Best practice recommendations for the management of anxiety during the pegvaliase journey.

BACKGROUND: Pegvaliase, an enzyme substitution therapy, is a treatment option for phenylketonuria (PKU). Due to the neuropathophysiology and disease burden of PKU, individuals can experience baseline anxiety unrelated to pegvaliase therapy. In addition, there are aspects of pegvaliase therapy that may be anxiety-inducing for those considering or receiving treatment. The aim of this manuscript is to present best practice recommendations for the identification and management of anxiety symptoms that can occur along the pegvaliase journey. METHODS: A modified Delphi approach was used to seek consensus among a multidisciplinary panel of experts. To this end, an in-person meeting was held that was preceded by a medical specialist- and patient-specific survey to develop preliminary recommendations on ways to address anxiety along the pegvaliase journey. After the meeting, an additional survey was conducted to rank the proposed solutions and mitigation strategies from which a set of recommendations was developed. All recommendations were voted on with the aim of consensus generation, defined as achieving ≥75% agreement among experts. RESULTS: The panel reached consensus on a total of 28 best practice recommendations for the management of anxiety during the pre-treatment, induction and titration, early maintenance (pre-efficacy), and late maintenance (post-efficacy) stages. The recommendations offer strategies to identify and address the most common causes of pegvaliase-related anxiety, including self-injection, side effects, the titration schedule, prescribed dietary changes, and variable time to efficacy. Overall, managing anxiety in those considering or receiving pegvaliase involves patient-centered communication, shared decision-making, and personalized treatment plans. CONCLUSIONS: The best practice recommendations described herein can guide healthcare providers in proactively addressing anxiety during the different stages of pegvaliase treatment, and support providers with initiating and managing pegvaliase in individuals who may experience baseline and treatment-related anxiety.

Nutritional status of adults with phenylketonuria on pegvaliase: A 15-month prospective study.

Background: Pegvaliase has allowed many adults with phenylketonuria (PKU) to achieve acceptable blood Phe control while eating an unrestricted diet. However, little is known about potential differences in nutritional status and eating behaviors after transitioning from a phenylalanine (Phe)-restricted to an unrestricted diet. Here we assessed change in nutritional status in adults with early-treated PKU who were consuming a Phe-restricted diet (intact protein ≤0.8 g/kg/day) prior to starting pegvaliase. Methods: A 15-month, prospective, longitudinal study to assess change in anthropometrics, dietary intake, laboratory indices of nutritional status, bone mineral density (BMD), body composition, measured resting energy expenditure (REE), and eating behaviors between baseline and Month 15. Results: Eleven adults (n = 7 female) aged 19.5-52.9 years completed the study. Six participants had a substantial blood Phe reduction (responders) and five participants had a modest blood Phe reduction (partial responders) by Month 15. Intact protein intake increased by an average of 49.4 g/day and 26.7 g/day in responders and partial responders, respectively. Plasma concentrations of most vitamins, minerals, and essential fatty acids assessed were normal, though micronutrient intakes decreased as participants decreased or discontinued PKU medical food(s). Responders had a more variable change in body mass index (BMI) and lean mass index (LMI) compared to partial responders, though there were no clear trends in BMD or body composition changes. Total protein intake was positively correlated with LMI. Responders, but not partial responders, self-reported increased in enjoyment of food and decreased food neophobia, uncontrolled eating, and emotional eating. Discussion: Participants transitioning to an unrestricted diet while on pegvaliase maintained adequate nutritional status overall with no clinically significant changes in cardiovascular or glycemic markers. Responders reported improvements in eating behaviors, including reduced food neophobia, uncontrolled eating, and emotional eating, and increased enjoyment of food. There were no consistent trends in BMD, body composition, or BMI changes. A larger sample size and longer follow-up period are needed to further assess potential changes.

Pegvaliase dosing in adults with PKU: Requisite dose for efficacy decreases over time.

Novel pharmaceutical therapies such as pegvaliase, phenylalanine ammonia lyase (PAL), have enhanced disease control for many individuals with phenylketonuria (PKU). We present a retrospective chart review to assess pegvaliase doses over time in individuals followed at the Boston Children's Hospital PAL Clinic, including those who started pegvaliase in a clinical trial ("trial patients") and those who started after drug came to market ("post-market patients"). Trial patients were on pegvaliase an average of 4.8 years longer, and their mean current pegvaliase dose was 126 ± 92 compared to 223 ± 147 mg/week for post-market patients (p = 0.0155), suggesting that the pegvaliase dose for target efficacy may decrease over time in adults with PKU. In post-market patients, we demonstrated a significant, inverse correlation with dose change and number of weeks from response (r = -0.46, p = 0.046). The entire cohort showed significant variability in terms of time to achieve a therapeutic response, response dose, and current dose. Our data suggest that patients tolerate a reduction in pegvaliase dose over time while maintaining efficacy. This is a clinically meaningful finding as it indicates that patients may reduce number of weekly injections over time on pegvaliase.

Simplified Diet for nutrition management of phenylketonuria: A survey of U.S. metabolic dietitians.

BACKGROUND: Phenylketonuria (PKU) is an inherited metabolic disorder affecting the conversion of phenylalanine (Phe) to tyrosine. Medical nutrition therapy, consisting of a Phe-restricted diet with medical formula, is the primary treatment for PKU. The Simplified Diet is an approach to PKU nutrition management that allows certain fruits, vegetables, and low-protein foods to be eaten without measuring or tracking, referred to as free/uncounted foods. There is no consensus on how to implement this approach in metabolic centers in the United States (U.S.), and clinical practice varies. AIM: This study describes the clinical experience of metabolic dietitians in U.S.-based metabolic centers related to the use and implementation of the Simplified Diet. METHODS: A survey was developed and sent out to metabolic dietitians to query current clinical practices related to the Simplified Diet. Descriptive statistics were used to analyze responses. RESULTS: Sixty-three dietitians managing ≥5 patients with PKU in U.S.-based metabolic centers responded to the survey. Ninety-eight percent of survey respondents reported using some version of the Simplified Diet in clinical practice. The survey identified areas of strong agreement, including introduction of the Simplified Diet at 6 to 12 months of age. The survey also identified areas of widespread variability, including specific Phe or protein thresholds for free/uncounted foods, and whether or not to set daily quantity limits on these foods. CONCLUSIONS: Significant variability related to implementation of the Simplified Diet exists across U.S.-based metabolic centers. This practice variability may contribute to differences in the patient experience across centers and may indicate a need for development of clinical guidelines.

Dosimetric impact of post-operative seroma reduction during radiotherapy after breast-conserving surgery.

PURPOSE: Three boost radiotherapy (RT) techniques were compared to evaluate the dosimetric effect of seroma reduction during RT after breast-conserving surgery (BCS). MATERIALS AND METHODS: Twenty-one patients who developed seroma after BCS were included. Each patient underwent three CT scans: one week before RT (CT(-1)), in the third (CT(3)) and fifth (CT(5)) week of RT. For each patient, three plans were generated. (1) SEQ: whole breast irradiation planned on CT(-1,) sequential boost planned on CT(5), (2) SIB: simultaneous integrated boost planned on CT(-1), (3) SIB adaptive radiation therapy (SIB-ART): planned on CT(-1) and re-planned on CT(3). Irradiated volumes, mean lung (MLD) and maximum heart dose (HD(max)) were projected and compared on CT(5). RESULTS: On average 62% seroma reduction during RT was observed. Volumes receiving ≥ 107% of prescribed whole breast dose were significantly smaller with SIB-ART compared to SEQ and SIB. The undesired volume receiving ≥ 95% of prescribed total dose was also significantly smaller with SIB-ART. For SEQ, SIB-ART and SIB, respectively, small but significant differences were found in MLD (4.2 vs. 4.6 vs. 4.7 Gy) and in HD(max) for patients with left-sided breast cancer (39.9 vs. 35.8 vs. 36.9 Gy). CONCLUSIONS: This study demonstrates a dosimetric advantage for patients with seroma when simultaneous integrated boost is used with re-planning halfway through treatment.

Effects of setup errors and shape changes on breast radiotherapy.

PURPOSE: The purpose of the present study was to quantify the robustness of the dose distributions from three whole-breast radiotherapy (RT) techniques involving different levels of intensity modulation against whole patient setup inaccuracies and breast shape changes. METHODS AND MATERIALS: For 19 patients (one computed tomography scan and five cone beam computed tomography scans each), three treatment plans were made (wedge, simple intensity-modulated RT [IMRT], and full IMRT). For each treatment plan, four dose distributions were calculated. The first dose distribution was the original plan. The other three included the effects of patient setup errors (rigid displacement of the bony anatomy) or breast errors (e.g., rotations and shape changes of the breast with respect to the bony anatomy), or both, and were obtained through deformable image registration and dose accumulation. Subsequently, the effects of the plan type and error sources on target volume coverage, mean lung dose, and excess dose were determined. RESULTS: Systematic errors of 1-2 mm and random errors of 2-3 mm (standard deviation) were observed for both patient- and breast-related errors. Planning techniques involving glancing fields (wedge and simple IMRT) were primarily affected by patient errors (∼6% loss of coverage near the dorsal field edge and ∼2% near the skin). In contrast, plan deterioration due to breast errors was primarily observed in planning techniques without glancing fields (full IMRT, ∼2% loss of coverage near the dorsal field edge and ∼4% near the skin). CONCLUSION: The influences of patient and breast errors on the dose distributions are comparable in magnitude for whole breast RT plans, including glancing open fields, rendering simple IMRT the preferred technique. Dose distributions from planning techniques without glancing open fields were more seriously affected by shape changes of the breast, demanding specific attention in partial breast planning techniques.

Clinical results of image-guided deep inspiration breath hold breast irradiation.

PURPOSE: To evaluate the feasibility, cardiac dose reduction, and the influence of the setup error on the delivered dose for fluoroscopy-guided deep inspiration breath hold (DIBH) irradiation using a cone-beam CT for irradiation of left-sided breast cancer patients. METHODS AND MATERIALS: Nineteen patients treated according to the DIBH protocol were evaluated regarding dose to the ipsilateral breast (or thoracic wall), heart, (left ventricle [LV] and left anterior descending artery [LAD]), and lung. The DIBH treatment plan was compared to the free-breathing (FB) treatment planning and to the dose data in which setup error was taken into account (i.e., actual delivered dose). RESULTS: The largest setup variability was observed in the direction perpendicular to the RT field (µ = -0.8 mm, Σ = 2.9 mm, σ = 2.0 mm). The mean (D(mean)) and maximum (D(max)) doses of the DIBH treatment plan was significantly lower compared with the FB treatment plan for the heart (34% and 25%, p < 0.001), LV (71% and 28%, p < 0.001), and LAD (52% and 39.8%, p < 0.001). For some patients, large differences were observed between the heart D(max) according to the DIBH treatment plan and the actual delivered dose (up to 71%), although D(max) was always smaller than the planned FB dose (mean group reduction = 29%, p < 0.001). CONCLUSION: The image-guided DIBH treatment protocol is a feasible irradiation method with small setup variability that significantly reduces the dose to the heart, LV, and LAD.