Chemotherapy-associated Liver Injury Research Articles

Indocyanine green clearance test as a predictor of chemotherapy liver toxicity and post-operative complications in patients with colorectal liver metastases.

This study aims to investigate the relationship between the pre-operative indocyanine green (ICG) test, the chemotherapy-associated liver injury (CALI), and the development of severe post-operative complications (POC) in patients operated of colorectal liver metastases (CRLMs). Sixty-nine patients previously treated with chemotherapy and submitted to liver resection for CRLM were retrospectively studied. Two pathologists independently reviewed the pathological specimens and assessed the presence of CALI. The correlation between ICG clearance and specific pathological features was analyzed. In addition, a logistic regression analysis was performed to seek for pre-operative factors associated with severe complications. After a mean of 10.6 (± 7.5) chemotherapy cycles, 44 patients (63.8%) developed CALI. ICG retention rate at 15 min (ICG-R15) was not statistically different between patients with and without CALI and it could only discriminate the presence of centrilobular fibrosis. Rate of severe complications was almost 6-fold in patients with CALI compared to patients without CALI (p = 0.024). ICG-R15 ≥ 10% was the only independent risk factor associated with severe POC at multivariable logistic regression (OR = 4.075 95% CI: 1.077-15.422, p = 0.039). Pre-operative ICG clearance test, although not useful to identify patients with hepatic drug toxicity, is a strong predictor for the development of severe post-hepatectomy complications.

Neoadjuvant chemotherapy for colorectal liver metastases: A contemporary review of the literature.

Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide, and up to 50% of patients with CRC develop colorectal liver metastases (CRLM). For these patients, surgical resection remains the only opportunity for cure and long-term survival. Over the past few decades, outcomes of patients with metastatic CRC have improved significantly due to advances in systemic therapy, as well as improvements in operative technique and perioperative care. Chemotherapy in the modern era of oxaliplatin- and irinotecan-containing regimens has been augmented by the introduction of targeted biologics and immunotherapeutic agents. The increasing efficacy of contemporary systemic therapies has led to an expansion in the proportion of patients eligible for curative-intent surgery. Consequently, the use of neoadjuvant strategies is becoming progressively more established. For patients with CRLM, the primary advantage of neoadjuvant chemotherapy (NCT) is the potential to down-stage metastatic disease in order to facilitate hepatic resection. On the other hand, the routine use of NCT for patients with resectable metastases remains controversial, especially given the potential risk of inducing chemotherapy-associated liver injury prior to hepatectomy. Current guidelines recommend upfront surgery in patients with initially resectable disease and low operative risk, reserving NCT for patients with borderline resectable or unresectable disease and high operative risk. Patients undergoing NCT require close monitoring for tumor response and conversion of CRLM to resectability. In light of the growing number of treatment options available to patients with metastatic CRC, it is generally agreed that these patients are best served at tertiary centers with an expert multidisciplinary team.

Virtual Biopsy for Diagnosis of Chemotherapy-Associated Liver Injuries and Steatohepatitis: A Combined Radiomic and Clinical Model in Patients with Colorectal Liver Metastases.

Simple SummaryPatients receiving chemotherapy for liver metastases from colorectal cancer may develop liver injuries that impair hepatic function and postoperative outcome. The non-invasive diagnosis of these damages is still an unmet need. Recently, advanced imaging analysis techniques, including the so-called “radiomics”, achieved adequate prediction of pathology data. The present study demonstrated that radiomic analysis of liver parenchyma in combination with clinical and laboratory data improves non-invasive diagnosis of chemotherapy-related liver injuries. Non-invasive diagnosis of chemotherapy-associated liver injuries (CALI) is still an unmet need. The present study aims to elucidate the contribution of radiomics to the diagnosis of sinusoidal dilatation (SinDil), nodular regenerative hyperplasia (NRH), and non-alcoholic steatohepatitis (NASH). Patients undergoing hepatectomy for colorectal metastases after chemotherapy (January 2018-February 2020) were retrospectively analyzed. Radiomic features were extracted from a standardized volume of non-tumoral liver parenchyma outlined in the portal phase of preoperative post-chemotherapy computed tomography. Seventy-eight patients were analyzed: 25 had grade 2–3 SinDil, 27 NRH, and 14 NASH. Three radiomic fingerprints independently predicted SinDil: GLRLM_f3 (OR = 12.25), NGLDM_f1 (OR = 7.77), and GLZLM_f2 (OR = 0.53). Combining clinical, laboratory, and radiomic data, the predictive model had accuracy = 82%, sensitivity = 64%, and specificity = 91% (AUC = 0.87 vs. AUC = 0.77 of the model without radiomics). Three radiomic parameters predicted NRH: conventional_HUQ2 (OR = 0.76), GLZLM_f2 (OR = 0.05), and GLZLM_f3 (OR = 7.97). The combined clinical/laboratory/radiomic model had accuracy = 85%, sensitivity = 81%, and specificity = 86% (AUC = 0.91 vs. AUC = 0.85 without radiomics). NASH was predicted by conventional_HUQ2 (OR = 0.79) with accuracy = 91%, sensitivity = 86%, and specificity = 92% (AUC = 0.93 vs. AUC = 0.83 without radiomics). In the validation set, accuracy was 72%, 71%, and 91% for SinDil, NRH, and NASH. Radiomic analysis of liver parenchyma may provide a signature that, in combination with clinical and laboratory data, improves the diagnosis of CALI.

O5: THE CLIFF AND CONOR STUDIES NOVEL ASSESSMENT TOOLS IN COLORECTAL LIVER METASTASES (CLIFF STUDY - CHANGE IN LIVER FUNCTION AND FAT IN PRE-OPERATIVE CHEMOTHERAPY FOR COLORECTAL LIVER METASTASES, CONOR STUDY

Abstract Introduction Hepatic resection is the only potentially curative treatment for patients with colorectal liver metastases (CLM). Patient selection is key, but there is wide variation in practice. Pre-operative chemotherapy can improve oncological outcomes, however chemotherapy-associated liver injury (CALI) may hinder liver regenerative capacity. Standard pre-operative assessments fail to accurately capture factors such as CALI and future liver remnant (FLR) function. The CLiFF and CoNoR studies utilise two novel assessment techniques, aiming to improve patient outcomes. Method The CLiFF study prospectively assesses two primary outcomes in 35 patients undergoing pre-operative chemotherapy for CLM: 1) change in liver function (via LiMAx test: direct assessment of hepatic functional capacity), and 2) change in liver fat (via advanced MR imaging (in-house spectroscopy and modified Dixon technique, scaled up via Perspectum LiverMultiScan)). The CoNoR study assesses potential added benefit of these novel tools in CLM resectability decision-making via sequential workstreams: a systematic review and international hepatobiliary expert interviews inform the online survey, assessing added benefit via online MDT scenarios. Result Preliminary CLiFF analysis suggests that CALI changes in liver fat and function are unrelated. Liver fat analysis techniques are compared and correlated with digital histological analysis. The CoNoR systematic review identifies key factors influencing CLM resectability decision-making and informs the international expert interviews, scheduled to occur during a February 2020 international hepatobiliary conference. Conclusion These studies are the first to assess where these novel tools might be utilised to maximal patient benefit within the Hepatobiliary MDT, and the first systematic review in CLM resectability decision-making. Take-home message These two linked studies evaluate the use of two novel assessment tools in the treatment of colorectal liver metastases, with the potential to improve patient selection for curative resection and patient outcomes. PATEY PRIZE SESSION

Comparison of Multimaterial Decomposition Fat Fraction with DECT and Proton Density Fat Fraction with IDEAL IQ MRI for Quantification of Liver Steatosis in a Population Exposed to Chemotherapy.

Introduction:Oncologic patients who develop chemotherapy-associated liver injury (CALI) secondary to chemotherapy treatment tend to have worse outcomes. Biopsy remains the gold standard for the diagnosis of hepatic steatosis. The purpose of this article is to compare 2 alternatives: Proton-Density-Fat-Fraction (PDFF) MRI and MultiMaterial-Decomposition (MMD) DECT.Materials and Methods:49 consecutive oncologic patients treated with Chemotherapy underwent abdominal DECT and abdominal MRI within 2 weeks of each other. Two radiologists tracked Regions of Interest independently both in the PDFF fat maps and in the MMD DECT fat maps. Non-parametric exact Wilcoxon signed rank test and Cohen’s K were used to compare the 2 sequences and to evaluate the agreement.Results:There was no statistically significant difference in the fat fraction measured as a continuous value between PDFF and DECT between 2 readers. Within the same imaging method (PDFF) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.88 (p-value < 0.05). Similarly, for single-source DECT(ssDECT) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.97 (p-value < 0.05).Conclusions:The results of this study demonstrate that the hepatic fat fraction of ssDECT with MMD are not significantly different from PDFF. This could be an advantage in an oncological population that undergoes serial CT scans for follow up of chemotherapy response.

Liver surface nodularity: a novel predictor of post-hepatectomy liver failure in patients with colorectal liver metastases following chemotherapy.

The goal of this study was to assess the relationship between liver surface nodularity (LSN), chemotherapy-associated liver injury (CALI), and clinically relevant post-hepatectomy liver failure (CR-PHLF) (i.e., ≥ grade B) in patients undergoing hepatectomy for colorectal liver metastases (CLM). Preoperative CT scans of patients who underwent chemotherapy followed by hepatectomy for CLM between 2010 and 2017 were retrospectively analyzed. LSN was measured using semi-automated CT software CT images in patients who had available preoperative CT scans within 6 weeks before hepatectomy, and was computed based on the means of one to 10 measurements by two abdominal radiologists consensually. The association of LSN, CALI, and CR-PHLF was analyzed. Two hundred fifty-six patients were analyzed (149 men and 107 women; overall median age, 61 [range, 29-88 years]). A total of 26 patients (10.2%) developed CR-PHLF. The optimal LSN cut-off value for detecting CR-PHLF was 2.5, as determined by receiver operative characteristic analysis (p < 0.001). LSN ≥ 2.5 was associated with prolonged chemotherapy (> 6 cycles, p = 0.018), but not with CALIs. After propensity score matching, LSN remained significantly associated with CR-PHLF (p = 0.031). Furthermore, multivariate analysis identified LSN ≥ 2.50 and future liver remnant (FLR) < 30% as significant preoperative predictors of CR-PHLF in 102 patients undergoing major hepatectomy. LSN ≥ 2.50 was more frequent in patients undergoing major hepatectomy despite FLR ≥ 30% (p = 0.008). LSN quantified on CT is an independent surrogate of CR-PHLF in patients who undergo chemotherapy followed by hepatectomy for CLM and may provide a valuable additional tool in the preoperative assessment of these patients. • LSN was not associated with chemotherapy- associated liver injury but high LSN (defined ≥ 2.5) was associated with prolonged chemotherapy (> 6 cycles). • High LSN was an independent predictor of clinically relevant postoperative liver failure in patients undergoing hepatectomy for CRLM. • LSN ≥ 2.50 was more frequent in patients with PHLF after major hepatectomy despite a future liver remnant ≥ 30%.

Chemotherapy associated liver injury and steatosis in Hispanic patients with colorectal cancer liver metastasis

Presenter: Lucas Thornblade MD, MPH | City of Hope Cancer Center Background: Chemotherapy associated liver injury and steatosis (CALI/CASH) is common among patients with colorectal cancer liver metastasis (CRC-LM). As Hispanic patients experience high rates of non-alcoholic fatty liver disease (NAFLD), there may be a bias to avoid extended courses of chemotherapy because of a perceived risk of CALI/CASH in this population. We aimed to compare the development of CALI/CASH between Hispanic and non-Hispanic White (nHW) patients with CRC-LM. Methods: A single-center retrospective cohort study of Hispanic and nHW patients with unoperated synchronous CRC-LM between (2014-2019). Patient records were reviewed for characteristics of CALI prior to initiation of (pre-chemo) and following up to six-months of chemotherapy (post-chemo). Non-contrast CT scans were sampled by investigators for characteristics of CASH (hepatic minus splenic attenuation (HSA)), and CALI (splenic and caudate lobe hypertrophy). Results: Among 64 patients (52% Hispanic, mean age 54.7 years, 48% female, 48% obese) mean chemotherapy treatment was 6.3 months and 98% received oxaliplatin (34% received irinotecan). There were no significant differences between groups in terms of age, sex, or body mass index. Both Hispanic and nHW patients demonstrated a significant increase (p = 0.03) in mean caudate diameter (+2.3mm in Hispanics, +4.5mm in nHW) over the course of treatment. The rate of thrombocytopenia (platelets < 100k) was similar in both nHW (22.6%) and Hispanic patients (6.1%, p = 0.06) following chemotherapy. Both groups exhibited similar rates of splenic enlargement over 6 months of treatment (mean +0.74cm Hispanics, +0.62cm nHW, p = 0.79). However, we found no differences in the incidence of low-grade (HSA < 6.5, 30% Hispanics, 42% NHW, p = 0.33)) or high-grade steatosis (HSA < 3.2, 15% Hispanics, 19% NHW, p = 0.66) following chemotherapy. Conclusion: Both nHW and Hispanic patients in this study had evidence of liver injury as a result of predominantly oxaliplatin-based therapy. Despite a high rate of baseline hepatic steatosis in both groups, we did not see differential progression of steatosis as a result of chemotherapy regardless of baseline BMI or exposure to irinotecan. These findings suggest that, despite high rates of NAFLD in Hispanic patients, this should not be a reason to withhold prolonged chemotherapy for CRC-LM in this group.

Validation of the APRI+ALBI smart phone application for preoperative risk assessment after liver resection in a routine clinical setting

Presenter: David Pereyra MD | Mayo Clinic, Rochester Background: Liver surgery obtains the risk of development of postoperative liver dysfunction (LD) and associated increased morbidity and mortality. In order to mitigate the individual risk for adverse postoperative outcome, predictive markers and scores have been developed. In this context, APRI and ALBI, both based on routine laboratory parameters, and their summative conjunction were previously established as predictive markers for postoperative LD in patients undergoing liver resection after neoadjuvant chemotherapy, as well as in a set of more than 12,000 patients in the NSQUIP database. Here, we aimed to validate APRI+ALBI and our Smart phone application system in a routine clinical set of patients undergoing liver surgery. Methods: We identified 160 patients with available data on preoperative albumin, bilirubin, aspartate aminotransferase and platelet count and postoperative outcome. APRI and ALBI were calculated and prognostic value for postoperative outcome was evaluated. Results: Using receiver operating curve analysis, APRI+ALBI was found to be superior to APRI alone or ALBI alone in prediction of postoperative LD (area under the curve [AUC]=0.717, AUC=0.669, AUC=0.691, respectively). Further, APRI+ALBI was superior to parameters of indocyanine green clearance (plasma disappearance rate: AUC=0.628, retention rate at 15 minutes: AUC=0.669). A preoperative cut-off at -2.46 was able to stratify patients at risk for postoperative LD (6.1% vs 18.0%, p=0.017), morbidity (32.7% vs 63.9%, p<0.001), severe morbidity (11.2% vs 34.4%, p<0.001), and mortality within 90 postoperative days (1.0% vs 8.5%, p=0.028). Utilizing our previously established smart phones application, we were able to validate appropriate classification patients in individual risk groups according to their preoperative APRI/ALBI score. Conclusion: Here, we validate APRI+ALBI as a predictive marker for postoperative adverse outcome in a clinical routine set of patients undergoing liver resection. The detection of multiple with pathophysiological processes , such as for example chemotherapy associated liver injury but also alcoholic liver disease, by the APRI/ALBI score, allowed prediction of outcome after liver resection in an routine clinical setting. Applying this twice validated marker based on routine laboratory parameters allows estimation of individual patient risk prior to liver resection and might ultimately reduce occurrence of postoperative complications. A specific and gradual risk assessment seems to be possible using the APRI/ALBI smart phone application in a routine clinical setting. Until more specific markers are available, this application represents a valuable tool to assess individualized patients risk for postoperative outcome based on routine laboratory parameters.

Virtual biopsy for diagnosis of steatohepatitis and chemotherapy-associated liver injuries. A combined radiomic and clinical model

Purpose: Chemotherapy-associated liver injuries (CALI) have a major clinical impact, but their non-invasive diagnosis is still an unmet need. We aim to elucidate the contribution of radiomics to diagnosis of sinusoidal dilatation (SinDil), nodular regenerative hyperplasia (NRH) and non-alcoholic steatohepatitis (NASH). Methods: Patients undergoing liver resection for colorectal metastases after oxaliplatin- or irinotecan-based chemotherapy between January 2018 and February 2020 were retrospectively analyzed. Radiomic features were extracted from a standardized volume of non-tumoral liver parenchyma outlined in the portal phase of preoperative post-chemotherapy computed tomography (CT). A multivariate logistic regression model was performed to identify predictors of CALI. The model was internally validated. Results: Overall, 78 patients were analyzed. Of these, 25 (32%) had grade 2-3 sinusoidal dilatation, 27 (35%) NRH, and 14 (18%) NASH. Three fingerprints derived from radiomic features were independent predictors of grade 2-3 sinusoidal dilatation: GLRLM_f3 (OR=12.25), NGLDM_f1 (OR=7.77), and GLZLM_f2 (OR=0.53). The combined clinical/radiomic predictive model had 82% accuracy, 64% sensitivity, and 91% specificity (AUC=0.87 vs AUC=0.77 of the model without radiomics). Three radiomic parameters were independent predictors of NRH: conventional_HUQ2 (OR=0.76), GLZLM_f2 (OR=0.05), and GLZLM_f3 (OR=7.97). The combined clinical/radiomic model had 85% accuracy, 81% sensitivity, and 86% specificity (AUC=0.91 vs AUC=0.85 without radiomic features). One radiomic feature was associated with NASH: conventional_HUQ2 (OR=0.79). Steatohepatitis was predicted with 91% accuracy, 86% sensitivity, and 92% specificity (AUC=0.93 vs AUC=0.83 without radiomic features). In the validation set, accuracy was 72%, 71%, and 91% for sinusoidal dilatation, NRH, and NASH, respectively. Conclusions: Radiomic analysis of liver parenchyma may provide a signature that, in combination with clinical and laboratory data, improves diagnosis of CALI.

Prospective study of change in liver function and fat in patients with colorectal liver metastases undergoing preoperative chemotherapy: protocol for the CLiFF Study

IntroductionPreoperative chemotherapy in patients undergoing resection for colorectal liver metastases (CLM) improves oncological outcomes. However, chemotherapy-associated liver injury (occurring in two patterns: vascular and fat deposition) is a real clinical...

ASO Author Reflections: Usage of Single Photon Emission CT (SPECT) Hepatobiliary Scintigraphy to Detect the Impact of Chemotherapy-Associated Liver Injuries (CALI) on Liver Function Before a Major Hepatectomy.

ASO Author Reflections: Usage of Single Photon Emission CT (SPECT) Hepatobiliary Scintigraphy to Detect the Impact of Chemotherapy-Associated Liver Injuries (CALI) on Liver Function Before a Major Hepatectomy.

Indocyanine Green Clearance Test for the Preoperative Assessment of Chemotherapy-Related Hepatic Injury in Patients with Colorectal Liver Metastasis.

PurposeThe aim of the present study was to determine the value of the indocyanine green (ICG) clearance test in the preoperative assessment of chemotherapy-related hepatic injury in patients with liver metastasis from colorectal cancer.MethodsA total of 218 patients who underwent hepatic dissection due to colorectal cancer liver metastasis at the Peking University Cancer Hospital between January 2016 and December 2017 were retrospectively evaluated; 179 patients who received chemotherapy prior to hepatic resection were further examined. Patient- and chemotherapy-related factors were analyzed in both groups with normal and abnormal ICG retention rate at 15 min (ICG-R15), and their intraoperative and postoperative outcomes were compared.ResultsThe chemotherapy group had a higher mean ICG-R15 value and a higher number of patients who exhibited abnormal ICG-R15, compared with the no-chemotherapy group. Under the guidance of ICG test, no patients experienced severe complications in the abnormal ICG-R15 group compared with the normal ICG-R15 group, and the overall morbidity was also not significantly different between the two groups. However, the incidence of severe complications was higher in patients who underwent major resection with a normal ICG-R15 value compared with patients with an abnormal ICG-R15 value who underwent minor resection (P<0.05). Multivariable logistic regression analyses revealed that body mass index (BMI) ≥28 and oxaliplatin use were independent predictors of abnormal ICG-R15. The ICG-R15 value was significantly higher in the two-risk factors group compared with the no-risk factor group (P=0.012), but not statistically different compared with the one risk factor group.ConclusionScreening of patients with chemotherapy-associated liver injury using the IGC test may help in performing safe hepatectomy by avoiding major resection. BMI ≥28 and oxaliplatin use were independent preoperative predictors of abnormal ICG-R15.

Chemotherapy-associated liver injury in colorectal cancer.

Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.

Splenic volume as a biomarker of hepatic damage after chemotherapy in patients with resected colorectal liver metastases (CRLM).

Chemotherapy-associated liver injury (CALI) is a matter of concern for hepatobiliary surgeons as it can entail postoperative liver failure after an extensive hepatectomy. Recent studies have taken special interest in liver function parameters which can correlate with CALI to decrease this adverse event. Therefore, the current study investigates the usefulness of splenic volume as a biomarker of CALI through a portal hypertension mechanism, in patients with colorectal liver metastases (CRLM). We carried out a study in patients with CRLM operated on between 2009 and 2014 in our center. All samples of healthy liver were graded for non-alcoholic fatty liver disease (NAFLD) and sinusoidal obstructive syndrome. Computarized tomography scans for spleen volumetry were analyzed for each patient at CRLM diagnosis, after neoadjuvant chemotherapy, 1 and 6months after resection. A group of 65 consecutive patients with CRLM of large bowel adenocarcinoma submitted to liver resection were included. Patients receiving neoadjuvant chemotherapy had a greater spleen volume increase than those who did not receive treatment (p = 0.053), finding a statistically significant spleen growth in patients with NAFLD (p = 0.036). There was no correlation between spleen enlargement and postoperative complications or average stay. However, survival was decreased in patients with spleen growth and CALI. Patients who receive neoadjuvant chemotherapy for liver metastasis surgery have a greater splenic volume increase, which correlates with NAFLD and a lower survival.

A simple method to identify undiagnosed drug-induced liver injury (DILI) and its application in oncology pharmacy practice.

To establish a simple method to identify chemotherapy-induced liver injury among oncological patients. To evaluate current clinical approach to elevated laboratory liver test results. A total of 289 patients admitted to oncology department who had systemic chemotherapy episodes for cancer treatment from 1 January 2017 to 31 December 2017 were identified. With aid of healthcare information system, Hy's law was applied to laboratory liver test results to identify potential hepatocellular drug-induced liver injury cases. Medical record review was carried out among identified patients to exclude liver dysfunction of alternative causes. Current clinical approach to elevated laboratory liver tests was evaluated through medical record review. Of 289 patients who were treated by systemic chemotherapies, there were 123 patients with elevated laboratory liver tests, among which 8 patients were suspected as potential Hy's law cases. After medical record review, there were two patients determined with chemotherapy-associated liver injury, caused by 5-fluorouracil, leucovorin, irinotecan, and S-1 plus paclitaxel separately. Of eight potential Hy's law cases, seven (87.5%) patients were prescribed with ≥2 kinds of liver protectants and remained treated with traditional Chinese medicine for decoction. A reliable and simple method to identify undiagnosed drug-induced liver injury was successfully established. An annual incidence of 0.69% of chemotherapy-associated liver injury in oncology department of the setting was found.

Risk of chemotherapy-associated liver injury (CALI) in PNPLA3 p.148M allele carriers: Preliminary results of a transient elastography-based study

Background and aimsLiver steatosis is one of the side effects of chemotherapy. The PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 p.G17E variants represent genetic determinants for progressive liver diseases. Here, we investigate their association with chemotherapy-associated steatosis. Patients and methodsProspectively, we recruited 87 patients undergoing systemic chemotherapy for gastrointestinal cancers. Hepatic fat (controlled attenuation parameter, CAP) and liver stiffness (LSM) were measured non-invasively before the initiation of chemotherapy (T0) and after at least two (T1) and four cycles (T2). Genetic variants were genotyped using allelic discrimination assays. ResultsIn the final dataset (n = 60) patients demonstrated the following CAP values: T0 – 215.0 ± 55.7 dB/m, T1 – 223.3 ± 53.6 dB/m, T2 – 223.4 ± 56.7 dB/m, consistent with mild steatosis. Initial CAP correlated with BMI (P < 0.01) and serum triglyceride concentrations (P = 0.03). Whereas at T0 none of the variants was associated with CAP or LSM, carriers of the prosteatotic PNPLA3 p.148M allele showed significantly (P = 0.008) higher steatosis at T1 as compared to patients carrying the homozygous wild-type genotype [II]. ConclusionsOur preliminary results show that patients carrying the PNPLA3 p.I148 M risk allele might be prone to hepatic fat accumulation during chemotherapy. Further studies are be needed to validate the clinical value of these findings.

Dynamic Changes in Normal Liver Parenchymal Volume During Chemotherapy for Colorectal Cancer: Liver Atrophy as an Alternate Marker of Chemotherapy-Associated Liver Injury.

The purpose of this study was to investigate the incidence, origin, and clinical significance of liver atrophy during chemotherapy for colorectal cancer. This study included 103 patients who underwent chemotherapy before resection for colorectal liver metastases (training set) and 171 patients who underwent adjuvant or first-line chemotherapy without liver resection (validation set). A greater than 10% decrease (atrophy) or increase (hypertrophy) of the liver volume from the baseline was defined as a significant change. In the training set, the numbers of patients who developed atrophy, no change of volume, and hypertrophy of the liver after chemotherapy were 15 (14.6%), 73 (70.9%), and 15 (14.6%), respectively. Liver atrophy was associated with impaired hepatic function, and the postoperative morbidity rate and refractory ascites/pleural effusion were higher in the patients with liver atrophy than those without (60.0% vs. 31.8%, P = 0.045 and 46.7% vs. 8.0%, P < 0.001, respectively). Histopathological examination revealed a strong association between sinusoidal injury and liver atrophy (P < 0.001). The cumulative incidence of liver atrophy increased with increasing duration of chemotherapy, whereas the incidence of liver atrophy was less frequent in patients who had received bevacizumab than those who had not in both the training set (odds ratio [OR], 0.13; P = 0.001) and the validation set (OR, 0.31; P = 0.007). Liver atrophy is associated with impaired hepatic functional reserve and observed at an increasing frequency as the duration of chemotherapy increases with frequent histopathological evidence of sinusoidal injury in the liver. Bevacizumab may protect against the development of liver atrophy.

The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy

BackgroundNeoadjuvant chemotherapy (NeoCTx) is performed for most patients with colorectal cancer liver metastases (CRCLM). However, chemotherapy-associated liver injury (CALI) has been associated with poor postoperative outcome. To date, however, no clinically applicable and noninvasive tool exists to assess CALI before liver resection.MethodsRoutine blood parameters were assessed in 339 patients before and after completion of NeoCTx and before surgery. The study assessed the prognostic potential of the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), the albumin-bilirubin grade (ALBI), and their combinations. Furthermore, an independent multi-center validation cohort (n = 161) was included to confirm the findings concerning the prediction of postoperative outcome.ResultsHigher ALBI, APRI, and APRI + ALBI were found in patients with postoperative morbidity (P = 0.001, P = 0.064, P = 0.001, respectively), liver dysfunction (LD) (P = 0.009, P = 0.012, P < 0.001), or mortality (P = 0.037, P = 0.045, P = 0.016), and APRI + ALBI had the highest predictive potential for LD (area under the curve [AUC], 0.695). An increase in APRI + ALBI was observed during NeoCTx (P < 0.001). Patients with longer periods between NeoCTx and surgery showed a greater decrease in APRI + ALBI (P = 0.006) and a trend for decreased CALI at surgery. A cutoff for APRI + ALBI at − 2.46 before surgery was found to identify patients with CALI (P = 0.002) and patients at risk for a prolonged hospital stay (P = 0.001), intensive care (P < 0.001), morbidity (P < 0.001), LD (P < 0.001), and mortality (P = 0.021). Importantly, the study was able to confirm the predictive potential of APRI + ALBI for postoperative LD and mortality in a multicenter validation cohort.ConclusionDetermination of APRI + ALBI before surgery enables identification of high-risk patients for liver resection. The combined score seems to dynamically reflect CALI. Thus, APRI + ALBI could be a clinically relevant tool for optimizing timing of surgery in CRCLM patients after NeoCTx.

Estimated remnant liver function prior to hepatectomy for CR metastasis is a better predictor of post-hepatectomy liver failure than APRI score.

Background: Posthepatectomy liver failure (PHLF) is a major complication after hepatectomy with a high mortality rate. The future remnant liver volume (FLRV%) and the total liver function both influence the occurrence of PHLF. Total liver function can be reduced in chemotherapy associated liver injury (CALI). Different tools predicting PHLF have been described in hepatectomy for colorectal liver metastasis after chemotherapy. Aspartate aminotransferase to platelet ratio index (APRI) has been shown to predict CALI and PHLF related to severe CALI. Estimation of the future liver remnant function (eFLRF) in a formula combining 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBS) and FLRV% liver volumetry has been shown to predict PHLF. No direct comparison between eFLRF and APRI has been performed up to now. Methods: Estimation of the future liver remnant function (eFLRF) was performed in 140 patients prior to liver resection for colorectal liver metastasis after preoperative systemic therapy. When the cut-off for eFLRF was under 2.3%/min/m2, portal vein embolization or ligation was performed. APRI scores was calculated in all patients. Results: In ROC analysis, FLRV% and eFLRF had a better predictive value for PHLF than HBS alone and APRI. In multivariate analysis, eFLRF seems to be the only predicting factor for PHLF. Conclusion: PHLF is best predicted by combining volumetry with liver function in one formula than by separate volumetric or functional evaluation of the liver.

Chemotherapy-associated Liver Injury prior Surgery of Hepatic Colorectal Metastases – Comparison of Functional and Histopathological Damage

Background: Chemotherapy prior liver resection of colorectal liver metastases (CLM) implies the risk of chemotherapy-associated liver injury (CALI) leading to increased postoperative morbidity and mortality. Methods: Retrospective analysis of patients with CLM prior resection. Preoperative assessment of liver function by LiMAx test. Histologic staging of resected tumor-free liver tissue. Analysis of 12-month history of chemotherapy prior surgery including the regime, the number of cycles and the therapy-free interval. Results: A total of 204 patients were analyzed. The majority (n=127; 62 %) had received previous chemotherapy. Impaired LiMAx results were determined in 49% of patients after chemotherapy. The extent of LiMAx impairment was dependent on number of oxaliplatin cycles, therapy-free interval and obesity in multivariate analysis. Patients with impaired LiMAx showed regeneration during chemotherapy cessation. Chemotherapy increased the incidence of steatosis (>33%; 29 vs. 17%) as well as of mild fibrosis (62 vs. 45%). The LiMAx was markedly decreased in steatosis (335 vs. 375 μg/kg/h, P=0.024), steatohepatitis (292 vs. 372 μg/kg/h, P=0.003), and severe fibrosis (318 vs. 395 μg/kg/h, P=0.001). While the degree of steatosis was associated with a short therapy-free interval, the degree of fibrosis was increased by the number of cycles. Conclusion: The LiMAx test enables preoperative assessment of CALI. Acute injury with steatohepatitis deteriorates LiMAx more severely than chronic injury with fibrosis.