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Objective: This study aimed to compare laparoscopic standard gastrectomy (LSG) and laparoscopic sentinel node navigation surgery (LSNNS) for EGC in terms of 5-year long-term oncologic outcomes., Summary Background Data: The oncological safety of LSNNS for early gastric cancer (EGC) has not been confirmed. Three-year disease-free survival (DFS), which is the primary endpoint of the phase III multicenter randomized controlled clinical trial (SEntinel Node ORIented Tailored Approach [SENORITA] trial), did not show the non-inferiority of LSNNS relative to LSG., Methods: The SENORITA trial, a multicenter randomized clinical trial, was designed to show that LSNNS is non-inferior to LSG in terms of 3-year DFS. In the present study, we collected 5-year follow-up data from 527 patients recruited in the SENORITA trial as the full analysis set (FAS). Disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and recurrence patterns were evaluated using the FAS of both LSG (n=269) and LSNNS (n=258)., Results: The 5-year DFS was not significantly different between the LSG and LSNNS groups (P=0.0561). During the 5-year follow-up, gastric cancer-related events, such as metachronous cancer, were more frequent in the LSNNS group than in the LSG group. However, ten recurrent cancers in the remnant stomach of both groups were curatively resected by additional gastrectomy and one by additional endoscopic resection. Two of the 198 patients who underwent local resection for stomach preservation based on the LSNNS results developed distant metastasis. However, there was no statistically significant difference in the 5-year OS and DSS (P=0.7403 and P=0.9586, respectively) between the two groups., Conclusion: The 5-year DFS, DSS and OS did not differ significantly between the two groups. Considering the benefits of LSNNS on postoperative quality of life, LSNNS could be recommended as an alternative treatment option for EGC., Competing Interests: Conflict of Interest Disclosure: Dr. Hyung received grants from Medtronic and GC Pharma, stocks from Hutom, and personal fees from SK Hynix (Wuxi, China) outside of the submitted work. No other disclosures are reported., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This randomized, phase II, multicenter clinical trial was conducted to evaluate the feasibility of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection compared with open distal gastrectomy (ODG) for the treatment of advanced gastric cancer (AGC)., Summary of Background Data: D2 lymph node dissection has been accepted as standard treatment for AGC. Although LADG is widely performed in early gastric cancer (EGC), the feasibility of LADG in AGC has not been proven yet., Methods: Patients with cT2-T4a and cN0-2 (AJCC 7 staging system) distal gastric cancer were randomly but not blindingly assigned to LADG or ODG groups using fixed block sizes with a 1:1 allocation ratio. The primary endpoint was the noncompliance rate of the lymph node dissection, which was used to evaluate feasibility. Secondary endpoints included 3-year disease-free survival (DFS), 5-year overall survival, complications, and surgical stress response., Results: Between June 2010 and October 2011, 204 patients enrolled and underwent either LADG (n = 105) or ODG (n = 99). Of these, 196 patients (100 in LADG and 96 in ODG) were included in the intention-to-treat analysis. There were no significant differences in the overall noncompliance rate of lymph node dissection between LADG and ODG groups (47.0% and 43.2%, respectively; P = 0.648). In the subgroup analysis, the noncompliance rate in the LADG group was significantly higher than the ODG group for clinical stage III disease (52.0% vs 25.0%, P = 0.043). No difference was found in the 3-year DFS rate between the groups (LADG, 80.1%; ODG, 81.9%; P = 0.448). Differences in postoperative complication rates and surgical stress response were found to be insignificant between the 2 arms., Conclusions: LADG was feasible for AGC treatment based on the noncompliance rate of D2 lymph node dissection. Subgroups analysis data suggest that further studies are needed for stage III gastric cancer.

Objective: The phase II randomized controlled trial aimed to compare the outcomes of robot-assisted surgery with those of laparoscopic surgery in the patients with rectal cancer., Background: The feasibility of robot-assisted surgery over laparoscopic surgery for rectal cancer has not been established yet., Methods: Between February 21, 2012 and March 11, 2015, patients with rectal cancer (cT1-3NxM0) were enrolled. Patients were randomized 1:1 to either robot-assisted or laparoscopic surgery, and stratified per sex and administration of preoperative chemoradiotherapy. The primary outcome was the quality of total mesorectal excision (TME) specimen. Secondary outcomes were the circumferential and distal resection margins, the number of harvested lymph nodes, morbidity, bowel function recovery, and quality of life., Results: A total of 163 patients were randomly assigned to the robot-assisted (n = 81) and laparoscopic (n = 82) surgery groups, and 139 patients were eligible for the analyses (73 vs 66, respectively). One patient (1.2%) in the robot-assisted group was converted to open surgery. The TME quality did not differ between the robot-assisted and laparoscopic groups (80.3% vs 78.1% complete TME, respectively; 18.2% vs 21.9% nearly complete TME, respectively; P = 0.599). The resection margins, number of harvested lymph nodes, morbidity, and bowel function recovery also were not significantly different. On analyzing quality of life, scores of the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ C30) and EORTC QLQ CR38 were similar in the 2 groups, but in the EORTC QLQ CR 38 questionnaire, sexual function 12 months postoperatively was better in the robot-assisted group than in the laparoscopic group (P = 0.03)., Conclusions: Robot-assisted surgery in rectal cancer showed TME quality comparable with that of laparoscopic surgery, and it demonstrated similar postoperative morbidity, bowel function recovery, and quality of life.

Objective: This study investigated the efficacy and safety of S-1 versus capecitabine in elderly patients with metastatic gastric cancer (MGC), and examined the association between cytochrome P450 2A6 (CYP2A6) polymorphisms and treatment outcomes., Materials and Methods: MGC patients 70-85 years old with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or 65-70 years old with ECOG PS 2 were randomized to receive S-1 40 mg/m, twice daily, or capecitabine 1250 mg/m, twice daily, on days 1-14 every 3 weeks., Results: From May 2007 up to July 2010, 107 patients were enrolled. G3/4 neutropenia developed in 3.8% of each arm, and the most common G3/4 nonhematological toxicities were anorexia and fatigue. Vomiting and tearing were more frequent with S-1 and hand-foot syndrome with capecitabine. The primary endpoint, the overall response rate, was 26.4% (14/53, 95% confidence interval: 14.5-38.3%) in S-1 and 24.1% (13/54, 95% confidence interval: 12.7-35.5%) in capecitabine, both of which exceeded the null hypothesis response rate of 10%. The median time to progression (TTP; 3.2 vs. 3.4 months, P=0.813) and overall survival (OS; 8.5 vs. 10.3 months, P=0.691) were similar in both arms. CYP2A6 polymorphisms were associated with S-1 efficacy. In the S-1 arm only, patients with CYP2A6 variant/variant alleles had worse TTP and OS than those with wild/wild or wild/variant alleles, and in multivariate analysis, the CYP2A6 genotype was predictive for TTP and OS., Conclusion: Both S-1 and capecitabine were active and tolerable for elderly MGC patients. The CYP2A6 genotyping might guide treatment selection.

Several nomograms for survival prediction after curative gastric cancer surgery have been published over the recent years. Previous validation studies failed to prove applicability of Eastern Asian nomograms in Western patients. Here we present data on a validation analysis of a newly developed Korean nomogram in a German patient cohort.Among a total of 2771 patients having been treated in the Department of Surgery of the Technische Universitaet Muenchen from 1982 to 2008, 908 patients were eligible to undergo this analysis. Patients were treated according to Japanese Gastric Cancer guidelines and followed up on a regular basis for at least 60 months postoperatively. Baseline characteristics were compared using χ-testing. Survival analyses were computed with the Kaplan-Meier method and multivariate regression analysis models. The C-statistics and Hosmer-Lemeshow chi-square statistics were computed for comparisons of the nomogram's predictive ability.All baseline characteristics were significantly different (P < 0.0001) between Korean and German patients except Union Internationale Contre le Cancer-stages (P = 0.427). Multivariate regression analysis revealed the same predictive factors for overall survival in the German and Korean cohorts, respectively, with the exception of tumor size >10 cm and an exclusive correlation of whole stomach spread and pN1-stage for German patients only. The C-index was 0.76, representing an adequate value for predictability of the Korea nomogram in German patients. The Hosmer-Lemeshow statistic implied applicability of the nomogram in the TUM-cohort.A newly developed multicenter Korean nomogram for survival prediction after curative gastric cancer surgery may be applicable for estimating survival prognosis in Western (European) patients., Competing Interests: The authors have no conflicts of interest to disclose.

Background: In the era of pre- or perioperative therapy for gastric cancer, clinical staging before treatment appears to be increasingly important for prognosis, yet there are no data on the subject for resectable gastric cancer patients., Objectives: To evaluate the prognostic role of preoperative locoregional staging in gastric cancer patients undergoing curative resection., Methods: We reviewed 1964 gastric cancer patients who underwent curative resection without preoperative therapy from 2001 to 2005. We performed computed tomography and clinical staging according to both the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) (sixth edition) classification system, which bases N stage on the number of involved nodes, and the Japanese Classification of Gastric Carcinoma (JCGC) system, which bases N stage on node location., Results: The 5-year survival rates for patients with clinical T1, T2, T3, and T4 disease were 94.5%, 83.6%, 57.7%, and 35.5%, respectively (P < 0.001). The 5-year survival rates were 89.4% and 68.3%, respectively, for patients with clinical UICC/AJCC N0 and N1 disease (P < 0.001) and 89.4%, 72.4%, 61.0%, and 41.9%, respectively, for patients with clinical JCGC n0, n1, n2, and n3 disease (P < 0.001). When the JCGC system was applied within the UICC/AJCC N1 category, the 5-year survival rates significantly decreased, going from n1 (72.4%) to n2 (61.0%) to n3 (38.2%) (P < 0.001). In multivariate analysis, clinical T and N stage remained significant prognostic factors for overall survival., Conclusions: Clinical stage is an independent predictor of long-term survival in the preoperative setting. It should be incorporated as a stratification factor in a randomized clinical trial of preoperative therapy for gastric cancer patients.

Objectives: There is increasing evidence that chemokines and chemokine receptors are causally involved in the metastasis of cancer. Little is known about the possible role of chemokine receptors in the metastasis of gastric cancer. The aim of this study was to investigate the expression of chemokine receptors and their prognostic role in patients with gastric cancer., Methods: We screened the expression of CCR and CXCR chemokine receptors in 12 gastric cancer cell lines using the semi-quantitative RT-PCR. The expression of CCR4, one of the most commonly expressed chemokines, was confirmed using Western blot and flow cytometry analysis of 8 gastric cancer cell lines. The function of CCR4 was examined using migration and proliferation assays. Then the migratory response of CCR4 was blocked using blocking antibodies. Finally, the clinical significance of the chemokine receptors was explored using tissue microarray methods and immunohistochemical staining of specimens from 753 gastric cancer patients., Results: We found that 6 out of 8 (75.0%) gastric carcinoma cell lines expressed a functional CCR4 for its ligand, chemokine CCL17, as demonstrated by the migration assays, and the migration was inhibited by anti-CCR4 antibodies. The clinical samples evaluated by immunohistochemical assay of tissue microarrays showed that CCR4-positive carcinoma cells were detected in 128 of 753 (17.0%) cases. In addition, there was a significant difference in recurrences between the CCR4-positive and -negative cases (P = 0.009). The patients with CCR4-positive tumors had significantly poorer prognosis than did those with CCR4-negative tumors (5-year survival rate; 71.6% versus 82.5%, respectively, P = 0.008)., Conclusion: These results suggest that CCR4 and its ligands were associated with increased tumor recurrence and impaired overall survival in patients with gastric cancer.

Objective: The purpose of this study was to evaluate the quality of life (QOL) after laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG) in patients with early gastric cancer., Summary Background Data: LADG has been beneficial in terms of pain, recovery, and morbidity when compared with open surgery with equal oncologic outcome. There has been no clinical study on QOL., Methods: From July 2003 to November 2005, 164 patients with newly diagnosed cT1N0M0 and cT1N1M0 distal gastric cancer were randomly assigned either to LADG or ODG. All patients were asked to complete the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-STO22 questionnaires preoperatively and postoperatively on regular follow-up visits., Results: Statistically significant differences were observed with a more favorable outcome noted in the LADG group with respect to intraoperative blood loss (P < 0.001), total amount of analgesics used (P = 0.019), the size of the wound (P < 0.0001), postoperative hospital stay (P < 0.0001), and QOL parameters of global health (P < 0.0001). Most of the scales on patient functioning including physical (P < 0.0005), role (P = 0.0011), emotional (P < 0.0001), social (P < 0.0001), and symptom scales such as fatigue (P < 0.0001), pain (P < 0.0001), appetite loss (P = 0.031), sleep disturbance (P = 0.003), dysphasia (P = 0.0024), gastro-esophageal reflux (P = 0.0127), dietary restriction (P = 0.0004), anxiety (P = 0.0036), dry mouth (P = 0.0007), and body image (P < 0.0001) were also significantly better in the LADG group compared with the ODG group., Conclusions: Comparison of LADG to ODG in patients with early gastric cancer resulted in improved QOL outcomes in the patients followed for up to 3 months in the LADG group.

Background: The relations of insulin sensitivity (IS) to hypertension incidence may vary according to baseline age, body mass index (BMI), and blood pressure (BP)., Methods and Results: We investigated the relations of IS (insulin sensitivity index, ISI(0,120)) to 4-year incidence of hypertension and BP progression in 1933 nonhypertensive Framingham Study participants (median age, 51 years; 56% women). Analyses were stratified by age (less than versus greater than or equal to median), BMI (<25 [normal], 25 to <30 [overweight], > or =30 kg/m2 [obese]), and BP category (systolic BP> or =130 or diastolic BP> or =85, "high normal" per the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP [JNC-VI] versus BP<130/85 mm Hg). On follow-up, 41% of participants had BP progression (> or =1 BP stage increase) and 18% had development of hypertension (systolic BP> or =140 or diastolic BP> or =90 mm Hg or antihypertensive medication use). In younger (<51 years) people with normal BMI and baseline BP<130/85 mm Hg, the second-to-fourth ISI(0,120) quartiles were associated with lower multivariable-adjusted odds for hypertension incidence (0.27; 95% CI, 0.09 to 0.83; P<0.05) and BP progression (0.37; 95% CI, 0.18 to 0.77; P<0.01) relative to the lowest (most insulin resistant) quartile. IS was not related to BP progression or hypertension incidence in older individuals, in obese participants, or in people with BP> or =130/85 mm Hg., Conclusions: In our large community-based sample, reduced IS predicted BP tracking principally in younger people with normal BMI and BP<130/85 mm Hg. Effect modification by age, BMI, and baseline BP may explain variation in the results of prior clinical investigations relating IS to hypertension incidence.

Background: A family history of coronary heart disease (CHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. We hypothesized that an important mediator of the familial predisposition to CHD is subclinical atherosclerosis, which is detectable by noninvasive imaging., Methods and Results: We studied 1662 subjects (mean age 57, 51% women) in the Framingham Offspring Study who underwent carotid ultrasonography and had both biological parents in the original (parental) cohort. Parental CHD events were validated prospectively by a physician endpoint committee. The associations of carotid intima-media thickness (IMT) with premature parental CHD (occurring before age 60) and any parental CHD (no age restriction) were examined in age- and multivariable-adjusted analyses. Age-adjusted mean internal carotid IMT was higher in subjects who had at least one parent with premature CHD than in those without a validated parental history of premature CHD (men 1.13 versus 1.04 mm, P<0.01; women 0.92 versus 0.85 mm, P=0.03). In both sexes, these differences remained significant after adjustment for cardiovascular risk factors. In analyses without a restriction on parental age of CHD onset, the association between carotid IMT and parental CHD was not statistically significant. There was also no significant association of common carotid IMT with premature or any parental CHD., Conclusions: These findings suggest that subclinical atherosclerosis, assessed in the carotid arteries, is more prevalent in individuals with a family history of CHD. Early-onset parental CHD, in particular, identifies offspring with a strong familial predisposition to atherosclerosis.

Hypothesis: One of the inflammatory mediators of otitis media, nitric oxide, can damage cochlear outer hair cells., Background: Free radicals, including nitric oxide, have been detected in middle ear effusion. Increasing evidence implicates free radicals in the pathogenesis of otitis media and possibly in the development of sensorineural hearing loss., Methods: Isolated outer hair cells from adult chinchilla cochlea were exposed to standard bathing solution (Control Group 1) or the nitric oxide-producing compounds, S-nitroso-N-acetyl, l-penicillamine (1-1.5 mg/ml, Experimental Group 1) or 3-morpholinosynonimine (1-1.5 mg/ml, Experimental Group 2). Since nitric oxide is readily converted to nitrite and nitrate in vivo, a second control group using sodium nitrite was used to separate potential effects of nitric oxide from nitrite (Control Group 2). All experiments were performed at an osmolality of 305 +/- 5 mOsm at room temperature, and with exposure time up to 90 minutes. The cells were observed using an inverted microscope, and the images were recorded and analyzed on the IMAGE Pro-Plus program., Results: Outer hair cells exposed to either standard bathing solution or sodium nitrite (Control Groups 1 and 2) showed no significant change in cell shape or length. Cells exposed to S-nitroso-N-acetyl and l-penicillamine or 3-morpholinosynonimine exhibited ballooning and significant shortening in mean cell length (p < 0.01)., Conclusion: This study demonstrates that exposure to nitric oxide causes irreversible morphologic changes in isolated outer hair cells, suggesting possible involvement of nitric oxide radical in the development of sensorineural hearing loss as a sequela of chronic otitis media.

Objective: The objective of this study was to examine the relationship between C-reactive protein (CRP) and carotid atherosclerosis., Background: Levels of CRP, a nonspecific marker of inflammation, predict risk for cardiovascular events. However, the association between CRP and direct measures of atherosclerosis is not well established., Methods and Results: Subjects (n=3173, 52% women, mean age 55) in the offspring cohort of the Framingham Heart Study received a CRP measurement and then underwent carotid ultrasonography 4 years later. Carotid stenosis (> or =25%) was present in 24% of men and 14% of women. Age-adjusted odds ratios for carotid stenosis were 1.62 (95%CI 1.12 to 2.36) for men and 3.90 (CI 2.44 to 6.44) for women in the fourth quartile of CRP compared with those in the lowest quartile. After further adjustment for traditional cardiovascular disease risk factors, the odds ratio remained significant for women (2.97, CI 1.72 to 5.25) but not for men. Similarly, after multivariable adjustment, women in the fourth CRP quartile had a higher mean internal carotid intima-media thickness than those in the lowest CRP quartile (P< or =0.001). There was no association between common carotid intima-media thickness and CRP., Conclusions: There is a graded association between CRP and carotid atherosclerosis in women but not in men. The significance of this difference between sexes merits further investigation.