Background The purpose of the present study is to investigate the utility of prognostic nutritional index (PNI) as a simple and readily available marker in esophageal squamous cell carcinoma (ESCC). Methods We retrospectively analyzed 169 patients who underwent potentially curative esophagectomy, for histo- logically veriﬁed ESCC. We decided to set the optimal cutoff value for preoperative PNI levels at 49.2, based on the cancer-speciﬁc survival (CSS) and the overall survival (OS) by receiver operating characteristic curve analysis. Results Multivariate logistic regression analysis identiﬁed that TNM pStage III [hazard ratio (HR) 3.261, p \ 0.0001] and PNI \ 49.2 (HR 3.887, p\ 0.0001) were conﬁrmed as independent poor predictive factors for CSS, and age [70 (HR 2.024, p\ 0.0042), TNM pStage III (HR 2.510, p = 0.0002), and PNI \ 49.2 (HR 2.248, p = 0.0013) were conﬁrmed as independent poor predictive factors for OS. In non-elderly patients, TNM pStage III (CSS; HR 3.488, p \ 0.0001, OS; HR 2.615, p = 0.0007) and PNI \ 49.2 (CSS; HR 3.849, p \ 0.0001, OS; HR 2.275, p = 0.001) were conﬁrmed as independent poor predictive factors for CSS, and OS when multivariate logistic regression analysis was applied. But in elderly patients, univariate analyses demonstrated that the TNM pStage III was the only signiﬁcant risk factor for CSS (HR 3.701, p = 0.0057) and OS (HR 1.974, p = 0.0224). Conclusions The PNI was a signiﬁcant and independent predictor of CSS and OS of ESCC patients after curative esophagectomy. The PNI was cost-effective and readily available, and it could act as a marker of survival. Introduction treatments, despite improvements in surgical techniques and perioperative care with reduced perioperative mortality Esophageal cancer is a disease of the elderly, with peak after esophagectomy. Therefore, there is a continuing incidence occurring in patients in their 70 s, and the elderly interest in prognostic factors to identify patients who are at population is rapidly increasing in worldwide. Early greater risks of recurrence in order to better tailor indi- detection and treatment confers the greatest chance of long- vidual treatments to those who are more likely to beneﬁt term survival in patients with esophageal cancer. However, from them. Progression and prognosis of cancer has been a common problem among esophageal cancer patients shown to be impacted by both the tumor features as well as (especially the elderly) is low tolerance to the available the patient’s nutritional and immunologic status [1, 2]. Several screening tools are now available for assessing the preoperative nutritional status of patients with cancer, & Noriyuki Hirahara including the subjective global assessment, nutritional risk email@example.com scoring 2002, body mass index, Glasgow Prognostic Score, and prognostic nutritional index (PNI) [3–6]. Many studies Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, have addressed the association between preoperative Shimane 693-8501, Japan 123 2200 World J Surg (2018) 42:2199–2208 nutritional status and postoperative outcomes. However, surgery with an elevation of the gastric conduit to the neck there is little data to show the impact of nutritional status via the posterior mediastinal approach or retrosternal on long-term outcomes in patients undergoing radical approach with an end-to-end anastomosis of the cervical thoracoscopic esophagectomy for esophageal squamous esophagus and gastric conduit. The patients’ clinical cell carcinoma (ESCC) [7, 8]. characteristics, laboratory data, treatment regimen, and The PNI was originally developed to predict the risk of pathological data were obtained from their medical postoperative morbidity and mortality after gastrointestinal records. None of the patients had clinical signs of infection surgery . However, the method for calculating PNI is or other systemic inﬂammatory conditions preoperatively. complicated and difﬁcult to use routinely in clinical prac- In this study, we excluded patients who had received pre- tice. In contrast, the simpliﬁed PNI proposed by Onodera or postoperative adjuvant chemotherapy and/or et al.  can be easily measured because it is based on only radiotherapy. two laboratory parameters, namely the serum albumin level We introduced a perioperative multidisciplinary man- and the peripheral blood lymphocyte count. Albumin is a agement team, including surgeon, anesthesiologist, dental widely used parameter of nutrition, and its levels have been hygienist doctor, pharmacist, nutritionist, and rehabilitation shown to correlate well with postoperative complications technician, and certiﬁed expert surgical nurse, which aimed and long-term outcomes in several malignancies . to decrease the incidence rate of postoperative complica- Similarly, reduced lymphocyte count and function also tions. This team mainly managed dental cleaning, medi- correlate with poor prognosis, by enabling cancer cells to cation assistance, physical exercise and rehabilitation, escape immune surveillance . PNI, therefore, is a respiratory training, and nutritional support. We provided favorable indicator and is more reﬂective of the overall preoperative enteral nutrition to optimize preoperative status of cancer patients. condition as possible. In the management of cancer patients, there has been a The severity of postoperative complications was evalu- continuing interest in preoperative prognostic indicators ated according to the Clavien–Dindo classiﬁcation, and that can allow more accurate patient stratiﬁcation, precise grade II or higher was recorded as a postoperative com- clinical decision-making, and improvement of short- and plication . long-term outcomes. The TNM classiﬁcation is widely We evaluated cancer-speciﬁc survival (CSS) and overall used as a good standard prognostic indicator of patients survival (OS) as the endpoints of the study. The observa- with cancer . However, since it includes pathological tion period started from the day of the operation and lasted ﬁndings of the tumor, a conclusive classiﬁcation can only for up to 5 years, loss to follow-up, withdrawal of consent, be made postoperatively. In contrast, the PNI is based on or until death. CSS was deﬁned as the interval from the the preoperative laboratory data alone and could be a date of operation to the date of cancer-speciﬁc death or the comprehensive indicator of postoperative morbidity, mor- last follow-up. Two patients who died of myocardial tality, and prognosis of cancer patients prior to surgery. infarction within 60 days after esophagectomy were Therefore, we have demonstrated the prognostic sig- excluded from the analysis. We deﬁned ‘elderly’ patients niﬁcance of the simpliﬁed PNI in overall and age-stratiﬁed as those aged 70 years or older and ‘non-elderly’ as those ESCC patients with a low versus high PNI, and evaluated aged less than 70 years of age . its potential as a useful surrogate marker for predicting Permission to perform this retrospective study was postoperative patient survival. obtained from the ethical board of our institution and the study was conducted in accordance with the Declaration of Helsinki. Methods Preoperative calculation of the PNI and its cutoff Patients value We retrospectively reviewed a database containing data The preoperative PNI was calculated using the following from 169 patients who underwent potentially curative formula: 10 9 serum albumin (g/dl) ? 0.005 9 total esophagectomy with R0 resection, for histologically veri- lymphocyte count (per mm ) in peripheral blood . ﬁed ESCC in our institute, between January 2006 and The receiver operating characteristics (ROC) curve of December 2015. R0 resection was deﬁned as complete preoperative PNI levels was generated for multiple logistic tumor removal without the involvement of any microscopic regression analysis using CSS and OS. The area under the resection margin. Video-assisted or thoracoscopic subtotal curve (AUC) estimation was used to assess the predictive esophagectomy with three-ﬁeld lymph node dissection was ability of the PNI. performed for all patients, followed by laparoscopic gastric 123 World J Surg (2018) 42:2199–2208 2201 We decided to set the optimal cutoff value for preop- All statistical analyses were performed using the sta- erative PNI levels at 49.2 in this study, based on the CSS tistical software JMP (version 11 for Windows; SAS (sensitivity: 52.99%; speciﬁcity: 80.77%; AUC of the ROC Institute, Cary, NC), and p values \0.05 were considered curve: 0.653) and the OS (sensitivity: 52.63%; speciﬁcity: statistically signiﬁcant. 70.27%; AUC of the ROC curve: 0.6132) at 5 years after surgery (Fig. 1). Based on their PNI values, patients were categorized as having a high PNI (49.2 or greater) or as Results having a low PNI (less than 49.2). Relationship between PNI and clinicopathological TNM pathological Stage (pStage) features The pathological classiﬁcation of the primary tumor, the The correlation between the PNI and clinicopathological degree of lymph node involvement, and the presence of parameters in the 169 patients enrolled in this study is organ metastasis were determined according to the TNM summarized in Table 1. The preoperative mean value of classiﬁcation system (7th edition of the cancer staging the PNI in this study was 47.3 ± 6.2, ranging from 26.8 to manual of the American Joint Committee on Cancer) . 65.7. Based on the cutoff value of 49.2, 98 patients (58%) were in the low PNI category and 71 patients (42%) were Statistical analysis in the high PNI category. The results of our analysis showed that the PNI value correlated signiﬁcantly with The mean and standard deviation were calculated, and the lymphocyte count (p \ 0.0001), tumor size (p = 0.0327), differences were analyzed using Student’s t test. Differ- depth of tumor (p\ 0.0001), TNM pStage (p = 0.0005), ences between the various clinicopathological features SCC antigen level (p = 0.0072), albumin level were analyzed using the Chi-square test. The CSS was (p\ 0.0001), and CRP level (p = 0.0012). analyzed using Kaplan–Meier statistics, and inter-group differences were assessed using the log-rank test. Prognostic factors for postoperative survival Univariate analyses were performed to determine vari- in patients with ESCC ables associated with CSS. Variables with p values \ 0.05 in the univariate analyses were included in a multivariate Univariate analyses identiﬁed advanced TNM pStage logistic regression analysis. The potential prognostic fac- [hazard ratio (HR), 4.170; 95% conﬁdence interval (CI), tors assessed were as follows: age (\70 vs. C70 years), sex 2.377–7.525; p\ 0.0001], large tumor size (HR 1.854; (female vs. male), TNM pStage (I/II vs. III), tumor size (\3 95% CI 1.093–3.678; p = 0.0233), prolonged operation vs. C3 cm), operation time (\600 vs. C600 min), intra- time (HR 1.756; 95% CI 1.012–3.035; p = 0.0452), and operative blood loss (\500 vs. C500 mL), serum squamous low PNI (HR 4.566; 95% CI 2.375–9.674; p \ 0.0001) as cell carcinoma antigen (SCC) value (\1.5 vs. C1.5), and signiﬁcant risk factors for shorter CSS. The TNM pStage PNI (\49.2 vs. C49.2). (HR 3.261; 95% CI 1.808–6.043; p\ 0.0001) and PNI (HR 3.887; 95% CI 1.999–8.309; p\ 0.0001) were Fig. 1 Receiver operating (a) 1.0 (b) 1.0 curves for postoperative survival were plotted to verify the optimum cutoff value for 0.8 0.8 PNI. a cancer-speciﬁc survival, b overall survival 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity 1-Specificity Sensitivity Sensitivity 2202 World J Surg (2018) 42:2199–2208 Table 1 Relationships between PNI and clinicopathological features in 169 patients with esophageal cancer Characteristics Total patients PNI \49.2 C49.2 p value (n = 98) (n = 71) Age (years) 67.1 ± 8.2 65.4 ± 8.0 0.1804 Sex 0.628 Male 150 86 64 Female 19 12 7 WBC 5830.0 ± 2404.6 6233.9 ± 1616.6 0.2209 Neutrophil 3773.6 ± 2197.3 3669.2 ± 1264.6 0.7199 Lymphocyte 1396.4 ± 562.7 1931.8 ± 599.2 \0.0001 Platelet 232.8 ± 75.5 225.5 ± 50.2 0.4796 Location of tumor 0.0696 Ce 13 12 1 Ut 10 6 4 Mt 73 39 34 Lt 59 31 28 Ae 14 10 4 Tumor size (mm) 5.27 ± 4.98 3.88 ± 2.53 0.0327 Depth of tumor \0.0001 T1a–1b 72 27 45 213 8 5 367 48 19 4a–4b 17 15 2 Lymph node metastasis 0.1573 N089 49 40 N148 28 20 N218 9 9 N314 12 2 Pathological stage 0.0005 1a–1b 62 24 38 2a–2b 39 28 11 3a–3c 68 46 22 Operation time (min) 656.1 ± 196.1 646.7 ± 158.6 0.7391 Intraoperative blood loss (ml) 665.5 ± 601.2 580.0 ± 612.3 0.3666 SCC antigen 1.67 ± 2.04 0.97 ± 0.85 0.0072 Albumin 3.64 ± 0.43 4.32 ± 0.30 \0.0001 CRP 0.658 ± 1.098 0.217 ± 0.314 0.0012 conﬁrmed as independent prognostic factors for CSS when 2.248; 95% CI 1.362–3.832; p = 0.0013) were conﬁrmed multivariate logistic regression analysis was applied as independent prognostic factors for OS in multivariate (Table 2). logistic regression analysis (Table 3). Univariate analyses identiﬁed advanced age (HR 1.930; 95% CI 1.205–3.061; p = 0.0066), advanced TNM pStage Prognostic factors for postoperative survival in non- (HR 2.725; 95% CI 1.714–4.349; p \ 0.0001), large tumor elderly patients with ESCC size (HR 1.868; 95% CI 1.149–3.141; p = 0.0112), and low PNI (HR 2.612; 95% CI 1.600–4.405; p \ 0.0001) as Among 110 non-elderly patients, univariate analyses signiﬁcant risk factors for shorter OS. The age (HR 2.024; identiﬁed advanced TNM pStage (HR 4.646; 95% CI 95% CI 1.255–3.236; p = 0.0042), TNM pStage (HR 2.281–10.027; p \ 0.0001), large tumor size (HR 2.872; 2.510; 95% CI 1.555–4.064; p = 0.0002), and PNI (HR 95% CI 1.349–6.825; p = 0.0054), and low PNI (HR 123 World J Surg (2018) 42:2199–2208 2203 Table 2 Prognostic factors for cancer-speciﬁc survival in patients with esophageal cancer Variables Patients (n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.14 0.499–3.290 0.7765 Age 59/110 (\70/C70) 1.42 0.790–2.480 0.2344 TNM pStage 101/68 (1,2/3) 4.17 2.377–7.525 \0.0001 3.261 1.808–6.043 \0.0001 Tumor size 64/105 (\3/C3) 1.854 1.093–3.678 0.0233 1.076 0.583–2.079 0.8203 Operation time 111/58 (\600/C600) 1.756 1.012–3.035 0.0452 1.595 0.910–2.786 0.1024 Intraoperative blood loss 87/82 (\500/C500) 0.973 0.562–1.685 0.9226 PNI 98/71 (C49.2/\49.2) 4.566 2.375–9.674 \0.0001 3.887 1.999–8.309 \0.0001 SCC 126/43 (\1.5/C1.5) 1.169 0.584–2.171 0.6425 Table 3 Prognostic factors for overall survival in patients with esophageal cancer Variables Patients(n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.12 0.550–2.687 0.773 Age 59/110 (\70/C70) 1.93 1.205–3.061 0.0066 2.024 1.255–3.236 0.0042 TNM pStage 101/68 (1,2/3) 2.725 1.714–4.349 \0.0001 2.51 1.555–4.065 0.0002 Tumor size 64/105 (\3/C3) 1.868 1.149–3.141 0.0112 1.219 0.7364–2.083 0.5582 Operation time 111/58 (\600/C600) 1.481 0.9288–2.344 0.0981 Intraoperative blood loss 87/82 (\500/C500) 1.308 0.825–2.098 0.2541 PNI 98/71 (C49.2/\49.2) 2.612 1.600–4.405 \0.0001 2.248 1.362–3.832 0.0013 SCC 126/43 (\1.5/C1.5) 1.589 0.934–2.609 0.0859 11.370; 95% CI 4.040–47.500; p \ 0.0001) as signiﬁcant PNI (HR 3.671; 95% CI 1.864–7.897; p = 0.0001) as risk factors for shorter CSS. The TNM pStage (HR 3.488; signiﬁcant risk factors for shorter OS. The TNM pStage 95% CI 1.948–6.424; p \ 0.0001) and PNI (HR 3.849; (HR 2.615; 95% CI 1.430–3.768; p = 0.0007) and PNI 95% CI 1.987–8.205; p\ 0.0001) were conﬁrmed as (HR 2.275; 95% CI 1.384–3.863; p = 0.001) were con- independent prognostic factors for CSS when multivariate ﬁrmed as independent prognostic factors for OS in multi- logistic regression analysis was applied (Table 4). variate logistic regression analysis (Table 5). Univariate analyses identiﬁed advanced TNM pStage (HR 3.772; 95% CI 2.027–7.234; p \ 0.0001), large tumor size (HR 2.539; 95% CI 1.315-5.298; p = 0.0050), and low Table 4 Univariate and multivariate analysis of cancer-speciﬁc survival in 110 non-elderly patients with esophageal cancer Variables Patients Category or Univariate Multivariate (n = 110) characteristics HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 0.865 0.307–3.612 0.8142 TNM pStage 64/46 (1,2/3) 4.646 2.281–10.027 \0.0001 3.488 1.948–6.424 \0.0001 Tumor size 44/66 (\3/C3) 2.872 1.349–6.825 0.0054 1.115 0.607–2.149 0.7313 Operation time 74/36 (\600/C600) 1.636 0.307–1.234 0.1664 Intraoperative blood 55/55 (\500/C500) 1.176 0.591–2.371 0.6437 loss PNI 61/49 (C49.2/\49.2) 11.37 4.040–47.500 \0.0001 3.849 1.987–8.205 \0.0001 SCC 83/27 (\1.5/C1.5) 1.307 0.516–2.914 0.5471 123 2204 World J Surg (2018) 42:2199–2208 Table 5 Univariate and multivariate analysis of overall survival in 110 non-elderly patients with esophageal cancer Variables Patients (n = 110) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 1.08 0.390–4.478 0.8968 TNM Stage 64/46 (1,2/3) 3.772 2.027–7.234 \0.0001 2.615 1.430–3.768 0.0007 Tumor size 44/66 (\3/C3) 2.539 1.315–5.298 0.005 1.281 0.769–2.202 0.3477 Operation time 74/36 (\600/C600) 1.254 0.661–2.320 0.4803 Intraoperative blood loss 55/55 (\500/C500) 1.524 0.822–2.911 0.1821 PNI 61/49 (C49.2/\49.2) 3.671 1.864–7.897 0.0001 2.275 1.384–3.863 0.001 SCC 83/27 (\1.5/C1.5) 1.515 0.697–3.028 0.2787 Prognostic factors for postoperative survival PNI and postoperative survival in all patients in elderly patients with ESCC with ESCC In 59 elderly patients, univariate analyses demonstrated Kaplan–Meier analysis and the log-rank test demonstrated that the TNM pStage was the only signiﬁcant risk factor for that patients with a low PNI had a signiﬁcantly worse shorter CSS and OS (HR 3.701; 95% CI 1.470–9.743; prognosis in terms of CSS and OS than those with a high p = 0.0057, HR 1.974; 95% CI 0.938–4.038; p = 0.0224, PNI (p\ 0.0001, and p = 0.0003, respectively). The respectively) (Table 6). 5-year CSS rates were 46.5 and 84.2%, and the 5-year OS rates were 38.3 and 74.1% for patients with a low PNI and a high PNI, respectively (Fig. 2). Table 6 Univariate and multivariate analysis of cancer-speciﬁc survival and overall survival in 59 elderly patients with esophageal cancer Variables Patients (n = 59) Category or characteristics Cancer-speciﬁc survival Overall survival Univariate Univariate HR 95% CI p value HR 95% CI p value Gender 8/51 (Female/male) 1.85 0.526–11.717 0.3755 1.577 0.615–5.349 0.37 TNM pStage 37/22 (1,2/3) 3.701 1.470–9.743 0.0057 1.974 0.938–4.038 0.0224 Tumor size 20/39 (\3/C3) 0.973 0.390–2.623 0.9542 1.073 0.526–2.313 0.8507 Operation time 37/22 (\600/C600) 1.909 0.768–4.815 0.1614 1.731 0.859–3.491 0.1235 Intraoperative blood loss 32/27 (\500/C500) 0.689 0.265–1.714 0.4235 1.023 0.506–2.088 0.9493 PNI 37/22 (C49.2/\49.2) 1.68 0.655–4.679 0.2838 1.748 0.845–3.784 0.1333 SCC 43/16 (\1.5/C1.5) 1.218 0.387–3.287 0.715 2.003 0.909–4.214 0.0828 Fig. 2 Kaplan–Meier curves of (a) (b) 1.0 1.0 postoperative survival based on PNI in 169 patients with ESCC. 0.8 0.8 a cancer-speciﬁc survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=71) 0.2 PNI 49.2 (n=71) 0.2 PNI <49.2 (n=98) PNI <49.2 (n=98) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival World J Surg (2018) 42:2199–2208 2205 PNI and postoperative survival in non-elderly low versus high PNI. Similarly, there were no signiﬁcant patients with ESCC differences in postoperative hospital stay (data not shown). Kaplan–Meier analysis and the log-rank test demonstrated that patients with a low PNI had a signiﬁcantly worse Discussion prognosis in terms of CSS and OS than those with a high PNI (p\ 0.0001, and p = 0.0003, respectively). The Treatment strategies for ESCC include surgery, radiation, 5-year CSS rates were 44.1, and 92.8% and the 5-year OS chemotherapy, or a combination thereof. Although a rates were 41.5 and 84.8% for patients with a low PNI and complete surgical resection of the tumor offers a chance for a high PNI, respectively (Fig. 3). cure, the rate of disease recurrence is very high in ESCC even after an aggressive surgery. Histopathology of surgi- PNI and postoperative survival in elderly patients cal specimens is widely used to estimate the prognosis after with ESCC surgery ; however, its predictive value is still limited. The precise evaluation of the risk of postoperative recur- Kaplan–Meier analysis and the log-rank test showed no rence is important in planning a customized risk-adapted signiﬁcant relationship between PNI and CSS (p = 0.1398) therapeutic strategy for individual patients. In particular, or OS (p = 0.1907) in elderly patients with ESCC (Fig. 4). identifying prognostic factors prior to surgery is important to determine the optimal preoperative therapy, and to PNI and postoperative complications improve postoperative short- and long-term outcomes . The original PNI consists of tests measuring albumin, The postoperative complications in the high and low PNI transferrin, triceps skin fold, and skin sensitivity reaction to groups are shown in Table 7. No signiﬁcant differences in common antigens , and it was developed to assess the incidence rates of postoperative complication were perioperative complications, including anastomotic leak- observed between overall and age-stratiﬁed patients with a age, delayed tissue repair, and length of hospital stay in patients undergoing gastrointestinal surgery [11, 18]. The Fig. 3 Kaplan–Meier curves of (a) (b) 1.0 1.0 survival based on PNI in 110 non-elderly patients with ESCC. 0.8 0.8 a Cancer-speciﬁc survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=49) PNI 49.2 (n=49) 0.2 0.2 PNI <49.2 (n=61) PNI <49.2 (n=61) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Fig. 4 Kaplan–Meier curves of (a) (b) survival based on PNI in 59 1.0 1.0 elderly patients with ESCC. a Cancer-speciﬁc survival, 0.8 0.8 b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=22) PNI 49.2 (n=22) 0.2 0.2 PNI <49.2 (n=37) PNI <49.2 (n=37) P=0.1398 P=0.1907 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival Cumulative survival Cumulative survival 2206 World J Surg (2018) 42:2199–2208 simpliﬁed PNI, on the other hand, consists of only two laboratory parameters, namely serum albumin concentra- tion and total lymphocyte count in the peripheral blood , both of which are measured routinely in clinical practice. Recently, several studies have reported that albumin is produced by hepatocytes and is regulated by pro-inﬂam- matory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-a (TNF-a) that adversely affect catabolic metabolism [19–21]. These cytokines produced by either the tumor itself or the host are crucial for car- cinogenesis, cancer progression, and neo-angiogenesis. In addition, albumin has been shown to help stabilize cell growth and DNA replication, buffer a variety of bio- chemical changes and maintain sex hormone homeostasis to protect against tumorigenesis . Albumin, therefore, is reﬂective of the inﬂammation and immune status of cancer, although it alone is not sufﬁcient to predict the ﬁnal outcome in cancer patients. Another element of the sim- pliﬁed PNI is the lymphocyte count. Lymphocytes are one of the fundamental components of cell-mediated immunity with inhibitory effects on the proliferation and invasion of tumor cells via cytokine-mediated cytotoxicity [11, 22]. Most patients with ESCC are malnourished, either due to poor dietary intake, protein loss from the primary lesion or due to catabolic metabolism . Impaired nutritional and immunologic status accelerates tumor progression due to a decline in tumor immunity [16, 22]. The PNI is, therefore, a comprehensive indicator of the nutritional and immuno- logic status in cancer patients . In this study, we evaluated the potential of simpliﬁed PNI as a prognostic marker of CSS and OS in ESCC patients who underwent radical thoracoscopic esophagec- tomy. Patients with a low PNI (less than 49.2) showed a signiﬁcantly shorter CSS and decreased OS in comparison with patients who had a high PNI (49.2 or greater). This is consistent with our ﬁnding that PNI is inversely related to the stage of cancer, the value being lower in patients with a larger, deeper and more aggressive tumor at an advanced TNM pStage . Recent studies have also demonstrated an association between the occurrences of postoperative complications with deteriorated CSS in patients with gas- trointestinal cancer [26, 27]. Patients with a low PNI are, therefore, more likely to develop postoperative complica- tions [11, 17, 18], including a systemic inﬂammatory response, which can also contribute to the decreased CSS and OS. However, this correlation between PNI and CSS/ OS was found only in non-elderly patients and not in the elderly patients. This difference could be due to the fact that irrespective of being a cancer patient or not, hypoal- buminemia and leukocytopenia are often associated with aging, leading to malnutrition and immune suppression . Previous studies have reported that cancer patients experiencing postoperative complications generally have a Table 7 Comparison between postoperative complications and PNI Overall patients PNI Non-elderly patients PNI Elderly patients PNI \49.2 C49.2 p value \49.2 C49.2 p value \49.2 C49.2 p value (n = 169) (n = 98) (n = 71) (n = 110) (n = 61) (n = 49) (n = 59) (n = 37) (n = 22) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Anastomotic leakage 17 (10.1) 9 (9.2) 8 (11.3) 0.657 8 (7.3) 4 (6.6) 4 (8.2) 0.747 9 (15.2) 5 (13.5) 4 (18.2) 0.63 Vocal code paresis 11 (6.5) 6 (6.1) 5 (7.0) 0.811 4 (3.6) 2 (3.3) 2 (4.1) 0.823 7 (11.9) 4 (10.8) 3 (13.6) 0.746 Pulmonary complication 48 (28.4) 30 (30.6) 18 (25.4) 0.454 20 (18.2) 12 (19.7) 8 (16.3) 0.651 28 (47.5) 18 (48.6) 10 (45.5) 0.812 Chylothorax 1 (0.6) 0 (0) 1 (1.4) 0.239 1 (0.9) 1 (1.6) 0 (0) 0.368 0 (0) 0 (0) 0 (0) NaN Surgical site infection 10 (5.9) 4 (4.1) 6 (8.5) 0.235 5 (4.5) 2 (3.3) 3 (6.1) 0.477 5 (8.5) 2 (5.4) 3 (13.6) 0.272 NaN Not a number World J Surg (2018) 42:2199–2208 2207 the institutional and national research committee and with the 1964 poorer prognosis [29–31]. Because patients with a low Helsinki declaration and its later amendments or comparable ethical preoperative PNI value are at a high risk of postoperative standards. complications, the preoperative PNI value may affect both postoperative short- and long-term outcomes. However, in Informed consent Informed consent was obtained from all individ- ual participants included in the study. this study, no signiﬁcant differences were observed between the PNI value and the rate of postoperative com- Open Access This article is distributed under the terms of the plications. Therefore, further studies are thus needed to Creative Commons Attribution 4.0 International License (http://crea address this issue. tivecommons.org/licenses/by/4.0/), which permits unrestricted use, The optimal cutoff points for PNI in predicting post- distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a operative survival in patients with malignant tumors is still link to the Creative Commons license, and indicate if changes were controversial. Thus, one of the aims of this study was to made. evaluate the prognostic value of the PNI and propose an optimal cutoff, which can predict CSS and OS with better accuracy, in patients with ESCC. Based on our study of References 169 patients who underwent curative esophagectomy, and using a ROC curve, we have arrived at 49.2 as the cutoff 1. Mainous MR, Deitch EA (1994) Nutrition and infection. Surg Clin N Am 74(3):659–676 value for PNI. The cutoff value for PNI in ESCC patients 2. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy seems to be much lower than those reported in another comes of age. Nature 480(7378):480–489 cancer, such as renal cell carcinoma, lung cancer, and 3. Weimann A, Braga M, Harsanyi L et al (2006) ESPEN guidelines gliomas [32–34]. The possible reason may be that most on enteral nutrition: surgery including organ transplantation. Clin Nutr 25:224–244 ESCC patients have some degree of swallowing difﬁculty 4. Oh SJ, Hyung WJ, Li C et al (2009) Effect of being overweight due to obstruction or stricture of the esophagus, which on postoperative morbidity and long-term surgical outcomes in results in the eating disorder, malnutrition, and subsequent proximal gastric carcinoma. J Gastroenterol Hepatol 24:475–479. poor nutritional status . https://doi.org/10.1111/j.1440-1746.2008.05704.x 5. Forrest LM, McMillan DC, McArdle CS et al (2004) Comparison Several limitations should be considered when inter- of an inﬂammation-based prognostic score (GPS) with perfor- preting the results of this study. The retrospective nature mance status (ECOG) in patients receiving platinum-based and a single-institution study, the involvement of a com- chemotherapy for inoperable non-small-cell lung cancer. Br J paratively small sample size, and short follow-up periods Cancer 90:1704–1706 6. Onodera T, Goseki N, Kosaki G (1984) Prognostic nutritional were the major limitations of this study. Minor limitations index in gastrointestinal surgery of malnourished cancer patients. included insufﬁcient evidence of the validity of the cutoff Nihon Geka Gakkai Zasshi 85:1001–1005 (in Japanese) values for the PNI. Regarding the PNI, a ﬁxed cutoff value 7. Nozoe T, Minomiya M, Maeda T et al (2010) Prognostic nutri- has not yet been established, and various values have been tional index: a tool to predict the biological aggressiveness of gastric carcinoma. Surg Today 40:440–443. https://doi.org/10. used in previous reports. Another limitation was that some 1007/s00595-009-4065-y other parameters involved in systemic inﬂammation, such 8. Kanda M, Fujii T, Kodera Y et al (2011) Nutritional predictors of as TNF-a and interleukins were not studied, since, these postoperative outcome in pancreatic cancer. Br J Surg inﬂammatory parameters are not routinely tested in clinical 98:268–274. https://doi.org/10.1002/bjs.7305 9. Smale BF, Mullen JL, Buzby GP et al (1981) The efﬁcacy of practice caused by its high cost and inconvenience. nutritional assessment and support in cancer surgery. Cancer Previous studies have shown that perioperative 47:2375–2381 immunonutrition support improves both nutritional and 10. Seaton K (2001) Albumin concentration controls cancer. J Natl immunologic status of patients undergoing elective surg- Med Assoc 93:490–493 11. Gupta D, Lis CG (2010) Pretreatment serum albumin as a pre- eries, thereby reducing postoperative morbidity and mor- dictor of cancer survival: a systematic review of the epidemio- tality [9, 36]. However, it is still unknown whether such logical literature. Nutr J 9:69. https://doi.org/10.1186/1475-2891- nutritional intervention can help improve the surgical 9-69 outcomes in patients with a low PNI. A larger randomized 12. Liu YP, Ma L, Wang SJ et al (2010) Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous multicenter prospective study is required to help determine cell carcinoma. Eur J Surg Oncol 36:155–159. https://doi.org/10. this. 1016/j.ejso.2009.09.005 13. Dind D, Demartines N, Clavien PS (2004) Classiﬁcation of sur- Compliance with ethical standards gical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213 Conﬂict of interest None of the authors have any conﬂicts of 14. Pohl H, Welch HG (2005) The role of over diagnosis and interest. reclassiﬁcation in the marked increase of esophageal adenocar- cinoma incidence. J Natl Cancer Inst 97:142–146 Ethical approval All procedures performed in the study involving 15. Sobin LH, Gospodarowicz MK, Wittekind CH (2009) TNM human participants were in accordance with the ethical standards of classiﬁcation of malignant tumours, 7th edn. Willey, Hoboken 123 2208 World J Surg (2018) 42:2199–2208 16. Lien YC, Hsieh CC, Wu YC et al (2004) Preoperative serum 28. Ahmed T, Haboubi N (2010) Assessment and management of albumin level is a prognostic indicator for adenocarcinoma of the nutrition in older people and its importance to health. Clin Interv gastric cardia. J Gastointest Surg 8:1041–1048 Aging 5:207–216 17. Buzby GP, Mullen JL, Matthews DC et al (1980) Prognostic 29. Aoyama T, Murakawa M, Katayama Y et al (2015) Impact of nutritional index in gastrointestinal surgery. Am J Surg postoperative complications on sutvival and recurrence inpan- 139:160–167 creatic cancer. Anticancer Res 35:2401–2409 18. Schwegler I, von Holzen A, Gutzwiller JP et al (2010) Nutritional 30. Kulu Y, Tarantio I, Warschkow R et al (2015) Anastomotic risk is a clinical predictor of postoperative mortality and mor- leakage is associated with impaired overall and disease-free bidity in surgery for colorectal cancer. Br J Surg 97:92–97. survival after curative rectal cancer resction: a propensity score https://doi.org/10.1002/bjs.6805 analysis. Ann Surg Oncol 22:2059–2067. https://doi.org/10.1245/ 19. Mantovani A, Allavena P, Sica A et al (2008) Cancer-related s10434-014-4187-3 inﬂammation. Nature 454:436–444. https://doi.org/10.1038/ 31. Tokunaga M, Tanizawa Y, Bando E et al (2013) Poor survival nature07205 rate in patients with postoperative intra-abdominal infectious 20. Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev complications following curative gastrectomy for gastric cancer. Cancer 9:361–371. https://doi.org/10.1038/nrc2628 Ann Surg Oncol 20:1575–1583. https://doi.org/10.1245/s10434- 21. Brenner D, Blaser H, Mak TW (2015) Regulation of tumour 012-2720-9 necrosis factor signalling: live or let die. Nat Rev Immunol 32. Jeon HG, Choi DK, Sung HH et al (2016) Preoperative prog- 15:362–374. https://doi.org/10.1038/nri3834 nostic nutritional index is a signiﬁcant predictor of survival in 22. Ray-Coquard I, Cropet C, Van Glabbeke M et al (2009) Lym- renal cell carcinoma patients undergoing nephrectomy. Ann Surg phopenia as a prognostic factor for overall survival in advanced Oncol 23:321–327. https://doi.org/10.1245/s10434-015-4614-0 carcinomas, sarcomas, and lymphomas. Cancer Res 33. Shimizu K, Okita R, Saisho S et al (2015) Prognostic nutritional 69:5383–5391. https://doi.org/10.1158/0008-5472.CAN-08-3845 index before adjuvant chemotherapy predicts chemotherapy 23. Ryan AM, Reynolds JV, Healy L et al (2009) Enteral nutrition compliance and survival among patients with non-small-cell lung enriched with eicosapentaenoic acid (EPA) preserves lean body cancer. Ther Clin Risk Manag 8(11):1555–1561. https://doi.org/ mass following esophageal cancer surgery: results of a double- 10.2147/TCRM.S92961 blinded randomized controlled trial. Ann Surg 249:355–363. 34. He ZQ, Ke C, Al-Nahari F et al (2017) Low preoperative prog- https://doi.org/10.1097/SLA.0b013e31819a4789 nostic nutritional index predicts poor survival in patients with 24. Esper DH, Harb WA (2005) The cancer cachexia syndrome: a newly diagnosed high-grade gliomas. J Neurooncol review of metabolic and clinical manifestations. Nutr Clin Pract 132(2):239–247. https://doi.org/10.1007/s11060-016-2361-0 20:369–376 35. Sun P, Zhang F, Chen C et al (2013) Comparison of the prog- 25. Coussens LM, Werb Z (2002) Inﬂammation and cancer. Nature nostic values of various nutritional parameters in patients with 420:860–867 esophageal squamous cell carcinoma from Southern China. 26. Yoo HM, Lee HH, Shim JH et al (2011) Negative impact of J Thorac Dis 5:484–491. https://doi.org/10.3978/j.issn.2072- leakage on survival of patients undergoing curative resection for 1439.2013.08.38 advanced gastric cancer. J Surg Oncol 104:734–740. https://doi. 36. Lai CC, You JF, Yeh CY et al (2011) Low preoperative serum org/10.1002/jso.22045 albumin in colon cancer: a risk factor for poor outcome. Int J 27. Takeuchi D, Koide N, Suzuki A et al (2015) Postoperative Colorectal Dis 26:473–481. https://doi.org/10.1007/s00384-010- complications in elderly patients with gastric cancer. J Surg Res 1113-4 198:317–326. https://doi.org/10.1016/j.jss.2015.03.095
World Journal of Surgery – Springer Journals
Published: Dec 31, 2017
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera