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Martin Stockmann

About Martin Stockmann:
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SEEK ID: https://seek.lisym.org/people/44

Location:  Germany

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Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org

Start date: 1st Jan 2016

LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Disorders of the liver show up through changes in blood tests. These blood tests indicate markers for events taking place in the liver. Usually studies of liver tissue cannot be performed: as liver samples would need to be obtained through a liver biopsy, and this procedure is not without risk, therefore these samples are usually unavailable. Complex metabolism models based on existing and new scientific data can simulate changes in the liver caused by disease. They often reveal unknown relationships
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Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/pillar-research/the-liver-is-very-patient

Start date: 1st Jan 2016

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and … intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated beta-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC.

Authors: N. Berndt, J. Eckstein, N. Heucke, T. Wuensch, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 8th Oct 2020

Publication Type: Journal

A novel variant of the (13)C-methacetin liver function breath test that eliminates the confounding effect of individual differences in systemic CO2 kinetics.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

The principle of dynamic liver function breath tests is founded on the administration of a (13)C-labeled drug and subsequent monitoring of (13)CO2 in the breath, quantified as time series delta over … natural baseline (13)CO2 (DOB) liberated from the drug during hepatic CYP-dependent detoxification. One confounding factor limiting the diagnostic value of such tests is that only a fraction of the liberated (13)CO2 is immediately exhaled, while another fraction is taken up by body compartments from which it returns with delay to the plasma. The aims of this study were to establish a novel variant of the methacetin-based breath test LiMAx that allows to estimate and to eliminate the confounding effect of systemic (13)CO2 distribution on the DOB curve and thus enables a more reliable assessment of the hepatic detoxification capacity compared with the conventional LiMAx test. We designed a new test variant (named "2DOB") consisting of two consecutive phases. Phase 1 is initiated by the intravenous administration of (13)C-bicarbonate. Phase 2 starts about 30 min later with the intravenous administration of the (13)C-labelled test drug. Using compartment modelling, the resulting 2-phasic DOB curve yields the rate constants for the irreversible elimination and the reversible exchange of plasma (13)CO2 with body compartments (phase 1) and for the detoxification and exchange of the drug with body compartments (phase 2). We carried out the 2DOB test with the test drug (13)C-methacetin in 16 subjects with chronic liver pathologies and 22 normal subjects, who also underwent the conventional LiMAx test. Individual differences in the systemic CO2 kinetics can lead to deviations up to a factor of 2 in the maximum of DOB curves (coefficient of variation CV approximately 0.2) which, in particular, may hamper the discrimination between subjects with normal or mildly impaired detoxification capacities. The novel test revealed that a significant portion of the drug is not immediately metabolized, but transiently taken up into a storage compartment. Intriguingly, not only the hepatic detoxification rate but also the storage capacity of the drug, turned out to be indicative for a normal liver function. We thus used both parameters to define a scoring function which yielded an excellent disease classification (AUC = 0.95) and a high correlation with the MELD score (RSpearman = 0.92). The novel test variant 2DOB promises a significant improvement in the assessment of impaired hepatic detoxification capacity. The suitability of the test for the reliable characterization of the natural history of chronic liver diseases (fatty liver-fibrosis-cirrhosis) has to be assessed in further studies.

Authors: H. G. Holzhutter, T. Wuensch, R. Gajowski, N. Berndt, S. Bulik, D. Meierhofer, M. Stockmann

Date Published: 6th Feb 2020

Publication Type: Not specified

Resection of hepatic and pulmonary metastasis from metastatic esophageal and gastric cancer: a nationwide study.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

The standard of care for gastroesophageal cancer patients with hepatic or pulmonary metastases is best supportive care or palliative chemotherapy. Occasionally, patients can be selected for curative … treatment instead. This study aimed to evaluate patients who underwent a resection of hepatic or pulmonary metastasis with curative intent. The Dutch national registry for histo- and cytopathology was used to identify these patients. Data were retrieved from the individual patient files. Kaplan-Meier survival analysis was performed. Between 1991 and 2016, 32,057 patients received a gastrectomy or esophagectomy for gastroesophageal cancer in the Netherlands. Of these patients, 34 selected patients received a resection of hepatic metastasis (n = 19) or pulmonary metastasis (n = 15) in 21 different hospitals. Only 4 patients received neoadjuvant therapy before metastasectomy. The majority of patients had solitary, metachronous metastases. After metastasectomy, grade 3 (Clavien-Dindo) complications occurred in 7 patients and mortality in 1 patient. After resection of hepatic metastases, the median potential follow-up time was 54 months. Median overall survival (OS) was 28 months and the 1-, 3-, and 5- year OS was 84%, 41%, and 31%, respectively. After pulmonary metastases resection, the median potential follow-up time was 80 months. The median OS was not reached and the 1-, 3-, and 5- year OS was 67%, 53%, and 53%, respectively. In selected patients with gastroesophageal cancer with hepatic or pulmonary metastases, metastasectomy was performed with limited morbidity and mortality and offered a 5-year OS of 31-53%. Further prospective studies are required.

Authors: M. F. J. Seesing, A. van der Veen, H. J. F. Brenkman, H. B. A. C. Stockmann, G. A. P. Nieuwenhuijzen, C. Rosman, F. J. H. van den Wildenberg, M. I. van Berge Henegouwen, P. van Duijvendijk, B. P. L. Wijnhoven, J. H. M. B. Stoot, M. Lacle, J. P. Ruurda, R. van Hillegersberg

Date Published: 31st Dec 2019

Publication Type: Not specified

Dynamic liver function is an independent predictor of recurrence-free survival after curative liver resection for HCC - A retrospective cohort study.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

BACKGROUND: Hepatocellular carcinoma is the fifth most prevalent cancer worldwide. High tumour recurrence is the most common cause of the impaired 5-year survival rate of 26-58% after hepatectomy. The … aim of this study was to investigate the impact of preoperative dynamic liver function on long-term outcome. MATERIALS AND METHODS: A total of 146 patients that underwent curative resection for HCC at our department from 2005 to 2016 were analysed. Univariate analysis was calculated using Kaplan-Meier method. Multivariable analysis was carried out with Cox regression. RESULTS: The cumulative 1-, 3-, 5-year survival rates were 83%, 42% and 14%, respectively. Multivariable Cox regression yielded that overall survival depends on disease recurrence, haemoglobin, number of tumours, liver cirrhosis, lymphatic vessel invasion, UICC stage and postoperative complications. The corresponding 1-, 3-, 5-year disease-free survival rates were 73%, 32% and 10%, respectively. Multivariable analysis yielded preoperative liver function capacity (HR 2.421; p=0.014), vascular invasion (HR 2.116; p=0.034) and UICC stage (HR 2.200; p=0.037) as risk factors associated with disease-free survival. A subanalysis with respect to the degree of functional impairment implicated that severity of liver function impairment is correlated with the disease-free survival rate. CONCLUSION: This study shows that preoperative dynamic liver function assessed by LiMAx test as well as severity of underlying liver disease have a significant impact on recurrence-free survival after curative hepatectomy. Patients presenting with impaired liver function should be evaluated for other treatment e.g. liver transplantation or receive closer oncological follow-up.

Authors: E. Bluthner, J. Bednarsch, M. Malinowski, P. Binder, J. Pratschke, M. Stockmann, M. Kaffarnik

Date Published: 9th Sep 2019

Publication Type: Not specified

Characterization of Lipid and Lipid Droplet Metabolism in Human HCC.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have … mainly focused on the glucose metabolism (Warburg effect), less attention has been paid to tumor-specific features of the lipid metabolism. Here, we applied a computational approach to analyze major pathways of fatty acid utilization in individual HCC. To this end, we used protein intensity profiles of eleven human HCCs to parameterize tumor-specific kinetic models of cellular lipid metabolism including formation, enlargement, and degradation of lipid droplets (LDs). Our analysis reveals significant inter-tumor differences in the lipid metabolism. The majority of HCCs show a reduced uptake of fatty acids and decreased rate of beta-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of beta-oxidation. Despite reduced fatty acid uptake in the majority of HCCs, the content of triacylglycerol is significantly enlarged compared to the tumor-adjacent tissue. This is due to tumor-specific expression profiles of regulatory proteins decorating the surface of LDs and controlling their turnover. Our simulations suggest that HCCs characterized by a very high content of triglycerides comprise regulatory peculiarities that render them susceptible to selective drug targeting without affecting healthy tissue.

Authors: N. Berndt, J. Eckstein, N. Heucke, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 27th May 2019

Publication Type: Not specified

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