Kinetic and Structural Characterization of Trypanosoma cruzi Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferases and Repurposing of Transition-State Analogue Inhibitors.

Over 70 million people are currently at risk of developing Chagas Disease (CD) infection, with more than 8 million people already infected worldwide. Current treatments are limited and innovative therapies are required. Trypanosoma cruzi, the etiological agent of CD, is a purine auxotroph that relies on phosphoribosyltransferases to salvage purine bases from their hosts for the formation of purine nucleoside monophosphates. Hypoxanthine-guanine-xanthine phosphoribosyltransferases (HGXPRTs) catalyze the salvage of 6-oxopurines and are promising targets for the treatment of CD. HGXPRTs catalyze the formation of inosine, guanosine, and xanthosine monophosphates from 5-phospho-d-ribose 1-pyrophosphate and the nucleobases hypoxanthine, guanine, and xanthine, respectively. T. cruzi possesses four HG(X)PRT isoforms. We previously reported the kinetic characterization and inhibition of two isoforms, TcHGPRTs, demonstrating their catalytic equivalence. Here, we characterize the two remaining isoforms, revealing nearly identical HGXPRT activities in vitro and identifying for the first time T. cruzi enzymes with XPRT activity, clarifying their previous annotation. TcHGXPRT follows an ordered kinetic mechanism with a postchemistry event as the rate-limiting step(s) of catalysis. Its crystallographic structures reveal implications for catalysis and substrate specificity. A set of transition-state analogue inhibitors (TSAIs) initially developed to target the malarial orthologue were re-evaluated, with the most potent compound binding to TcHGXPRT with nanomolar affinity, validating the repurposing of TSAIs to expedite the discovery of lead compounds against orthologous enzymes. We identified mechanistic and structural features that can be exploited in the optimization of inhibitors effective against TcHGPRT and TcHGXPRT concomitantly, which is an important feature when targeting essential enzymes with overlapping activities.

Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer.

Effective treatments for advanced/recurrent head and neck squamous-cell carcinoma are limited. For cases not curable by conventional local therapies, the immune checkpoint inhibitor pembrolizumab shows modest response rates. Quad-shot, a hypofractionated palliative radiotherapy regimen (14.8 Gy in four twice-daily fractions), can provide symptomatic relief, contributes to local control and may potentiate the effects of immune checkpoint inhibitors. In this study, 15 patients with advanced/recurrent head and neck squamous-cell carcinoma will be treated with pembrolizumab combined with up to three administrations of quad-shot before cycles four, eight and 13. Outcomes include disease response, survival and treatment toxicity. Correlative multiomics analysis of blood and saliva will identify molecular biomarkers of response to immune checkpoint inhibitor and the immune-related impact of quad-shot. Clinical trial registration: This study (WFBCCC 60320) is registered on NCT04454489 (ClinicalTrials.gov).

Advanced and recurrent head and neck cancers are difficult to treat. Most patients receive systemic therapies, such as chemotherapy or immunotherapy, with modest rates of cancer control. We aim to test the effectiveness of an immunotherapy drug called pembrolizumab in combination with a type of low-dose radiation therapy called quad-shot. Patients will receive pembrolizumab every 3 weeks and will be treated with one to three low-dose radiation therapy courses targeted at their cancer in the head and neck approximately every 12 weeks. We plan to measure how well the cancer responds to treatment, how long this response lasts, how long patients survive and treatment side effects.

Survival and Swallowing Function after Primary Radiotherapy versus Transoral Robotic Surgery for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

INTRODUCTION: The aim of this study was to investigate the impact of primary transoral robotic surgery (TORS) versus radiotherapy (RT) on progression-free survival (PFS), overall survival (OS), and 1-year swallowing function for patients with early-stage HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Patients with stage I-II (AJCC 8th Ed.) HPV-associated OPSCC treated with TORS followed by risk-adapted adjuvant therapy or (chemo)radiotherapy between 2014 and 2019 were identified. PFS, OS, and swallowing outcomes including gastrostomy tube (GT) use/dependence, and Functional Oral Intake Scale (FOIS) change over 1 year were compared. RESULTS: One hundred sixty-seven patients were analyzed: 116 treated with TORS with or without adjuvant RT and 51 treated with RT (50 chemoRT). The RT group had more advanced tumor/nodal stage, higher comorbidity, and higher rates of concurrent chemotherapy. There were no differences in 3-year PFS (88% TORS vs. 75% RT) or OS (90% vs. 81%) between groups, which persisted after adjusting for stage, age, and comorbidity. GT use/dependence rates were higher in the RT group. Mean (SD) FOIS scores in the TORS group were 6.9 (0.4) at baseline and 6.4 (1.0) at 1 year, compared with 6.7 (0.6) and 5.6 (1.7) for the RT group. Only clinical nodal stage was found to be significantly associated with FOIS change from baseline to 1 year. CONCLUSION: There were no differences in PFS or OS between patients treated with primary TORS or RT for early-stage HPV-associated OPSCC. Clinical N2 status is associated with FOIS change at 1 year and may be the major factor affecting long-term swallowing function, irrespective of primary treatment modality.

Hypothalamic-Extended Amygdala Circuit Regulates Temporal Discounting.

Choice behavior is characterized by temporal discounting, i.e., preference for immediate rewards given a choice between immediate and delayed rewards. Agouti-related peptide (AgRP)-expressing neurons located in the arcuate nucleus of the hypothalamus (ARC) regulate food intake and energy homeostasis, yet whether AgRP neurons influence choice behavior and temporal discounting is unknown. Here, we demonstrate that motivational state potently modulates temporal discounting. Hungry mice (both male and female) strongly preferred immediate food rewards, yet sated mice were largely indifferent to reward delay. More importantly, selective optogenetic activation of AgRP-expressing neurons or their axon terminals within the posterior bed nucleus of stria terminalis (BNST) produced temporal discounting in sated mice. Furthermore, activation of neuropeptide Y (NPY) type 1 receptors (Y1Rs) within the BNST is sufficient to produce temporal discounting. These results demonstrate a profound influence of hypothalamic signaling on temporal discounting for food rewards and reveal a novel circuit that determine choice behavior.SIGNIFICANCE STATEMENT Temporal discounting is a universal phenomenon found in many species, yet the underlying neurocircuit mechanisms are still poorly understood. Our results revealed a novel neural pathway from agouti-related peptide (AgRP) neurons in the hypothalamus to the bed nucleus of stria terminalis (BNST) that regulates temporal discounting in decision-making.

Timing of radiotherapy and chemotherapy start for patients treated with definitive concurrent chemoradiation for head and neck cancer.

BACKGROUND: The ideal timing for the initiation of chemotherapy and radiation therapy (RT) in the use of definitive chemoradiation (CRT) for patients with head and neck cancer is not well established. We sought to evaluate the impact of the timing of initiating these two modalities on clinical outcomes. MATERIALS AND METHODS: Patients with squamous cell carcinoma of the head and neck who were treated using definitive chemoradiation from 2012 to 2018 were identified. Patients undergoing re-irradiation, post-op CRT, had recurrent or second primaries, or ECOG 3-4 were excluded. Outcomes including locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated and compared between subgroups of the cohort based on the timing in which chemotherapy or RT were initiated: chemotherapy first, same day start, within 24 h, or start on Monday/Tuesday/Wednesday. RESULTS: A total of 131 patients were included for analysis consisting of oropharynx (64%), larynx (22.9%), nasopharynx (6.9%), hypopharynx (3.1%), oral cavity (1.5%), and unknown primary (1.5%). Chemotherapy was administered as bolus cisplatin every 3 weeks in 40% of patients and weekly cisplatin in 60% with a median cumulative dose of 240 mg/m2. In the multivariable analysis (MVA), starting chemotherapy before RT was associated with improved LRC (HR 0.33, 95% CI: 0.11-0.99). Three-year LRC for patients starting chemotherapy first was 90.9% compared to 78.2% in those starting RT first. In the MVA, cisplatin regimen and cumulative cisplatin dose were associated with improved OS, while no factors were significantly associated with DC or PFS. CONCLUSION: Starting chemotherapy prior to radiation therapy improves LRC, but did not impact DC, PFS, or OS. Clinical outcomes were not different when stratifying by the other differences in the timing of initiating chemotherapy or RT.

Stereotactic body radiotherapy for synchronous early stage non-small cell lung cancer.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) who present with multiple pulmonary nodules, it is often difficult to distinguish metastatic disease from synchronous primary lung cancers (SPLC). We sought to evaluate clinical outcomes after stereotactic body radiotherapy (SBRT) alone to synchronous primary lesions. MATERIAL AND METHODS: Patients with synchronous AJCC 8th Edition Stage IA-IIA NSCLC and treated with stereotactic body radiation therapy (SBRT) to all lesions between 2009-2018 were reviewed. SPLC was defined as patients having received two courses of SBRT within 180 days for treatment of separate early stage tumors. In total, 36 patients with 73 lesions were included. Overall survival (OS), progression-free survival (PFS), cumulative incidence of local failure (LF), and regional/distant failure (R/DF) were estimated and compared with a control cohort of solitary early stage NSCLC patients. RESULTS: Median PFS was 38.8 months (95% CI 14.3-not reached [NR]); 3-year PFS rates were 50.6% (35.6-72.1). Median OS was 45.9 months (95% CI: 35.9-NR); 3-year OS was 63.0% (47.4-83.8). Three-year cumulative incidence of LF and R/DF was 6.6% (3.7-13.9) and 35.7% (19.3-52.1), respectively. Patients with SPLC were compared to a control group (n = 272) of patients treated for a solitary early stage NSCLC. There was no statistically significant difference in PFS (p = .91) or OS (p = .43). Evaluation of the patterns of failure showed a trend for worse cumulative incidence of R/DF in SPLC patients as compared to solitary early stage NSCLC (p = .06). CONCLUSION: SBRT alone to multiple lung tumors with SPLC results in comparable PFS, OS, and LF rates to a cohort of patients treated for solitary early stage NSCLC. Those with SPLC had non-significantly higher R/DF. Patients with SPLC should be followed closely for failure and possible salvage therapy.

OleD Loki as a Catalyst for Hydroxamate Glycosylation.

Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Software for designing rigorous and replicable preclinical research: The Experimental Design Accelerator.

In recent years, there have been concerns about research practices in basic and preclinical biomedical research. There have been problems with non-replicable results, and experimental designs lacking internal validity or external or translational validity. The Experimental Design Accelerator (XDA) is Internet-based, interactive software designed to help those trying to design, conduct and document rigorous, replicable and relevant experiments. It leads the investigator step-by-step through a series of decisions that will define the experimental design. It provides background regarding the significance of each decision and the advantages and disadvantages of each possible choice. For example, it leads the researcher to address issues such as choosing a research model, developing testable hypotheses, identifying extraneous variables, dealing with random and systematic error, picking appropriate sample size and picking appropriate statistical analyses. There are also sections to help conduct the experiment consistent with its design and to document the study to facilitate accurate replication. Helpful features include access to an online statistics book and provisions for rapid contact with consulting experts. A number of potential uses for such novel interactive software tools will be discussed.

Surgical resection and postoperative radiosurgery versus staged radiosurgery for large brain metastases.

PURPOSE: The purpose of this study was to retrospectively evaluate the new treatment paradigm of staged stereotactic radiosurgery (SRS) for the treatment of large brain metastases (BM) compared to the standard of surgical resection followed by SRS. METHODS: We evaluated 78 patients with large BM treated 2012-2017 with surgical resection and postoperative SRS (surgery + SRS) or staged SRS separated by 1 month. Overall survival (OS) was estimated using the Kaplan Meier method and compared across groups using the log-rank test. Cumulative incidence of neurologic death and local and distant brain failure (LF, DBF) were estimated using competing risk methodology. RESULTS: Forty patients were treated with surgery + SRS and 38 patients were treated with staged SRS. Median follow-up was 23.2 months (95% CI 20.5-39.3). Median OS was 13.2 months for staged SRS compared to surgery + SRS 9.7 months (p = 0.53). Cumulative incidence of neurologic death at 1 year was 23% after surgery + SRS, 27% after staged SRS (p = 0.69); cumulative incidence of LF at 1 year was 6% and 8% (p = 0.65) and 1-year DBF was 59% and 21% (p ≤ 0.01). Overall rates of leptomeningeal failure and radiation necrosis were similar between the groups (p = 0.63 and p = 1.0). CONCLUSIONS: Though surgery and postoperative SRS is the standard, staged SRS represents an attractive treatment paradigm for treating large BM without sacrificing LC or survival, and potentially decreases DBF. Prospective studies are needed to validate these findings.

Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes?

PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS). A limitation in the application of BMV is it cannot be applied until time of first BM failure after SRS. We developed initial BM velocity (iBMV), a new metric that accounts for the number of BM at first SRS and the time since initial cancer diagnosis. MATERIALS/METHODS: We reviewed patients with BM treated at our institution with upfront SRS without WBRT. iBMV was calculated as the number of BM at initial SRS divided by time (years) from initial cancer diagnosis to first SRS. We performed a linear regression to correlate BMV as a continuous variable and with low, intermediate, and high BMV risk groups. Kaplan-Meier estimation of OS was calculated from time of first SRS to death. iBMV was not calculated for patients who presented with BM at initial cancer diagnosis. RESULTS: 994 patients were treated with upfront SRS without WBRT between 2000 and 2017. Median OS was 8.5 mos. 595 (60%) patients developed BM after cancer diagnosis and median time to first SRS from time of initial diagnosis was 2.2 years. Median iBMV was 0.79 BM/year. iBMV correlated with BMV (ß = 1.57 p = 0.021) and independently predicted for mortality [Cox proportional hazard ratio (HR) 1.11, p = 0.036] after accounting for histology, number of initial brain metastases (HR 1.03, p = 0.32), time from cancer diagnosis to SRS (HR 0.98, p = 0.157) in a multivariate model. CONCLUSION: iBMV correlates with BMV and OS. With further validation, iBMV could serve as a metric to risk stratify patients for WBRT or SRS at time of first BM presentation.

OleD Loki as a Catalyst for Tertiary Amine and Hydroxamate Glycosylation.

We describe the ability of an engineered glycosyltransferase (OleD Loki) to catalyze the N-glycosylation of tertiary-amine-containing drugs and trichostatin hydroxamate glycosyl ester formation. As such, this study highlights the first bacterial model catalyst for tertiary-amine N-glycosylation and further expands the substrate scope and synthetic potential of engineered OleDs. In addition, this work could open the door to the discovery of similar capabilities among other permissive bacterial glycosyltransferases.

Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning.

The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity.

A simple strategy for glycosyltransferase-catalyzed aminosugar nucleotide synthesis.

A set of 2-chloro-4-nitrophenyl glucosamino-/xylosaminosides were synthesized and assessed as potential substrates in the context of glycosyltransferase-catalyzed formation of the corresponding UDP/TDP-α-D-glucosamino-/xylosaminosugars and in single-vessel model transglycosylation reactions. This study highlights a robust platform for aminosugar nucleotide synthesis and reveals OleD Loki to be a proficient catalyst for U/TDP-aminosugar synthesis and utilization

Prognostication methods for patients treated with palliative radiotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Palliative radiotherapy (PRT) practice patterns among radiation oncologists are heterogeneous. Appropriate selection of PRT regimen must balance symptom/disease control with patient quality of life. The aim of this review is to summarize prognostic scoring systems for PRT in order to help guide clinical decision making and selection of appropriate PRT regimens. METHODS: A PubMed search was conducted for articles published between 01/2000 and 07/2023. Standardized search terms including "palliative", "radiotherapy" and "survival" were used. Only English-language, peer-reviewed articles that presented a prognostic scoring system of PRT were included in this review. KEY CONTENT AND FINDINGS: In this study, we review the published literature on prognostic scoring systems for patients treated with PRT. Multiple models have been developed and each pertains to a specific patient population or primary tumor type. While they are specific to a particular patient population, all models incorporate patients' clinical characteristics such as primary site, performance status, location of metastatic disease, and indication for PRT to estimate overall survival (OS) after PRT. For each model, the salient points of the scoring system are described. Based on survival estimates from each prognostic system, different PRT regimens are recommended. CONCLUSIONS: PRT scoring systems can be used to help clinicians assess patient prognosis. With the information provided by the included studies, radiation oncologists will be better prepared to formulate an optimal, individualized treatment plan for patients to be treated with PRT.

Histology-driven hypofractionated radiation therapy schemes for early-stage lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND AND PURPOSE: Histology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). MATERIAL AND METHODS: The least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. RESULTS: A fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1-30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively. CONCLUSION: We presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.

Clinical outcomes of oropharyngeal squamous cell carcinoma stratified by human papillomavirus subtype: A systematic review and meta-analysis.

PURPOSE: We aim to determine if there is a survival difference between patients with oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) 16 versus HPV-non16 subtypes. PATIENT AND METHODS: Databases were queried for full length, peer-reviewed, English language, articles published between 01/01/1980 and 06/08/2022. Studies reporting clinical outcomes of OPSCC associated with HPV16 and HPV-non16 subtypes with at least 10 patients were included. Primary outcome was the overall survival (OS) of patients with HPV16- versus HPV-non16-associated OPSCC. Secondary outcomes were recurrence-free survival (RFS) and pooled rate of p16 positivity by immunohistochemistry (IHC). RESULTS: A total of 9 studies met inclusion criteria and included 1,310 patients with HPV16 and 219 with HPV-non16 subtypes of OPSCC. The prevalence of HPV-non16 was 14.3 %. The pooled 5-year OS rates for patients with HPV16 and HPV-non16 were 83.4 %(95 % CI 77.8-89.0 %) and 69.3 %(95 % CI 58.5-80.1 %), respectively. OS at 5 years was significantly worse for HPV-non16 subtype, compared to HPV16 (log odds ratio [OR] -0.54, p = 0.008). There was a trend towards worse 5-year RFS with HPV-non16 compared to HPV16 (log OR -0.55, p = 0.063). Patients with HPV-non16 disease were less likely to be p16 positive by IHC (log OR -0.91, p = 0.02). CONCLUSION: Patients with HPV-non16OPSCC may experience worse OS and were less likely to be p16 positive compared to patients with HPV16 disease. While future prospective validation is warranted, routine assessment of both p16 IHC and HPV subtype could be considered prior to pursuing treatment de-escalation for HPV-associated OPSCC.

Randomized Pilot Study of a Keratin-based Topical Cream for Radiation Dermatitis in Breast Cancer Patients.

Purpose: Radiotherapy (RT) is commonly used in the treatment of breast cancer and often, despite advances in fractionated dosing schedules, produces undesirable skin toxicity. The purpose of this study was to evaluate the feasibility of using a keratin-based topical cream, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA) to manage the symptoms of radiation dermatitis (RD) in breast cancer patients undergoing RT. Materials and Methods: A total of 24 subjects were enrolled on this single-center, randomized, open-label study. Participants were randomly assigned to KC or standard of care (SOC, patient's choice of a variety of readily available creams or moisturizers). Patients were asked to apply the assigned treatment to the irradiated area twice daily, beginning with day 1 of RT, through 30 days post-RT. The primary outcome was compliance of use. Secondary outcomes included safety and tolerability of KC, as well as RD severity assessed using the Radiation Therapy Oncology Group (RTOG) scale and the patient-reported Dermatology Life Quality Index (DLQI). Results: All subjects in the KC group were assessed as compliant with no adverse events. The rate of RTOG Grade 2 RD was lower in the KC group (30.8%) compared to the SOC group (54.5%, P = .408). At the final RT visit, the mean RTOG RD score was lower in the KC group (1.0) versus the SOC group (1.4). Similarly, patient-reported quality of life measured by the DLQI at the end of RT was improved in the KC group (mean 4.25, small effect) versus the SOC group (mean 6.18, moderate effect, P = .412). Conclusions: KC was safe and well tolerated with no adverse events. Though efficacy measures were not powered to draw definitive conclusions, trends and clinical assessments suggest that there is a benefit of using KC compared to SOC for breast cancer patients treated with RT, and a larger powered study for efficacy is warranted. Trial Registry: This clinical trial is registered as NCT03374995 titled KeraStat(R) Cream for Radiation Dermatitis.

Radiotherapy for Advanced Hodgkin Lymphoma with Initial Bulk: A Combined Analysis of Two Randomized Trials.

Purpose: The role of consolidative radiation therapy (RT) in patients with advanced Hodgkin lymphoma with initial bulk is unclear. GITIL/FIL HD0607 and FIL HD0801, 2 randomized controlled trials with similar design and methodologies, did not identify a benefit to consolidative RT after a metabolic complete response to 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine. However, their limited sample sizes reduced statistical power to detect a small but clinically meaningful benefit to RT. Methods and Materials: In a secondary analysis of these 2 phase 3 trials, reconstructed patient data were used to compare outcomes for early and complete responders randomized to no RT or RT to the site(s) of initial bulk. Estimates of progression-free survival (PFS) in the intent-to-treat (ITT) and per-protocol (PP) analyses were generated using the combined data and compared between groups using the log-rank test. Results: A total of 412 patients were included in the ITT analysis, and 373 patients were included in the PP analysis. Median age was 30 to 32 years, 42% of patients were stage IIB, and 73% of bulky sites were located in the mediastinum. For the no RT versus RT groups, 5-year ITT PFS estimates were 90.1% versus 90.1%, respectively (P = .81). Five-year PP PFS rates were 90.9% versus 92.9%, respectively (P = .31). There was no observed difference between no RT and RT groups in subgroups according to size of bulky disease: 5 to 7 cm (P = .78), 7 to 10 cm (P = .25), and >10 cm (P = .69). Conclusions: In this combined analysis of 2 randomized phase 3 clinical trials, consolidative RT to initial sites of bulky nodal involvement was not associated with a PFS benefit in patients with advanced Hodgkin lymphoma in metabolic complete response after 2 and 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine.