BI 907828, a highly potent mouse double minute-2 (MDM2)-p53 antagonist, has shown potent preclinical antitumour activity. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. Here we report safety and efficacy for all pts who received BI 907828 once every 3 weeks (Q3W). During dose escalation (phase Ia), pts received escalating doses of BI 907828 on day 1 of 21-day cycles (Q3W) or days 1 and 8 of 28-day cycles; recommended dose for expansion (RDE) was 45 mg Q3W (Gounder et al, ESMO 2021 ). During dose expansion (phase Ib), pts were enrolled in Cohort 1 (TP53wt, MDM2-amplified liposarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and the number of pts with grade ≥3 treatment-related adverse events (TRAEs). At data cut off (April 2023), 140 pts had been enrolled to receive BI 907828 Q3W (29 in phase Ia; 111 in phase Ib); 78 (55.7%) were male, 77/62 (55.0%/44.3%) had ECOG PS 0/1, the median number of prior systemic therapies was 2. Of the 140 pts who received BI 907828 Q3W, 130 (92.9%) and 65 (46.4%) had any-grade and grade ≥3 TRAEs, respectively. The most common any-grade TRAEs were nausea (73.6%) and fatigue (57.9%). The most common grade ≥3 TRAEs were neutropenia (26.4%), thrombocytopenia (22.9%) and anemia (12.1%). Forty pts had serious AEs; the most common were thrombocytopenia (n=5), nausea, pulmonary embolism and neutropenia (n=4 each). At data cut off, 16/140 pts (11.4%) had a confirmed partial response (PR), and 89 pts had stable disease (SD), giving a disease control rate (DCR; at least SD) of 75.0%. Preliminary median PFS was 7.8 months; 36 pts (25.7%) had PFS >6 months. A total of 10 pts with advanced biliary tract cancer (BTC) received BI 907828 Q3W; of these, 3 (30%) had a confirmed PR and 5 had SD (DCR 80%). Two pts with BTC achieved PFS >12 months. BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including those with BTC; dose expansion is ongoing. BI 907828 is being further assessed in pts with BTC in the phase IIa/IIb open-label Brightline-2 trial (NCT05512377).

The understanding of human cancers has increased substantially within the past decade. However, translation of the acquired knowledge into clinical success is still remarkably low. This gap between scientific progress and clinical application is decisively driven by limitations of preclinical models, which often do not sufficiently mimic the complex microenvironment and heterogeneity of human tumors. Therefore, assays allowing for enrichment of human tumors responsive to complex immunotherapies, such as oncolytic virotherapy, are urgently needed. Here, we employed a patient-derived tumor biopsy culture system to assess susceptibility of individual human tumor ecosystems to the oncolytic virus VSV-GP ex vivo. A simplified ex vivo culture system of patient-derived tumor biopsies was established and compared to the tumor slice culture approach previously set up in our laboratories. Viability and tissue integrity of human colorectal and pancreatic cancer samples were studied by metabolic activity and histopathology, respectively. Susceptibility of biopsies and slice cultures derived from murine tumors, as well as more heterogenous human tumors to the oncolytic virus VSV-GP was assessed. In particular, virus replication kinetics was monitored over time by using reporter protein-tagged VSV-GP variants and fluorescence microscopy in combination with quantification of viral genomes via qRT-PCR. Patient derived tumor samples retained viability and histological integrity during overnight storage at 4°C, mimicking the transport from the clinics to the lab, as well as during ex vivo cultivation for up to 72h. Biopsies and slice cultures derived from murine tumors showed similar susceptibility to VSV-GP. These results could furthermore be substantiated in more complex patient-tumor derived samples, where VSV-GP propagated to a similar extent in tumor biopsies and tumor slice cultures. The here-described assay allows simple and straightforward ex vivo analysis of patient-derived tumor biopsies for susceptibility towards oncolytic viruses. This assay may open new avenues towards enrichment of cancer patients responsive to VSV-GP based oncolytic virotherapy.

Introduction: We here report on our final results of a phase I study of intraperitoneal (i.p.) administration of the virotherapeutic drug GL-ONC1 in patients exhibiting advanced stage peritoneal carcinomatosis (PC). GL-ONC1 is a recombinant Vaccinia virus genetically engineered to selectively replicate in and destroy cancer cells.

Anamnese und klinischer Befund: Wir berichten über einen 41-jähriger Patient mit Kopfschmerzen, Fieber, zunehmenden Schweißausbrüchen und Polydipsie unklarer Genese, der aus einem auswärtigem Krankenhaus zur weiteren Abklärung übernommen wurde. Untersuchungen: In der Blutkultur konnte Klebsiella pneumoniae isoliert werden. Im CT zeigte sich ein 7,6 × 7,2 × 9,9 cm großer Leberabszess in den Segmenten VI und VII. Diagnose, Therapie und Verlauf: Zunächst erfolgte eine empirische antibiotische Therapie mit Meropenem, Linezolid und Fluconazol. Nach Erhalt des Antibiogramms wurde resistenzgerecht auf Ciprofloxacin umgestellt. Diese Therapie wurde für 4 Wochen durchgeführt. Ebenso wurde CT-gesteuert die Abszesshöhle drainiert und gespült. Im weiteren Verlauf normalisierten sich die Entzündungsparameter. Sonographisch war die Abszessgröße im Verlauf regredient. Folgerung: Ein pyogener Leberabszess ist eine seltene, aber schwerwiegende entzündliche Erkrankung. Die Genese des Abszesses lässt sich häufig nicht genau eruieren. Je nach Befallsmuster ist eine konservative, eine operative oder eine Therapie durch gezielte Drainage notwendig. In jedem Fall sollte durch Isolierung des Erregers eine angepasste antibiotische Therapie über einen längeren Zeitraum gegeben werden.

Oncolytic viruses are replication competent "live" viruses. They infect tumor cells, replicate highly selective inside and thereby destroy them. Because of the enormous advances in the field of genetic engineering and biotechnology during the last decade, virotherapy is increasingly used within clinical trials and proved to be safe and effective. In particular, treatment of ovarian cancer patients is one main focus of research. On the one hand, this is due to the poor prognosis of this dismal entity, resulting in the urgent need for novel therapeutics. On the other hand, as ovarian cancer typically spreads within the peritoneal cavity, intraperitoneal administration of oncolytic viruses is feasible. This paper provides an overview of promising results from clinical trials to treat ovarian cancer patients with oncolytic viruses.

Einleitung: Hepatoide Adenokarzinome sind extrahepatische Tumore mit morphologischen und immunhistochemischen Eigenschaften hepatozellulärer Karzinome. In der Literatur wurden bisher lediglich einzelne Fälle mit hepatoiden Pankreaskarzinomen beschrieben. Über ein wirksames Chemotherapieregime für diese seltene Entität wurde bisher nicht berichtet.

Zielsetzung: Trotz der Verfügbarkeit von Hormontherapie, Chemotherapie und moderner Biologika ist Brustkrebs in der metastasierten Form nicht heilbar und die 5-Jahres-Überlebensrate beträgt in diesem Stadium weniger als 20%.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Einleitung: Hepatoide Adenokarzinome sind extrahepatische Tumore mit morphologischen und immunhistochemischen Eigenschaften hepatozellulärer Karzinome. In der Literatur wurden bisher lediglich einzelne Fälle mit hepatoiden Pankreaskarzinomen beschrieben. Über ein wirksames Chemotherapieregime für diese seltene Entität wurde bisher nicht berichtet.

Innovative gentherapeutischer Ansätze beim Hepatozellulären Karzinom (HCC) erfordern die Generierung von Genexpressionsprofilen des HCC zur Entwicklung entsprechend restringierter Vektorsysteme. Aus 150 Leberraumforderungen unterschiedlicher Entitäten (HCC, Leberzirrhose, Cholangiozelluläres Karzinom, Lebermetastasen, Fokalnoduläre Hyperplasie, Leberadenom) wurde RNA isoliert und mit Affymetrix GenChips (22.000 Proben) hybridisiert. Mit komplexen hierarchischen Clusteranalysen konnte eine Gruppe von 1087 Genen identifiziert werden, die in 60–100% der Tumoren konstant differentiell im Vergleich zu nicht-malignem Gewebe exprimiert wird. Damit ist es möglich, HCC-Proben zweifelsfrei gegenüber anderen Entitäten zu differenzieren. Insbesondere konnten funktionell zusammengehörige, differentiell exprimierte Gengruppen wie Rezeptoren, Transkriptionsfaktoren sowie Glycoproteinen identifiziert werden, die als neue molekulartherapeutische Targets für die Entwicklung spezifischer Vektorsysteme angesehen werden können. Für deren Einsatz ist es erforderlich, die Interaktionen ausgewählter Gentransfersysteme mit den zu adressierenden Zielzellen mittels Genexpressionsprofilierung zu charakterisieren. Hierfür wurden mit GenChips die Genexpressionsmuster von HepG2 Hepatomazellen sowie deren Kinetik unter Transduktion mit dem Sendai Virus (SeV)-Gentransfersystem untersucht. Dabei konnten zu unterschiedlichen Zeitpunkten der SeV-Infektion eine signifikante Änderung der Genexpression von Proteinen festgestellt werden, die am Zellwachstum, an der Zelladhäsion, an der Apoptose, bei der Modulation der Immunantwort sowie bei der Entgiftung beteiligt sind. Diese neu gewonnenen Erkenntnisse über die Wechselwirkung zwischen SeV-Vektoren und hepatischen Zielzellen ist von grosser Bedeutung für zukünftige Anwendungen in der HCC-Gentherapie und finden Eingang in das künftige Design weiterentwickelter Generationen des SeV-Gentransfersystemes.

A physical map of the apple proliferation phytoplasma strain AT chromosome was constructed from genomic DNA extracted from diseased tobacco plants. The map was generated with single and double digestions of the chromosome with BssHII, SmaI, MluI, and ApaI restriction endonucleases and resolving the fragments by pulsed-field gel electrophoresis. Partial digestion and Southern blot analysis were used to assist in the arrangement of the 14 contiguous restriction fragments obtained. From the restriction fragments generated by double digestions, the size of the circular chromosome was calculated to be approximately 645 kb. Locations of the two rRNA operons, the operon including the fus and tuf genes, and three other genes were placed on the map. Genome sizes and BssHII restriction profiles of apple proliferation strain AP15 and the pear decline and European stone fruit yellows phytoplasmas were different from that of strain AT.

Sendai virus (SV) infection and replication lead to a strong cytopathic effect with subsequent death of host cells. We now show that SV infection triggers an apoptotic program in target cells. Incubation of infected cells with the peptide inhibitor z-VAD-fmk abrogated SV-induced apoptosis, indicating that proteases of the caspase family were involved. Moreover, proteolytic activation of two distinct caspases, CPP32/caspase-3 and, as shown for the first time in virus-infected cells, FLICE/caspase-8, could be detected. So far, activation of FLICE/caspase-8 has been described in apoptosis triggered by death receptors, including CD95 and tumor necrosis factor (TNF)-R1. In contrast, we could show that SV induced apoptosis did not require TNF or CD95 ligand, We further found that apoptosis of infected cells did not influence the maturation and budding of SV progeny. In conclusion, SV-induced cell injury is mediated by CD95- and TNF-R1-independent activation of caspases, leading to the death of host cells without impairment of the viral life cycle.

Chromosome sizes of 71 phytoplasmas belonging to 12 major phylogenetic groups including several of the aster yellows subgroups were estimated from electrophoretic mobilities of full-length chromosomes in pulsed-field gels. Considerable variation in genome size, from 660 to 1,130 kilobases (kb), was observed among aster yellows phytoplasmas. Chromosome size heterogeneity was also observed in the stolbur phytoplasma group (range 860 to 1,350 kb); in this group, isolate STOLF contains the largest chromosome found in a phytoplasma to date. A wide range of chromosome sizes, from 670 to 1,075 kb, was also identified in the X-disease group. The other phytoplasmas examined, which included members of the apple proliferation, Italian alfalfa witches' broom, faba bean phyllody, pigeon pea witches' broom, sugarcane white leaf, Bermuda grass white leaf, ash yellows, clover proliferation, and elm yellows groups, all have chromosomes smaller than 1 megabase, and the size ranges within each of these groups is narrower than in the aster yellows, stolbur, and X-disease groups. The smallest chromosome, ≈530 kb, was found in two Bermuda grass white leaf phytoplasma isolates. This not only is the smallest mollicute chromosome found to date, but also is the smallest chromosome known for any cell. More than one large DNA band was observed in several phytoplasma preparations. Possible explanations for the occurrence of more than one band may be infection of the host plant by different phytoplasmas, the presence of more than one chromosome in the same organism, or the presence of large extrachromosomal DNA elements.