Inflammatory and nutritional statuses of patients submitted to resection of gastrointestinal tumors

Fruchtenicht Estado inflamatório e nutricional em pacientes submetidos à ressecção cirúrgica de tumores do trato gastrointestinal 10 Rev Col Bras Cir. 2018; 45(2):e1614 REFERÊNCIAS 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E35986. 2. Silva MPN. Síndrome da anorexia-caquexia em portadores de câncer. Rev Bras Cancerol. 2006;52(1):59-7. 3. Nourissat A, Mille D, Delaroche G, Jacquin JP, Vergnon JM, Fournel P, et al. Estimation of the risk for nutritional state degradation in patients with cancer: development of a screening tool based on results from a cross-sectional survey. Ann Oncol. 2007;18(11):1882-6. 4. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223-6. 5. Silva JB, Maurício SF, Bering T, Correia MI. 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Nutritional status, systemic inflammation and prognosis of patients with gastrointestinal cancer. Nutr Hosp. 2012;27(3):70714. 17. Read JA, Choy ST, Beale PJ, Clarke SJ. Evaluation of nutritional and inflammatory status of advanced colorectal cancer patients and its correlation with survival. Nutr Cancer. 2006;55(1):78-85. 18. Poziomyck AK, Fruchtenicht AV, Kabke GB, Volkweis BS, Antoniazzi JL, Moreira LF. Reliability of nutritional assessment in patients with gastrointestinal tumors. Rev Col Bras Cir. 2016;43(3):189-97. 19. Costa MD, Vieira de Melo CY, Amorim AC, Cipriano Torres O, Dos Santos AC. Association between nutritional status, inflammatory condition, and prognostic indexes with postoperative complications and clinical outcome of patients with gastrointestinal neoplasia. Nutr Cancer. 2016;68(7):1108-14. 20. Maurício SF, da Silva JB, Bering T, Correia MI. Relationship between nutritional status and the Glasgow Prognostic Score in patients with colorectal cancer. Nutrition. 2013;29(4):625-9. 21. Daniele A, Divella R, Abbate I, Casamassima A, Garrisi VM, Savino E, et al. Assessment of nutritional and inflammatory status to determine the prevalence of malnutrition in patients undergoing surgery for colorectal carcinoma. Anticancer Res. 2017;37(3):1281-7. 22. Quyen TC, Angkatavanich J, Thuan TV, Xuan VV, Tuyen Fruchtenicht Estado inflamatório e nutricional em pacientes submetidos à ressecção cirúrgica de tumores do trato gastrointestinal 11 Rev Col Bras Cir. 2018; 45(2):e1614 LD, Tu DA. Nutrition assessment and its relationship with performance and Glasgow prognostic scores in Vietnamese patients with esophageal cancer. Asia Pac J Clin Nutr. 2017;26(1):49-58. 23. Maeda K, Shibutani M, Otani H, Nagahara H, Ikeya T, Iseki Y, et al. Inflammation-based factors and prognosis in patients with colorectal cancer. World J Gastrointest Oncol. 2015;7(8):111-7. 24. Crumley AB, McMillan DC, McKernan M, Going JJ, Shearer CJ, Stuart RC. An elevated C-reactive protein concentration, prior to surgery, predicts poor cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer. Br J Cancer. 2006;94(11):1568-71. 25. Deans DA, Tan BH, Wigmore SJ, Ross JA, de Beaux AC, Paterson-Brown S, et al. The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastrooesophageal cancer. Br J Cancer. 2009;100(1):63-9. 26. Pinato DJ, North BV, Sharma R. A novel, externally validated inflammation-based prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI). Br J Cancer. 2012;106(8):1439-45. 27. Hirahara N, Matsubara T, Hayashi H, Takai K, Fujii Y, Tajima Y. Impact of inflammation-based prognostic score on survival after curative thoracoscopic esophagectomy for esophageal cancer. Eur J Surg Oncol. 2015;41(10):1308-15. 28. Proctor MJ, Morrison DS, Talwar D, Balmer SM, O Reilly DS, Foulis AK, et al. An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow inflammation outcome study. Br J Cancer. 2011;104(4):726-34. 29. La Torre M, Nigri G, Cavallini M, Mercantini P, Ziparo V, Ramacciato G. The Glasgow prognostic score as a predictor of survival in patients with potentially resectable pancreatic adenocarcinoma. Ann Surg Oncol. 2012;19(9):2917-23. 30. Sun K, Chen S, Xu J, Li G, He Y. The prognostic significance of the prognostic nutritional index in cancer: a systematic review and meta-analysis. J Cancer Res Clin Oncol. 2014;140(9):1537-49. 31. Walsh SM, Casey S, Kennedy R, Ravi N, Reynolds JV. Does the modified Glasgow Prognostic Score (mGPS) have a prognostic role in esophageal cancer? J Surg Oncol. 2016;113(7):732-7. 32. Jaramillo-Reta KY, Velázquez-Dohorn ME, MedinaFranco H. Neutrophil to lymphocyte ratio as predictor of surgical mortality and survival in complex surgery of the upper gastrointestinal tract. Rev Invest Clin. 2015;67(2):117-21. 33. Rashid F, Waraich N, Bhatti I, Saha S, Khan RN, Ahmed J, et al. A pre-operative elevated neutrophil: lymphocyte ratio does not predict survival from oesophageal cancer resection. World J Surg Oncol. 2010;8:1. 34. Poziomyck AK, Cavazzola LT, Coelho LJ, Lameu EB, Weston AC, Moreira LF. Nutritional assessment methods as predictors of postoperative mortality in gastric cancer patients submitted to gastrectomy. Rev Col Bras Cir. 2017;44(5):482-90. 35. Hirashima K, Watanabe M, Shigaki H, Imamura Y, Ida S, Iwatsuki M, et al. Prognostic significance of the modified Glasgow prognostic score in elderly patients with gastric cancer. J Gastroenterol. 2014;49(6):1040-6. Recebido em: 30/01/2018 Aceito para publicação em: 13/03/2018 Conflito de interesse: nenhum. Fonte de financiamento: FIPE HCPA, Fundo de Pesquisa e Programa de Pós-Graduação em Ciências Cirúrgicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. Endereço para correspondência: Luis Fernando Moreira E-mail: lufmoreira@hcpa.edu.br / anavaleria.1012@hotmail.com


INTRODUCTION
C ancer has become a public health problem throughout the world, and it is unquestionable that the sharp increase in its incidence represents a crisis for the health systems of several countries 1 .Malnutrition, which is highly evident when the neoplasm reaches the gastrointestinal tract (GIT), is associated with decreased response to specific treatment and quality of life, with greater risks of postoperative infection and increased morbidity and mortality 2 .Several methods and tools for nutritional assessment have been proposed over the years to detect early malnutrition.However, there is no gold standard nutritional evaluation method established for cancer patients.The assessment is highly variable in clinical practice due to a large number of metabolic changes that affect these patients in different ways 3 .
There is growing evidence that the systemic inflammatory response associated with cancer has a great influence on disease-related outcomes 4 .A variety of prognostic methods for different types of cancer derive from a combination of several pre-existing, simple-to-use biochemical markers, easily measured and often available in clinical practice.On the other hand, inflammatory markers have been consistently studied because of the easy and potential application for cancer prognosis, such as the modified Glasgow Prognostic Score (mGPS), the Neutrophil/Lymphocyte Ratio (NLR), the Onodera Prognostic Nutrition Index (mPNI), the Inflammatory-Nutritional Index (INI) and the adapted version of the Prognostic Inflammatory-Nutritional Index (mPINI).Such markers and instruments based on inflammation could 1 -Federal University of Rio Grande do Sul, Post-Graduation Program in Surgical Sciences, Porto Alegre, RS, Brazil.

Original Article A B S T R A C T
Objective: to evaluate the association between the nutritional and the inflammatory statuses of patients with cancer of the gastrointestinal tract undergoing surgical resection and to identify predictors of mortality in these patients.Methods: we conducted a prospective study of 41 patients with gastrointestinal tract cancer submitted to surgery between October 2012 and December 2014.We evaluated the nutritional status by subjective and objective methods.We assessed the inflammatory response and prognosis using the modified Glasgow Prognostic Score (mGPS), Neutrophil/Lymphocyte Ratio (NLR), Onodera Prognostic Nutritional Index (mPNI), Inflammatory-Nutritional Index (INI) and C-Reactive Protein/Albumin ratio (mPINI).Results: half of the patients were malnourished and 27% were at nutritional risk.
On multivariate analysis, albumin was the only inflammatory marker independently related to death (p=0.004).Conclusion: inflammatory markers were significantly associated with malnutrition, demonstrating that the higher the inflammatory response, the worse the PG-SGA (B and C) scores and the higher the %WL in these patients.However, further studies aimed at improving surgical outcomes and determining the role of these markers as predictors of mortality are required.Keywords: Gastrointestinal Neoplasms.Nutritional Status.Inflammation.Mortality.
be useful tools for assessing nutritional status in cancer patients, based on the premise that these patients are in a persistent state of chronic inflammation, a factor that contributes to nutritional depletion and the development of cachexia 5 .Therefore, recognizing the effects of systemic inflammation on nutritional depletion could allow appropriate nutritional strategies with the objective of preventing progressive weight loss 5,6 , reversing the clinical picture through appropriate and targeted nutritional intervention 7 , and minimizing or even eliminating the resulting morbimortality 8 .Thus, the main objective of this study was to evaluate the association between the nutritional and the inflammatory statuses in patients with GIT cancer submitted to surgical resection, as well as to identify predictors of mortality in such patients.We included patients older than 18 years, with diagnosis of gastrointestinal cancer in different clinical stages 9 , with indication of surgical treatment.All patients were able to communicate, understand, and provide written consent to participate in the study.We excluded patients with previous history of antineoplastic treatment or patients undergoing chemotherapeutic and radiotherapeutic treatment, as well as those with other immunological or catabolic diseases, such as chronic kidney disease and autoimmune diseases.

METHODS
All patients had their nutritional status assessed during the preoperative outpatient visits through the Patient-Generated Subjective Global Assessment (PG-SGA).We also recorded classical anthropometric variables, including current body weight (BW) and height, percentage of weight loss (%WL) and body mass index (BMI).Results of PG-SGA were classified as A (well nourished), B (moderately undernourished), and C (severely malnourished) 10 .BMI was classified according to the tables proposed by WHO 11 and by Lipschitz et al. 12 for adult and elderly patients, respectively.We calculated the %WL according to the formula [(usual weight -actual weight) x 100 / usual weight] and classified it according to Blackburn & Bistrian 13 .
For the evaluation of the inflammatory and prognostic statuses, we used the inflammatory markers

The adapted version of the Inflammatory and Nutritional
Prognostic Index (mPINI), determined by the CRP/albumin ratio, stratifies patients as having no risk (<0.4), low risk (0.4 to 1.2), moderate risk (1.2 to 2.0) or high risk (>2) of infectious and inflammatory complications 16 .For the mortality rate, we verified death through the electronic medical record or, when this information was not available, by telephone contact with patients' relatives.The mean follow-up time was 1.5 years (30 days to 4 years).
For statistical analysis, due to the small sample size, we grouped the patients with mGPS scores 1 and 2, associated with a worse prognosis, and compared them with patients with score 0. We did the same for the PG-SGA, in which patients classified as grades B and C were considered undernourished, while patients classified as grade A were considered well nourished. We
We observed statistically significant associations between %WL at three months with NLR (r s =0.334, p=0.047) and %WL at six months with mPINI (r s =0.422, p=0.014) and INI (r s =-0.420, p=0.015), demonstrating that the more altered the inflammatory markers, the higher the percentage of weight loss during the months (Figure 1).We found no statistically significant association between the PG-SGA and the markers mGPS (p=0.090),NLR (p=0.432) and mPNI (p=0.417).In contrast, the markers INI (p=0.026),mPINI (p=0.026) and albumin (p=0.015) were significantly associated with the PG-SGA categories (Table 2).There was a statistically significant association between mortality and tumor staging (p=0.008),BMI (p=0.021),PG-SGA (p=0.030) and %WL at one month (p=0.002),three months (p=0.003) and six months (p=0.014).However, there was no association between the inflammatory markers and mortality outcome in the bivariate analysis (Table 3).The NLR was the marker that most correlated with death.Significantly higher NLR values were found in death cases (p=0.033), when comparing patients who died (median 5.12) with those who did not (median 2.95).After multivariate analysis, however, NLR did not remain statistically significant as a predictor of mortality (p=0.139).In the multivariate analysis assessing factors independently associated with death, tumor staging (p=0.001) and albumin (p=0.004) were the only independent predictors of mortality (Table 4). of malnutrition and BMI was able to detect malnutrition in only 40% of the patients 16 .In another study conducted with 51 patients with advanced colorectal cancer, PG-SGA was able to detect 56% of malnourished patients or at nutritional risk, whereas BMI was not a sensitive measure according to the authors 17 .
Although BMI is a commonly used measure in the evaluation of nutritional status, including surgical and oncological patients, these results demonstrate that BMI cannot be relied upon to evaluate malnutrition, because it is not an appropriate tool to differentiate body components 16,18 .In the present study, the results for BMI were not statistically significant in the multivariate analysis to assess independent factors associated with PG-SGA malnutrition (RR 0.98, 95% CI 0.93-1.04,p=0.491).
Due to the inadequacy of several methods for evaluating nutritional status when used alone, studies have been undertaken with the objective of combining the evaluation measures, such as anthropometric, laboratory and subjective tools, in order to increase the sensitivity and specificity of the methods, which would allow to evaluate and to draw nutritional strategies more suitable for these patients 18 .
Recently, studies have demonstrated an important association between nutritional depletion and inflammation in cancer patients [4][5][6]14,16,17,[19][20][21][22] , including GIT tumors. Since cancer ptients are in a constant state of inflammation, and considering the role of this systemic inflammation in progressive weight loss and muscle mass, cancer cachexia can be identified by the presence and alteration of certain inflammatory markers [5][6][7] .In our study, several inflammatory markers were altered, especially in patients with high weight loss and malnourished, demonstrating that, as marker values were inadequate, inflammation was worse and %WL was higher.Lima et al. 16 and Costa et al. 19 evaluated the association between %WL and different inflammatory markers in patients with GIT tumors, and found a positive association between %WL and different markers, including mPINI (p<0.05 and p=0.002, respectively).However, few studies focused on the association between inflammatory markers and methods of nutritional assessment.In addition, other studies that evaluated such associations did not do so in populations solely of patients with tumors, which may compromise the comparison and extrapolation of the data 6,14 .
Both mGPS and NLR have been proposed as markers of inflammatory response and predictors of prognosis in surgical procedures 23 , and the association between these markers and nutritional status has been previously assessed 14,22 .A recent Asian study of 64 patients with esophageal cancer found a strong association between nutritional status by PG-SGA and performance scores.However, such association was weak in relation to prognostic scores such as GPS 22 .On the other hand, in a study including patients with advanced tumors (n=114), the authors found that 60% of the patients who were malnourished by the PG-SGA presented high mGPS when compared with well-nourished ones (p=0.046).Although in our study 79% of malnourished patients had high mGPS compared with well-nourished individuals, this difference was not significant.The same occurs with NLR, since the authors found a significant association between the PG-SGA categories with this inflammatory marker, which we did not observe, and that can be justified by the inclusion, in our study, only patients with GIT tumors, or even by the size of the sample 14 .
When we compared the PG-SGA with the inflammatory markers, only INI, mPINI and albumin were significantly associated with the subjective evaluation categories.The Inflammatory-Nutritional Index (INI) was developed with the purpose of investigating the relationship between the inflammatory state and the nutritional status.In the present study, malnourished patients had significantly lower INI values when compared with well-nourished ones, a result similar to that reported in a study conducted by Alberici et al. 6 .
We also assessed the CRP/albumin ratio (mPINI), considered an alternative for the simplification of the original formula of the Inflammatory and Nutritional Prognostic Index (PINI) to determine the association between the nutritional status and the systemic inflammatory response in patients with gastrointestinal cancer 16,19 .In our study, the PG-SGA scores were significantly associated with mPINI and albumin, demonstrating that malnourished patients had a high risk of complications and lower albumin values when compared with well-nourished individuals.This was similar to that shown in the study including patients with GIT tumors (n=30) conducted by Lima et al. 16 in which patients considered to be undernourished by the global subjective assessment had significantly higher values of mPINI (p=0.014), as well as lower values of albumin (p=0.017)compared with well-nourished ones.
CRP is an important marker of systemic inflammatory response expressed by some tumor cells.
Elevated CRP values have been demonstrated as a reliable marker of malignancy potential and of predicted prognosis in several solid tumors 24 .Some studies found a positive association between altered CRP levels and weight loss in patients with GIT tumors 16,19,25 .In this study, despite the altered CRP values in most cases, the association between CRP, malnutrition and mortality was not observed, mainly due to its high variability or due to the small number of subgroups.On the other hand, in a study conducted by Read et al. 17 with patients with advanced colorectal cancer, they initially found a positive correlation between PG-SGA and CRP (r=0.430;p=0.003).However, when two outliers were excluded, the association did not remain significant (r=0.278,p=0.065).
Although initially proposed as a marker for the nutritional status of patients with GIT neoplasms, mPNI is likely to reflect the degree of systemic inflammation that affects cancer patients.Pinato et al. 26  the use of these markers as predictors of short-term outcomes and morbidity and mortality, and the results are still contradictory 27,[31][32][33][34] .
Hypoalbuminemia is a consequence of systemic inflammation and is associated with a worse prognosis in cancer patients 35 .With the exception of albumin, no other inflammatory marker in our study was a predictor of mortality in the multivariate analysis.Poziomyck et al. 34 reported a similar result in gastric cancer patients (n=44), in whom albumin was highly capable of predicting 30day mortality (p=0.026).Albumin has been widely used as a measure of nutritional and inflammatory statuses of cancer patients.Altered preoperative albumin levels have proven to be a better predictor of postoperative mortality for various types of cancer, including GIT tumors.However, this marker is not a reliable indicator of nutritional assessment, because its results are influenced by non-nutritional factors 6,7 .
We found a high prevalence of malnutrition and systemic inflammation in patients with GIT cancer submitted to surgical resection.The results showed a significant association between nutritional status and inflammatory markers, evidenced by the worse PG-SGA scores and percentage of weight loss, in addition to the high inflammatory response.Regarding mortality, only albumin and tumor staging were independently related to death in the population.Because of the lack of studies associating inflammatory markers with nutritional assessment methods, such as PG-SGA for example, and studies evaluating the use of these markers for mortality outcomes, more research is needed to better compare and discuss such results adequately.

R E S U M O
We conducted a prospective study of 41 patients(20 women and 21 men), with mean age (±SD) of 59 years (±12), attended at the Ambulatory Service of Gastrointestinal Neoplasms of Porto Alegre Clinics Hospital (HCPA/UFRGS) from October 2012 to December 2014.This work belongs to the gastrointestinal tumors research line of the Southern Surgical Oncology Research Group (SSORG), and was approved by the Ethics in Research Committee (HCPA/UFRGS) under protocol number IRB #13-0520.

modified
Glasgow Prognostic Score (mGPS), Neutrophil/ Lymphocyte Ratio (NLR), Onodera Prognostic Nutrition Index (mPNI), Inflammatory-Nutritional Index (INI), and modified Prognostic Inflammatory-Nutritional Index (mPINI).At the time of the preoperative interview, we requested the laboratory tests CRP, albumin, neutrophils and lymphocytes, necessary for classification of the markers, and the results were retrieved from the electronic medical records.We considered levels of albumin <35g/L and CRP>10mg/L in the sample as altered.For classification of mGPS, we evaluated albumin and CRP and defined the score based on the combination of the results.Patients with high CRP (>10mg/L) and hypoalbuminemia (<35g/L) received a score equal to 2, associated with a worse prognosis.Patients with only altered serum CRP (>10 mg/L) received a score equal to 1, and those with no alterations in these values (serum CRP≤10mg/L and albumin ≥35g/L) received score 0 4 .For the classification of NLR (defined as the ratio between the absolute neutrophil counts and the absolute lymphocyte count), we considered abnormal values ≥5 14 .We calculated the mPNI by the formula: 10 x serum albumin (g/dL) + 0.005 × lymphocyte count (per mm 3 ).Values <40 were related to the worse prognosis 15 .The INI, based on the albumin/CRP ratio, classifies patients as well-nourished (ASG A) with values =1.25, while malnourished ones (ASG C) display values =0.10 6 .

4
Rev Col Bras Cir.2018; 45(2):e1614 Most patients presented disease in advanced clinical stages, with 34 (83%) in stages III/IV.Twenty-five (61%) patients died during the postoperative period.The mean time of death was ten months (one day to two years) and the mean time (md) of hospitalization was 17 (10 to 24) days, with no relation to mortality in these patients (p=0.702).According to the evaluation of nutritional status by the PG-SGA, almost half of the patients were malnourished (49%) or at risk of malnutrition (27%) (classification of subgroups in C and B, respectively), while the BMI classified only 24% of the patients as malnourished.

Table 1 -
Characterization of the sample.

Table 2 .
Association of PG-SGA with inflammatory markers.

Table 3 .
Association of variables with death.

Table 4 .
Multivariate Analysis through the Poisson regression model to evaluate factors independently associated with death.
subjective assessment (PG-SGA), 76% of the patients were malnourished or at risk of malnutrition (categories B and C), whereas BMI detected less than a quarter of undernourished patients.A similar result was found in a previous study (n=30) that evaluated preoperatively patients with GIT tumors, where PG-SGA detected 83%