Abstract OBJECTIVES Our goal was to present histopathological findings of human explants of a tissue-engineered bovine pericardium CardioCel (Admedus Regen Pty Ltd, Malaga, WA, Australia) used for heart valve repair in patients with congenital and acquired heart valve disease. METHODS Sixty patients underwent heart valve repair from May 2014 to November 2018 using CardioCel as a substitute for valve tissue. We identified 9 cases in which the CardioCel patch was explanted following valve repair and available for histomorphological analyses. CardioCel explants were evaluated histologically using haematoxylin and oeosin, Elastica van Gieson and immunohistochemical stains. RESULTS The indications for explantation were related to the CardioCel patch in 6 patients. Median time between the implantation and explantation was 242 (range 3–1247) days. We demonstrated a characteristic remodelling pattern with superficial coating of the tissue-engineered bovine pericardium by granulation tissue composed of histiocytes, few lymphocytes and fibrin. We had 2 cases with a multifocal nodular disruption, fragmentation and sclerosis of the decellularized collagen matrix with focal calcification after 795 and 1247 days in situ. CONCLUSIONS Our data suggest that the tissue-engineered CardioCel patch is initially tolerated in the valvular position in the majority of patients. However, we also experienced graft failures that showed degeneration with fragmentation of the collagen matrix and even 2 cases with focal calcification evident from the histopathological analysis. Further analyses of mid- and long-term performance are mandatory.
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates. Results We analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan–Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions. Conclusion Our method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer–stroma communication.
Abstract Background Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recently, mutations in the PINK1 (PARK6) gene were shown to rarely cause autosomal-recessively transmitted, early-onset parkinsonism. In order to evaluate whether PINK1 contributes to the risk of common late-onset PD we analysed PINK1 sequence variations. A German (85 patients) and a Norwegian cohort (90 patients) suffering from late-onset PD were screened for mutations and single nucleotide polymorphisms (SNPs) in the PINK1 gene. Both cohorts consist of well-characterized patients presenting a positive family history of PD in ~17%. Investigations were performed by single strand conformation polymorphism (SSCP), denaturating high performance liquid chromatography (DHPLC) and sequencing analyses. SNP frequencies were compared by the χ 2 test Results Several common SNPs were identified in our cohorts, including a recently identified coding variant (Q115L) in exon 1. Genotyping of the Q115L variation did not reveal significant frequency differences between patients and controls. Pathogenic mutations in the PINK1 gene were not identified, neither in the German nor in the Norwegian cohort. Conclusion Sequence variation in the PINK1 gene appears to play a marginal quantitative role in the pathogenesis of the late-onset form of PD, in German and Norwegian cohorts, if at all.
TPS2670 Background: Claudin-18.2 (CLDN18.2), whose expression is normally restricted to short-lived gastric epithelial cells, is ectopically expressed in tumors with unmet needs such as gastric, gastroesophageal junction (GEJ), pancreatic, ovarian, and biliary tract tumors. CLDN18.2 has thus emerged as a promising target for therapeutic antibody development. BNT141 is a novel RNA-based therapeutic that comprises two pseudouridine-modified mRNAs encapsulated in lipid nanoparticles. Upon intravenous injection, BNT141 is preferentially taken up by the liver where RNAs are translated and released into the circulation as fully assembled anti-CLDN18.2 antibodies. The resulting antibody is sequence identical to IMAB362, a CLDN18.2-targeted antibody that provided clinical benefit as an add-on to chemotherapy in the Phase III SPOTLIGHT trial (Shitara et al. J Clin Oncol. 2023). RNA-encoded antibodies can be developed more rapidly compared with recombinant antibodies and have the potential for favorable PK/PD properties and improved tolerability. Methods: This is a Phase I/II, open-label, multisite, dose escalation and expansion trial to examine safety, efficacy, and PK/PD of BNT141 in patients with CLDN18.2+ tumors (NCT04683939). The trial comprises 3 parts: dose escalation with BNT141 as monotherapy, dose escalation with BNT141 in combination with nab-paclitaxel and gemcitabine, and dose expansion. For monotherapy dose escalation, patients with CLDN18.2+ gastric, GEJ, pancreatic, mucinous ovarian, and biliary tract cancers who have exhausted or are ineligible for the current standard of care are eligible. CLDN18.2 positivity is defined as intermediate/strong staining intensity in ≥50% of tumor cells evaluated using a validated immunohistochemistry assay. Doses of BNT141 are escalated in up to 8 planned dose levels (DLs) until the maximum tolerated dose (MTD) is reached. For combination dose escalation, patients with advanced CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for treatment with nab-paclitaxel/gemcitabine will be included. Combination therapy will start at the first safe DL where the target antibody concentration is reached during monotherapy. Combination dose escalation will continue in parallel with the monotherapy part and will define the recommended Phase II dose (RP2D). For both parts, up to 10 additional patients may be enrolled at the MTD level to collect further safety and PK/PD data. For dose expansion, 2 cohorts of patients with CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma will receive combination therapy (nab-paclitaxel/gemcitabine) together with BNT141 at the defined RP2D. The study was initiated in January 2022 and recruitment is ongoing in the USA and Canada. Sites in Spain, Portugal, Germany, Denmark, Netherlands and the UK will be opened in 2023. Clinical trial information: NCT04683939 .
