Hypofractionated Stereotactic Radiation Therapy Dosimetric Tolerances for the Inferior Aspect of the Brachial Plexus: A Systematic Review.

We sought to systematically review and summarize dosimetric factors associated with radiation-induced brachial plexopathy (RIBP) after stereotactic body radiation therapy (SBRT) or hypofractionated image guided radiation therapy (HIGRT). From published studies identified from searches of PubMed and Embase databases, data quantifying risks of RIBP after 1- to 10-fraction SBRT/HIGRT were extracted and summarized. Published studies have reported <10% risks of RIBP with maximum doses (Dmax) to the inferior aspect of the brachial plexus of 32 Gy in 5 fractions and 25 Gy in 3 fractions. For 10-fraction HIGRT, risks of RIBP appear to be low with Dmax < 40 to 50 Gy. For a given dose value, greater risks are anticipated with point volume-based metrics (ie, D0.03-0.035cc: minimum dose to hottest 0.03-0.035 cc) versus Dmax. With SBRT/HIGRT, there were insufficient published data to predict risks of RIBP relative to brachial plexus dose-volume exposure. Minimizing maximum doses and possibly volume exposure of the brachial plexus can reduce risks of RIBP after SBRT/HIGRT. Further study is needed to better understand the effect of volume exposure on the brachial plexus and whether there are location-specific susceptibilities along or within the brachial plexus structure.

Radiation-induced inferior brachial plexopathy after stereotactic body radiotherapy: Pooled analyses of risks.

INTRODUCTION: Radiation-induced brachial plexopathy (RIBP), resulting in symptomatic motor or sensory deficits of the upper extremity, is a risk after exposure of the brachial plexus to therapeutic doses of radiation. We sought to model dosimetric factors associated with risks of RIBP after stereotactic body radiotherapy (SBRT). METHODS: From a prior systematic review, 4 studies were identified that included individual patient data amenable to normal tissue complication probability (NTCP) modelling after SBRT for apical lung tumors. Two probit NTCP models were derived: one from 4 studies (including 221 patients with 229 targets and 18 events); and another from 3 studies (including 185 patients with 192 targets and 11 events) that similarly contoured the brachial plexus. RESULTS: NTCP models suggest ≈10% risks associated with brachial plexus maximum dose (Dmax) of ∼32-34 Gy in 3 fractions and ∼40-43 Gy in 5 fractions. RIBP risks increase with increasing brachial plexus Dmax. Compared to previously published data from conventionally-fractionated or moderately-hypofractionated radiotherapy for breast, lung and head and neck cancers (which tend to utilize radiation fields that circumferentially irradiate the brachial plexus), SBRT (characterized by steep dose gradients outside of the target volume) exhibits a much less steep dose-response with brachial plexus Dmax > 90-100 Gy in 2-Gy equivalents. CONCLUSIONS: A dose-response for risk of RIBP after SBRT is observed relative to brachial plexus Dmax. Comparisons to data from less conformal radiotherapy suggests potential dose-volume dependences of RIBP risks, though published data were not amenable to NTCP modelling of dose-volume measures associated with RIBP after SBRT.

Patient Perceptions of Sexual Orientation and Gender Identity Data Collection in an Outpatient Radiation Oncology Setting.

PURPOSE: Sexual and gender minority patients with cancer experience significant health disparities requiring tailored care. Collecting sexual orientation and gender identity (SOGI) data in the electronic medical record (EMR) could allow care to be tailored and is in line with radiation oncology's mission to better serve diverse patients. This article describes a systematic method for collecting SOGI data for all patients starting radiation treatment in a department of radiation oncology (DRO). METHODS AND MATERIALS: During a 3-month experimental period, DRO staff administered a demographic questionnaire and attitude survey to new adult patients. SOGI demographic data, entered into the EMR by nursing staff, were extracted and analyzed for all patients from the experimental period and from the 3 months prior (control period). Descriptive and categorical data completion rates were compared between the experimental and control periods using independent-samples t tests and Pearson χ2 tests. RESULTS: A total of 788 patients were included in this analysis: 368 in the control period and 420 in the experimental period. Of the 420 patients enrolled in the experimental period, 267 (63.6%) were offered a survey, of whom 211 (79.0%) completed the survey. There were higher rates of sexual orientation responses entered into the EMR for the experimental group compared with the control group (56.9% vs 27.1%; P <.001), with the highest response rates for patients who completed a survey (82.9%). Ten patients (2.9%) identified as gay or lesbian and 100% identified as cisgender. The majority of patients were not upset by the form, with only 11 patients (5.2%) stating that any specific question caused them distress. CONCLUSIONS: Collecting SOGI data via a demographic form is feasible in an outpatient DRO. This approach was well received by the majority of patients and could lead to provision of higher-quality, tailored care.

Sexual and gender minority cultural humility training for oncology settings: An example of iterative adaptation and implementation.

Background: Multiple national organizations recommend that cancer care providers and oncology practices be responsive to the needs of sexual and gender minority (SGM) patients. Oncology practices have attempted to incorporate this recommendation through SGM-focused cultural humility training interventions. It is unclear how best to adapt and implement such training across practices. This manuscript outlines one process for adapting a widely-used SGM training from The Fenway Institute to the context of oncology settings using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) model. Methods: We conducted training sessions in two oncology care settings: a breast oncology center and a radiation oncology department. Subsequently, we conducted in-depth interviews with the three trainers involved in adapting The Fenway Institute's training to these two practices. Two independent investigators coded the interviews using components of the FRAME model as an analytic guide. Results: Training team members described the mechanisms by which FRAME adaption occurred both proactively and reactively; the importance of involving SGM-identified trainers of diverse backgrounds as well as champions from within oncology practices in which trainings were conducted; the importance of adapting both the context and content of training to be relevant to oncology audiences; and the ways in which fidelity to the core principles of improving health care for SGM patients was maintained throughout the process. Discussion: SGM cultural humility training for oncology providers and staff must undergo iterative adaptation to address the political and social context of specific practice environments and advocate for broader institutional culture change to achieve responsiveness to SGM health needs.

Risk of adverse pathological features for intermediate risk prostate cancer: Clinical implications for definitive radiation therapy.

BACKGROUND: Intermediate risk prostate cancer represents a largely heterogeneous group with diverse disease extent. We sought to establish rates of adverse pathological features important for radiation planning by analyzing surgical specimens from men with intermediate risk prostate cancer who underwent immediate radical prostatectomy, and to define clinical pathologic features that may predict adverse outcomes. MATERIALS AND METHODS: A total of 1552 men diagnosed with intermediate risk prostate cancer who underwent immediate radical prostatectomy between 1/1/2005 and 12/31/2015 were reviewed. Inclusion criteria included available preoperative PSA level, pathology reports of transrectal ultrasound-guided prostate biopsy, and radical prostatectomy. Incidences of various pathological adverse features were evaluated. Patient characteristics and clinical disease features were analyzed for their predictive values. RESULTS: Fifty percent of men with high risk features (defined as PSA >10 but <20 or biopsy primary Gleason pattern of 4) had pathological upstage to T3 or higher disease. The incidence of upgrade to Gleason score of 8 or higher and the incidence of lymph node positive disease was low. Biopsy primary Gleason pattern of 4, and PSA greater than 10 but less than 20, affected adverse pathology in addition to age and percent positive biopsy cores. Older age and increased percentage of positive cores were significant risk factors of adverse pathology. CONCLUSION: Our findings underscore the importance of comprehensive staging beyond PSA level, prostate biopsy, and CT/bone scan for men with intermediate risk prostate cancer proceeding with radiation in the era of highly conformal treatment.

Survival of Patients With Second Primary Hodgkin Lymphoma.

INTRODUCTION: The increased risk for second malignancies after Hodgkin lymphoma (HL) diagnosis is well known. However, to our knowledge, no study has investigated the outcomes of patients diagnosed with HL after an antecedent malignancy (HL-2). We aimed to investigate overall survival (OS), disease-specific survival (DSS), and correlates of survival in HL-2 using the Surveillance, Epidemiology and End Results (SEER) database. PATIENTS AND METHODS: HL-2 patients (n = 821) identified from the 2000-2014 SEER-18 registries were compared to first primary HL patients (HL-1, n = 31,355) from the same registries. Multivariable, propensity score-matched (PSM), and competing risks regression analyses were conducted to assess the effect of antecedent malignancy on survival. RESULTS: Hematologic (n = 309, 37.6%), prostate (n = 169, 20.6%), and breast (n = 76, 9.3%) malignancies were common antecedent malignancies in HL-2. Median latency between antecedent malignancy and HL diagnosis was 39 months. Median ages at HL diagnosis for HL-1 and HL-2 were 36 and 66 years, respectively (P < .001). The 5-year OS and HL-DSS rates for HL-2 versus HL-1 were 53.2% versus 82.7% and 79.1% versus 90.9%, respectively (P < .001). On multivariable analysis, antecedent malignancy was associated with decreased OS (hazard ratio [HR] = 1.27; 95% confidence interval [CI], 1.13-1.42; P < .001). With PSM balancing across covariables, antecedent malignancy was associated with decrements in HL-DSS (HR = 1.46; 95% CI, 1.12-1.92; P = .006) and OS (HR = 2.09; 95% CI, 1.74-2.51; P < .001). CONCLUSION: The decrement in DSS in HL-2 relative to HL-1 may be related to biological differences in HL, age, and/or other unanalyzed factors. Further study of HL-2 patients is warranted.

Slow conformational changes in MutS and DNA direct ordered transitions between mismatch search, recognition and signaling of DNA repair.

MutS functions in mismatch repair (MMR) to scan DNA for errors, identify a target site and trigger subsequent events in the pathway leading to error removal and DNA re-synthesis. These actions, enabled by the ATPase activity of MutS, are now beginning to be analyzed from the perspective of the protein itself. This study provides the first ensemble transient kinetic data on MutS conformational dynamics as it works with DNA and ATP in MMR. Using a combination of fluorescence probes (on Thermus aquaticus MutS and DNA) and signals (intensity, anisotropy and resonance energy transfer), we have monitored the timing of key conformational changes in MutS that are coupled to mismatch binding and recognition, ATP binding and hydrolysis, as well as sliding clamp formation and signaling of repair. Significant findings include (a) a slow step that follows weak initial interaction between MutS and DNA, in which concerted conformational changes in both macromolecules control mismatch recognition, and (b) rapid, binary switching of MutS conformations that is concerted with ATP binding and hydrolysis and (c) is stalled after mismatch recognition to control formation of the ATP-bound MutS sliding clamp. These rate-limiting pre- and post-mismatch recognition events outline the mechanism of action of MutS on DNA during initiation of MMR.

Selectivity and potency of the retroprogesterone dydrogesterone in vitro.

Dydrogesterone is widely used for menstrual disorders, endometriosis, threatened and habitual abortion and postmenopausal hormone replacement therapy. Although progestins have a promiscuous nature, dydrogesterone does not have clinically relevant androgenic, estrogenic, glucocorticoid or mineralocorticoid activities. To date, systematic biochemical characterization of this progestin and its active main metabolite, 20α-dihydrodydrogesterone, has not been performed in comparison to progesterone. The objective of this study was to evaluate the selectivity and potential androgenic/antiandrogenic effects of dydrogesterone and its metabolite in comparison to progesterone and medroxyprogesterone acetate by analyzing their interference with AR signaling in vitro. We characterized dydrogesterone and its metabolite for their binding and transactivation of androgen and other steroid hormone receptors and for their potential inhibitory effects against androgen biosynthetic enzymes, 17ß-hydroxysteroid dehydrogenase types 3 and 5 and 5α-reductase types 1 and 2. We found that dydrogesterone resembled progesterone mainly in its progestogenic effects and less in its androgenic, anti-androgenic, glucocorticoid and antiglucocorticoid effects; whereas, 20α-dihydrodydrogesterone showed reduced progestogenic potency with no androgenic, glucocorticoid and mineralocorticoid effects. Effects on the androgen and glucocorticoid receptor differed depending on the technology used to investigate transactivation. Progesterone, but not dydrogesterone and 20α-dihydrodydrogesterone, exerted anti-androgenic effects at the pre-receptor level by inhibiting 5α-reductase type 2. Dydrogesterone, 20α-dihydrodydrogesterone and progesterone inhibited the biosynthesis of testosterone catalyzed by 17ß-hydroxysteroid dehydrogenase types 3 and 5; however, due to their micromolar K(i) values, these activities appeared to be not of relevance at therapeutic levels. Overall, our data show that the anti-androgenic potential of dydrogesterone and 20α-dihydrodydrogesterone is less pronounced compared to progesterone.

Application of stopped-flow kinetics methods to investigate the mechanism of action of a DNA repair protein.

Transient kinetic analysis is indispensable for understanding the workings of biological macromolecules, since this approach yields mechanistic information including active site concentrations and intrinsic rate constants that govern macromolecular function. In case of enzymes, for example, transient or pre-steady state measurements identify and characterize individual events in the reaction pathway, whereas steady state measurements only yield overall catalytic efficiency and specificity. Individual events such as protein-protein or protein-ligand interactions and rate-limiting conformational changes often occur in the millisecond timescale, and can be measured directly by stopped-flow and chemical-quench flow methods. Given an optical signal such as fluorescence, stopped-flow serves as a powerful and accessible tool for monitoring reaction progress from substrate binding to product release and catalytic turnover(1,2). Here, we report application of stopped-flow kinetics to probe the mechanism of action of Msh2-Msh6, a eukaryotic DNA repair protein that recognizes base-pair mismatches and insertion/deletion loops in DNA and signals mismatch repair (MMR)(3-5). In doing so, Msh2-Msh6 increases the accuracy of DNA replication by three orders of magnitude (error frequency decreases from approximately 10(-6) to 10(-9) bases), and thus helps preserve genomic integrity. Not surprisingly, defective human Msh2-Msh6 function is associated with hereditary non-polyposis colon cancer and other sporadic cancers(6-8). In order to understand the mechanism of action of this critical DNA metabolic protein, we are probing the dynamics of Msh2-Msh6 interaction with mismatched DNA as well as the ATPase activity that fuels its actions in MMR. DNA binding is measured by rapidly mixing Msh2-Msh6 with DNA containing a 2-aminopurine (2-Ap) fluorophore adjacent to a G:T mismatch and monitoring the resulting increase in 2-aminopurine fluorescence in real time. DNA dissociation is measured by mixing pre-formed Msh2-Msh6 G:T(2-Ap) mismatch complex with unlabeled trap DNA and monitoring decrease in fluorescence over time(9). Pre-steady state ATPase kinetics are measured by the change in fluorescence of 7-diethylamino-3-((((2-maleimidyl)ethyl)amino)carbonyl) coumarin)-labeled Phosphate Binding Protein (MDCC-PBP) on binding phosphate (Pi) released by Msh2-Msh6 following ATP hydrolysis(9,10). The data reveal rapid binding of Msh2-Msh6 to a G:T mismatch and formation of a long-lived Msh2-Msh6 G:T complex, which in turn results in suppression of ATP hydrolysis and stabilization of the protein in an ATP-bound form. The reaction kinetics provide clear support for the hypothesis that ATP-bound Msh2-Msh6 signals DNA repair on binding a mismatched base pair in the double helix. F