Implementing an intravenous ketamine protocol for acute pain in the medical-surgical setting.

ABSTRACT: A subanesthetic intravenous ketamine infusion is a safe and effective acute pain management modality for moderate to severely painful surgical procedures and may be useful in patients who are at increased risk for opioid-related adverse events. Despite its safety profile, intravenous ketamine is often restricted to the intensive care unit, which results in decreased patient access to this effective therapy. For clinicians who wish to implement an intravenous ketamine protocol in the medical-surgical setting, there are few resources available. In this brief report, we present our ketamine infusion protocol for acute pain and the clinical and financial outcomes 1 year after implementation. In our experience, ketamine infusions on the medical-surgical ward are safe and cost-effective when an established acute pain service protocol is followed. Nurse practitioners play an essential role in increasing patient access to intravenous ketamine infusions and leading change by collaborating with stakeholders to develop a protocol, training nurses and interdisciplinary team members, and providing ongoing support to nursing staff.

Evidence supports blind screening for internal malignancy in dermatomyositis: Data from 2 large US dermatology cohorts.

The association between dermatomyositis and internal malignancy is well established, but there is little consensus about the methods of cancer screening that should be utilized.We wished to analyze the prevalence and yield of selected cancer screening modalities in patients with dermatomyositis.We performed a retrospective analysis of 2 large US dermatomyositis cohorts comprising 400 patients.We measured the frequency of selected screening tests used to search for malignancy. Patients with a biopsy-confirmed malignancy were identified. Prespecified clinical and laboratory factors were tested for association with malignancy. For each malignancy we identified the screening test(s) that led to diagnosis and classified these tests as either blind (not guided by suspicious sign/symptom) or triggered (by a suspicious sign or symptom).Forty-eight patients (12.0% of total cohort) with 53 cancers were identified with dermatomyositis-associated malignancy. Twenty-one of these 53 cancers (40%) were diagnosed within 1 year of dermatomyositis symptom onset. In multivariate analysis, older age (P = .0005) was the only significant risk factor for internal malignancy. There was no significant difference in cancer incidence between classic and clinically amyopathic patients. Twenty-seven patients (6.8% of the total cohort) harbored an undiagnosed malignancy at the time of dermatomyositis diagnosis. The majority (59%) of these cancers were asymptomatic and computed tomography (CT) scans were the most common studies to reveal a cancer.This is the largest US cohort studied to examine malignancy prevalence and screening practices in dermatomyositis patients. Our results demonstrate that, while undiagnosed malignancy is present in <10% of US patients at the time of dermatomyositis onset, it is often not associated with a suspicious sign or symptom. Our data suggest that effective malignancy screening of dermatomyositis patients often requires evaluation beyond a history, physical examination, and "age-appropriate" cancer screening-these data may help to inform future guidelines for malignancy screening in this population.

Macrophage phagocytosis alters the MRI signal of ferumoxytol-labeled mesenchymal stromal cells in cartilage defects.

Human mesenchymal stem cells (hMSCs) are a promising tool for cartilage regeneration in arthritic joints. hMSC labeling with iron oxide nanoparticles enables non-invasive in vivo monitoring of transplanted cells in cartilage defects with MR imaging. Since graft failure leads to macrophage phagocytosis of apoptotic cells, we evaluated in vitro and in vivo whether nanoparticle-labeled hMSCs show distinct MR signal characteristics before and after phagocytosis by macrophages. We found that apoptotic nanoparticle-labeled hMSCs were phagocytosed by macrophages while viable nanoparticle-labeled hMSCs were not. Serial MRI scans of hMSC transplants in arthritic joints of recipient rats showed that the iron signal of apoptotic, nanoparticle-labeled hMSCs engulfed by macrophages disappeared faster compared to viable hMSCs. This corresponded to poor cartilage repair outcomes of the apoptotic hMSC transplants. Therefore, rapid decline of iron MRI signal at the transplant site can indicate cell death and predict incomplete defect repair weeks later. Currently, hMSC graft failure can be only diagnosed by lack of cartilage defect repair several months after cell transplantation. The described imaging signs can diagnose hMSC transplant failure more readily, which could enable timely re-interventions and avoid unnecessary follow up studies of lost transplants.

PPARγ Promotes Growth and Invasion of Thyroid Cancer Cells.

Undifferentiated (anaplastic) thyroid cancer (ATC) is one of the most aggressive human malignancies and no effective therapy is currently available. We show here that PPARγ levels are elevated in cells derived from ATC. Depletion of PPARγ in HTh74 ATC cells resulted in decreased cell growth, cell cycle arrest and a reduction in pRb and cyclin A and B1 levels. We further showed that both flank and orthotopic thyroid tumors derived from PPARγ-depleted cells grew more slowly than PPARγ-expressing cells. When PPARγ was overexpressed in more differentiated thyroid cancer BCPAP cells which lack PPARγ, there was increased growth and raised pRb and cyclin A and B1 levels. Finally, PPARγ depletion in ATC cells decreased their invasive capacity whereas overexpression in PTC cells increased invasiveness. These data suggest that PPARγ may play a detrimental role in thyroid cancer and that targeting it therapeutically may lead to improved treatment of advanced thyroid cancer.

Thyroid cancer resistance to vitamin D receptor activation is associated with 24-hydroxylase levels but not the ff FokI polymorphism.

BACKGROUND: The vitamin D receptor (VDR) has been studied as a novel target for cancer therapy in many tissue types as VDR ligands decrease cell proliferation in vitro and decrease tumor growth in vivo in sensitive cells. The objective of this study was to analyze the response to VDR agonist therapy in a panel of validated thyroid cancer cells and assess genetic markers predicting sensitivity and resistance to calcitriol and the noncalcemic analog DP006. METHODS: Thyroid cancer cell lines were analyzed for VDR and RXR protein by Western blot. Cell growth after VDR agonist treatment (calcitriol or DP006) was assessed after 6 days of treatment by viable cell assay. To investigate calcitriol/DP006 resistance in VDR-expressing cells, the VDR was sequenced and 1-α and 24-hydroxylase mRNA expression was assessed. RESULTS: VDR protein was variably expressed in the thyroid cancer cell lines and its presence was not sufficient for decreased viable cell count in response to calcitriol or DP006. The most sensitive cells (TPC1) have an ff FokI VDR polymorphism and the most resistant cells (HTh7 and 8505C) have an FF FokI VDR. This is a unique finding given that the balance of the literature of VDR polymorphisms describes an association of the ff FokI polymorphism with cancer risk and/or decreased VDR transactivation. 1-α and 24-hydroxylase mRNA expression before and after VDR agonist therapy was examined. 1-α-Hydroxylase levels did not change after calcitriol treatment. However, we found that higher baseline 24-hydroxylase levels and/or lower stimulation of 24-hydroxylase levels after calcitriol treatment were associated with relative resistance to calcitriol/DP006. CONCLUSIONS: The VDR represents a novel therapeutic target in poorly differentiated thyroid cancer; however, the efficacy of VDR agonist therapy to decrease viable thyroid cancer cell count cannot be predicted solely on the presence of the VDR. The FF FokI VDR genotype and high baseline 24-hydroxylase levels were associated with relative resistance to calcitriol and DP006. Therefore, identifiable markers of sensitivity or resistance to VDR agonist therapy may allow for a personalized use of these agents in poorly differentiated thyroid cancer.

Tumor-associated lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary thyroid cancer.

CONTEXT: Ten to 30% of patients with papillary thyroid cancer (PTC) develop recurrent disease and may benefit from innovative adjuvant therapies. Immune-based therapies are under investigation to treat many types of cancer. The role of the immune system in PTC is poorly understood. OBJECTIVE: We investigated whether tumor-associated lymphocytes (TAL), in the absence of background thyroiditis (LT), contribute to disease severity. We hypothesized that the type of lymphocytes associated with PTC would correlate with parameters of disease. DESIGN: This retrospective study analyzed archived PTC samples for the presence of TAL and/or LT. A group of patients with TAL was evaluated for lymphocyte subsets by immunohistofluorescence. PATIENTS AND SETTING: One hundred PTC patients were analyzed for LT and TAL, and 10 PTC patients with TAL were assessed for lymphocyte subsets at University of Colorado Hospital. MAIN OUTCOME: We assessed correlations between disease and the presence of TAL, LT, and lymphocyte subset frequency. RESULTS: Patients with TAL exhibited higher disease stage and increased incidence of invasion and lymph node metastasis compared with patients without lymphocytes or with LT. CD4(+) T cell frequency correlated with tumor size (r = 0.742; P = 0.017). FoxP3(+) regulatory T cell (Treg) frequency correlated with lymph node metastases (r = 0.858; P = 0.002), and CD8 to Treg ratio correlated inversely with tumor size (r = -0.804; P = 0.007). CONCLUSIONS: TAL and high Treg frequency in primary thyroid tumors correlates with more aggressive disease. Future prospective studies may identify Treg frequency as a predictive factor in PTC, and the suppressive effects of Treg should be considered in the design of immune-based therapies.