Reliability and Variability of Ki-67 Digital Image Analysis Methods for Clinical Diagnostics in Breast Cancer.

Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods.

Author Correction: Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer.

Purpose: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.

Experimental Design: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases.

Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors.

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases.

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants.

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.

To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq.

A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent.

Molecular target characterization and antimyeloma activity of the novel, insulin-like growth factor 1 receptor inhibitor, GTx-134.

Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM.

Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples.

Cyproheptadine displays preclinical activity in myeloma and leukemia.

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine.

The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan.

Purpose: The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma.

Experimental Design: The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated.

Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells.

Hematopoietic cell transplantation can impact lysosomal storage disorders (LSDs) and will be enhanced by gene therapy. Transduced cells in LSDs often secrete the therapeutic hydrolase, which can be used by bystander cells. However, toxicity associated with myeloablative transplant preparative regimens limits many applications of this approach in gene therapy.

The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells.

The association of fibroblast growth factor receptor 3 (FGFR3) expression with t(4;14) multiple myeloma (MM) and the demonstration of the transforming potential of this receptor tyrosine kinase (RTK) make it a particularly attractive target for drug development. We report here a novel and highly specific anti-FGFR3-neutralizing antibody (PRO-001). PRO-001 binds to FGFR3 expressed on transformed cells and inhibits FGFR3 autophosphorylation and downstream signaling.

Efficient transfer of PSA and PSMA cDNAs into DCs generates antibody and T cell antitumor responses in vivo.

Gene therapy for prostate cancer may be realized through transduction of whole genes, such as PSA or PSMA, into immunotherapeutic dendritic cells (DCs). An oncoretroviral vector encoding human PSMA and a bicistronic oncoretroviral vector encoding human PSA and cell surface CD25 cDNAs were constructed. Remarkably, transfer of PSA/CD25 or PSMA cDNA during murine hematopoietic cell differentiation into DCs occurred with approximately 80% efficiency.

Down-regulation of a novel actin-binding molecule, skeletrophin, in malignant melanoma.

In the present study, we cloned and characterized a novel actin-binding molecule, designated skeletrophin, from aggregated neuroblastoma cells. The putative amino acid sequence of human skeletrophin cDNA contained a cysteine-rich zinc-finger motif which was also found in dystrophin and five ankyrin repeats. Northern blot analysis revealed that the 3.

Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal cell carcinoma of the skin.

T-cadherin appears to act as a tumor-suppressor factor in various cancers. Downregulation of T-cadherin is caused by a combination of allelic loss and hypermethylation of the T-cadherin promoter region and is related to cancer invasion. To elucidate the molecular mechanism of invasiveness of basal cell carcinoma of the skin, T-cadherin expression was investigated in archival pathological tissue sections made up of normal counterparts of skin and various types of basal cell carcinoma.

Loss of T-cadherin (CDH13, H-cadherin) expression in cutaneous squamous cell carcinoma.

We previously reported that T-cadherin (CDH13, H-cadherin), a unique cadherin molecule, was expressed on the basal cell layer in normal murine and human epidermis. In the present study, T-cadherin expression in archival human skin specimens comprising a spectrum of human squamous cell neoplasia was investigated. T-cadherin expression was observed in both normal epidermal basal cells and adnexal epithelial cells of formalin-fixed and paraffin-embedded tissue sections.

Expression of T-cadherin in Basal keratinocytes of skin.

T-cadherin is a unique member of the cadherin superfamily that shares the ectodomain organization with classical cadherins, but lacks both transmembrane and cytoplasmic regions and is instead anchored to the plasma membrane through a glycosyl-phosphatidylinositol (GPI) moiety. The function of T-cadherin has not been revealed yet. The special structure of T-cadherin might endow this molecule with specific intracellular targeting properties and functions that are distinct from classical cadherins.