Safety evaluation of curative gastrectomy for gastric cancer patients who underwent liver transplantation: a comparative study with conventional gastrectomy for gastric cancer patients.

BACKGROUND: We aimed to examine the technical and oncological safety of curative gastrectomy for gastric cancer patients who underwent liver transplantation. METHODS: In this study, we compared the surgical and oncological outcomes of two groups. The first group consisted of 32 consecutive patients who underwent curative gastrectomy for gastric cancer after liver transplantation (LT), while the other group consisted of 127 patients who underwent conventional gastrectomy (CG). In addition, a subgroup analysis was performed to evaluate the impact of the background differences and the surgical outcomes on the involvement of a specialized liver transplant surgery team. RESULTS: The mean operative time was significantly longer in the LT group (p < 0.05). Furthermore, there were more frequent cases of postoperative transfusion in the LT group compared to the CG group (p < 0.05). However, there were no significant differences in the overall complications between the groups (25.00 vs 23.62%, p = 0.874). The 5-year overall survival rates of the LT and CG groups were 76.7% and 90.1%, respectively (p < 0.05). The results of the subgroup analysis demonstrated no statistically significant difference in various early surgical outcomes, such as time to transfusion during surgery, first flatus, time to first soft diet, postoperative complications, hospital stay after surgery, and the number of harvested lymph nodes except for operation time. CONCLUSIONS: Despite one's medical history of undergoing LT, our study demonstrated that curative gastrectomy could be a surgically safe treatment for gastric cancer. However, further study should be conducted to identify the reason gastric cancer patients who underwent liver transplant surgery have lower overall survival rate.

Comparison of Standard D2 and Limited Lymph Node Dissection in Elderly Patients with Advanced Gastric Cancer.

BACKGROUND: Knowledge on the optimal extent of lymphadenectomy among elderly patients with advanced gastric cancer is limited. This study was designed to compare standard D2 and limited lymphadenectomy for evaluating the appropriate extent of lymphadenectomy. PATIENTS AND METHODS: We retrospectively reviewed patient's data based on a prospectively collected gastric cancer registry. The inclusion criteria were age above 75 years and histologically confirmed stage II or more advanced gastric cancer. In this study, 103 patients who underwent limited lymph node dissection and 134 patients who underwent standard D2 lymph node dissection were included to evaluate surgical and oncological outcomes using propensity score matching (PSM) analysis. RESULTS: The mean age after PSM was approximately 78 years in both groups. The Charlson Comorbidity Index was 5.81 ± 0.87 and 5.75 ± 0.76, respectively, and 12.5% of the patients in both groups had American Society of Anesthesiologists scores of more than 3. The limited lymphadenectomy group showed a shorter operation time and fewer retrieved lymph. However, other surgical outcomes and pathological data were not significantly different between the groups. No postoperative mortality within 30 days was observed. There were no significant differences in overall complications between the groups. The 3-year overall survival rates of the limited and standard lymphadenectomy groups were 58.3% and 73.6%, respectively. The 3-year recurrence-free survival rate of the limited lymphadenectomy group was lower than that of the standard lymphadenectomy group; however, the difference was not statistically significant. CONCLUSIONS: Standard D2 lymphadenectomy has better oncological outcomes in elderly patients with advanced gastric cancer.

A comparative study of laparoscopic near-total and total gastrectomy for patient nutritional status and quality of life using a propensity score matching analysis.

BACKGROUND: Previous studies of LNTG had small sample sizes and short follow-up periods and did not evaluate quality of life after LNTG. We aimed to compare surgical, oncological, nutritional outcomes, and quality of life of patients after laparoscopic near-total and total gastrectomy (LNTG and LTG, respectively). METHODS: We retrospectively collected and analyzed data of 167 and 294 patients who underwent LNTG and LTG, respectively, for treatment of upper or middle third gastric cancer between January 2008 and December 2018. After propensity score matching, the surgical, oncological, and nutritional outcomes of 324 patients were analyzed. Moreover, we measured quality of life after surgery using a postgastrectomy syndrome scale. RESULTS: The operation time and the length of hospital stay was significantly shorter in the LNTG group than in the LTG group. In addition, patients with anastomotic complications were fewer in the LNTG group. No significant difference was found in the 5-year overall survival rate between the two groups. However, patients in the LNTG group had a significantly smaller body weight loss after 3 months postoperatively. Furthermore, patients in the LNTG group had significantly healthier albumin and cholesterol than those in the LTG group. The mean scores on the postgastrectomy symptom scale at 3, 6, and 12 months postoperatively were higher in the LNTG group than in the LTG group. CONCLUSION: LNTG is a surgically safe and oncologically favorable method compared with LTG. Furthermore, patients who underwent LNTG had improved nutritional status and quality of life than those who underwent LTG.

Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity.

The induction of endoplasmic reticulum (ER) stress has been reported as a key contributor to the cardiotoxicity of doxorubicin. Previous in vitro and in vivo studies suggest that sacubitril/valsartan, a novel angiotensin receptor-neprilysin inhibitor, could be effective against doxorubicin-induced cardiotoxicity. However, the precise mechanisms are not fully understood. Therefore, we investigated whether the cardioprotective effects of sacubitril/valsartan are associated with ER stress modulation in a rat model of doxorubicin-induced cardiotoxicity. Male Sprague-Dawley rats were treated with intraperitoneal injections of doxorubicin (15 mg/kg; cumulative) or saline for 3 weeks. From the day before the first treatment, control animals were gavaged daily with water (n = 8), whereas doxorubicin-treated animals were gavaged daily with water (n = 8) or sacubitril/valsartan (60 mg/kg/day; n = 8) for 6 weeks. Echocardiography was performed 6 weeks after the initiation of doxorubicin. In addition, serum troponin I and N-terminal brain natriuretic peptide levels were determined, and the extent of apoptosis and protein levels related to ER stress in the cardiac tissue and doxorubicin-treated H9c2 cardiomyocytes were analyzed. Sacubitril/valsartan significantly reduced doxorubicin-induced cardiac dysfunction and apoptosis in the myocardium. In addition, sacubitril/valsartan significantly downregulated the expression levels of proteins related to apoptosis and ER stress, including BAX, caspase 3, GRP78, PERK, IRE-1α, ATF-6, eIF-2α, ATF-4, and CHOP, in the myocardium of a rat model of doxorubicin-induced cardiotoxicity in vivo and doxorubicin-treated H9c2 cardiomyocytes in vitro. Sacubitril/valsartan significantly alleviated doxorubicin-induced cardiotoxicity, which may be associated with the reduction of ER stress.

Preoperative nutritional risk index and postoperative one-year skeletal muscle loss can predict the prognosis of patients with gastric adenocarcinoma: a registry-based study.

BACKGROUND: Patients with gastric cancer have an increased nutritional risk and experience a significant skeletal muscle loss after surgery. We aimed to determine whether muscle loss during the first postoperative year and preoperative nutritional status are indicators for predicting prognosis. METHODS: From a gastric cancer registry, a total of 958 patients who received curative gastrectomy followed by chemotherapy for stage 2 and 3 gastric cancer and survived longer than 1 year were investigated. Clinical and laboratory data were collected. Skeletal muscle index (SMI) was assessed based on the muscle area at the L3 level on abdominal computed tomography. RESULTS: Preoperative nutritional risk index (NRI) and postoperative decrement of SMI (dSMI) were significantly associated with overall survival (hazards ratio: 0.976 [95% CI: 0.962-0.991] and 1.060 [95% CI: 1.035-1.085], respectively) in a multivariate Cox regression analysis. Recurrence, tumor stage, comorbidity index were also significant prognostic indicators. Kaplan-Meier analyses exhibited that patients with higher NRI had a significantly longer survival than those with lower NRI (5-year overall survival: 75.8% vs. 63.0%, P <  0.001). In addition, a significantly better prognosis was observed in a patient group with less decrease of SMI (5-year overall survival: 75.7% vs. 66.2%, P = 0.009). A logistic regression analysis demonstrated that the performance of preoperative NRI and dSMI in mortality prediction was quite significant (AUC: 0.63, P <  0.001) and the combination of clinical factors enhanced the predictive accuracy to the AUC of 0.90 (P <  0.001). This prognostic relevance of NRI and dSMI was maintained in patients experiencing tumor recurrence and highlighted in those with stage 3 gastric adenocarcinoma. CONCLUSIONS: Preoperative NRI is a predictor of overall survival in stage 2 or 3 gastric cancer patients and skeletal muscle loss during the first postoperative year was significantly associated with the prognosis regardless of relapse in stage 3 tumors. These factors could be valuable adjuncts for accurate prediction of prognosis in gastric cancer patients.

Discovery and validation of an expression signature for recurrence prediction in high-risk diffuse-type gastric cancer.

BACKGROUND: Diffuse type gastric cancer (DGC), represented by low sensitivity to chemotherapy and poor prognosis, is a heterogenous malignancy in which patient subsets exhibit diverse oncological risk-profiles. This study aimed to develop molecular biomarkers for robust prognostic risk-stratification and improve survival outcomes in patients with diffuse type gastric cancer (DGC). METHODS: We undertook a systematic and comprehensive discovery and validation effort to identify recurrence prediction biomarkers by analyzing genome-wide transcriptomic profiling data from 157 patients with DGC, followed by their validation in 254 patients from 2 clinical cohorts. RESULTS: Genome-wide transcriptomic profiling identified a 7-gene panel for robust prediction of recurrence in DGC patients (AUC = 0.91), which was successfully validated in an independent dataset (AUC = 0.86). Examination of 180 specimens from a training cohort allowed us to establish a gene-based risk prediction model (AUC = 0.78; 95% CI 0.71-0.84), which was subsequently validated in an independent cohort of 74 GC patients (AUC = 0.83; 95% CI 0.72-0.90). The Kaplan-Meier analyses exhibited a consistently superior performance of our risk-prediction model in the identification of high- and low-risk patient subgroups, which was significantly improved when we combined our gene signature with the tumor stage in both clinical cohorts (AUC of 0.83 in the training cohort and 0.89 in the validation cohort). Finally, for an easier clinical translation, we established a nomogram that robustly predicted prognosis in patients with DGC. CONCLUSIONS: Our novel transcriptomic signature for risk-stratification and identification of high-risk patients with recurrence could serve as an important clinical decision-making tool in patients with DGC.

Overlap method versus functional method for esophagojejunal reconstruction using totally laparoscopic total gastrectomy.

BACKGROUND: Laparoscopic intracorporeal esophagojejunostomy (EJ) is a useful method in totally laparoscopic total gastrectomy (TLTG) for treating upper-third gastric cancer. The two methods of laparoscopic intracorporeal EJ-functional and overlap-have not been compared side-by-side in terms of safety and feasibility. METHODS: Retrospective review and analysis of the data of 490 consecutive patients who underwent TLTG by either functional method (n = 365) or overlap (n = 125) method for upper- or middle-third gastric cancer was conducted between January, 2011 and May, 2018 at Asan Medical Center (Seoul, Korea). One-to-one propensity score matching (PSM) was performed to compare age, sex, body mass index, American Society of Anesthesiologist score, the presence of comorbidity, number of comorbidities, clinical T stage, clinical nodal stage, clinical TNM stage, history of previous abdominal surgery, and combined surgery. After PSM, 244 patients were divided into functional method group and overlap method group (n = 122, each). The surgical outcomes and EJ-related complications were compared between the two groups. RESULTS: No significant difference was found between the two groups in terms of early surgical outcomes such as operative time, time to first flatus, postoperative hospital stay, transfusion during surgery, transfusion after surgery, and administration of analgesics. However, the pain score was significantly lower in overlap method group (6.21 ± 1.83) than functional method group (6.97 ± 2.09, p < 0.05). The overlap method was also associated with significantly fewer late complications (3.28% vs. 12.30%; p < 0.05), lower Clavien-Dindo classification grade (p < 0.05), and fewer EJ-related complications (0.82% vs. 6.56%; p < 0.05), as compared with the functional method. CONCLUSION: The overlap method was safer and more feasible than the functional method for TLTG in gastric cancer patients, based on the finding of significantly lower incidence of EJ-related complications.

Granulocyte colony-stimulating factor reduces the endoplasmic reticulum stress in a rat model of diabetic cardiomyopathy.

Prolonged endoplasmic reticulum (ER) stress contributes to the apoptosis of cardiomyocytes, which leads to the development of diabetic cardiomyopathy. Previously, we reported that the granulocyte colony-stimulating factor (G-CSF) reduces the cardiomyocyte apoptosis in diabetic cardiomyopathy; however, the precise mechanisms associated with this process are not yet fully understood. Therefore, in this study, we investigated whether the mechanism of the anti-apoptotic effect of G-CSF was associated with ER stress in a rat model of diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in rats using a high-fat diet combined with the administration of a low-dose of streptozotocin. Diabetic rats were treated with G-CSF or saline for 5 days. Cardiac function was evaluated using serial echocardiography before and 4 weeks after treatment. The rate of cardiomyocyte apoptosis and the expression levels of proteins related to ER stress, including glucose-regulated protein 78 (GRP78), caspase-9, and caspase-12 were analyzed in the cardiac tissue. G-CSF treatment significantly reduced cardiomyocyte apoptosis in the diabetic myocardium and downregulated the expression levels of these proteins in diabetic rats treated with low-dose streptozotocin when compared to that in rats treated with saline. In addition, G-CSF treatment significantly downregulated the expression levels of proteins related to ER stress, such as GRP78, inositol-requiring enzyme-1α (IRE-1α), and C/EBP homologous protein (CHOP) in H9c2 cells under high glucose (HG) conditions. Moreover, G-CSF treatment significantly improved the diastolic dysfunction in serial echocardiography assessments. In conclusion, the anti-apoptotic effect of G-CSF may be associated with the downregulation of ER stress.

Effects of depth of neuromuscular block on postoperative pain during laparoscopic gastrectomy: A randomised controlled trial.

BACKGROUND: Evidence on whether the use of deep neuromuscular block (NMB) influences postoperative pain after laparoscopic surgery is limited, and existing studies have shown conflicting results. We studied the effect of the depth of NMB during laparoscopic gastrectomy on postoperative pain. OBJECTIVE: The aim of this study was to evaluate the effect of depth of NMB during laparoscopic gastrectomy on postoperative pain by allocating patients randomly to either deep or moderate NMB with a standard-pressure pneumoperitoneum. DESIGN: A randomised, controlled, double-blind study. SETTING: A university-affiliated hospital. PARTICIPANTS: One hundred patients. INTERVENTIONS: Patients were allocated randomly to receive either deep (posttetanic count 1 to 2) or moderate (train-of-four count 1 to 2) levels of NMB. Following surgery, the patients were asked to rate their pain every 10 min using a visual analogue scale (VAS) (0 = no pain, 10 = most severe pain) in the postanaesthesia care unit (PACU). Patients received intravenous oxycodone, 2 mg every 10 min, until the pain intensity (VAS) had decreased to less than 3 at rest and less than 5 on wound compression, at which point the minimum effective analgesia dose (MEAD) of oxycodone was determined. MAIN OUTCOME MEASURES: The primary endpoint was the MEAD of oxycodone. Secondary endpoints included area under the curve of VAS for wound pain, VAS scores for wound and shoulder pain at 6 and 24 h after the end of surgery, rescue analgesics, a five-point surgical rating scale, Rhodes index of nausea vomiting retching at 6 and 24 h after the end of surgery and duration of pneumoperitoneum. RESULTS: The median value for the MEAD of oxycodone was 8 mg in both groups. Area under the curves of VAS over time were similar in both groups. Variables associated with postoperative pain including mean VAS at PACU and frequency of rescue analgesics in the ward did not differ significantly between the two groups. The duration of pneumoperitoneum was a significant variable in determining the MEAD of oxycodone (linear regression, R = 0.07, P = 0.008). The number of patients who reached the acceptable surgical score was not significantly different between the two groups. However, the moderate NMB group did have a significantly higher proportion of cases that required additional muscle relaxants (P < 0.001). CONCLUSION: Deep, compared with moderate, NMB did not significantly reduce the MEAD of oxycodone administered in the PACU. The duration of pneumoperitoneum was positively correlated with the MEAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03266419.

Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers.

BACKGROUND & AIMS: Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS: We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS: We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS: In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.

Long-term outcomes of endoscopic submucosal dissection versus surgery in early gastric cancer meeting expanded indication including undifferentiated-type tumors: a criteria-based analysis.

BACKGROUND: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) meeting the expanded indication is considered investigational. We aimed to compare long-term outcomes of ESD and surgery for EGC in the expanded indication based on each criterion. METHODS: This study included 1823 consecutive EGC patients meeting expanded indication conditions and treated at a tertiary referral center: 916 and 907 patients underwent surgery or ESD, respectively. The expanded indication included four discrete criteria: (I) intramucosal differentiated tumor, without ulcers, size >2 cm; (II) intramucosal differentiated tumor, with ulcers, size ≤3 cm; (III) intramucosal undifferentiated tumor, without ulcers, size ≤2 cm; and (IV) submucosal invasion <500 µm (sm1), differentiated tumor, size ≤3 cm. We selected 522 patients in each group by propensity score matching and retrospectively evaluated each group. The primary outcome was overall survival (OS); the secondary outcomes were disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related complications. RESULTS: In all patients and subgroups meeting each criterion, OS and DSS were not significantly different between groups (OS and DSS, all patients: p = 0.354 and p = 0.930; criteria I: p = 0.558 and p = 0.688; criterion II: p = 1.000 and p = 1.000; criterion III: p = 0.750 and p = 0.799; and criterion IV: p = 0.599 and p = 0.871). RFS, in all patients and criterion I, was significantly shorter in the ESD group than in the surgery group (p < 0.001 and p < 0.003, respectively). The surgery group showed higher rates of late and severe treatment-related complications than the ESD group. CONCLUSIONS: ESD may be an alternative treatment option to surgery for EGCs meeting expanded indications, including undifferentiated-type tumors.

Combinatory RNA-Sequencing Analyses Reveal a Dual Mode of Gene Regulation by ADAR1 in Gastric Cancer.

BACKGROUND: Adenosine deaminase acting on RNA 1 (ADAR1) is known to mediate deamination of adenosine-to-inosine through binding to double-stranded RNA, the phenomenon known as RNA editing. Currently, the function of ADAR1 in gastric cancer is unclear. AIMS: This study was aimed at investigating RNA editing-dependent and editing-independent functions of ADAR1 in gastric cancer, especially focusing on its influence on editing of 3' untranslated regions (UTRs) and subsequent changes in expression of messenger RNAs (mRNAs) as well as microRNAs (miRNAs). METHODS: RNA-sequencing and small RNA-sequencing were performed on AGS and MKN-45 cells with a stable ADAR1 knockdown. Changed frequencies of editing and mRNA and miRNA expression were then identified by bioinformatic analyses. Targets of RNA editing were further validated in patients' samples. RESULTS: In the Alu region of both gastric cell lines, editing was most commonly of the A-to-I type in 3'-UTR or intron. mRNA and protein levels of PHACTR4 increased in ADAR1 knockdown cells, because of the loss of seed sequences in 3'-UTR of PHACTR4 mRNA that are required for miRNA-196a-3p binding. Immunohistochemical analyses of tumor and paired normal samples from 16 gastric cancer patients showed that ADAR1 expression was higher in tumors than in normal tissues and inversely correlated with PHACTR4 staining. On the other hand, decreased miRNA-148a-3p expression in ADAR1 knockdown cells led to increased mRNA and protein expression of NFYA, demonstrating ADAR1's editing-independent function. CONCLUSIONS: ADAR1 regulates post-transcriptional gene expression in gastric cancer through both RNA editing-dependent and editing-independent mechanisms.

Comparison the sixth and seventh editions of the AJCC staging system for T1 gastric cancer: a long-term follow-up study of 2124 patients.

BACKGROUND/AIM: The aim of this study was to establish an appropriate TNM staging system for early gastric cancer. METHODOLOGY: We evaluated 2124 patients who had undergone gastrectomy for early gastric cancer between 1989 and 2001. RESULTS: Using the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, we found no significant differences in tumor recurrence and survival between N1 and N2 cancers or between N3a and N3b cancers, whereas the survival curves for N2 and N3 cancers were quite different. Similarly, using the classification in the sixth edition of the AJCC staging system, we found no significant difference in survival between the N2 and N3 cancer groups, whereas the survival curves for N1 versus N2 or N3 cancers were quite different. CONCLUSIONS: The classifications in the sixth and seventh editions of the AJCC staging system have a limitation for T1 gastric cancer (early gastric cancer).

Phase 2 study of adjuvant chemotherapy with docetaxel, capecitabine, and cisplatin in patients with curatively resected stage IIIB-IV gastric cancer.

OBJECTIVE: Postoperative chemotherapy with S-1 or capecitabine plus oxaliplatin is a standard treatment for resectable gastric cancer (GC). However, survival outcomes of stage IIIB-IV (M0) GC cases are still poor. We investigated the efficacy and safety of docetaxel, capecitabine, and cisplatin (DXP) in patients with stage IIIB-IV GC. METHODS: This was a single-arm phase 2 study that included patients with stage IIIB-IV GC who underwent D2 gastrectomy. Patients received six cycles of docetaxel [60 mg/m2 on day 1 (D1)], capecitabine (1,875 mg/m2/day on D1-14), and cisplatin (60 mg/m2 on D1) every 3 weeks. The primary end-point was recurrence-free survival (RFS). RESULTS: A total of 46 GC patients between January 2007 and August 2008 were included. After a median follow-up of 56.1 months (range 52.2-64.1), the median RFS and overall survival (OS) were 26.9 months (95 % CI 7.5-46.4) and 43.9 months (95 % CI 29.2-58.7), respectively. The 5-year RFS and OS rates were 39.1 and 41.3 %, respectively. The most common grade 3/4 toxicities were neutropenia (40 %), anorexia (22 %), and febrile neutropenia (15 %). CONCLUSIONS: Adjuvant DXP is feasible and effective for patients with stage IIIB-IV GC. A phase 3 study comparing triplet and doublet regimens for these patients is ongoing.

Phase I/II study of a combination of capecitabine, cisplatin, and intraperitoneal docetaxel (XP ID) in advanced gastric cancer patients with peritoneal metastasis.

BACKGROUND: This study was conducted to determine the recommended dose (RD) of intraperitoneal docetaxel (ID) in combination with systemic capecitabine and cisplatin (XP) and to evaluate its efficacy and safety at the RD in advanced gastric cancer (AGC) patients with peritoneal metastasis. METHODS: AGC patients with peritoneal metastasis received XP ID, which consists of 937.5 mg/m2 of capecitabine twice daily on days 1-14, 60 mg/m2 of intravenous cisplatin on day 1, and intraperitoneal docetaxel at 3 different dose levels (60, 80, or 100 mg/m2) on day 1, every 3 weeks. In the phase I study, the standard 3 + 3 method was used to determine the RD of XP ID. In the phase II study, patients received RD of XP ID. RESULTS: In the phase I study, ID 100 mg/m2 was chosen as the RD, with one dose-limiting toxicity (ileus) out of six patients. The 39 AGC patients enrolled in the phase II study received the RD of XP ID. The median progression-free survival was 11.0 months (95% CI 6.9-15.1), and median overall survival was 15.1 months (95% CI 9.1-21.1). The most frequent grade 3/4 adverse events were neutropenia (38.6%) and abdominal pain (30.8%). The incidence of abdominal pain cumulatively increased in the later treatment cycles. CONCLUSIONS: Our study indicated that XP ID was effective, with manageable toxicities, in AGC patients with peritoneal metastasis. As the cumulative incidence of abdominal pain was probably related to bowel irritation by ID, it might be necessary to modify the dose.

Associations between CYP2A6 polymorphisms and outcomes of adjuvant S-1 chemotherapy in patients with curatively resected gastric cancer.

BACKGROUND: Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients. METHODS: Patients received adjuvant S-1 (40 mg/m2 twice daily, days 1-28, every 6 weeks for eight cycles) after curative surgery for pathological stage II-III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity. RESULTS: Patients (n = 200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57 years (range, 32-83 years); 128 men, 72 women. With a median follow-up of 46.4 months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1 % (95 % CI, 77.7-88.5 %) and 94.8 % (95 % CI, 91.6-98.0 %), respectively. Genotype distributions were as follows: W/W (n = 49, 24.5 %), W/V (n = 94, 47.0 %), and V/V (n = 57, 28.5 %). Overall toxicity did not differ according to genotype for any grade (p = 0.612) or grade ≥3 (p = 0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9 % for W/W, 83.1 % for W/V, and 72.5 % for V/V (p = 0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95 % CI, 1.01-11.52; p = 0.049) and 4.03 (95 % CI, 1.16-13.93; p = 0.028), respectively, compared with the W/W genotype. CONCLUSIONS: CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.

Comparison of long-term outcomes of endoscopic submucosal dissection and surgery for esophagogastric junction adenocarcinoma.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become accepted as the standard treatment for early gastric cancer. However, comparative outcomes of ESD and surgery have not been evaluated for adenocarcinoma in the esophagogastric junction (EGJ). We investigated the long-term outcomes of ESD compared with those of surgery for adenocarcinoma in the EGJ. METHODS: Patients who underwent ESD or surgery for Siewert type II adenocarcinoma between 2005 and 2010 and who met the absolute and expanded criteria for endoscopic resection were eligible. Clinical features and treatment outcomes were retrospectively reviewed using medical records. RESULTS: Of the 79 patients included, 40 underwent ESD and 39 underwent surgery. During the median follow-up period of 60.9 months (range, 13.1-125.4 months), the 5-year overall survival rates were 93.9% and 97.3% for the ESD and surgery groups, respectively (p = 0.376). There were no gastric cancer-related deaths in either group. Adverse events occurred in 11 patients (13.9%) overall, and the incidence of treatment-related adverse events was similar between the two groups (10.0% vs. 17.9%, p = 0.308). CONCLUSIONS: ESD may be an effective alternative to surgery for the treatment of early gastric cancer in the EGJ based on the comparable long-term outcomes.

Clinical application of early gastric carcinoma with lymphoid stroma based on lymph node metastasis status.

BACKGROUND: Gastric carcinoma with lymphoid stroma (GCLS) is characterized by undifferentiated carcinoma mixed with prominent lymphoid infiltration. GCLS has unique clinicopathological features and a better prognosis compared to other types of gastric cancer. We analyzed the clinicopathological features of early GCLS in relation to lymph node metastasis (LNM). METHODS: We performed a retrospective analysis of 241 patients diagnosed with GCLS confined to the mucosa or the submucosa between March 1998 and December 2015. Their data were compared with those from 1219 patients who underwent resection for differentiated early gastric cancer (EGC). RESULTS: Of the 241 patients analyzed, 33 (13.7%) had intramucosal cancers and 208 (86.3%) had cancers that penetrated the submucosa. Compared to differentiated EGC, early GCLS was more prevalent in younger individuals and in men, tended to be proximally located, was highly associated with Epstein-Barr virus (EBV) infection (89.2%), and had a lower risk of LNM. The 5-year disease-specific survival rate of patients with early GCLS was 98.3% but depended significantly on LNM status (p < 0.001) and EBV infection status (p = 0.039). The risk of LNM from mucosal GCLS and submucosal GCLS was 0% [95% confidence interval (CI) 0-9.1] and 10% (95% CI 6.8-15.2), respectively. On multivariate analysis, LNM was found to be associated with tumor size (p = 0.022) and lymphovascular invasion (p = 0.002) in addition to tumor depth. CONCLUSIONS: Early GCLS has distinct clinicopathological features depending on age, sex, tumor location, EBV infection status, and LNM status. Tailored therapies, including endoscopic treatment, are needed based on the distinct clinicopathological features of early GCLS.

Totally laparoscopic total gastrectomy using the overlap method; early outcomes of 50 consecutive cases.

BACKGROUND: Construction of an esophagojejunostomy is still a challenging procedure in totally laparoscopic total gastrectomy (TLTG), and there is no standard anastomosing method. The aims of this study were to describe our TLTG with the overlap method using a linear stapler and report surgical outcomes. METHODS: From January 2015 to April 2016, 50 patients underwent TLTG using the overlap method for gastric cancer. The procedures were performed by a single surgeon, and the patients' medical records were reviewed. Their clinicopathologic characteristics, operation time, date of flatus, hospital stay, morbidity, and mortality were analyzed. RESULTS: The median age and body mass index were 56 years and 23.5, respectively. Stage 1A tumors were the most common. Mean operating time was 144.6 min, and no cases required changing to open laparotomy during surgery. On average, flatus occurred 3.5 days after surgery, and patients were discharged 6.8 days after surgery. No patient experienced anastomosis leakage, stricture, duodenal stump leakage, luminal bleeding, pancreatic fistula, or wound problems. There were two cases of intra-abdominal bleeding that required additional surgery. Intra-abdominal fluid collection and mechanical ileus occurred in two patients, respectively, and were successfully managed with conservative treatment. CONCLUSIONS: We reported favorable surgical outcomes of TLTG using the overlap method. It is a feasible and safe option for treatment of gastric cancer.

Can further gastrectomy be avoided in patients with incomplete endoscopic resection?

BACKGROUND: Endoscopic resection (ER) is a widely accepted treatment for patients with early gastric cancer (EGC) with no lymph node metastasis. Occasionally, however, additional surgery is needed due to an incomplete resection. The purpose of this study was to detect clinical factors which might identify patients at greater risk of additional surgery after ER and to suggest an alternative treatment strategy for these patients. METHODS: This study retrospectively analyzed 350 patients with gastric cancer who underwent radical gastrectomy and lymphadenectomy after ER in a single institution between July 2004 and July 2014. Risk factors for incomplete resection were identified using binary logistic multiple regression tests and a classification and regression tree analysis. RESULTS: Residual cancer cells were found in the remnant stomach or lymph node in 96 patients (27.4%). In multivariate analysis, lymphovascular invasion (p < 0.001, odds ratio [OR] 5.619) and depth of invasion greater than the second submucosal layer (SM2) (p < 0.01, OR 3.224) were independent risk factors for lymph node metastasis. Positive resection margin (p < 0.001, OR 7.565), depth of invasion to mucosa (M) and the first submucosal layer (SM1) (p < 0.001, OR 4.219), and size over 3 cm (p < 0.029, OR 2.306) were significant risk factors for residual tumor in the remnant stomach. Of 106 patients who had invasion of the M or SM1 without lymphatic invasion at the time of ER, residual cancer was found in 53 patients. Of these 53 patients, 50 (94.3%) had residual cancer in the mucosal layer and only one had lymph node metastasis. CONCLUSION: In patients with EGC with M or SM1 invasion without lymphovascular invasion at the time of ER, who had an incomplete resection, additional endoscopic treatment or close monitoring can be performed instead of additional surgery, especially in patients who are unable to tolerate gastrectomy, for example elderly patients or those with comorbidities.