Chemotherapy-associated Steatohepatitis Research Articles

PNPLA3 I148M increases hepatic susceptibility to chemotherapy-associated steatohepatitis and affects overall survival

PNPLA3 I148M increases hepatic susceptibility to chemotherapy-associated steatohepatitis and affects overall survival

Key CT and MRI findings of drug-associated hepatobiliary and pancreatic disorders.

Obtaining an imaging diagnosis of various hepatobiliary and pancreatic disorders caused by certain drugs can often be challenging. Familiarity with these conditions may improve diagnostic accuracy and patient management. This review aimed to describe the imaging findings of drug-associated hepatobiliary and pancreatic disorders and identify suggestions for obtaining a correct diagnosis. We focused on relatively common disorders or those that can present with characteristic imaging findings, such as drug-induced acute hepatitis, sinusoidal obstruction syndrome, focal nodular hyperplasia-like lesions, hepatocellular adenoma, pseudocirrhosis, chemotherapy-associated steatohepatitis, amiodarone deposition in the liver, secondary iron overload, drug-induced pancreatitis, pancreatic enlargement after epoprostenol therapy, ceftriaxone-associated gallbladder pseudolithiasis, immune-related adverse events, and methotrexate-associated lymphoproliferative disorders.

FRI-402 - Dysregulated lipolysis increases intrahepatic concentrations of non-esterified fatty acids in chemotherapy-associated steatohepatitis

FRI-402 - Dysregulated lipolysis increases intrahepatic concentrations of non-esterified fatty acids in chemotherapy-associated steatohepatitis

The impact of single nucleotide polymorphisms on chemotherapy associated steatohepatitis

Background: Elective liver surgery represents an important cornerstone in the treatment of patients suffering from colorectal liver metastases (CRCLM). To improve resectability in those patients, neoadjuvant chemotherapy (NAC) is frequently utilized. However, NAC induces chemotherapy associated steatohepatitis (CASH). The extent of CASH induction can greatly vary between patients, and some appear particularly receptive to this side effect. CASH has been shown to result in postoperative failure of hepatic regeneration/recovery, greatly affecting overall patients’ outcome. Although testing for certain gene mutations is part of the preparations for adequate treatment, single nucleotide polymorphisms (SNPs) have not been sufficiently assessed in this scenario. Through a difference in one single base position in the DNA, SNPs are in some cases responsible for an altered cell metabolism. This can be observed in genetic variants such as the rs738409 polymorphism in the patatin-like phospholipase domain containing protein 3 gene (PNPLA3 I148M), which is closely associated with progression of chronic liver disease.

Chemotherapy-associated steatohepatitis was concomitant with epicardial adipose tissue volume increasing in breast cancer patients who received neoadjuvant chemotherapy.

To investigate the prevalence of chemotherapy-associated steatohepatitis, quantitate the epicardial adipose tissue (EAT) volume in breast cancer patients, and explore the mediating effect of liver fat content on EAT volume in breast cancer patients who received neoadjuvant chemotherapy (NAC). From October 2018 to April 2020, patients were retrospectively reviewed and divided into breast cancer non-NAC and NAC groups. The prevalence of chemotherapy-associated steatohepatitis was evaluated through quantitative MRI mDIXON-Quant examinations by using defined proton density fat fraction cutoffs of liver fat. The EAT volume was quantified on chest CT by semi-automatic volume analysis software. Bootstrap analysis was used in the breast cancer NAC group to test the significance of the mediating effect of liver fat content on EAT volume. A total of 662 breast cancer patients (non-NAC group: 445 patients; NAC group: 217 patients) were included. The prevalence of chemotherapy-associated steatohepatitis in the NAC group was significantly higher than the prevalence of hepatic steatosis in the non-NAC group (42.8% vs. 33.3%, p < 0.001). EAT volume was measured in 561 of 662 breast cancer patients, and was significantly higher in the NAC group than in the non-NAC group (137.26 ± 53.48 mL vs. 125.14 ± 58.77 mL, p = 0.020). In the breast cancer NAC group, the indirect effect of liver fat content on EAT volume was 2.545 (p < 0.001), and the contribution rate to the effect was 69.1%. EAT volume was significantly higher in the BC-NAC group than in the BC-non-NAC group. • The prevalence of CASH was as high as 42.8% in BC patients. • NAC significantly increased the EAT volume in BC patients. • The liver fat content caused the change of EAT volume through mediating effect.

Quantified MRI and 25OH-VitD3 can be used as effective biomarkers for patients with neoadjuvant chemotherapy-induced liver injury in CRCLM?

BackgroundTo evaluate proton-density fat-fraction (PDFF) and intravoxel incoherent motion (IVIM) techniques, and human 25-hydroxyvitamin D3 (25OH-VitD3) levels, as potential biomarkers in patients with colorectal cancer with liver metastasis (CRCLM). Changes were compared with those related to chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS).Methods63 patients with pathologically confirmed colorectal adenocarcinoma received 4–6 courses of NC before liver resection and underwent magnetic resonance imaging (MRI) with iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantification and IVIM sequences. Blood samples were analyzed using CTCAE. Pathological changes of liver tissues outside the metastases were assessed as the gold standard, and receiver operating characteristic (ROC) curves were analyzed.Results16 cases had CASH liver injury, 14 cases had SOS changes, and 4 cases had CASH and SOS, and 7 showed no significant changes. Consistency between biochemical indices and pathological findings was poor (kappa = 0.246, p = 0.005). The areas under the ROC curve (AUCs) of ALT, AST, ALP, GGT, and TBIL were 0.571–0.691. AUCs of D, FF, and 25OH-VitD3 exceeded 0.8; when considering these markers together, sensitivity was 85.29% and specificity was 93.13%. ANOVA showed statistically significant differences among D, FF, and 25OH-VitD3 for different grades of liver injury (F = 4.64–26.5, p = 0.000–0.016).ConclusionsD, FF, and 25OH-VitD3 are biomarkers for accurate prediction of NC-induced liver injury in patients with CRCLM, while FF and 25OH-VitD3 might be beneficial to distinguish liver injury grades.Trial registrationCurrent Trials was retrospectively registered as ChiCTR1800015242 at Chinese Clinical Trial Registry on March 16, 2018.

Liver radiologic findings of chemotherapy-induced toxicity in liver colorectal metastases patients.

There are a number of chemotherapy-effects that should be assessed with liver imaging since they have an influence on surgical morbidity. Chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH), and SOS might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection. The main role of a radiologist is to provide an accurate diagnosis of the lesion. With constant advances in medicine, a radiologist's role should extend beyond just reporting the data of tumor, providing additional information that may greatly improve patient care. Radiologists should assess both chemotherapy effects on the hepatic metastasis itself, as well as chemo-induced focal and diffuse modifications of non-tumor hepatic parenchyma, since it is important to avoid impaired hepatic function after hepatic resection.

Abstract 809: Response of metabolic phenotype to chemotherapy agents in a simulated tumor microenvironment

Abstract Chemotherapeutic agents inhibiting fatty acid oxidation can sensitize cells to the tumor microenvironment. Chemotherapeutic agents (CA), while standard-of-care for treating numerous types of cancer are, by nature, poisonous. Studies have shown that treatment with certain CA, such as Irinotecan, leads to chemotherapy associated steatohepatitis (CASH) resulting from the inhibition of mitochondrial fatty acid oxidation (FAO). While inhibition of FAO may have harmful effects on the liver, it may have a different effect in the tumor microenvironment (TME). Within the TME exists a unique metabolic environment, consisting of low [O2], low pH and high concentrations of fatty acids. Occupying the TME are immunosuppressive myeloid derived suppressor cells (MDSCs), which aid in tumor growth by suppressing T cells, which would normally attack the tumor. It is thought that the MDSCs localized to the TME undergo an alteration in metabolic phenotype, allowing them to utilize the high concentrations of fatty acids found in the TME as their primary carbon source, becoming reliant on FAO. It is therefore hypothesized that normoxic MDSCs will alter their metabolic phenotype in response to a simulated TME to favor FAO. This altered metabolic phenotype will sensitize MDSCs to inhibition of FAO by SN-38, the active metabolite of Irinotecan. The response of metabolic phenotype to hypoxic conditions will also be examine in HCT116 colorectal carcinoma cells. Note: This abstract was not presented at the meeting. Citation Format: David L. Hoffman, Julie M. Rumble. Response of metabolic phenotype to chemotherapy agents in a simulated tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 809.

Estimation of the future remnant liver function is a better tool to predict post-hepatectomy liver failure than platelet-based liver scores

IntroductionRecently, there has been increasing interest in the preoperative prediction and prevention of post-hepatectomy liver failure (PHLF). This is a particular concern in colorectal liver metastases (CRLM), when surgery follows potentially hepatotoxic chemotherapy. Platelet-based liver scores (PBLS) such as APRI and FIB-4 are predictive of chemotherapy-associated liver injury (CALI) and PHLF. Estimation of the future liver remnant function (eFLRF) by combining 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBSBSA) with future liver remnant volume ratio (FLRV%), is predictive of PHLF and related mortality. We hypothesized that a HBSBSA based formula was a better predictor for PHLF than PBLS in chemotherapy-pretreated CRLM. MethodsBetween 2012 and 2016, 140 patients underwent liver resection for CRLM following systemic therapy. HBSBSA, FLRV%, eFLRF and PBLS were calculated and compared for their value in predicting PHLF. ResultseFLRF and FLRV% had a better predictive value for PHLF than HBSBSA alone and APRI and FIB-4 (AUC = 0.800, 0.843 versus 0.652, 0.635 and 0.658 respectively). In a subgroup analysis (Oxaliplatin all, Oxaliplatin ≥ 6 cycles, Irinotecan all and Irinotecan ≥ 6 cycles), eFLRF was the only factor predictive for PHLF in all subgroups (all: p ≤ 0.05). Prediction of HBSBSA for chemotherapy associated steato-hepatitis (CASH) reached almost significance (p = 0.06). FIB-4 was predictive for sinusoidal obstruction syndrome (SOS) (p = 0.011). Only weak correlation was found between HBSBSA and PBLS. ConclusioneFLRF is a better predictor of PHLF than PBLS or HBSBSA alone. PBLS seem to measure other aspects of liver function or damage than HBSBSA.

Abstract 4795: Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity

Abstract The indiscriminating protection of either normal or cancerous cells against electrophilic stresses by nuclear factor E2-related factor 2 (Nrf2) has evoked continuous controversy over its Janus face in cancer. However, both normal and cancerous cells co-exist in cancer patients, and the outcome of therapy is determined by responses of both. Here we systemically analyzed the correlation between Nrf2 expression in normal cells and chemotherapy-associated myelosuppression, steatohepatitis and peripheral neurotoxicity, and explored the possibility to predict and prevent these adverse effects by targeting Nrf2 signaling. Firstly, the toxicities of 22 clinically-used chemotherapeutic drugs were tested in bone marrow cells, liver cells and embryonic fibroblasts derived from either Nrf2 (-/-) or wild type mice, and the toxicities of drugs with IC50 in wild type cells &amp;gt; 2 folds higher than their Nrf2(-/-) counterparts are considered as significantly dependent on Nrf2. The dependency of taxol-induced myelosuppression on Nrf2 was confirmed in vivo, and the mRNA level of Nrf2 in peripheral blood mononuclear cells from cancer patients was reversely correlated to taxol-associated myelosuppression. Then steatohepatitis induced by irinotecan (CPT-11) and peripheral neurotoxicity induced by oxaliplatin were further investigated. CPT-11 induced intestinal toxicity in wild type mice but no significant steatohepatitis/liver toxicity was observed; however, CPT-11 treatment in Nrf2 (-/-) mice caused severer intestinal toxicity and pronounced steatohepatitis, associated with dramatically elevated serum biomarkers, accumulation of fat in liver cells, and altered liver histology. Similar results were observed for oxaliplatin-induced hepatotoxicity. Furthermore, Nrf2 deficiency significantly exaggerated oxaliplatin-induced peripheral neurotoxicity, as indicated by Von Frey test and cold plate assay. Interestingly, CDDO-Me was found to activate Nrf2 signaling in both normal tissues and xenograft tumors, while sulforaphane selectively activated Nrf2 in liver, bone marrow and peripheral nerves but not in tumors. As expected, sulforaphane significantly alleviated CPT-11-induced intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity, while did not impact the therapeutic efficacy of drugs. Taken together, our results demonstrate that the toxicities of some of chemotherapeutic drugs currently in clinic usage are significantly affected by Nrf2, therefore it is possible to personalize therapeutic regimens according to Nrf2 expression in tumors and normal tissues. Specifically, CPT-11-induced steatohepatitis and intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity are significantly determined by Nrf2, and Nrf2 could be selectively targeted to prevent or treat chemotherapy-induced toxicities. The present works were supported by the NSFC (No. 81272468, 91429305 and 81372266). Note: This abstract was not presented at the meeting. Citation Format: Liu He, Linling Que, Wenchen Yin, Baoshan Cao, Siwang Yu. Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4795. doi:10.1158/1538-7445.AM2017-4795

Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice.

Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis.Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal β-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression.

Analysis of molecular mechanisms of 5-fluorouracil-induced hepatic steatosis and inflammation in vitro and in mice

Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases.

Effect of oxaliplatin combined with polyenephosphatidylcholine on the proliferation of human gastric cancer SGC-7901 cells.

Oxaliplatin (L-OHP) is a platinum compound that is widely used to treat certain solid tumors, including gastric tumors. L-OHP is an effective anti-cancer treatment; however, its usage increases the probability of patients developing hepatic injury with inflammation, referred to as chemotherapy-associated steatohepatitis. The present study aimed to evaluate the outcome of L-OHP treatment combined with polyenephosphatidylcholine (PPC), a major component of essential phospholipids used to treat steatohepatitis, on SGC-7901 gastric cancer cell proliferation. This would help to determine whether combination therapy with L-OHP and PPC is clinically beneficial for patients with gastric cancer. The viability of SGC-7901 cells was verified by an MTT assay; flow cytometry was used to analyze the cell cycle and rates of cell apoptosis; oxidation-related indicators were measured by spectrophotometry, and the expression of cell cycle- and apoptosis-related proteins was determined by western blotting. The results demonstrated that L-OHP significantly inhibited SGC-7901 cell growth in a dose- and time-dependent manner (F=194.193, P<0.01 and F=12.428, P=0.01, respectively). Furthermore, PPC stimulated the growth of SGC-7901 cells and greatly promoted their apoptosis induced by L-OHP, which was supported by the upregulation of cytochrome c and the downstream activation of caspases 3 and 9. Finally, following treatment with a combination of PPC and L-OHP, the expression of cyclins D1 and E was downregulated; however, PPC did not alter the production of reactive oxygen species caused by L-OHP (P=0.88). The present study determined that the combination of L-OHP and PPC exerts a synergistic anti-tumor effect, suggesting that L-OHP and PPC combination therapy may be used as a treatment for patients with gastric cancer that reduces the side effects of L-OHP without inhibiting its efficacy.

Hepatic steatosis : Differential diagnostics and current aspects

The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed.

Autophagy impairment and ERK and p38 activation are central mediators of irinotecan-induced steatohepatitis

Treatment with irinotecan is associated with the development of chemotherapy-associated steatohepatitis (CASH), which significantly increases the risk of perioperative morbidity and mortality.

Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model.

Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature. Swiss male mice were distributed in groups (n = 8) and injected with saline (5 mL/kg, i.p.; control) or IRI (25, 50, 75 or 100 mg/kg, i.p.) thrice a week for 7 weeks. Blood samples were collected to measure the serum concentrations of proteins, alanine and aspartate aminotransferases (ALT and AST). Each week animals were euthanized, and the livers were submitted to myeloperoxidase (MPO) assay, lipid dosage, immunohistochemistry for inducible nitric oxide synthase (iNOS), TNF-α and interleukin-1β (IL-1β), and histopathological analysis. Survival rates were also determined. Mice treated with IRI had a significantly (p < 0.05) lower survival rate than controls and time- and dose-dependent body weight loss. ALT and AST plasma levels increased in relation to controls only in mice receiving IRI 50 mg/kg (p < 0.05). The histopathological features characteristic of NASH was observed, including steatosis, lobular neutrophil infiltration and ballooning hepatocytic degeneration. Additional findings included increased MPO, lipid accumulation, portal neutrophil infiltration, IL-1β and iNOS expression and fibrosis in liver tissues and low serum protein levels compared to controls. This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.

Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice.

Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.

Prediction of portal pressure from intraoperative ultrasonography

BackgroundPortal hypertension is a major risk factor for hepatic failure or bleeding in patients who have undergone hepatectomy, but it cannot be measured indirectly. We attempted to evaluate the intraoperative ultrasonography parameters that correlate with portal pressure (PP) in patients undergoing hepatectomy. MethodsWe examined 30 patients in whom PP was directly measured during surgery. The background liver conditions included chronic viral liver disease in seven patients, chemotherapy-associated steatohepatitis in four patients, fatty liver in one patient, hepatolithiasis in one patient, obstructive jaundice in one patient, and a normal liver in 16 patients. A multivariate logistic analysis and linear regression analysis were conducted to develop a predictive formula for PP. ResultsThe mean PP was 10.4 ± 4.1 mm Hg. The PP tended to be increased in patients with chronic viral hepatitis. A univariate analysis identified the association of the six following parameters with PP: the platelet count and the maximum (max), minimum (min), endo-diastolic, peak-systolic, and mean velocity in the portal vein (PV) flow. Using multiple linear regression analysis, the predictive formula using the PV max and min was as follows: Y (estimated PP) = 18.235−0.120 × (PV max.[m/s])−0.364 × (PV min). The calculated PP (10.44 ± 2.61 mm Hg) was nearly the same as the actual PP (10.43 ± 4.07 mm Hg). However, there was no significant relationship between the calculated PP and the intraoperative blood loss and post hepatectomy morbidity. ConclusionsThis formula, which uses ultrasonographic Doppler flow parameters, appears to be useful for predicting PP.

Comprehensive review of post-liver resection surgical complications and a new universal classification and grading system

Liver resection is the gold standard treatment for certain liver tumors such as hepatocellular carcinoma and metastatic liver tumors. Some patients with such tumors already have reduced liver function due to chronic hepatitis, liver cirrhosis, or chemotherapy-associated steatohepatitis before surgery. Therefore, complications due to poor liver function are inevitable after liver resection. Although the mortality rate of liver resection has been reduced to a few percent in recent case series, its overall morbidity rate is reported to range from 4.1% to 47.7%. The large degree of variation in the post-liver resection morbidity rates reported in previous studies might be due to the lack of consensus regarding the definitions and classification of post-liver resection complications. The Clavien-Dindo (CD) classification of post-operative complications is widely accepted internationally. However, it is hard to apply to some major post-liver resection complications because the consensus definitions and grading systems for post-hepatectomy liver failure and bile leakage established by the International Study Group of Liver Surgery are incompatible with the CD classification. Therefore, a unified classification of post-liver resection complications has to be established to allow comparisons between academic reports.

Hyaluronic Acid as a Marker of Sinusoidal Obstruction Syndrome after Oxaliplatin-based Chemotherapy for Colorectal Liver Metastases: Don’t Forget the Tumor

A few decades ago, patients with colorectal cancer liver metastases were considered incurable, and treatment was mainly supportive. Treatment options for patients with metastatic colorectal cancer have changed greatly since then, as has the outcome of these patients. Although in the past survival of these patients was within the range of a few months, with no 5-year survivors, current studies report median survival rates of 20–25 months and 5-year survival rates of 30–60 %. What has happened? Numerous studies have taught us that in selected patients, surgical resection of metastases prolongs survival. As hepatic resection has evolved to a safe procedure even in patients requiring extended, complex, and/or two-stage resection for complete tumor clearance, its use has increased and has added to the improved long-term outcome. However, only approximately 15 % to 20 % of patients are initially amenable to potentially curative resection; therefore, further factors must have played a role in the marked improvement in survival. The development and increased use of effective chemotherapeutic regimens has contributed significantly to the treatment results we are currently documenting for metastatic colorectal cancer. Several phase III trials proved that the addition of oxaliplatin or irinotecan to the backbone of 5-fluorouracil (5-FU) and folinic acid is able to achieve objective response rates of 40–50 %. The antitumor activity of these combined chemotherapy regimens has clearly improved median survival rates compared to historic data of patients who received 5-FU monotherapy, which was the standard of care in the late 1980s. Moreover, these improved regimens rendered the disease of a higher proportion of patients resectable. Resectability rates in firstline chemotherapy trials with palliative intent range from 5 to 15 % and go up to 30 % in patients with more limited yet still unresectable disease receiving chemotherapy for the intent of downstaging. Furthermore, the addition of biological agents such as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), and cetuximab or panitumumab, monoclonal antibodies against the epidermal growth factor receptor, seem to further enhance response and resectability rates. Although the effectiveness of modern chemotherapy protocols in patients with metastatic colorectal cancer is undisputed, issues associated with these regimens, such as acquired resistance and increased toxicity, remain important future challenges for interdisciplinary management. In particular, liver toxicity related to the administration of irinotecanand oxaliplatin-containing regimens represents a significant concern; their development may interfere with the planned treatment concept. It has been demonstrated that preoperative chemotherapy correlates with significantly higher perioperative complications. Furthermore, the development of histological alterations in the liver parenchyma may impede the antitumor effects of systemic therapies. The pathological changes of the liver are specific to the administered agents. Irinotecan has been associated with chemotherapy-associated steatohepatitis. Oxaliplatin has been more frequently reported to cause hepatic injury, which typically manifests as sinusoidal obstruction syndrome (SOS) and occurs in up to 50 % of patients who receive an oxaliplatin-based regimen. SOS is considered to Society of Surgical Oncology 2013