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Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD).The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment.We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI).Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (β-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory.iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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U87/Centrin2-EGFP/H2B-mCherry/puro cells were seeded on dishes with cover slip bottoms, treated with AZ32 (3 uM), and irradiated (5 Gy). Time-lapse videos were recorded intermittently (every 7 min) over 16 hrs. Treatment results in 11% aberrant mitoses (see Fig. 3F).

U87/shp53/Centrin2-EGFP/H2B-mCherry/shp53 cells were seeded on dishes with cover slip bottoms and irradiated (5 Gy). Time-lapse videos were recorded intermittently (every 7 min) over 16 hrs. Treatment results in 12% aberrant mitoses (see Fig. 3F).

U87/Centrin2-EGFP/H2B-mCherry/puro cells were seeded on dishes with cover slip bottoms and irradiated (5 Gy). Time-lapse videos were recorded intermittently (every 7 min) over 16 hrs. Treatment results in 2.7% aberrant mitoses (see Fig. 3F).

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro. AZ32, with enhanced blood–brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses. Mol Cancer Ther; 17(8); 1637–47. ©2018 AACR.

Percent change in E-cadherin expression after treatment.

Purpose: Pregnancy increases breast cancer risk for all women for at least 5 years after parturition. During weaning and involution, the breast microenvironment becomes tumor promotional. Exosomes provide cell–cell communication during physiologic processes such as lactation, but also in breast cancer. We determined whether molecules in milk exosomes from healthy lactating women modulate the development and progression of breast cancer.Experimental Design: Thirteen nursing women provided three (transitional, mature, and wean) milk samples. Exosomes were extracted and MCF7 and MCF10A breast cells labeled. The expression of six proteins linked to breast cancer was measured. On the basis of the findings, TGFβ2 concentration in exosome samples was measured, breast cells incubated with the exosomes and effect (epithelial–mesenchymal transition, EMT) on EMT-related proteins [E-cadherin, α-smooth muscle actin (α-SMA), filamentous (F)-actin and vimentin] measured.Results: Human milk exosomes entered benign and malignant breast cells. The greatest change in wean milk protein was in TGFβ2 (P = 0.01). Exosomes with a high (but not low) level of TGFβ2 led to EMT in both cancer and benign cells, based on (i) change in cell morphology, actin cytoskeleton, and loss of cell–cell junction structure and (ii) increased α-SMA and vimentin and decreased E-cadherin.Conclusions: TGFβ2 is significantly upregulated in breast milk exosomes during weaning/early involution. Breast milk exosomes containing high levels of TGFβ2 induce changes in both benign and malignant breast epithelial cells, consistent with the development and progression of breast cancer, suggesting a role for high TGFβ2-expressing breast milk exosomes in influencing breast cancer risk. Clin Cancer Res; 22(17); 4517–24. ©2016 AACR.

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Purpose: In this study, the relation between radiation pneumonitis (RP) and a wide spectrum of clinical, radiographic and treatment-related factors was investigated. As scoring of low-grade RP can be subjective, RP grade ≥3 (RP ≥ G3) was chosen as a more objective and clinically significant endpoint for this study. Methods and Materials: 105 consecutive patients with locally advanced non-small cell lung cancer underwent conventionally fractionated radio-(chemo-)therapy to a median dose of 64 Gy. A retrospective analysis of 25 clinical (gender, race, pulmonary function, diabetes, statin use, smoking history), radiographic (emphysema, interstitial lung disease) and radiotherapy dose- and technique-related factors was performed to identify predictors of RP ≥ G3. Following testing of all variables for statistical association with RP using univariate analysis (UVA), a forward selection algorithm was implemented for building a multivariate predictive model (MVA) with limited sample size. Results: Median follow-up of surviving patients was 33 months (9–132 months). RP ≥ G3 was diagnosed in 10/105 (9·5%) patients. Median survival was 28·5 months. On UVA, predictors for RP ≥ G3 were diabetes, lower lobe location, planning target volume, volumetric modulated arc therapy (VMAT), lung V5 Gy (%), lung Vspared5 Gy (mL), lung V20 Gy (%) and heart V5 Gy (% and mL). On MVA, VMAT was the only significant predictor for RP ≥ G3 (p = 0·042). Lung V5 Gy and lung V20 Gy were borderline significant for RP ≥ G3. Patients with RP ≥ 3 had a median survival of 10 months compared to 29·5 months with RP < G3 (p = 0·02). Conclusions: In this study, VMAT was the only factor that was significantly correlated with RP ≥ G3. Avoiding RP ≥ G3 is important as a toxicity per se and as a risk factor for poor survival. To reduce RP, caution needs to be taken to reduce low-dose lung volumes in addition to other well-established dose constraints.

PURPOSE Clinical trials determine safety and efficacy of cancer therapeutics and establish standards of care. Minority patient participation in cancer clinical trials is dismal. We aimed to determine the impact of eligibility criteria on disparities in pancreatic ductal adenocarcinoma (PDAC) clinical trial candidacy. METHODS Traditional PDAC trial eligibility criteria were obtained from ClinicalTrials.gov. Patients with PDAC who sought care at Virginia Commonwealth University Health from 2010 to 2019 were included. Clinical data were obtained from billing codes and discrete values in the electronic medical record. Eligibility criteria differences between racial groups were determined using chi-squared tests and unconditional maximum likelihood-based odds ratios. RESULTS Among 676 patients, most identified as Black or White race (42.5% and 51.6%, respectively). Using traditional criteria, Black patients were more likely to be ineligible for participation compared with White patients (42.4% v 33.2%, P = .023) secondary to hypoalbuminemia (14.1% v 7.9%, P = .023), HIV (3.1% v 0.3%, P = .010), hepatitis B (1.7% v 0%, P = .043), and hepatitis C (9.1% v 3.4%, P = .005). Black patients were also numerically more likely to be ineligible because of renal dysfunction, recent coronary stenting, and uncontrolled diabetes mellitus. Prior cancer treatment excluded fewer Black than White patients (9.1% v 14.0%, P = .072), most attributable to lower rates of neoadjuvant chemotherapy received. Strategic eligibility criteria revisions could equalize ineligibility rates between Black and White patients (26.8% v 24.8%, P = .581). CONCLUSION Traditional eligibility criteria differentially exclude Black patients from participating in PDAC clinical trials. These criteria perpetuate disparities, limit generalizability, and are often not medically justifiable. Revised criteria may improve participant diversity, without compromising safety or study results.

The benefit of radiation therapy (RT) becomes uncertain in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab, positron emission topography (PET), and computed tomography (CT). We sought to retrospectively review modern patients with early stage I-II DLBCL treated with rituximab and staged by PET-CT to better define which patients benefit from consolidative RT.Patients with early stage I-II DLBCL from 1998 to 2017 were reviewed coinciding with our institutional utilization of rituximab with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and PET-CT. Relevant clinical information was used to calculate National Comprehensive Cancer Network international prognostic index (IPI) scores. Kaplan-Meier survival analysis and a Cox proportional hazards model were used for overall survival (OS).Seventy-seven patients received chemoimmunotherapy alone, and 41 received chemoimmunotherapy plus RT. Median follow-up time was 9.5 years. On univariate analysis, extranodal disease (The current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit on multivariate analysis. Further prospective randomized data are needed to confirm these findings.

e24079 Background: Fatigue is common in patients undergoing radiotherapy (RT). Melatonin, an inexpensive natural supplement, may improve symptoms and attenuate the side effects of RT. The effect of melatonin for prevention of fatigue and other symptoms was evaluated in a double-blind placebo-controlled trial. Methods: Early-stage or ductal carcinoma in-situ breast cancer patients ≥ 18 years, female, Eastern Cooperative Oncology Group performance status (ECOG PS) < 3, hemoglobin ≥9 g/dL. RT with curative intent, randomized 1:1 to melatonin 20 mg or oral placebo, starting night before RT initiation until 2 weeks post-RT. Sample size of 142 evaluable patients in each arm for 80% power and interim analysis at mid recruitment using the unified family method rho = 0.3. Randomization stratified to RT duration (< 3 weeks, ≥3 weeks) and prior chemotherapy. Primary outcome : Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale after completion of RT with additional scores measured at baseline, 2 and 8 weeks post-RT. Secondary outcomes : FACIT-F subscales, Edmonton Symptom Assessment System (ESAS) and Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue-Short Form 8a. Secondary analyses reported using an F-test at a 5% significance level. Results: For this interim analysis, 85 patients screened; 80 randomized; 39 received melatonin and 38 placebo. 72 included in the analysis as 5 patients had no post baseline FACIT score. Characteristics of age, race, and ECOG PS similar in both arms. Treatment X time for FACIT-Fatigue not significant for melatonin compared to placebo (p .83). FACIT physical, emotional, and functional well-being scores not significantly different (p .35, .62, and .71) but showing a trend for social well-being (p .06). PROMIS scores not changed over time (p .34). ESAS individual symptoms of anxiety, well-being, drowsiness, poor appetite, nausea, pain, shortness of breath, sleep and tiredness not significant, except for depression (p.04). However, a decrease of 0.01 unit in depression score is not considered clinically significant. No grade 3 or 4 adverse events. No participants died during study, 2 died after study completion from breast cancer recurrence. 16 withdrew prior to study completion because of adverse events, unrelated hospitalizations, RT discontinuation, and COVID-19 precautions. Trial was stopped based on statistical analysis demonstrating no difference for primary outcome and imminent expiry of available drug. Discontinuation was approved by Data Safety Monitoring Committee. Conclusions: Melatonin did not prevent fatigue in patients with early stage breast cancer undergoing RT. Melatonin also demonstrated no benefit for other symptoms, except depression. Analysis showed little evidence of an effect, and the trial was terminated early. Clinical trial information: NCT02332928.

Introduction: Clinical trials determine efficacy and safety of cancer therapeutics and set the standard of care. Inequitable representation of participants leaves gaps in our knowledge, limits opportunities to investigational therapeutics and subsequently perpetuates disparities in survivorship. Clinical trial eligibility criteria have been postulated to differentially impact certain racial/ethnic groups which have higher prevalence of infectious and chronic diseases. We aimed to determine the impact of eligibility criteria on disparities in pancreatic cancer clinical trial candidacy. Methods: Common eligibility criteria for Phase 2 and 3 pancreatic cancer trials listed in clinicaltrials.gov were compiled for simulation of a clinical trial screening process. Patients with pancreatic ductal adenocarcinoma who sought care at VCU Massey Cancer Center (Richmond, VA) from 2010-2019 were included. Clinical variables pertaining to eligibility criteria were obtained from billing codes and discrete values in the medical record. Inclusion/exclusion criteria were applied to determine overall eligibility and for individual criterion. Chi-squared tests were utilized to identify statistically significant differences in patient eligibility between racial groups. Results: A total of 676 patients with pancreatic cancer were identified, with Black (42%) and White (52%) patients comprising the majority of the patient population. Black patients were significantly more likely than White patients to be deemed ineligible based on Creatinine (6.08% vs 2.27%, p = 0.036), HIV (3.136% vs 0.286%, p = 0.01), Hepatitis B (1.742% vs 0%, p = 0.043), and Hepatitis C (9.06 vs 3.43%, p = 0.005). Black patients were also more likely to be ineligible based on Albumin (12.45% vs 7.47%, p = 0.076), history of coronary stenting in the past 6 months (1.39% vs 0%, p = 0.087), and uncontrolled diabetes (8.96% vs 6.07%, p = 0.244), although differences in these criteria did not achieve statistical significance at 5% level. History of prior cancer treatment was the only variable that excluded less Black patients than White patients (9.06% vs 14.0%, p = 0.072) and was attributable to more White patients initiating neoadjuvant chemotherapy for their pancreatic cancer prior to seeking care at VCU. After applying all criteria, Black patients were more likely to be ineligible for participation compared to White patients (42.0% vs 33.3%, p = 0.039). Conclusion: Standard pancreatic cancer clinical trial eligibility criteria differentially exclude Black patients from participating in clinical trials. These criteria perpetuate racial disparities, limit generalizability to real world clinical scenarios, and are often not medically justifiable. Alternative eligibility criteria can improve representation of diverse participants, provide more equitable access to investigational therapeutics and reduce disparities in survivorship, without compromising patient safety or study results. Citation Format: Andrea N. Riner, Selamawit Girma, Nevena Skoro, Tamas S. Gal, Kelly M. Herremans, Nitai Mukhopadhyay, Vignesh Vudatha, Shreya Raman, Thomas George, Jose G. Trevino. Eligibility criteria perpetuate disparities in enrollment and participation in pancreatic cancer clinical trials [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-09.

BACKGROUND Although Web-based questionnaires are an efficient, increasingly popular mode of data collection, their utility is often challenged by high participant dropout. Researchers can gain insight into potential causes of high participant dropout by analyzing the dropout patterns. OBJECTIVE This study proposed the application of and assessed the use of user-specified and existing hypothesis testing methods in a novel setting—survey dropout data—to identify phases of higher or lower survey dropout. METHODS First, we proposed the application of user-specified thresholds to identify abrupt differences in the dropout rate. Second, we proposed the application of 2 existing hypothesis testing methods to detect significant differences in participant dropout. We assessed these methods through a simulation study and through application to a case study, featuring a questionnaire addressing decision-making surrounding cancer screening. RESULTS The user-specified method set to a low threshold performed best at accurately detecting phases of high attrition in both the simulation study and test case application, although all proposed methods were too sensitive. CONCLUSIONS The user-specified method set to a low threshold correctly identified the attrition phases. Hypothesis testing methods, although sensitive at times, were unable to accurately identify the attrition phases. These results strengthen the case for further development of and research surrounding the science of attrition.