Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer

doi:10.21203/rs.2.10892/v2

Download PDF

Research article

Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer

https://doi.org/10.21203/rs.2.10892/v2

This work is licensed under a CC BY 4.0 License

Journal Publication

published 29 Oct, 2019

Read the published version in BMC Cancer →

You are reading this older preprint version

Read the latest preprint version →

Background: Accumulating evidence suggests that Gamma-glutamyltransferase (GGT) may be involved in cancer occurrence and progression. However, the prognostic role of serum GGT in pancreatic cancer (PC) survival lacks adequate evaluation. In this study, we aimed to analyze the association between serum GGT measured at diagnosis and overall survival (OS) in patients with metastatic PC. Methods: We identified 320 patients with histopathologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC) diagnosed during 2015 and 2016 at a specialized cancer hospital in southwestern China. Univariate and multivariate Cox proportional-hazards models were used to determine associations between serum GGT and OS in metastatic PDAC. Results: Controlled for possible confounding factors, serum GGT was significantly associated with OS: serum GGT >48 U/L yielded a hazard ratio of 1.53 (95%CI: 1.19-1.97) for mortality risk. A significant dose-response association between serum GGT and OS was also observed. Subgroup analysis showed a possible interaction between GGT and blood glucose level. Conclusion: Serum GGT could be a potential indicator of survival in metastatic PDAC patients. Underlying mechanisms for this association should be investigated.

Cancer Biology

Oncology

biomarkers

pancreatic cancer

survival

The enzyme gamma-glutamyltransferase (GGT) plays a key role in glutathione metabolism. Located primarily on the plasma membrane of the cell, it has key functions in passing amino acids across the cell membrane and in transferring glutamyl into water, peptides and other recipient molecules. Although GGT is nearly omnipresent in human tissues [1], circulating GGT is thought to be derived predominantly from the liver [2]. Therefore, in clinical practice, it is widely used as a sensitive albeit nonspecific diagnostic biomarker for liver dysfunction, hepatitis and excessive alcohol consumption. In the past two decades, elevated GGT levels have also been associated with increased risk of various chronic diseases, such as cardiovascular events [3], hypertension [4], type II diabetes [5], metabolic syndrome [6], and renal failure [7].

Pro-oxidation and pro-inflammatory properties of GGT have been suggested to underlie etiological mechanisms leading to these adverse disease outcomes [8]. Oxidative stress and inflammation are also pathways implicated in cancer development and progression, and positive GGT associations with various cancer types have been demonstrated by several prospective studies [9-12]. Quite opposite to the abundance of cancer risk studies, only a few studies have investigated a prognostic role of serum GGT in cancer outcomes: increased serum GGT has been inversely associated with survival in gastric cancer [13], colorectal cancer [14], ovarian cancer [15], breast cancer [16], endometrial cancer [17, 18], cervical cancer [19], and renal cell carcinoma [20].

Pancreatic cancer (PC) remains one of the most lethal malignant tumors worldwide, with a dismal 5-year survival proportion of less than 5% [21]. Thus, identification of factors that are of prognostic significance is imperative. In parallel to the aforementioned inverse associations with other malignancies, it is possible that serum GGT may also relate to PC survival. Two studies have examined the relations of serum GGT and GGT-to-albumin ratio to PC survival in early stage PC patients, with positive findings [22, 23]. Few studies have investigated the prognostic relevance of serum GGT in advanced PC patients [24]. Therefore, the aim of this study is to assess the association between serum GGT measured at disease diagnosis and the overall survival (OS) in PC patients with metastatic disease.

Study design

After the Institutional Research Ethics Board of Kunming Medical University reviewed and approved the protocol, we performed a retrospective study at The Third Affiliated Hospital of Kunming University, the largest cancer hospital in southwestern China Yunnan province. This hospital has a comprehensive computerized information system, which collects, verifies and updates all parts of medical practice-relevant data from inpatients and outpatients on a daily basis, including hospitalization records, imaging examinations, body-fluids tests, drug prescriptions, diagnoses, surgical procedures, etc. In this study, we screened for histopathologically confirmed stage IV (metastatic) pancreatic ductal adenocarcinoma (PDAC) patients who were diagnosed between January 1, 2015 and December 31, 2016 in this computerized information system. Other information that was obtained from the system included age at diagnosis, sex, blood indicators and chemotherapy data. Death information of the included patients through January 1, 2018, was ascertained by external matching with the Chinese Residents Death Registration System, using an individual personal ID number possessed by every Chinese citizen. Because of the retrospective nature of the study, informed consents from the subjects were waived by the institutional review board.

Variables and definitions

The outcome of interest in this study was OS. Survival duration was defined as the time between histopathological diagnosis date and date of death. Data on baseline serum GGT level for each included patient, tested within 7 days of diagnosis, were extracted from the information system. Considering that nutritional status, liver function, hyperglycemia and systemic inflammation may introduce confounding in analyses of the association between serum GGT and OS, we also extracted baseline test results of several other blood indicators: albumin (ALB), an indicator of nutritional status; total bilirubin (TBIL) and alanine transaminase (ALT), measurements of liver function; fasting plasma glucose (FPG), a marker of blood glucose level; and neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammation. Chemotherapy of the patients was with palliative intention, and was defined as the single or combination use of any of the following commonly used drugs: gemcitabine, nab-paclitaxel, 5-fluorouracil, irinotecan, and oxaliplatin.

Statistical analysis

Descriptive statistics were used to delineate and compare general characteristics of the study subjects. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between baseline serum GGT level and OS of PDAC. Subgroup analyses based on chemotherapy, NLR value, and blood glucose levels were performed to examine possible GGT interaction roles. All statistical analyses were done in SAS (version 9.3, SAS Institute Inc., Cary, NC.). Except for the exploratory univariate Cox models, which employed a less strict standard (p<0.10) for initial identification of possible influencing factors, the threshold for statistical significance was defined as a two-tailed probability less than 0.05.

General characteristics of PDAC patients

Over the two years of subject eligibility, we identified 357 patients with histologically confirmed metastatic PDAC, of whom 37 had missing values in critical variables. Thus, our analyses comprised 320 patients. Major characteristics of the patients are described and compared in Table 1. The mean diagnosis age of patients was 65.3 years, males and females were comparable. Median survival length was 177 days. Although serum GGT can mildly vary by age and sex, in clinical practice, a uniform cut-off of 48 units/liter (U/L) is the most commonly used threshold for defining GGT elevation. We used this value to dichotomize the PDAC patients based on baseline serum GGT level and found that, except for age, sex and serum FPG, other ascertained characteristics were all significantly different between the two groups: compared to patients with normal baseline serum GGT, patients with elevated serum GGT had a much shorter median survival length (138 days versus 281 days), as well as generally increased other blood markers.

Baseline serum GGT and OS of metastatic PDAC

Product-limit survival curves of elevated and normal baseline serum GGT patients are displayed in Figure 1. The OS of the elevated GGT group was notably inferior to survival of the normal GGT group (log-rank statistic: 23.52, p=10^-6). Univariate Cox proportional hazards models identified 4 potential prognostic covariates: age at diagnosis, palliative chemotherapy, baseline FPG and GGT. With multivariate adjustment, only age at diagnosis, FPG and GGT remained significant: age at diagnosis was positively associated with mortality, the adjusted hazard ratio (HR) was 1.08 (95%CI 1.01-1.15) per 5 years increase; elevated baseline FPG and serum GGT were associated with 1.39 (95%CI: 1.08-1.79) and 1.53 (95%CI: 1.19-1.97) fold mortality hazard, respectively (Table 2).

We further divided PDAC patients into 4 strata by using quartiles of baseline serum GGT: Q₁ (GGT < 30.0 U/L), Q₂ (30.0 U/L ≤ GGT < 85.5 U/L), Q₃ (85.5 U/L ≤ GGT < 338.0 U/L), and Q₄ (GGT ≥ 338.0 U/L). By using Q₁ as the reference group, controlling for age at diagnosis, palliative chemotherapy, baseline FPG and baseline ALB, we found that the adjusted HRs for Q₂ through Q₄ were 1.36 (95%CI: 0.96-1.93), 1.53 (95%CI: 1.07-2.19), and 1.76 (95%CI: 1.24-2.49), respectively. The multiplicative continuous dose-response association between GGT and OS was statistically significant: every 10-fold increase in GGT was associated with a HR of 1.33 (95%CI: 1.09-1.61), and the p value for trend was 0.0043 (Figure 2).

Subgroup analysis

We further performed a small series of subgroup analyses based on GGT stratification by categories of palliative chemotherapy, baseline FPG and NLR. No obvious interaction was found between palliative chemotherapy, baseline NLR and serum GGT. However, an appreciable difference in the GGT-OS association was found when metastatic PDAC patients were dichotomized by baseline FPG: in patients with elevated baseline FPG (defined as ≥ 7.0mmol/L), GGT was not associated with OS, but in patients with normal baseline FPG (defined as < 7.0mmol/L), elevated serum GGT was associated with 2.14-fold mortality (95%CI: 1.48-3.09) (Table 3). This interaction did not reach statistical significance however (p =0.07).

Among the 320 PDAC patients, 76 and 97 were extra measured for baseline C-reactive protein (CRP) and carbohydrate antigen 19-9 (CA19-9). Correlation analysis revealed that: serum GGT was positively related to CA19-9 (r=0.43, p=10^-3.9), whereas the linear relationship between GGT and CRP was statistically insignificant (r=-0.01, p=0.97). Considering the prominent correlation between GGT and CA19-9, we fitted multivariate Cox regression model by including the two indicators simultaneously in 97 PDAC patients with baseline CA19-9 measurements: after adjustment, GGT was still a significant prognostic factor (HR=1.531, 95%CI: 1.10-2.13), and CA19-9 was not associated with OS (HR=1.496, 95%CI: 0.78-2.85).

In this study, we examined the prognostic relevance of serum GGT measured at diagnosis among histopathologically diagnosed metastatic PDAC patients. We found that baseline serum GGT was positively associated with OS: compared to patients with normally ranged GGT, elevated GGT conveyed a 54% increase in mortality hazard. A previous study by Engelken et al. also reported a significant association between elevated GGT and deteriorated survival in unresectable PDAC patients. However, the authors adopted a 3.4-fold higher cut-off (165 U/L) to dichotomize GGT [24]. Besides, our findings were further supported by an appreciable dose-response trend of increasing death hazard with increasing GGT level. This association is of potential clinical significance: as a prognostic factor, the possible role of serum GGT in cancer survival should be investigated, in the hope of elucidating modifiable survival mechanisms in these cancer patients.

Existing pathological findings may reflect the involvement of serum GGT in metastatic PDAC prognosis. First, laboratory evidence supports a role of inflammation in cancer progression. For example, nuclear factor-κB (NF-κB) is involved in inflammation-induced tumor growth [25]. The association of GGT with inflammation has been observed bidirectionally: elevated serum GGT can reflect inflammation-related oxidative stress [26], or can be a consequence of inflammatory cytokines such as tumor necrosis factor alpha [20]. However, our observed mortality association with serum GGT was not affected by adjustment for baseline NLR, a sensitive marker of systemic inflammation, raising the possibility that mechanisms other than inflammation may also exist in this association. For example, GGT may directly participate in progression of cancer, as studies on melanoma cells found that elevated GGT activity resulted in growth advantage both in vitro and in vivo [27]. Moreover, a newly published study using gene set enrichment analysis (GSEA) reported that in gastric cancer patients, GGT was significantly associated with EMT, KRAS, SRC and PKCA signaling pathways [13], which are involved in cancer progression and metastasis [28, 29].

The connection between hyperglycemia and cancer progression has been well established [30]. Our study results are consistent with this association, as we observed that elevated baseline fasting glucose level was associated with increased mortality hazard. However, subgroup analysis in strata of FPG found that serum GGT was significantly associated with increased hazard of mortality primarily in patients with normal blood glucose levels rather than their hyperglycemic counterparts. A reasonable assumption could be that, a reduced rather than increased plasma glucose level may considerably enhance the bioactivity of serum GGT. However, we cannot find direct laboratory evidence to support this assumption. Two previous studies have discussed the association between GGT activity and serum blood glucose level: one reported a positive association [31], whereas the other reached insignificant conclusion [32]. Another possible explanation could be the pro-inflammatory effect of hypoglycemia that has been gradually realized recently [33, 34], as the induced inflammation may exacerbate the hazardous role of elevated GGT. Nevertheless, it is also well known that hyperglycemia has the same pro-inflammation propensity [35, 36]. Therefore, this issue needs to be further discussed.

The findings of this study may have clinical significance. As an identified prognostic factor, serum GGT level in metastatic PDAC patients could be periodically monitored. If serum GGT is an accompanying indicator of disease progression, then it can help to predict more imminent mortality. On the other hand, if serum GGT independently promotes disease progression, then reducing its level could be a promising strategy in improving survival. Although currently only toxic GGT inhibitors are available [37, 38], low toxicity analogs that can be used in humans are in the process of development.

The strength of our study is the comparatively large sample size for this uncommon disease. Nevertheless, several limitations should also be noted. First, all of our study subjects were metastatic PDAC patients chosen from a single Chinese institution, thus generalization of the study results to PC patients of other stages of disease or other ethnic backgrounds should be made cautiously. Second, although we included some potentially important factors with which to adjust the study results, as the information of other potential confounders, such as tumor location, smoking, and alcohol consumption, was unavailable, therefore, the risk of unadjusted confounding bias could exist.

To conclude, increased baseline GGT was associated with inferior OS of metastatic PDAC patients. Some evidence for mortality interaction was observed between blood glucose level and serum GGT. Our study results suggest that serum GGT might be used as an indicator to identify late stage PDAC patients with increased mortality hazard. These findings warrant corroboration by studies with larger sample sizes, and mechanisms to explain this association also need to be investigated.

GGT: gamma-glutamyltransferase (GGT); PDAC: pancreatic adenocarcinoma; ALB: albumin; TBIL: total bilirubin; ALT: alanine transaminase; FPG: fasting plasma glucose; NLR: neutrophil-to-lymphocyte ratio; HR: hazard ratio.

Ethics approval and consent to participate

This study was approved by Institutional Research Ethics Board of Kunming University. Because of the retrospective nature, plus no individually identifiable or sensitive information was involved, informed consents from all patients had been waived.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study are not publicly available due to confidentiality agreement, but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by National Natural Science Foundation of China (No. 81703324), Yunnan Applied Basic Research Projects-Kunming Medical University Union Foundation (Grant No. 2018FE001(-132)), National Key R&D Program of China (Grant nos. 2017YFC0907302), and the China Scholarship Council (Grant No. 201808535098)

Authors’ contributions

YX, CX, and HAR conceptualized the study. HY, JL and DL collected and sorted the data. YX, JL, and DL performed data analysis. YX drafted the manuscript, HY, JL, DL, CX, and HAR critically revised the paper. All authors had read and approved the final manuscript.

Acknowledgments

None.

Goldberg D M. Structural, functional, and clinical aspects of gamma-glutamyltransferase. CRC Crit Rev Clin Lab Sci. 1980;12:1–58.
Whitfield JB. Gamma-glutamyltransferase. Crit Rev Clin Lab Sci. 2001;38:263-355.
Emdin M, Passino C, Pompella A, Paolicchi A. Gammaglutamyltransferase as a cardiovascular risk factor. Eur Heart J. 2006;27:2145-6.
Lee DH, Jacobs DR Jr, Gross M, Kiefe CI, Roseman J, Lewis CE, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem. 2003;49:1358-66.
Lee DH, Silventoinen K, Jacobs DR Jr, Jousilahti P, Tuomileto J. Gamma-glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. J Clin Endocrinol Metab. 2004;89:5410-4.
Lee DS, Evans JC, Robins SJ, Wilson PW, Albano I, Fox CS, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2007;27:127-33.
Ryu S, Chang Y, Kim DI, Kim WS, Suh BS. Gammaglutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men. Clin Chem. 2007;53:71-7.
Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation. 2005;112:2078–80.
Mok Y, Son DK, Yun YD, Jee SH, Samet JM. γ-Glutamyltransferase and cancer risk: The Korean cancer prevention study. Int J Cancer. 2016;138:311-9.
Kunutsor SK, Laukkanen JA. Gamma-glutamyltransferase and risk of prostate cancer: Findings from the KIHD prospective cohort study. Int J Cancer. 2017;140:818-24.
Strasak AM, Goebel G, Concin H, Pfeiffer RM, Brant LJ, Nagel G, et al. Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer. Cancer Res. 2010;70:3586-93.
Van Hemelrijck M, Jassem W, Walldius G, Fentiman IS, Hammar N, Lambe M, et al. Gamma-glutamyltransferase and risk of cancer in a cohort of 545,460 persons-the Swedish AMORIS study. Eur J Cancer. 2011;47:2033-41.
Wang Q, Shu X, Dong Y, Zhou J, Tang R, Shen J, et al. Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer. Oncotarget. 2017;8:36171-84.
He WZ, Guo GF, Yin CX, Jiang C, Wang F, Qiu HJ, et al. Gamma-glutamyl transpeptidase level is a novel adverse prognostic indicator in human metastatic colorectal cancer. Colorectal Dis. 2013;15:e443-52.
Grimm C, Hofstetter G, Aust S, Mutz-Dehbalaie I, Bruch M, Heinze G, et al. Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer. Br J Cancer. 2013;109:610-4.
Staudigl C, Concin N, Grimm C, Pfeiler G, Nehoda R, Singer CF, et al. Prognostic relevance of pretherapeutic gamma-glutamyltransferase in patients with primary metastatic breast cancer. PLoS One. 2015;10:e0125317.
Edlinger M, Concin N, Concin H, Nagel G, Ulmer H, Göbel G. Lifestyle-related biomarkers and endometrial cancer survival: Elevated gamma-glutamyltransferase as an important risk factor. Cancer Epidemiol. 2013;37:156-61.
Seebacher V, Polterauer S, Grimm C, Rahhal J, Hofstetter G, Bauer EM, et al. Prognostic significance of gamma-glutamyltransferase in patients with endometrial cancer: a multi-centre trial. Br J Cancer. 2012;106:1551-5.
Polterauer S, Hofstetter G, Grimm C, Rahhal J, Mailath-Pokorny M, Kohl M, et al. Relevance of gamma-glutamyltransferase-a marker for apoptotic balance-in predicting tumor stage and prognosis in cervical cancer. Gynecol Oncol. 2011;122:590-4.
Luo C, Xu B, Fan Y, Yu W, Zhang Q, Jin J. Preoperative gamma-glutamyltransferase is associated with cancer-specific survival and recurrence-free survival of nonmetastatic renal cell carcinoma with venous tumor thrombus. Biomed Res Int. 2017;2017:3142926.
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:2140–1.
Zhou B, Zhan C, Wu J, Liu J, Zhou J, Zheng S. Prognostic significance of preoperative gamma-glutamyltransferase to lymphocyte ratio index in nonfunctional pancreatic neuroendocrine tumors after curative resection. Sci Rep. 2017;7:13372.
Li S, Xu H, Wu C, Wang W, Jin W, Gao H, et al. Prognostic value of γ-glutamyltransferase-to-albumin ratio in patients with pancreatic ductal adenocarcinoma following radical surgery. Cancer Med. 2019;8:572-84.
Engelken FJ, Bettschart V, Rahman MQ, Parks RW, Garden OJ. Prognostic factors in the palliation of pancreatic cancer. Eur J Surg Oncol. 2003;29:368-73.
Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749-59.
Corti A, Franzini M, Paolicchi A, Pompella A. Gamma-glutamyltransferase of cancer cells at the crossroads of tumor progression, drug resistance and drug targeting. Anticancer Res. 2010;30:1169-81.
Franzini M, Corti A, Lorenzini E, Paolicchi A, Pompella A, De Cesare M, et al. Modulation of cell growth and cisplatin sensitivity by membrane gamma-glutamyltransferase in melanoma cells. Eur J Cancer. 2006;42:2623-30.
Lewis AD, Hayes JD, Wolf CR. Glutathione and glutathionedependent enzymes in ovarian adenocarcinoma cell lines derived from a patient before and after the onset of drug resistance: intrinsic differences and cell cycle effects. Carcinogenesis. 1988;9:1283-7.
Hanigan MH, Gallagher BC, Townsend DM, Gabarra V. Gammaglutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. Carcinogenesis. 1999;20:553-9.
Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 2014;38:330-6.
Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci. 2001; 38:263–355.
Franzini M, Fornaciari I, Rong J, Larson MG, Passino C, Emdin M, et al. Correlates and reference limits of plasma gammaglutamyltransferase fractions from the Framingham Heart Study. Clin Chim Acta. 2013;417:19-25.
Dandona P, Chaudhuri A, Dhindsa S. Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care. 2010;33:1686-7.
Ratter JM, Rooijackers HM, Tack CJ, Hijimans AGM, Netea MG, de Galan BE, et al. Proinflammatory effects of hypoglycemia in humans with or without diabetes. Diabetes. 2017;66:1052-61.
Aljada A, Ghanim H, Mohanty P, Syed T, Bandyopadhyay A, Dandona P. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am J Clin Nutr. 2004;80:51–7.
Ceriello A. Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes. 2005;54:1–7.
Han L, Hiratake J, Kamiyama A, Sakata K. Design, synthesis, and evaluation of gamma-phosphono diester analogues of glutamate as highly potent inhibitors and active site probes of gamma-glutamyl transpeptidase. Biochemistry. 2007;46:1432-7.
Mena S, Benlloch M, Ortega A, Carretero J, Obrador E, Asensi M, et al. Bcl-2 and glutathione depletion sensitizes B16 melanoma to combination therapy and eliminates metastatic disease. Clin Cancer Res. 2007;13:2658-66.

Table 1 General characteristics of 320 metastatic PDAC patients

Characteristics	All patients (N=320)	Elevated serum GGT (GGT>48 U/L, N=183)	Normal serum GGT (GGT≤48 U/L, N=137)	p value
Characteristics	Mean (SD)/Median (SD)/N (%)	Mean (SD)/Median (SD)/N (%)	Mean (SD)/Median (SD)/N (%)	p value
Age at diagnosis (Years)	65.28 (10.05)^a	65.93 (9.97)^a	64.41 (10.14)^a	0.18
Sex (Male)	158 (49.38)^c	93 (50.82)^c	65 (47.45)^c	0.57
Palliative chemotherapy (Yes)	150 (46.88)^c	63 (34.43)^c	87 (63.50)^c	10^-6.5
Survival length (Days)	177 (231.93)^b	138 (271.65)^b	281 (234.19)^b	10^-6.0
Baseline serum indicators
ALB (g/L)	37.00 (7.32)^b	36.00 (6.96)^b	39.30 (7.12)^b	10^-6.5
TBIL (μmol/L)	15.40 (113.14)^b	34.80 (137.81)^b	11.20 (15.36)^b	10^-14
ALT (U/L)	29.00 (107.87)^b	58.00 (110.61)^b	17.10 (91.23)^b	10^-8.1
FPG (mmol/L)	6.67 (3.26)^b	6.70 (3.78)^b	6.42 (2.32)^b	0.15
NLR (Unit free)	4.46 (8.26)^b	5.08 (8.13)^b	3.74 (8.45)^b	10^-2.3
GGT (U/L)	85.5 (393.02)^b	NA	NA	NA

^aMean with standard deviation (SD) ^bMedian with standard deviation (SD) ^cFrequency with proportion (%)

Table 2 Univariate and multivariate Cox proportional hazards model results

Covariates	Univariate Cox model		Multivariate Cox model
Covariates	Crude HR (95%CI)	p value	Adjusted HR (95%CI)	p value
Age at diagnosis (+5 years)	1.10 (1.03, 1.16)	10^-2.9	1.08 (1.01, 1.15)	10^-1.7
Sex (Male)	1.02 (0.81, 1.29)	0.87
Palliative chemotherapy (Yes)	0.69 (0.54, 0.87)	10^-2.9	0.81 (0.62, 1.04)	0.10
Baseline serum ALB (< 35g/L)	1.25 (0.98, 1.59)	10^-1.0
Baseline serum TBIL (> 20.5μmol/L)	1.19 (0.93, 1.50)	0.16
Baseline serum ALT (> 60U/L)	1.17 (0.91, 1.50)	0.22
Baseline serum NLR (+10)	1.10 (0.97, 1.25)	0.15
Baseline FPG (≥7.0 mmol/L)	1.32 (1.04, 1.68)	10^-1.7	1.39 (1.08, 1.79)	10^-2.0
Baseline serum GGT (>48 U/L)	1.78 (1.40, 2.26)	10^-6.0	1.53 (1.19, 1.97)	10^-3.2

Table 3 Subgroup analysis results by chemotherapy, baseline FPG and NLR.

Stratification variable	Stratum	Elevated serum GGT (>48 U/L)
		Adjusted HR (95%CI)	Interaction p-value
Palliative chemotherapy	Yes	1.70 (1.16, 2.51)^a	0.84
	No	1.61 (1.10, 2.34)^a
Baseline NLR	≥ 4.46	1.38 (0.95, 2.00)^b	0.91
	< 4.46	1.42 (0.99, 2.03)^b
Baseline FPG	≥ 7.0mmol/L	1.31 (0.90, 1.92)^c	0.07
	< 7.0mmol/L	2.14 (1.48, 3.09)^c

^aAdjusted for age at diagnosis, baseline NLR, baseline FPG

^bAdjusted for age at diagnosis, palliative chemotherapy, baseline FPG

^cAdjusted for age at diagnosis, palliative chemotherapy, baseline NLR

Download PDF

Journal Publication

published 29 Oct, 2019

Read the published version in BMC Cancer →

Editorial decision: Minor revision
03 Oct, 2019
Review #2 received at journal
01 Oct, 2019
Reviewer #2 agreed at journal
30 Sep, 2019
Review #1 received at journal
02 Sep, 2019
Reviewer #1 agreed at journal
20 Aug, 2019
Editor assigned by journal
19 Aug, 2019
Reviewers invited by journal
19 Aug, 2019
Submission checks completed at journal
18 Aug, 2019
Editor invited by journal
18 Aug, 2019

You are reading this older preprint version

Read the latest preprint version →

Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer

Status:

Journal Publication

Version 2

Abstract

Figures

Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Status:

Journal Publication

Version 2