Connecting the changing trace elements spectrum and survival in sarcoma: a pilot study.

Objectives: While some metals have been reported as carcinogens or potential carcinogens, only few modern-standard datasets including a large number of elements are available. The present analysis established a first trace elements spectrum by relating the concentration of metals and trace elements in the serum of sarcoma patients with survival data.

Methods: Patients with sarcoma and controls were retrospectively selected from the International Sarcoma Kindred Study database (ISKS).

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8PD-1 T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.

Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

Background: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers.

Patients And Methods: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm.

Added value of whole-exome and RNA sequencing in advanced and refractory cancer patients with no molecular-based treatment recommendation based on a 90-gene panel.

Introduction: The objective was to determine the added value of comprehensive molecular profile by whole-exome and RNA sequencing (WES/RNA-Seq) in advanced and refractory cancer patients who had no molecular-based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array-based comparative genomic hybridization (aCGH).

Materials And Methods: In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90-gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA-Seq.

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors.

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas.

Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABA R and Anti-Hu Paraneoplastic Neurological Syndromes.

Objective: Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABA R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABA R or anti-Hu PNS compared with SCLC without PNS.

Methods: A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABA R, and 28 SCLC without PNS.

Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor.

Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers.

Sorafenib in Molecularly Selected Cancer Patients: Final Analysis of the MOST-Plus Sorafenib Cohort.

Background: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes.

Methods: The MOST-plus trial used a randomized discontinuation design.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile.

Staging of newly diagnosed Ewing sarcoma: Results of bone marrow aspiration and biopsy versus (18)FDG-PET/CT imaging for bone marrow involvement.

Background: Ewing sarcoma (ES) is an aggressive bone or extraosseous tumour with an unfavourable prognosis when bone marrow metastases are present at diagnosis. The gold standard diagnosis for bone marrow (BM) involvement is cytological and pathological analysis through bone marrow aspiration and biopsy (BMAB). Several recent studies suggest that these invasive and painful procedures could be replaced by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT), as this nuclear imaging technique is highly sensitive at detecting bone and extraosseous metastases of ES.

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition.

Ribosome biogenesis-based predictive biomarkers in endocrine therapy (Anastrozole) combined with mTOR inhibitor (Vistusertib) in endometrial cancer: translational study from the VICTORIA trial in collaboration with the GINECO group.

Resistance of advanced hormone-dependent endometrial carcinoma to endocrine therapy remains a worldwide clinical issue. We recently reported that the combination of Vistusertib (V, mTOR inhibitor) and Anastrozole (A, aromatase inhibitor) improves the progression-free rate compared to Anastrozole alone. However, a better patient selection based on biomarkers would improve patient outcome.

PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.

Unlabelled: Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors.

Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models.

: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. : Three paired PDAC preclinical models-patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)-were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG).

Niche anchorage and signaling through membrane-bound Kit-ligand/c-kit receptor are kinase independent and imatinib insensitive.

Kit ligand (KitL) and its tyrosine kinase receptor c-kit are critical for germ cells, melanocytes, mastocytes, and hematopoietic stem cells. Alternative splicing of KitL generates membrane-bound KitL (mb-KitL) or soluble KitL, providing survival or cell migration, respectively. Here we analyzed whether c-kit can function both as an adhesion and signaling receptor to mb-KitL presented by the environmental niche.

Peripheral blood CD56(bright) NK cells respond to stem cell factor and adhere to its membrane-bound form after upregulation of c-kit.

CD56(bright) NK cells express receptors for IL-2, IL-7, IL-15, and SCF. We found that human peripheral blood CD56(bright) NK cells responded to IL-2, IL-7, IL-15 by phosphorylating STAT-5, ERK, and Akt but did not respond to SCF. However, CD56(bright) NK cells in culture upregulated c-kit transcription three to fourfold, which led to a steady increase in c-kit and a concomitant acquisition of responsiveness to SCF.

Gene expression patterns of hemizygous and heterozygous KIT mutations suggest distinct oncogenic pathways: a study in NIH3T3 cell lines and GIST samples.

Objective: Most gain of function mutations of tyrosine kinase receptors in human tumours are hemizygous. Gastrointestinal stromal tumours (GIST) with homozygous mutations have a worse prognosis. We aimed to identify genes differentially regulated by hemizygous and heterozygous KIT mutations.

Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas.

Leiomyosarcoma (LMS) represent 15 % of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile.

Effects of endoplasmic reticulum stressors on maturation and signaling of hemizygous and heterozygous wild-type and mutant forms of KIT.

Gain of function mutations of KIT are frequent in some human tumors, and are sensible to tyrosine kinase inhibitors. In most tumors, oncogenic mutations are heterozygous, however most in vitro data of KIT activation have been obtained with hemizygous mutation. This study aimed to investigate the maturation and activation of wild-type (WT) and mutant (M) forms of KIT in hemizygous and heterozygous conditions.

Membrane-bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche.

Morphogenesis, as illustrated by melanocyte migration and homing to the skin, requires cadherin adhesion, integrin-dependent migration and Kit-ligand growth factor signaling. However, it is not known how Kit ligand regulates integrin or cadherin-dependent intraepidermal melanocyte behavior. To answer this question, we developed specific 2-dimensional (2D) and 3D culture systems analyzing how soluble or immobilized Kit-ligand-regulated melanocyte migration on vitronectin and laminin, or within a monolayer of kidney epithelial cells.

Prognosis and predictive value of KIT exon 11 deletion in GISTs.

Background: KIT exon 11 mutations are observed in 60% of gastrointestinal stromal tumours (GIST). Exon 11 codes for residues Tyr568 and Tyr570, which play a major role in signal transduction and degradation of KIT. Our aim was to compare the outcome of patients with deletion of both Tyr568-570 (delTyr) and the most frequent deletion delWK557-558 (delWK).

Dimerization of Kit-ligand and efficient cell-surface presentation requires a conserved Ser-Gly-Gly-Tyr motif in its transmembrane domain.

Kit-ligand (Kitl), also known as stem cell factor, is a membrane-anchored, noncovalently bound dimer signaling via the c-kit receptor tyrosine kinase, required for migration, survival, and proliferation of hematopoietic stem and germ cells, melanocytes, and mastocytes. Despite its fundamental role in morphogenesis and stem cell biology, the mechanisms that regulate Kitl dimerization are not well understood. By employing cell-permeable cross-linker and quantitative bimolecular fluorescence complementation of wild-type and truncated forms of Kitl, we determined that Kitl dimerization is initiated in the endoplasmic reticulum and mediated to similar levels by the transmembrane and the extracellular growth factor domain.

Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs.

Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization.

KIT mutations induce intracellular retention and activation of an immature form of the KIT protein in gastrointestinal stromal tumors.

Purpose: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KIT expression.

Experimental Design: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11-mutated human KIT cDNA.