Citations

Abstract Introduction Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study. Methods Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of treatment with Rd ± DARA. R: 25 mg (oral) QD on Days 1-21; d: 40 mg (oral) on Days 1, 8, 15 and 22. In the D-Rd arm, DARA was given at 16 mg/kg (intravenously) QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. In both arms, patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), minimal residual disease (MRD)-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. Results This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients ≥75 years, and 52% were male. Two thirds of patients had ECOG scores ≥1: ECOG score 0, 34%; 1, 50%; ≥2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P <0.0001), representing a 45% reduction in the risk of progression or death in patients treated with D-Rd (Figure). The median PFS for the Rd arm was 31.9 months and not reached for the D-Rd arm. Adding DARA to Rd resulted in deeper responses with a complete response (CR) or better rate of 47.6% in the D-Rd arm compared with 24.7% in the Rd arm (odds ratio [OR] 2.75, 95% CI, 2.01 to 3.76; P <0.0001). The very good partial response (VGPR) or better rate was 79.3% in the D-Rd arm compared with 53.1% in the Rd arm (OR 3.4, 95% CI, 2.45 to 4.72; P <0.0001). A total of 19% of patients have died and the HR for OS was 0.78 (95% CI, 0.56 to 1.1); follow-up is ongoing. Higher rates (5% or more difference) of grade 3/4 pneumonia, neutropenia, and leukopenia were observed in the D-Rd arm. The safety profile is consistent with previously reported DARA studies. The complete topline data set will be presented with additional efficacy endpoints, including MRD negativity rate. Conclusion The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase 3 ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant. Disclosures Facon: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Orlowski:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX: Research Funding; Spectrum Pharma: Research Funding. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hulin:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. O'Dwyer:Janssen: Consultancy. Perrot:Janssen: Consultancy, Equity Ownership, Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Weisel:Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ahmadi:Genmab: Employment, Equity Ownership. Chiu:Janssen Research & Development, LLC: Employment, Equity Ownership. Wang:Janssen Research & Development, LLC: Employment. Van Rampelbergh:Janssen: Employment. Uhlar:Janssen: Employment. Kobos:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral condition and the second most common chronic illness in children. The observance of specific behaviors in multiple settings have remained the most successful method for diagnosing the condition, and although there are differences in specific areas of the brain, and a high heritability estimate (∼76%), they are not diagnostically specific. Medications, and particularly stimulant medication, have undergone rigorous studies to document their efficacy dating back to the 1970s. Likewise, behavioral interventions in the form of parent training and classroom programs have demonstrated robust efficacy during the same time period. Both medication and behavioral interventions are symptomatic treatments. The availability of only symptomatic treatments places ADHD in the same category as other chronic conditions such as diabetes and asthma. Successful treatment of most individuals requires ongoing adherence to the therapy. Improved communication between patients and their families, primary and mental health providers, and school personnel is necessary for effective ADHD treatment. Further enhancement of electronic systems to facilitate family, school, and provider communication can improve monitoring of ADHD symptoms and functional performance. The American Academy of Pediatrics ADHD guidelines were initially developed to help primary care clinicians address the needs of their patients with ADHD and were further refined with the second revision in 2019.

Purpose To pilot test the impact of the ICAN Discussion Aid on clinical encounters. Methods A pre–post study involving 11 clinicians and 100 patients was conducted at two primary care clinics within a single health system in the Midwest. The study examined clinicians’ perceptions about ICAN feasibility, patients’ and clinicians’ perceptions about encounter success, videographic differences in encounter topics, and medication adherence 6 months after an ICAN encounter. Results 39/40 control encounters and 45/60 ICAN encounters yielded usable data. Clinicians reported ICAN use was feasible. In ICAN encounters, patients discussed diet, being active and taking medications more. Clinicians scored themselves poorer regarding visit success than their patients scored them; this effect was more pronounced in ICAN encounters. ICAN did not improve 6-month medication adherence or lengthen visits. Conclusion This pilot study suggests that using ICAN in primary care is feasible, efficient and capable of modifying conversations. With lessons learned in this pilot, we are conducting a randomised trial of ICAN versus usual care in diverse clinical settings. Trial registration number NCT02390570 .

PURPOSE: We aimed to better understand how similarly patients with colorectal cancer and caregivers view care quality and to assess factors that may influence concordance. MATERIALS AND METHODS: We conducted a secondary analysis of paired patient and caregiver quality ratings of colorectal cancer care in three specific domains: surgery, chemotherapy overall, and chemotherapy nursing. Agreement was assessed with difference scores, concordance with Gwet second-order agreement statistics (AC2), and variation in agreement with stratified analyses. We examined whether the care experiences of patients and caregivers were associated with top-box (most-positive) ratings and examined variations in concordance on the basis of the presence of a top-box score. RESULTS: Four hundred seventeen patient-caregiver dyads completed the surveys. Quality-of-care ratings were positively skewed, with most dyads indicating top-box ratings. Patient and caregiver care experiences were highly associated with top-box ratings. Overall patient-caregiver concordance was very high for all three care domains (surgery: AC2, 0.87 [95% CI, 0.83 to 0.90]; chemotherapy overall: AC2, 0.84 [95% CI, 0.79 to 0.88]; chemotherapy nursing: AC2, 0.91 [95% CI, 0.87 to 0.94]). Stratified analyses of patient and caregiver characteristics did not identify any patterns that consistently affected concordance. The concordance statistic significantly decreased for all three outcomes ( P < .001), however, when the patient or caregiver assessed quality as anything other than top box. CONCLUSION: Caregiver and patient reports on care quality were highly concordant for top-box care and did not vary with patient or caregiver factors. Additional exploration is needed to identify reasons for increased variability when the quality scores were less than a top-box response.

Abstract Around fifteen to thirty percent of stage IV breast cancer metastasizes to the brain, severely decreasing the quality of life of these patients by causing neurological decline and eventually death. In metastatic cancers there is a small subset of cells in the primary tumor bulk called Metastatic Tumor Initiating Cells (MTICs) which are able to escape and produce a niche establishment at distal sites where they can quickly become resistant to surgery and radiation. Melatonin has shown an inhibitory role in the viability and invasiveness of breast cancer and in modulating the expression of proteins related to Breast Cancer Stem Cells (BCSCs). These findings suggest its potential anti-metastatic role in different breast cancer cell lines. In this study we aimed to evaluate the effects of melatonin treatment in vitro for breast cancer brain metastasis. The cell line MDA-BT was originally obtained from MDA-MB-231, passed through the rat’s heart and then isolated once engrafted as a tumor in the brain. After a dose response assay, cells were treated with melatonin at doses of 1500 and 3000 µM for 48hrs. Clonogenic assay, MTT, as well as a stem cell signature through RT-qPCR, including CD44, CD24 and ALDH1 markers, were performed to evaluate the malignancy of the MTICs. The results showed that melatonin at high doses impacts morphology, declines viability, reduces colony formation ability, and decreases stemness in MDA-BT cells. Therefore, our findings highlight melatonin as a relevant therapeutic candidate to target breast cancer brain metastases.

Abstract Patients with primary cancers often develop delayed brain metastases. One of the most common cancer types and sources of brain metastasis is lung cancer. For metastasis from lung cancer the 3-year survival is &lt; 5%. Cancer cells in circulation are responsible for metastatic spread. The mechanical microenvironment plays an important role in cancer cells behavior. When cancer cells reach the bloodstream they are exposed to hemodynamic shear stress. It has been shown that most of the circulating tumor cells die once they reach the bloodstream, but the biology of the survival cells is poorly understood. We designed a microfluidics system that simulated the mechanical stress in the human circulating system such as turbulence, change in pressure (0.4-15dyn/cm2) and flow rate (1.06–106.1mm/s). Lung adenocarcinoma cells (A549) were put into circulation and collected after 72 hours. It was found that, 1.4±0.3% of the cells survived, and viability was evaluated by LDH and calcein. CD133, SOX2, and NANOG were downregulated and EMT genes were upregulated in the circulating cancer cells (CCCs) compared with cells in static-suspension or 2D. After re-seeding in 2D, CCCs overexpressed CD133. Female athymic nude rats (6-8weeks,n=16) received intracardiac injections of CCCs or 2D cells (GFP-LUC lentivirus traduced). Bioluminescence imaging was performed every week; the survival in of the CCCs group was lower than the 2D group. One-way ANOVA test was used to analyze survival and gene expression. Survival data was plotted on a Kaplan-Meier curve and compared using the Mantel-Cox logrank test, p=&lt; 0.05. We have isolated a cellular subpopulation of lung adenocarcinoma with high resistance to hemodynamic shear stress that shows a higher metastatic capacity and genetic plasticity compared with cells growing in suspension or 2D. Targeting these cells would potentially allow us to develop personalized treatments to help to stop metastatic spread and improve actual therapeutical strategies.