarker of Host Status for Patients with Metastatic Colorectal Cancer

Numerous biomarkers that reflect host status have been identified for patients with metastatic colorectal cancer (mCRC). However, there has been a paucity of biomarker studies that comprehensively indicate body composition, nutritional assessment, and systemic inflammation status. The advanced lung cancer inflammation index (ALI), initially introduced as a screening tool for patients with non-small-cell lung cancer in 2013, emerges as a holistic marker encompassing all body composition, nutritional status, and systemic inflammation status. The index is calculated by the simple formula: body mass index × albumin value / neutrophil-to-lymphocyte ratio. Given its accessibility in routine clinical practice, the ALI has exhibited promising clinical utility in prognosticating outcomes for patients with multiple types of cancer. In this review, we focus on the significance of host status and the clinical applicability of the ALI in the treatment and management of patients with malignancies, including mCRC. We also suggest its potential in guiding the formulation of treatment strategies against mCRC and outline future perspectives

Extracellular water to total body water ratio, a novel predictor of recurrence in patients with colorectal cancer

Abstract Background Total body water (TBW) fraction, which accounts for 60% of body weight, is an important indicator of body composition, and the extracellular water to TBW ratio (ECW/TBW) is reportedly useful in predicting clinical outcomes of patients with organ disorders. We aimed to clarify the clinical impact of preoperative ECW/TBW status on survival outcomes in cancer patients. Methods We used a database of 320 colorectal cancer (CRC) patients who underwent potentially curative resections. Preoperative ECW/TBW was measured using a bioelectrical impedance analysis (BIA), and its correlation with patient survival outcomes, clinicopathological factors, laboratory data, and comorbidities were analyzed. Results A high preoperative ECW/TBW was significantly associated with poorer relapse‐free survival (RFS; p = 0.001) and overall survival (OS; p = 0.003). A high ECW/TBW ratio was significantly associated with older age (p < 0.001), low BMI (p = 0.009), and right‐sided tumors (p = 0.03). In a multivariate analysis, a high ECW/TBW significantly predicted a higher RFS mortality (HR: 2.07, 95% CI: 1.10–3.88, p = 0.024) and OS mortality (HR: 3.23, 95% CI: 1.25–8.36, p = 0.016). Furthermore, a high ECW/TBW was significantly associated with lower hemoglobin (p < 0.001) and albumin levels (p < 0.001), but not comorbidities. Conclusions A high preoperative ECW/TBW was a predictive factor for recurrence and poorer overall survival independent of the tumor, node, and metastasis (TNM) stage. Our data suggest that preoperative evaluation of ECW/TBW using BIA might serve as a novel tool for developing CRC treatment strategies

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy.

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment

Negative Impact of Skeletal Muscle Loss after Systemic Chemotherapy in Patients with Unresectable Colorectal Cancer.

Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study evaluated the prognostic significance of skeletal muscle status before and after chemotherapy in patients with unresectable colorectal cancer (CRC).We conducted a retrospective analysis of 215 consecutive patients with unresectable CRC who underwent systemic chemotherapy. Skeletal muscle cross-sectional area was measured by computed tomography. We evaluated the prognostic value of skeletal muscle mass before chemotherapy and the rate of skeletal muscle change in cross-sectional area after chemotherapy.One-hundred-eighty-two patients met our inclusion criteria. There were no significant differences in progression-free survival (PFS) or overall survival (OS) associated with skeletal muscle mass before chemotherapy. However, 22 patients with skeletal muscle loss (>5%) after chemotherapy showed significantly shorter PFS and OS compared with those without skeletal muscle loss (PFS, log-rank p = 0.029; OS, log-rank p = 0.009). Multivariate Cox regression analysis revealed that skeletal muscle loss after chemotherapy (hazard ratio, 2.079; 95% confidence interval, 1.194-3.619; p = 0.010) was independently associated with OS.Skeletal muscle loss after chemotherapy was an independent, negative prognostic factor in unresectable CRC

B cell and B cell-related pathways for novel cancer treatments.

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, -21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies

Outlooks on Epstein-Barr virus associated gastric cancer.

Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC

Colorectal cancer: epigenetic alterations and their clinical implications.

Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients

Molecular Profiling of Appendiceal Adenocarcinoma and Comparison with Right-sided and Left-sided Colorectal Cancer.

PURPOSE The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma. EXPERIMENTAL DESIGN A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC. RESULTS We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC. CONCLUSIONS Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment

Molecular differences between lymph nodes and distant metastases compared with primaries in colorectal cancer patients.

Lymph nodes (LNs) and distant metastases can arise from independent subclones of the primary tumor. Herein, we characterized the molecular landscape and the differences between LNs, distant metastases and primary colorectal cancers (CRCs). Samples were analyzed using next generation sequencing (NGS, MiSeq on 47 genes, NextSeq on 592 genes) and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. In total, 11,871 samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs metastases (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant metastases (9 mut/MB, p < 0.0001). TMB-high (≥17mut/MB) and MSI-H (8.8% and 6.9% vs 3.7%, p < 0.001 and p = 0.017, respectively) classifications were more frequent in primaries and LNs vs distant metastases (9.5% and 8.8% vs 4.2%, p < 0.001 and p = 0.001, respectively). TMB-high is significantly more common in LNs vs distant metastases and primaries (P < 0.0001), regardless MSI-H status. Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (p < 0.01) vs primaries, while presenting a distinct molecular profile compared to distant metastases. Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant metastases. Our data support the hypothesis that lymphatic and distant metastases harbor different mutational landscape. Our findings are hypothesis generating and need to be examined in prospective studies