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Objectives: The 2 main forms of treatment for distal femur fractures are locked lateral plating and retrograde nailing. The goal of this trial was to determine whether there are significant differences in outcomes between these forms of treatment. Design: Multicenter randomized controlled trial. Setting: Twenty academic trauma centers. Patients/Participants: One hundred sixty patients with distal femur fractures were enrolled. One hundred twenty-six patients were followed 12 months. Patients were randomized to plating in 62 cases and intramedullary nailing in 64 cases. Intervention: Lateral locked plating or retrograde intramedullary nailing. Main Outcome Measurements: Functional scoring including Short Musculoskeletal Functional Assessment, bother index, EQ Health, and EQ Index. Secondary measures included alignment, operative time, range of motion, union rate, walking ability, ability to manage stairs, and number and type of adverse events. Results: Functional testing showed no difference between the groups. Both groups were still significantly affected by their fracture 12 months after injury. There was more coronal plane valgus in the plating group, which approached statistical significance. Range of motion, walking ability, and ability to manage stairs were similar between the groups. Rate and type of adverse events were not statistically different between the groups. Conclusions: Both lateral locked plating and retrograde intramedullary nailing are reasonable surgical options for these fractures. Patients continue to improve over the course of the year after injury but remain impaired 1 year postoperatively. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

LINKED CONTENTThis article is linked to Chen et al papers. To view these articles, visit https://doi.org/10.1111/apt.16959 and https://doi.org/10.1111/apt.17176

Importance Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective To develop recommendations for the safe and effective use of LADD. Evidence Review A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline’s 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.

AbstractPurposeTo investigate the dependency of dose‐volume histogram (DVH) behavior and precision on underlying discretization using shapes and dose distributions with known analytical DVHs for five commercial DVH calculators.MethodsDVHs and summary metrics were extracted from all five systems using synthetic cone and cylinder objects for which the true volume and DVH curves were known. Trends in the curves and metrics were explored by varying the underlying voxelization of the CT image, structure set, and dose grid as well by varying the geometry of the structure and direction of a linear dose gradient. Using synthetic structures allowed for comparison with ground truth DVH curves to assess their accuracy while an algorithm was additionally developed to assess the precision of each system. The precision was calculated with a novel algorithm that treats any “stair step” behavior in a DVH curve as an uncertainty band and calculates the width, characterized as a percent difference, of the band for various DVH metrics. The underlying voxelization was additionally changed and DVHs were extracted for two clinical examples. The details of how each system calculated DVHs were also investigated and tendencies in the calculated curves, metrics, and precision were related to choices made in the calculation methodology.ResultsCalculation methodology differences that had a noticeable impact on the DVH curves and summary metrics include supersampling beyond the input grids and interpretation of the superior and inferior ends of the structures. Among the systems studied, the median precision ranged from 0.902% to 3.22%, and interquartile ranges varied from 1.09% to 3.91%.ConclusionsCommercial dose‐evaluation solutions can calculate different DVH curves, structure volume measures, and dose statistics for the same input data due to differences in their calculation methodologies. This study highlights the importance of understanding and investigating the DVH calculation when considering a new clinical system and when using more than one system for data transfer.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Importance Given that mycosis fungoides−cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT ( P &lt; .001 vs cycle 1 hypericin) and to 49% after 3 cycles ( P &lt; .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration ClinicalTrials.gov Identifier: NCT02448381