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Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan. We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

Alternative splicing, regulated by DEAD‐Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT‐qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56‐knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2‐M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1. We identified DDX56 as a novel oncogene on chromosome 7p and a prognostic biomarker of colorectal cancer (CRC). DDX56 can induce oncogenic splicing abnormalities of the G2‐M cell cycle checkpoint gene WEE1 which contributes to the inhibition of proliferation and cell cycle progression.

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3 -knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

Background Osteosarcopenia, characterized by muscle loss and osteoporosis, has emerged as a prognostic marker for various malignancies. However, its impact on the immune response in gastric cancer remains unclear. This study aimed to assess the clinical significance of osteosarcopenia and its relationship with the immune microenvironment in patients with advanced gastric cancer. Methods This study included 105 patients with pathological stage II/III gastric cancer who underwent gastrectomy between 2018 and 2022. Preoperative computed tomography was used to measure muscle mass and bone density, with sarcopenia and osteoporosis defined as values below the respective standard thresholds. Sarcopenia and osteoporosis were identified when both conditions were present. We explored the relationships between osteosarcopenia, clinicopathological factors, and prognoses. Additionally, immune marker expression was evaluated via immunohistochemistry. Results Among the 105 patients, 37 (35%) were diagnosed with osteosarcopenia. This condition significantly correlated with performance status, body mass index, and disease recurrence (all p  < 0.05). Overall survival and relapse-free survival were significantly lower in the osteosarcopenia group than those in the non-osteosarcopenia group (all p  < 0.05). Moreover, the osteosarcopenia group had significantly fewer CD8-positive, programmed cell death protein 1-positive, and programmed death-ligand 1-positive cells than that of the control group (all p  < 0.05). Conclusions Our findings suggest that osteosarcopenia is associated with the tumor microenvironment and might serve as a prognostic indicator in patients with advanced gastric cancer.

The clinical significance of laparoscopic subtotal gastrectomy (LsTG) with a small remnant stomach remains unclear in patients with gastric cancer, including at an advanced stage. The present study assessed postoperative quality of life (QOL) and survival after LsTG compared with laparoscopic total gastrectomy (LTG). We retrospectively analyzed consecutive patients with gastric cancer who underwent LsTG (n=26) or LTG (n=26). Surgical outcome, postoperative nutritional status, QOL, and prognosis were compared between the LsTG and LTG groups. The Postgastrectomy Syndrome Assessment Scale was used to evaluate postoperative QOL. Operating time was significantly shorter (p<0.01) and postoperative morbidity was significantly lower (p=0.04) in the LsTG than in the LTG group. The reduction in body weight after surgery was significantly greater in the LTG than in the LsTG group (p<0.01). The Postgastrectomy Syndrome Assessment Scale revealed that, compared with LTG, LsTG significantly improved postoperative QOL (p<0.05). There was no significant difference in relapse-free survival and cancer-specific survival between the two groups. Three patients in the LTG group died of pneumonia and overall survival was significantly longer in the LsTG group (p=0.01). This study demonstrated the efficacy of LsTG with a small remnant stomach to prevent a decline in postoperative QOL and non-cancer-related death.

The CheckMate 649 trial demonstrated the clinical benefit of nivolumab plus chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer. However, the background discrepancy between clinical practice and randomized controlled trials may impact the therapeutic strategy and prognosis of patients. This study aimed to assess the clinical significance of eligibility criteria determined by the CheckMate 649 trial and identify prognostic factors in clinical practice. A total of 160 patients with HER2-negative metastatic gastric cancer who underwent chemotherapy were retrospectively enrolled and classified into two groups based on eligibility criteria. Among the 160 patients, 76 (47.5%) and 84 (52.5%) were included in the eligible and ineligible groups, respectively. The ineligible group had a significantly lower induction of second- and third-line chemotherapy than the eligible group ( P  = 0.02 and P  = 0.02, respectively). The median overall survival in the eligible and ineligible groups was 22.9 and 10.5 months, respectively, with the ineligible group having a significantly poorer prognosis than the eligible group ( P  < 0.01). Responders to first-line chemotherapy had a better prognosis than non-responders in both groups ( P  = 0.01 and P  < 0.01, respectively). Multivariate analyses identified disease control as an independent prognostic factor in both groups ( P  < 0.01 and P  < 0.01, respectively). Patients with a poor general condition who fulfilled the ineligibility criteria as determined using randomized controlled trials are included in clinical practice, and these criteria are related to tumor response and prognosis.

PurposeMinimally invasive esophagectomy (MIE) has been widely accepted as a treatment for esophageal cancer. This retrospective study compared the short-term outcomes and surgical invasiveness between thoracoscopic esophagectomy (TE) and mediastinoscopic esophagectomy with pneumomediastinum (pneumatic mediastinoscopic esophagectomy [PME]).MethodsA total of 72 patients who underwent TE or PME were included and assessed for their surgical findings, postoperative complications, and inflammatory responses on postoperative day (POD) 1, 3, 5, and 7.ResultsThe PME group exhibited a significantly shorter operative time and fewer lymph nodes retrieved than the TE group. Furthermore, the PME group tended to have greater incidences of recurrent laryngeal nerve palsy and lower incidences of atelectasis than the TE group. The PME group had significantly lower white blood cell counts on POD 5, serum C-reactive protein (CRP) levels on POD 3 than the TE group.ConclusionPME seems to be less invasive than TE and can be considered the preferred option for patients with lower-stage esophageal cancer expected to have severe pleural adhesion or who cannot tolerate TE.

The Kocher maneuver is the most common surgical approach for duodenal tumors. However, the extensive dissection required for the second and third portions of the duodenum complicates laparoscopic procedures. This study introduces the anterior and transmesocolic approaches in laparoscopic and endoscopic cooperative surgery for duodenal neoplasms (D-LECS). Thirty patients who underwent D-LECS at our institute between November 2016 and August 2024 were included. The median age was 62.5 years, and the median pathological tumor size was 15 mm. Tumors were located in the first, second, and third portions of the duodenum in 5, 20, and 5 patients, respectively. The anterior approach was performed in the first to upper second portion of the duodenum in seven patients; the transmesocolic approach was performed in the second to third portions of the duodenum in 23 patients. All patients underwent full-thickness suture reinforcement after endoscopic submucosal dissection. The median operation time and bleeding volume were 281 min and 10 mL, respectively, for the anterior approach and 297 min and 0 mL, respectively, for the transmesocolic approach. Postoperative complications, such as delayed perforation, were not observed. All patients underwent curative resection. Pathological analyses revealed 21, 7, 1, and 1 case of adenoma, adenocarcinoma, gastrointestinal tumor, and neuroendocrine tumor, respectively. Disease recurrence was not observed during the follow-up (median, 35 months). D-LECS using the anterior and transmesocolic approaches based on tumor location may allow for individualized surgical management in patients with early duodenal neoplasms.

Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC. We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells. In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells. LOXL1 is associated with PD in GC, possibly through the induction of EMT.

Background Osteosarcopenia, recognized as a consequence of aging, has garnered attention as a prognostic marker in recent years; however, its clinical significance in esophageal cancer remains uncertain. This study aimed to investigate the impact of osteosarcopenia on esophageal cancer surgery outcomes. Methods This retrospective study included patients with advanced esophageal cancer who underwent surgical resection between 2018 and 2021. Skeletal muscle index at the L3 vertebral level and bone density at the Th11 vertebral level were measured on preoperative computed tomography scans. Based on the findings, we divided patients into sarcopenia, osteopenia, and osteosarcopenia groups, and analyzed the relationship between osteosarcopenia and clinicopathological factors, including prognosis. Results Of the 124 patients included, 59 (48%) were diagnosed with osteosarcopenia. Among all, 46 (37%) patients experienced postoperative recurrence, and a significant correlation was observed between osteosarcopenia and recurrence ( p  < 0.05). Overall survival and relapse-free survival were significantly shorter in the osteosarcopenia group than in the non-osteosarcopenia group ( p  < 0.05 for both). In a subgroup analysis, overall survival and relapse-free survival were significantly shorter in the osteosarcopenia group than in the non-osteosarcopenia group, or in the sarcopenia and osteopenia alone groups (all p  < 0.05). Conclusions The presence of preoperative osteosarcopenia was found to affect the prognosis following esophageal cancer surgery.