A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Neurologic complications of breast cancer.

Breast cancer is a heterogeneous disease with unique neurologic complications that can arise from central nervous system (CNS) involvement or secondary to treatments themselves. As progress is made, with more targeted therapies and combinations available, particularly in the realm of human epidermal growth factor receptor 2 (HER2)-positive disease, the role of these new agents in patients with CNS disease is gradually evolving, although intracranial efficacy itself is lagging. At the same time, both systemic and local standard therapies pose clinical challenges regarding neurologic complications, such as peripheral neuropathy and cognitive changes. The development of new agents, such as immunotherapy, and new strategies, such as incorporating systemic therapies into local therapy, unveil new presentations of neurological complications.

Epidemiological Studies of Pan-Azole Resistant Aspergillus fumigatus Populations Sampled during Tulip Cultivation Show Clonal Expansion with Acquisition of Multi-Fungicide Resistance as Potential Driver.

Pan-azole resistant isolates are found in clinical and environmental Aspergillus fumigatus (Af) populations. Azole resistance can evolve in both settings, with Af directly targeted by antifungals in patients and, in the environment, Af unintendedly exposed to fungicides used for material preservation and plant disease control. Resistance to non-azole fungicides, including methyl benzimidazole carbamates (MBCs), quinone outside inhibitors (QoIs) and succinate dehydrogenase inhibitors (SDHIs), has recently been reported. These fungicide groups are not used in medicine but can play an important role in the further spread of pan-azole resistant genotypes. We investigated the multi-fungicide resistance status and the genetic diversity of Af populations sampled from tulip field soils, tulip peel waste and flower compost heaps using fungicide sensitivity testing and a range of genotyping tools, including STRAf typing and sequencing of fungicide resistant alleles. Two major clones were present in the tulip bulb population. Comparisons with clinical isolates and literature data revealed that several common clonal lineages of TR34/L98H and TR46/Y121F/T289A strains that have expanded successfully in the environment have also acquired resistance to MBC, QoI and/or SDHI fungicides. Strains carrying multiple fungicide resistant alleles have a competitive advantage in environments where residues of multiple fungicides belonging to different modes of action are present.

The use of a CYP51C gene based PCR-RFLP assay for simultaneous detection and identification of Fusarium avenaceum and F. tricinctum in wheat.

Contamination of cereals with mycotoxins such as beauvericin (BEA), enniatins (Ens) and moniliformin (MON) is mainly caused by Fusarium avenaceum and F. tricinctum. This is a world-wide problem which requires rapid and sensitive detection methods. To allow for high throughput screening of large numbers of samples, a diagnostic PCR method was developed for the simultaneous detection of F. avenaceum and F. tricinctum. The interspecific divergence found in the Fusarium-specific CYP51C gene was used to design species-specific PCR primers. The specificity of the assay was demonstrated for DNA samples extracted from a wide range of Fusarium species belonging to the Fusarium head blight (FHB) complex, as well as for naturally-infected grain samples. The PCR-amplified products were digested with the restriction enzyme XbaI to enable differentiation between F. avenaceum and F. tricinctum. This PCR- restriction fragment length polymorphism (RFLP) assay proved to be a simple and relatively inexpensive method highly suited for routine detection and identification of F. avenaceum and F. tricinctum in wheat samples.

The CYP51C gene, a reliable marker to resolve interspecific phylogenetic relationships within the Fusarium species complex and a novel target for species-specific PCR.

Early diagnosis and control of different Fusarium species is essential for successful management of plant disease and subsequent prevention of toxins entering the food chain. This issue can be addressed using phylogenetic analyses and other molecular techniques, including the design of species-specific primers and corresponding PCR assays. In practice, only a few genes are sequenced for most species and insights into the evolutionary mechanisms at the species level usually stem from phylogenetic analyses of only one or a small number of genetic loci. This poses the question of whether the recovered tree accurately reflects the relationships among species or rather more local interrelationships particular to the genetic marker employed. This study examined if the Fusarium-specific CYP51C gene can be used to establish evolutionary relationships between Fusarium species and enable species-specific detection. The resolving power of the CYP51C gene was studied for 46 Fusarium isolates representing 18 different species. The resulting phylogeny analysis showed clear and well-structured separation of the isolates according to their species rank, synthesised toxin and Fusarium section. Moreover, a comparison between the individual CYP51C phylogeny and a reference tree (inferred from the concatenation of ITS, CYP51C, ß-tubulin and TEF-1α sequences) indicated superior resolution of CYP51C relative to ITS and ß-tubulin sequences. In addition to its suitability as a reliable marker for diagnosis of different toxigenic Fusarium species, we also show that the CYP51C gene is a promising target for development of species-specific PCR. This was demonstrated by the specific detection of Fusarium cerealis in grain samples of wheat.