2,8-Dimethyl-10-p-tolyl-10H-phenoxaphosphine

The title compound (systematic name: 3,6-dimethyl-10-p-tolyl-9-oxa-10-phosphaanthracene), C21H19OP, is a precursor for the preparation of a bidentate xanthene-based ligand, in which the dihedral angle between the toluene ring and the phenoxaphosphine ring system is 83.26 (3)°. The geometry at the P atom is pyramidal, resulting in a longer C—P bond length as compared to the two ring C—P bonds

CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM)

CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells. Moreover, we evaluated the therapeutic capacity of Matrix-Metalloproteinases-inhibitors TMI-1 and GI254023X in combination with the anti-HER2 antibody trastuzumab in vitro and in vivo. TMI-1 and GI254023X caused a reduced shedding of CX3CL1 and of HER2 in vitro but without effects on tumor cell proliferation or viability. In addition, trastuzumab treatment did not retard MDA-MB-453 cell expansion in vitro unless CX3CL1 was overexpressed upon transfection (MDA-MB-453CX3CL1). In humanized tumor mice, which show a coexistence of human tumor and human immune system, CX3CL1 overexpression resulted in a slightly enhanced tumor growth. However, trastuzumab treatment attenuated tumor growth of both MDA-MB-453CX3CL1 and empty vector transfected MDA-MB-453 transplanted mice but showed enhanced efficiency especially in preventing lung metastases in CX3CL1 overexpressing cancer cells. However, TMI-1 did not further enhance the trastuzumab treatment efficacy

The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations

OBJECTIVE POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data. METHODS TCGA-defined molecular groups were determined by immunohistochemistry and sequencing in n = 142 endometrioid EC. WHO-defined histopathological grading was performed. The immunologic microenvironment (iTME) was characterised by the quantification of intraepithelial and stromal populations of tumor-infiltrating lymphocytes (TIL: overall T-cells; T-Killer cells; regulatory T-cells (Treg)). Immunologic parameters were correlated with WHO-grading, TCGA-subgroups and prognosis. RESULTS High density TIL were significantly more frequent in high-grade (G3) compared to low-grade (G1/2) EC in the whole cohort and in the subgroup of POLE-wildtype-/microsatellite-stable-EC. MSI was associated with high-level TIL-infiltration when taking into account the type of mismatch repair defect (MLH1/PMS2; MSH2/MSH6). Prognostic impact of biomarkers depended on molecular subgroups: In p53-mutant EC, Treg were independently prognostic, in NSMP, the unique independently prognostic biomarker was WHO-grading. CONCLUSIONS EC morphology and immunology differ depending on genetics. Our study delineated two molecularly distinct subgroups of immunogenic EC characterized by high-density TIL-infiltration: MSI EC and high-grade POLE-wildtype/microsatellite-stable-EC. Prognostic impact of TIL-populations relied on TCGA-subgroups indicating specific roles for TIL depending on molecular background. In NSMP, histopathological grading was the only prognostic biomarker demonstrating the relevance of WHO-grading in an era of molecular subtyping

Risk for pelvic metastasis and role of pelvic lymphadenectomy in node-positive vulvar cancer - results from the AGO-VOP.2 QS vulva study

Simple Summary In node-positive vulvar squamous cell cancer, questions of when and how to perform pelvic lymphadenectomy (LAE) as well as the optimal extent of pelvic treatment in general have been surrounded by considerable controversy. In Germany, systematic pelvic LAE is currently recommended as a staging procedure in patients at risk for pelvic nodal involvement in order to prevent morbidity caused by pelvic radiotherapy (RT) in patients without histologically-confirmed pelvic involvement. However, the population at risk for pelvic metastases remains insufficiently described, resulting in the potential overtreatment of a considerable proportion of patients with groin-positive disease. This applies to the indication to perform surgical staging but also to adjuvant RT of the pelvis without previous pelvic staging. Our study aims to describe the risk for pelvic lymph node metastasis with regard to positive groin nodes and to clarify the indication criteria for pelvic treatment in node-positive vulvar cancer. Abstract The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data

There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Proteolytic chemokine cleavage as a regulator of lymphocytic infiltration in solid tumors

In the past decade, immune-based therapies such as monoclonal antibodies against tumor epitopes or immune checkpoint inhibitors have become an integral part of contemporary cancer treatment in many entities. However, a fundamental prerequisite for the success of such therapies is a sufficient trafficking of tumor-infiltrating lymphocytes into the tumor microenvironment. This infiltration is facilitated by chemokines, a group of about 50 small proteins capable of chemotactically guiding leukocytes. Proteolytic inactivation of chemokines leading to an impaired infiltration of immune effector cells appears to be an efficient immune escape mechanism of solid cancers. The CXCR3 and CX3CR1 chemokine receptor ligands CXCL9-11 and CX3CL1, respectively, are mainly responsible for the tumor-suppressive lymphocytic infiltration into the tumor micromilieu. Their structure explains the biochemical basis of their proteolytic cleavage, while in vivo data from mouse models and patient samples shed light on the corresponding processes in cancer. The emerging roles of proteases, e.g., matrix metalloproteinases, cathepsins, and dipeptidyl peptidase 4, in chemokine inactivation define new resistance mechanisms against immunotherapies and identify attractive new targets to enhance immune intervention in cancer.(VLID)442088

Kallikrein-related peptidases represent attractive therapeutic targets for ovarian cancer

Introduction: Aberrant levels of kallikrein-related peptidases (KLK1-15) have been linked to cancer cell proliferation, invasion and metastasis. In ovarian cancer, the KLK proteolytic network has a crucial role in the tissue and tumor microenvironment. Publically available ovarian cancer genome and expression data from multiple patient cohorts show an upregulation of most KLKs. Areas covered: Here, we review the expression levels of all 15 members of this family in normal and ovarian cancer tissues, categorizing them into highly and moderately or weakly expressed KLKs, and their association with patient prognosis and survival. We summarize their tumor-biological functions determined in cell-based assays and xenograft models, further highlighting their suitability as cancer biomarkers and attractive candidates for drug development. Finally, we discuss some different pharmaceutical approaches, including peptide-based and small molecule inhibitors, cyclic peptides, depsipeptides, engineered natural inhibitors, antibodies, RNA/DNA-based aptamers, prodrugs, miRNA and siRNA. Expert opinion: In light of the results from clinical and tumor-biological studies, together with the available pharmaceutical tools, we suggest KLK4, KLK5, KLK6 and possibly KLK7 as preferred targets for inhibition in ovarian cancer.</p