Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Long term oncologic outcomes from the international PSOGI registry.

The laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) in highly selected patients was previously reported from the PSOGI registry with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to update this international PSOGI registry with a larger cohort of patients and a longer follow-up period. METHODS: An international registry was designed through a networking database (REDCAP®). All centers performing L-CRS + HIPEC were invited through PSOGI to submit data on their cases. Variables such as demographics, clinical outcomes, and survival were analyzed. RESULTS: A total of 315 L-CRS + HIPEC cases were provided by 14 worldwide centers. A total of 215 patients were included in the L-CRS + HIPEC group. The median peritoneal cancer index (PCI) was 3 (3-5). The median length of stay was 7 days (5-10) and the major morbidity (Clavien-Dindo ≥3) was 6.1% after 30 days. The 5-year disease-free survival (DFS) per tumor origin was: 94% for PMP-LG, 85% for PMP-HG, 100% for benign multicyst peritoneal mesothelioma (MPM), 37.4% for colonic origin, and 54%(at 3 years) for ovarian origin. The 5 years overall survival (OS) per tumor origin was: 100% for PMP-LG, PMP-HG and MPM; 61% for colonic origin, and 74% (at 3 years) for ovarian origin. In addition, a total of 85 patients were analyzed in the laparoscopic risk-reducing HIPEC (L-RR + HIPEC). The median length of stay was 5 days (4-6) and the major morbidity was 6% after 30 days. The 5-year DFS per tumor origin was: 96% for perforated low grade appendiceal mucinous neoplasm (LAMN II) and 68.1% for colon origin. The 5 years OS per tumor origin was: 98% for LAMN II and 83.5% for colonic origin. CONCLUSIONS: Minimally invasive CRS + HIPEC is a safe procedure for selected patients with peritoneal carcinomatosis in specialized centers. It improves perioperative results while providing satisfactory oncologic outcomes. L-RR + HIPEC represents a promising strategy that could be evaluated in patients with high risk of developing peritoneal carcinomatosis into prospective randomized trials.

Effect of oxaliplatin-based chemotherapy on chemosensitivity in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: proof-of-concept study.

BACKGROUND: Chemosensitivity testing, including collagen gel droplet-embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision-making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer. METHODS: All patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease-free (DFS) survival. RESULTS: Of 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin-based regimen. Mean(s.d.) follow-up was 23·4(22·9) months. The median overall survival of all patients was 19·0 (i.q.r. 5·7-36·1) months, with a progression-free survival time of 10·1 (4·5-17·0) months. Patients who received oxaliplatin-based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin-based NACT (P = 0·046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18·8 versus 18·1 months; P = 0·835). The choice of HIPEC agents in patients who received oxaliplatin-based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20·6 (10·9-24·8) versus 19·0 (10·5-34·6) months, P = 0·811; DFS 6·6 (2·8-25·7) versus 9·3 (4·1-13·9) months, P = 0·191). CONCLUSION: Patients who had oxaliplatin-based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for limited peritoneal metastasis. The PSOGI international collaborative registry.

INTRODUCTION: A laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS+HIPEC) in highly selected patients has been reported in small cohorts with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to analyse individual patient data from these international centres collected through the Peritoneal Surface Oncology Group International (PSOGI) L-CRS+HIPEC registry. METHODS: An international registry was designed through a networking database (REDCAP®). All centres performing L-CRS+HIPEC were invited through PSOGI to submit data on their cases. Patient's characteristics, postoperative outcomes and survival were analysed. RESULTS: Ten international centres contributed a total of 143 L-CRS+HIPEC patients during the study period. The most frequent indication was low grade pseudomyxoma peritonei in 79/143 (55%). Other indications were benign multicyst mesothelioma in 21/143(14%) and peritoneal metastasis from colon carcinoma in 18/143 (12,5%) and ovarian carcinoma in 13/143 (9%). The median PCI was 3 (2-5). The median length of stay was 6 (5-10) days, with 30-day major morbidity rate of 8.3% and 30-day mortality rate of 0.7%. At a median follow-up of 37 (16-64) months 126/143 patients (88.2%) were free of disease. CONCLUSIONS: Analysis of these data demonstrates that L-CRS+HIPEC is a safe and feasible procedure in highly selected patients with limited peritoneal disease when performed at experienced centres. While short to midterm outcomes are encouraging in patients with less invasive histology, longer follow up is required before recommending it for patients with more aggressive cancers with peritoneal dissemination.

Downstaging of lymph node metastasis after neoadjuvant intraperitoneal and systemic chemotherapy in gastric carcinoma with peritoneal metastasis.

PURPOSE: The aim of the present study was to evaluate the clinical features and prognosis of lymph node metastasis (LNM) in gastric cancer patients with peritoneal metastasis (PM) after neoadjuvant intraperitoneal and systemic chemotherapy. METHODS: A total of 69 gastric cancer patients with PM and LNM who received neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) of intraperitoneal docetaxel (DXT) and cisplatin (CDDP); intravenous chemotherapy of DXT and CDDP and oral S-1in Kishiwada Tokushukai Hospital between January 2008 and February 2017. After surgical resection, the response of LNMs was studied to confirm the effect of NIPS on LNMs. RESULTS: After NIPS, 197 lymph nodes (LNs) (42.5%) were graded as G3, the progression in LNMs were significantly better than in the primary tumors. Until the last follow-up, 1-year overall survival rate was 82.6%, and the median survival period was 22.0 ±â€¯3.7 months. In the group of patients who had achieved a more than 50% G3 grade of the response of LNMs, the median survival period is 38 months; in the less than 50% G3 grade group, it is 14 months, that is a significantly different result. Multivariate analyses showed that the factors PCI, Post-therapeutic N status and response of the LNMs were found to be as independent prognostic factors. CONCLUSION: Downstaging of LNMs were achieved in patients of gastric cancer with PM who received NIPS. Downstaging of LNMs after NIPS is related with the prognosis of gastric cancer and should be valued in subsequent surgery for gastric cancer with peritoneal and lymph nodes metastasis.

Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.

BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Should total gastrectomy and total colectomy be considered for selected patients with severe tumor burden of pseudomyxoma peritonei in cytoreductive surgery?

BACKGROUND: This study aims to evaluate the safety and efficacy of cytoreductive surgery (CRS) including total gastrectomy and total colectomy in selected pseudomyxoma peritonei (PMP) patients with entire stomach and colon covered by mucinous tumor. METHODS: A total of 48 patients received this extensive treatment between January 2006 and January 2014. The main focus of this study was survival after CRS as well as perioperative morbidity and mortality. RESULTS: Twenty-eight patients were male, and median age was 52.5 years. Median peritoneal cancer index was 33. Complete cytoreduction was achieved in all 48 patients, and 26 patients received hyperthermic intraperitoneal chemotherapy (HIPEC). Until last follow-up, the estimated median survival after CRS was 54.0 months (95% CI 36.5-71.6 months). The 1-, 2-, 3-, and 5-year survival rates were 91.7%, 81.3%, 70.1%, and 48.6%, respectively. Histology was significantly associated with survival (P = 0.020). The median disease-free survival was 32.0 (95% CI 25.7-38.3) months. HIPEC (P = 0.048) and histology (P = 0.002) was significantly associated with disease-free survival after CRS. Overall Grade 3-5 complications occurred in 18 (37.5%) patients with mortality of 2.1%. For patients who received surgery over 6 months, they could gradually have an acceptable quality-of-life similar as other patients receiving ordinary CRS and HIPEC. CONCLUSION: CRS including total gastrectomy and total colectomy can be performed in experienced specialized institutions as a feasible option to achieve complete cytoreduction with acceptable safety in selected PMP patients with stomach and colon covered by mucinous tumor. Perioperative management should be carried out cautiously to decrease and avoid complications.

Effect of intraperitoneal chemotherapy and peritoneal lavage in positive peritoneal cytology in gastric cancer. Systematic review and meta-analysis.

INTRODUCTION: The most common cause of tumour progression in advanced gastric cancer is peritoneal carcinosis (PC). The necessity to increase the survival in advanced diseases suggested to deliver the chemotherapy directly in the peritoneal cavity also in Cy+/PC- and to experiment the effect of massive peritoneal lavage to wash out the tumour cells. The aim of this study is to investigate the gain in term of survival and peritoneal recurrence rate of the intraperitoneal chemotherapy and/or peritoneal lavage in patients with Cy+/PC-. MATERIAL AND METHODS: A systematic review with meta-analysis of trials about the effect of intraperitoneal chemotherapy (IPC) and/or peritoneal lavage (PL) on positive cytology in gastric cancer without carcinosis. RESULTS: Three trials have been included (164 patients: 76 received surgery alone, 51 surgery + IPC and 37 surgery + IPC + PL). Two- and five-years survival is increased by IPC (RR = 1.62, RR = 3.10). 2 and 5 years survival is further increased by IPC + PL (RR = 2.33, RR = 6.19). Peritoneal recurrence is reduced by IPC (OR = 0.45) and by IPC + PL (OR = 0.13). CONCLUSIONS: Two- and five-years overall survival in patients with free cancer cells without carcinosis is incremented by intraperitoneal chemotherapy. Peritoneal lavage further increases these survival rates and also it further decreases the peritoneal recurrence rate.

A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent.

Recently, Peritoneal Surface Oncology Group International (PSOGI) developed a novel comprehensive treatment consisting of cytoreductive surgery (CRS) and perioperative chemotherapy (POC) for the treatment of peritoneal metastases (PM) from gastric cancer with curative intent. This article reviews the results of this treatment and verifies its indication. In this strategy, peritoneal cancer index (PCI) is determined by laparoscopy, and a peritoneal port is placed. Neoadjuvant bidirectional intraperitoneal/systemic chemotherapy (NIPS) is performed for 3 cycles, and then laparotomy is performed. Cytoreductive surgery with peritonectomy procedures and hyperthermic intraperitoneal chemoperfusion (HIPEC) are performed. Multivariate analyses showed that completeness of cytoreduction, pathologic response to NIPS and PCI level and cytologic status after NIPS, as independent prognostic factors. PCI less than cut-off level after NIPS, negative cytology after NIPS, and positive response to NIPS were identified as the indications for comprehensive treatment. Patients who hold these criteria should be considered as the candidates for CRS and HIPEC.

Complete versus incomplete cytoreduction in peritoneal carcinosis from gastric cancer, with consideration to PCI cut-off. Systematic review and meta-analysis.

INTRODUCTION: The completeness of cytoreduction has been considerated as fundamental in increasing the life expectancy in patients with peritoneal carcinosis (PC) in gastric cancer. However no definitive data about the real effect of complete cytoreduction (CC) have still been published. Moreover the PCI cut-off to attempt CC with a reasonable risk-benefit ratio still lacks. MATERIAL AND METHODS: A systematic review with meta-analysis of trials of complete vs incomplete cytoreduction in patients with peritoneal carcinosis from GC was performed. RESULTS: Nine trials have been included (748 patients: 417 with CC0-CC1 and 324 with CC2-CC3 cytoreduction). 1, 2, 3 and 5 years survival is favorable to CC0-CC1 (Risk Ratio: 2.41, 8.18, 8.66, and 7.96 respectively). CC0 vs. CC1 survival benefit at 1 and 3 years: RR 2.28 and 6.36 respectively, favoring CC0. 1, 2, 3 and 5 years survival changes significantly above and below a PCI of 12. CONCLUSIONS: 1, 2, 3 and 5-year overall survival is increased by CC0-CC1 cytoreduction in patients with PC from gastric origin. Moreover CC0 increases the 1 and 3 years survival when compared to CC1 cytoreduction.

Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials.

INTRODUCTION: An important component of treatment failure in gastric cancer (GC) is cancer dissemination within the peritoneal cavity and nodal metastasis. Intraperitoneal chemotherapy (IPC) is considered to give a fundamental contribute in treating advanced GC. The purpose of the study is to investigate the effects of IPC in patients with advanced GC. MATERIAL AND METHODS: A systematic review with meta-analysis of randomized controlled trials (RCTs) of IPC + surgery vs. control in patients with advanced GC was performed. RESULTS: Twenty prospective RCTs have been included (2145 patients: 1152 into surgery + IPC arm and 993 into control arm). Surgery + IPC improves: 1, 2 and 3-year mortality (OR = 0.31, 0.27, 0.29 respectively), 2 and 3-year mortality in patients with loco-regional nodal metastasis (OR = 0.28, 0.16 respectively), 1 and 2-year mortality rate in patients with serosal infiltration (OR = 0.33, 0.27 respectively). Morbidity rate was increased by surgery + IPC (OR = 1.82). The overall recurrence and the peritoneal recurrence rates were improved by surgery + IPC (OR = 0.46 and 0.47 respectively). There was no statistically significant difference in lymph-nodal recurrence rate. The rate of haematogenous metastasis was improved by surgery + IPC (OR = 0.63). CONCLUSIONS: 1, 2 and 3-year overall survival is incremented by the IPC. No differences have been found at 5-year in overall survival rate. 2 and 3-year mortality rates in patients with nodal invasion and 1 and 2-year mortality rates in patients with serosal infiltration are improved by the use of IPC. IPC has positive effect on peritoneal recurrence and distant metastasis. Morbidity rate is incremented by IPC. Loco-regional lymph-nodes invasion in patients affected by advanced gastric cancer is not a contraindication to IPC.

Surgical results of patients with peritoneal carcinomatosis treated with cytoreductive surgery using a new technique named aqua dissection.

During 2004 to 2011, 81, 420, and 166 patients with colorectal cancer (CRC), epithelial appendiceal neoplasm (APN), and gastric cancer (GC) with PC were treated with cytoreductive surgery (CRS) plus perioperative chemotherapy. CRS was performed by peritonectomy techniques using an aqua dissection. Results. Complete cytoreduction was done in 62/81 (76.5%), 228/420 (54.3%), and 101/166 (60.8%) of patients with CRC, APN, and GC. The main reasons of incomplete resections were involvement of all peritoneal regions and diffuse involvement of small bowel. The incidence (64%, 302/470) of CC-0 resection after introduction of an aqua dissection was significantly higher than before (42%, 82/197). A total of 41 (6.1%) patients died postoperatively. Major complication (grade 3-4 complications) occurred in 126 patients (18.9%). A reoperation was necessary in 36 patients (5.4%). By the multivariate analysis, PCI scores capable of serving as thresholds for favorable versus poor prognosis in each group and CC scores demonstrated as the independent prognostic factors. Conclusions. Peritonectomy using an aqua dissection improves the incidence of complete cytoreduction, and improves the survival of patients with PC. Patients with PCI larger than the threshold values should be treated with chemotherapy to improve the incidences of complete cytoreduction.

Surgical treatment for peritoneal carcinomatosis from gastric cancer.

This review describes the latest surgical treatments for peritoneal carcinomatosis (PC) arising from gastric cancer. Systemic chemotherapy is less effective against PC because of the existence of the blood-peritoneal barrier. Accordingly, perioperative intraperitoneal chemotherapy plus cytoreductive surgery (CRS) is a new trend of multidisciplinary therapy for PC. Intraperitoneally administered drugs penetrate directly into the peritoneal dissemination, resulting in the high loco-regional intensity of drugs. A new bidirectional chemotherapy called neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) has been developed. After NIPS, the disappearance of PFCCs has been reported, and the incidence of complete cytoreduction has increased accordingly. Complete cytoreduction, a low peritoneal carcinomatosis index, and negative PFCCs are significant favorable prognostic factors. Hyperthermic intraperitoneal chemotherapy (HIPEC) after CRS is associated with improved survival with an acceptable postoperative mortality and morbidity. Early postoperative intraperitoneal chemotherapy (EPIC) has also contributed to improving survival after CRS.

Deceleration of regenerative response improves the outcome of rat with massive hepatectomy.

Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS-398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS-398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS-398 treatment. In the 90% PH model, administration of NS-398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver.

Estimation of standard liver volume for Japanese adults.

INTRODUCTION: Accurate pretransplant estimation of the recipient's standard liver volume (SLV) is important. The purpose of this study was to compare reported formulas for clinical estimation of liver volume among Japanese adults. METHODS: We reviewed data on 70 healthy adults (46 men, 24 women, ages 20 to 65 years old) evaluated for living donor liver transplantation. Liver volume (LV) was measured using two- or three-dimensional computed tomography volumetry (CTV). The formulas of DeLand (LV = 1020 x body surface area [BSA] - 220), Urata (LV = 706.2 x BSA + 2.4), Noda (LV = 50.12 x BW(0.78)), Heinemann (LV = 1072.8 x BSA - 345.7), Vauthey (LV = 18.51 x BW + 191.8) and Yoshizumi (LV = 772 x BSA) were applied to estimate LV. We calculated the differences for individual donors betwen CTV and LV estimated by each formula. RESULTS: Mean LVs as estimated by the formulae of DeLand and Heinemann et al were significantly greater (P < .01) than the mean CTV, while LV estimated by the formula of Urata was significantly less (P < .05) than the CTV. The formulas of DeLand and Heinemann overestimated LV, while the formula of Urata underestimated it. The formulae of Noda et al and Yoshizumi et al tended to underestimate the LV when the CTV was greater than 1600 cm(3). When the Yoshizumi formula was applied, the number of donors with an acceptable difference (+/-15%) between CTV and estimated LV was 55 (78.6%). CONCLUSIONS: The Yoshizumi formula was applicable, especially for patients with a BSA < 2.0, whereas the well-known Urata formula made LV underestimates.

Metastasis in para-aortic lymph nodes in patients with advanced gastric cancer, treated with extended lymphadenectomy.

BACKGROUND/AIMS: Lymph node dissection is an essential component of curative resection for advanced gastric cancer. To improve the survival of N2 patients, Asian surgeons have been performing D2+para-aortic lymph node dissection. The current study presents the results of lymph node status from multicenter trial of D2 and D2 + para-aortic nodal (No.16) dissection (D4 dissection). METHODOLOGY: Patients enrolled in the study had potentially curable gastric adenocarcinoma in an advanced stage, T2, T3 or T4/N1 or N2. Patients were randomized to undergo either D2 or D4 gastrectomy. RESULTS: Two hundred and seventy patients were registered and 136 and 134 patients were allocated into the D2 or D4 group, respectively. The average nodal yield of No.16 in D4 group was 18.4 +/- 14.1, ranging from 2 to 84. No.16 metastasis was detected in 12 (9.0%) of 134 D4 patients. One, 9 and 2 patients had simultaneous involvement in N1, N2, and N3 (No.8p, 12, 13 or 14). Namely, in 39 patients who were diagnosed as N2 from the lymph node status in N1 and N2 levels, nine (23.0%) patients had No.16 metastasis. The stage migration by D4 was found in 10 (7.5%). Logistic regression analysis revealed that the stations of No.7 and No.8 were the significant predictors of No.16 involvement. CONCLUSIONS: The present study may strongly suggest that prophylactic D4 dissection may be indicated for patients with N2 involvement, and that No.7 and No.8 are the junctional nodes for D4 dissection.