The Augural Interplay of Myosteatosis and Gamma-Glutamyltransferase in Patients Undergoing Comprehensive Surgical Intervention for Cholangiocarcinoma

doi:10.21203/rs.3.rs-3160601/v1

Background: Myosteatosis, an established inauspicious prognostic factor prevalent among patients battling gastric cancer, pancreatic cancer, and other malignant neoplasms, has demonstrated associations with unfavourable outcomes in cholangiocarcinoma (CCA) cases. Concurrently, studies have proposed that preoperative elevation in γ-glutamyltransferase (GGT) levels might serve as autonomous harbingers of dismal outcomes in intrahepatic cholangiocarcinoma (ICC) sufferers. Yet, the conjoined prognostic potency of GGT and myosteatosis in patients diagnosed with CCA undergoing comprehensive surgical excision remains shrouded in uncertainty.

Methods: This retrospective examination encompassed 156 CCA patients undergoing comprehensive surgical resection at the Affiliated Hospital of Qingdao University between January 2017 and March 2022. Serum gamma-glutamyltransferase (GGT) data, among other pertinent clinical intel, were harvested within a month preceding the surgical intervention. Body composition assessment was executed utilising computed tomography (CT) scans at the third lumbar vertebrae level, aided by the application of the Slice-O-Matic software. Group classification of myosteatosis and GGT was conducted based on reference and cut-off values, computed through receiver operating characteristic (ROC) curves. The Kaplan-Meier method was employed for survival analysis, while the log-rank test was used for evaluating differences in recurrence and survival. Cox regression models were ultimately utilised to discern risk factors impacting overall survival (OS) and recurrence-free survival (RFS) in CCA patients.

Result: The myosteatosis group, with a mean age of 64.3 ± 8.0 years, included 83 patients, whereas the non-myosteatosis group, with a mean age of 58.3 ± 9.8 years, comprised 73 patients. Employing the receiver operating characteristic (ROC) curve and Youden's index, the optimal cut-off value for gamma-glutamyltransferase (GGT) was calculated to be 136.5. Both overall survival (OS) and recurrence-free survival (RFS) were significantly curtailed in the myosteatosis group relative to the non-myosteatosis group (P = 0.017 and P = 0.013, respectively). Furthermore, the OS and RFS were reduced in the GGT ≥ 136.5 group compared to the GGT < 136.5 group (P = 0.007 and P = 0.006, respectively). Yet, these factors did not surface as independent predictors of adverse prognosis in cholangiocarcinoma (CCA) patients. Notably, those patients exhibiting both myosteatosis and GGT ≥ 136.5 experienced the direst OS and RFS outcomes (P = 0.008 and P = 0.006, respectively).

Conclusion: Myosteatosis, combined with gamma-glutamyltransferase (GGT) levels ≥ 136.5, portend a truncated overall survival (OS) and recurrence-free survival (RFS) in patients with cholangiocarcinoma (CCA) undergoing comprehensive surgical resection. Patients exhibiting both myosteatosis and preoperative GGT levels ≥ 136.5 bore the gravest prognosis, thereby necessitating heightened vigilance in clinical praxis.

Cholangiocarcinoma

Myosteatosis

Gamma-glutamyltransferase

Radical resection

Prognosis

Cholangiocarcinoma, a notorious subcategory of hepatic malignancies, originates from the bile duct cells within the liver, as a malevolent and aggressive tumor[1]. Although its occurrence may be overshadowed by hepatocellular carcinoma—the paramount archetype of primary liver cancer—its aggressiveness reigns supreme[2]. Two quintessential facets underpin the grim prognosis faced by cholangiocarcinoma patients: Primarily, the absence of distinctive early clinical manifestations, such as icterus, dyspepsia, malignant emesis, and superior abdominal discomfort, culminates in a suboptimal early diagnostic rate[3]. Secondly, despite the existence of a plethora of therapeutic tactics encompassing chemotherapy, radiotherapy, and targeted therapy, comprehensive surgical excision is the solitary beacon of hope for protracted survival among these patients[4, 5]. Regrettably, the post-surgical five-year survival rate hovers dismally between 5% and 10%, concomitant with a high five-year recurrence rate.

Myosteatosis, the aberrant agglomeration of triglycerides—neutral fats—within muscle tissues, is a recurrent body composition deviation discernible in patients beleaguered by malignant neoplasms, inclusive of gastric cancer, pancreatic cancer, and pulmonary cancer[9–12]. Academic endeavours have elucidated that patients suffering from pancreatic cancer concurrent with myosteatosis endure abbreviated survival spans and encounter less favourable prognoses[9]. Our anterior meta-analysis endeavours have also laid bare the palpable influence of myosteatosis on the prognosis of cholangiocarcinoma patients, heralding curtailed overall survival (OS) and recurrence-free survival (RFS).

Gamma-glutamyltransferase (GGT), a distinct classification of mercaptoenzyme, plays a pivotal role in glutathione metabolism and the conveyance of gamma-glutamyl groups to additional peptides or amino acids. Clinically, GGT acts as a beacon indicating liver function[13, 14]. In the physiologically healthy populace, serum GGT is primarily liver-derived, and its levels tend to escalate in response to hepatic damage[15, 16]. GGT exhibits a close affinity with systemic oxidative stress and inflammation, frequently displaying overexpression in malignant neoplasms, thereby bolstering tumor cell survival and proliferation[17]. Previous academic explorations have attested that amplified pre-treatment GGT levels augur adverse prognosis in patients afflicted with various malignant tumors, including esophageal cancer, renal cancer, prostate cancer, and intrahepatic cholangiocarcinoma [14, 18, 19]. Nonetheless, as of this moment, no academic pursuit has delved into the prognostic worth of the amalgamation of myosteatosis and GGT in cholangiocarcinoma (CCA) patients undergoing radical excision.

2.1 Participants

The present retrospective investigation scrutinized a database incorporating 757 patients diagnosed with cholangiocarcinoma at the Department of Pathology, Affiliated Hospital of Qingdao University, spanning from January 2017 to February 2022. The inclusion parameters were as follows: 1) comprehensive surgical resection undertaken with postoperative pathology corroborating cholangiocarcinoma; 2) acquisition of comprehensive computed tomography (CT) image data a month preceding surgery; 3) preoperative identification of serological markers, inclusive of γ-glutamyltransferase; and 4) availability of follow-up data. In the end, the investigation encompassed 156 cholangiocarcinoma patients who underwent comprehensive surgical resection, excluding individuals who received auxiliary therapy preceding comprehensive surgical resection, such as chemoradiotherapy, targeted therapy, or alternative neoplastic treatments, and those who failed to comply with follow-up. This study received approval from the Ethics Committee of the Affiliated Hospital of Qingdao University (QYFYWZLL27647). As the study's data were sourced from extant records and the study's nature was retrospective, the Ethics Committee did not impose additional informed consent prerequisites for the patients.

2.2 Accumulation of Clinicopathologic Data

Clinicopathologic data, deemed potentially influential upon survival and recurrence in cholangiocarcinoma (CCA) patients, were accumulated within a month preceding comprehensive surgical resection. Demographic particulars encompassed age, sex, Body Mass Index (BMI), smoking history, alcoholic intake, hypertension, diabetes, cirrhosis, and HBsAg status. Neoplasm-associated particulars consisted of tumor diameter, differentiation extent, nerve invasion, vascular invasion, lymph node metastasis, and recurrence. Serological particulars included albumin, prealbumin levels, cancer antigen 199 (CA199), cancer antigen 125 (CA125), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), alanine transaminase (ALT), aspartate transaminase (AST), bilirubin levels, renal function, and GGT. Inflammatory markers incorporated leukocyte, neutrophil, lymphocyte, monocyte, and platelet levels, in addition to the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR). All clinical data in this investigation were procured from the electronic medical system of the Affiliated Hospital of Qingdao University. The follow-up period of the investigation spanned until January 2023. Overall survival (OS), defined as the period from comprehensive surgical resection to either death or the concluding follow-up deadline in CCA patients, acted as the primary study endpoint. The secondary study endpoint was recurrence-free survival (RFS), representing the interval from comprehensive surgical resection to either recurrence or the last follow-up in CCA patients. The criteria for diagnosing tumor recurrence revolved around typical CT and/or MRI imaging findings.

2.3 Body Composition Analysis via CT

Preoperative computed tomography (CT) image data were procured from patients and scrutinized using Slice-O-Matic software (Tomovision, Montreal, Canada) to evaluate muscle adipose degeneration and disease diminution at the third lumbar level of abdominal CT scans. Sarcopenia was ascertained by the skeletal muscle mass index (SMI) [skeletal muscle area (SMA)/height² (m²)], while myosteatosis was evaluated by the mean skeletal muscle decay (SMA20). The system parameters were calibrated with Hounsfield unit (HU) attenuation values as follows: -190 to -30 HU for subcutaneous and intramuscular adipose tissue, -150 to 50 HU for visceral adipose tissue, and − 29 to + 150 HU for skeletal muscle (Fig. 1)[21]. The diagnostic parameters were formulated based on the patient's BMI: for patients with a BMI ≥ 25 kg/m², an SMI < 53 signified sarcopenia, and an SMA < 33 HU signified myosteatosis. For cholangiocarcinoma patients with a BMI < 25 kg/m², sarcopenia was defined as an SMI < 41 cm²/m² for women and < 43 cm²/m² for men, and myosteatosis was defined as an SMA < 41 HU[12, 22]. All images were procured from the Image System of the Affiliated Hospital of Qingdao University, and data analysis was undertaken by a pair of clinical researchers.

2.4 Statistical Analysis

The entire data were examined using SPSS 26.0, with a two-sided p-value < 0.05 deemed statistically momentous. Continuous variables were articulated as mean ± SD or median (P25-P75), while categorical variables were voiced as frequency and percentage. Quantitative data were dissected using the T-test or Wilcoxon Mann-Whitney (U test), and qualitative data were dissected using the Pearson Chi-square test or Fisher's exact test to compare clinicopathologic attributes between groups. The optimal threshold value of GGT was determined via the ROC curve and Youden index. Kaplan-Meier and Log-rank tests were employed to analyze and test overall survival (OS) and recurrence-free survival (RFS), while univariate and multivariate Cox regression analyses were conducted to pinpoint factors impacting survival and relapse in cholangiocarcinoma (CCA) patients.

3.1 Clinicopathological Characteristics

The inquiry incorporated 156 cholangiocarcinoma (CCA) patients who underwent radical resection. Baseline data are exhibited in Tables 1 and 2. According to the diagnostic criteria, 83 patients were classified in the myosteatosis cohort and 73 in the non-myosteatosis cohort. Fifty-four cases exhibited GGT ≥ 136.5, while 102 cases manifested GGT < 136.5. Table 1 portrays the clinicopathological characteristics of both cohorts. Patients within the myosteatosis group were significantly elder (mean age, 64.3 vs. 58.3, P < 0.001), more likely to be female (60.2% vs. 24.7%, P < 0.001), and had a higher prevalence of diabetes (22.9% vs. 9.6%, P = 0.026) and a BMI < 25 kg/m² (74.7% vs. 43.8%, P < 0.001) as compared to the non-myosteatosis group. Conversely, the non-myosteatosis group had a higher proportion of patients with a history of tobacco use (35.6% vs. 16.9%, P = 0.007) and alcohol consumption (30.1% vs. 16.9%, P = 0.050). No statistically notable differences were observed between the two cohorts regarding hypertension, history of hepatitis B, cirrhosis, tumor diameter, tumor differentiation, nerve and vascular invasion, lymph node metastasis, presence of gallstones, or recurrence.

Table 2 illustrates the differential serological and body composition attributes between the two cohorts. There was no significant distinction observed in serum GGT levels between the groups (median: 91.0 vs. 65.0, P = 0.379). Compared to the myosteatosis group, the albumin (ALB) levels (mean ± SD: 40.6 ± 5.2 vs. 37.7 ± 6.0, P = 0.002), prealbumin levels (mean ± SD: 226.7 ± 81.0 vs. 191.1 ± 84.5, P = 0.008), hemoglobin (HB) levels (median: 138.0 vs. 131.0, P = 0.010), indirect bilirubin (IBIL) levels (median: 11.8 vs. 10.0, P = 0.033), and creatinine levels (mean ± SD: 71.8 ± 22.0 vs. 60.0 ± 19.6, P < 0.001) were statistically elevated. On the other hand, the cancer antigen 125 (CA125) levels (median: 13.7 vs. 17.9, P = 0.033) were statistically lower.

In terms of body composition, patients with myosteatosis exhibited a higher incidence of sarcopenia (57.8% vs. 38.4%, P = 0.015) and increased intramuscular adipose tissue (IMAT) (mean ± SD: 8.0 ± 5.0 vs. 5.8 ± 3.7, P = 0.003). Both skeletal muscle area (SMA) (median: 108.0 vs. 139.7, P < 0.001) and visceral to subcutaneous fat ratio (VSR) (median: 0.7 vs. 1.0, P = 0.009) were statistically lower in the myosteatosis group compared to the non-myosteatosis group.

The optimal cut-off value for gamma-glutamyltransferase (GGT) was determined using SPSS software. The Receiver Operating Characteristic (ROC) curve of GGT is depicted in Fig. 2. The best cut-off value for GGT in predicting overall survival (OS) was identified as 136.5 U/L, achieving a statistically significant p-value of 0.036 using the method of significance testing.

The ROC curve was utilized to appraise the discriminative capability of GGT as a prognostic biomarker in cholangiocarcinoma patients. This statistical method allows for the determination of the cut-off that maximizes the sensitivity and specificity of the biomarker, thus ensuring its effectiveness in prognostication. The results suggest that a pre-treatment GGT level above 136.5 U/L may serve as a predictor of poorer overall survival in cholangiocarcinoma patients, subject to further validation in prospective studies.

Table 1

Clinicopathologic features of patients.
Factors	Myosteatosis N = 83	Non-myosteatosis N = 73	P-value
Age(years)	64.3 ± 8.0	58.3 ± 9.8	0.000
Gender Male Female	33(39.8%) 50(60.2%)	55(75.3%) 18(24.7%)	0.000
BMI(kg/m²) ༜25kg/m² ≥25kg/m²	62(74.7%) 21(25.3%)	32(43.8%) 41(56.2%)	0.000
Smoke	14(16.9%)	26(35.6%)	0.007
Drink	14(16.9%)	22(30.1%)	0.050
Hypertension	25(30.1%)	19(26%)	0.571
Diabetes	19(22.9%)	7(9.6%)	0.026
Hepatitis B	9(10.8%)	10(13.7%)	0.586
Liver cirrhosis,n(%)	9(10.8%)	13(17.8%)	0.212
Tumor size,n(%) ≥ 5cm ༜5cm	41(49.4%) 42(50.6%)	30(41.1%) 43(58.9%)	0.299
Tumor differentiation, n(%) low median-low median high	21(25.3%) 20(24.1%) 40(48.2%) 2(2.4%)	18(24.7%) 24(32.9%) 30(41.1%) 1(1.4%)	0.724
Nerve invasion,n(%)	39(47%)	35(47.9%)	0.905
Vacular invasion,n(%)	26(31.3%)	26(35.6%)	0.571
Lymph node metastasis,n(%)	22(26.5%)	16(21.9%)	0.505
Biliary calculus,n(%)	18(21.7%)	13(17.8%)	0.545
Recurrence Yes No	22(26.5%) 61(73.5%)	16(21.9%) 57(78.1%)	0.505

Table 2

Serological and body composition characteristics of patients.
Factors	Myosteatosis N = 83	Non-myosteatosis N = 73	P-value
ALB	37.7 ± 6.0	40.6 ± 5.2	0.002
Prealbumin	191.1 ± 84.5	226.7 ± 81.0	0.008
CA 199 ༜1000 ≥1000	68(81.9%) 15(18.1%)	55(75.3%) 18(24.7%)	0.315
CA 125	17.9(11.2–40.6)	13.7(9.9–22.1)	0.033
CEA	3.3(2.2–6.4)	3.0(1.9–4.9)	0.237
AFP	3.5(2.4–4.8)	2.9(2.2–4.4)	0.143
ALT	25.0(17.6–67.4)	27.0(16.5–65.7)	0.793
AST	28.0(20.0–55.0)	23.0(18.0-43.9)	0.235
WBC	6.3(5.1-8.0)	6.8(5.6–7.6)	0.640
Neutrophil	3.8(2.9–5.2)	4.1(3.2–5.2)	0.695
Lymphocyte	1.7 ± 0.5	1.8 ± 0.6	0.400
Monocyte	0.5(0.4–0.6)	0.5(0.4–0.6)	0.624
Thrombocyte	238.5 ± 79.4	229.6 ± 79.6	0.482
PLR	130.9(107.8-191.6)	133.6(90.2-184.8)	0.291
NLR	2.3(1.7–3.6)	2.5(1.7–3.3)	0.984
LMR	3.8 ± 1.9	3.7 ± 1.6	0.761
HB	131.0(114.0-140.0)	138.0(129.0-151.0)	0.000
TBIL	16.0(11.0-42.5)	17.0(12.6–37.9)	0.560
DBIL	5.6(3.9–26.5)	4.9(3.3–19.5)	0.373
IBIL	10.0(6.7–16.0)	11.8(8.6–19.9)	0.033
Alkaline phosphatase	111.0(81.3–236.0)	88.0(67.5-189.2)	0.054
Ureophil	5.4 ± 1.7	5.7 ± 1.7	0.276
Uric Acid	270.3 ± 104.5	303.1 ± 104.0	0.052
Creatinine	60.0 ± 19.6	71.8 ± 22.0	0.000
SMI,cm²	41.7 ± 6.9	49.5 ± 8.5	0.000
SMA, HU	108.0(97.4-127.6)	139.7(116.0-163.0)	0.000
SAT, cm²	135.9 ± 63.7	132.2 ± 65.5	0.461
VAT, cm²	100.5(60.4-165.1)	129.2(73.7-209.1)	0.123
IMAT, cm²	8.0 ± 5.0	5.8 ± 3.7	0.003
VSR	0.7(0.5–1.1)	1.0(0.7–1.3)	0.009
Sarcopenia Yes No	48(57.8%) 35(42.2%)	28(38.4%) 45(61.6%)	0.015
GGT	91.0(43.0-280.0)	65.0(30.5–219.0)	0.379

3.2 Correlation between Myosteatosis, Elevated GGT, and Overall Survival

Comparison of the overall survival (OS) rates revealed that the myosteatosis group demonstrated a significantly lower survival rate than the non-myosteatosis group. The median OS time in the myosteatosis group was 25.3 months, as opposed to 42.2 months in the non-myosteatosis group (P = 0.017) (Fig. 3a).Likewise, cholangiocarcinoma patients with gamma-glutamyltransferase (GGT) levels ≥ 136.5 U/L had a notably worse prognosis than those with GGT levels < 136.5 U/L. The median OS in patients with elevated GGT (≥ 136.5 U/L) was 16.3 months, compared to 42.2 months in patients with lower GGT (< 136.5 U/L) levels (P = 0.007) (Fig. 3b).These results underline the significant correlation between myosteatosis, elevated GGT levels, and poor OS in cholangiocarcinoma patients. This suggests that both myosteatosis and GGT levels could be used as potential prognostic factors in these patients.

3.3 Univariate and Multivariate Cox Regression Analysis for Overall Survival

Univariate Cox regression analysis identified several significant predictors for overall survival (OS). Factors including age (hazard ratio (HR) 1.034, P = 0.024), lymph node metastasis (HR 3.287, P < 0.001), albumin (ALB) (HR 0.924, P < 0.001), prealbumin (HR 0.994, P < 0.001), CA199 ≥ 1000 (HR 2.150, P = 0.007), CA125 (HR 1.002, P = 0.004), hemoglobin (HB) (HR 0.980, P = 0.001), direct bilirubin (DBIL) (HR 1.003, P < 0.001), alkaline phosphatase (HR 1.007, P = 0.023), indirect bilirubin (IBIL) (HR 1.001, P = 0.007), uric acid (HR 0.997, P = 0.013), GGT ≥ 136.5 (HR 2.080, P = 0.006), and myosteatosis (HR 1.879, P = 0.022) were found to be statistically significant. Inflammatory markers such as white blood cell (WBC) count (HR 1.185, P < 0.001), neutrophil count (HR 1.211, P < 0.001), platelet-to-lymphocyte ratio (PLR) (HR 1.004, P = 0.026), neutrophil-to-lymphocyte ratio (NLR) (HR 1.186, p < 0.001), and lymphocyte-to-monocyte ratio (LMR) (HR 0.829, P = 0.024) were also significantly correlated with OS.

However, factors such as gender, body mass index (BMI), smoking status, alcohol consumption, liver cirrhosis, nerve invasion, vascular invasion, alpha-fetoprotein (AFP), and carcinoembryonic antigen (CEA) were not found to significantly correlate with OS (P > 0.05).

Subsequent multivariate Cox regression analysis further refined these findings, identifying lymph node metastasis (HR 3.224, P < 0.001), CA199 ≥ 1000 (HR 2.394, P = 0.007), and CA125 (HR 1.002, P = 0.013) as independent predictors of overall survival in cholangiocarcinoma patients following radical resection (Table 3).

3.4 Univariate and Multivariate Cox Regression Analysis for Recurrence-Free Survival

Table 4 shows the results of univariate and multivariate Cox regression analyses for recurrence-free survival (RFS). The univariate analysis identified age (HR 1.033, P = 0.026), GGT (HR 2.122, P = 0.005), vascular invasion (HR 1.684, p = 0.047), lymph node metastasis (HR 3.301, P < 0.001), albumin (ALB) (HR 0.920, P < 0.001), prealbumin (HR 0.994, P < 0.001), CA199 ≥ 1000 (HR 2.575, P = 0.001), CA125 (HR 1.002, P = 0.003), hemoglobin (HB) (HR 0.978, P = 0.001), total bilirubin (TBIL) (HR 1.002, P = 0.029), direct bilirubin (DBIL) (HR 1.003, P = 0.026), indirect bilirubin (IBIL) (HR 1.006, P = 0.046), alkaline phosphatase (HR 1.001, P = 0.008), uric acid (HR 0.997, P = 0.016), and myosteatosis (HR 1.926, P = 0.017) as predictors of RFS. Inflammatory markers such as white blood cell (WBC) count (HR 1.180, P < 0.001), neutrophil count (HR 1.205, P < 0.001), platelet-to-lymphocyte ratio (PLR) (HR 1.004, P = 0.031), neutrophil-to-lymphocyte ratio (NLR) (HR 1.254, P < 0.001), and lymphocyte-to-monocyte ratio (LMR) (HR 0.805, P = 0.012) were also found to be significantly related to RFS. However, gender, smoking status, alcohol consumption, tumor size, nerve invasion, and recurrence were not significantly correlated with RFS.

Following multivariate analysis, vascular invasion (HR 2.182, P = 0.008), lymph node metastasis (HR 3.215, P < 0.001), CA199 ≥ 1000 (HR 3.235, P < 0.001), CA125 (HR 1.002, P = 0.006), and myosteatosis (HR 1.996, P = 0.043) were identified as independent prognostic factors for RFS.

Patients in the myosteatosis group demonstrated significantly shorter RFS compared to those in the non-myosteatosis group (median, 21.8 vs. 34.5 months, P = 0.013) (Fig. 3c). Similarly, patients with GGT ≥ 136.5 experienced shorter RFS compared to those with GGT < 136.5 (median, 14.5 vs. 39.9 months, P = 0.006) (Fig. 3d).

3.5 Prognostic Value of Myosteatosis Combined with Gamma-Glutamyltransferase

The study investigated the prognostic value of myosteatosis combined with gamma-glutamyltransferase (GGT) for patients with cholangiocarcinoma (CCA). For this purpose, all patients were divided into four groups based on the presence or absence of myosteatosis and the level of GGT. The groups were: myosteatosis with GGT ≥ 136.5, myosteatosis with GGT < 136.5, non-myosteatosis with GGT ≥ 136.5, and non-myosteatosis with GGT < 136.5.

The median overall survival (OS) and recurrence-free survival (RFS) for these four groups were 14.6, 35.8, 16.3, and 42.2 months, and 13.4, 35.8, 16.3, and 39.7 months, respectively. This data showed that patients with both myosteatosis and GGT ≥ 136.5 experienced the worst prognosis, having the shortest median OS and RFS (Fig. 3e, f).

Figure 3 provides the Kaplan-Meier curves for OS and RFS in all patients. Subfigures illustrate comparisons of OS and RFS between myosteatosis and non-myosteatosis patients (Fig. 3a, c), between patients with GGT ≥ 136.5 and those with GGT < 136.5 (Fig. 3b, d), and between all patient groups based on the presence or absence of myosteatosis and GGT levels (Fig. 3e, f). The key takeaway from these figures is that myosteatosis, especially in combination with elevated GGT levels, negatively impacts both overall and recurrence-free survival.

Figure 3 Kaplan-Meier curves of OS and RFS for all patients. (a) Comparison of OS between myosteatosis and non-myosteatosis patients. (b) Comparison of OS between patients with a GGT ≥ 136.5 and those with a GGT༜136.5. (c) Comparison of RFS between myosteatosis and non-myosteatosis patients. (d) Comparison of RFS between patients with a GGT ≥ 136.5 and those with a GGT༜136.5. (e) Kaplan-Meier curves of OS for all patient groups based on the presence or absence of myosteatosis and the GGT. (f) Kaplan-Meier curves of RFS for all patient groups based on the presence or absence of myosteatosis and the GGT. OS, overall survival; RFS, recurrence-free survival; GGT, gamma-glutamyltransferase.

Table 3 Univariate and multivariate Cox proportional hazard regression analysis of OS

Variables	Univariate analysis	Multivariate analysis
	HR (95% CI) P	HR (95% CI) P
Age	1.034（1.004-1.064）0.024	1.030（0.993-1.069）0.117
Gender	1.162（0.700-1.928）0.562
BMI	0.904（0.541-1.511）0.699
Smoke	0.824（0.451-1.505）0.529
Drink	1.268（0.722-2.228）0.408
Hypertension	0.959（0.546-1.683）0.884
Diabetes	1.213（0.644-2.285）0.551
Hepatitis B	0.595（0.238-1.488）0.267
Liver cirrhosis	0.484（0.194-1.209）0.120
Tumor size	1.430（0.860-2.377）0.168
Nerve invasion	1.562（0.938-2.601）0.086
Vascular invasion	1.572（0.940-2.629）0.084
Lymph node metastasis	3.287（1.966-5.497）0.000	3.224（1.813-5.732）0.000
Biliary calculus	1.226（0.651-2.310）0.528
ALB	0.924（0.885-0.965）0.000	0.986（0.909-1.070）0.739
Prealbumin	0.994（0.991-0.997）0.000	1.000（0.994-1.006）0.951
CA199 ≥1000 ＜1000	2.150（1.235-3.742）0.007	2.394（1.268-4.519）0.007
CA125	1.002（1.001-1.003）0.004	1.002（1.000-1.004）0.013
CEA	1.000（0.998-1.002）0.918
AFP	0.997（0.983-1.010）0.616
ALT	1.001（0.999-1.003）0.522
AST	1.001（0.999-1.004）0.388
WBC	1.185（1.097-1.281）0.000	1.066（0.536-2.119）0.856
Neutrophil	1.211（1.117-1.313）0.000	1.146（0.489-2.684）0.754
Lymphocyte	0.702（0.434-1.136）0.149
Monocyte	0.978（0.900-1.062）0.600
Thrombocyte	1.001（0.998-1.005）0.380
PLR	1.004（1.000-1.008）0.026	0.995（0.989-1.001）0.122
NLR	1.186（1.104-1.275）0.000	1.046（0.863-1.267）0.649
LMR	0.829（0.704-0.976）0.024	1.033（0.804-1.326）0.801
HB	0.980（0.968-0.992）0.001	1.002（0.980-1.023）0.876
TBIL	1.002（1.000-1.004）0.014	1.014（0.982-1.048）0.381
DBIL	1.003（1.001-1.005）0.013	0.983（0.941-1.027）0.448
IBIL	1.007（1.001-1.013）0.023	NA
Alkaline phosphatase	1.001（1.000-1.003）0.007	0.999（0.997-1.001）0.511
Ureophil	0.917（0.787-1.068）0.264
Uric Acid	0.997（0.994-0.999）0.013	0.998（0.994-1.002）0.351
Creatinine	0.992（0.980-1.005）0.212
SMI	0.989（0.960-1.019）0.470
SMA	0.997（0.989-1.006）0.545
SAT	0.999（0.995-1.003）0.570
VAT	1.000（0.996-1.003）0.776
IMAT	1.037（0.983-1.094）0.184
VSR	0.855（0.553-1.322）0.481
Recurrence	1.078（0.614-1.891）0.794
GGT	2.080（1.238-3.495）0.006	1.447（0.649-3.226）0.367
Myosteatosis	1.879（1.097-3.218）0.022	1.877（0.968-3.641）0.062
Sarcopenia	1.069（0.644-1.775）0.795

Table 4 Univariate and multivariate Cox proportional hazard regression analysis of RFS.

Variables	Univariate analysis	Multivariate analysis
	HR (95% CI) P	HR (95% CI) P
Age	1.033（1.004-1.063）0.026	1.027（0.991-1.065）0.145
Gender	0.842（0.507-1.398）0.506
BMI	0.917（0.549-1.532）0.740
Smoke	0.807（0.442-1.474）0.485
Drink	1.215（0.691-2.135）0.500
Hypertension	0.923（0.526-1.621）0.781
Diabetes	1.156（0.613-2.180）0.655
Hepatitis B	0.626（0.250-1.564）0.316
Liver cirrhosis	0.507（0.203-1.267）0.146
Tumor size	1.587（0.955-2.637）0.075
Nerve invasion	1.550（0.931-2.581）0.092
Vascular invasion	1.684（1.007-2.815）0.047	2.182（1.225-3.884）0.008
Lymph node metastasis	3.301（1.969-5.533）0.000	3.215（1.799-5.744）0.000
Biliary calculus	1.210（0.642-2.279）0.556
ALB	0.920（0.882-0.960）0.000	0.987（0.909-1.073）0.765
Prealbumin	0.994（0.991-0.997）0.000	0.998（0.992-1.004）0.570
CA199 ≥1000 ＜1000	2.575（1.473-4.501）0.001	3.235（1.733-6.037）0.000
CA125	1.002（1.001-1.003）0.003	1.002（1.001-1.004）0.006
CEA	1.000（0.998-1.002）0.881
AFP	0.997（0.988-1.007）0.576
ALT	1.000（0.998-1.003）0.744
AST	1.001（0.998-1.003）0.566
WBC	1.180（1.096-1.270）0.000	1.481（0.759-2.890）0.249
Neutrophil	1.205（1.116-1.301）0.000	0.728（0.321-1.652）0.448
Lymphocyte	0.729（0.455-1.166）0.187
Monocyte	0.990（0.913-1.073）0.804
Thrombocyte	1.002（0.999-1.006）0.225
PLR	1.004（1.000-1.007）0.031	0.995（0.989-1.001）0.102
NLR	1.254（1.150-1.367）0.000	1.240（1.010-1.522）0.040
LMR	0.805（0.680-0.954）0.012	0.967（0.750-1.247）0.798
HB	0.978（0.966-0.990）0.000	1.000（0.978-1.022）0.996
TBIL	1.002（1.000-1.004）0.029	1.021（0.987-1.057）0.232
DBIL	1.003（1.000-1.005）0.026	0.973（0.928-1.020）0.250
IBIL	1.006（1.000-1.012）0.046	NA
Alkaline phosphatase	1.001（1.000-1.003）0.008	0.999（0.997-1.001）0.339
Ureophil	0.896（0.770-1.043）0.155
Uric Acid	0.997（0.994-0.999）0.016	1.000（0.996-1.003）0.840
Creatinine	0.992（0.980-1.004）0.214
SMI	0.984（0.955-1.015）0.310
SMA	0.996（0.988-1.005）0.385
SAT	0.999（0.995-1.003）0.538
VAT	0.999（0.996-1.002）0.641
IMAT	1.031（0.976-1.089）0.274
VSR	0.830（0.539-1.280）0.399
Recurrence	1.615（0.917-2.843）0.097
GGT	2.122（1.261-3.570）0.005	1.716（0.763-3.859）0.191
Myosteatosis	1.926（1.125-3.297）0.017	1.996（1.021-3.900）0.043
Sarcopenia	1.098（0.662-1.822）0.718

Changes in body composition are common occurrences in patients suffering from malignant tumors, the primary of which include sarcopenia and myosteatosis. These changes are independent of each other and can be evaluated using imaging techniques such as computed tomography (CT)[23, 24]. Current research indicates that sarcopenia, which refers to the progressive and generalized loss of skeletal muscle mass and strength, is associated with poorer prognosis in patients with various types of cancers, including pancreatic cancer, esophageal cancer, and colorectal cancer[25].

However, the results from this study present a different perspective. In the context of cholangiocarcinoma (CCA), we found that isolated sarcopenia was not associated with patient outcomes following radical resection. This emphasizes the complex relationship between body composition and cancer outcomes, which can vary across different types of cancers and individual patient characteristics. It also underscores the need for more specific and individualized approaches in assessing and addressing body composition changes in cancer patients, particularly in the context of CCA.

Myosteatosis, which refers to the increased infiltration of fat within muscle tissues, has been linked to reduced survival rates in patients with malignant tumors. This is largely attributed to the role myosteatosis plays in promoting oxidative stress and chronic inflammatory responses in the body[26, 27]. Firstly, the onset of myosteatosis leads to the accumulation of harmful substances such as diacylglycerol and ceramides[26]. These substances contribute to an increased state of oxidative stress, creating an environment conducive to the survival and proliferation of tumor cells.In addition to promoting oxidative stress, myosteatosis can also spur the onset of chronic inflammation. Specifically, the deposition of ectopic adipose tissue within muscle can trigger the production of pro-inflammatory mediators, thereby disrupting normal metabolic processes and inducing a chronic inflammatory state[28]. In alignment with these previous research findings, our study also illustrates the negative impact of myosteatosis on the prognosis of patients with cholangiocarcinoma (CCA). Our results reveal that patients who develop myosteatosis prior to undergoing surgical resection have poorer overall survival (OS) and recurrence-free survival (RFS) when compared to their counterparts without this condition. This underscores the importance of accounting for myosteatosis when assessing patient prognosis and planning treatment strategies in the context of CCA.

To this juncture, explorations delving into the underpinnings of the correlation between gamma-glutamyl transferase (GGT) and adverse prognoses in malignant neoplasms remain regrettably sparse. Esteemed as a mercaptan-rich enzyme, GGT is most profuse within the renal system, trailed by the pancreas, pulmonary organs, and hepatic structures, where it partakes in the conveyance of glutamine molecules throughout the organism[29, 30]. The current corpus of scientific literature posits that GGT plays a cardinal role in contributing to unfavorable outcomes in oncology patients by stimulating the generation of reactive oxygen species (ROS) within the neoplastic microcosm, thereby spurring the proliferation, expansion, and infiltration of the malignant growth[31]. A surge in GGT concentrations may be discerned in a diversity of hepatobiliary maladies, cementing its reputation as a sensitive and invaluable clinical barometer for these disorders[32–34]. Upon the event of biliary obstruction, GGT measurements may skyrocket, reaching between 5 to 30 times the standard parameters. Given the anatomical locale of cholangiocarcinoma (CCA), it is to be anticipated that patients in the later stages are predisposed to biliary obstructions, resulting in a commensurate escalation in GGT concentrations[35]. Empirical findings have shown that heightened preoperative GGT indices are inextricably linked with adverse outcomes in intrahepatic cholangiocarcinoma (ICC) sufferers[36]. In harmonious accordance with preceding studies, our investigation determined a GGT cut-off point of 136.5. Our observations revealed that CCA patients bearing GGT levels equal to or surpassing 136.5 exhibited significantly diminished overall survival (OS) and recurrence-free survival (RFS) rates, compared to their counterparts with GGT levels below 136.5.

In marked departure from preceding research endeavours, our scholarly probe was the inaugural exploration into the prognostic connotations of a twofold constellation of factors implicated in unfavourable outcomes in cholangiocarcinoma (CCA) patients, namely myosteatosis and gamma-glutamyl transferase (GGT). The fruits of our investigation, culled from a cohort of 156 CCA patients subjected to radical resection, unveiled that those bearing the dual affliction of preoperative myosteatosis and GGT concentrations equal to or exceeding 136.5 suffered the most dire prognosis, a revelation in consonance with our initial hypotheses.

However, our study was not devoid of encumbrances. At the forefront, it was essentially a petite, single-institution, case-control scrutiny with circumscribed representational capacity, thus making it imperative for more expansive, high-caliber, multicenter inquiries to substantiate our deductions. Secondly, we restricted our assessment of the prognostic merits of GGT, conjoined with myosteatosis, to CCA patients who underwent radical resection, oblivious to its potential impact on those subjected to transarterial chemoembolization (TACE) or isolated adjuvant therapy, a lacuna that beckons future explorations.

In conclusion, of the 156 cholangiocarcinoma (CCA) patients who were subjected to radical resection, those afflicted with myosteatosis and gamma-glutamyl transferase (GGT) levels equal to or surpassing 136.5 bore the brunt of the most grievous prognosis and the briefest overall survival (OS) and recurrence-free survival (RFS) intervals. Given that GGT is a readily procurable hematological bioindicator in clinical practice and muscular steatosis is assessable via computed tomography (CT), amalgamating these two elements as prognostic biomarkers for CCA patients could magnify sensitivity and specificity, thus empowering medical practitioners to pinpoint patients with a bleak prognosis at the earliest juncture for nutritional interventions and enhanced outcomes.

Disclosure conflicts of interest: The authors declare no conflict of interest.

Ethics approval and consent to participate

Approval - All data used in this study were anonymized prior to use.

Informed consent - The study received an informed consent exemption, and the full name of the Ethics Committee that waived the need for informed consent is as follows: The Ethics Committee of the Affiliated Hospital of Qingdao University.

Guidelines - All methods were carried out in accordance with relevant guidelines and regulations - Declaration of Helsinki.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Conflict of Interests

The authors declare no conflict of interest.

Funding

This work was supported by grants from the National Natural Science Foundation of Shandong Province (grant number No.ZR 202103040311).

Authors' contributions

L.Y. and J.X. were responsible for the main editing tasks of the manuscript;

S.X and Z.J were responsible for the main aspects of imaging;

S.G and L.Y were mainly responsible for the editing and proofreading of images and tables;

L.Q., Z.L and L.X. were jointly responsible for the data sorting task.

All authors reviewed the manuscript.

Acknowledgements

We would like to thank Taylor & Francis (www.tandfeditingservices.cn) for the English language editing and pre-submission expert review.

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No competing interests reported.

The Augural Interplay of Myosteatosis and Gamma-Glutamyltransferase in Patients Undergoing Comprehensive Surgical Intervention for Cholangiocarcinoma

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Participants

2.2 Accumulation of Clinicopathologic Data

2.3 Body Composition Analysis via CT

2.4 Statistical Analysis

3. Results

3.1 Clinicopathological Characteristics

3.2 Correlation between Myosteatosis, Elevated GGT, and Overall Survival

3.3 Univariate and Multivariate Cox Regression Analysis for Overall Survival

3.4 Univariate and Multivariate Cox Regression Analysis for Recurrence-Free Survival

3.5 Prognostic Value of Myosteatosis Combined with Gamma-Glutamyltransferase

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Status:

Version 1