Clinical utility of a regional precision medicine molecular tumor board and challenges to implementation.

PURPOSE: Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation. METHODS: An observational cohort study included patients reviewed by the PMMTB between September 2015 to December 2017. Patients who had consented to the registry study were included. The primary endpoint of this study was time on treatment (ToT) ratio. Clinical utility was established if the primary endpoint had least 15% of patients achieving a ToT ratio of ≥1.3. RESULTS: Overall, 278 patients were presented to the PMMTB and 113 cases were included in the final analysis. The PMMTB identified at least one nonstandard of care (SOC) clinically actionable mutation for 69.0% (78/113) of cases. In patients who received non-SOC treatment, 43.8% (7/16) achieved a ToT ratio of 1.3 or more (p < 0.001). Fifty-nine patients did not receive non-SOC recommendations. Reasons for not pursuing treatment included 35.6% having response to current treatment, 20.3% died prior to starting or considering PMMTB recommendations, 13.6% pursued other treatment options based on clinician discretion, another 10.2% pursued other treatment options because clinical trials recommended were not geographically accessible, 8.5% had rapid decline of performance status, 6.8% lacked of financial support for treatment, and 5.1% were excluded from clinical trials due to abnormal laboratory values. CONCLUSION: The regional PMMTB non-SOC recommendations benefitted a majority of patients and additional processes were implemented to assist with non-SOC treatment accessibility.

Extemporaneous compounding and administration of tretinoin slurry for acute promyelocytic leukemia.

INTRODUCTION: Acute promyelocytic leukemia (APL) is a potentially curable malignancy with 4-year overall survival rates >90%. Early complications from the disease or its treatment may result in a loss of oral access and require alternative administration of medications. Tretinoin has been the backbone of APL therapy since the late 1990s and is only available as a liquid filled capsule. CASE REPORT: Two patients with high-risk APL were unable to safely swallow tretinoin capsules due to complications of their disease. MANAGEMENT & OUTCOME: We prepared a tretinoin slurry using tretinoin 10 mg capsules, sterile water, and mineral oil at a ratio of 1 capsule to 2.75 mL sterile water to 1.25 mL mineral oil. This was successfully administered to both patients and no doses of tretinoin slurry were missed by either patient. In the patient who has long-term follow up available, a complete remission was achieved. DISCUSSION: Due to tretinoin's known teratogenicity, this capsule should not be crushed, cut, or open, which limits its use in patients without oral access. Alternative routes of administration, such as via a nasogastric tube or sublingually, have not been safe and effective. By preparing a tretinoin slurry in our hazardous extemporaneous compounding area, we were able to safely and effectively prepare a tretinoin slurry that was successfully administered to two patients. This alternative preparation did not alter long-term outcomes and represents a viable option for patients who do not have oral access.

Comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed/refractory acute myeloid leukemia.

We compared the outcomes of salvage chemotherapy in 146 patients with relapsed (57.5%) or refractory (42.5%) AML who received CLAG-M (51%), MEC (39%) or CLAG (10%). Minimal residual disease (MRD) was assessed by flow cytometry. Bivariate, Kaplan-Meier, and Cox regression analyses were conducted. Complete remission (CR) rate of 46% (CLAG-M 54% versus MEC/CLAG 40%, p = .045) was observed with MRD-negative CR of 33% (CLAG-M 39% versus MEC/CLAG 22%, p = .042). Median overall survival (OS) was 9.7 months; the longest OS occurred with CLAG-M (13.3, 95%CI 2.4-24.3) versus MEC (6.9, 95%CI 2.9-10.9) or CLAG (6.2, 95%CI 2.4-12.6) (p = .025). When adjusted for age, gender, relapsed/refractory AML, poor risk AML, MRD, chemotherapy and transplant, CLAG-M (HR 0.63, 95% CI 0.40-0.98, p = .042), MRD-negativity (HR 0.15, 95% CI 0.07-0.30, p < .001) and transplant (HR 0.22, 95% CI 0.13-0.39, p < .001) were associated with higher OS. Our findings confirm that CLAG-M is a reasonable salvage regimen for RR-AML followed by transplant.

Current state assessment survey of challenges of pharmacogenomics within oncology pharmacy practice.

PURPOSE: The goal of this survey was to identify opportunities for health systems to increase implementation and adoption of oncology-focused pharmacogenomics services. METHODS: An online survey assessing respondent demographics, baseline knowledge and training in pharmacogenomics, comfort level with pharmacogenomic data, and challenges of implementing clinical pharmacogenomic platforms was distributed to professional colleagues and over national oncology pharmacy listservs. Pharmacists were grouped based on their comfort level with pharmacogenomic data. Results were analyzed utilizing Pearson chi-square test. A p value of <0.05 was considered significant. RESULTS: A total of 84 participants from 58 cancer centers participated in the survey. Most participants were post-graduate year 2 trained and a majority reported being comfortable assessing oncology pharmacogenomic data. Respondents indicated that pharmacogenomics reported within the electronic medical record was the most common institutional process to support pharmacogenomics for oncology patients. Despite this, poor visibility of pharmacogenomics within the electronic medical record was the most challenging aspect of implementing a pharmacogenomic program. Additional challenges included lack of resources for pharmacogenomic programs, insurance denials for pharmacogenomic-driven testing and medication, and prolonged turnaround time of pharmacogenetic results. Length of practice, post-graduate year 2 residency training, institutions with pharmacist involvement on hematology/oncology molecular tumor board, and institutions where a pharmacist helped create local pharmacogenomic policies were significantly associated with respondents' comfortability in assessing pharmacogenomics. CONCLUSION: Oncology pharmacists reported substantial challenges in implementing a pharmacogenomic program. Future efforts to assist in developing pharmacogenomic efforts should focus on increasing pharmacist involvement, expanding education and training, and improving clinical decision support tools.

Retrospective analysis of goal drug level attainment of posaconazole for invasive fungal infection prophylaxis in patients with acute myeloid leukemia pre- and post-switch to tablet formulation.

BACKGROUND: Posaconazole is approved for invasive fungal infection prophylaxis in patients with hematologic malignancies. Posaconazole suspension is plagued by poor oral absorption and dietary requirements that are difficult for patients to meet. The delayed-release tablet formulation of posaconazole may be taken without regards to meals and has significantly better oral absorption than posaconazole suspension. OBJECTIVES: We sought to determine if a switch to posaconazole tablets improved steady-state drug level attainment for invasive fungal infection prophylaxis in patients with acute myeloid leukemia. METHODS: All adult inpatients with acute myeloid leukemia undergoing chemotherapy, who received posaconazole for invasive fungal infection prophylaxis between 2012 and 2015, were included. The primary outcome was proportion of patients with first posaconazole level greater than 700 ng/mL. Secondary outcomes included proportion of patients with first posaconazole level greater than 1000 ng/mL, invasive fungal infection within 100 days, and adverse drug events. RESULTS: Forty patients received posaconazole tablets and 34 patients received suspension. Posaconazole levels were significantly higher at first measurement in patients receiving tablet than suspension (1296 ng/mL vs. 788 ng/mL, p < 0.01). Thirty-seven patients receiving tablets had a serum drug level greater than 700 ng/mL on first measurement versus 18 receiving suspension (p < 0.01). Patients receiving tablets were also more likely to have a serum drug level over 1000 ng/mL on first measurement (26 vs. 11, p < 0.01). Rates of invasive fungal infection and adverse events were not statistically different. CONCLUSIONS: Patients receiving posaconazole tablets attained significantly higher serum drug levels than those receiving suspension.

Utilization and evaluation of noncore chemotherapy regimens within an academic medical center.

Uniformity of evidence-based chemotherapy prescribing using approved, standard, or "core" regimens provides systems-based safety. Noncore chemotherapy regimens are non-standard-of-care regimens requested by physicians on a patient-by-patient basis. Chemotherapy Council, a Pharmacy & Therapeutics subcommittee, assesses all requests and determines approval status based upon submitted evidence and patient-specific factors. This study's purpose is to describe noncore chemotherapy regimens utilization, efficacy, and clinical outcomes in patients receiving noncore chemotherapy regimens. This retrospective chart review includes a two-stage utilization and outcomes evaluation of patients receiving noncore chemotherapy regimens. Stage I, a demographics and utilization assessment of patients receiving noncore chemotherapy regimens, has data collection including patient age, sex, performance score, malignancy, and noncore chemotherapy regimen use justification. Stage II assesses noncore chemotherapy regimen-related, patient-specific outcomes of breast cancer noncore chemotherapy regimen patients. Breast cancer patients were evaluated on regimen and clinical outcomes including disease stage, regimen duration, discontinuation reason, subsequent chemotherapy, survival, and time from noncore chemotherapy regimen until death. Within stage I, 307 patient-specific noncore chemotherapy regimen requests were submitted. The most commonly submitted rationale was modification of a core regimen (33%), followed by patient-specific factors (29%) and salvage therapy (22%). For stage II, 29 breast cancer patients received a noncore chemotherapy regimen and most (54%) received a modified core regimen. The vast majority of noncore chemotherapy regimen discontinuation was due to either regimen completion (42%) or disease progression (42%). Nonelective hospitalizations (35%) and mortality (30%) were found during the median 13.3 months of follow up. Noncore chemotherapy regimen use provides regimen tailoring for patients who are candidates for further therapy, but nonelective hospitalizations, end-of-life chemotherapy, and mortality warrant further investigation to improve patient outcomes.

Fatal Stevens-Johnson syndrome/toxic epidermal necrolysis induced by allopurinol-rituximab-bendamustine therapy.

Stevens-Johnson syndrome/toxic epidermal necrolysis overlap is an acute hypersensitivity reaction that compromises the integrity of mucous membranes and cutaneous tissue. While the pathophysiology of this syndrome has not been fully elucidated, it is commonly associated with the medication use and carries a significant mortality risk of approximately 30%. No commonalities among causative medications have been identified, and determining the offending agent can be challenging. This case report describes fatal Stevens-Johnson syndrome/toxic epidermal necrolysis overlap in a patient after receiving his first cycle of allopurinol, rituximab, and bendamustine treatment for non-Hodgkin's B-cell lymphoma. An analysis of FDA Medwatch adverse reaction case reports involving allopurinol, rituximab, and bendamustine is also presented.

Beta-cell alpha-ketoglutarate hydroxylases may acutely participate in insulin secretion.

The presence of Fe(II) alpha-ketoglutarate hydroxylases in rat and human pancreatic islets and INS-1 832/13 cells was demonstrated with the reverse transcriptase polymerase chain reaction (PHD1, 2, and 3; lysyl hydroxylases 1, 2, and 3; and phytanoyl-coenzyme A hydroxylase were seen) and/or immunoblotting (high levels of proline hydroxylase P4Halpha1, PHD2, and PHD4 and low levels of PHD2 and PHD3 in human islets, and high levels of PHD2 in rat islets and INS-1 cells were seen). Prolyl hydroxylase enzyme activity in INS-1 832/13 cells was purified with polyproline affinity chromatography. Inhibitors of alpha-ketoglutarate hydroxylases lowered glucose-induced and leucine-plus-glutamine-induced insulin release in rat pancreatic islets, suggesting that there may be acute unknown effects of alpha-ketoglutarate hydroxylases in insulin secretion. It is possible that an increase in mitochondrially generated alpha-ketoglutarate derived from insulin secretagogue carbon and translocated to the cytosol may be part of the signal for insulin secretion.

Functional MRI near vascular anomalies: comparison of cavernoma and arteriovenous malformation.

BACKGROUND AND PURPOSE: Mapping of eloquent cortex using blood-oxygen-level-dependent (BOLD) contrast functional MRI (fMRI) has rapidly gained acceptance as part of the evaluation of patients being considered for neurosurgical interventions. The BOLD signal measures local susceptibility in the blood, which can change during periods of increased neuronal activation as a result of alteration in blood flow and cerebral oxygen utilisation. Vascular anomalies could influence the BOLD signal via their effects on both blood flow and susceptibility. METHODS: In the present study we have compared the fMRI signal associated with functional activation near arteriovenous malformations and cavernomas in a group of patients referred for pre-surgical mapping of eloquent cortex. RESULTS: The magnitude of the BOLD signal was not different for the cavernoma group and the AVM group (mean percentage signal change 6.3% vs. 5.5%). For subjects with cavernoma, there was an increase in cavernoma volume on the functional images compared to T1-weighted anatomical images (mean 570%), and a BOLD signal was only detected outside the enlarged cavernoma. CONCLUSION: The findings show that susceptibility effects associated with cavernoma, most likely due to hemosiderin deposition, can result in an apparent increase in the separation between the BOLD signal and the cavernoma itself. This could lead to falsely high levels of surgical confidence during neurosurgical resection. Differential patterns of blood flow associated with cavernoma and AVM do not appear to significantly affect the BOLD signal magnitude.

Citrate oscillates in liver and pancreatic beta cell mitochondria and in INS-1 insulinoma cells.

Oscillations in citric acid cycle intermediates have never been previously reported in any type of cell. Here we show that adding pyruvate to isolated mitochondria from liver, pancreatic islets, and INS-1 insulinoma cells or adding glucose to intact INS-1 cells causes sustained oscillations in citrate levels. Other citric acid cycle intermediates measured either did not oscillate or possibly oscillated with a low amplitude. In INS-1 mitochondria citrate oscillations are in phase with NAD(P) oscillations, and in intact INS-1 cells citrate oscillations parallel oscillations in ATP, suggesting that these processes are co-regulated. Oscillations have been extensively studied in the pancreatic beta cell where oscillations in glycolysis, NAD(P)/NAD(P)H and ATP/ADP ratios, plasma membrane electrical activity, calcium levels, and insulin secretion have been well documented. Because the mitochondrion is the major site of ATP synthesis and NADH oxidation and the only site of citrate synthesis, mitochondria need to be synchronized for these factors to oscillate. In suspensions of mitochondria from various organs, most of the citrate is exported from the mitochondria. In addition, citrate inhibits its own synthesis. We propose that this enables citrate itself to act as one of the cellular messengers that synchronizes mitochondria. Furthermore, because citrate is a potent inhibitor of the glycolytic enzyme phosphofructokinase, the pacemaker of glycolytic oscillations, citrate may act as a metabolic link between mitochondria and glycolysis. Citrate oscillations may coordinate oscillations in mitochondrial energy production and anaplerosis with glycolytic oscillations, which in the beta cell are known to parallel oscillations in insulin secretion.

Tremorgenic mycotoxicosis in four dogs from a single household.

Mycotoxins are fungal metabolites that induce undesirable effects. The effects of these mycotoxins vary depending on the chemical structure of the toxin and degree of toxicity. Mycotoxins that induce muscle tremors, ataxia, and convulsions are termed tremorgenic mycotoxins. Our report documents the clinical course of 4 dogs from a single household that were simultaneously affected by tremorgenic mycotoxins. Diagnosis of tremorgenic mycotoxicosis was confirmed by stomach content analysis from 1 of the dogs. The mycotoxins identified were penitrem A and roquefortine, which are both produced by Penicillium spp. Treatment goals following tremorgenic mycotoxin ingestion include minimizing absorption, controlling tremors and seizures with methocarbamol and pentobarbital sodium administration, and providing supportive care. Two of the affected dogs required ventilatory support. With early aggressive treatment, prognosis is good and recovery is complete without sequelae. It is helpful for the clinician to be familiar with the typical clinical signs at the time of admission, treatment, and clinical course of dogs with tremorgenic mycotoxicosis.