The upper limit for partial hepatectomy (PH) in rats is 90%, which is associated with an increased risk of post-hepatectomy liver failure (PHLF), correlating with high mortality. Sixty-eight rats ...were randomized to 90% PH, sham operation, or no surgery. Further block randomization was performed to determine the time of euthanasia, whether 12, 24, or 48 h after surgery. A general distress score (GDS) was calculated to distinguish between rats with reversible (GDS < 10) and irreversible PHLF (GDS ≥ 10). At euthanasia, the liver remnant and blood were collected. Liver-specific biochemistry and regeneration ratio were measured. Hepatocyte proliferation and volume were estimated using stereological methods. All rats subjected to 90% experienced biochemical PHLF. The biochemical and morphological liver responses did not differ between the groups until 48 h after surgery. At 48 h, liver regeneration and function were significantly improved in survivors. The peak mean regeneration ratio was 15% for rats with irreversible PHLF compared to 26% for rats with reversible PHLF. The 90% PH rat model was associated with PHLF and high mortality. Irreversible PHLF was characterized by impaired liver regeneration capacity and an insufficient ability to metabolize ammonia.
Introduction
The European Neuroendocrine Tumor Society, ENETS, reports variables of prognostic significance in pancreatic neuroendocrine tumors (PNET). However, studies have short follow-ups, and the ...optimal treatment remains controversial. We aimed to determine overall survival (OS), progression-free survival (PFS) after conservative treatment, and recurrence-free survival (RFS) after surgery and further to find predictors of aggressive PNET behavior to support treatment decisions.
Methods
174 patients with PNET treated at Aarhus University Hospital from 2011 to 2021 were included in a retrospective cohort study. Patients were divided into surgically resected (
SUR
, n=91) and medically or conservatively treated (
MED
, n=83). Variables were tested in univariate and multivariate survival analysis. Median follow-up time was 3.4 years in the MED group and 4.5 years in the SUR group.
Results
The 5-year OS was 95% and 65% for the SUR and MED groups, respectively. The 5-year RFS in the SUR group was 80% whereas the 5-year PFS in the MED group was 41%. Larger tumor size, Ki67 index, tumor grade, and stage were predictive of shorter OS, RFS, and PFS. Further, chromogranin A was a predictor of OS. Larger tumor size was associated with higher stage and grade. Only 1 of 28 patients with stage 1 disease and size ≤2 cm developed progression on a watch-and-wait strategy during a median follow-up of 36 months.
Conclusion
This study supported the ENETS staging and grading system to be useful to predict OS, PFS, and RFS in PNET. Further, our data support that small, localized, low-grade PNETS can be followed with active surveillance.
Peritoneal metastases (PM) and liver metastases (LM) are present simultaneously in up to 2 % of patients at the time of their colorectal cancer (CRC) diagnosis. Curatively intended treatment includes ...cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined with LM resection. A less invasive treatment for LM is ablation. We aimed to estimate overall survival (OS), disease-free survival (DFS) and postoperative data in patients managed simultaneously with CRS, HIPEC and radiofrequency ablation (RFA) as first choice.
This was a retrospective national cohort study. All patients were treated at Aarhus University Hospital; the only CRS+HIPEC centre in Denmark. We included CRC patients managed with curative intent for simultaneously diagnosed PM and LM in the period January 2016 - December 2021. LM was treated with RFA as first choice, if possible. Survival was calculated by the Kaplan-Meier method.
A total of 25 patients were included, the median age was 60 years (range 43-75 years) and 15 (60 %) were females. The median peritoneal cancer index was 7 (range 0-12), the median number of LM was 1 (range 1-3). Ablation was performed as the only treatment for LM in 18 (72 %) patients. After a median follow-up time of 17.1 months (range 4-36 months), the median OS was 28.6 months (95 % confidence interval (Cl) 15.8;36.1), 1-year OS was 84.0 % (95 % Cl 62.8;93.7). Median DFS was 6.1 months (95 % Cl 4.0;10.3). Median LOS was ten days (range 5-26 days). Both 30-day and 90-day mortality were 0 %.
The selected treatment modality (RFA) for CRC patients with both LM and PM was safe. However, DFS was low. Further research is warranted to investigate if RFA is as effective as LM resection.
Background
The upper limit for liver resections in rats is approximately 90%. In the early postoperative phase, mortality increases. The aim of the present study was to validate the rat model of 90% ...partial hepatectomy (PH) as a model of post‐hepatectomy liver failure (PHLF). Further, we wanted to test a quantitative scoring system as a detector of lethal outcomes caused by PHLF in rats.
Methods
Sixty‐eight rats were randomized to 90% PH, sham operation, or no surgery. Further, block randomization was performed based on time of euthanization: 12, 24, or 48 h after surgery. A general distress score (GDS) ≥10 during the day or ≥6 at midnight prompted early euthanization and classification as nonsurvivor. Animals euthanized as planned were classified as survivors. During euthanization, blood and liver tissue were collected, and liver‐specific biochemistry was evaluated.
Results
Based on the biochemical results, all animals subjected to 90% PH experienced PHLF. Seventeen rats were euthanized due to irreversible PHLF. The GDS increased for nonsurvivors within 12–18 h after surgery. The mean time for euthanization was 27 h after surgery.
Conclusion
Based on the GDS and liver‐specific biochemistry, we concluded that the model of 90% PH seems to be a proper model for investigating PHLF in rats. As a high GDS is associated with increased mortality, the GDS appears to be valuable in detecting lethal outcomes caused by PHLF in rats.
In the present study, we evaluated the rat model of 90% partial hepatectomy (PH) as a model of post‐hepatectomy liver failure (PHLF). We also investigated the use of a quantitative scoring system to detect lethal outcomes caused by PHLF in rats. Based on our clinical scoring system and supported by liver‐specific biochemistry, the model of 90% PH seems to be relevant for investigating PHLF in rats. By including both physiological and behavioral parameters, GDS appears to be valuable in detecting lethal outcomes caused by PHLF in rats.
Background Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to accelerate growth of the future liver remnant. We investigated alternative methods for ...increasing the future liver remnant. Methods A total of 152 rats were randomized as follows: (1) sham; (2) portal vein ligation; (3) portal vein ligation/surgical split (ALPPS); (4) portal vein ligation/split of the liver with a radiofrequency ablation needle; (5) portal vein ligation/radiofrequency ablation of the deportalized liver (portal vein ligation/radiofrequency ablation necrosis in the deportalized liver); (6) portal vein ligation/radiofrequency ablation of the future liver remnant (portal vein ligation/radiofrequency ablation–future liver remnant); and (7) controls. Animals were evaluated on postoperative days 2 and 4. Bodyweight, liver parameters, hepatic regeneration rate, proinflammatory cytokines, hepatocyte proliferation, and gene expression were measured. Results Hepatic regeneration rate indicated a steady increase in all intervention groups compared with sham rats ( P < .001). At postoperative day 2, the hepatic regeneration rate was significantly higher in the portal vein ligation/radiofrequency ablation necrosis in the deportalized liver group than in the portal vein ligation group ( P = .039). On postoperative day 4, we found significant differences between the portal vein ligation group and the ALPPS ( P = .015), portal vein ligation/split of the liver with a radiofrequency ablation needle ( P = .010), and portal vein ligation/radiofrequency ablation necrosis in the deportalized liver ( P = .046) groups. Hepatocyte proliferation was significantly higher at all times compared with sham rats. On postoperative day 4, we found a significantly higher proliferation in groups 3, 4, 5, and 6 compared to portal vein ligation. Gene analysis revealed upregulation of genes involved in cellular proliferation and downregulation of genes involved in cellular homeostasis in all intervention groups. Between the intervention groups, gene expression was nearly identical. Biochemical markers and proinflammatory cytokines were comparable between groups. Conclusion The surplus liver regeneration after ALPPS is probably mediated through parenchymal damage and subsequent release of growth stimulators, which again upregulates genes involved in cellular regeneration and downregulates genes involved in cellular homeostasis. We also demonstrate that growth of the future liver remnant, comparable to that seen after ALPPS, could be achieved by radiofrequency ablation treatment of the deportalized liver, that is, a procedure in which the initial step in humans can be performed percutaneously.
Extended hepatectomies may result in posthepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression ...profiles in rats subjected to increasing size of partial hepatectomy (PH). Thirty Wistar rats
were subjected to 30%, 70%, or 90% PH, sham operation, or no operation. Twenty-four hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Cluster analysis revealed two main groupings, one containing the PH(90%) and one containing the remaining
groups baseline, sham, PH(30%), and PH(70%). Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic function degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated
in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved
in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for posthepatectomy liver failure.
Abstract Background Sorafenib, a multikinase inhibitor, has been shown to halt the growth of hepatocellular carcinoma. The aim of the present study was to investigate the effect of Sorafenib on liver ...regeneration in healthy rats. Methods In two substudies we examined the effect of pre- or post-operative treatment with Sorafenib (15 mg/kg/d). Wistar rats ( n = 120) received either Sorafenib (S) or placebo (P). After 70% partial hepatectomy, the rats were euthanized on postoperative days 2, 4, or 8. Body weight and liver weight were recorded and regeneration rate (RR) calculated. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using unbiased stereological methods. Results Eleven animals (9%) died after surgery. In the preoperative substudy, lower body weight gains during the gavage period in the S group were found. No difference between groups S and P regarding liver weight gain, liver RRs, and hepatocyte proliferation on postoperative days 2 and 4 were found. In the postoperative substudy, significantly lower values of liver weight gain, liver RRs, and hepatocyte proliferation were found in the S group. Conclusions In our rat model, Sorafenib did not increase posthepatectomy mortality. Postoperative treatment significantly impaired liver regeneration. Preoperative treatment impaired body weight during the gavage period, but was without effect on liver regeneration.
The recurrence rate of colorectal liver metastases (CRLM) patients treated with curative intent is above 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging as ...well as carcinoembryonic antigen (CEA) measurements. Nonetheless, relapse detection often happens too late to resume curative treatment. This longitudinal cohort study enrolled 115 patients with plasma samples (N = 439) prospectively collected before surgery, postoperatively at day 30 and every third month for up to 3 years. Droplet digital PCR (ddPCR) was used to monitor serial plasma samples for somatic mutations. Assessment of ctDNA status either immediately after surgery, or serially during surveillance, stratified the patients into groups of high and low recurrence risk (hazard ratio HR, 7.6; 95% CI, 3.0‐19.7; P < .0001; and HR, 4.3; 95% CI, 2.3‐8.1; P < .0001, respectively). The positive predictive value (PPV) of ctDNA was 100% in all postoperative analyses. In multivariable analyses, postoperative ctDNA status was the only consistently significant risk marker associated with relapse (P < .0001). Indeterminate CT findings were observed for 30.8% (21/68) of patients. All patients (9/21) that were ctDNA positive at the time of the indeterminate CT scan later relapsed, contrasting 42.6% (5/12) of those ctDNA negative (P = .0046). Recurrence diagnoses in patients with indeterminate CT findings were delayed (median 2.8 months, P < .0001). ctDNA status is strongly associated with detection of minimal residual disease and early detection of relapse. Furthermore, ctDNA status can potentially contribute to clinical decision‐making in case of indeterminate CT findings, reducing time‐to‐intervention.
What's new?
Current surveillance methods after surgery for colorectal cancer liver metastasis are too often inadequate, and the cancer recurs after resection in more than half of patients. Here, the authors assess the predictive value of ctDNA analysis. They collected plasma from 115 patients before surgery, 30 days after surgery and then quarterly for up to 3 years. For each patient, one tumor‐associated mutation was assessed in the plasma. Postoperative detection of tumor ctDNA was highly predictive of relapse. Analysis of ctDNA could complement other surveillance methods to guide treatment decisions.
Abstract Background The upper limit for the size of hepatectomy is approximately 90% in rats. The aim of the study was to assess quantitatively using stereological methods the impact on liver ...function, regeneration rate and hepatocyte proliferation of varying hepatectomy size in a rat model. Materials and methods 104 male Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation, or no operation. Euthanization and harvesting of liver tissue and blood took place at post-operative day 1, 3, and 5 (n=8 per group). Liver specific biochemistry and regeneration rate were evaluated. Hepatocyte proliferation was estimated by immunohistochemical staining for Ki-67 antigen using unbiased stereological principles. Results Liver regeneration rate in the 90%-group increased by a 6.6 fold during the 5 post operative days compared with only a minor increase in both the 70% and 30% partial hepatectomy groups. The highest number of Ki-67 positive hepatocytes was observed in the 70%-group at post-operative day 1 and for the 90%-group at post-operative day 3. Prothrombin-proconvertin ratio was significantly lower in the 90%-group one day after surgery compared to all other groups however, nearly normalized at post-operative day 5. Conclusions We show that liver regeneration rate and the number of proliferating hepatocytes increase, while the initial hepatic synthetic capacity decreases with increasing hepatectomy size.
Despite limited evidence, technique efficacy and complications may be important short-term outcomes after ablation for hepatocellular carcinoma (HCC). We aimed to report these outcomes after ablation ...as the first surgical intervention for HCC.
This nationwide cohort study was based on data from the Danish Liver and Biliary Duct Cancer Database and medical records. Variables associated with outcomes were investigated using logistic regression.
From 2013 to 2023, 433 patients were included of which 79% were male, 73% had one tumor, and 90% had cirrhosis. Complete ablation was achieved after percutaneous, laparoscopic, and open approach in 84%, 100%, and 96% of the procedures, respectively. Most patients did not experience complications (76%). Open ablation compared with percutaneous was associated with higher risk of complications in multivariable adjusted analysis (Clavien-Dindo grade 2–5 (odds ratio 5.34, 95% confidence interval 2.36; 12.08) and 3B-5 (5.70, 2.03; 16.01), and lower risk of incomplete ablation (0.19 0.05; 0.65). Number of tumors ≥3 was associated with a higher risk of incomplete ablation (3.88, 1.45; 10.41). Tumor diameter ≥3 cm was associated with increased risk of complications grade 2–5 (2.84, 1.29; 6.26) and 3B-5 (4.44, 1.62; 12.13). Performance status ≥2 was associated with risk of complications grade 3B-5 (5.98, 1.58; 22.69). Tumor diameter was not associated with technique efficacy.
Open ablation had a higher rate of complete ablation compared with percutaneous but was associated with a higher risk of complications. Tumor diameter ≥3 cm and performance status ≥2 were associated with a higher risk of complications.
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