A Scoping Review on the Attributes of Cluster Randomized Controlled Trials in Long-Term Care Facilities.

Cluster randomized trial design, where groups of participants are randomized instead of individual participants, is increasingly being used in long-term care research. The purpose of this review was to determine the characteristics of cluster randomized trials in long-term care facilities. A medical librarian conducted the literature search. Two independent reviewers reviewed each paper. Studies were included if the design was cluster randomized and participants were from long-term care facilities. For each included study, two independent data extractors captured data on study attributes, including: journal, location, year published, author discipline, funding, methodology, number of participants, and intervention target. The literature search yielded 7,679 unique studies, with 195 studies meeting the selection criteria and being included for data extraction. The included studies were published between 1976 and 2017, with 53% of studies published after 2009. The term cluster randomized was in the title of only 45% of the studies. The studies were conducted worldwide; the United States had the largest number of studies (23%), followed by the United Kingdom (18%). Ten percent of studies were published in journals with an impact factor >10. The most frequent discipline of the first and last authors was medicine (34%), followed by nursing (17%). Forty-nine percent of the studies had government funding, while only 20% had medical industry funding. In studies with <1000 residents, 85% of the studies obtained consent from the resident and/or their proxy, while in studies with ≥ 1000 residents, it was 31%. The most frequent intervention targets were infection (13%), falls/fracture (13%), and behavior/physical restraint (13%). Cluster randomized controlled trials in long-term care have a unique set of characteristics. Results of this review will provide guidance to researchers conducting studies in long-term care facilities.

What are the most common conditions in primary care? Systematic review.

OBJECTIVE: To identify the most commonly presenting conditions in primary care globally, and to compare common reasons for visits (RFVs) as reported by clinicians and patients, as well as among countries of different economic classifications. DATA SOURCES: Twelve scientific databases were searched up to January 2016, and a dual independent review was performed to select primary care studies. STUDY SELECTION: Studies were included if they contained 20 000 visits or more (or equivalent volume by patient-clinician interactions) and listed 10 or more RFVs. Dual independent data extraction of study characteristics and RFV rankings was performed. Data analysis was descriptive, with pooled rankings of RFVs across studies. SYNTHESIS: Eighteen studies met inclusion criteria (median 250 000 patients or 83 161 visits). Data were from 12 countries across 5 continents. The 10 most common clinician-reported RFVs were upper respiratory tract infection, hypertension, routine health maintenance, arthritis, diabetes, depression or anxiety, pneumonia, acute otitis media, back pain, and dermatitis. The 10 most common patient-reported RFVs were symptomatic conditions including cough, back pain, abdominal symptoms, pharyngitis, dermatitis, fever, headache, leg symptoms, unspecified respiratory concerns, and fatigue. Globally, upper respiratory tract infection and hypertension were the most common clinician-reported RFVs. In developed countries the next most common RFVs were depression or anxiety and back pain, and in developing countries they were pneumonia and tuberculosis. There was a paucity of available data, particularly from developing countries. CONCLUSION: There are differences between clinician-reported and patient-reported RFVs to primary care, as well as between developed and developing countries. The results of our review are useful for the development of primary care guidelines, the allocation of resources, and the design of training programs and curricula.

SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice.

DESIGN: Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). RESULTS: nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, Kras(G12D);p53(flox/-);p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. CONCLUSIONS: nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8(+) T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP(+) CAF, may direct tumor immune evasion in a model of human PDA.

Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.

The pancreas cancer microenvironment.

Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.