Survival benefits of gastrectomy compared to conservative observation for older patients with resectable gastric cancer: a propensity score matched analysis.

PURPOSE: Radical gastrectomy is considered the first choice of curative treatment for older patients with gastric cancer (GC). However, there is limited data on the survival benefits of gastrectomy for older patients with GC. METHODS: This was a retrospective observational study where medical records of patients aged ≥ 75 years with clinically resectable primary GC, comprising 115 patients who underwent radical surgery (S group) and 33 patients who received conservative therapy (non-S group) (total cohort) and 44 propensity-matched patients (matched cohort), were reviewed. Survival and independent risk factors, including comorbidities and systemic nutritional and inflammatory statuses, were evaluated. RESULTS: In the total cohort, the 5-year overall survival (OS) in the S group was significantly higher than that in the non-S group (53.7% vs 19.7%, P < 0.0001). In the matched cohort, the 3-year OS in the S group was significantly higher than that in the non-S group (59.4% vs 15.9%, P < 0.01). Multivariate analysis of the total cohort showed that no surgery was an independent prognostic factor for poor OS (hazard ratio (HR) 3.70, 95% confidence interval (CI) 1.91-7.20, P = 0.0001). In the S group in the total cohort, the multivariate analysis showed that renal disease (HR 2.51, 95% CI 1.23-5.12, P < 0.05) was an independent prognostic factor for poor OS. CONCLUSIONS: Gastrectomy for older patients improved the prognosis; however, careful patient selection is essential, especially among those with renal disease.

Population-based incidence of hospitalized Clostridioides difficile infection among older adults in Ota-ku, Japan: A prospective surveillance study.

OBJECTIVES: Clostridioides difficile infection (CDI) burden is not well-characterized in Japan. Therefore, we conducted a population-based, hospitalized CDI incidence study, compared the results with standard-of-care (SOC) CDI testing, and generalized the results for nationwide incidence estimates. METHODS: Surveillance identified inpatients ≥50 years-of-age with diarrhea in nine Tokyo hospitals from December 17, 2018-March 30, 2020. A CDI case was defined as a patient with a PCR-positive/cell cytotoxicity neutralization assay (CCNA)-positive stool or a PCR-positive stool and pseudomembranous colitis (PMC). Incidence estimates were adjusted for the hospitalization share of participating hospitals and, in the sensitivity analysis, for missing CDI test results. SOC specimen collection and CDI testing occurred independently. RESULTS: Surveillance during 318 840 patient-days identified 4633 inpatients with diarrhea. Sixty-three CDI cases were identified; 11 (17·5%) had PMC, eight (12·7%) recurrent CDI, and nine (14·3%) died. The hospitalized CDI incidence was 97/100 000 population per year (PPY) in persons ≥50 years-of-age and, in the sensitivity analysis, 324/100 000 PPY. The incidence was 170 and 481/100 000 PPY in persons ≥65 and ≥85 years-of-age, respectively; these estimates increased to 569 and 1609/100 000 PPY in the sensitivity analysis, respectively. There were 12 primary SOC CDI cases in persons ≥50 years-of-age (18/100 000 PPY). CONCLUSIONS: The CDI incidence was high in older adults, with severe clinical consequences. SOC specimen collection and testing under-estimated CDI burden. There are >57 000 hospitalized CDI cases per year in Japan in persons ≥50 years-of-age. Public health interventions are needed to reduce the CDI burden in Japan.

The influence of the interval between percutaneous transhepatic gallbladder drainage and cholecystectomy on perioperative outcomes: a retrospective study.

BACKGROUND: Percutaneous transhepatic gallbladder drainage (PTGBD) is recommended for acute cholecystitis patients at high risk for surgical treatment. However, there is no evidence about the best timing of surgery after PTGBD. Here, we retrospectively investigated the influence of the interval between PTGBD and surgery on perioperative outcomes and examined the optimal timing of surgery after PTGBD. METHODS: We performed a retrospective analysis of 22 patients who underwent cholecystectomy after PTGBD from January 2008 to August 2019. We examined perioperative factors between patients with an interval of ≤ 7 days between PTGBD and cholecystectomy (≤ 7-day group; n = 12) and those with an interval of ≥ 8 days (≥ 8-day group; n = 10). Moreover, we also examined perioperative factors between patients with an interval of ≤ 14 days from PTGBD to cholecystectomy (≤ 14-day group; n = 10) and those with an interval of ≥ 15 days (≥ 15-day group; n = 12). RESULTS: Of the 22 patients, 9 had Grade I cholecystitis, 12 had Grade II cholecystitis, and 2 had Grade III cholecystitis. Nine patients had high-grade cholecystitis before PTGBD and 13 had a poor general condition. We examined perioperative factors between patients with an interval of ≤ 7 days between PTGBD and cholecystectomy (≤ 7-day group; n = 12) and those with an interval of ≥ 8 days (≥ 8-day group; n = 10). The C-reactive protein (CRP) level before surgery was significantly higher (12.70 ± 1.95 mg/dL vs. 1.13 ± 2.13 mg/dL, p = 0.0007) and the total hospitalization was shorter (17.6 ± 8.0 days vs. 54.1 ± 8.8 days, p = 0.0060) in the ≤ 7-day group than in the ≥ 8-day group. We also examined perioperative factors between patients with an interval of ≤ 14 days from PTGBD to cholecystectomy (≤ 14-day group; n = 14) and those with an interval of ≥ 15 days (≥ 15-day group; n = 8). The CRP level before surgery was significantly higher (11.13 ± 2.00 mg/dL vs. 0.99 ± 2.64 mg/dL, p = 0.0062) and the total hospitalization was shorter (19.5 ± 7.2 days vs. 59.9 ± 9.5 days, p = 0.0029) in the ≤ 14-day group than in the ≥ 15-day group. However, there were no significant differences between the ≤ 14-day group and the ≥ 15-day group in the levels of hepatic enzymes before surgery, adhesion grade, amount of bleeding during surgery, operative duration, frequency of surgical complications, or length of hospitalization after surgery. CONCLUSIONS: The interval between PTGBD and surgery has little influence on perioperative outcomes.

GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor-suppressor gene TGFßR2 in colorectal cancer.

Chromosome 7q (Ch.7q) is clonally amplified in colorectal cancer (CRC). We aimed to identify oncogenes on Ch.7q that are overexpressed through DNA copy number amplification and determine the biological and clinical significance of these oncogenes in CRC. We identified general transcription factor 2I repeat domain-containing protein 1 (GTF2IRD1) as a potential oncogene using a CRC dataset from The Cancer Genome Atlas with a bioinformatics approach. We measured the expression of GTF2IRD1 in 98 patients with CRC using immunohistochemistry and RT-quantitative PCR (RT-qPCR). The biological effects of GTF2IRD1 expression were explored by gene set enrichment analysis (GSEA). Next, we undertook in vitro cell proliferation and cell cycle assays using siGTF2IRD1-transfected CRC cells. We further investigated the oncogenic mechanisms through which GTF2IRD1 promoted CRC progression. Finally, we assessed the clinical significance of GTF2IRD1 expression by RT-qPCR. GTF2IRD1 was overexpressed in tumor cells and liver metastatic lesions. The GSEA revealed a positive correlation between GTF2IRD1 expression and cell cycle progression-related genes. GTF2IRD1 knockdown inhibited cell proliferation and induced cell cycle arrest in Smad4-mutated CRC. GTF2IRD1 downregulated the expression of the gene encoding transforming growth factor ß receptor 2 (TGFßR2), a tumor-suppressor gene in Smad4-mutated CRC. On multivariate analysis, high GTF2IRD1 expression was an independent poor prognostic factor. Clinicopathological analysis showed that GTF2IRD1 expression was positively correlated with liver metastasis. In conclusion, GTF2IRD1 promoted CRC progression by downregulating TGFßR2 and could be a prognostic biomarker on Ch.7q in CRC. GTF2IRD1 could also be a novel oncogene in CRC.

Circulating PD-1 mRNA in Peripheral Blood is a Potential Biomarker for Predicting Survival of Breast Cancer Patients.

BACKGROUND: Programmed cell death 1 (PD-1) inhibitors have shown significant therapeutic promise in various cancers. However, the clinical significance of PD-1 expression remains not fully understood. In this study, we evaluated the clinical and prognostic relevance of PD-1 expression in breast cancer (BC). METHODS: First, we analyzed PD-1 mRNA expression in BC tissues and performed a survival analysis using a dataset from The Cancer Genome Atlas. Next, we measured PD-1 mRNA expression in peripheral blood (PB) in BC patients by quantitative reverse-transcription polymerase chain reaction. We performed a survival analysis and evaluated the association between PD-1 mRNA expression in PB and the clinicopathological features of 372 BC patients who underwent curative resection. Flow cytometry (FCM) analysis was performed to identify PD-1-expressing cells in PB. Finally, we determined whether there was a correlation of PD-1 mRNA expression in PB and tumor tissue. RESULTS: PD-1 mRNA expression was significantly higher in tumor tissues compared with normal tissues. Decreased PD-1 mRNA expression in tumor tissue was associated with poor overall survival (OS). PD-1 mRNA expression in PB of BC patients was higher than that of healthy volunteers, and increased PD-1 mRNA expression in PB was associated with poor OS. FCM revealed that PD-1 was mostly expressed on T cells in PB, predominantly in CD4+ T cells. PD-1 mRNA expression in PB was negatively correlated with PD-1 mRNA expression in tumor tissue. CONCLUSION: High expression of PD-1 mRNA in preoperative PB could serve as an effective biomarker that indicates poor prognosis in BC.

Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer.

INTRODUCTION: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. METHODS: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. RESULTS: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. CONCLUSIONS: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.

Identification of ARL4C as a Peritoneal Dissemination-Associated Gene and Its Clinical Significance in Gastric Cancer.

BACKGROUND: In gastric cancer (GC), peritoneal dissemination (PD) occurs frequently and is incurable. In this study, we aimed to identify PD-associated genes in GC. METHODS: We identified a PD-associated gene using three GC datasets: highly disseminated peritoneal GC cell lines, the Singapore dataset and The Cancer Genome Atlas (TCGA) dataset. We assessed the clinicopathological significance of the gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and performed immunohistochemical analysis for the gene in our patient cohort. We also performed survival analyses of the gene in our patient cohort, the Singapore dataset and the GSE62254 datasets. Moreover, gene set enrichment analysis (GSEA) was performed using the Singapore and TCGA datasets. Finally, in vitro experiments such as invasion/migration assays, immunofluorescence staining of actin filaments, epidermal growth factor (EGF) treatment analysis, and gene expression analysis were conducted using three gene-knockdown GC cell lines (AGS, 58As9, MKN45). RESULTS: ADP-ribosylation factor-like 4c (ARL4C) was identified as a PD-associated gene, and immunohistochemical analysis showed that ARL4C was overexpressed in GC cells. High ARL4C expression was associated with the depth of invasion (p < 0.01) and PD (p < 0.05) and was a poor prognostic factor (p < 0.05) in our patient cohort, the Singapore dataset and the GSE62254 dataset. ARL4C expression positively correlated with the epithelial-mesenchymal transition (EMT) gene set in GSEA. Moreover, ARL4C knockdown reduced invasion/migration capacity, SLUG expression, and the formation of lamellipodia or filopodia in AGS and 58As9 cells. Finally, EGF treatment increased ARL4C expression in MKN45 cells. CONCLUSIONS: ARL4C was associated with PD and was a poor prognostic factor in GC, possibly through promoting invasive capacity by activation of both EMT and motility.

Prognostic Impact of Immune-Related Gene Expression in Preoperative Peripheral Blood from Gastric Cancer Patients.

BACKGROUND: Anti-PD-1 therapy has shown a promising clinical outcome in gastric cancer (GC). We evaluated the clinical significance of systemic immune-related gene expression in GC patients who underwent surgery. METHODS: The correlation between the preoperative PD-1, PD-L1, and CD8 mRNA levels in peripheral blood (PB) and clinicopathological factors, including survival, in 372 GC patients was evaluated using quantitative RT-PCR. PD-1- and PD-L1-expressing cells were identified by flow cytometric analysis. RESULTS: The PD-1, PD-L1, and CD8 mRNA levels in GC patients were significantly higher than those in normal controls, respectively (all P < 0.0001). The levels of each gene were positively correlated with those of the other two genes (all P < 0.0001). GC patients with low PD-1, high PD-L1, and low CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, low PD-L1, and high CD8 mRNA levels, respectively (P < 0.01, P < 0.05, and P < 0.05, respectively). Multivariate analysis showed that low PD-1 and high PD-L1 mRNA levels were independent poor prognostic factors for OS (PD-1: HR 2.38, 95% CI 1.27-4.78, P < 0.01; PD-L1: HR 1.81, 95% CI 1.15-2.78, P < 0.05). PD-1 and PD-L1 expression occurred on T cells (> 90%) and T cells or monocytes (> 70%), respectively. CONCLUSIONS: The PD-1, PD-L1, and CD8 mRNA levels in preoperative PB reflected the anti-tumour immune response, and the low PD-1 and high PD-L1 mRNA levels in PB were independent poor prognostic markers in GC patients who underwent surgery.

Identification of UHRF2 as a Negative Regulator of Epithelial-Mesenchymal Transition and Its Clinical Significance in Esophageal Squamous Cell Carcinoma.

OBJECTIVE: The involvement of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Here, we aimed to identify EMT-related genes associated with TGF-ß in ESCC and to clarify the role of these genes in the progression of ESCC. METHODS: EMT-related genes associated with TGF-ß expression were identified in patients with ESCC using microarray analysis and public datasets. The effects of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) expression were analyzed in ESCC cell lines. Cell proliferation and invasion were measured using MTT and invasion assays, respectively. UHRF2 mRNA expression was also analyzed in 75 ESCC specimens to determine the clinical significance of UHRF2 in ESCC. RESULTS: Treatment of ESCC cell lines with TGF-ß increased UHRF2 expression. UHRF2 overexpression increased CDH1 (E-cadherin) expression and decreased invasive capacity. The 75 ESCC specimens were divided into the UHRF2 high-expression group (n = 61) and the UHRF2 low-expression group (n = 14). Low UHRF2 expression was significantly correlated with vascular invasion (p = 0.034) and was an independent prognostic factor for poor prognosis (p = 0.005). CONCLUSION: UHRF2 may be a negative regulator of EMT and a novel prognostic biomarker for ESCC.

Programmed death-ligand 1 expression at tumor invasive front is associated with epithelial-mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma.

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-ß1-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-ß1 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.

Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC). METHODS: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro. RESULTS: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells. CONCLUSIONS: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.

The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers.

Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.

Long-term outcome of adipose-derived regenerative cell-enriched autologous fat transplantation for reconstruction after breast-conserving surgery for Japanese women with breast cancer.

PURPOSE: More effective methods are needed for breast reconstruction after breast-conserving surgery for breast cancer. The aim of this clinical study was to assess the perioperative and long-term outcomes of adipose-derived regenerative cell (ADRC)-enriched autologous fat grafting. METHODS: Ten female patients who had undergone breast-conserving surgery and adjuvant radiotherapy for breast cancer were enrolled. An ADRC-enriched fat graft prepared from the patient's adipose tissue was implanted at the time of adipose tissue harvest. The perioperative and long-term outcomes of the grafts, which included safety, efficacy, and questionnaire-based patient satisfaction, were investigated. RESULTS: The mean operation time was 188 ± 30 min, and the mean duration of postoperative hospitalization was 1.2 ± 0.4 days. No serious postoperative complications were associated with the procedure. Neither recurrence nor metastatic disease was observed during the follow-up period (7.8 ± 1.5 years) after transplantation. Of 9 available patients, "more than or equal to average" satisfaction with breast appearance and overall satisfaction were reported by 6 (66.7%) and 5 (55.6%) patients, respectively. CONCLUSIONS: ADRC-enriched autologous fat transplantation is thus considered to be safe perioperatively, with no long-term recurrence, for patients with breast cancer treated by breast-conserving surgery, and it may be an option for breast reconstruction, even after adjuvant radiotherapy.

Expression of PD-L1 and HLA Class I in Esophageal Squamous Cell Carcinoma: Prognostic Factors for Patient Outcome.

BACKGROUND: Programmed cell death 1 ligand 1 (PD-L1) and human leukocyte antigen (HLA) class I molecules on malignant cell surfaces are pivotal for tumor immunity. The clinical significance of their expression in patients with esophageal squamous cell carcinoma (ESCC) remains to be determined. METHODS: PD-L1 and HLA class I protein expression was investigated by immunohistochemical staining of resected specimens from 90 ESCC patients who underwent radical surgery without preoperative therapy. The relationships between the expression of PD-L1 and HLA class I and clinicopathologic factors and patient prognosis were assessed. RESULTS: High expression of PD-L1 and HLA class I were observed in 17 (18.9 %) and 35 (38.9 %) of 90 cases, respectively. High PD-L1 expression was correlated with the depth of tumor invasion (P = 0.0379), lymph node metastasis (P = 0.0031), recurrence (P = 0.0085), and poor overall survival (OS) (5-year survival rate; low/high: 60.9/28.4 %, P = 0.0110). Among those patients with high expression of HLA class I, high PD-L1 expression was correlated with significantly poorer recurrence-free survival (median survival time, low/high: 102.5/3.1 months, P = 0.0016) and poorer OS (median survival time, low/high: 102.5/13.1 months, P = 0.0027). Multivariate analysis showed that combined high PD-L1/high HLA class I expression was an independent prognostic factor for recurrence-free survival (hazard ratio 2.88, 95 % confidence interval 1.02-7.04, P = 0.0455) and OS (hazard ratio 2.95, 95 % confidence interval 1.03-7.50, P = 0.0447). CONCLUSIONS: High PD-L1 expression was a significant independent prognostic factor in ESCC patients with high HLA class I expression.

Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.

Novel sex-dependent differentially methylated regions are demethylated in adult male mouse livers.

In mammalian livers, sexual dimorphisms are observed in tissue-specific functions and diseases such as hepatocellular carcinoma. We identified sex-dependent differentially methylated regions (S-DMRs) which had been previously been characterized as growth hormone- STAT5 dependent. In this study, we performed genome-wide screening and identified ten additional hypomethylated S-DMR gene regions in male livers. Of these S-DMRs, Uggt2 and Sarnp were hypomethylated in both male and female livers compared to brain and embryonic stem (ES) cells. Similarly, Adam2, Uggt2, and Scp2 were hypomethylated in female embryonic germ (EG) cells and not in male EG cells, indicating that these S-DMRs are liver-specific male hypo-S-DMRs. Interestingly, the five S-DMRs were free from STAT5 chromatin immunoprecipitation (ChIP) signals, suggesting that S-DMRs are independent of the growth hormone-STAT5-pathway. Instead, the DNA methylation statuses of the S-DMRs of Adam2, Snx29, Uggt2, Sarnp, and Rnpc3 genes were under the control of testosterone. Importantly, the hypomethylated S-DMRs of the Adam2 and Snx29 regions showed chromatin decondensation. Epigenetic factors could be responsible for the sexual dimorphisms in DNA methylation status and chromatin structure, as the expression of Dnmt1, Dnmt3b, and Tet2 genes was lower in male mice compared to female mice and TET2 expression recovered following orchidectomy by testosterone treatment. In conclusion, we identified novel male-specific hypomethylated S-DMRs that contribute to chromatin decondensation in the liver. S-DMRs were tissue-specific and the hypomethylation is testosterone-dependent.

Clinical significance of surgical resection for the recurrence of esophageal cancer after radical esophagectomy.

BACKGROUND: This study aimed to clarify the clinical significance of surgical resection for recurrent lesions after esophagectomy for esophageal cancer. METHODS: Recurrence was detected in 113 of 365 consecutive patients who underwent surgical resection for esophageal cancer, and some treatment was performed for recurrence in 100 of the 113 patients. The treatments were classified into two groups: chemotherapy and/or radiation with surgery (surgery group, n = 14) and chemotherapy and/or radiation without surgery (no surgery group, n = 86). The outcomes were retrospectively analyzed. RESULTS: Of the 14 patients in the surgery group, 3 underwent repeated resection. Thus, a total of 22 resections were performed for these patients. The resected organs were the lymph nodes in nine patients, the lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, the liver in one patient, the brain in one patient, and the parotid gland in one patient. Among the 22 recurrent cases, 20 involved solitary lesions or multiple lesions located in a small resectable region. When the two groups were compared, the surgery group showed a more favorable prognosis in terms of both survival after esophagectomy (median survival time, 103.3 vs 23.1 months; p = 0.0060) and survival after initial recurrence (92.1 vs 12.2 months; p = 0.0057). CONCLUSIONS: Multimodal treatment provides a significant benefit for patients with recurrence after esophagectomy for esophageal cancer. Surgical intervention should be aggressively included in the treatment strategy when the recurrent lesion is solitary or localized.

Clinicopathological characteristics of esophageal squamous cell carcinoma in patients younger than 50 years.

PURPOSE: This study clarifies age differences in clinicopathologic characteristics and risk factor exposure of patients who have undergone esophagectomy for esophageal cancer (EC). METHODS: Clinical results of esophagectomy were compared between 22 patients younger than 50 years of age (Group I) and 327 patients older than 50 years of age (Group II) with esophageal squamous cell carcinoma. RESULTS: The two groups did not significantly differ in clinicopathological characteristics, including prognosis. Postoperative pulmonary complication incidence rates were 4.2 % (Group I) and 14.4 % (Group II). In Group I, the incidence of multiple ECs was 36.4 %, and association with head and neck cancer was 31.8 %, which were significantly higher than in Group II (13.4 %, p = 0.021; and 9.2 %, p = 0.015, respectively). Furthermore, the patients in Group I with multiple cancers were almost all heavy smokers and/or users of alcohol. CONCLUSIONS: These results suggest that multiple upper aerodigestive tract cancers are associated with heavy exposure to risk factors in patients younger than 50 years of age.

Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma.

BACKGROUND: Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis. RESULTS: The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability. CONCLUSIONS: Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC.

Technical improvement of total pharyngo-laryngo-esophagectomy for esophageal cancer and head and neck cancer.

PURPOSE: Total pharyngo-laryngo-esophagectomy (PLE) is highly invasive, and the subsequent reconstruction is difficult. The purpose of this study was to clarify the techniques that can decrease the surgical stress and allow for safe reconstruction after this operation. METHODS: The surgical method and clinical outcomes of total PLE were reviewed in 12 patients with either cervicothoracic esophageal cancer or double cancer of the esophagus and pharynx. Microscopic venous anastomosis was principally performed, and arterial anastomosis was added, if needed. RESULTS: A narrow gastric tube was used in ten patients, including two patients who underwent free jejunal interposition, while the colon was used as the main reconstructed organ in two other patients. Staged operations were performed in three high-risk patients. All six patients treated after 2010 were able to undergo thoracoscopic and/or laparoscopic surgery. No critical postoperative complications developed, although minor anastomotic leakage developed in two patients who were successfully treated conservatively. CONCLUSION: When performing PLE, it is important to decrease the surgical stress and ensure a reliable reconstruction by adopting techniques that are appropriate for each case, such as thoracoscopic and laparoscopic surgery, staged operations, microvascular anastomosis, and muscular flaps.