Prognostic predictive value of sarcopenia and systemic immune-inflammatory index in patients after radical surgery for distal cholangiocarcinoma

Abstract

To investigate the predictive value of sarcopenia and systemic immune-inflammatory index (SII) for short-term complications and long-term outcome after radical surgery in patients with distal cholangiocarcinoma. Retrospective collection of clinical data from patients who underwent radical surgery for distal cholangiocarcinoma was conducted. The patients were then divided into two groups: sarcopenia group and normal group, based on their skeletal muscle index (SMI). Logistic regression was employed to analyze the risk factors for major postoperative complications (Clavien-Dindo ≥ grade III). Additionally, Cox proportional hazards model was used to identify independent risk factors for overall survival (OS) and disease-free survival (DFS). Also, a nomogram model was developed for predicting OS and DFS at 1 and 3 years after surgery. A total of 111 patients were finally included in the study based on the inclusion-exclusion criteria. Multifactorial logistic regression analysis revealed that sarcopenia was an independent risk factor for major postoperative complications in distal cholangiocarcinoma patients (P < 0.001). Furthermore, multifactorial Cox regression analysis indicated that sarcopenia and high SII levels were independent risk factors affecting OS and DFS (P < 0.05). A nomogram model, incorporating preoperative sarcopenia, SII, and other factors, exhibited strong predictive efficacy, calibration, and clinical utility for OS and DFS after radical surgery. Sarcopenia and high SII levels are associated with poor prognosis and are independent risk factors for OS and DFS in patients undergoing radical surgery for distal cholangiocarcinoma. Sarcopenia and SII are convenient, inexpensive, and reliable markers for improving postoperative prognosis and new therapeutic strategies for patients with distal cholangiocarcinoma.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-30485-5.

Introduction

Cholangiocarcinoma is a profoundly invasive malignancy originating from the biliary epithelium. Depending on its anatomical location, cholangiocarcinoma can be categorized as intrahepatic cholangiocarcinoma (ICCA), perihilar cholangiocarcinoma (PCCA), or distal cholangiocarcinoma (DCCA)¹. Cholangiocarcinoma (CCA) is typically asymptomatic and is often diagnosed at advanced stages. Approximately 30% of patients have the possibility of undergoing radical surgical resection². Numerous previous investigations have explored the factors affecting the prognosis of cholangiocarcinoma. These factors include tumor dimensions, lymph node metastasis, tumor differentiation, vascular invasion, and positive surgical margins. It is noteworthy that the majority of these factors are tumor-specific^3,4. However, the above tumor-specific factors were obtained from postoperative pathological data with a certain lag. Furthermore, the prognostic outcome of patients with malignant tumors after radical surgery is related to surgical and host factors in addition to tumor characteristics⁵. Among these factors, the nutritional and inflammatory status of the patient is considered to be the key host-related factors⁶. The identification of patients at risk of poor postoperative outcomes and the subsequent administration of consolidation therapy pose significant challenges for clinicians. Consequently, there is a pressing need for objective and practical markers to accurately predict the prognosis of patients with distal cholangiocarcinoma.

Sarcopenia is characterized as a progressive, generalized skeletal muscle disorder that impacts both muscle mass and function. This definition, put forth by the European Working Group on Sarcopenia in Older People (EWGSOP), has gained widespread global acceptance⁷. Among body components, reduced skeletal muscle content or mass is a key factor reflecting malnutrition or cachexia in patients, most often seen in patients with various wasting diseases^8,9. In recent years, computed tomography (CT) and magnetic resonance imaging (MRI) have emerged as widely adopted gold standards for diagnosing sarcopenia and evaluating body composition¹⁰. Accurately determining clinically relevant body composition parameters during a clinical examination can be achieved through straightforward measurements on a single axial CT or MRI slice^11,12. This study employed the skeletal muscle index (SMI) to evaluate both muscle content and nutritional status in patients, aiming to investigate its correlation with short-term complications and long-term outcomes following radical surgery for distal cholangiocarcinoma.

Inflammation, a hallmark of cancer, has been shown to play a key role in tumorigenesis, angiogenesis, metastasis and invasion^13–15. Recently, several studies have shown that inflammatory markers such as neutrophil count, lymphocyte count, platelet count, neutrophil–to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with patient survival and have prognostic value in a variety of malignancies including colorectal, renal cell, ovarian and endometrial cancers^16–19. Hu et al. formulated a Systemic Immune-Inflammation Index (SII) by amalgamating inflammatory markers, including lymphocyte, neutrophil, and platelet counts. This index has demonstrated efficacy in predicting an unfavorable prognosis in patients diagnosed with hepatocellular carcinoma²⁰. The connection between the SII and both short-term complications and long-term survival in patients with distal cholangiocarcinoma undergoing radical surgery has not been extensively examined. In essence, this study aims to investigate the accuracy of prognostic predictions for distal cholangiocarcinoma patients following radical resection by integrating sarcopenia with SII.

Method

Study population

This retrospective study recruited 111 patients diagnosed with distal cholangiocarcinoma who underwent surgical treatment at the First Hospital of Lanzhou University from January 2017 to September 2022. The inclusion criteria were as follows: (1) confirmed pathological diagnosis of distal cholangiocarcinoma based on surgically resected specimens; (2) absence of preoperative antitumour therapies, such as radiotherapy and chemotherapy; and (3) availability of comprehensive clinicopathological and imaging data along with follow-up information. The exclusion criteria were as follows: (1) a pathological diagnosis indicating intrahepatic or hilar cholangiocarcinoma among others; (2) distal cholangiocarcinoma with a history of previous surgical or complementary treatment; and (3) incomplete clinicopathological or imaging data.

Data regarding patient sex, age, albumin-to-globulin ratio (AGR), carcinoembryonic antigen (CEA), carbohydrate antigen 19 − 9 (CA 19 − 9), TNM tumor stage, differentiation grade, obstructive jaundice and postoperative complication status were collected through electronic medical records. SII was calculated as “platelet count x neutrophil count/lymphocyte count”. Follow-up were made every three months after surgery, continuing for two years after surgery and every six months thereafter. Until the patient loses the follow-up or dies. Overall survival (OS) was calculated from the date of surgery to the date of death or the last follow-up. Disease-free survival (DFS) was defined as the interval between surgery and tumor recurrence, including distant metastasis and local recurrence.

Image analysis

All the examinations were performed using a Siemens Sensation 16 CT scanner. Skeletal muscle area was measured at the level of the third lumbar vertebra using a segmentation tool (TOMOVISION-sliceOmatic, Version 5.0). Cross-sectional skeletal muscle area was measured at the level of the third lumbar vertebra (L3), as reported in previous articles²¹. Skeletal muscle regions were identified and quantified based on attenuation values falling within the range of -29 to + 150 Hounsfield units (HU), as illustrated in Fig. 1. Skeletal muscle mass was assessed using the SMI, which is calculated from the skeletal muscle area (cm²) normalized by the patient’s height (m²).

Fig. 1.

Cross-sectional computed tomography (CT) findings at the third lumbar vertebra. The red shadows show the skeletal muscle areas.

Statistical analysis

Statistical analysis was performed using R software (version 4.2.2). For intergroup comparisons, Fisher’s exact test or the Chi-squared test was used for categorical variables, while the independent samples T-test or the Mann‒Whitney U test was used for continuous variables. Continuous variables are expressed as the mean (standard deviation) or median (interquartile range), and categorical variables are presented as percentages. The Kaplan–Meier method was used to estimate OS and DFS in different subgroups. Pancreatic fistula, delayed gastric emptying, bile leakage, postoperative bleeding, abdominal infection, and pulmonary infection were defined by the International Pancreatic Surgery Study Group. Major postoperative complications were defined as Class III or higher on the Clavien-Dindo classification²². Multivariate logistic regression was used to investigate the factors related to major postoperative complications. Cox proportional hazards models were used to identify the factors that influence OS and DFS. The R package rms was used to construct the nomogram models, and calibration curve, decision curve analysis (DCA) and C-index were used to verify their predictive ability. P < 0.05 was considered indicative of statistical significance.

X-tile software(Yale University, New Haven, CT, version 3.6.1), a novel bioinformatics tool for biomarker assessment and outcome-based cut-point optimization²³, was used to determine thresholds for preoperative SMI, SII, and AGR levels. Considering the differences in body composition between genders, the optimal cut-off values for SMI were 38.00 cm²/m² for males and 36.65 cm²/m² for females, and sarcopenia was defined as SMI below the optimal cut-off values. the optimal cut-off values for SII and AGR were 355 and 1.6.

Result

Baseline characteristics

Table 1 shows the baseline information. A total of 111 distal cholangiocarcinoma patients (sarcopenia group: 19; normal group: 92) who underwent radical surgery were included in the study. The mean value of BMI in the normal group was higher than in the sarcopenia group (P = 0.001). Age (P = 0.004) and TNM stage (P = 0.047) were significantly higher in the sarcopenia group.

Table 1.

Baseline characteristics of patients with and without sarcopenia.

Variables	Total Cohort (n = 111)	Normal Cohort (n = 92)	Sarcopenia Cohort (n = 19)	P value
Age [mean (SD), years]	60.14(10.30)	58.89(10.15)	66.21(8.94)	0.004*
Gender (female, %)	41.00(36.90)	32.00(34.80)	9.00(47.40)	0.439
BMI [mean (SD), Kg/m2]	23.36(2.99)	23.79(2.79)	21.26(3.11)	0.001*
Hypertensive (%)	17.00(15.30)	13.00(14.10)	4.00(21.10)	0.680
Diabetes (%)	8.00(7.20)	5.00(5.40)	3.00(15.80)	0.271
AGR [median (IQR)]	1.47(1.31,1.62)	1.45(1.32,1.61)	1.58(1.32,1.64)	0.655
SII (high, (%)	91.00(82.00)	74.00(80.40)	17.00(89.50)	0.545
CEA [median (IQR), ng/mL]	2.40(1.65,3.45)	2.30(1.60,3.52)	2.40(1.95,3.15)	0.592
CA19-9 [median (IQR), U/mL]	111.00(41.20,294.50)	102.60(37.30,290.75)	173.00(96.55,331.65)	0.172
Obstructive jaundice (%)	95.00(85.60)	79.00(85.90)	16.00(84.20)	1.000
Tumor differentiation (%)				0.403
Well	6.00(5.40)	5.00(5.40)	1.00(5.30)
Moderate	96.00(86.50)	81.00(88.00)	15.00(78.90)
Poor	9.00(8.10)	6.00(6.50)	3.00(15.80)
T Stage (T3-T4, %)	40.00(36.00)	32.00(34.80)	8.00(42.10)	0.732
N Stage (N1-N2, %)	44.00(39.60)	35.00(38.00)	9.00(47.40)	0.618
TNM Stage (III-IV, %)	12.00(10.80)	7.00(7.60)	5.00(26.30)	0.047*
Lymphatic invasion (%)	47.00(42.30)	43.00(46.70)	4.00(21.10)	0.071
Vascular invasion (%)	28.00(25.20)	25.00(27.20)	3.00(15.80)	0.453
Perineural invasion (%)	87.00(78.40)	74.00(80.40)	13.00(68.40)	0.394
Blood Transfusion (%)	30.00(27.00)	26.00(28.30)	4.00(21.10)	0.719
Surgical Approach (%)				0.374
Open	95.00(85.60)	77.00(83.70)	18.00(94.70)
Laparoscopic	16.00(14.40)	15.00(16.30)	1.00(5.30)

Note: BMI, body mass index; AGR, albumin/globulin; SII, systemic immune-inflammatory index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; TNM, tumor node metastasis; SD, standard deviation; IQR, interquartile range; * Statistically significant.

Postoperative complications and risk factors

Patients who underwent radical surgery developed complications as shown in Supplementary Table 1. Patients in the sarcopenia group who developed major postoperative complications (P = 0.001) and patients who developed death within 90 days after surgery (P < 0.001) were significantly higher than those in the normal group.

The analysis of risk factors for major postoperative complications in patients with distal cholangiocarcinoma is shown in Table 2. Logistic regression analysis showed that sarcopenia (OR: 7.69, 95% CI: 2.38-25.00, P < 0.001), intraoperative blood transfusion (OR: 3.12, 95% CI: 1.08–9.42, P = 0.038), and hypertension (OR: 3.55, 95% CI: 1.01–12.82, P = 0.048) were independent risk factors for major postoperative complications in patients with distal cholangiocarcinoma.

Table 2.

Univariate and multivariate logistic regression analysis of risk factors for major postoperative complications.

Factors	Univariable analysis		Multivariable analysis
	OR (95%CI)	P value	OR (95%CI)	P value
Age (years)	1.05(1.00,1.11)	0.048*	1.01(0.95,1.06)	0.850
Gender (male/female)	0.65(0.24,1.62)	0.360
BMI (Kg/m2)	0.95(0.82,1.10)	0.490
Hypertensive (Yes/No)	3.51(1.18,10.42)	0.020*	3.55(1.01,12.82)	0.048*
Diabetes (Yes/No)	3.48(0.77,15.77)	0.090
AGR (< 1.6/≥1.6)	0.29(0.05,1.41)	0.150
CEA (µg/L)	1.00(0.99,1.04)	0.280
CA19-9(U/mL)	1.00(1.00,1.00)	0.760
SII(High/Low)	1.04(0.31,3.03)	0.940
Obstructive jaundice (Yes/No)	2.13(0.65,6.25)	0.190
Tumor differentiation (Well/Moderate or Poor)	1.58(0.48,5.27)	0.450
T Stage (T1-T2/ T3-T4)	1.60(0.65,3.88)	0.300
N Stage (N0/N1-N2)	1.94(0.81,4.71)	0.140
TNM Stage (I-II/III-IV)	2.50(0.68,8.62)	0.150
Lymphatic invasion (Yes/No)	0.61(0.24,1.47)	0.290
Vascular invasion (Yes/No)	0.60(0.18,1.68)	0.360
Perineural invasion (Yes/No)	0.72(0.27,2.10)	0.530
Blood Transfusion (Yes/No)	2.35(0.92,5.92)	0.050*	3.12(1.08,9.42)	0.038*
Laparoscopic surgery (Yes/No)	0.66(0.22,2.29)	0.490
Sarcopenia (Yes/No)	6.67(2.27, 20.00)	< 0.001*	7.69(2.38,25.00)	< 0.001*

Note: BMI, body mass index; AGR, albumin/globulin; SII, systemic immune-inflammatory index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; TNM, tumor node metastasis; OR, Odds ratio; IQR, interquartile range; CI, Confidence interval; * Statistically significant.

Clinical prediction models for survival and disease-free in distal cholangiocarcinoma patients after radical surgery

The median follow-up period was 36.0 months. Survival curves showed that patients with sarcopenia had significantly worse OS and DFS than those normal group, patients with high SII had also significantly worse OS and DFS than those normal group (Fig. 2A-D). The results from the Cox regression analysis revealed independent risk factors for both OS and DFS. Sarcopenia, high SII, TNM stage III, diabetes, and low AGR emerged as independent risk factors for OS (refer to Table 3). Additionally, sarcopenia, high SII, diabetes, and low AGR were identified as independent risk factors for DFS (refer to Supplementary Table 2). We visualized the models by developing nomogram model combining sarcopenia and SII to assess OS and DFS after radical surgery in distal cholangiocarcinoma patients (Fig. 3A-B). The receiver operating characteristics (ROC) results showed that the 1-year OS nomogram model area under the curve (AUC) = 0.77 (95%CI: 0.65–0.89), the 3-year OS nomogram model AUC = 0.80 (95%CI: 0.71–0.90), the 1-year DFS nomogram model AUC = 0.73 (95%CI: 0.63–0.83), the 3-year DFS nomogram model AUC = 0.74 (95%CI: 0.62–0.87), indicating that the nomogram models were well differentiated (Fig. 4A-D). Calibration plots of OS and DFS at 1 and 3 years showed good concordance between the nomogram model predictions and the actual observations (Fig. 5A-D). The C-index of the OS nomogram is 0.75(95%CI: 0.68–0.81) and the C-index of the DFS nomogram is 0.71 (95%CI: 0.64–0.78), which shows that the nomogram model has a strong prediction ability. By plotting the decision curve analysis (DCA) for OS and DFS, it can be seen that the nomogram model has better clinical utility than a single predictor (Supplementary Fig. 1A-D).

Fig. 2.

Overall survival analysis using the SMI and SII as predictors. Kaplan-Meier curves for overall survival (A) and disease-free survival (C) in the low SMI (sarcopenia) or high SMI (normal) groups. Kaplan-Meier curves for overall survival (B) and disease-free survival (D) in the low SII or high SII groups. Abbreviations: SMI, skeletal muscle index; SII, systemic immune-inflammatory index.

Table 3.

Univariate and multivariate Cox regression analysis of factors associated with overall survival.

Factors	Univariable analysis		Multivariable analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Age (years)	1.41(0.83,2.40)	0.200
Gender (male/female)	0.70(0.40,1.23)	0.220
Hypertensive (Yes/No)	0.90(0.43,1.91)	0.790
Diabetes (Yes/No)	4.10(1.83,9.20)	< 0.001*	5.27(2.23,12.44)	< 0.001*
AGR (< 1.6/≥1.6)	2.58(1.50,4.45)	< 0.001*	3.13(1.72,5.68)	< 0.001*
CEA (µg/L)	1.73(0.74,4.05)	0.210
CA19-9(U/mL)	1.89(0.92,3.85)	0.080
SII(High/Low)	2.95(1.25,6.94)	0.013*	3.02(1.22,7.47)	0.017*
Obstructive jaundice (Yes/No)	3.20(1.15,8.95)	0.026*	1.38(0.45,4.16)	0.570
Tumor differentiation (Well/Moderate or Poor)	1.98(0.36,10.96)	0.430
T Stage (T1-T2/ T3-T4)	1.35(0.80,2.29)	0.270
N Stage (N0/N1-N2)	1.61(0.95,2.72)	0.074
TNM Stage (I-II/III-IV)	2.24(1.00,5.02)	0.050*	2.46(1.03,5.83)	0.042
Lymphatic invasion (Yes/No)	0.84(0.49,1.44)	0.530
Vascular invasion (Yes/No)	0.97(0.53,1.75)	0.910
Perineural invasion (Yes/No)	2.13(0.96,4.71)	0.062
Blood Transfusion (Yes/No)	1.43(0.81,2.52)	0.210
Laparoscopic surgery (Yes/No)	2.08(0.75,5.76)	0.160
Sarcopenia (Yes/No)	2.70(1.45, 5.00)	0.002*	2.77(1.47, 5.26)	0.002*

Note: AGR, albumin/globulin; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; SII, systemic immune-inflammatory index; TNM, tumor node metastasis; HR, Hazard ratio; Confidence interval; * Statistically significant.

Fig. 3.

Nomogram for OS and DFS prediction. (A) Nomogram for OS, (B) Nomogram for DFS. Abbreviations: SMI, skeletal muscle index; SII, systemic immune-inflammatory index; TNM, tumor node metastasis.

Fig. 4.

Nomogram and associated factors predicting ROC curves for overall survival (OS) and disease-free survival (DFS). (A) ROC curve for OS at 1-year after surgery, (B) ROC curve for OS at 3-year after surgery, (C) ROC curve for DFS at 1-year after surgery; (D) ROC curve for DFS at 3-year after surgery; Abbreviations: SMI, skeletal muscle index; SII, systemic immune-inflammatory index; TNM, tumor node metastasis; ROC, receiver operating characteristics.

Fig. 5.

Calibration curve for overall survival (OS) and disease-free survival (DFS). (A) Calibration curve for OS at 1-year after surgery, (B) Calibration curve for OS at 3-year after surgery, (C) Calibration curve for DFS at 1-year after surgery, (D) Calibration curve for DFS at 3-year after surgery; Abbreviations: SMI, skeletal muscle index; SII, systemic immune-inflammatory index; TNM, tumor node metastasis;

Discussion

Existing research has substantiated the significance of nutritional status and the systemic inflammatory response as pivotal factors affecting both postoperative complications and the long-term prognosis of cancer patients^24,25. This study demonstrated that sarcopenia and high SII levels are associated with poor prognosis and are independent risk factors for OS and DFS in patients undergoing radical surgery for distal cholangiocarcinoma. The nomogram prediction model based on sarcopenia and SII can be used to better stratify the prognosis of patients with distal cholangiocarcinoma before surgery and to develop a better treatment strategy for the patients, which has certain clinical application value.

Sarcopenia serves as a common indicator of malnutrition, primarily characterized by the loss of skeletal muscle mass²⁶. Following the guidelines set by EWGSOP, ASW or ALM by BXA or DIA stands as the gold standard for assessing muscle mass in research studies²⁷. Given its preoperative detectability, numerous studies are now exploring the influence of muscle mass on the prognostic outcomes of oncology patients. Recent investigations have revealed a correlation between sarcopenia and unfavorable prognostic outcomes in individuals subjected to radical resection for diverse malignancies, including hepatocellular carcinoma, colorectal cancer, lung cancer, pancreatic cancer, and cholangiocarcinoma^21,28–31. There are several possible explanations for the correlation between sarcopenia and unfavorable prognostic outcomes in cancer patients. Firstly, highly aggressive tumors tend to have higher metabolic activity, which may lead to sarcopenia^21,32. Previous studies have confirmed that CA19-9 affects hematogenous transfer, mediates immune responses and angiogenesis by modifying proteins and through binding to selectins³³. Secondly, skeletal muscle is considered to be a secretory organ with the function of secreting myokines³⁴. Myokines tend to reduce levels of pro-inflammatory cytokines and growth factors such as tumor necrosis factor-α, insulin-like growth factor-I and leptin, which have been shown to play a role in tumor progression. Cancer patients with reduced muscle mass naturally begin to have a reduced ability to secrete myokines, which promotes tumor progression^35–37. Various interventions, including exercise, medication, and nutritional support, are available for managing sarcopenia and mitigating adverse postoperative outcomes in cancer patients. Preoperative administration of high-protein nutritional supplements, with a focus on essential amino acids such as leucine and its metabolite β-hydroxy β-methylbutyrate, has demonstrated positive effects on enhancing muscle mass and function^38,39. Nonetheless, the broad applicability of these interventions requires validation through additional research.

Peripheral cells linked to inflammation, including neutrophils, lymphocytes, and platelets, exhibit significant associations with the progression, metastasis, and immune response in diverse tumor types^40,41. Neutrophils play a pivotal role in influencing the recruitment and activation of inflammatory cells by producing cytokines and chemokines, thereby significantly impacting the tumor microenvironment. Furthermore, neutrophils contribute to the regulation of tumor cell proliferation, angiogenesis, and metastasis through the production of reactive oxygen species and proteases⁴². Recent studies underscore the pivotal role of platelets in both tumorigenesis and progression. Platelets contribute to the induction of epithelial-mesenchymal transition (EMT) and tumor metastasis by synergistically activating the TGFβ1/Smad and NF-κB pathways^43,44. Lymphocytes mediate the immune response to tumor cells and inhibit their proliferation, invasion and migration^45,46. In this study, we also evaluated the prognostic significance of SII, and our results suggest that SII can be used as a strong predictor of poor outcomes in patients after radical surgery for distal cholangiocarcinoma. For patients with high SII, we can reduce the high inflammatory state by taking antibiotics before surgery, which may improve the survival rate of patients after surgery. However, this idea needs to be further confirmed in future research.

Cancer prognosis relies on two pivotal factors: the tumor proliferation rate and the extent of metastatic spread. In numerous malignancies, metastatic spread is a critical determinant, distinguishing between potential curative interventions and the need for palliative care. TNM staging stands out as a robust prognostic parameter across various malignancies⁴⁷. This study also suggests that TNM stage is an independent risk factor for the long-term prognosis of patients with distal cholangiocarcinoma who underwent radical surgery (P < 0.05), and it can be used as a prognostic parameter. Many studies have shown that albumin, which is used to assess nutritional status, is an independent prognostic predictor in patients with various cancers^48,49. Serum globulins play an important role in the inflammatory process of the host by regulating inflammatory cytokines. AGR has been shown to be an independent indicator of different cancers, including colorectal, gastric and breast cancers^50,51. Our findings align with existing evidence, indicating that reduced serum AGR levels correlate with an unfavorable prognosis among surgically treated patients with distal cholangiocarcinoma. Numerous comprehensive cohort studies and meta-analyses have consistently reported an association between diabetes and an elevated risk of various cancers^52–54. The intricate mechanisms underlying the link between diabetes and cancer remain elusive, with the prevailing hypothesis suggesting that hyperinsulinemia may amplify the production of free insulin-like growth factor 1 (IGF-1). The activation of downstream pathways upon IGF-1 binding to its receptor is believed to contribute to processes such as proliferation, invasion, and metastasis^55,56. In alignment with these observations, our study revealed that individuals with distal cholangiocarcinoma and coexisting diabetes mellitus experienced diminished overall survival and disease-free survival following radical surgery.

There are some limitations to this study. Firstly, our study was a retrospective study and there was subject selection bias due to the small sample size included in this study as well as the lack of Absence of internal or external validation of the constructed nomogram model. Secondly, adjuvant therapy after radical surgery has an important impact on survival and disease-free survival. However, this study has not yet analyzed the information related to patients’ postoperative adjuvant therapy, such as whether adjuvant therapy was performed after surgery, the number of adjuvant therapies, and the adjuvant therapy regimen. Therefore, the association between SMI and SII scores and postoperative adjuvant therapy requires further study. Finally, the optimal cut-off values for SMI are lacking because of the large differences in SMI between different geographic regions, races, genders, and age stages; this study refers to the results of Yu Haitao et al.²⁶ to delineate the cut-off values, and the optimal cut-off values for SMI and SII scores will need to be validated using other cohorts.

Conclusion

In summary, sarcopenia and high SII levels are associated with poor prognosis and are independent risk factors for OS and DFS in patients undergoing radical surgery for distal cholangiocarcinoma. Sarcopenia and SII are convenient, inexpensive, and reliable markers for improving postoperative prognosis and new therapeutic strategies for patients with distal cholangiocarcinoma.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AGR

Albumin to globulin ratio

AUC

Area under the curve

CA 19-9

Carbohydrate antigen 19-9

CEA

Carcinoembryonic antigen

CT

Computerized tomography

DCA

Decision curve analysis

DCCA

Distal cholangiocarcinoma

DFS

Disease-free survival

EWGSOP

European working group on sarcopenia in older people

HU

Hounsfield units

ICCA

Intrahepatic cholangiocarcinoma

OS

Overall survival

PCCA

Perihilar cholangiocarcinoma

ROC

Receiver operating characteristic

SMI

Skeletal muscle index

SII

Systemic immune-inflammatory index

TNM

Tumor node metastasis

Author contributions

Z.M. contributed to the conception and design of this work, and wrote and revised the manuscript. Y.L. provided revision and modification on the organization and content of the manuscript. and B.Z. contributed to make tables. P.Y. helped in preparation of the figures. B.L. helped to revise the structure and language of the manuscript. Z.M. performed the analysis of the manuscript. W.M. provided guidance, edited and revised the manuscript, and is responsible for all aspects of the manuscript. All authors contributed to the manuscript and approved the submitted version.

Funding

This study was funded by the Foundation of the Youth Fund of the First Hospital of Lanzhou University, No. ldyyyn2020-64; Science and Technology Planning Project of Chengguan District in Lanzhou, No. 2019JSCX0092; National Natural Science Foundation of China, No. 82460568.

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The data that support the findings of this study are available from the corresponding author, [Wenbo Meng], upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the ethics committee of the First Hospital of Lanzhou University, in accordance with the guidelines of the 1975 Declaration of Helsinki. The Institutional Review Board approved this study (LDYYLL-2023-362). Patient consent was not required to review their medical records by the ethics committee of the First Hospital of Lanzhou University of its retrospective design, and exemption from informed consent did not adversely affect the health and rights of subjects. This study kept confidentiality of patient data and strictly complied with the Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent for this study had been waived by the ethic committee of the First Hospital of Lanzhou University.