Multiple Sclerosis: Systemic Challenges to Cost-Effective Care.

Background: Multiple sclerosis (MS) is a progressive autoimmune disorder of the central nervous system characterized by symptoms including reduced mobility, pain, fatigue, and spasticity. MS affects nearly 1 million people in the United States, with significant negative impact on a patient's quality of life, and an average lifetime cost of care in excess of $4 million. The cost-effective management of patients with MS faces several challenges. Objective: To review the challenges to the cost-effective management of patients with MS, and to offer healthcare stakeholders a roadmap to address them. Discussion: The cost-effective management of patients with MS, which is driven largely by how quickly a patient receives effective medication therapy, is challenged by a paucity of between-office-visit clinical data, variability of provider expertise with magnetic resonance imaging (MRI), MRI machine quality, lack of standards for MRI machines and reports, misaligned financial incentives, the limited number of available Current Procedural Terminology (CPT) codes for brain MRI, the complexity of disease-modifying therapy (DMT) selection, poor patient adherence to treatment plans, poor communication among providers, and a lack of objective measures of disease progression. Conclusion: Insurers, neurologists, researchers, and patient advocacy groups must address the needs of patients with MS holistically. These efforts should include establishing standards for MRI machines and reports, matching patients with MS specialists, aligning financial incentives, including creating a new CPT code for complex brain MRI, streamlining prior authorization processes of DMTs, using technology to gather patient data and improve coordination of care, and developing better measurement tools of disease activity.

Tolerability of Cefazolin in Nafcillin-Intolerant Patients for the Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

BACKGROUND: Non-immunoglobulin E (IgE)-mediated hypersensitivity reactions (HSRs) to nafcillin are commonly reported, but scarce data are available to guide appropriate antibiotic change following these reactions. Although cefazolin is an attractive therapeutic alternative in methicillin-susceptible Staphylococcus aureus (MSSA) infections when patients experience an HSR to nafcillin, more data are needed to evaluate the tolerability of cefazolin after switching from nafcillin. The purpose of this study was to describe the tolerability of cefazolin in patients who develop a suspected non-IgE-mediated HSR to nafcillin. METHODS: This was a retrospective, descriptive case series of patients who received nafcillin for an MSSA infection, experienced a suspected non-IgE-mediated HSR, and were switched to cefazolin between October 2015 and November 2019 at a single academic medical center. The primary objective was to identify the percentage of patients who completed cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin. RESULTS: There were 80 patients with 87 prespecified non-IgE-mediated HSRs during the study period. Seventy-one (89%) patients completed cefazolin, with 53 (75%) of these patients completing at least 2 weeks of therapy. One patient was ultimately switched from cefazolin to daptomycin due to concern for treatment failure. Eight patients (10%) did not tolerate cefazolin after switching from nafcillin. Of these, 3 patients experienced an unrelated HSR, whereas 5 patients experienced the same non-IgE-mediated HSR that was attributed to nafcillin and discontinued cefazolin within 7 days. The most common HSR cited was immune-mediated nephritis; however, the majority were clinically presumed but did not meet objective diagnostic criteria. CONCLUSIONS: Treatment with cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin appears to be safe, even for patients requiring a prolonged duration of cefazolin.

Hypothyroidism in Pancreatic Cancer: Role of Exogenous Thyroid Hormone in Tumor Invasion-Preliminary Observations.

According to the epidemiological studies, about 4.4% of American general elderly population has a pronounced hypothyroidism and relies on thyroid hormone supplements daily. The prevalence of hypothyroidism in our patients with pancreatic cancer was much higher, 14.1%. A retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (Whipple procedure) or distal pancreatectomy and splenectomy (DPS) at Thomas Jefferson University Hospital, Philadelphia, from 2005 to 2012. The diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. To further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, MiaPaCa-2 and AsPC-1. We found that hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion, and about twice as likely to have higher T stage, nodal spread, and overall poorer prognostic stage (P < 0.05). Pancreatic cancer cell line studies demonstrated that exogenous thyroid hormone treatment increased cell proliferation, migration, and invasion (P < 0.05). We conclude that exogenous thyroid hormone may contribute to the progression of pancreatic cancer.

Conserved Metabolic Changes in Nondiabetic and Type 2 Diabetic Bariatric Surgery Patients: Global Metabolomic Pilot Study.

The goal of this study was to provide insight into the mechanism by which bariatric surgical procedures led to weight loss and improvement or resolution of diabetes. Global biochemical profiling was used to evaluate changes occurring in nondiabetic and type 2 diabetic (T2D) patients experiencing either less extreme sleeve gastrectomy or a full gastric bypass. We were able to identify changes in metabolism that were affected by standard preoperation liquid weight loss diet as well as by bariatric surgery itself. Preoperation weight-loss diet was associated with a strong lipid metabolism signature largely related to the consumption of adipose reserves for energy production. Glucose usage shift away from glycolytic pyruvate production toward pentose phosphate pathway, via glucose-6-phosphate, appeared to be shared across all patients regardless of T2D status or bariatric surgery procedure. Our results suggested that bariatric surgery might promote antioxidant defense and insulin sensitivity through both increased heme synthesis and HO activity or expression. Changes in histidine and its metabolites following surgery might be an indication of altered gut microbiome ecology or liver function. This initial study provided broad understanding of how metabolism changed globally in morbidly obese nondiabetic and T2D patients following weight-loss surgery.

Osteopontin (OPN) isoforms, diabetes, obesity, and cancer; what is one got to do with the other? A new role for OPN.

Alternative splicing of osteopontin (OPN) produces three isoforms: OPNa, OPNb, and OPNc. The aims of this study were to examine the expression profile of OPN isoforms in sera from patients with pancreatic lesions and to determine their correlation with the presence of comorbid systemic inflammatory conditions, such as diabetes and/or obesity. Sera from 90 patients undergoing pancreatic surgery and 29 healthy volunteers were analyzed. Seventeen patients were diabetics, 17 were obese, and 6 had both diabetes and obesity. In patients with pancreatic lesions, OPNb was expressed in 48% of the patients' sera, OPNc in 34%, and both in 5%. The presence of diabetes and/or obesity was associated with complete disappearance of OPNb and expression of only OPNc. OPNc presence was significantly associated with diabetes and obesity (OR = 7.06 [95% CI 1.97-23.3]; p = 0.003). No OPNb or OPNc was detected in the normal sera. Overexpression of OPNb and OPNc isoforms in PDA cells significantly (p < 0.05) increased their activity in soft-agar colony formation and wound healing assays, induced the transcription of interleukin (IL)-6, and reduced tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and IL-10. Our data show for the first time the significant association between serum OPNc and diabetes and/or obesity. Unraveling the functional role of OPN isoforms in systemic inflammation is essential to understanding their significance as therapeutic targets in diabetes and obesity, and during metastasis development in PDA.

Overexpressing TNF-alpha in pancreatic ductal adenocarcinoma cells and fibroblasts modifies cell survival and reduces fatty acid synthesis via downregulation of sterol regulatory element binding protein-1 and activation of acetyl CoA carboxylase.

The effect of tumor necrosis factor-alpha (TNF-α) gene delivery has been suggested as a potentially useful therapeutic approach to improve the chemotherapeutic treatment of patients with pancreatic ductal adenocarcinoma (PDA), but the exact mechanism of its action is not clearly understood. In this study, we analyzed the expression profile of TNF-α in PDA tissue and explored its potential role in fatty acid synthase (FAS) regulation in PDA cells and in fibroblasts. Quantitative real-time polymerase chain reaction was used to examine the expression of TNF-α in PDA, matching adjacent tissues, and benign lesions. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated. In vitro, we overexpressed the TNF-α gene in PDA cells and fibroblasts and analyzed its effect on cell survival, migration, and on members of the FAS signaling pathway. We also evaluated TNF-α effects on a panel of inflammation-, angiogenesis-, and metastasis-related markers. In the tumor tissue of PDA patients, compared with their matched adjacent tissue, expression levels of TNF-α were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-α significantly (p < 0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-α, this was associated with a significant reduction of FAS mRNA and protein expression levels and significant (p < 0.05) reduction of SREBP-1 and ACC mRNA. Reduction of FAS by TNF-α was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-α displayed differential regulation of several inflammation-related markers and reduced levels of metastasis-related genes. Our data demonstrate a previously unknown multi-targeted involvement of TNF-α in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-α may have the potential as a novel therapeutic approach in human PDA.

Differential expression of cytochrome P450 omega-hydroxylase isoforms and their association with clinicopathological features in pancreatic ductal adenocarcinoma.

BACKGROUND: The cytochrome P450 (CYP) superfamily consists of enzymes that catalyze the oxidation of lipids, steroids, and drugs. In particular, the CYP4 family plays an essential role in lipid metabolism by the ω-hydroxylation of terminal ends of fatty acids. Disturbance of this system has been associated with increased angiogenesis, proliferation, and metastasis of several cancers. This study aimed to detect the expression of CYP4 isoforms (CYP4A11, CYP4F2, CYP4F3) in pancreatic ductal adenocarcinoma (PDA) and their association with clinicopathological features. METHODS: Pancreatic specimens were collected from 73 patients who underwent surgical resection at the Thomas Jefferson University Hospital. Quantitative polymerase chain reaction was used to examine the cytochrome P450 isoforms in PDA (n = 62), adjacent-normal (n = 30), and benign tissues (n = 11). Logistic regression models were used to analyze gene expression among tissue types. Spearman rank correlations were calculated for isoform expression and for age. Differences in expression by gender were assessed via t test. Other clinicopathological variables (diabetes, smoking, obesity, T stage, perineural invasion, nodal status) were analyzed by Wilcoxon rank sum. RESULTS: CYP4 expression for isoforms was significantly higher in PDA tissues versus matched-adjacent tissues (p < 0.01). PDA tumors expressed significantly higher levels of CYP4F2 and CYP4F3 when compared to benign lesions (p < 0.01). Significant associations were found between low levels of CYP4F2 and CYP4F3 and increased age of PDA patients. Interestingly, all isoforms were expressed at higher levels in male patients. CONCLUSIONS: Transcriptional upregulation of cytochrome P450 ω-hydroxylase suggests that these enzymes have the potential to be used as distinguishing markers in pancreatic pathology.

RAN GTPase and Osteopontin in Pancreatic Cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis among cancers, mainly due to the high incidence of early metastases. RAN small GTPase (RAN) is a protein that plays physiological roles in the regulation of nuclear transport and microtubule spindle assembly. RAN was recently shown to mediate the invasive functions of the prometastatic protein osteopontin (OPN) in breast cancer cells. We and others have shown previously that high levels of OPN are present in PDA. In this study, we analyzed the expression and correlation of RAN with OPN in human pancreatic lesions, and explored their regulation in PDA cell lines. METHODS: Real time PCR was used to analyze RAN and OPN mRNA levels in PDA, adjacent non-malignant, and benign pancreatic tissues. Expression levels were correlated with survival and different clinicopathological parameters using different statistical methods. Transient transfection studies using OPN and RAN plasmids, and knockdown experiments using siRNA were used to examine their mutual regulation. RESULTS: OPN and RAN levels highly correlated with each other (p<0.0001). OPN or RAN levels did not correlate with venous lymphatic invasion, diabetes, obesity, T stage, BMI, or survival. However, we found a significant association between RAN levels and perineural invasion (HR=0.79, 95% CI 0.59, 1.07; p=0.0378.). OPN and RAN colocalized in PDA tissues and cell lines. Increasing RAN expression in PDA cells induced OPN transcription and RAN silencing reduced total OPN levels. OPN did not have any significant effect on RAN transcription. CONCLUSIONS: The high levels of RAN in PDA and its correlation with OPN and with perineural invasion suggest that RAN may contribute to PDA metastasis and progression through the induction of OPN. RAN's role in the regulation of OPN in PDA is unique and could provide potential novel therapeutic strategies to combat PDA aggressiveness.