Fractal Dimension of Tc-99m DTPA GSA Estimates Pathologic Liver Injury due to Chemotherapy in Liver Cancer Patients



Chemotherapy-induced liver injury after potent chemotherapy is a considerable problem in patients undergoing liver resection. The aim of this study was to assess the relationship between the fractal dimension (FD) of Tc-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) and pathologic change of liver parenchyma in liver cancer patients who have undergone chemotherapy.


We examined 34 patients (10 female and 24 male; mean age, 68.5 years) who underwent hepatectomy. Hepatic injury was defined as steatosis more than 30 %, grade 2–3 sinusoidal dilation, and/or steatohepatitis Kleiner score ≥4. Fractal analysis was applied to all images of Tc-99m DTPA GSA using a plug-in tool on ImageJ software (NIH, Bethesda, MD). A differential box-counting method was applied, and FD was calculated as a heterogeneity parameter. Correlations between FD and clinicopathological variables were examined.


FD values of patients with steatosis and steatohepatitis were significantly higher than those without (P > .001 and P > .001, respectively). There was no difference between the FD values of patients with and without sinusoidal dilatation (P = .357). Multivariate logistic regression showed FD as the only significant predictor for steatosis (P = .005; OR 36.5; 95 % CI 3.0–446.3) and steatohepatitis (P = .012; OR, 29.1; 95 % CI 2.1–400.1).


FD of Tc-99m DTPA GSA was the significant predictor for fatty liver disease in patients who underwent chemotherapy. This new modality is able to differentiate steatohepatitis from steatosis; therefore, it may be useful for predicting chemotherapy-induced pathologic liver injury.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. 1.

    Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065–72.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1–7.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008; 371:1007–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Garufi C, Torsello A, Tumolo S, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010;103:1542–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol. 2009;10:278–86.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Cleary JM, Tanabe KT, Lauwers GY, Zhu AX. Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver. Oncologist. 2009;14:1095–105.

    Article  PubMed  Google Scholar 

  8. 8.

    Krieger PM, Tamandl D, Herberger B, Faybik P, Fleischmann E, Maresch J, et al. Evaluation of chemotherapy-associated liver injury in patients with colorectal cancer liver metastases using indocyanine green clearance testing. Ann Surg Oncol. 2011;18:1644–50.

    Article  PubMed  Google Scholar 

  9. 9.

    Wakiya T, Kudo D, Toyoki Y, et al. Evaluation of the usefulness of the indocyanine green clearance test for chemotherapy-associated liver injury in patients with colorectal cancer liver metastasis. Ann Surg Oncol. 2014;21:167–72.

    Article  PubMed  Google Scholar 

  10. 10.

    Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51:433–45.

    Article  PubMed  Google Scholar 

  11. 11.

    Torizuka K, Ha-Kawa SK, Kudo M, et al. Phase II clinical study on 99mTc-GSA, a new agent for functional imaging of the liver. Kaku Igaku. 1992;29:85–95 [in Japanese].

    CAS  PubMed  Google Scholar 

  12. 12.

    Kira T, Tomiguchi S, Takahashi M, Yoshimatsu S, Sagara K, Kurano R. Correlation of 99mTc-GSA hepatic scintigraphy with liver biopsies in patients with chronic active hepatitis type C. Radiat Med. 1999;17:125–30.

    CAS  PubMed  Google Scholar 

  13. 13.

    Iguchi T, Sato S, Kouno Y, et al. Comparison of Tc-99m-GSA scintigraphy with hepatic fibrosis and regeneration in patients with hepatectomy. Ann Nucl Med. 2003;17:227–33.

    Article  PubMed  Google Scholar 

  14. 14.

    Mandelbrot B. The Fractal Geometry of Nature. New York: W.H. Freeman and Company, 1982.

  15. 15.

    Kido S, Kuriyama K, Higashiyama M, Kasugai T, Kuroda C. Fractal analysis of small peripheral pulmonary nodules in thin-section CT: evaluation of the lung-nodule interfaces. J Comput Assist Tomogr. 2002;26:573–8.

    Article  PubMed  Google Scholar 

  16. 16.

    Huang YL, Chen JH, Shen WC. Diagnosis of hepatic tumors with texture analysis in nonenhanced computed tomography images. Acad Radiol. 2006;13:713–20.

    Article  PubMed  Google Scholar 

  17. 17.

    Hung SH, Lin CY, Lee JY, Tseng H. Computed tomography image characteristics of metastatic lymph nodes in patients with squamous cell carcinoma of the head and neck. Auris Nasus Larynx. 2012;39:606–10.

    Article  PubMed  Google Scholar 

  18. 18.

    Cui C, Cai H, Liu L, Li L, Tian H, Li L. Quantitative analysis and prediction of regional lymph node status in rectal cancer based on computed tomography imaging. Eur Radiol. 2011;21:2318–25.

    Article  PubMed  Google Scholar 

  19. 19.

    Abramyuk A, Wolf G, Shakirin G, et al. Preliminary assessment of dynamic contrast-enhanced CT implementation in pretreatment FDG-PET/CT for outcome prediction in head and neck tumors. Acta Radiol. 2010; 51:793–9.

    Article  PubMed  Google Scholar 

  20. 20.

    Baksi BG, Fidler A. Fractal analysis of periapical bone from lossy compressed radiographs: a comparison of two lossy compression methods. J Digit Imaging. 2011;24:993–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Zorzi D, Mullen JT, Abdalla EK, et al. Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases. J Gastrointest Surg. 2006;10:86–94.

    Article  PubMed  Google Scholar 

  22. 22.

    Tomiyasu S, Hirota M, Ohsima H, Sakamoto Y, Yamazaki K, Ogawa M. Estimation of ICG-R15 from the parameters of 99mTc-GSA liver scintigraphy and application for hepatectomy. Jpn J Gastroenterol Surg. 2000;33:579–83.

    Article  Google Scholar 

  23. 23.

    Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460–6.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  25. 25.

    DeAngelis RA, Markiewski MM, Taub R, Lambris JD. A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaB alpha. Hepatology. 2005;42:1148–57.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Cressman DE, Greenbaum LE, Haber BA, Taub R. Rapid activation of post-hepatectomy factor/nuclear factor kappa B in hepatocytes, a primary response in the regenerating liver. J Biol Chem. 1994;269:30429–35.

    CAS  PubMed  Google Scholar 

  27. 27.

    Bednarsch J, Jara M, Lock JF, Malinowski M, Pratschke J, Stockmann M. Noninvasive diagnosis of chemotherapy induced liver injury by LiMAx test—two case reports and a review of the literature. BMC Res Notes. 2015; 8:99.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Kodama Y, Ng CS, Wu TT, et al. Comparison of CT methods for determining the fat content of the liver. AJR Am J Roentgenol. 2007;188:1307–12.

    Article  PubMed  Google Scholar 

  29. 29.

    Cho CS, Curran S, Schwartz LH, et al. Preoperative radiographic assessment of hepatic steatosis with histologic correlation. J Am Coll Surg. 2008;206:480–8.

    Article  PubMed  Google Scholar 

  30. 30.

    Cowin GJ, Jonsson JR, Bauer JD, et al. Magnetic resonance imaging and spectroscopy for monitoring liver steatosis. J Magn Reson Imaging. 2008;28:937–45.

    Article  PubMed  Google Scholar 

Download references


This study was supported in part by JSPS KAKENHI (Grant 26830081 to Y.H. and Grant 24592009 to K.T.).

Author information



Corresponding author

Correspondence to Kuniya Tanaka MD, PhD.

Ethics declarations



Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hiroshima, Y., Shuto, K., Yamazaki, K. et al. Fractal Dimension of Tc-99m DTPA GSA Estimates Pathologic Liver Injury due to Chemotherapy in Liver Cancer Patients. Ann Surg Oncol 23, 4384–4391 (2016).

Download citation


  • Fractal Dimension
  • Irinotecan
  • Oxaliplatin
  • DTPA
  • Portal Vein Embolization