Patrick Hilden

Background: Many antibiotic stewardship programs have sought to reduce fluoroquinolone use due to their association with a myriad of negative consequences. In hospital settings with fewer resources, initiatives that are less labor intensive may offer a more feasible approach to addressing fluoroquinolone use and improving patient care. Objective: This study assessed the impact of a non-restrictive fluoroquinolone reduction initiative on antibiotic use and resistance. Methods: This was a retrospective pre- and post-interventional ecological study conducted from 2016 to 2017. The fluoroquinolone reduction initiative consisted of education on risks and alternatives. Buttons promoting “Save the Quinolones” were also worn to increase visibility. Outcome measures were the rate of fluoroquinolone use and antibiotic resistance in Staphylococcus aureus, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa before and after the intervention. Results: Overall, fluoroquinolone use decreased throughout the study, but there was a significantly greater rate of decrease in the post-intervention period (monthly decrease of 3.3% (1.3, 5.1) v. 7.4% (5, 9.8) p = 0.043). S. aureus susceptibility to oxacillin increased from 47.2% to 55.2% (difference 8.0, 95%CI 1.2 to 14.7). P. aeruginosa susceptibility to levofloxacin increased from 60% to 70.7% (difference 10.7, 95%CI 0.8 to 20.6). No differences in susceptibility rates of E. coli, P. mirabilis or K. pneumoniae were detected. Conclusion: This non-restrictive fluoroquinolone reduction initiative led to a significant decrease in fluoroquinolone use that was associated with decreased antibiotic resistance in S. aureus and P. aeruginosa.

T cell depletion by CD34⁺ cell selection of hematopoietic stem cell allografts ex vivo reduces the incidence and severity of GvHD, without increased risk of relapse in patients with acute leukemia in remission or MDS. The optimal candidate for CD34⁺‐selected HCT remains unknown, however. Objective To determine outcomes based on both disease‐ and patient‐specific factors, we evaluated a prognostic model combining the Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT‐CI), an approach recently shown to predict overall survival in a broad population of allograft recipients (Kongtim P, Parmar S, Milton DR, et al. Impact of a novel prognostic model, hematopoietic cell transplant‐composite risk (HCT‐CR), on allogeneic transplant outcomes in patients with acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2019;54(6):839‐48). Methods This was a retrospective analysis of 506 adult recipients of first allogeneic HCT with CD34 + selected PBSCs from 7/8‐ or 8/8‐matched donors for AML (n = 290), ALL (n = 72), or MDS (n = 144). The Kaplan‐Meier method estimated OS and RFS. The cumulative incidence method for competing risks estimated relapse and non‐relapse mortality (NRM). We evaluated the univariate association between variables of interest and OS and RFS using the log‐rank test. Cox regression models assessed the adjusted effect of covariates on OS/RFS. Results Stratification of patients based on a composite of DRI (low/intermediate vs high/very high) and HCT‐CI (0‐2 vs ≥3) revealed differences in OS and RFS between the four groups. Compared with reference groups of patients with low/intermediate DRI and low or high HCT‐CI, those with high DRI had a greater risk of death (HR 2.30; 95% CI 1.39, 3.81) and relapse or death (HR 2.50; 95% CI 1.55, 4.05) than patients with any HCT‐CI but low/intermediate DRI (HR death 1.80; 95% CI 1.34, 2.43; HR relapse/death 1.68; 95% CI 1.26, 2.24). Conclusions and Clinical Implications A model combining DRI and HCT‐CI predicted survival after CD34⁺ cell‐selected HCT. Application of this combined model to other cohorts, both in retrospective analyses and prospective trials, will enhance clinical decision making and patient selection for different transplant approaches.

Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear. Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided. Survivors exposed to abdRT (median age = 31.6 years, range = 10.2–58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RR_{per 10 years} = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RR_{BMI 30+} = 5.00, 95% CI = 3.19 to 7.83 with reference_{BMI 18}._5–24.₉), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk. Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk.

Background: Autologous hematopoietic stem cell transplantation (AHCT) is a mainstay of therapy for eligible patients with multiple myeloma (MM) and light chain (AL) amyloidosis and confers a progression free and overall survival benefit in most studies. Yet, AHCT requires specialized care at a transplant center and investment from patients and caregivers. To decrease the burden of therapy and increase access to AHCT, we studied the safety and feasibility of delivering transplant care in a homebound setting. Methods: Eligible MM and AL patients undergoing AHCT resided in designated zip codes, had 24hr caregiver support, adequate Wi-Fi connection, Sorror Co-morbidity index ≤ 3 and Karnofsky performance status ≥ 80. Following high-dose melphalan (day -2) and stem cell reinfusion (day 0) in the outpatient clinic, protocol-specific homecare commenced (day +1) until engraftment. Care included daily assessments by advanced practice providers and interventions were delivered by registered nurses in the afternoons. Attending physicians communicated through telemedicine daily. Due to regulation, blood products required infusion in the outpatient clinic. Patient and caregiver quality-of-life (QOL) and satisfaction were assessed using patient/caregiver reported outcome instruments (Functional Assessment of Cancer Therapy (FACT)-General and FACT-Bone Marrow Transplant (FACT-BMT) questionnaires, MD Anderson Symptom Inventory (MDASI), Caregiver QOL Index--Cancer (CQOL-C) and satisfaction surveys). Video diaries and one-on-one interviews provided detailed qualitative evaluations. The primary objective was feasibility defined by readmission within 21 days of AHCT. Descriptive statistics were used to describe the population, toxicities and QOL measures. Results: Between 2/2016 - 5/2018, 15 patients (60% MM; 40% AL) and caregivers met inclusion criteria. Patient median age was 62 years (range 40-71) with 80% male. AHCT was part of 1^st line therapy in most patients (N=13); 2 with MM underwent 1^st AHCT as part of salvage. Melphalan dose was 200mg/m2 (N=11) or less (N=4) in patients ≥70 or AL. All patients received pegfilgrastim 6mg on day +1; thereafter, intravenous fluids and electrolytes were the most common interventions administered at home. During homecare, a median of 2 (range 1-3) visits to clinic were required for platelet transfusions and only 1 patient required 1 red cell transfusion. Median time to neutrophil and platelet engraftment was 9 (range 8-10) and 18 (range 11-22) days, respectively. Overall 7/15 (47%) (95% CI; 0.21-0.73) of patients were admitted for a median of 4 (range 3-10) days. Admission occurred on day +7 (N=5), day +8 (N=1) and day +12(N=1). Reasons for admission included neutropenic fever (NF) (N=2), fever attributed to engraftment syndrome (N=2), diarrhea (N=2), and dehydration (N=1). Only 1 (7%) patient had a documented infection (C. difficile) and 1 admitted for NF required ICU care (2 days) for GI bleed. Overall, 47% of patients experienced grade ≥ 3 non-hematologic toxicities. There were no deaths on study. Results of thematic content analysis of transcripts for patient-caregiver dyads demonstrate that while feeling challenged, caregivers derived satisfaction from assisting with the patient's recovery through maintaining hygiene of the home environment, managing dietary needs and responding to symptoms. Caregivers reported that living with the patient during AHCT strengthened their relationship by being able to provide for one another in unanticipated ways. Patients reported positive support from the medical team, connection to the world and the ability to engage in relaxing activities and physical exercise as important during AHCT. Caregivers and patients unanimously described the homebound program as preferable to a hypothesized experience in the hospital and satisfaction surveys indicated favorable responses (Figure). Symptom burden and QOL data are being analyzed. Conclusion: Homebound AHCT is safe and feasible with less than half of patients requiring inpatient admission. Patients required an average of two outpatient visits while receiving homebound care for blood products. Qualitative evaluations of the program by patients and caregivers were overwhelmingly positive. Based on these results we intend to expand the homebound program and investigate other potential biologic (microbiota diversity preservation) and economic benefits.

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.