DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity ...during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS.
This review summarizes how DNA replication stress is induced and determines the cell destiny in the process of tumor development. This review also explains how cancer therapeutic drugs exploit the stress in malignant tumors.
Programmed death‐ligand 1 (PD‐L1) plays a crucial role in the host immune system in cancer progression. The gene promoter region of PD‐L1 also contains a binding site for ZEB1, a transcription factor ...related to epithelial‐mesenchymal transition (EMT). The purpose of this study was to clarify the relationship between PD‐L1 and EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). PD‐L1 and ZEB1 expression at the tumor invasive front was examined by immunohistochemistry in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy, and their expression and clinicopathological factors were compared. ZEB1 and PD‐L1 expression was determined in TE8 cells, which demonstrate the EMT phenotype, following ZEB1 knockdown by siZEB1. TE5, TE6 and TE11 cells with non‐EMT phenotype were also used for studies of TGF‐β1‐dependent EMT induction and ZEB1 and PD‐L1 expression. In cases of high PD‐L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ lymphocyte infiltration were observed. High PD‐L1 expression was also associated with worse overall and relapse‐free survival. A correlation was observed between PD‐L1 and ZEB1 expression. In TE8 cells, siZEB1 suppressed PD‐L1 and promoted E‐cadherin mRNA and protein expression. TGF‐β1 induced EMT and surface expression of PD‐L1 in TE5, TE6 and TE11 cell lines. PD‐L1 expression at the ESCC invasive front was related to ZEB1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC.
PD‐L1 plays a crucial role in the host immune system in cancer progression. Its gene promoter region contains a binding site for ZEB1. Our report shows that high PD‐L1 expression at the invasive front of esophageal squamous cell carcinoma (ESCC) was associated with greater depth of tumor invasion, epithelial‐mesenchymal transition (EMT), and less CD8+ lymphocyte infiltration.
Background
Laparoscopic proximal gastrectomy (LPG) is performed as a function-preserving surgery for patients with early proximal gastric malignant tumors; however, whether LPG has advantages ...postoperatively compared with laparoscopic total gastrectomy (LTG) is debatable, especially with regard to nutritional outcomes.
Methods
We evaluated 20 patients who underwent LTG and 10 patients who underwent LPG with double tract reconstruction (LPG-DT) who were diagnosed preoperatively with T1a or T1b N0 Stage IA gastric cancer in our department in the same time period. The statistical relevance of complications, surgical maneuvers, clinical factors and changes in weight, skeletal muscle index (SMI) and serum albumin levels after surgery was compared between the LPG-DT group and the LTG group.
Results
No differences between groups were observed in patient demographics, operation time, blood loss, complications, number of dissected lymph nodes and pathological stage. The body weight reduction rate was significantly lower in the LPG-DT group compared with the LTG group at 6 months (5.7 vs. 14.9%, respectively;
p
= 0.0045) and 1 year after surgery (9.6 vs. 17.9%, respectively;
p
= 0.0042). The SMI reduction rate of the LPG-DT group in the first postoperative year was significantly lower than that of the LTG group (9.3 vs. 18.3%, respectively;
p
= 0.0057).
Conclusions
Patients with early gastric cancer who underwent LPG-DT had acceptable morbidity and mortality, similar to those who underwent LTG. Body weight and SMI reduction rates were lower in the LPG-DT group than in the LTG group. Thus, LPG-DT is an appropriate procedure for patients with clinical Stage IA proximal gastric cancer.
Purpose
This study aims to clarify the influence of the COVID-19 pandemic on cancer surgery in Gunma Prefecture.
Methods
A total of 9839 cases (1406 gastric cancer, 3569 colorectal cancer, 1614 lung ...cancer, and 3250 breast cancer) from 17 hospitals in Gunma Prefecture were investigated. We compared the number of surgical cases, proportion of cases found by screening, and cStage at the time of the first visit by month in 2020 and 2021 with those in 2019.
Results
The rate of decline in cancer surgery was 8.9% in 2020 compared with 2019 (
p
= 0.0052). Compared with the same month of 2019, in some months of 2020 and 2021, significant decreases were observed in the number of surgeries for gastric and colorectal cancer, the percentage of surgical cases detected by screening in all four cancers, and the proportion of cancers with a relatively early cStage in gastric and breast cancer.
Conclusions
The number of surgical cases of the four cancer types detected by cancer screening decreased in Gunma Prefecture owing to the influence of the COVID-19 pandemic. Furthermore, for some cancer types, the number of operations performed in patients with early-stage cancer is also decreased.
Background
The necessity of surgical treatment of liver metastases of gastric cancer is still controversial.
Patients and methods
We conducted a multicenter retrospective cohort study of ...liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria.
Results
Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival.
Conclusions
To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.
Purpose
The significance of sarcopenia after colorectal cancer (CRC) resection has only been discussed with relatively small samples or short follow-up periods. This study aimed to clarify the ...clinical significance of sarcopenia in a large-sample study.
Methods
We retrospectively analyzed the relationship between sarcopenia and clinical factors, surgical outcomes, and the survival in 494 patients who underwent CRC surgery between 2004 and 2013. Sarcopenia was defined based on the sex-specific skeletal muscle mass index measured by preoperative computed tomography.
Results
Sarcopenia was associated with sex (higher rate of male,
P
< 0.0001), and low body mass index (
P
< 0.0001), but not age or tumor stage. Sarcopenia was associated with higher incidence of all postoperative complications (
P
= 0.02), especially for patients with Clavien–Dindo classification grade ≥2 (CDC;
P
= 0.0007). Postoperative hospital stays were significantly longer for sarcopenic patients than for non-sarcopenic patients (
P
= 0.02). In a multivariate analysis, sarcopenia was an independent predictor for postoperative complications (
P
= 0.01, odds ratio 1.82, 95% confidence interval 1.13–3.00). Among postoperative complications (CDC grade ≥2), sarcopenia was correlated with non-surgical-site infections (
P
= 0.03). Sarcopenia was not correlated with the overall or recurrence-free survival.
Conclusions
Sarcopenia was an independent predictive factor for postoperative complications after CRC surgery.
Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in ...multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.
Background
CD44 variant 9 (CD44v9) has been reported to suppress reactive oxygen spices (ROS) in association with antioxidant factors such as glutathione (GSH) and glutathione peroxidase 2 (GPx2), ...resulting in promoted tumor growth.
Methods
CD44v9 and GPx2 expression were investigated by immunohistochemistry in resected specimens from 193 gastric cancer (GC) patients without preoperative chemotherapy and in pretreatment biopsy specimens from 29 GC patients with preoperative chemotherapy. We analyzed the relationship between CD44v9 expression and clinicopathological factors, prognosis, and pathological response to chemotherapy. In GC cell lines, we examined the relationship between CD44v9 expression and chemotherapeutic sensitivity.
Results
In patients without preoperative chemotherapy, CD44v9 expression was significantly associated with depth of invasion, lymphatic permeation, vascular invasion, distant metastasis and GPx2 expression. In multivariate analysis, CD44v9 expression was an independent poor prognosis factor for overall survival and recurrence-free survival. In patients with preoperative chemotherapy, CD44v9 expression was significantly associated with worse pathological response and GPx2 expression. In GC cell lines, downregulation of CD44v9 expression enhanced chemotherapeutic sensitivity to 5-fluorouracil with changing GSH and ROS levels.
Conclusions
CD44v9-positive expression was associated with chemotherapeutic resistance by controlling intracellular accumulated ROS, suggesting that CD44v9 may be a predictive biomarker for chemotherapy in GC.
Background
Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare type of tumor characterized by a high malignant potential, rapid growth, and poor prognosis. Because the standard therapy ...for ENEC has been poorly defined, we herein aimed to attain a clear view of the current state of treatment for ENEC by performing a large-scale, multicenter study.
Methods
We conducted a questionnaire-based, retrospective clinical review of 142 patients with ENEC treated at 37 hospitals accredited by the Japan Esophageal Society from January 2010 to December 2015.
Results
The most frequent main treatment performed was an operation, followed by chemoradiotherapy, chemotherapy, and endoscopic submucosal dissection. Among the 67 patients who underwent surgery, 28 (19.7%) were not accurately diagnosed with NEC or a combined NEC tumor by pretreatment biopsy. The 5-year overall survival rate of all patients was 33.2%. Among patients with Stages III and IV disease, the prognosis was significantly better in patients who underwent chemoradiotherapy than in patients who underwent other treatments. Among patients with Stages I and II disease, however, there was no difference in survival rates between those who underwent surgery and chemoradiotherapy.
Conclusions
This nationwide survey is a valuable report of the current status of treatment of ENEC in a limited number of cases experienced at each participating institution. The survival benefit obtained from surgery was considered to be limited, especially for Stages III and IV ENEC. Accurate pretreatment histological diagnosis is essential to determine the most appropriate treatment strategy for patients with ENEC.
PDF
