Training Hematologists/Oncologists for the Academic-Community Hybrid: Creating a Fellowship Framework for the Future.

PURPOSE: Conventional hematology/oncology fellowship training is designed to foster careers in academic practice through intensive exposure to clinical and laboratory research. Even so, a notable proportion of graduating fellows opt to pursue a clinically focused career outside the realm of academic medicine. Given the corresponding shortage of oncologists in nonurban and rural settings, improving the representation of hematologists/oncologists in the community setting is a national priority. METHODS: We reviewed current national challenges and changing models of cancer care delivery in the context of the traditional academic training model along with trends in practice patterns for recent hematology/oncology graduates. We defined the Academic-Community hybrid (ACH) and how it supports the evolution in contemporary models of cancer care. We then drew on the authors' experiences to formulate an innovative goal-concordant training paradigm for fellows seeking careers in the ACH model. RESULTS: The ACH hematology/oncology fellowship training pathway emphasizes and optimizes professional development domains including clinical care, patient safety and quality improvement, business and operations, cancer care equity and community access, healthy policy and alignment with professional organizations, and medical education. CONCLUSION: This novel hematology/oncology training model provides a paradigm for optimizing preparedness for practice in an increasingly complex cancer care delivery environment while addressing workforce shortages and health disparities.

Implementing Electronic Patient-Reported Outcomes for Patients With New Oral Chemotherapy Prescriptions at an Academic Site and a Community Site.

PURPOSE: Oral chemotherapy challenges providers' abilities to safely monitor patients' symptoms, adherence, and financial toxicity. COVID-19 has increased the urgency of caring for patients remotely. Collection of electronic patient-reported outcomes (ePROs) has demonstrated efficacy for patients on intravenous chemotherapy, but limited data support their use in oral chemotherapy. We undertook a pilot project to assess the feasibility of implementing an ePRO system for patients starting oral chemotherapy at our cancer center, which includes both an academic site and a community site. METHODS: Patients initiating oral chemotherapy were asked to participate. A five-question tool was built in REDCap. Concerning responses triggered outreach within one business day. The primary outcome was time to first symptom assessment. For comparison, we used a historical cohort of patients who had been prescribed oral chemotherapies by providers in the same disease groups at the cancer center. RESULTS: Twenty-five of 62 (40%) patients completed ePRO assessments. Fifty historical charts were reviewed. Time to first symptom assessment was 7 days (IQR, 4-14 days) in the historical group compared with 3 days (IQR, 2-4 days) in the ePRO group. Time to clinical action was 14 days (7-35 days) in the historical group compared with 8 days (4-19 days) in the ePRO group. No statistically significant differences were detected in 30-day emergency department visit or hospitalization (12% for both groups) or 90-day emergency department visit or hospitalization rates (historical 28% and ePRO 20%). CONCLUSION: An ePRO tool monitoring patient concerns about adherence, cost, and toxicities for patients with new oral chemotherapy regimens is feasible and improves time to symptom assessment. Further investigation is needed to improve patient engagement with ePROs and evaluate the long-term impacts for patients on oral chemotherapy.

Lieb-Robinson Bound and the Butterfly Effect in Quantum Field Theories.

As experiments are increasingly able to probe the quantum dynamics of systems with many degrees of freedom, it is interesting to probe fundamental bounds on the dynamics of quantum information. We elaborate on the relationship between one such bound-the Lieb-Robinson bound-and the butterfly effect in strongly coupled quantum systems. The butterfly effect implies the ballistic growth of local operators in time, which can be quantified with the "butterfly" velocity v_{B}. Similarly, the Lieb-Robinson velocity places a state-independent ballistic upper bound on the size of time evolved operators in nonrelativistic lattice models. Here, we argue that v_{B} is a state-dependent effective Lieb-Robinson velocity. We study the butterfly velocity in a wide variety of quantum field theories using holography and compare with free-particle computations to understand the role of strong coupling. We find that v_{B} remains constant or decreases with decreasing temperature. We also comment on experimental prospects and on the relationship between the butterfly velocity and signaling.

Holographic Complexity Equals Bulk Action?

We conjecture that the quantum complexity of a holographic state is dual to the action of a certain spacetime region that we call a Wheeler-DeWitt patch. We illustrate and test the conjecture in the context of neutral, charged, and rotating black holes in anti-de Sitter spacetime, as well as black holes perturbed with static shells and with shock waves. This conjecture evolved from a previous conjecture that complexity is dual to spatial volume, but appears to be a major improvement over the original. In light of our results, we discuss the hypothesis that black holes are the fastest computers in nature.

Contract research organizations in oncology clinical research: Challenges and opportunities.

Contract research organizations (CROs) represent a multibillion dollar industry that is firmly embedded in the contemporary clinical trial process. Over the past 30 years, and especially within the last decade, the reach of CROs has extended to service all phases of drug trials in an increasingly global research environment. The presence of CROs is particularly noticeable in medical oncology because of the large number of investigational compounds developed to treat cancer that are currently undergoing testing in human subjects. Although limited data are available with which to objectively define the effects that CROs have had on the clinical trial process, with the expansion of these organizations, several reports have called into question whether ethical and professional standards in research conduct are at times secondary to economic considerations. CROs can add considerable value to the clinical trial process, but difficulty communicating with CRO representatives and time spent answering trivial data queries generated by CROs are current obstacles for study site personnel interacting with CROs. Further study of the effect of the CRO industry on the clinical trial process is needed to ensure efficient data collection and patient safety while collaboratively developing novel therapies in an expedited fashion. Cancer 2016;122:1476-82. © 2016 American Cancer Society.

Diagnosing Chaos Using Four-Point Functions in Two-Dimensional Conformal Field Theory.

We study chaotic dynamics in two-dimensional conformal field theory through out-of-time-order thermal correlators of the form ⟨W(t)VW(t)V⟩. We reproduce holographic calculations similar to those of Shenker and Stanford, by studying the large c Virasoro identity conformal block. The contribution of this block to the above correlation function begins to decrease exponentially after a delay of ~t_{*}-(ß/2π)logß^{2}E_{w}E_{v}, where t_{*} is the fast scrambling time (ß/2π)logc and E_{w},E_{v} are the energy scales of the W,V operators.

Outlook and Management of Patients with Myelodysplastic Syndromes Failed by Hypomethylating Agents.

The DNA hypomethylating agents (HMAs) azacitidine and decitabine are currently the most frequently administered disease-modifying therapies for patients with higher-risk myelodysplastic syndromes (MDS). However, azacitidine and decitabine are not curative, the median response duration is 11-15 months, and only 10-20 % of patients experience complete hematologic and cytogenetic response. Moreover, once an HMA fails the patient, the prognosis is poor, with a median survival of less than 6 months unless the patient undergoes hematopoietic stem cell transplantation (HSCT). Recent insights into the genetic basis of MDS have enhanced biological understanding and prognostication accuracy, but these developments have not yet led to regulatory approval of new therapies. While there are multiple potential approaches to patients with MDS for whom HMAs have failed, including supportive care alone, cytotoxic therapy, lenalidomide, histone deacetylase inhibitors, and HSCT, favorable responses to these approaches are limited and new therapies are greatly needed. Here, we review clinical and biological data about the population of patients failed by HMAs, evaluate currently available approaches to patients in this clinical situation, and discuss prospects for development of novel active agents.

Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes.

Clofarabine, a second-generation nucleoside analog, has clinical activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of clofarabine in populations of patients not enrolled in clinical trials. We reviewed outcomes for 84 patients treated with clofarabine for relapsed or refractory AML or MDS, either with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR=CR+CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal variation in response rates when comparing different risk factors. The 30-day mortality was 21% and median survival was 3 months; a subset of 12 patients who were able to go to transplant had an 18-month median survival. Clofarabine's efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate.

Rasburicase-induced methemoglobinemia in two African-American female patients: an under-recognized and continued problem.

Rasburicase-induced methemoglobinemia is a known adverse effect of patients administered rasburicase for tumor lysis syndrome who have concomitant glucose-6-phosphate dehydrogenase deficiency. This phenomenon has been described in multiple case reports but has been limited to male patients. We present the first case series illustrating this adverse effect in two female patients where morbidity and mortality associated with rasburicase-induced methemoglobinemia were evident. Screening protocols at the reporting institutions were lacking. The prevalence of G6PD may be underestimated based on the epidemiology of sample subjects in previous studies of rasburicase. We argue that both male and female patients should be suspected of G6PD in this setting; however, more data on prevalence and cost-effectiveness are needed on screening protocols for G6PD.

Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity.

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy-induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-fluorouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies.