Is an intraoperative liver function assessment possible? Application of the 13C-methacetin-breath-test during major liver resections - a pilot study.

BACKGROUND: As prevention of posthepatectomy-liver-failure is crucial, there is need of dynamic assessment of liver function, even intraoperatively. 13C-methacetin-breath-test estimates the organ's microsomal functional capacity. This is its first intraoperative evaluation in major liver surgery. METHODS: 30 patients planed for resection of ≥3 liver segments, between March-November 2019, were prospectively enrolled in this "single-center", pilot study. Using the 13C-methacetin-breath-test, liver function was assessed four times: preoperatively, intraoperatively before and after resection and postoperatively. The resulted maximum-liver-function-capacity (LiMAx)-values and delta-over-baseline (DOB)-curves were compared, further analyzed and correlated to respective liver volumes. RESULTS: The intraoperative LiMAx-values before resection were mostly lower than the preoperative ones (-11.3% ± 28%). The intraoperative measurements after resection resulted to mostly higher values than the postoperative ones (42.35% ± 46.19%). Pharmacokinetically, an interference between the two intraoperative tests was observed. There was no strong correlation between residual liver volume and function with a percentual residual-LiMAx mostly lower than the percentual residual volume (-17.7% ± 4.1%). CONCLUSIONS: Intraoperative application of the 13C-methacetin-breath-test during major liver resections seems to deliver lower values than the standard preoperative test. As multiple intraoperative tests interfere significantly to each other, a single intraoperative measurement is suggested. Multicentric standardized measurements could define the "normal" range for intraoperative measurements and control their predictive value.

Hippocampal synaptic connectivity in phenylketonuria.

In humans, lack of phenylalanine hydroxylase (Pah) activity results in phenylketonuria (PKU), which is associated with the development of severe mental retardation after birth. The underlying mechanisms, however, are poorly understood. Mutations of the Pah gene in Pah(enu2)/c57bl6 mice result in elevated levels of phenylalanine in serum similar to those in humans suffering from PKU. In our study, long-term potentiation (LTP) and paired-pulse facilitation, measured at CA3-CA1 Schaffer collateral synapses, were impaired in acute hippocampal slices of Pah(enu2)/c57bl6 mice. In addition, we found reduced expression of presynaptic proteins, such as synaptophysin and the synaptosomal-associated protein 25 (SNAP-25), and enhanced expression of postsynaptic marker proteins, such as synaptopodin and spinophilin. Stereological counting of spine synapses at the ultrastructural level revealed higher synaptic density in the hippocampus, commencing at 3 weeks and persisting up to 12 weeks after birth. Consistent effects were seen in response to phenylalanine treatment in cultures of dissociated hippocampal neurones. Most importantly, in the hippocampus of Pah(enu2)/c57bl6 mice, we found a significant reduction in microglia activity. Reorganization of hippocampal circuitry after birth, namely synaptic pruning, relies on elimination of weak synapses by activated microglia in response to neuronal activity. Hence, our data strongly suggest that reduced microglial activity in response to impaired synaptic transmission affects physiological postnatal remodelling of synapses in the hippocampus and may trigger the development of mental retardation in PKU patients after birth.

The AhR is constitutively activated and affects granulosa cell features in the human cell line KGN.

A well-balanced activity of the aryl hydrocarbon receptor (AhR) is necessary for normal ovarian function. As known from murine AhR knock-out (KO) models, the AhR is involved in folliculogenesis, gonadotrophin receptor expression, proliferation of granulosa cells and intraovarian estrogen signalling. Highly potent, non-physiological ligands such as the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lead to a blockade of ovulation, estrogen receptor degradation and reduction of estrogen levels. Estrogen synthesis is a typical function of granulosa cells and essential for normal cyclicity and fertility. We employed the human granulosa cell line KGN to further characterize AhR signalling and AhR function in granulosa cell physiology. Real-time PCR quantification of the target genes Cyp1a1 and Cyp1b1 and reporter gene assays after stimulation with TCDD or beta-naphthoflavone (BNF) or inhibition with alpha-naphthoflavone (ANF) or 3'-methoxy-4'-nitroflavone (3,4-MNF) of the AhR demonstrated constitutive activity and functionality of AhR pathway in KGN granulosa cells. In untreated KGN cells, AhR protein was exclusively detected in the nuclear fraction. TCDD stimulation affected the gonadotrophin receptor but not estrogen receptor ß (ERß) protein expression. Additionally, the constitutively activated AhR suppressed aromatase expression and estrogen synthesis (enzyme-linked immunoassay, ELISA) and enhanced proliferation [Bromodeoxyuridine (BrdU) ELISA] of KGN cells. Activation of the AhR by BNF did not override this inhibitory effect on estrogen synthesis or proliferation. In conclusion, the AhR pathway is constitutively activated and functional in human KGN granulosa cells. It is a potential target for endocrine disruption by exogenous ligands and subsequent dysfunction of granulosa cells.

Benign Liver Tumors.

BACKGROUND: Due to the frequent use of medical imaging including ultrasonography, the incidence of benign liver tumors has increased. There is a large variety of different solid benign liver tumors, of which hemangioma, focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA) are the most frequent. Advanced imaging techniques allow precise diagnosis in most of the patients, which reduces the need for biopsies only to limited cases. Patients with benign liver tumors are mostly asymptomatic and do not need any kind of treatment. Symptoms can be abdominal pain and pressure effects on adjacent structures. The 2 most serious complications are bleeding and malignant transformation. SUMMARY: This review focuses on hepatic hemangioma (HH), FNH, and HCA, and provides an overview on clinical presentations, surgical and interventional treatment, as well as conservative management. Treatment options for HHs, if indicated, include liver resection, radiofrequency ablation, and transarterial catheter embolization, and should be carefully weighed against possible complications. FNH is the most frequent benign liver tumor without any risk of malignant transformation, and treatment should only be restricted to symptomatic patients. HCA is associated with the use of oral contraceptives or other steroid medications. Unlike other benign liver tumors, HCA may be complicated by malignant transformation. HCAs have been divided into 6 subtypes based on molecular and pathological features with different risk of complication. KEY MESSAGE: The vast majority of benign liver tumors remain asymptomatic, do not increase in size, and rarely need treatment. Biopsies are usually not needed as accurate diagnosis can be obtained using modern imaging techniques.

Undifferentiated embryonal sarcoma of the liver treated with associating liver partition and portal vein ligation for staged hepatectomy in a young adult: A case report.

INTRODUCTION: Embryonal sarcomas of the liver (ESL) are extremely rare solid tumors appearing mainly in children. The therapeutic standard for an ESL is a margin free resection combined with chemotherapy. The Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure as a surgical therapy offers a curative approach for liver tumors of various origins where the future liver remnant (FLR) would be insufficient after a one-staged (extended) hemihepatectomy. PRESENTATION OF CASE: A 19-year-old patient was diagnosed with an undifferentiated embryonal sarcoma of the liver (UESL) in the right liver lobe with oligometastatic spread to the lungs. After neoadjuvant chemotherapy remission was enough to plan a resection of the liver tumor. During the operation we changed our strategy from one-stage hepatectomy to ALPPS because of borderline FLR and macroscopic and histologic liver damage to avoid posthepatectomy liver failure. The interstage and postoperative course of the patient was uneventful beside postoperative bile leakage, which was treated by interventional drainage and stenting. DISCUSSION: The ALPPS-procedure as a comparatively new surgery was considered over a portal vein ligation or embolization. ALPPS shows a faster hypertrophy compared to standard one-staged hemihepatectomy with decreased or similar proliferation, apoptosis or angiogenesis (at least for CRLM) CONCLUSION: In experienced centers the ALPPS-procedure is evolving as the safer approach in hemihepatectomys where the FLR is critical. Additionally, ALPPS can serve as an intraoperative option when liver volume and quality seem not to be sufficient and is to be considered when facing new tumor-entities.

Extended liver resection including hypertrophy concept with portal venous embolisation for giant haemangioma. Too much surgery?

Haemangiomas of the liver are benign tumours, which are often diagnosed randomly. With an increase in size haemangiomas could become symptomatic. In this case therapeutic options, surgical or interventional, have to be weighted to a conservative approach. We present a case of a 36-year old woman with a symptomatic giant haemangioma of the right liver lobe. Because of the size of the tumor and the small future liver remnant we decided to perform a major liver resection after hypertrophy induction with a preoperative portal vein embolization; an option mainly used for major hepatectomies in malignant tumors of the liver. But however, this case shows, that using a hypertrophy concept also for benign liver tumours is the safer approach, if an extended resection is necessary and the future liver remnant is critical.

Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor ß.

In the hippocampus, synaptic proteins, as studied so far, have been shown to be upregulated by 17ß-estradiol, while inhibition of local estradiol synthesis consistently downregulates them. As an exception to this rule, we have previously shown that synaptopodin, an actin-associated postsynaptic protein, is downregulated in response to estradiol in dissociated cultured hippocampal neurons. In this study, we show, unexpectedly, that synaptopodin is downregulated in the hippocampus of aromatase knock-out mice and that inhibition of neuronal estradiol synthesis using the aromatase inhibitor letrozole also downregulates synaptopodin in these cultures. Moreover, the effects of estradiol and letrozole are additive, suggesting a subtle balance between available ligand and receptor. Using selective estrogen receptor agonists and antagonists, we consequently studied the effects of estrogen receptor subtypes on synaptopodin expression in our hippocampal cultures. We found that estradiol-induced downregulation of synaptopodin is mediated by estrogen receptor ß. Estrogen receptor ß in turn, is upregulated in response to intracellular estradiol ablation following inhibition of estradiol synthesis by letrozole in dissociated hippocampal cultures, as well as in the hippocampus of the aromatase knock-out mouse. Thus, it appears that both the application of estradiol, via binding to estrogen receptor ß, and letrozole, via upregulation of estrogen receptor ß, eventually result in a downregulation of synaptopodin. Our data show that the synaptic plasticity caused by estradiol is subject to a subtle balance of the levels of estrogen receptor subtypes regulated by the available ligands. In addition, both seem to be part of a homeostatic feedback mechanism.