CYP2D6-guided opioid therapy for adults with cancer pain: A randomized implementation clinical trial.

INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.

Safety and efficacy of a single total dose infusion (1020 mg) of ferumoxytol.

PURPOSE: Iron deficiency anemia (IDA) is the most common type of anemia. A single dose infusion of intravenous (IV) iron is a convenient treatment option. Ferumoxytol is an IV formulation of iron that is typically given in two doses of 510 mg each. Utilizing a single dose of 1020 mg over 15 min has previously been described as safe and effective. In July 2018, we began to administer a single 1020 mg dose of ferumoxytol to patients needing IV iron replacement at the North Florida/South Georgia Veterans Health System. To evaluate the impact of this change, a utilization review was conducted. METHODS: Outcomes of all patients who received ferumoxytol injections in the 6 months prior to and after the dosing strategy change were analyzed. A total of 140 patients, who received 270 separate IV ferumoxytol infusions, were included in the analysis. RESULTS: No significant difference in safety was observed, with one infusion reaction occurring in each group (p = 1.00). Efficacy also appeared equivalent with no significant difference between the change in hemoglobin for those who received a single 1020 mg dose versus those who received two 510 mg doses (p = 0.764). As expected, those who received a single total dose infusion of 1020 mg had less clinic utilization (p < 0.0001). CONCLUSION: In summary, ferumoxytol administered as a 1020 mg single dose infusion was more convenient and should be considered a safe and effective treatment option for IDA.

Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial.

INTRODUCTION: Pain is one of the most burdensome symptoms associated with cancer and its treatment, and opioids are the cornerstone of pain management. Opioid therapy is empirically selected, and patients often require adjustments in therapy to effectively alleviate pain or ameliorate adverse drug effects that interfere with quality of life. There are data suggesting CYP2D6 genotype may contribute to inter-patient variability in response to opioids through its effects on opioid metabolism. Therefore, we aim to determine if CYP2D6 genotype-guided opioid prescribing results in greater reductions in pain and symptom severity and interference with daily living compared to a conventional prescribing approach in patients with cancer. METHODS: Patients with solid tumors with metastasis and a self-reported pain score ≥ 4/10 are eligible for enrollment and randomized to a genotype-guided or conventional pain management strategy. For patients in the genotype-guided arm, CYP2D6 genotype information is integrated into opioid prescribing decisions. Patients are asked to complete questionnaires regarding their pain, symptoms, and quality of life at baseline and 2, 4, 6, and 8 weeks after enrollment. The primary endpoint is differential change in pain severity by treatment strategy (genotype-guided versus conventional pain management). Secondary endpoints include change in pain and symptom interference with daily living. CONCLUSION: Pharmacogenetic-guided opioid selection for cancer pain management has potential clinical utility, but current evidence is limited to retrospective and observational studies. Precision Medicine Guided Treatment for Cancer Pain is a pragmatic clinical trial that seeks to determine the utility of CYP2D6 genotype-guided opioid prescribing in patients with cancer.

A Case of Plasmablastic Lymphoma Achieving Complete Response and Durable Remission after Lenalidomide-Based Therapy.

BACKGROUND: Plasmablastic lymphoma (PBL) is an uncommon variant of diffuse large B-cell lymphoma that is characterized by its plasmacytoid features, aggressive tendencies, and frequent association with human immunodeficiency virus (HIV) infection or other immunocompromised states. Multi-agent, intensive chemotherapy regimens are recommended as first-line treatment by the National Comprehensive Cancer Network. However, the toxicity of these regimens is high and prognosis remains poor. CASE REPORT: We report a patient with HIV-negative PBL who achieved complete response and durable remission using a lenalidomide-based chemotherapy regimen as first-line therapy. CONCLUSION: Cyclophosphamide, lenalidomide, dexamethasone (CRD) may provide an alternative initial therapeutic option for patients with PBL who cannot tolerate the intensive chemotherapy regimens currently recommended.

Perspectives on death and dying: a study of resident comfort with End-of-life care.

BACKGROUND: Despite the benefits to early palliative care in the treatment of terminal illness, barriers to timely hospice referrals exist. Physicians who are more comfortable having end-of-life (EOL) conversations are more likely to refer to hospice. However, very little is known about what factors influence comfort with EOL care. METHODS: An anonymous survey was sent to all the residents and fellows at a single institution. Self-reported education, experience and comfort with EOL care was assessed. Using multivariate logistic regression analysis, variables that influenced comfort with EOL conversations were analyzed. RESULTS: Most residents (88.1%) reported little to no classroom training on EOL care during residency. EOL conversations during residency were frequent (50.6% reported > 10) and mostly unsupervised (61.9%). In contrast, EOL conversations during medical school were infrequent (3.7% reported >10) and mostly supervised (78.6%). Most (54.3%) reported little to no classroom training on EOL care during medical school. Physicians that reported receiving education on EOL conversations during residency and those who had frequent EOL conversations during residency had significantly higher comfort levels having EOL conversations (p = 0.017 and p = 0.003, respectively). Likewise, residents that felt adequately prepared to have EOL conversations when graduating from medical school were more likely to feel comfortable (p = 0.030). CONCLUSIONS: Most residents had inadequate education in EOL conversation skills during medical school and residency. Despite the lack of training, EOL conversations during residency are common and often unsupervised. Those who reported more classroom training during residency on EOL skills had greater comfort with EOL conversations. Training programs should provide palliative care education to all physicians during residency and fellowship, especially for those specialties that are most likely to encounter patients with advanced terminal disease.

Two novel RUNX1 mutations in a patient with congenital thrombocytopenia that evolved into a high grade myelodysplastic syndrome.

Here we report two new RUNX1 mutations in one patient with congenital thrombocytopenia that transformed into a high grade myelodysplastic syndrome with myelomonocytic features. The first mutation was a nucleotide base substitution from guanine to adenine within exon 8, resulting in a nonsense mutation in the DNA-binding inhibitory domain of the Runx1 protein. This nonsense mutation is suspected a de novo germline mutation since both parents are negative for the mutation. The second mutation identified was an in-frame six nucleotide base pair insertion in exon 5 of the RUNX1 gene, which is predicted to result in an insertion in the DNA-binding runt homology domain (RHD). This mutation is believed to be a somatic mutation as it was mosaic before allogeneic hematopoietic cell transplantation and disappeared after transplant. As no other genetic mutation was found using genetic screening, it is speculated that the combined effect of these two RUNX1 mutations may have exerted a stronger dominant negative effect than either RUNX1 mutation alone, thus leading to a myeloid malignancy.

Failures of feedback: rush hour along the highway to obesity.

From hot dogs to Hashimoto's and inheritance to inactivity, many "entrance ramps" converge onto the "Highway to Obesity", each contributing caloric intake that exceeds expenditure. Initially, the hypothalamus regulates appetite and energy based on leptin feedback, until feedback failure increases appetite, and allows deposition of abdominal fat, metabolic dysregulation, and metabolic syndrome. Without feedback controls, progress toward obesity is unimpeded unless diet, exercise, and/or medications provide an exit ramp.

Beyond obesity: the diagnosis and pathophysiology of metabolic syndrome.

Metabolic syndrome (MSX) identifies clinical symptoms and lab results, including abdominal obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension, that lead to an increased risk of cardiovascular disease (CVD). Obesity typically results in insulin and leptin resistance and a shift from expansion of subcutaneous fat to deposition of abdominal and ectopic fat. These conditions cause metabolic dysregulation, elevated fatty acids (FFA), and increased secretion of pro-inflammatory "adipokines". Left untreated, these conditions cause lipotoxicity, chronic inflammation, hypertension, atherosclerosis, and CVD.