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Biliary tract cancers are rare, with a poor patient prognosis. Leptin and programmed death-ligand 1 (PD-L1) influence CD8Immunohistochemistry for leptin signaling-related proteins (leptin, leptin receptor, pSTAT3, extracellular-regulated kinase, mammalian target of rapamycin), PD-L1, CD8, and FOXP3 and in situ hybridization for Epstein-Barr virus-encoded small RNAs were performed in 147 cases of surgically-resected biliary tract cancers.Immune cell PD-L1-positivity, tumor size 3 cm, adjuvant chemotherapy, no recurrence, and early-stage tumors were correlated with better 5-year survival in the tumoral PD-L1The prognostic implication of the variables may depend upon tumoral protein expression and the anatomical site. Immune cell PD-L1-positivity and the administration of adjuvant chemotherapy may indicate the favorable survival of patients with surgically-resected biliary tract cancers, specifically, in the tumoral PD-L1

Purpose Patients who have undergone gastrectomy have unique symptoms that are not appropriately assessed using currently available tools. This study developed and validated a symptom-focused quality of life (QoL) questionnaire for patients who have received gastrectomy for gastric cancer. Materials and Methods Based on a literature review, patient interviews, and expert consultation by the KOrean QUality of life in Stomach cancer patients Study group (KOQUSS), the initial item pool was developed. Two large-scale developmental studies were then sequentially conducted for exploratory factor analyses for content validity and item reduction. The final item pool was validated in a separate cohort of patients and assessed for internal consistency, test-retest reliability, construct validity, and clinical validity.Results The initial questionnaire consisted of 46-items in 12 domains. Data from 465 patients at 11 institutions, followed by 499 patients at 13 institutions, were used to conduct item reduction and exploratory factor analyses. The final questionnaire (KOQUSS-40) comprised 40 items within 11 domains. Validation of KOQUSS-40 was conducted on 413 patients from 12 hospitals. KOQUSS-40 was found to have good model fit. The mean summary score of the KOQUSS-40 was correlated with the EORTC QLQ-C30 and STO22 (correlation coefficients, 0.821 and 0.778, respectively). The KOQUSS-40 score was also correlated with clinical factors, and had acceptable internal consistency (> 0.7). Test-retest reliability was greater than 0.8. Conclusion The KOQUSS-40 can be used to assess QoL of gastric cancer patients after gastrectomy and allows for a robust comparison of surgical techniques in clinical trials.

Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. Results PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines. Conclusions The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8+ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.

Laparoscopic distal gastrectomy for early gastric cancer has been widely accepted, but laparoscopic total gastrectomy has still not gained popularity because of technical difficulty and unsolved safety issue. We conducted a single-arm multicenter phase II clinical trial to evaluate the safety and the feasibility of laparoscopic total gastrectomy for clinical stage I proximal gastric cancer in terms of postoperative morbidity and mortality in Korea. The secondary endpoint of this trial was comparison of surgical outcomes among the groups that received different methods of esophagojejunostomy (EJ). The 160 patients of the full analysis set group were divided into three groups according to the method of EJ, the extracorporeal circular stapling group (EC; n = 45), the intracorporeal circular stapling group (IC; n = 64), and the intracorporeal linear stapling group (IL; n = 51). The clinicopathologic characteristics and the surgical outcomes were compared among these three groups. There were no significant differences in the early complication rates among the three groups (26.7% vs. 18.8% vs. 17.6%, EC vs. IC vs. IL; p = 0.516). The length of mini-laparotomy incision was significantly longer in the EC group than in the IC or IL group. The anastomosis time was significantly shorter in the EC group than in the IL group. The time to first flatus was significantly shorter in the IL group than in the EC group. The long-term complication rate was not significantly different among the three groups (4.4% vs. 12.7% vs. 7.8%; EC vs. IC vs. IL; p = 0.359), however, the long-term incidence of EJ stenosis in IC group (10.9%) was significantly higher than in EC (0%) and IL (2.0%) groups (p = 0.020). The extracorporeal circular stapling and the intracorporeal linear stapling were safe and feasible in laparoscopic total gastrectomy, however, intracorporeal circular stapling increased EJ stenosis.

Understanding the natural progression of untreated gastric cancer is critical for determining the disease prognosis as well as treatment options and timing. The aim of this study is to analyze the natural history of gastric cancer. We included patients with gastric cancer who had not received any treatment and were staged using endoscopy/endoscopic ultrasonography and computed tomography on at least two follow-up visits during intervals of nontreatment. Tumor volumes were also measured in addition to the staging. Survival of each stage at diagnosis was also analyzed. A total of 101 patients were included. The mean follow-up period was 35.1 ± 34.4 months. The gastric cancer doubling time was 11.8 months for T1 and 6.2 months for T4. The progression time from early gastric cancer to advanced gastric cancer was 34 months. It decreased as the stages advanced: from 34 months between tumor-nodes-metastasis stage I and II to 1.8 months between stage III and IV. No variable was identified as a risk factor for cancer progression. The 5-year survival rates of untreated patients were 46.2% in stage I and 0% in stage II, stage III, and stage IV. The progression and doubling times of gastric cancer shorten as the stages advance. Objective data reported in this study can be a critical factor in determining treatment timing and screening interval.

The aim of this study was to examine the effect of a perioperative oral nutritional supplement in malnourished patients who undergo gastrectomy.Patients who were determined as being moderately or severely malnourished according to a patient-generated subjective global assessment or who had a body mass index18.5, were enrolled. The oral nutritional supplement group received 500 mL/d of standard oral nutritional supplement for 2 weeks before gastrectomy and for 4 weeks postoperatively. The primary endpoint was postoperative complications (Clavien-Dindo classification ≥II). The secondary endpoints included body weight changes, biochemical parameters, and quality of life survey results.A total of 127 patients (65 in the oral nutritional supplement group and 62 in the control group) were enrolled. The complication rates were not significantly different (29.2% versus 37.1%, P = .346). However, the incidences of overall complications, complications persisting until postoperative week 3 or 5, and severe complications (grade ≥IIIa) were significantly lower in the oral nutritional supplement group for patients with patient-generated subjective global assessment grade C. Total lymphocyte counts were significantly higher in the oral nutritional supplement group at postoperative weeks 3 and 5. For most patients, oral nutritional supplement was well tolerated preoperatively. However, only 26.2% and 50.8% of the patients in the oral nutritional supplement group could consume250 mL/d of oral nutritional supplement postoperatively during the 2nd and 4th weeks, respectively.The routine application of perioperative oral nutritional supplement is not recommended for malnourished patients receiving gastrectomy. However, perioperative standard oral nutritional supplement administration may reduce the incidence, severity, and duration of complications after gastrectomy in severely malnourished patients (patient-generated subjective global assessment grade C).

Peritoneal recurrence (PR) is a major relapse pattern of colorectal cancer (CRC). We investigated whether peritoneal immune cytokines can predict PR. Cytokine concentrations of peritoneal fluid from CRC patients were measured. Patients were grouped according to peritoneal cancer burden (PCB): no tumor cells (≤ pT3), microscopic tumor cells (pT4), or gross tumors (M1c). Cytokine concentrations were compared among the three groups and the associations of those in pT4 patients with and without postoperative PR were assessed. Of the ten cytokines assayed, IL6, IL10, and TGFB1 increased with progression of PCB. Among these, IL10 was a marker of PR in pT4 (N = 61) patients based on ROC curve (p = 0.004). The IL10 cut-off value (14 pg/mL) divided patients into groups with a low (7%, 2 of 29 patients) or high (45%, 16 of 32 patients) 5-year PR (p

IMPORTANCE: The incidence of gallstones has been reported to increase after gastrectomy. However, few studies have been conducted on the prevention of gallstone formation in patients who have undergone gastrectomy. OBJECTIVE: To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) in preventing gallstone formation after gastrectomy in patients with gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: The PEGASUS-D study (Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study) was a randomized, double-blind, placebo-controlled clinical trial conducted at 12 institutions in the Republic of Korea. Adults (aged ≥19 years) with a diagnosis of gastric cancer who underwent total, distal, or proximal gastrectomy were enrolled between May 26, 2015, and January 9, 2017; follow-up ended January 8, 2018. Efficacy was evaluated by both the full analysis set, based on the intention-to-treat principle, and the per-protocol set; full analysis set findings were interpreted as the main results. INTERVENTIONS: Eligible participants were randomly assigned to receive 300 mg of UDCA, 600 mg of UDCA, or placebo at a ratio of 1:1:1. Ursodeoxycholic acid and placebo were administered daily for 52 weeks. MAIN OUTCOMES AND MEASURES: Gallstone formation was assessed with abdominal ultrasonography every 3 months for 12 months. Randomization and allocation to trial groups were carried out by an interactive web-response system. The primary end point was the proportion of patients developing gallstones within 12 months after gastrectomy. RESULTS: A total of 521 patients (175 received 300 mg of UDCA, 178 received 600 mg of UDCA, and 168 received placebo) were randomized. The full analysis set included 465 patients (311 men; median age, 56.0 years [interquartile range, 48.0-64.0 years]), with 151 patients in the 300-mg group, 164 patients in the 600-mg group, and 150 patients in the placebo group. The proportion of patients developing gallstones within 12 months after gastrectomy was 8 of 151 (5.3%) in the 300-mg group, 7 of 164 (4.3%) in the 600-mg group, and 25 of 150 (16.7%) in the placebo group. Compared with the placebo group, odds ratios for gallstone formation were 0.27 (95% CI, 0.12-0.62; P = .002) in the 300-mg group and 0.20 (95% CI, 0.08-0.50; P

With improved short-term surgical outcomes, laparoscopic distal gastrectomy has rapidly gained popularity. However, the safety and feasibility of laparoscopic total gastrectomy (LTG) has not yet been proven due to the difficulty of the technique. This single-arm prospective multi-center study was conducted to evaluate the use of LTG for clinical stage I gastric cancer. Between October 2012 and January 2014, 170 patients with pathologically proven, clinical stage I gastric adenocarcinoma located at the proximal stomach were enrolled. Twenty-two experienced surgeons from 19 institutions participated in this clinical trial. The primary end point was the incidence of postoperative morbidity and mortality at postoperative 30 days. The severity of postoperative complications was categorized according to Clavien–Dindo classification, and the incidence of postoperative morbidity and mortality was compared with that in a historical control. Of the enrolled patients, 160 met criteria for inclusion in the full analysis set. Postoperative morbidity and mortality rates reached 20.6% (33/160) and 0.6% (1/160), respectively. Fifteen patients (9.4%) had grade III or higher complications, and three reoperations (1.9%) were performed. The incidence of morbidity after LTG in this trial did not significantly differ from that reported in a previous study for open total gastrectomy (18%). LTG performed by experienced surgeons showed acceptable postoperative morbidity and mortality for patients with clinical stage I gastric cancer.

Background Few reliable blood markers are available for detecting gastric cancer, mainly owing to the heterogeneity of the cancer. Objective To establish gastric cancer diagnostic markers, we evaluated the levels of plasma cadherin 17 (CDH17) and trefoil factor 3 (TFF3), which are secretory proteins and known markers for intestinal metaplasia (IM), in patients with gastric cancer. Method The protein expression level was analyzed in blood plasma samples from 111 gastric cancer patients and 44 healthy individuals, using a sandwich ELISA kit, followed by statistical analyses. Result Overall, the plasma levels of CDH17 and TFF3 were not significantly different between groups (p= 0.160 and p= 0.113, respectively). However, CDH17 expression was significantly elevated in patients with stage II and III gastric cancers compared to that in healthy controls (p= 0.023 and p= 0.037, respectively). In contrast, TFF3 levels were significantly elevated in patients with stage I (p= 0.001) and T1 gastric cancer (p= 0.013). The sensitivity and specificity of CDH17 were 66.7 and 61.4%, respectively (cutoff point: 0.189 ng/mL); for TFF3, these values were 62.2 and 56.8%, respectively (cutoff point: 5.215 ng/mL). Conclusions These findings indicate that secretory protein markers for metaplastic lineages can be used as blood markers for gastric cancer.

Background Surgery for remnant gastric cancer (RGC) frequently fails to obtain the >15 lymph nodes necessary for tumor-node-metastasis (TNM) staging. We aimed to evaluate the utility of the recently developed tumor-ratio-metastasis (TRM) staging system. We also examined the pattern of lymph node metastasis and the role of prophylactic splenectomy in RGC. Methods Between May 2003 and December 2012, data from 170 patients who underwent surgery for RGC were retrospectively analyzed. Results RGC arising after previous benign disease (n = 46) was associated with retrieval of more lymph nodes (27.3 vs 10.0; P

PURPOSE The preoperative diagnosis of acute appendicitis is often challenging. Sometimes, pathologic results of the appendix embarrass or confuse surgeons. Therefore, more and more imaging studies are being performed to increase the accuracy of appendicitis diagnoses preoperatively. However, data on the effect of this increase in preoperative imaging studies on diagnostic accuracy are limited. We performed this study to explore unexpected appendiceal pathologies and to delineate the role of preoperative imaging studies in the diagnosis of acute appendicitis. METHODS The medical records of 4,673 patients who underwent an appendectomy for assumed appendicitis between 1997 and 2012 were reviewed retrospectively. Pathological results and preoperative imaging studies were surveyed, and the frequencies of pathological results and preoperative imaging studies were investigated. RESULTS The overall rate of pathology compatible with acute appendicitis was 84.4%. Unexpected pathological findings, such as normal histology, specific inflammations other than acute appendicitis, neoplastic lesions, and other pathologies, comprised 9.6%, 3.3%, 1.2%, and 1.5%, respectively. The rate of unexpected pathological results was significantly reduced because of the increase in preoperative imaging studies. The decrease in normal appendices contributed the most to the reduction while other unexpected pathologies did not change significantly despite the increased use of imaging studies. This decrease in normal appendices was significant in both male and female patients under the age of 60 years, but the differences in females were more prominent. CONCLUSION Unexpected appendiceal pathologies comprised 15.6% of the cases. Preoperative imaging studies reduced them by decreasing the negative appendectomy rate of patients with normal appendices.

Laparoscopic distal gastrectomy for early gastric cancer has been widely accepted, but laparoscopic total gastrectomy has still not gained popularity because of technical difficulty and unsolved safety issue. We conducted a single-arm multicenter phase II clinical trial to evaluate the safety and the feasibility of laparoscopic total gastrectomy for clinical stage I proximal gastric cancer in terms of postoperative morbidity and mortality in Korea. The secondary endpoint of this trial was comparison of surgical outcomes among the groups that received different methods of esophagojejunostomy (EJ).The 160 patients of the full analysis set group were divided into three groups according to the method of EJ, the extracorporeal circular stapling group (EC; n = 45), the intracorporeal circular stapling group (IC; n = 64), and the intracorporeal linear stapling group (IL; n = 51). The clinicopathologic characteristics and the surgical outcomes were compared among these three groups.There were no significant differences in the early complication rates among the three groups (26.7% vs. 18.8% vs. 17.6%, EC vs. IC vs. IL; p = 0.516). The length of mini-laparotomy incision was significantly longer in the EC group than in the IC or IL group. The anastomosis time was significantly shorter in the EC group than in the IL group. The time to first flatus was significantly shorter in the IL group than in the EC group. The long-term complication rate was not significantly different among the three groups (4.4% vs. 12.7% vs. 7.8%; EC vs. IC vs. IL; p = 0.359), however, the long-term incidence of EJ stenosis in IC group (10.9%) was significantly higher than in EC (0%) and IL (2.0%) groups (p = 0.020).The extracorporeal circular stapling and the intracorporeal linear stapling were safe and feasible in laparoscopic total gastrectomy, however, intracorporeal circular stapling increased EJ stenosis.

Health-related quality of life consists of multi-dimensional measurements of physical and mental health domains. Health-related quality of life is often followed up to evaluate efficacy of treatments in clinical studies. During the follow-up period, a missing data problem inevitably arises. When missing data occur for reasons related to poor health-related quality of life, a complete-case only analysis can lead to invalid inferences. We propose a Bayesian approach to analyze longitudinal moderate to high-dimensional multivariate outcome data in the presence of non-ignorable missing data. To account for non-ignorable missing data, we employ a selection model for the joint likelihood factorization where we apply Bayesian spike and slab variable selection in the missing data mechanism to detect informative factors among multiple outcomes. We model the relationship between multiple outcomes and covariates using linear mixed effects models where multiple outcome correlations are captured by a hierarchical structure. We conduct simulation studies to evaluate the performance of the proposed method compared with the conventional last observation carried forward approach. We use a motivating example that originates from a longitudinal study of quality of life in gastric cancer patients who underwent distal gastrectomy. In this application, we demonstrate that our proposed method can offer efficiency gain in the marginal associations and provide the associations between outcomes and the absence of patients' information.

Purpose The impact of the interval between previous endoscopy and diagnosis on the treatment modality or mortality of undifferentiated (UD)-type gastric cancer is unclear. This study aimed to investigate the effect of endoscopic screening interval on the stage, cancer-related mortality, and treatment methods of UD-type gastric cancer. Materials and Methods We reviewed the medical records of newly diagnosed patients with UD gastric cancer in 2013, in whom the interval between previous endoscopy and diagnosis could be determined. The patients were classified into different groups according to the period from the previous endoscopy to diagnosis (

Purpose Gastrectomy for elderly patients can significantly deteriorate the health-related quality of life (HRQoL). There was no report comparing HRQoL of elderly patients with young patients after gastrectomy for gastric cancer. This study assessed the differences in the changes of HRQoL at one year after gastrectomy according to age. Methods From May 2014 to Feb 2016, we prospectively enrolled patients undergoing gastrectomy for gastric cancer. They completed the European Organization for Research and Treatment of Cancer and gastric questionnaires preoperatively and at postoperative 1, 3, 6, 9, and 12 months. Results We included 57 elderly patients (≥70 years old) and 74 younger patients. The elderly had similar demographic, surgical, and pathological characteristics with young patients except that elderly had more comorbidity, laparoscopic gastrectomies, and lesser postoperative chemotherapy. One month after gastrectomy, the score of global health status/quality of life, physical, role, and social functioning were significantly impaired in elderly patients. Among them, physical and role functioning were more impaired than those of young patients. The scores of physical functioning, role functioning, cognitive functioning, and social functioning were not fully recovered till 1 year after surgery. There was a significant age group difference in the changes in physical function over the 1-year follow-up. Conclusion Elderly patients' global health status/quality of life and social functioning significantly decreased at postoperative 1 month and recovered by 6 months after gastrectomy. There was a significant age-specific difference in physical functioning throughout the 1-year follow-up. Surgeons need to pay more attention to recovery of the elderly patients' HRQoL after gastrectomy.

Controversy surrounds adjuvant chemotherapy (CTx) for T3N0M0 and T1N2M0 in the American Joint Committee on Cancer (AJCC) 7th edition stage IIA gastric cancer patients. The purpose of this study was to evaluate the benefit of adjuvant CTx for stage IIA cancer, including T3N0M0 and T1N2M0. A total of 630 patients with stage IIA cancer who underwent a radical gastrectomy between January 1999 and December 2009 at Seoul National University Hospital were retrospectively analyzed. We compared the outcomes of 434 patients who did not receive CTx (the non-CTx group) with those of 196 patients who received CTx comprising of 5-fluorouracil-based regimens (the CTx group). The 5-year overall survival (OS) rates of the non-CTx and CTx groups were 86.4 and 89.3 %, respectively (p = 0.047). In the subgroup analysis of T2N1M0 (6th II/7th IIA), there was a significant difference in OS between the non-CTx and CTx groups (p = 0.003), but no differences were observed in T3N0M0 and T1N2M0 (6th IB/7th IIA) (p = 0.574 and p = 0.934). The multivariate analysis showed that a tumor size greater than 5 cm in T3N0M0 [odds ratio (OR) 1.929; p = 0.030], no adjuvant CTx in T2N1M0 (OR 4.853; p = 0.025), and no factors in T1N2M0 were found to be risk factors for recurrence-free survival. Adjuvant CTx may be associated with an improved outcome of patients with T2N1M0 (6th II/7th IIA), but not T3N0M0 or T1N2M0 (6th IB/7th IIA), gastric cancer. To confirm these results, further studies are needed.

Purpose The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis. Materials and Methods Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients. Results CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393). Conclusion DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC.

Although the frequency of laparoscopic total gastrectomy (LTG) has been increasing, the procedure requires considerable experience because of its technical difficulty and the concern for oncological safety. This study intended to define the learning curve associated with the procedure. All 256 cases of LTG performed from June 2003 to December 2012 were enrolled. The cases were divided into ten groups of 25 cases based on when they occurred. The learning curve was defined using the moving average method. LTG, performed in the absence of other procedures (pure-LTG, 132 cases), was extracted from the ten groups, and the mean operative time and estimated blood loss (EBL) were compared to define the learning curve. Retrieved lymph nodes, hospital stay, and complications were compared across the phases of the learning curve. LTG with spleen resection, performed in the absence of other procedures (pure-srLTG, 53 cases), was also analyzed by the same method. A three-phase learning curve of LTG was defined: the first two groups, the following two groups, and the final six groups (mean operative time: 223.0, 244.8, and 207.8 min, respectively, p = 0.003; mean EBL: 94.6, 237.0, and 116.5 ml, respectively, p

High body mass index (BMI) and high visceral fat area (VFA) are known to be a preoperative risk factor for laparoscopic gastrectomy (LG) for gastric cancer. However, the impact of obesity on LG still remains controversial. In the present study, we compared the operative outcomes of LG with those of OG in patients with BMI of 30 kg/m2 or more. Seventy-seven patients who underwent distal or total gastrectomy for gastric cancer were enrolled. The patients were divided into two groups by approach method; an OG group (n = 19) and a LG group (n = 62). Aquarius iNtuition® program was used to measure VFA. The operation time, estimated blood loss, complication rate, the number of retrieved lymph nodes, and patient survival were compared between two groups. The mean BMI and VFA were 31.6 kg/m2 and 195.3 cm2. The complication rate was 42.1 % in OG group and 14.5 % in LG group, respectively (P = 0.010). LG group showed less estimated blood loss (P = 0.030) and fast recovery of bowel movement (P

The aim of this study was to evaluate the efficacy and safety of a new articulating bipolar energy device, the EndoWristPatients (n = 17) with cT1/2 gastric cancer who underwent robotic gastrectomy using the VS were prospectively enrolled in the study group (VS group). The clinicopathological outcomes, including operative time, intraoperative blood loss, amount of postoperative drainage, postoperative biochemical analysis results, and complication rates, were prospectively collected and compared with those of patients who underwent robotic gastrectomy using conventional ultrasonic shear force ([US] group, n = 52) during the same time period.Although the VS provided a good direction for dissection because of the articulating function, the ancillary use of conventional bipolar coagulation was occasionally needed due to the blunt, nonactive end tip of the VS. The operative time, intraoperative blood loss, postoperative drainage, and absence of complication rates did not differ between the VS and US groups, but the C-reactive protein levels on the second postoperative day (8.06 versus 11.7, P = .002) and serum albumin levels on the fifth postoperative day (3.51 versus 3.32, P = .019) were superior in the VS group.Use of the VS in robotic gastrectomy was feasible and provided good configuration in the direction of dissection. The learning process for use of the VS in the initial series was relatively rapid, resulting in comparable results between the VS and US groups. Reduced inflammation and albumin loss were identified as possible benefits of the VS.

The comprehensive complication index (CCI) integrates all complications of the Clavien–Dindo classification (CDC) and offers a metric approach to measure morbidity. The aim of this study was to evaluate the CCI at a high-volume center for gastric cancer surgery and to compare the CCI to the conventional CDC. Clinical factors were collected from the prospective complication data of gastric cancer patients who underwent radical gastrectomy at Seoul National University Hospital from 2013 to 2014. CDC and CCI were calculated, and risk factors were investigated. Correlations and generalized linear models of hospital stay were compared between the CCI and CDC. The complication monitoring model with cumulative sum control-CCI (CUSUM-CCI) was displayed for individual surgeons, for comparisons between surgeons, and for the institution. From 1660 patients, 583 complications in 424 patients (25.5%) were identified. The rate of CDC grade IIIa or greater was 9.7%, and the overall CCI was 5.8 ± 11.7. Age, gender, Charlson score, combined resection, open method, and total gastrectomy were associated with increased CCI (p

The three-dimensional view and articulating devices in robot system might have a benefit performing the delicate procedure of pylorus-preserving gastrectomy. This study was conducted to evaluate the feasibility and safety of robot-assisted pylorus-preserving gastrectomy (RAPPG) and to compare the perioperative outcomes and oncologic safety between RAPPG and laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) for middle-third early gastric cancer. Between June 2008 and December 2013, we retrospectively collected data of 68 patients with RAPPG and propensity score matched 68 patients with LAPPG for the treatment of early gastric cancer at Seoul National University Hospital. The covariates for propensity score matching were: age, sex, American Society of Anesthesiologists score, body mass index, and operators. Clinicopathologic characteristics and surgical outcomes were compared between the two groups. All RAPPG cases were performed successfully without open or laparoscopic conversion. Patient demographics and perioperative outcomes did not differ between the two groups except in operation time (258.3 vs. 193.9 min; P

Background and Objectives Reoperation is recommended for resectable retroperitoneal sarcoma (RS) recurrence; however, the long-term overall survival (OS) benefit varies. Although histologic grade is an important OS predictor after primary tumor resection, its prognostic value tends to diminish with subsequent reoperations. The objective of this study was to identify prognostic factors of OS after reoperation for recurrent RS. Methods The medical records of 95 patients who underwent resection for RS at Seoul National University Hospital between January 1999 and July 2011 were retrospectively reviewed. Of the 95 patients, 50 patients underwent second resection for recurrence, and 26 of these patients underwent third resection. Prognostic factors were analyzed at each reoperation. Results Higher histologic grade and gross residual disease were poor prognostic factors of OS after first resection. After second resection, higher histologic grade and time since previous operation of within 1 year were poor prognostic factors. After third resection, only contiguous organ resection was a significant independent prognostic factor. Conclusions The significance of prognostic factors changes with repetitive reoperations for RS recurrence. The prognostic value of histologic grade diminishes after the third resection, whereas other clinical factors such as time since previous operation and contiguous organ resection achieve significance. J. Surg. Oncol. 2015 111:165–172. © 2014 Wiley Periodicals, Inc.

There are two major stage classification systems for gastric cancer: the tumor-node-metastasis (TNM) stages by the International Union against Cancer (UICC) and the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association (JGCA). Preoperative stage classification using either of these systems is essential for deciding on the treatment strategy in the era of various multimodal therapeutic options. Evolution of multidetector computerized tomography with isotropic volumetric imaging and various 3D images has increased the accuracy of T and N staging in patients with gastric cancer, although detection of peritoneal deposits and nodal metastasis in the absence of lymphadenopathy remain problematic with the imaging tools currently available. The TNM and JGCA classifications have undergone revisions independent of each other, and the discrepancies were not helpful when international comparisons and cooperation were needed. More recently, the JGCA and TNM classifications were merged to have identical T and N categories, in addition to the more straightforward M categories that indicate the presence of distant metastasis. The result of these efforts is that researchers in Japan and the rest of the world are now looking at a similar disease when they discuss cancer that belongs to the same stage. A nomogram that incorporates other established prognostic determinants in addition to the TNM component may be a future direction for a more sophisticated means of predicting outcome. The increasing incidence of junctional (esophagogastric junction) cancer in the Far East has spurred researchers from this region to adequately stage the disease and to consider suitable treatment modalities for this disease entity, whereas Western researchers are more inclined to treat this disease as esophageal cancer. This could be an area for future international debate. For the next more accurate staging, we suggest the collaboration between Eastern and Western high-volume centers in gastric cancer because the inconsistency of surgical approaches, especially with respect to nodal resection, remains a barrier to mutual understanding.

Purpose: This study was conducted to evaluate the initial experience of 24 cases of laparoscopic liver resection by a single surgeon to determine its feasibility and report perioperative complications associated with this technique. Methods: A retrospective analysis of data from 24 patients who received attempted laparoscopic liver resections for primary liver tumors from November 2008 to April 2012 was conducted. Sixteen benign and eight primary malignant lesions were included. The patient’s electronic medical records including age, gender, underlying disease, past medical history, type of operations, operative time, complications, conversion rates, and length of hospital stay were reviewed. Results: The mean age of the patients was 52.6 years and the mean operation time was 263.7 minutes. The overall morbidity was 12.5% and the mortality was zero. One case was converted to open surgery (4.2%), while intraoperative transfusion was conducted in four cases. The types of operations included left hepatectomy (n=12, 50%; 3 with CBD exploration), left lateral sectionecectomy (n=4, 16.7%; 1 with cholecystectomy), partial hepatectomy for benign tumor (n=3, 12.5%: 1 with cholecystectomy), right hepatectomy (n=1, 4.1%), S6 segmentectomy (n=1, 4.1%), and tumorectomy (n=3, 12.5%). The mean estimated blood loss during operation was 375.3 cc and the postoperative hospital stay was 7.7 days. Additionally, one intraoperative complication and two postoperative complications occurred (12.5%). There was no postoperative mortality. Conclusion: The results of this study indicate that laparoscopic surgery with HBP training is suitable for laparoscopic liver resection. However, to ensure safety of the liver resection and the advantages of laparoscopic surgery, a thorough understanding of hepatic anatomy and elaborate surgical planning is essential.

The number of elderly patients undergoing gastric cancer surgery has recently increased. We therefore evaluated the short- and long-term outcomes of elderly patients after curative gastrectomy.Overall, 824 patients were included in this retrospective study, which comprised of a non-elderly group (60-64 years; n = 558), an early-elderly group (75-79 years; n = 198), and a late-elderly group (≥80 years; n = 68) who underwent curative gastrectomy for gastric cancer between 2005 and 2009. Postoperative complications, according to the Clavien-Dindo classification, and survival of both elderly groups were compared with the non-elderly group. Postoperative life expectancy of the late-elderly group was compared with the corresponding aged general population.Overall and severe (grade III or higher) complications in the early-elderly group were comparable with the non-elderly group; however, those in the late-elderly group were significantly more common than in the non-elderly group (p = 0.013 and p = 0.043, respectively). Multivariable analysis revealed that age ≥80 years was an independent risk factor for severe complications (hazard ratio 3.02, 95 % confidence interval 1.12-8.17; p = 0.029), and the disease-specific survivals of both elderly groups were comparable with the non-elderly group in all TNM stages. Postoperative life expectancy of late-elderly patients eliminating death from recurrence was comparable with the corresponding aged general population eliminating death from gastric cancer.Gastric cancer surgery in elderly patients aged ≥80 years achieves reasonable long-term survival despite the increased risk of severe complications.

Background Several studies have suggested that carbon dioxide (CO2) pneumoperitoneum may have an effect on liver function. This study aimed to compare liver function after laparoscopically assisted distal gastrectomy (LADG) and open distal gastrectomy (ODG) for patients with liver disease. Methods Between January 2006 and December 2007, the study enrolled 50 patients with EGC and liver disease including 18 liver cirrhosis patients, 3 fatty liver patients (n = 3), and 29 healthy hepatitis B or C virus carriers. Albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels as well as the volume of drainage in the LADG (n = 18) and ODG (n = 32) groups were determined to assess liver function. Results The albumin level on postoperative day 7 was significantly higher in the LADG group (3.5 mg/dl) than in the ODG group (3.1 mg/dl; p = 0.042), and the volume of drainage on postoperative day 2 was significantly lower in the LADG group (154.3 ml) than in the ODG group (403.1 ml; p = 0.013). Diuretics were needed by three patients (16.7%) in the LADG group and six patients (18.7%) in the ODG group for control of ascites (p = 0.587). For the patients with liver cirrhosis, none of the parameters between the two groups were significantly different. Conclusion For gastric cancer patients with chronic liver disease, LADG can be considered a safe surgical procedure showing surgical outcomes comparable with those for ODG.

This study evaluated the effects of a three-dimensional (3D) imaging system on laparoscopy performance compared with the conventional 2D system using a novel one-camera 3D system. In this study, 21 novices and 6 experienced surgeons performed two tasks with 2D and 3D systems in 4 consecutive days. Performance time and error as well as subjective parameters such as depth perception and visual discomforts were assessed in each session. Electromyography was used to evaluate the usage of muscles. The 3D system provided significantly greater depth perception than the 2D system. The errors during the two tasks were significantly lower with 3D system in novice group, but performance time was not different between the 2D and 3D systems. The novices had more dizziness with the 3D system in first 2 days. However, the severity of dizziness was minimal (less than 2 of 10) and overcome with the passage of time. About 54% of the novices and 80% of the experienced surgeons preferred the 3D system. Electromyography (EMG) showed a tendency toward less usage of the right arm and more usage of the left arm with the 3D system. The new 3D imaging system increased the accuracy of laparoscopy performance, with greater depth perception and only minimal dizziness. The authors expect that the 3D laparoscopic system could provide good depth perception and accuracy in surgery.

We investigated the clinicopathological implications of leptin-signaling proteins and Epstein-Barr virus (EBV)-infection status in gastric carcinomas. Immunohistochemistry for leptin signalling-related proteins (leptin, leptin-receptor, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha), and in situ hybridization for EBV-encoded small RNAs was performed in 343 cases of gastric carcinomas. The siRNA against leptin-receptor was transfected into three stomach cancer cell lines, and western blot for caspase 3 was performed. The TNM stage was a prognostic factor in all 343 patients, and was negatively correlated with expression of leptin, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha (P < 0.05). Leptin-receptor expression was correlated with poor survival in 207 patients of the advanced gastric cancer (AGC) subgroup, 139 of the Lauren diffuse group, and in 160 patients with lymph node metastasis (P < 0.05, respectively). Additionally, in stomach cancer cells, cleaved caspase 3 level increased by leptin-receptor inhibition, that is, apoptosis increased. Interestingly, EBV-positive AGC (n = 29) tended to show better survival of patients than EBV-negative AGC (n = 178) (P = 0.06). pAkt expression was related with a good survival of 32 patients (9%) in the EBV-positive subgroup, but was not an independent prognostic factor. Among, leptin signaling-related proteins, expressions of leptin-receptor and mTOR were different between EBV-positive subgroup and EBV-negative subgroup (P < 0.05, respectively). In conclusion, leptin-signaling proteins and EBV status show different significance on patient survival, according to subsets of gastric carcinomas. The leptin-receptor may predict poor patient prognosis in the AGC, Lauren diffuse and lymph node metastasis subgroups, while EBV-positive status can show a good prognosis in the AGC. Each leptin signaling-related protein may be differently involved in carcinogenesis of EBV-negative and EBV-positive subsets.

Reoperation is recommended for resectable retroperitoneal sarcoma (RS) recurrence; however, the long-term overall survival (OS) benefit varies. Although histologic grade is an important OS predictor after primary tumor resection, its prognostic value tends to diminish with subsequent reoperations. The objective of this study was to identify prognostic factors of OS after reoperation for recurrent RS.The medical records of 95 patients who underwent resection for RS at Seoul National University Hospital between January 1999 and July 2011 were retrospectively reviewed. Of the 95 patients, 50 patients underwent second resection for recurrence, and 26 of these patients underwent third resection. Prognostic factors were analyzed at each reoperation.Higher histologic grade and gross residual disease were poor prognostic factors of OS after first resection. After second resection, higher histologic grade and time since previous operation of within 1 year were poor prognostic factors. After third resection, only contiguous organ resection was a significant independent prognostic factor.The significance of prognostic factors changes with repetitive reoperations for RS recurrence. The prognostic value of histologic grade diminishes after the third resection, whereas other clinical factors such as time since previous operation and contiguous organ resection achieve significance.

Background Neoadjuvant chemotherapy has been shown to improve the rate of complete (R0) resection and downstaging in patients with localized gastric cancer. There are few reports, however, regarding its impact on postoperative morbidity and mortality. The aims of this study were to analyse complication and mortality rates after neoadjuvant chemotherapy using a modified regimen of folinic acid, 5-fluorouracil and oxaliplatin (mFOLFOX6) for locally advanced gastric cancer (AGC), compared with rates in patients who underwent surgery without neoadjuvant chemotherapy. Methods Data were collected from patients with AGC enrolled in a phase II trial of four cycles of neoadjuvant mFOLFOX6 followed by surgery, between January 2005 and June 2008 at two of three institutions, and compared with those from a cohort of patients with AGC who underwent surgery alone at one of the institutions in 2006. Results Among 51 patients who received neoadjuvant chemotherapy, there were no deaths and a morbidity rate of 24 per cent after surgery. Comparison of 48 patients in one institution who received neoadjuvant chemotherapy with 92 patients who had surgery alone in the same institution showed no increase in postoperative morbidity (23 versus 29 per cent; P = 0·417). Combined resection was the only risk factor for postoperative morbidity after neoadjuvant chemotherapy. Conclusion Neoadjuvant chemotherapy with mFOLFOX is a safe treatment for patients with localized AGC, and does not increase postoperative morbidity or mortality.

Purpose An intestinal perforation is a rare condition, but has a high mortality rate, even after immediate surgical intervention. The clinical predictors of postoperative morbidity and mortality are still not well established, so this study attempted to identify risk factors for postoperative morbidity and mortality after surgery for an intestinal perforation. Methods We retrospectively analyzed the cases of 117 patients who underwent surgery for an intestinal perforation at a single institution in Korea from November 2008 to June 2014. Factors related with postoperative mortality at 1 month and other postoperative complications were investigated. Results The mean age of enrolled patients was 66.0 ± 15.8 years and 66% of the patients were male. Fifteen patients (13%) died within 1 month after surgical treatment. Univariate analysis indicated that patient-related factors associated with mortality were low systolic and diastolic blood pressure, low serum albumin, low serum protein, low total cholesterol, and high blood urea nitrogen; the surgery-related factor associated with mortality was feculent ascites. Multivariate analysis using a logistic regression indicated that low systolic blood pressure and feculent ascites independently increased the risk for mortality; postoperative complications were more likely in both females and those with low estimated glomerular filtration rates and elevated serum C-reactive protein levels. Conclusion Various factors were associated with postoperative clinical outcomes of patients with an intestinal perforation. Morbidity and mortality following an intestinal perforation were greater in patients with unstable initial vital signs, poor nutritional status, and feculent ascites.

Backgrounds/Aims: We aimed to to evaluate the feasibility of laparoscopic common bile duct exploration (LCBDE) in patients with previous upper abdominal surgery. Methods: Retrospective analysis was performed on data from the attempted laparoscopic common bile duct exploration in 44 patients. Among them, 5 patients with previous lower abdominal operation were excluded. 39 patients were divided into two groups according to presence of previous upper abdominal operation; Group A: patients without history of abdominal operation. (n=27), Group B: patients with history of upper abdominal operation. Both groups (n=12) were compared to each other, with respect to clinical characteristics, operation time, postoperative hospital stay, open conversion rate, postoperative complication, duct clearance and mortality. Results: All of the 39 patients received laparoscopic common bile duct exploration and choledochotomy with T-tube drainage (n=38 [97.4%]) or with primary closure (n=1). These two groups were not statistically different in gender, mean age and presence of co-morbidity, mean operation time (164.5±63.1 min in group A and 134.8±45.2 min in group B, ρ=0.18) and postoperative hospital stay (12.6±5.7 days in group A and 9.8±2.9 days in group B, ρ=0.158). Duct clearance and complication rates were comparable (ρ＞0.05). 4 cases were converted to open in group A and 1 case in group B respectively. In group A (4 of 27 (14.8%) and 1 of 12 (8.3%) in group B, ρ=0.312) Trocar or Veress needle related complication did not occur in either group. Conclusions: LCBDE appears to be a safe and effective treatment even in the patients with previous upper abdominal operation if performed by experienced laparoscopic surgeon, and it can be the best alternative to failed endoscopic retrograde cholangiopancreatography for difficult cholelithiasis. (Korean J Hepatobiliary Pancreat Surg 2012;16:154-159)

The purpose of this study is to analyze the relationship between the number of examined lymph nodes (NexLN) and survival in gastric cancer and to determine whether the metastatic/examined lymph node ratio (LN ratio) system can compensate for the shortcomings of the UICC/AJCC staging.Prospective data of 8949 primary T1-T4a gastric cancer patients who underwent curative surgery were reviewed. The patients were stratified by T-stage and grouped according to NexLN; 1 to 14 exLN denoted the first group and every subsequent 10 LNs thereafter. Numbers of LN and 5-year survival rates were analyzed according to NexLN. "The NR-staging system" was generated using 0.2 and 0.5 as the cut-off values of LN ratio and then compared with UICC/AJCC stages.The proportion of advanced N-stage increased with NexLN. Survival and the LN ratio were constant regardless of NexLN when combining all N0-N3b patients, however, T2/3 and T4a patients showed an increasing tendency toward survival in N1/2 and N3a as NexLN increased, mainly due to a stage migration effect. The LN ratio system showed better patterns of distribution of the LN stage and survival graph. The power of the differential staging of the LN ratio system was fortified with higher NexLN.The relationship between NexLN and survival is probably affected by stage migration in a high-volume gastric cancer center. The LN ratio system could be a better option to compensate for this effect, and the value of the prognosis prediction in this system increases with a higher NexLN.

Purpose: We designed this study to evaluate the efficacy of carcinoembryonic antigen in draining venous blood (vCEA) as a predictor of recurrence. Methods: Draining venous and supplying arterial bloods were collected separately during the operation of 82 colorectal cancer patients without distant metastasis from September 2004 to December 2006. Carcinoembryonic antigen was measured and assessed for the efficacy as a prognostic factor of recurrence using receiver operating characteristic (ROC) and Kaplan-Meier curves. Results: vCEA is a statistically significant factor that predicts recurrence (P = 0.032) and the optimal cut-off value for vCEA from ROC curve is 8.0 ng/mL. The recurrence-free survival between patients with vCEA levels ＞8 ng/mL and ≤8 ng/mL significantly differed (P ＜ 0.001). The significance of vCEA as a predictor of recurrence gets higher when limited to patients without lymph node metastasis. The proper cut-off value for vCEA is 4.0 ng/mL if confined to patients without lymph node metastasis. The recurrence-free survival between the patients of vCEA levels ＞4 ng/mL and ≤4 ng/mL significantly differed (P ＜ 0.001). Multivariate analysis revealed vCEA is an independent prognostic factor in patients without lymph node metastasis. Conclusion: vCEA is an independent prognostic factor of recurrence in colorectal cancer patients especially in patients without lymph node metastases.

Manipulation and improper handling of a tumor during surgery may increase the risk of cancer cell dissemination after a curative gastrectomy. This study investigated the effect of improper handling of lymphovascular pedicles of stomach on tumor spillage during surgical procedure. Thirty-eight gastric cancer patients were enrolled. Three pairs of wash samples were obtained from each patient: (1) intraperitoneal wash samples obtained before (P0) and after gastrectomy (P1), (2) intragastric wash samples obtained before any manipulation (G0) and just before resection of the stomach (G1), and (3) ex vivo wash samples obtained by rinsing resected stomach with the lymphovascular pedicles closed by clips (S0) or with the pedicles open (S1). Cytologic examination was performed from all washes, and real-time reverse transcriptase–polymerase chain reaction analysis for carcinoembryonic antigen was performed from washes P0, P1, S0, and S1. Cytologic examination detected cancer cells in 34.2% (13 of 38) of G0 samples and in 39.5% (15 of 38) of G1 samples. The rate of conversion from G0-negative to G1-positive increased as T stage increased. Cytologic examination detected cancer cells in 2.6% (1 of 38) of S0 samples and in 13.2% (5 of 38) of S1 samples. The carcinoembryonic antigen mRNA level of the S1 sample was 2-fold greater than that of the S0 sample in 50.0% (7 of 14). Free cancer cells can be released from gastric lumen or lymphovascular pedicles opened during gastric cancer surgery, especially in advanced-stage disease. Care should be taken to minimize spillage from the gastric lumen and lymphovascular pedicles.

BACKGROUND: The seventh TNM staging system for gastric cancer of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) had a more detailed classification than the sixth TNM staging system for both the tumor (T) and lymph nodes (N). The authors compared survival rates assessed by the seventh staging system with those by the sixth system. METHODS: The authors analyzed the prospectively collected database on patients with gastric cancer who underwent surgery at Seoul National University Hospital between 1986 and 2006, and calculated the survival rates of 9998 cases with primary cancer, R0 resection, and >14 retrieved lymph nodes. RESULTS: The 5-year cumulative survival rates (5YSR) according to the seventh edition T or N classifications were significantly different. The 5YSR according to seventh edition of the TNM staging system were 95.1% (stage IA), 88.4% (stage IB), 84.0% (stage IIA), 71.7% (stage IIB), 58.4% (stage IIIA), 41.3% (stage IIIB), and 26.1% (stage IIIC), which were significantly different from each other. The 5YSR of the seventh edition T2 and T3 classifications had significant differences in patients with every N classification, and the 5YSR of seventh edition N1 and N2 classifications had significant differences in T2 patients, T3 patients, and T4 patients. Each stage in the sixth edition was divided into the seventh edition stage with different survival rates. In addition, the number of homogenous groupings in seventh edition TNM stages was increased from 1 to 2. CONCLUSIONS: The seventh system provided a more detailed classification of prognosis than the sixth system, especially between T2 and T3 tumors and N1 and N2 tumors, although further studies were found to be needed for the N3a and N3b classification. Cancer 2010. © 2010 American Cancer Society.