Faculty Bibliography

Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H₂O₂ induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with other transcription factors to induce genes that sustain PDAC metabolic demands. The self-amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to-PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter.

PURPOSE/OBJECTIVE:Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS:The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS:alterations. CONCLUSION/CONCLUSIONS:The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

CONTEXT:Abortion is generally prohibited in Catholic hospitals, but less is known about abortion restrictions in other religiously affiliated health care facilities. As religiously affiliated health systems expand in the United States, it is important to understand how religious restrictions affect the practices of providers who treat pregnant patients. METHODS:From September 2016 to May 2018, in-depth interviews were conducted with 31 key informants (clinical providers, ethicists, chaplains and health system administrators) with experience working in secular, Protestant or Catholic health care systems in Illinois. A thematic content approach was used to identify themes related to participants' experiences with abortion policies, the role of ethics committees, the impact on patient care and conflicts with hospital policies. RESULTS:Few limitations on abortion were reported in secular hospitals, while Catholic hospitals prohibited most abortions, and a Protestant-affiliated system banned abortions deemed "elective." Religiously affiliated hospitals allowed abortions in specific cases, if approved through an ethics consultation. Interpretation of system-wide policies varied by hospital, with some indication that institutional discomfort with abortion influenced policy as much as religious teachings did. Providers constrained by religious restrictions referred or transferred patients desiring abortion, including for pregnancy complications, with those in Protestant hospitals having more latitude to directly refer such patients. As a result of religiously influenced policies, patients could encounter delays, financial obstacles, restrictions on treatment and stigmatization. CONCLUSIONS:Patients seeking abortion or presenting with pregnancy complications at Catholic and Protestant hospitals may encounter more delays and fewer treatment options than they would at secular hospitals. More research is needed to better understand the implications for women's access to reproductive health care.

CONTEXT:Catholic systems control a growing share of health care in the United States. Because patients seeking contraceptives in Catholic facilities face doctrinal restrictions that may affect access to and quality of care, it is important to understand whether and how providers work within and around institutional policies regarding contraception. METHODS:In 2016-2018, in-depth interviews were conducted in Illinois with 28 key informants-including providers (obstetrician-gynecologists, other physicians, nurse-midwives) and nonclinical professionals (ethicists, administrators, chaplains)-who had experience in secular, Protestant or Catholic health care systems. Interviews addressed multiple aspects of reproductive care and hospital and system policy. A thematic content approach was used to identify themes related to participants' experiences with and perspectives on contraceptive care. RESULTS:While respondents working in secular and Protestant systems reported few limitations on contraceptive care, those working in Catholic systems reported multiple barriers. Providers who had worked in Catholic systems described variable institutional policies and enforcement practices, ranging from verbal admonishments to lease agreements prohibiting contraceptive provision in secular clinics on church-owned land. Despite these restrictions, patients' needs motivated many providers to utilize work-arounds; some providers reported having been pressured or directly instructed to document false diagnoses in patients' medical records. Interviewees described how these obstacles burdened patients, especially those with social and financial constraints, and resulted in delayed or lower quality care. CONCLUSIONS:Providers working in Catholic hospitals are limited in their ability to serve women of reproductive age. Work-arounds intended to circumvent restrictions may inadvertently stigmatize contraception and negatively affect patient care.

BACKGROUND:Since 2005, the Lung Allocation Score (LAS) has prioritized patient benefit and post-transplant survival, reducing waitlist to transplant time to <200 days and decreasing mortality on the waitlist. A current challenge is the wait for the waitlist-the time between the patient's transplant-eligible diagnosis and waitlist registration. METHODS:] percent of predicted, body mass index, depression/anxiety, alcohol/substance misuse, absolute/relative contraindications) factors influenced referral and waitlist registration. We conducted a retrospective cohort study through chart review of hospitalized patients on the University of Chicago general medicine service from 2006 to 2014 who met transplant-eligible criteria and ICD-9 billing codes for cystic fibrosis (CF) and pulmonary fibrosis (PF). We analyzed the times from transplant eligibility to referral, work-up and waitlisting using Kaplan-Meier curves and log-rank tests. RESULTS:Overall, the referral rate for transplant-eligible patients was 64%. Of those referred, approximately 36% reach the lung transplant waitlist. Referred CF patients were significantly more likely to reach the transplant waitlist than PF patients (CF 60% vs PF 22%, p < 0.05). In addition, CF patients had a shorter wait from transplant eligibility to waitlist than PF patients (329 vs 2,369 days, respectively [25th percentile], p < 0.05). Patients with PF and CF both faced delays from eligibility to referral and waitlist. CONCLUSIONS:Quality improvement efforts are needed to better identify and refer appropriate patients for lung transplant evaluation. Targeted interventions may facilitate more efficient evaluation completion and waitlist appearance.