Abstract: Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

Abstract: Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10 −8 ). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10 −2 ). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog ( MRAS ) gene (beta = −0.51, P = 2.43 × 10 −5 ). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

Abstract: Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Abstract: Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and Methods Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). Results Eighty-one patients were included. Seventy-two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. Conclusion In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.

Abstract: Background: Relapsed or refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. Recently checkpoint blockade therapy (CBT) has shown striking activity in this setting, but the complete response (CR) rate is modest. Patients who relapse after CBT have limited therapeutic options. A prior, retrospective study showed that after anti-PD-1 therapy the objective response rate to chemotherapy alone was 61% (Rossi et al 2017). We investigated the effect of treatment subsequent to CBT in a large international multicenter retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify HL patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of this analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD), preparation for stem cell transplant (SCT), or toxicity. Patients who discontinued CBT due to CR, and patients whose best response could not be determined due to death from another cause were excluded from analysis. Responses were assessed using Lugano criteria. Survival status was analyzed for the entire study population and stratified by post-CBT treatment regimen and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) was calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P 〈 0.05 was considered to be statistically significant. Results: To date, out of 121 total lymphoma patients, a total of 77 HL patients received a subsequent line of therapy after CBT. Their median age was 37 (range 23-74); there were 38 men and 39 women. Fifty of these patients met inclusion criteria. Of the included patients, 15 were stages 1-2 and 35 were stages 3-4. These patients were heavily pre-treated with a median of 4 prior therapies before CBT (range 1-10). Thirty-one patients received prior brentuximab vedotin (BV) and 28 patients had undergone allogeneic (3) or autologous (25) SCT. The median duration of response (DOR) to the line of therapy prior to CBT was 3.5 months; 18 (36%) patients had relapsed disease, and the remaining 32 (64%) had refractory disease prior to CBT. The best response to CBT included: 2 (4%) CR, 21 (42%) partial response (PR), 13 (26%) SD, 14 (28%) PD. Patients discontinued CBT due to PD (72%), preparation for transplant (16%), toxicity (8%), CR after the addition of chemotherapy (2%), and an infectious complication (2%). Post-CBT treatment regimens included standard chemotherapy (46%), targeted therapy (22%), conditioning regimens for SCT (16%), other immunotherapy (4%), or clinical trial drugs (12%). The objective response rate (ORR) for all patients to post-CBT treatment was 52%: 17 (34%) CR and 9 (18%) PR. Eight (16%) patients achieved SD, while 16 (32%) patients progressed. Overall response rate to post-CBT treatment correlated with response to CBT itself. Among patients with a CR or PR to CBT, their ORR to post-CBT treatment was 70%, whereas for non-responders to CBT the ORR to post-CBT treatment was 37%. At a median time of follow-up of 14 months, the median PFS for patients who achieved a CR, PR, or SD to post-CBT treatment (n=34) is 10.7 months (Figure 1). Twenty (58.8%) of these patients have not yet progressed, and the OS has not been reached (Figure 2), as 85% of patients remain alive. Currently there is no statistical difference in survival based upon post-CBT treatment received (Figure 3, Table 1). However, of note 21 patients received SCT subsequent to their post-CBT treatment: 8 allo and 13 auto. All of these patients remain alive, however, 9 of 12 (75%) have progressed post SCT. Conclusions: In a heavily pretreated R/R HL population, treatment with CBT may sensitize patients to subsequent therapy, even after they progress on CBT. A response to CBT appears to correlate with response to post-CBT treatment, but PD to CBT did not preclude a response to subsequent therapy. Patient survival does not appear to be dependent upon the subsequent treatment regimen, although the majority of patients with at least stable disease went on to SCT. The long PFS in these patients is encouraging and may warrant further investigation. We plan to expand this analysis with additional patients prior to the December meeting. Disclosures Advani: Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Janssen: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Agensys: Research Funding; Infinity: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Herrera:AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Inc.: Consultancy, Research Funding; Gilead Sciences: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding; KiTE Pharma: Consultancy, Research Funding. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding; Genentech Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau. Ramchandren:Janssen: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding. Assouline:BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wagner-Johnston:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Novartis: Research Funding. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Persky:Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Genentech: Honoraria; Merck: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. Diefenbach:Trillium: Research Funding; Denovo: Research Funding; Millenium/Takeda: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy.

Abstract: Most stars generate winds and move through the interstellar medium that surrounds them. This movement creates a cocoon formed by the deflection of these winds that envelops and protects the stars. We call these “cocoons” astrospheres. The Sun has its own cocoon, the heliosphere. The heliosphere is an immense shield that protects the Solar System from harsh, galactic radiation. The radiation that enters the heliosphere affects life on Earth as well as human space exploration. Galactic cosmic rays are the dominant source of radiation and principal hazard affecting space missions within our Solar System. Current global heliosphere models do not successfully predict the radiation environment at all locations or under different solar conditions. To understand the heliosphere’s shielding properties, we need to understand its structure and large-scale dynamics. A fortunate confluence of missions has provided the scientific community with a treasury of heliospheric data. However, fundamental features remain unknown. The vision of the Solar wind with Hydrogen Ion charge Exchange and Large-Scale Dynamics (SHIELD) DRIVE Science Center is to understand the nature and structure of the heliosphere. Through four integrated research thrusts leading to the global model, SHIELD will: 1) determine the global nature of the heliosphere ; 2) determine how pickup ions evolve from “cradle to grave” and affect heliospheric processes; 3) establish how the heliosphere interacts with and influences the Local Interstellar Medium (LISM); and 4) establish how cosmic rays are filtered by and transported through the heliosphere. The key deliverable is a comprehensive, self-consistent, global model of the heliosphere that explains data from all relevant in situ and remote observations and predicts the radiation environment. SHIELD will develop a “digital twin” of the heliosphere capable of: (a) predicting how changing solar and LISM conditions affect life on Earth, (b) understanding the radiation environment to support long-duration space travel, and (c) contributing toward finding life elsewhere in the Galaxy. SHIELD also will train the next-generation of heliophysicists, a diverse community fluent in team science and skilled working in highly transdisciplinary collaborative environments.

Abstract: Drawing from examples of career development initiatives implemented by SAGE 2YC Faculty Change Agents, this chapter illustrates the role of career development in supporting the success of all community college students and guides faculty, administrators, and professional societies on how to advance student career development on a variety of scales. Career development as an integral component of community college science courses has major implications for increasing the diversity of science professionals, conveying the importance of science and scientific literacy in career sectors within and outside of the sciences, reducing equity gaps in students’ career development as undergraduates, and facilitating skill‐building necessary for the workforce. We urge community college science faculty and administrators to consider the powerful impact that career skill‐building and career exploration have on students and encourage the adoption of career development activities at the classroom, program, and institutional levels.