Search

Objective Hepatocellular carcinoma (HCC) accounts for 75–85% of all primary liver malignancies. Curative treatments in early-stage HCC are hampered by high recurrence rates, and targeted therapies against HCC are rare. Little is known about the impact of tumor microenvironment (TME) in HCC. One immunomodulatory strategy used by malignant tumors is the expression of programmed cell death receptor 1 ligand (PD-L1), whose receptor is expressed on activated T cells (PD-1). The use of immune checkpoint inhibitors (ICI) blocking this interaction has shown antitumor activity and unprecedented rates of durable clinical responses in various cancer types. In HCC, ICI are described as possible second-line therapies. It is known from other tumor entities that expression of PD-1 and PD-L1 in the TME has prognostic importance and can predict response to ICI. The aim of our study was to investigate the impact of PD-1 and PD-L1 expression on HCC recurrence and its relation to cancer-immune phenotypes. Methods Immunohistochemical staining was performed on archival tissue from 94 HCC, primary and recurrent, using the following antibodies: NAT105 (PD-1) and Ventana SP263 (PD-L1). Based on this protein expression, tumors were classified as immunologically active, excluded or deserted. PD-1 and PD-L1 immunoreactivity was evaluated as the proportion of positive cells compared to the total number of immune cells (0%, 1%). Results Basic tumor characteristics were not related to recurrence of HCC. PD-1 expression >1% (78%; 38/49) was associated with a significantly lower recurrence rate compared to tumors with 1% (77%; 49/64). Additionally, they also showed a significantly lower recurrence rate, especially in combination with PD-1 expression of >1% (p=0.066). Conversely, an association between HCC recurrence and PD-L1 expression on tumor cells was not found. Conclusion Consistent with previous reports, an association between PD-1 expression on immune cells and lower HCC recurrence was found. Furthermore, the results suggest that HCC recurrence is less frequent in immune-activated tumors. The use of therapeutic anti-PD-1 antibodies as an adjuvant therapy should thus be further investigated.

Study Purpose The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. Methods The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. Results Not applicable. Conclusion DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. Trial Registration Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

Objective Numerous publications describe percutaneous cholecystostomy (PC) as a possible treatment option for acute cholecystitis (AC) in selected cases where laparoscopic or open cholecystectomy (CHE) is not feasible due to limited health conditions. Whereas certain experts propose PC as a definitive therapy option for AC, a number of studies question the use of PC, due to high complication rates, no additional benefit of PC compared to CHE, and an increased mortality. The aim of our study was to retrospectively analyze the outcome of patients treated with PC over an extended period of time. Methods We conducted a retrospective study of patients who underwent PC for AC at a tertiary referral hospital during the last 10 years. The collected data included basic demographics, details about PC procedure, outcome, surgical-rate and final histologic diagnosis. Results Out of 158 patients (median age 75 years) treated with PC for AC, 47 (30%) died without undergoing subsequent CHE. Half of the PC patients (79) underwent subsequent CHE (8% in the hot phase), with 97% of these patients undergoing subsequent CHE within one year after PC. Seven (5%) of them died within the first year. The overall Charlson Comorbidity Index (CCI) was 6.4 (CHE vs. no CHE 5.3 vs. 7.4). Histologically, 22 (29%) of the 75 analyzed specimens showed chronic cholecystitis (CC), and 57 patients (68%) had signs of an AC. In 48 patients (30%), a complication after PC occurred. Conclusion In our collective, the 1-year survival after PC was 72%. The majority of these patients were in limited health conditions with a mean pre-PC CCI > 5, which implies a potential one-year mortality rate of over 85%. Histologic examination of almost all cholecystectomy specimens showed persistent inflammation. To our knowledge, this is the first extensive report of histologic findings in gallbladder specimens after PC. Based on our findings, especially in view of the high mortality rate of PC patients, we propose CHE as the treatment of choice in AC, even in chronically ill and elderly patients after stabilization, e.g. with a PC. PC represents no definitive treatment for AC and should remain a short-term solution because of the persistent inflammatory focus. Because CHE in a critically ill patient can be challenging, it should be performed by the most experienced surgeons.

The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.

OVEREXPRESSION of the D2dopamine receptor has been proposed to be part of the pathology of schizophrenia1.The isolation of a D2dopamine receptor clone has assisted the molecular characterization of D2 receptors2. We have now isolated an identical rat clone along with two other clones — a second related rat clone (RD-2in) and a homologous bovine clone (BD-2in), both of which contain an insert encoding an additional 29 amino acids relative to the original rat clone (RD-20). All three clones encode D2 receptor binding sites when expressed in COS-7 cells. The a mi no-acid insert encoded by D-2in lies in the domain of the receptor believed to interact with the GTP-binding proteins (G proteins) of various signal transduction pathways3. By using oligonucleotide probes specific for either D-20 or D-2in RNA transcripts, we have found that the level of expression of the D-2in-encoded form of the receptor is seven times that of the D-20 form in the caudate nucleus, the richest brain source of D2receptors4.

Genes involved in the biosynthesis of leucine have been mapped in Bacillus megaterium QM B1551, using transducing phage MP13. Mutations were designated leuA, leuB, or leuC on the basis of enzyme assays. Two mutant strains were deficient in the enzyme activities of leuA (alpha-isopropylmalate synthase) and leuC (beta-isopropylmalate dehydrogenase) and so may contain polar mutations. Fine-structure transduction mapping established the gene order leuC-leuB-leuA-ilv-hem-phe. The orientation of the leu genes to the ilv gene is the same as in Bacillus subtilis, but the relationship in respect to two other linked markers, hem and phe, differs.