Preoperative Controlling Nutritional Status (CONUT) Score Predicts Short-term Surgical Outcomes in Patients with Gastric Cancer After Laparoscopy-assisted Radical Gastrectomy

Background: The Controlling Nutritional Status (CONUT) score is an emerging nutrition assessment tool that is useful in gastric cancer (GC) patients. The aim of our study was to assess the predictive ability of the preoperative CONUT score for short-term outcomes in GC patients undergoing laparoscopy-assisted gastrectomy. Methods: We retrospectively reviewed the medical records of 309 patients who underwent curative laparoscopy-assisted gastrectomy. The patients were divided into two groups according to the optimal cut-off value of the CONUT score. The clinical characteristics and postoperative complications were evaluated and analysed in the low- and high-score groups. The risk factors for complications were identied by univariate and multivariate analysis. Results: The preoperative CONUT score showed a good predictive ability for postoperative complications (area under the curve (AUC)=0.718, Youden index=0.343) compared with other indexes, with an optimal cut-off value of 2.5. Patients with high CONUT scores had a higher incidence of overall complications (P<0.001) and mild complications (P<0.001). Univariate and multivariate analyses revealed that the CONUT score was independently associated with postoperative complications (P=0.012; odds ratio (OR)=2.433; 95% condence interval (CI): 1.218-4.862). Conclusions: The preoperative CONUT score is a reliable and useful nutritional assessment tool for predicting short-term outcomes in GC patients after laparoscopy-assisted gastrectomy.


Introduction
Gastric cancer (GC) remains a major public health problem worldwide and is the fth most common cancer and the third leading cause of cancer-related deaths 1 . Despite recent advances in the diagnosis and treatment of GC, the prognosis of patients remains poor. Adequate surgical resection is the main curative therapeutic option for GC 2,3 , which inevitably comes with some postoperative complications, leading to prolonged hospitalization, greater expenses, impaired quality of life, and delayed adjuvant chemotherapy treatment.
Patients with GC always have to endure unpleasant symptoms, such as early satiety, anorexia and dysphagia, caused by obstruction by the tumour mass and chronic anaemia due to malignant ulcers.
These factors result in progressive weight loss, compromised immunity and ultimately malnutrition 4 .
Malnutrition is a speci c state resulting from the lack of nutrition that leads to altered body composition (decreased fat-free mass) and body cell mass, leading to diminished physical and mental function and impaired clinical outcomes of disease 5 . Malnutrition is quite common and severe among patients with GC, especially advanced GC. Therefore, multiple nutritional assessment systems have emerged with the aim of identifying applicable parameters or tools, detecting malnutrition, and predicting the outcomes of patients with GC. Oh et al 6 analysed a study of patients with GC and con rmed that various perioperative nutritional parameters, including the Prognostic Nutritional Index (PNI) and albumin (ALB), were independent prognostic factors in GC patients. Sun et al 7 reported that ALB and neutrophils could predict postoperative overall survival (OS) in GC patients. Kim et al 8 observed the predictive ability of the platelet-to-lymphocyte ratio (PLR) for the prognosis of GC. In addition, other nutritional assessment tools have been reported for cancer patients, including the Nutritional Risk Screening (NRS), Skeletal Muscle Index (SMI), Naples Prognostic Score (NPS), modi ed Glasgow Prognostic Score (mGPS), and Malnutrition Universal Screening Tool (MUST) [9][10][11][12][13] .
The Controlling Nutritional Status (CONUT) score was rst reported by Ignacio de Ulíbarri J in 2005, as a nutritional tool for the early detection and continuous control of malnutrition 14 . It is calculated based on serum albumin, the total lymphocyte count and cholesterol level. In recent years, several studies have revealed that the CONUT score is a validated and effective nutritional assessment tool for predicting multiple cancer outcomes after surgery, including for colorectal cancer 15 , hepatocellular carcinoma 16 , oesophageal cancer 17 , and GC 9, 18-22 . However, there has been little research on the CONUT score for evaluating postoperative complications in GC patients after radical gastrectomy. Therefore, the primary aim of our study was to assess the predictive ability of the preoperative CONUT score for short-term outcomes in GC patients who underwent laparoscopic radical gastrectomy.

Study patients
There were consecutive clinical records of 412 patients who underwent curative laparoscopic gastrectomy, at the Department of General Surgery of Sir Run Run Shaw Hospital, the a liated hospital of the Medical School of Zhejiang University, from January 2016 to June 2019. The inclusion criteria were as follows: (1) con rmed pathological diagnosis of gastric carcinoma by gastroscopic biopsy, (2) underwent curative laparoscopic gastrectomy, and (3) age > 18 y. The exclusion criteria were as follows: (1) received neoadjuvant chemotherapy before gastrectomy, (2)R1/2 resection, (3) diagnosed with gastric stump cancer, (4) combined with distant metastasis (liver, colon, ovary, etc.), (5) underwent extended or palliative surgery, and (6) incomplete data to follow-up at 30 days. Ultimately, 309 patients were enrolled in the retrospective analysis. The detailed ow-chart is shown in Fig. 1. Written informed consent for the usage of clinical records was granted by each patient, as required by the Institutional Review Board at the hospital and in accordance with ethical guidelines of the Declaration of Helsinki in 1964.

Perioperative management
Routine case history collection, physical examination and preoperative laboratory measurements were performed. Abdominal enhanced computed tomography and endoscopy together with tissue biopsy were carried out for the overall assessment of gastric tumours. Standard surgical laparoscopic gastrectomy with a su cient resection margin was performed in accordance with Japanese Gastric Cancer Treatment Guidelines 2014 (ver. 4) 3 , which involved either total or distal gastrectomy coupled with systematic lymphadenectomy abiding by the D level criteria. The following alimentary tract reconstruction methods were usually employed: Roux-en-Y oesophagojejunostomy was performed after total gastrectomy, whereas Billroth I, Billroth II or Roux-en-Y gastrojejunostomy was selected after distal gastrectomy. For all patients, reasonable perioperative management was in line with the Enhanced Recovery After Surgery (ERAS) programme, including preoperative disease education, shrinking fasting time, the intraoperative use of minimally invasive techniques, and uid restriction avoided from overload, postoperative early drain removal, off-bed mobilization and oral feeding until discharge [23][24][25] . Thereafter, patients diagnosed with advanced gastric carcinoma were recommended to receive subsequent adjuvant chemotherapy.

Data collection
Clinical records of baseline characteristics, laboratory data, imaging scanning examinations and pathological diagnosis were collected from the database. Blood tests were performed within 3 days before surgery. The CONUT score was calculated according to Table 1. The PNI and PLR were calculated using the following formulas: PNI = 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm 3 ); PLR = platelet count/total lymphocyte count. Short-term outcomes were mainly postoperative complications that occurred within 30 days after surgery or before hospital discharge. Mortality was regarded as any death occurring from the date of operation up to 30 days after operation.

Results
ROC curve of the CONUT score, PNI, ALB, and PLR According to the inclusion and exclusion criteria, 309 patients were enrolled in the study. The ROC curves of the CONUT score, PNI, ALB, and PLR are depicted, and the areas under the curve (AUCs) were 0.718, 0.694, 0.680, and 0.635, respectively. The CONUT score was the most useful predictor. The demarcated values of the CONUT score that correlated with outcomes differed from those in previous studies 9, [15][16][17][18][19][20] . In our study, the optimal cut-off value for predicting postoperative complications was identi ed as 2.5. The Youden index of the CONUT score was 0.343, with a sensitivity of 0.549 and speci city of 0.794. The positive predictive value for postoperative complications was 52.3%, and the negative predictive value was 80.8%.
Study population and baseline characteristics based on the cut-off value of the CONUT score According to the cut-off value of the CONUT score, patients were subdivided into the low CONUT score group (score < 2.5, n = 214) and the high CONUT score group (score > 2.5, n = 95). The average age was signi cantly higher in the high CONUT score group than the low score group (62.  Table 2. Postoperative complications in patients with low and high CONUT scores The incidence of postoperative complications in patients with a CONUT score < 2.5 was signi cantly lower than that in patients with a CONUT score > 2.5 (19.2% vs 52.6%, p < 0.001) ( Table 3). The incidence of mild complications was signi cantly higher in patients with high CONUT scores than low CONUT scores (7.9% vs 26.3%, p < 0.001). The incidence of major complications was also signi cantly higher in high CONUT group than low CONUT group (18.7% vs 31.6%, p = 0.013) ( Table 3). Only 1 patient died from severe cachexia and multiple organ dysfunction syndrome (MODS) after surgery. With regard to surgical site infection (SSI), there were 5 (1.6%) cases of surface incisional infection and 20 (6.5%) cases of deep space infection. The incidence of SSIs in high CONUT score group was almost signi cantly higher than in low CONUT score group (6.1% vs 12.6%, p = 0.051).

Discussion
A clinical database with a consecutive patient cohort was reviewed to determine whether the preoperative CONUT score effectively predicted postoperative complications for GC patients who underwent laparoscopic gastrectomy. The ndings showed that the preoperative CONUT score served as a signi cant predictor of short-term outcomes for patients with GC.
The prognosis of cancer is not only related to tumour factors but is also associated with patient status, especially nutritional status 29,30 . The CONUT score was originally proposed by Ignacio de Ulíbarri J in 2005 14 as an integrated scale for assessing the nutritional status of inpatients. The CONUT score is calculated by parameters that are easy to acquire, including serum albumin, the total lymphocyte count and cholesterol level, which re ect protein reserves, immune function and lipid metabolism, respectively. The condition of hypoalbuminemia suggests that the body is in a stage of hypercatabolism, which is prevalent among cancer patients, especially with cachexia. Lymphocytes are important cellular components of the human immune response system that help to ght tumours by inhibiting cancer cell proliferation, invasion and migration 31 . Saka et al 32 reported that the exhaustion of T cells was closely associated with poor prognosis in cancer. Cholesterol plays a vital role in modulating the activity of membrane proteins, which may be associated with the initiation and progression of cancer and interactions with the immune system. Yang et al 33 reported that cholesterol inhibited hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts. Therefore, this assessment scale is able to provide an integrated, rapid and low-cost nutritional evaluation of patients.
Previous studies have proposed diversi ed prognostic predictors for GC, such as the PNI 6,19,[34][35][36][37] , PLR 8, 38, 39 , etc. These nutrition score scales are based on routine parameters from blood examinations and are applied to assess the prognosis of cancer patients. In our study, we analysed the assessment capability of these scales for predicting postoperative complications with ROC curves, and the CONUT score showed the best performance. In addition, we identi ed age and RBC counts as independent risk factors for complications. In other words, old age, anaemia and malnutrition had an adverse effect on short-term outcomes in patients after gastrectomy for GC, which was consistent with prior studies 40,41 .
In previous studies, most researchers focused on the long-term survival associated with the CONUT score among GC patients 9,[18][19][20][21][22] , with little focus on postoperative complications. Ryo et al 18 mentioned the incidence of some complications, such as anastmostic leakage and intra-abdominal abscess, in relation to the CONUT score. Huang et al 40 reported that the CONUT score was a signi cant risk factor for total complications and one-year survival in elderly GC patients. In our study, strati ed analysis of postoperative complications was further performed comparing low and high CONUT scores. Sometimes some patients suffered multiple complications. For example, after surgery, one patient suffered a sudden stomach ache and subsequent fever, with abdominal tenderness and rebound tenderness as a result of duodenal stump rupture, rapidly developed grievous intra-abdominal abscess, and had to undergo a second operation with suturing, irrigation and drainage. Our analysis indicated that a higher ratio of patients with a high CONUT score developed postoperative complications. We speculated that patients with hypoalbuminemia, decreased lymphocytes and hypocholesterolaemia were more likely to experience negative conditions with slow tissue repair and delayed wound healing, increasing their susceptibility to infection, prolonging their reliance on parenteral nutrition support, and increasing their probability of abdominal effusion. SSIs are infections of the incision, organ or nearby space that occur after surgery, which can be combined with complex comorbidities and antimicrobial-resistant pathogens, and increase the challenges and expenses of treatment 42 . There was almost signi cant difference in SSIs between two groups in this study. The respiratory complications after surgery included pneumonia and hydrothorax, which occurred more frequently in the high CONUT score group, as Song Ryo et al reported 18 . We considered that long stays in bed and infrequent cough and sputum may be to blame. In summary, the CONUT score acts as an evaluation strategy for precise risk strati cation for postoperative complications, which allows doctors to implement active nutritional interventions for GC patients.
Despite our ndings, there were still some limitations of the present study. First, this single-centre study included a homogeneous cohort of patients with a xed surgical team. Second, a retrospective study cannot rule out selection bias. Finally, follow-up assessments of the CONUT score after surgery were not available, which resulted in a lack of dynamic observations of the nutrition status. Therefore, prospective multi-center studies should be warranted to con rm the predictive signi cance of the CONUT score for GC patients, to validate the effectiveness of preoperative nutritional interventions and to compare the CONUT score with other commonly used nutritional assessments.

Conclusion
As a simple and feasible nutrition assessment tool, the CONUT score reliably predicts postoperative complications for patients with GC after laparoscopic gastrectomy, allowing precise risk strati cation and preoperative nutritional interventions before surgery.