Patient-derived Organoid Pharmacotyping As A Predictive Tool for Therapeutic Selection in Pancreatic Ductal Adenocarcinoma.

Objective: We integrate a new approach to chemosensitivity data for clinically-relevant regimen matching, and demonstrate the relationship with clinical outcomes in a large PDO biobank.

Summary Background Data: Pancreatic ductal adenocarcinoma (PDAC) usually recurs following potentially curative resection. Prior studies related patient-derived organoid (PDO) chemosensitivity with clinical responses.

Transcription Factor Profiling Identifies Spatially Heterogenous Mediators of Follicular Thyroid Cancer Invasion.

While minimally invasive follicular thyroid cancer (miFTC) generally has low risk of recurrence or death, encapsulated angioinvasive (eaFTC) or widely invasive (wiFTC) histological subtypes display significantly worse prognosis. Drivers of invasion are incompletely understood. Therefore, tissue samples including miFTC, eaFTC, and wiFTC tumors, as well as histologically normal thyroid adjacent to benign follicular adenomas, were selected from a cohort (n = 21) of thyroid tumor patients, and the gene expression of selected transcription factors was characterized with quantitative PCR.

Recurrent Amplification of the Osmotic Stress Transcription Factor in Adrenocortical Carcinoma.

Tumorigenesis requires mitigation of osmotic stress and the transcription factor nuclear factor of activated T cells 5 (NFAT5) coordinates this response by inducing transcellular transport of ions and osmolytes. NFAT5 modulates in vitro behavior in several cancer types, but a potential role of NFAT5 in adrenocortical carcinoma (ACC) has not been studied. A discovery cohort of 28 ACCs was selected for analysis.

Association of Treatment Inequity and Ancestry With Pancreatic Ductal Adenocarcinoma Survival.

Importance: Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown.

Objectives: To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity.

Whole-Exome Sequencing of Syndromic Adrenocortical Carcinoma Reveals Distinct Mutational Profile From Sporadic ACC.

Next-generation sequencing has provided genetic profiles of a large number of sporadic adrenocortical carcinomas (ACCs), but the applicability of these results to ACC cases associated with tumor predisposition syndromes is unclear. Although the germline features of these syndromes have been well described, the somatic mutational landscape of the tumors they give rise to is less clear. Our group obtained germline and tumor tissue from a pediatric patient who developed ACC during her first year of life, which was treated successfully.

Immune cell infiltrate-associated dysregulation of DNA repair machinery may predispose to papillary thyroid carcinogenesis.

Background: An altered immune microenvironment may contribute to papillary thyroid cancer development, as immune infiltrates are identified postoperatively in many papillary thyroid cancer cases with or without diagnosed thyroiditis. Oxygen radicals, endogenous or inflammation-induced, can generate DNA damage, which causes mutations when repaired incorrectly. We hypothesized that infiltrating immune cells might promote aberrant DNA repair, predisposing thyrocytes to papillary thyroid cancer.

Next-generation Sequencing in the Management of Gastric and Esophageal Cancers.

Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely driving forces behind tumorigenesis and progression. The abundance of available genomic data has immense potential to redefine management paradigms for these difficult disease processes.

Insulin-Like Growth Factor and SLC12A7 Dysregulation: A Novel Signaling Hallmark of Non-Functional Adrenocortical Carcinoma.

Background: Insulin-like growth factor (IGF) dysregulation and gene copy number variations (CNV) are hallmarks of adrenocortical carcinoma (ACC). The contribution of IGF CNVs in adrenal carcinogenesis has not been studied previously. In addition, studies demonstrating an association between SLC12A7 gene amplifications and enhanced metastatic behavior in ACC, as well as reported IGF-SLC12A7 signaling interactions in other cancers, suggest a potential IGF-SLC12A7 signaling circuitry in ACC.

Adrenocortical cancer cell line mutational profile reveals aggressive genetic background.

Adrenocortical carcinomas are rare tumors with poor prognosis and limited treatment options. Although widely used as in vitro models to test novel therapeutic strategies, the adrenocortical carcinoma-derived cell lines NCI-H295R and SW-13 have only partially been described genetically. Our aim was to characterize the mutational landscape of these cells to improve their experimental utility and map them to clinical subtypes of adrenocortical carcinoma.

Desmoplastic melanoma.

Desmoplastic melanoma (DM) is a rare melanoma variant that has unique biology and pathology compared with conventional melanoma (non-DM). Importantly, DM is classified into pure and mixed histologic subtypes, which have been correlated with outcomes. Management of DM broadly mirrors that of non-DM; however, there are unique considerations for DM that influence treatment approaches.

Clonal evolution analysis of paired anaplastic and well-differentiated thyroid carcinomas reveals shared common ancestor.

Foci of papillary or follicular thyroid carcinoma are frequently noted in thyroidectomy specimens of anaplastic thyroid carcinoma (ATC). However, whether ATCs evolve from these co-existing well-differentiated thyroid carcinomas (WDTCs) has not been well-understood. To investigate the progression of ATC in patients with co-existing WDTCs, five ATC tumors with co-existing WDTCs and matching normal tissues were whole-exome sequenced.

Comprehensive Genetic Analysis of Follicular Thyroid Carcinoma Predicts Prognosis Independent of Histology.

Context: Follicular thyroid carcinoma (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment but have not been described.

Objective: Identify and describe the genetic underpinnings of subtypes of FTC.

Characterization of Cell Membrane Extensions and Studying Their Roles in Cancer Cell Adhesion Dynamics.

The cell membrane's extension repertoire modulates various malignant behaviors of cancer cells, including their adhesive and migratory potentials. The ability to accurately classify and quantify cell extensions and measure the effect on a cell's adhesive capacity is critical to determining how cell-signaling events impact cancer cell behavior and aggressiveness. Here, we describe the in vitro design and use of a cell extension quantification method in conjunction with an adhesion capacity assay in an established in vitro model for adrenocortical carcinoma (ACC).

Whole-Exome Sequencing Identifies Two Discrete Druggable Signaling Pathways in Follicular Thyroid Cancer.

Background: Thyroid cancer is the most common endocrine malignancy, with continuously increasing incidence. Follicular thyroid cancer (FTC) accounts for approximately 10% to 15% of these cases and is known to be associated with several gene mutations. The purpose of this study was to identify novel therapeutic targets in FTC using whole-exome sequencing (WES) and bioinformatics analysis.

BCL9 Upregulation in Adrenocortical Carcinoma: A Novel Wnt/β-Catenin Activating Event Driving Adrenocortical Malignancy.

Background: B-Cell CLL/Lymphoma 9 (BCL9) is a recently described oncogene that promotes tumorigenesis via activation of the Wnt/β-Catenin signaling cascade. Though constitutively active Wnt/β-Catenin signaling is a molecular hallmark of adrenocortical carcinoma (ACC), a potential role for BCL9 to promote Wnt/β-Catenin pathway dysregulation in adrenocortical tumorigenesis remains to be elucidated.

Study Design: This study involved a retrospective analysis at a tertiary academic referral center of 27 patients with adrenocortical tumors, including in vitro investigation of BCL9.

DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

Background: Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis.

Methods: MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples.

Advances in understanding the molecular underpinnings of adrenocortical tumors.

Purpose Of Review: Adrenocortical tumors are divided into benign adenomas and malignant carcinomas. The former is relatively common and carries a favorable prognosis, whereas the latter is rare and frequently presents at an advanced stage, with poor outcomes. Advances in next-generation sequencing, genome analysis, and bioinformatics have allowed for high-throughput molecular characterization of adrenal tumorigenesis.

Abdominal compartment syndrome in trauma patients: New insights for predicting outcomes.

Context: Abdominal compartment syndrome (ACS) is associated with high morbidity and mortality among trauma patients. Several clinical and laboratory findings have been suggested as markers for ACS, and these may point to different types of ACS and complications.

Aims: This study aims to identify the strength of association of clinical and laboratory variables with specific adverse outcomes in trauma patients with ACS.

Resuscitative thoracotomy for pediatric trauma in Illinois, 1999 to 2009.

Background: Outcomes in adults who undergo resuscitative thoracotomy are poor. Few studies have examined the procedure's use in pediatric trauma.

Methods: The Illinois State Trauma Registry was queried for thoracotomy performed in the emergency department from 1999 to 2009, for patients aged 0 to 15.

Emergency department alcohol and drug screening for Illinois pediatric trauma patients, 1999 to 2009.

Background: Recent guidelines recommend universal substance abuse screening for all trauma patients aged 12 years and older because brief interventions can help prevent future trauma. However, little is known about actual rates of screening in this setting.

Methods: The Illinois State Trauma Registry was queried for severely injured patients from 1999 to 2009.