Citations

The microbiome plays an important role in human health by mediating the path from environmental exposures to health outcomes. The relative abundances of the high‐dimensional microbiome data have an unit‐sum restriction, rendering standard statistical methods in the Euclidean space invalid. To address this problem, we use the isometric log‐ratio transformations of the relative abundances as the mediator variables. To select significant mediators, we consider a closed testing‐based selection procedure with desirable confidence. Simulations are provided to verify the effectiveness of our method. As an illustrative example, we apply the proposed method to study the mediation effects of murine gut microbiome between subtherapeutic antibiotic treatment and body weight gain, and identify Coprobacillus and Adlercreutzia as two significant mediators.

Abstract Background: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%–20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. Methods: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10−8. Results: Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47–6.25; P < 7.8 × 10−9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. Conclusions: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. Impact: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Abstract The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19–infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies were previously shown to have some clinical efficacy, however, long-term outcomes of BPDCN patients remain poor. In a recent clinical trial, SL-401 demonstrated an overall response rate (ORR) of 90% in previously untreated BPDCN patients. Despite promising outcomes observed in SL-401 studies, there remains a lack of data regarding the optimal first-line therapy. In this single institution retrospective study, we explored the survival outcomes based on front-line treatment and allogeneic stem cell transplant (allo-SCT). A total of 49 patients with confirmed diagnosis of BPDCN were included in the study. Median age at diagnosis was 71.4 (32.0-91.4) years with a male predominance (82%). Among these, 11 (22%) patients had concurrent hematologic neoplasms at the time of BPDCN diagnosis. The most common site of disease involvement was skin (n=42, 86%) followed by bone marrow (BM) (n=32, 65%), lymph node (LN) (n=13, 27%), and nasopharynx (n=2, 4%) with 14 (29%) and 5 (10%) patients having skin and BM involvement only, respectively. Of note, 17 (35%) patients had both skin and BM disease and 8 (16%) had simultaneous skin, BM, and LN involvement. In the front-line setting, CHOP-based regimens, hyper-CVAD, and SL-401 were used in 10 (20%), 11 (22%), and 12 (24%) patients, respectively. The median cycle number of SL-401 treatment was 6 (1-73). Allo-SCT was performed in 10 (20%) patients and 4 (8%) patients received autologous stem cell transplant (auto-SCT). Transplant was performed following first-line therapy in 11 patients (CR, n=10; PR, n=1) and second-line therapy in 3 patients (CR, n=3). Among 21 vs. 12 patients who received chemotherapy vs. SL-401 as their first-line therapy, a total of 11 (52%) and 3 (25%) patients underwent transplant. A total of 23 (55%), 13 (31%), and 6 (14%) patients achieved a complete response (CR), partial response (PR), and progressive disease (PD), respectively. CR rate was higher in patients who were treated with hyper-CVAD compared to others, however, it was not statistically significant (50% in CHOP-based regimens vs. 91% in hyper-CVAD, P=0.064; 50% in SL-401 vs. 91% in hyper-CVAD, P=0.069). The median PFS was 9.9 months and the median OS was not reached when all patients were included for the analyses. In the subgroup analyses, patients who were treated with hyper-CVAD had longest PFS compared to patients treated with CHOP-based regimens (HR=0.217, 95%CI=0.050-0.933, P=0.003) or SL-401 (HR=0.385, 95%CI=0.126-1.179, P=0.075) although the PFS difference between hyper-CVAD and SL-401 did not reach the statistical significance. There was no PFS difference between SL-401 and CHOP-based regimen treated groups (HR=0.931, 95%CI=0.321-2.70, P=0.894). In the OS analysis based on first-line therapy, there was no difference between patients treated with SL-401 compared to patients treated with chemotherapy regimens (HR=1.597, 95%CI=0.460-5.548, P=0.431). Further, there was no OS difference between individual types of front-line therapies (P=0.678). In contrast, patients who received allo-SCT showed significantly longer OS outcomes compared to patients with no transplant (HR=0.160, 95%CI=0.0453-0.56, P=0.041). Additional OS analyses based on age (<60 vs. ≥60) (HR=0.481, 95%CI=0.146-1.582, P=0.258), ASXL1 mutation (HR=1.705, 95%CI=0.2773-10.48, P=0.5649), or presence of previous or concurrent hematologic malignancy (HR=2.97, 95%CI=0.65-13.57, P=0.1602) did not show any statistical difference. In a multivariate Cox model (adjusting for age, front-line therapy, gender, and transplant) allo-SCT was significant factor for OS (HR=0.137, 95%CI=0.020-0.959, P=0.045). In conclusion, our study supports current recommendations of using SL-401 or hyper-CVAD as the first-line treatments followed by consolidation with allo-SCT in the eligible responders to induction therapy to further improve survival outcomes in BPDCN patients. Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Sokol:Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees.

High-intensity endurance exercise elicits acute cardiac imbalances that may be an important stimulus for adaptive cardiac remodeling. This study highlights that following a bout of high-intensity exercise that is typical of routine day-to-day cycling training, exercise-induced autonomic, biochemical, and functional cardiac imbalances are attenuated in middle-aged relative to young well-trained cyclists. These findings suggest that aging may alter exercise-induced stress stimulus response that initiates cardiac remodeling in Athlete’s Heart.