CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [68Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [68Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [68Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [18F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [68Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes.

There was no clinical evidence of any beneficial effect, as defined by main outcome measures, of ascorbic acid on IVF-ET. Our data suggest there is no obvious value of high dosed intake of vitamin C during luteal phase in infertility treatment.

Chemokine receptors form a large family of G-protein coupled receptors that mediate chemotaxis of cells towards a gradient of chemokines. The C-X-C chemokine receptor-4 (CXCR4, also known as fusin, CD184) exerts its biological effects by binding its ligand CXCL12 (or Stromal-cell derived factor-1, SDF-1) which activates downstream pathways, ultimately resulting in altered cell adhesion and cell homing. Physiologically, the CXCR4/CXCL12 interaction plays a pivotal role in the recruitment and homing of hematopoietic stem/ progenitor cells (HSPC) and immune cells. In cancer, CXCR4 expression is associated with tumor dissemination and prognosis. Using multiple myeloma (MM) as an exemplary CXCR4-expressing cancer entity, we report the evaluation of [68Ga]Pentixafor-PET as a method for in vivo mapping of CXCR4 expression density by means of Positron Emission Tomography. [68Ga]Pentixafor-PET provides images with excellent specificity and contrast when assessed in mice xenografted with human CXCR4-positive MM. We next analyzed CXCR4 expression using [68Ga]Pentixafor-PET in a cohort of fourteen patients with advanced MM. These patients also underwent standard [18F]Fluoro-Deoxyglucose-PET (FDG-PET). Nine of fourteen FDG-PET scans were rated visually positive, whereas ten of fourteen Pentixafor-PET scans revealed MM manifestations. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes or alterations in HSPC frequency associated with tracer application. These data document the first methodology for clinical PET imaging of CXCR4 in a cohort of MM patients. [68Ga]Pentixafor-PET opens a broad field of clinical investigations on CXCR4 expression and regulation in the cancer field and beyond. Disclosures Wester: SCINTOMICS, > Radiopharmaceutical Technology: Employment.

Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45- Ter119- cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population.