Screen failures in clinical trials in retina.

PURPOSE: Disparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Determine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) CONCLUSION: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis.

Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCreER™; LSL-KrasG12D) and functional WT Ptf1aCreER™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.

Acute Pancreatitis: Current Clinical Approaches, Molecular Pathophysiology, and Potential Therapeutics.

OBJECTIVE: Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS: A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS: Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS: Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.

Asthma is associated with a lower incidence of metastatic colorectal cancer in a US patient cohort.

In previous pre-clinical studies, we examined the contribution of interleukin 4 receptor (IL4R) signaling in the progression and metastasis of colorectal cancer (CRC). Aberrant activation of this receptor can result in atopic diseases such as asthma. We hypothesized that further evidence for the contribution of excessive IL4R being associated with CRC progression could be seen in medical records, and specifically that chronic asthma patients were more likely to be diagnosed with metastatic CRC. To test this hypothesis, we took advantage of the Synthetic Derivative, a resource developed at Vanderbilt University Medical Center that hosts de-identified data taken from the electronic medical record. We developed search protocols that produced retrospective cohorts of invasive CRC patients and cancer-free equivalents. In comparing 787 metastatic CRC patients to 238 non-metastatic patients, we actually found significantly fewer asthmatics went on to develop metastatic CRC (P=0.0381). By comparing these groups together against 1197 cancer-free patients, even fewer asthmatic patients would develop invasive CRC (P<0.0001). While these results are clearly in opposition to our original hypothesis, they still support a link between chronic asthma and metastatic CRC development. One intriguing possibility, that will be examined in the future, is whether treatment for chronic asthma may be responsible for the reduction in metastatic cancer.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy.

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.