Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy.

In this article, we review the past applications of in vitro models in identifying human hepatotoxins and then focus on the use of multiscale experimental models in drug development, including the use of zebrafish and human cell-based, 3-dimensional, microfluidic systems of liver functions as key components in applying Quantitative Systems Pharmacology (QSP). We have implemented QSP as a platform to improve the rate of success in the process of drug discovery and development of therapeutics.

Serum B vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Background: Vitamin B is an important enzymatic cofactor in pathways relevant for the development of pancreatic cancer. In order to evaluate vitamin B as a preventive factor for pancreatic cancer, a biomarker approach is needed to overcome the limitations inherent in self-reported dietary information.

Methods: To determine whether levels of serum B vitamers, including pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), and the PA/(PLP + PL) ratio (PAr), were associated with risk of pancreatic cancer, two nested case-control studies of 187 incident pancreatic cancer cases and 258 individually matched controls were conducted within two prospective cohorts of 81,501 participants in Shanghai, China, and Singapore.

Phenotypic and functional testing of circulating regulatory T cells in advanced melanoma patients treated with neoadjuvant ipilimumab.

Background: We have previously investigated neoadjuvant ipilimumab (ipi) for patients with locally/regionally advanced melanoma. That initial assessment of peripheral blood mononuclear cells (PBMC) showed a significant increase in shared tumor associated antigen specific CD4(+) and CD8(+) T cell activation. We also observed a transient increase in circulating T regulatory cells (Treg) with a parallel increase in total CD4(+) T cells, as well as a significant decrease in circulating myeloid derived suppressor cells (MDSC).

Neoadjuvant treatment for melanoma: current challenges and future perspectives.

There will be an estimated 76,100 new cases of melanoma diagnosed in 2015 and 9710 deaths. Patients with stage I/II disease have excellent outcomes, and the treatment landscape for patients with metastatic disease has been transformed by the approval of several immune checkpoint inhibitors and molecular targeted therapies. Patients with stage III disease, however, continue to have very limited options, as the only agent shown to improve survival in the adjuvant setting is high-dose IFN-α.

Polymorphisms in DNA repair and oxidative stress genes associated with pre-treatment cognitive function in breast cancer survivors: an exploratory study.

Purpose: The purpose of this exploratory candidate gene association study was to examine relationships between polymorphisms in oxidative stress and DNA repair genes and pre-adjuvant therapy cognitive function (CF) in postmenopausal women diagnosed with early stage-breast cancer.

Methods: Using a neuropsychological test battery, CF was assessed in 138 women diagnosed with breast cancer prior to initiation of adjuvant therapy and 81 age- and education-matched controls and summarized across eight composites. Participants were genotyped for 39 functional or tagging single nucleotide polymorphisms (SNPs) of select oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) and DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) genes.

Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer.

Background: The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports.

Methods: Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles.

Minimally Invasive Hepatic Surgery.

This review provides an overview of the background and progress that has been made in minimally invasive liver surgery. The essential steps of minimally invasive right and left lobectomy as well as left lateral sectionectomy are reviewed. In addition, existing data regarding the feasibility and oncologic outcomes of minimally invasive hepatic resection for malignancy are discussed.

Minimally Invasive Approaches to Pancreatic Surgery.

Minimally invasive techniques have the potential to revolutionize the surgical management of pancreatic disease in the setting of benign and malignant processes. Pancreatic surgery, in particular, may be aided significantly by minimal access surgery given the high morbidity associated with traditional open pancreatic procedures. This article presents a review of two minimally invasive techniques for distal pancreatectomy and pancreaticoduodenectomy, focusing on metrics of technique, safety, morbidity, and oncologic outcomes and potential benefits.

Characterization of human papillomavirus antibodies in individuals with head and neck cancer.

Background: Human papillomavirus type 16 (HPV16) E6 antibodies are a promising biomarker of oropharyngeal cancer (OPC); however, seropositivity among non-OPC cases is not well characterized.

Methods: Pre-treatment sera from 260 (38 OPC, 222 non-OPC) incident head and neck cancers diagnosed at the University of Pittsburgh between 2003 and 2006 were tested for HPV16 (L1,E1,E2,E4,E6,E7) and non-HPV16 E6 (HPV6,11,18,33) antibodies. Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven tumors was evaluated among tumors with known HPV status (n=25).

On Predicting lung cancer subtypes using 'omic' data from tumor and tumor-adjacent histologically-normal tissue.

Background: Adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most prevalent histological types among lung cancers. Distinguishing between these subtypes is critically important because they have different implications for prognosis and treatment. Normally, histopathological analyses are used to distinguish between the two, where the tissue samples are collected based on small endoscopic samples or needle aspirations.

Impact of a community-based lifestyle intervention program on health-related quality of life.

Background: The presence of risk factors for type 2 diabetes and cardiovascular disease, or the conditions themselves, contributes to lower health-related quality of life (HRQoL) among adults. Although community-based lifestyle intervention programs have been shown to be effective for improving risk factors for these diseases, the impact of these interventions on HRQoL has rarely been described.

Purpose: To examine changes in HRQoL following participation in the Group Lifestyle Balance program, a community translation of the Diabetes Prevention Program lifestyle intervention for adults with prediabetes and/or the metabolic syndrome.

Bar Coding and Tracking in Pathology.

Bar coding and specimen tracking are intricately linked to pathology workflow and efficiency. In the pathology laboratory, bar coding facilitates many laboratory practices, including specimen tracking, automation, and quality management. Data obtained from bar coding can be used to identify, locate, standardize, and audit specimens to achieve maximal laboratory efficiency and patient safety.

Antioxidant Approaches to Management of Ionizing Irradiation Injury.

Ionizing irradiation induces acute and chronic injury to tissues and organs. Applications of antioxidant therapies for the management of ionizing irradiation injury fall into three categories: (1) radiation counter measures against total or partial body irradiation; (2) normal tissue protection against acute organ specific ionizing irradiation injury; and (3) prevention of chronic/late radiation tissue and organ injury. The development of antioxidant therapies to ameliorate ionizing irradiation injury began with initial studies on gene therapy using Manganese Superoxide Dismutase (MnSOD) transgene approaches and evolved into applications of small molecule radiation protectors and mitigators.

Clinical effectiveness and safety outcomes associated with prothrombin complex concentrates.

Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of warfarin and used for reversal of novel oral anticoagulants, in patients with acute major bleeding or need for an urgent procedure. The research goal was to evaluate effectiveness and safety outcomes with PCC usage at our institution. A retrospective review of electronic medical records identified patients that received a PCC commercially available in the United States (KCentra(®) or Profilnine(®)) at twelve hospitals in a tertiary care health system from July 1, 2013 to April 30, 2014.

Near complete response after single dose of nivolumab in patient with advanced heavily pre-treated KRAS mutant pulmonary adenocarcinoma.

The programmed death 1 (PD-1) receptor is expressed by activated T-cells and engaged by ligands PD-L1 and PD-L2 normally expressed by infiltrating immune cells in response to viral infection. The PD-1/PD-L1 axis is a negative inhibitory pathway that down-regulates T-cells but is also used by tumors to evade anti-tumor immunity. Antibodies targeting PD-1/PD-L1 axis are capable of restoring functional anti-tumor immunity and have demonstrated efficacy in a broad range of tumor types including non-small cell lung cancer in both squamous and adenocarcinoma histologies.

KRAS mutant lung cancer: progress thus far on an elusive therapeutic target.

The KRAS mutation remains the most common driver mutation in patients with non-small cell lung cancer (NSCLC) and confers a poor prognosis. Thus far, efforts to target this mutation over the last two decades have been unsuccessful. Over the past 5 years, many efforts to develop drugs that target the RAS-RAF-MEK-ERK (MAPK) pathway have resulted in enhanced understanding of the KRAS mutant NSCLC and have provided optimism that this disease can be targeted.

Adjuvant Therapy of Melanoma.

The incidence of melanoma is rapidly increasing, especially in younger female and older male patients. Recent fundamental advances in our knowledge of melanoma tumorigenesis have established roles for inhibitors of the MAPK pathway and regulatory immune checkpoints CTLA-4 and PD-1/PD-L1. However, the majority of patients continue to present with non-metastatic disease-typically managed with surgical resection and adjuvant therapy.

Pesticide exposure and hepatocellular carcinoma risk: A case-control study using a geographic information system (GIS) to link SEER-Medicare and California pesticide data.

Background: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is associated with low survival. U.S.

The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831.

Introduction: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab.

Methods: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer.

Immunotherapy in Sarcoma: Future Horizons.

Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions.

Tumor associated PD-L1 expression pattern in microscopically tumor positive sentinel lymph nodes in patients with melanoma.

Background: Characterization of PD-L1 expression within clinically/radiologically negative but microscopically tumor positive sentinel lymph nodes (SLN) is important to our understanding of the relevance of this immune checkpoint pathway for adjuvant therapy.

Methods: Patients included had primary cutaneous melanoma, Breslow thickness of 2.01-4.

Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma.

Background: We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.

Methods: Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab).

Psychological Impact of Nuclear Disasters in Children and Adolescents.

Although much has been written about the psychological impact of natural disasters, the impact of nuclear disasters has not been extensively studied in children. Nuclear disasters are unique because they are man-made and represent a failure of the safety systems put in place to contain dangerous radioactive materials. This article summarizes the available literature on 3 of the biggest nuclear disasters in history.

Predicting length of stay and conversion to open cholecystectomy for acute cholecystitis using the 2013 Tokyo Guidelines in a US population.

Background: The 2013 Tokyo Guidelines (TG13) for acute cholecystitis have not been studied extensively in US populations.

Methods: A retrospective review of patients with acute cholecystitis within a single system from 2009 to 2013 was performed. The diagnosis and severity of acute cholecystitis were assigned by the TG13.