{'fraction_non_alphanumeric': 0.039268064645385334, 'fraction_numerical': 0.032589822358755176, 'mean_word_length': 4.9904, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Survival analysis following resection of AJCC stage III gallbladder carcinoma based on different combinations of T and N stages

Backgrounds/Aims According to 7th AJCC TNM staging system, gallbladder carcinoma (GBC) with lymph node (LN) metastasis is classified as N1 or N2; thus making the stage IIIB (N1) or IVB (N2). Stage IIIB consists of N1 status with wide coverage of T1-3, but T3N1 group often showed poorer outcomes than T1-2N1 groups. This study intended to assess post-resection prognosis of T3N1 versus other stage III subgroups. Methods We selected 103 patients from our institutional database of GBC who underwent R0 resection between July 1996 and June 2009 and whose GBC was confined to stage T3N0, T1-3N1 or T1-3N2. These patients were stratified into five groups, namely, T3N0 (n=26), T1N1 (n=13), T2N1 (n=35), T3N1 (n=20) and T1-3N2 (n=9), and were followed for ≥5 years or until death. Results Surgical procedures were minor liver resection (n=53), minor liver resection with bile duct resection (n=23), major liver resection (n=12), major liver resection with bile duct resection (n=5), and hepatopancreatoduodenectomy (n=12). Mean follow-up period was 57.2±68.5 months. Overall 5-year survival rate based on all-cause death and cancer-associated death, respectively, was 57.7% and 60.6% in T3N0, 15.4% and 15.4% in T1N1 (n=13), 28.6% and 28.6% in T2N1 (n=35), 5.0% and 5.7% in T3N1 (n=20), and 22.2% and 22.2% in T1-3N2. The survival outcome of T3N1 group was the poorest among the four stage III groups and was comparable to that of stage IVB (p=0.53). Conclusions The prognosis of T3N1 GBC is unusually poor even after R0 resection, thus we suggest extensive LN dissection may be necessary in patients with T3 tumors for accurate prognostic evaluation and radical removal of potential nodal micrometastasis. Further validation of this result is necessary in large patient populations from multiple centers.


INTRODUCTION
Gallbladder carcinoma (GBC) is a relatively rare malignancy and its prognosis depends primarily on the extent of tumor and the possibility of curative surgical resection.
Due to the anatomical proximity of the gallbladder to the liver and other organs and to the unique patterns of tumor cell spread, resection for advanced GBC requires aggressive surgical approaches. [1][2][3][4] For stage T2 or more advanced tumors, radical resection includes partial hepatectomy and wide lymph node (LN) dissection, with or without bile duct resection.
To estimate the survival outcomes after curative re-section of GBC, several staging systems were proposed.
The American Joint Committee on Cancer (AJCC) staging system, which differentiates GBC based on the depth of invasion (T stage), LN metastasis (N stage) and distant metastasis (M stage), has been widely adopted. According to the 7th edition of the AJCC TNM staging system for GBC, LNs are divided into hilar LNs (N1) and other regional LNs (N2) and thus the presence of LN metastasis divides the tumor stage into IIIB (N1) and IVB (N2). 5 In GBC of stage IIIB, the LN status becomes the most important prognostic factor with wide coverage of stage

Data analysis and statistics
The primary endpoint of this study was overall patient

Clinicopathological profiles
The mean age was 61.6±10.0 years (range, 35-84) and female gender was predominant (n=67, 65.1%). According to the 7th AJCC TNM staging system, the T stages of the primary tumors were pT1 in 14 patients, pT2 in 28 patients, and pT3 in 51 patients. LN stages were pN0 in 26 patients, pN1 in 68 patients, and N2 in 9 patients.
The clinicopathological profiles of the five groups are presented in Table 1. The surgical procedures were minor liver resection (n=51), minor liver resection with bile duct resection (n=23), major liver resection (n=12), major liver resection with bile duct resection (n=5), and hepatopancreatoduodenectomy (n=12).    The overall survival curves based on GBC-related death are depicted in Fig. 2

DISCUSSION
Nodal tumor cell spread is the most common form of progression of GBC, and LN status is an important predictor of survival after resection. [9][10][11][12] In the 7th AJCC TNM staging system, LN classification was changed to distinguish hilar nodes (N1: LNs adjacent to the cystic duct, bile duct, hepatic artery and portal vein) from other regional nodes (N2: celiac, periduodenal and peripancreatic LNs and those along the superior mesenteric artery). 6 This change might reflect the uniquely poor survival outcomes of patients with regional LN metastasis beyond the mid portion of the hepatoduodenal ligament.
In contrast to the 7th AJCC staging system, the At this time, we presume that occult metastasis or micrometastasis may have been present in remote regional LNs at the time of surgery. [15][16][17] Sasaki et al. 15  Aggressive resection may improve long-term survival, even in patients with far advanced GBC. 18 Radical re-section should not be abandoned for patients with para-aortic LN metastasis in biliary adenocarcinoma. 19 However, unlike bile duct cancers, the survival outcome of GBC patients with N2 nodal metastasis has been usually dismal despite aggressive surgery, thus M1 nodal metastasis may not be indicated for aggressive resection. 20 By contrast, adjuvant chemoradiotherapy improves overall survival in patients with advanced GBC having undergone resection. [21][22][23] The survival of the T1-2N1 subgroup is relatively favorable after aggressive resection, probably because extensive LN dissection may provide the curative removal of overt LN metastasis and potential micrometastasis.
However, with regards to the poor survival of the T3N1 subgroup, we presume that the extent of LN dissection routinely performed may not be sufficient to remove all of the tumor cell spreads in the regional LNs. [15][16][17] Therefore, we suggest that more extensive LN dissection is necessary for T3 GBC tumors than for T1-2 tumors.
Extensive resection, including resection of the duodenum and pancreatic head, is effective in selected patients with up to N2 lymph node metastasis as long as complete removal of the cancer can be achieved. 24 In our study, hepatopancreatoduodenectomy was performed to obtain tumor-free resection margins or to remove peripancreatic nodes in 12 patients, among whom 10 had T3 tumors.
The present study has several limitations. First, this is a retrospective single-center study and thus the results may not be generalizable. In addition, some cases of N2 metastasis might have been underestimated and classified as N1 metastasis because LN classification was retrospectively redefined according to the 7th AJCC staging system. By contrast, a uniquely strong point of this study is that the survival status of all of the patients was nearly completely traced through the assistance of National Health Insurance Service. By contrast, this approach focused on survival status did not provide complete follow-up information regarding tumor recurrence and thus lack of tumor recurrence analysis becomes the weak point of this study.
In conclusion, the results of our study demonstrate that the prognosis of patients with T3N1 GBC is unusually poor and similar to that of N2 lesions. We suggest extensive LN dissection is necessary for GBC patients with T3 tumor for accurate prognostic evaluation and radical removal of potential nodal micrometastasis. Further validation of our result is necessary in large patient populations from multiple centers.