Childhood Allergy and the NeOnatal Environment (CANOE) Research Protocol and Recruitment Redesign during the COVID-19 Pandemic

Rationale: Recruitment for research studies is a challenging endeavor that has been further complicated by the COVID-19 pandemic. While clinical research was temporarily halted due to the pandemic, it was hypothesized that study and recruitment restructuring would enable brisk enrollment when research resumed. Methods: A new NIH/ECHO-supported multi-center birth cohort, “Childhood Allergy and the NeOnatal Environment” (CANOE) was launched in January 2019 across four sites to determine how pre-, peri-, and post-natal factors influence development of recurrent wheezing and atopic dermatitis. Study recruitment was halted for nine months due to the COVID-19 pandemic, during which recruitment and study procedures were redesigned. Results: Recruitment strategies were modified to limit in-person contact, shifting toward alternative HIPAA-compliant methods like clinician referrals, institutional social media, and telemedicine consenting. Protocol changes included reducing frequency of in-person visits, leveraging clinical care visits to collect bio-samples, expanded self-collection of samples at home, and posting study materials online. Recruitment rates range from 3-12 families per month per site. In-clinic recruitment with modifications for social distancing has been successful across all sites. Other successful strategies have included targeted social media posts, mailed letters, and email. Rates of consent have been similar across recruitment strategies and the implementation of multiple recruitment strategies has yielded the highest rates of ongoing consent and enrollment of mother-infant dyads. Conclusions: Study procedures that prioritize health and safety measures such as social distancing, study participant convenience, and diversification of recruitment strategies enable continued birth cohort recruitment and data collection while adhering to public health restrictions during the pandemic

Examining virtual research recruitment and participant diversity in a multi-center birth cohort, Childhood Allergy and the NeOnatal Environment (CANOE)

Rationale: Recruitment for a NIH/ECHO-supported multi-center birth cohort, “Childhood Allergy and the NeOnatal Environment” (CANOE) stopped due to the COVID-19 pandemic. Redesign of study procedures emphasized virtual and socially distanced activities. We hypothesized that “virtual” recruitment methods (social media, websites, email) would surpass “traditional” methods (in-clinic, telephone, flyers/print materials) and increase enrollment of families from diverse backgrounds and communities. Methods: Pregnant women (n=439, target 500) were recruited from four academic medical centers in Detroit MI, Madison WI, Nashville TN, and St. Louis MO. We collected demographic and social information by questionnaires and examined race, ethnicity, age, parity, and employment status in relation to recruitment method using chi-square tests. Results: In-clinic and telephone recruitment comprised 55% of enrollment, followed by print materials (17%), and social media and email (15%). The cohort includes families self-identifying as Caucasian/White (63%), African American/Black (27%), Hispanic/Latino (3.3%), Asian (3.5%), and mixed races (1.2%). This reflects site demographics for White and Black patients, while other populations are not as well recruited into this cohort. Recruitment method success did not vary by race, ethnicity, maternal age, or employment status (p=ns for each comparison). Most (63%) multigravida mothers (9.1% of participants) were recruited in clinic, while primigravida participants were recruited more evenly via all methods. Conclusions: “Virtual” recruitment methods comprised a smaller proportion of cohort enrollment than hypothesized and study recruitment method did not vary by race/ethnicity; however, consideration of combined, varied, and novel recruitment methods may add to the development of best practices for more representative research study recruitment

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

BCL2 mutations do not confer adverse prognosis in follicular lymphoma patients treated with rituximab

International audienceBCL2 mutations have been suggested to confer an adverse prognosis to follicular lymphoma (FL) patients, but their prognostic value has not been assessed in patients treated with a rituximab-containing regimen. Here we evaluated the prognostic value of BCL2 mutations in a large prospective cohort of 252 patients with FL treated with immunochemotherapy in the PRIMA randomized trial. Using a DNA-targeted sequencing approach, we detected amino acid altering mutations in 135 patients (54%) and showed that these mutations were probably mediated by the over-activation of AICDA (activation-induced cytidine deaminase) in the context of the t(14;18) translocation. The BCL2 variants identified in PRIMA patients affected the BH1, BH2, and BH3 functional motifs at a lower frequency than the N-terminus and flexible loop domain, with mostly conservative aminoacid changes. With a median follow-up of 6.7 years, we did not observe any impact of BCL2 mutations either on overall survival or progression-free survival

The combined endocrine receptor in breast cancer, a novel approach to traditional hormone receptor interpretation and a better discriminator of outcome than ER and PR alone

Background: The functional role of progesterone receptor (PR) signalling was previously unclear and PR testing in breast cancer is controversial. Recent defining work has highlighted the functional crosstalk that exists between the oestrogen receptor (ER) and PR. The purpose of this retrospective cohort study was to compare the prognostic value of the combined ER and PR score with either ER or PR alone. Methods: Tumour Allred ER and PR scores were reclassified as negative, low and high. The combined endocrine receptor (CER) was calculated as the average of the reclassified ER and PR scores, resulting in three groups: CER negative, impaired and high. Cox proportional hazards models were used to estimate disease-free survival (DFS) and breast cancer-specific survival (BCSS). Results: The CER was a more powerful predictor of 5-year DFS and BCSS than either ER or PR alone. In multivariate analysis that included ER, PR and CER, only CER remained an independent prognostic variable for 5-year DFS (hazard ratio (HR) 0.393; CI: 0.283–0.548, P¼ 0.00001) and BCSS (HR 0.553; CI: 0.423–0.722; P¼ 2.506 10 8 ). In ER-positive (ERþ ) patients impaired CER was an independent marker of poor outcome for 5-year DFS (HR 2.469; CI: 1.049–5.810; P¼ 0.038) and BCSS (HR 1.946; CI: 1.054–3.596; P¼ 0.033) in multivariate analysis that included grade, lymph node, tumour size, HER2 status and PR status. The results were validated in a separate cohort of patients. Conclusions: Combined endocrine receptor is a more powerful discriminator of patient outcome than either ER or PR alone. Economical and simple, it can identify risk in ERþ early breast cancer and potentially be used for adjuvant cytotoxic chemotherapy decision-making