A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Developing guidance for feeding tube administration of oral medications.

BACKGROUND: Drug administration through feeding tubes presents many challenges to the healthcare provider. There is little information available on medications than can be delivered safely when crushed and what efforts can be implemented to minimize clogging the feeding tube. Our institution requested a comprehensive examination of all oral medications for the feeding tube route. METHODS: This report is a synopsis of the physical evaluation of 323 different oral medications for their appropriateness for feeding tube administration with distal site in either the stomach or jejunum. A worksheet was created for each medication. This document contained a review of the chemical and physical properties that would contribute to delivery of the medication. Each medication was then studied for the degree of disintegration, pH, osmolality, and potential to form clogs. For drugs that needed to be crushed, the volume of water needed to dissolve the drug, time for that process, and volume needed to rinse the tube after administration was also studied. RESULTS: The results of this review are summarized in a table and based on a composite of the documents cited, tests conducted, and author's judgements based all the data collected. Thirty-six medications were identified as inappropriate for feeding tube administration, and an additional 46 medications were identified as inappropriate for direct jejunal administration. CONCLUSION: The information produced by this study will enable clinicians to make informed choices in selecting, compounding, and rinsing medications through feeding tubes. Using the template provided, they will be able to evaluate a drug not studied here for potential issues in feeding tube administration.

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema.

Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.

TGF-ß1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation.

BACKGROUND: Secondary lymphedema is a common complication of cancer treatment, and previous studies have shown that the expression of transforming growth factor-beta 1 (TGF-ß1), a pro-fibrotic and anti-lymphangiogenic growth factor, is increased in this disease. Inhibition of TGF-ß1 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown. METHODS: Expression of TGF-ß1 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL). The effects of TGF-ß1 inhibition using neutralizing antibodies or a topical formulation of pirfenidone (PFD) were analyzed in mouse models of lymphedema. We also assessed the direct effects of TGF-ß1 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant-negative TGF-ß receptor selectively on LECs (LECDN-RII ). RESULTS: The expression of TGF-ß1 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF-ß1 in mouse models of lymphedema using neutralizing antibodies or with topical PFD decreased ECM deposition, increased the formation of collateral lymphatics, and inhibited infiltration of T cells. In vitro studies showed that TGF-ß1 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF-ß1 responsiveness in LECDN-RII resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls. CONCLUSIONS: Our results show that TGF-ß1 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema.

ASPEN Safe Practices for Enteral Nutrition Therapy [Formula: see text].

Enteral nutrition (EN) is a valuable clinical intervention for patients of all ages in a variety of care settings. Along with its many outcome benefits come the potential for adverse effects. These safety issues are the result of clinical complications and of process-related errors. The latter can occur at any step from patient assessment, prescribing, and order review, to product selection, labeling, and administration. To maximize the benefits of EN while minimizing adverse events requires that a systematic approach of care be in place. This includes open communication, standardization, and incorporation of best practices into the EN process. This document provides recommendations based on the available evidence and expert consensus for safe practices, across each step of the process, for all those involved in caring for patients receiving EN.

Quality Control Analytical Methods: Method Validation.

To properly determine the accuracy of a pharmaceutical product or compounded preparation, tests must be designed specifically for that evaluation. The procedures selected must be verified through a process referred to as method validation, an integral part of any good analytical practice. The results from a method validation procedure can be used to judge the quality, reliability, and consistency of analytical results. The purpose of this article is to deliver the message of the importance of validation of a pharmaceutical product or compounded preparation and to briefly discuss the results of a lack of such validation.

PFAT5 and the Evolution of Lipid Admixture Stability.

PFAT5 is defined by United States Pharmacopeia Chapter 729 as follows: the "percentage of fat residing in globules larger than 5 µm (PFAT5) for a given lipid injectable emulsion [is] not to exceed 0.05%." The unstable aggregates are trapped in lungs, liver, and the reticuloendothelial system. Large particles will accumulate in pulmonary capillaries, which are between 4 and 9 µm in diameter. Over the years, there has been an evolution of methods to characterize and define intravenous fat emulsion (IVFE) stability when combined as a total nutrient admixture (TNA). Many studies have claimed IVFE stability measuring mean particle size, zeta potential, and visual checks. Interestingly, none of the studies that claimed the TNA as stable identified an unstable one through testing. This report reviews those parameters and shows they were not a valid measure of lipid stability. The PFAT5 parameter has emerged as the only validated measure of lipid stability. There are clinical consequences of using lipids that exceed the PFAT5 limit. This parameter is applicable to both manufactured and compounded lipid preparations. The clinician should be aware of the limitations of much of the literature concerning the lipid stability assessment. More stability studies are needed using PFAT5 to identify the actual limits of TNA compounding.