bluuebunny/crossref_metadata_2025 huggingface dataset:
The joint i3+3 (Ji3+3) design for phase I / II adoptive cell therapy clinical trials.
Authors: Ji Yuan
Published: May 2020

e14083

Background: Adoptive cell therapy (ACT), such as chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects. However, it has been shown by previous studies that dose-response of ACTs may be complex and non-monotonic. For example, a ten-fold increase in dose level may not necessarily lead to higher anti-cancer response. This creates a new challenge for dose-finding trials with ACTs since higher dose may not lead to higher probability of efficacy. Methods: We propose a novel statistical design called the joint i3+3 design (Ji3+3) which extends our previous work of the i3+3 design (ASCO 2019 abstract 268979) and addresses the dose-finding challenge for ACT trials. In particular, Ji3+3 is a rule-based method that can be easily understood, visualized, and implemented by clinicians. It uses a set of smart rules based on observed efficacy and toxicity outcomes, and conducts up-and-down dose escalation decisions based on dose-response intervals. The entire dose-finding algorithm and decision rules can be presented as a precalculated table, which can be examined, discussed, modified, and approved as part of trial design. Results: Motivated by a CAR T trial (NCT03971799) we demonstrate the superiority of the Ji3+3 design through extensive computer simulations. Compared with the 3+3 design and i3+3 design, we show that Ji3+3 has a much higher chance finding the BOD and allocates more patients to desirable doses. The impact of these results will be to help investigators and drug developers identify a dose that is efficacious and safe, thereby increasing the probability of success to market the ACT and improving patient care. Conclusions: The Ji3+3 design is a novel, simple, and effective method that can potentially significantly improve the dose finding for ACT clinical trials.
Harnessing tumor immunity with chemotherapy: Mathematical modeling for decision-making in combinatorial regimen with immune-oncology drugs.
Authors: Cuplov Vesna , Sicard Guillaume , Barbolosi Dominique , Ciccolini Joseph , Barlesi Fabrice
Published: May 2020

e14095

Background: Combining chemotherapy and immune checkpoint inhibitors (ICI) is challenging due to the near-infinite choice of dosing, scheduling and sequencing between drugs. The aim of this work is to develop a phenomenological model that describes the synergistic effect between cytotoxics and immune check point inhibitors in patients with cancer. Methods: Inspired from literature, we have developed an integrative mathematical model that includes tumor cells, cytotoxic T cells (CTLs) and regulatory T cells (TREGs) plus pharmacokinetics (PK) inputs. Loss in tumor mass is due to combined effect of direct chemotherapy-induced cytotoxicity and CTLs immune response, which is in turn inhibited by the tumor and mitigated by TREGs in the tumor micro-environment. The model describes as well the impact of chemotherapy-induced lymphodepletion on immune tolerance, whereas ICIs protect CTLs against tumor inhibition. Identification of model’s parameters and simulations of various scheduling were performed using Mlxplore software and a Python standalone code. In vitro and in vivo experiments using lung cancer models generate experimental data to adjust model parameters. Results: Complex interplays between cytotoxics and immune cells were best described by a 10-parameters model so as to ensure better identifiability. PK/PD relationships were integrated using compartmental modeling. In silico simulations show how changes in dosing and scheduling impact efficacy endpoints, an observation in line with data from the literature. Ongoing in vitro and in vivo experiments with pemetrexed-cisplatin doublet and anti-PD1 pembrolizumab help optimizing the model’s parameters in a self-learning loop. Conclusions: This work is at the frontier between mathematical modeling and experimental therapeutics with ICIs. In silico modeling and simulations could help narrow down the treatment choices and define optimal combinations prior to running clinical trials. Such model will help identify optimal dosing and scheduling, so as to achieve better synergism and efficacy.
Pilot study for the use of wearable devices for patients undergoing oral chemotherapy.
Authors: Patel Monaliben , Cooney Matthew M. , Caimi Paolo Fabrizio , Randall Rory Eric , Metheny Leland L. , Mendiratta Prateek , Bruno Debora S. , Silverman Paula
Published: May 2020

e14103

Background: The rapid development of digital technology holds enormous potential to transform the delivery of cancer care. Despite these digital innovations, we still face significant challenges in healthcare in using these emerging digital technologies in the clinical setting. Clinicians generally underestimate the severity and extent of chemotherapy toxicity of patients. This project seeks to conduct an exploratory field study to collect patient feedback on their experiences, and the design/functionality of the prototype of the digital health service platform designed to monitor their symptoms. Methods: Using the National Cancer Institute item library addressing the most common symptoms for chemotherapy toxicity, a digital health platform was designed by Samsung Research America (SRA) and University Hospitals. Patients age ≥ 18 years old, willingness to agree to the consent document, ability to understand use of wearable device and willingness to answer patient reported outcomes questions were included in this study. Patients who are not undergoing oral chemotherapy treatment for their cancer were excluded. Patients were given a phone that had our designed platform along with a watch. The watch had the capability of tracking blood pressure, heart rate, and pulse oximetry. Patients were set up with an electronic account that queried them on patient Reported Outcomes (PRO) regarding potential toxicity they may be experiencing. They were also able to track medication consumption and input their weight. Subjects were be asked to use the wearable device and phone for at least 28 days and no more than 90 days. At the end of the study, a phone survey was attempted. Results: Total patients enrolled: 21. 18/21 (85.7%) patients completed the 90 days of the study. Only 9 patients provided PRO with total number of side effects reported 28 times. Watch device was only utilized by 15/21 (71.4%) patients. On an average across 90 days, these patients wore the watch 430 minutes per day. At the end of the treatment, 5 patients agreed to participate in the phone survey. Three patients stated that they would do similar study in the future noting that the digital platform helped them stay on track and monitor symptoms accurately. Every patient questioned had a complaint regarding the watch functionality. Patients also found it difficult to carry a second phone in addition to their personal phone. Conclusions: Improving our digital health service platform will get us closer to achieving effective bi-lateral patient communication and ultimately improving patient care.
Continuous monitoring of mobility performance trajectory in patients receiving chemotherapy.
Authors: Yarlagadda Sudha , Najafi Bijan , Chu Jinna , Wang Changhong , Sada Yvonne
Published: May 2020

e14104

Background: Accurate performance status (PS) assessment is important for chemotherapy decisions, but current tools such as the Eastern Cooperative Oncology Group (ECOG) PS assessment are subjective, static, and prone to inter-observer and recall biases. Continuous patient monitoring technology can enhance PS assessment by providing an objective and dynamic measurement of mobility performance (MP), defined as mobility in real-life situations. This study examined the feasibility of a pendant sensor to continuously track MP during a 4-week period of chemotherapy. Methods: Patients on chemotherapy were recruited from a single center. Patients were asked to continuously wear a water-resistant pendant sensor (PAMSys, Biosensics, USA) for 4-weeks during the day and night. Patients completed psychosocial surveys (cognitive, depression, and fatigue) and a technology acceptance survey measured on a Likert scale from 1 (strongly disagree) to 5 (strongly agree). Chart review was completed for demographics, medical history, and baseline ECOG PS. Using a validated algorithm, postures (lying and sitting postures: LSP) and walking parameters (cadence, longest walking bout, total steps per day) were extracted from the pendant. We also calculated percent change from baseline activity to the lowest activity level during the 4-week period. To determine clinically meaningful digital biomarkers, we compared these MP measures between two groups: ECOG 0 or ECOG ≥1. Results: Fifteen patients (median age 68), with either a solid (n = 14) or hematologic (n = 1) malignancy, stages II-IV, with ECOG 0 (n = 7) and ECOG ≥1 (n = 8) were evaluated. Baseline psychosocial parameters were not significantly different. ECOG ≥1 tend to have poorer baseline walking compared to ECOG 0 with the largest effect size observed for cadence (79.2 ± 10.0 vs 73.3±3.7, Cohen’s d effect size d = 0.78). The percentage of MP decline was higher in ECOG 0 compared to ECOG ≥1 (89.0±22.9% vs 79.9±34.5%). None of the observed trends reached statistical significance. Patients reported that the pendant was comfortable to wear (4.9±0.30) and did not interfere with activities (4.9±0.25). Conclusions: This study showed the feasibility of a pendant sensor to continuously monitor MP and its trajectory during chemotherapy. Results suggest continuous MP monitoring may provide objective information to enhance PS assessment. Larger studies are needed to confirm statistical significance of digital MP metrics and its potential effect on clinical decisions such as dose reduction, rehabilitation, and palliative care.
Using a bi-directional digital health platform for cancer care coordination and monitoring to enhance the cancer care continuum between patients, clinicians and caregivers.
Authors: Hensley Alford Sharon , Mahatma Shilpa , Mahatma Rohit , Amode Sagar , Sethia Rupal , Mahatma Kartik , Mahatma Hitesh , Mahatma Varun , Sonawane Nayan , Chawla Kanchan , Patil Pooja , Solankar Pravin , Belote Shital , Wasu Sneha , Mahatma Srishti , Kumar Tarun
Published: May 2020

e14105

Background: It has been recognized that current electronic medical record (EMR) systems detract from the patient-provider relationship and that an innovative technology is needed to re-center medical encounters on the patient-provider engagement. This is especially important in oncology during new patient onboarding, care coordination in between medical visits and survivorship planning. Methods: We built a HIPAA compliant role-based digital health platform to support providers in patient engagement and care coordination. In this pilot at a non-profit oncology center in India, nurse navigators onboarded the patients using the mobile application. The technology was used to digitize past medical records and parse the clinical history. In addition, self-reported patient past medical history, family history, as well as social, reproductive and surgical history was collected as needed. The system collated the information into an easy to consume case summary for the oncologists. The system was tested with 3 clinicians and consented cancer patients. Results: Nearly 200 cancer patients participated in the pilot study. Patients’ medical records were digitized by oncology nurse navigators. The summarized longitudinal view of the patient’s medical history was used by oncologists for diagnosis and treatment planning. Participating clinicians noted that the digital case summary saved time and effort in treatment planning. In addition, it was noted that collaboration between nursing staff, medical oncologist, surgical oncologist and radiation oncologist was substantially improved. Conclusions: We demonstrate the value of using digital health technology to support the care coordination of cancer patients in a low-resource, non-profit clinical center in India.
Adherence to remote versus clinic-based collection of patient-reported outcomes in patients with advanced lung cancer.
Authors: Gabriel Peter Edward , Kaufmann Tara L. , Blauch Abigail N. , Pucci Donna A. , Jacobs Linda A. , Bekelman Justin E. , Shulman Lawrence N. , Takvorian Samuel U
Published: May 2020

e14109

Background: Routine collection of patient-reported outcomes (PROs) is an evidence-based practice to improve communication, symptom management, and health outcomes in cancer care. However, optimal implementation strategies are poorly understood. Previous studies have mostly assessed PROs collected during clinic visits, which may be less actionable and more subject to recall bias than those collected in real time. Behavioral economics-informed digital approaches have shown increasing promise as sustainable and scalable strategies for remote patient monitoring. We compared remote text-messaging versus usual clinic-based PRO collection approaches. Methods: Between September 2018 and May 2019, we conducted a prospective pilot feasibility study of remote PRO monitoring via text-messaging among 20 patients with advanced non-small cell lung cancer (NSCLC). Pilot participants consented to enroll in a HIPAA-compliant, bidirectional text-messaging platform, which allowed for direct reporting of PRO measures at home. Data were integrated into the electronic health record in real time, and clinicians were notified of severe or escalating symptoms. We compared patient-level adherence over 12 weeks among: 1) pilot participants and 2) patients with advanced NSCLC reporting via usual clinic-based collection methods. We identified predictors of adherence using multivariable logistic regression, and surveyed pilot participants on feasibility outcomes. Results: During the study period, 20 patients with advanced NSCLC participated in the remote text-messaging pilot study (mean age, 63y; 60% male; 85% white), and 328 patients with advanced NSCLC participated in usual clinic-based PRO collection (mean age, 66y; 48% male; 69% white). Baseline characteristics were similar between groups. Mean adherence was 88.4% for remote text-messaging vs 71.2% for clinic-based collection (p < 0.001). Pilot participation predicted > 80% adherence after adjusting for age, sex, race, and marital status (OR 3.5, p = 0.029). Pilot participants reported high levels of usability (97%) and satisfaction (96%) with text-messaging, and 90% noted that text messages reminded them to report symptoms to their clinical team. Conclusions: Among patients with advanced NSCLC, remote PRO monitoring via text-messaging was feasible and enabled significantly higher adherence to reporting than usual clinic-based collection. These results are based on a small pilot study, and further research on text messaging as a PRO implementation strategy is warranted. Clinical trial information: NCT03616522.
The changing atlas of clinical research in cancer: Measuring accessibility to clinical trials.
Authors: Mazzarella Luca , Tini Giulia , Fabio Pammolli , Lorenzo Righetto , Curigliano Giuseppe , Pelicci Pier Giuseppe
Published: May 2020

e14123

Background: The recent global economic growth produced dramatic social changes that impacted healthcare. Private industries, low and middle income countries increased their interest in clinical research. How these changes impact on accessibility to clinical trials has not been sufficiently studied, an issue becoming more relevant as trials increasingly constitute a relevant source of access to innovative drugs. Methods: We analyzed changes related to funding source, phase and locations involved in all interventional clinical trials on cancer extracted from clinicaltrials.gov from 2005 to 2019. We studied the evolution of accessibility to clinical trials on worldwide scale, by developing a family of indexes weighted on population, distance from the site location, numbers of trials. These indexes were also used to simulate different resource allocation models. Results: The absolute involvement of industry in clinical trials consistently increased (~6 fold over 2005), with a significant bias for phase 1 trials; however, its relative impact has globally remained the same. The geographical distribution of trial sites changed dramatically: some nations (China, Korea) increased their total number of trials 50 fold. The number of countries with ≥10 multicentric studies grew from 3 to 16. Our accessibility index (Table, relative increment on 2005 in parenthesis) shows that Asia had the highest improvement, with Korea and Taiwan as leading countries. The analysis captures significant trends associated with changing policies on trial conduct, such as the introduction in 2012 and abandonment in 2015 of centralized ethical committees in Brazil, or the introduction of EUdract in Europe in 2015. Simulations allowed to identify specific resource allocations to maximize accessibility. Conclusions: Accessibility to clinical trials is improving worldwide, but with important differences across continents and countries, which follow social, economic and political changes. Our accessibility indexes can inform national and continental healthcare/research policies, as they predict the impact of different resource allocation models, representing useful tools to facilitate access to innovative treatments. [Table: see text]
The validity of VALID act: Cost modeling cancer diagnostics regulation by the FDA.
Authors: Huang Richard , Lasiter Laura , Young Christina , Allen Jeff , Lennerz Jochen K
Published: May 2020

e14124

Background: VALID Act is a bipartisan draft legislation proposing to ensure the quality and safety of diagnostic tests through direct FDA oversight. Currently, FDA exercises enforcement discretion and exempts from premarket review tests that are developed and used in the same clinical laboratory. Many stakeholders have pointed out that the lack of direct FDA oversight has led to erroneous results that have serious patient consequences. However, the maintenance cost after the implementation of the Act is unknown. Thus, we estimate the additional financial burden of genotyping all new late stage cancer patients under a fully implemented VALID Act precertification framework. Methods: Based on our laboratory with 36 high-complexity clinical assays, we modeled the cost increase by dividing the total anticipated cost for annual FDA precertification by our 2019 patient volume. To model the stringency of complying with the Act, we calculated either 3, 6, or 9 assays as representative of the laboratory’s test complexity. To make the estimated additional annual national healthcare cost relatable, we expressed the increase as a distributed cost per newly diagnosed late stage cancer patient in 2019 (NCI SEER) or per employed person in 2019 (Bureau of Labor Statistics). Results: FDA precertification for 3 assays was estimated at $638,310.13, or when divided by our annual late stage patient volume (n = 10,232), an increased cost of $62.38/patient. Precertification for 6 or 9 assays costs $684,751.60 (+$66.92/patient) or $1,253,717.25 (+$122.53/patient), respectively. If only 1 cancer center per state/DC/PR got precertified (n = 52), multiplied by the cost of precertifying 3 assays, then the annual national healthcare cost would increase by $33,192,126.50, or +$42.37/new late stage patient (n = 783,476) or +$0.21/employed (n = 158,803,000). Precertification for 52 centers for 6 or 9 assays would cost $35,607,083.20 (+$45.45/patient, +$0.22/employed) or $65,193,297.00 (+$83.21/patient, +$0.41/employed), respectively. Nationally, there are ~886 centers and the increased cost was estimated at < $7/employed. Even though the VALID Act will affect more than late stage cancer patients, thus costs will vary, our data show how a specific change of the Act will impact oncology practice. Conclusions: We provided a concrete cost model for late stage cancer patients under the proposed VALID Act. Cost modeling is important in informing the balanced legislative language needed to ensure patient access to validated cancer diagnostics, while supporting continued innovation by clinical laboratories.
Reduced blood product utilization via implementation of an anemia clinic and consult service in a large health system hospital.
Authors: Bowers Reid Christian , Thompson Michael A. , Korman Sandra Tomany , Sana Sherjeel , Pant Manish Krishna , Sanchez Federico Augusto
Published: May 2020

e14142

Background: An Anemia Clinic program was started Sept. 2016 as part of system wide implementation of Patient Blood Management (PBM) initiated in 2015. Methods: The Anemia Clinic accepted referrals for non-cancer anemia, predominantly preoperative cardiovascular surgery (CVS) Pts. Hgb thresholds were < 13 g/dL in men and < 12 g/dL in women. Non-anemia cytopenias triggered Hematology referral. All Pts were screened for iron, B12, folate, and reticulocyte. Nutrient deficiencies were supplemented. Pts with CKD or chronic disease were considered for erythropoiesis stimulating agents. Results: PBM implementation resulted in a drop in packed red blood cell (PRBC) usage (Table). Of CVS Pts pre-operatively anemic in 2019, 180 were referred to the Anemia Clinic and 301 were not. Anemia Clinic identified iron (N = 114), vitamin B12 (N = 24), and folate (N = 18) deficiencies. The percentage of Pts who received PRBCs after Anemia Clinic referral was not statistically different from those who were not referred (65.6% vs. 61.8% Chi-Square p = 0.44). Of preoperatively anemic Pts who were transfused in 2019, an average of 2.34 PRBCs were used in the referred group vs. an average of 2.21 PRBCs in those in the not referred group (Poisson Means p = 0.46). Length of stay (LOS) which was a median 10d ( P25= 7d, P75 =17d) in the referred group vs a median 12d ( P25= 7d, P75 =19d) in the non-referred group was not statistically different between groups (Smirnov p = 0.39). LOS analyses of observed-to-expected (O/E) ratios used the Premier Healthcare Providers Alliance Database (PHD) which contains data on approximately 45% of US hospital discharges. For 2019 through Nov. the referred group had an O/E = 1.03 (observed LOS μgeo = 11.58 days, expected LOS μgeo = 11.21 days, N = 167). The not referred group had an O/E = 1.06 (observed LOS μgeo = 12.24 days, expected LOS μgeo = 11.58 days, N = 272). Conclusions: PBM decreased PRBC use through systematization of best practices during the initial year. Subsequent addition of Anemia Clinic services has not decreased PRBC use further. There is a trend toward shorter LOS for patients referred to Anemia Clinic but it is not statistically significant. Our methods improved nutrient deficiency identification which may improve both later health outcomes not detected here and access to treatment for hematologic malignancies. [Table: see text]
Incremental oncology workload generated by immunotherapy in the first-year of treatment.
Authors: Cinausero Marika , Garattini Silvio Ken , Minisini Alessandro Marco , Valent Francesca , Riosa Chiara , Iacono Donatella , Macerelli Marianna , Andreotti Victoria , Giavarra Marco , Vitale Maria Grazia , Fasola Gianpiero
Published: May 2020

e14143

Background: The rapid development of immunotherapy (IO) has transformed the cancer therapy landscape with growing impact on oncology workload. Given the few data on this topic, we conducted a study to estimate the shift in workload generated by any new metastatic cancer patient treated with IO and referred to the Oncology Department of the Academic Academic Cancer Center of Udine, Italy, within the 12 months of first consultation. Methods: We collected from our “Data Warehouse” electronic accountability system all new diagnosis of metastatic cancer between 01.01.2017 and 31.12.2018, resulting in a first consultation and leading to a second clinical episode during the following year, in order to assess the oncology workload. The population was divided into patients that received IO (anti-CTLA-4/PD-1/PDL1) versus patients treated with “other treatments”. Mean number per patient and standard deviation were calculated for clinical episodes (first consultations, treatment sessions, unplanned presentations, hospitalizations, re-evaluations, follow-up and inpatient oncology advices). The total number of patients treated and the number of episodes were recorded. Mean numbers of episodes in the IO group and “other treatments” group were compared using Student’s t-test (significance p < 0.005). Follow-up data was collected up to 31.12.2019. Results: A total number of 969 patients were considered (854 “other treatments” group and 115 IO group), resulting in a total of 12407 clinical episodes over the period of 12 months (first consultations excluded). Compared to “other treatments” group, patients in the IO group generated a greater workload in terms of treatment sessions (9.59 vs 6.83 per patient, p < 0.0001), re-evaluations (2.55 vs 1.88, p = 0.0002), and unplanned presentations (2.19 vs 1.51, p = 0.08). On the other hand, follow-up visits workload was greater for “other treatments” group (0.83 vs 0.63, p = 0.0002). No differences were found regarding hospitalizations and inpatient oncology advices. Further analysis will be presented. Conclusions: IO represents a new frontier in oncology landscape, leading to outcome’s improvement and longer lasting treatment periods. The estimate of oncology workload generated by new diagnosis of metastatic cancer requiring IO, is crucial for implementing more sustainable systems and for planning clinical activities.
Underutilization of low-dose computed tomography in a high-risk population.
Authors: Ashraf Sara , Konala Venu Madhav , Jafri Mohammad Ali Syed
Published: May 2020

e14145

Background: Lung cancer is the leading cause of cancer death in the United States, contributing to one-quarter of all cancer-related deaths. State statistics reveal per capita that Kentucky has the highest incidence and mortality rate for lung cancer. One would assume that in a community setting in Kentucky, the rate of utility of low dose Computed Tomography (CT) and detection of lung cancer would be high. Methods: We did a retrospective analysis of Low Dose Computed Tomography (CT) for lung cancer screening based on the United States Preventative Services Task Force (USPSTF) guidelines from 2017-2019 at a community hospital in Ashland, Kentucky. Charts were reviewed to analyze the number of patients who received screening, total number of patients diagnosed with lung cancer, and how many patients could have received screening based on the guidelines. We also analyzed how many are alive and those that are deceased. Results: Our analysis showed that a total of 175 patients were diagnosed with lung cancer at the hospital in 3 years. Out of these, 118 had qualified for screening (67%) based on USPSTF guidelines. Only seven patients received screening (5.9%). All seven patients who received screening are currently alive. Forty-eight patients (41%) are now deceased that could have had the screening but did not. Conclusions: Low dose screening CT is being underutilized in the community setting with high incidence and mortality from lung cancer. The mortality rate is high likely from the late detection of the tumor. Implementation of guidelines to the general population for lung cancer screening will require systems to facilitate identifying eligible patients. It also involves training of physicians with information that should be delivered during the shared decision-making conversation. We also suggest low dose screening CT to be included in global quality pay for performance program for primary care providers which includes screening for breast and cervical cancer as well as smoking cessation.
Effects of the growing prevalence in oncology: A real-world study on the estimated workload.
Authors: Garattini Silvio Ken , Minisini Alessandro Marco , Valent Francesca , Riosa Chiara , Andreetta Claudia , Cardellino Giovanni Gerardo , Mansutti Mauro , Rizzato Simona , Rossetto Ciro , Sacco Cosimo Stanislao Pio , Follador Alessandro , Fasola Gianpiero
Published: May 2020

e14148

Background: The increasing prevalence of cancer patients due to new effective treatments is leading to a growing demand in oncology activities, thus requiring a re-modelling towards more sustainable systems. The aim of this study is to estimate the workload generated by each new cancer patient referred to the Oncology Department of the Academic Cancer Center of Udine, Italy, within the two years from first consultation. Methods: We have utilised our electronic “Data Warehouse” accountability system to retrieve anonymous aggregate data of the 2-year oncology workload generated by each new diagnosis, leading to an initial consultation, occurring between 01.01.2012 and 31.12.2017. Initial consultations with no clinical episode in the following 12 months were excluded. Mean value per patient and standard deviations were calculated for the following clinical activities: treatment sessions, unplanned presentations, hospitalisations, re-assessments, follow-up visits and inpatient oncology advices. The total number of patients treated and of episodes were recorded. Follow-up data was collected up to 31.12.2019. Results: During the observation period, 7,454 newly diagnosed patients were referred to our Oncology Unit, resulting in a total of 92,830 clinical activities occurring over an 8-year period. In 1,788 pts (24.0%) only follow-up was needed; 3,152 pts (42.3%) were referred for adjuvant treatment and 2,514 (33.7%) for advanced disease management. Overall, the mean number of clinical activities per patient within the first 2 years was: 6.04 pre-treatment evaluations (52.9%; SD 8.81; 45,003 total episodes), 2.00 follow-up visits (17.5%; SD 1.89; 14,922 total episodes), 0.42 hospitalisations (3.7%; SD 1.21; 3,141 total episodes), 0.36 inpatient oncology advices (3.2%; SD 0.83; 2,705 total episodes), 1.57 re-assessments (13.8%; SD 2.28; 11,723 total episodes) and 1.02 unplanned presentations (8.9%; SD 2.17; 7,601 total episodes). Subgroup analysis in the different tumors and settings are ongoing. Conclusions: The landscape of cancer care is changing due to the growing prevalence of cancer patients that experience longer overall survival. Trying to estimate the amount of clinical activities generated by any new diagnosis is crucial for implementing new models of oncology management and for programming an adequate workforce supply.
Overcoming clinical trial accrual barriers at UPMC: A successful experience.
Authors: Reyes Vincent Edgar , Evans Terry L. , VanderWeele Robert Alan , Marsh Christopher Ritchie , Peracha Sajid M. , Kiefer Gauri J. , Tageja Nishant , Choksi Rushir J. , Pappu Bhanu , Wozniak Antoinette J. , Ferris Robert L. , Marks Stanley M.
Published: May 2020

e14152

Background: UPMC Hillman Cancer Center Medical Oncology Network is one of the largest integrated community oncology network in the United States. A large gap exists between trial participation rates and the willingness of patients and physicians. There are numerous barriers to clinical trial accrual in the medical oncology community. UPMC identified and created solutions to overcome barriers, and thus dramatically increase clinical trial accrual in 2019. Methods: A physician led advisory board was created to identity problems and find solutions to increase clinical trial accrual in the community. Processes that were implemented in the community to increase physician engagement included identifying more community friendly clinical trials, highlighting high impact clinical trials, and reprioritizing available clinical trials. Also, community physician champions were selected and directly linked with the academic faculty by disease site at UPMC Hillman Cancer Center. Other marketing tools were utilized like a newly developed mobile clinical trial app, community physician dedicated clinical trial retreat, and clinical trial newsletter. High volume community sites were identified as flagship clinical trial accrual centers. Results: With the implementation of physician led initiatives, total (interventional + non interventional) clinical trial accrual increased in the UPMC medical oncology network from 216 in 2018 to 660 in 2019. In 2019 there were 631 interventional trial accruals and 363 therapeutic trial accruals. In 2018 there were only 186 interventional trial accruals and 46 therapeutic trial accruals. Conclusions: The community oncology-directed initiatives created a culture change among the community physicians. UPMC implemented new processes in the medical oncology network that significantly increased clinical trial accrual. [Table: see text]
Stereotatic radiosurgery for residual lesions of pineal nongerminomatous germ cell tumors after conventional radiotherapy: A retrospective study.
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Zhou Jiangfen , Wen Lei , Zhou Cheng , Zhou Zhaoming , Li Shaoqun , Shan Changguo , Cai Linbo
Published: May 2020

e14516

Background: To evaluate the safety and efficacy of stereotatic radiosurgery (SRS) in treating residual lesions of pineal non-germinomatous germ cell tumors (NGGCTs) after conventional radiotherapy. Methods: The patients admitted to Guangdong Sanjiu Brain Hospital from 1 January 2008 to 31 December 2018 who diagnosed with pineal NGGCTs pathologically or clinically were retrospectively analyzed. Among those, the patients received conventional radiotherapy with or without SRS were included. The residual lesions after radiotherapy were defined with a maximum diameter > 10mm. Prognosis related parameters such as local control rate, progress-free survival, overall survival and treatment-related toxicity were determined. Results: The median follow-up time was 34 months (range 8-142 months). The objective response rate and disease control rate were 71.4% and 95.2%, respectively. Three-year progression-free survival rate was 85.2% and 3-year total survival rate was 88.0%. The univariate analysis revealed that both age and concurrent chemotherapy were not correlated with the prognosis (P = 0.286, 0.824). Partial tumor resection before radiotherapy and chemotherapy, AFP>500ng/ml, and no more than 4 cycles of adjuvant chemotherapy were poor prognostic factors (P = 0.037, 0.010, 0.006). Moreover, no acute radiation response was observed after treatment with SRS. Only 1 out of 27 patients (3.7%) had brain neurotoxicity related to a prolonged course of radiochemotherapy. Conclusions: SRS for residual lesions of NGGCTs following conventional radiotherapy appears to be well tolerant and improved local control. However, the combination of conventional radiotherapy and SRS warrants further investigations in a large-scale randomized controlled clinical trials.
Therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone in children with DIPG: A single-center experience with 82 cases.
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Li Shaoqun , Zhou Jiangfen , Zhou Cheng , Wen Lei , Zhou Zhaoming , Shan Changguo , Cai Linbo
Published: May 2020

e14518

Background: To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG. Methods: The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy. Results: A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2-16 years). The median follow-up was 8.6 months (range 2-28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P= 0.010). Moreover, bevacizumab and nimotuzumab didn't bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found. Conclusions: Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.
Effect of early integration of diabetic services in primary brain tumor patients receiving radical radiotherapy on steroid-induced diabetic complications and hospital admission.
Authors: Keshwani Karim , Raymond Lorna , Shawe-Taylor Marianne , Lowe Hannah , Plowman Piers N. , Lewis Rachel
Published: May 2020

e14522

Background: Corticosteroids are commonly used in neuro-oncology both in the perioperative setting and with chemotherapy and radiotherapy to manage cancer and treatment-associated cerebral oedema and neurological deficits. Corticosteroids are associated with significant morbidity. We sought to identify primary brain tumour patients affected by steroid complications within our centre, the repercussions on their treatment and whether these consequences are avoidable. Methods: This retrospective study curated the last 50 primary brain tumour patients treated radically and therefore at risk of long term steroid use between November 2018 and August 2019. Patient demographics, tumour and treatment type, as well as diabetic and steroid history were collected. A second cohort of primary brain patients undergoing radical radiotherapy were recruited between November 2019 and January 2020. HbA1c blood tests were performed and NICE guidelines used for HbA1c diagnostic criteria with referral to diabetic services and outcomes recorded. Results: Tumour types ranged from Glioblastoma (36%), meningioma (32%), oligodendroglioma (16%), astrocytoma (14%) and hemangioblastoma (2%). 12 (24%) had a known diabetes diagnosis. Forty-two (84%) had an operation (biopsy (30%), partial (18%) or full debulking (16%). 82% of patients were exposed to dexamethasone at some point during their neurosurgical or oncological treatment. Initial doses varied but 36% were placed on 8mg twice daily. Steroid-induced hyperglycaemia occurred in 8 (16% of the cohort) with admission to hospital as a consequence in half of these cases, of whom two were newly diagnosed diabetes patients. HbA1c testing prior to or during treatment occurred in 16 (32%) patients. In the second cohort, All 15 patients (100%) had HbA1c testing with 5 (33%) patients diagnosed with diabetes or at risk of diabetes. Diabetic team advice was sought and recommended blood glucose testing in all these patients with oral hypoglycaemic and/or insulin dose modification in 3 (60%). There were no hyperglycaemic recordings or subsequent admissions to hospital in this cohort. Conclusions: We therefore recommend HbA1c testing and early diabetic team involvement in all primary brain tumour patients receiving radical radiotherapy.
Effect of cumulative dexamethasone dose during concomitant chemoradiation on lymphopenia in patients with newly diagnosed glioblastoma.
Authors: Ahn Stephen , Park Jae-Sung , Song Jin Ho , Jeun Sin-Soo , Hong Yong-Kil
Published: May 2020

e14533

Background: Lymphopenia frequently occurs after concomitant chemoradiation (CCRT) in patients with glioblastoma (GBM) and is associated with worse overall survival (OS). A few studies have tried to identify risk factors for lymphopenia; however, the results were not clear. We aimed to identify potential risk factors for lymphopenia, focusing on the use of dexamethasone to control cerebral edema in patients with GBM. Methods: The electronic medical records of 180 patients with newly diagnosed GBM treated at our institution between 2009 and 2017 were retrospectively examined. Acute lymphopenia was defined as TLC (total lymphocyte count) less than 1,000 cells/mm3 at 4 weeks after completion of CCRT. Multivariate logistic regression analysis was used to identify independent risk factors for lymphopenia, and Cox regression analysis was used to identify independent risk factors for OS. Results: Of the 125 eligible patients, 40 patients (32.0%) developed acute lymphopenia. Female sex and median daily dexamethasone dose > 2mg after initiation of CCRT were independent risk factors for acute lymphopenia on multivariate analysis. Acute lymphopenia, extent of surgical resection, and performance status were associated with OS; however, dexamethasone use itself was not an independent risk factor for poor OS. Conclusions: Female sex, median daily dexamethasone dose > 2 mg after initiation of CCRT until four weeks after completion of CCRT may be associated with acute lymphopenia. However, dexamethasone use itself did not affect OS in patients newly diagnosed with GBM. These results should be validated by further prospective studies controlling for other confounding factors.
Impact of CD38 knockout in NK cells on daratumumab-mediated cytotoxicity and cellular metabolism.
Authors: Nagai Yuya , Kararoudi Meisam Naeimi , Ali Syed Abbas , Imus Philip H. , Pereira Marcelo , Elmas Ezgi , Borrello Ivan , Lee Dean Anthony , Ghiaur Gabriel
Published: May 2020

e15018

Background: Multiple myeloma (MM) is a neoplasm of plasma cells. These cells express high levels of CD38 and are sensitive to daratumumab (DARA), a CD38-targeting monoclonal antibody. DARA kills MM cells via several mechanisms including antibody dependent cellular cytotoxicity (ADCC). Although DARA has improved the outcome of patients, CR is not achieved in all the cases. Besides, most patients that achieve CR will experience relapse. A potential explanation for blunted efficacy of DARA is downregulation of CD38 levels on MM cells and impaired ADCC due to depletion of CD38high NK cells during therapy. ATRA upregulates CD38 levels on target cells and was proposed to improve the efficacy of DARA. NK cell supplementation was tested in a preclinical model, but that had only a modest effect on DARA efficacy, likely due to their short life via DARA-mediated elimination. Methods: We generated CD38 knockout (CD38KO) NK cells from healthy donors via Cas9 RNPs and investigate if these cells boost DARA activity against MM. RNA-seq and cellular metabolic analysis were performed to examine the effect of CD38 deletion on NK cell function. Results: Knockout efficiency was 81.9 ± 6.9% (mean ± SD, N = 5). Very low off-target effects were seen by whole genome sequencing. When compared to paired CD38 wild type (CD38WT) NK cells, CD38KO NK cells showed lower conjugation (2.57% vs. 11.85%, N = 3, p = 0.04), less fratricide (97.3% vs. 54.2%, mean viability, N = 3, p = 0.01), and superior persistence in mice (18.16% vs. 0.42%, mean frequency in blood, N = 5, p < 0.01) in the presence of DARA. Additionally, CD38KO NK cells exhibited enhanced ADCC against all tested MM cell lines and primary samples including CD38low cell lines and primary MM cells from a patient with disease relapse on DARA. Transcriptomic and cellular metabolic analysis revealed that CD38KO NK cells have favorable metabolic shift with higher mitochondrial respiratory capacity (N = 3, p < 0.01). Although ATRA upregulates CD38 levels on MM cell lines, we observed that ATRA treatment upregulates CD38 levels on circulating NK cells in patients. ATRA upregulated CD38 levels on CD38WT NK cells, but not on CD38KO NK cells, and increased their fratricide. Thus, CD38WT NK cells showed impaired overall DARA-mediated cytotoxicity against MM cells in the presence of ATRA, even though those MM cells were sensitized to DARA. Conclusions: We present proof of concept that adoptive CD38KO NK cell therapy has the potential to maximize the efficacy of DARA against MM. Further investigation into the role of metabolic reprogramming of CD38KO NK cells is warranted.
TCR-engineered T-cell therapy through personalized identification of CDR3 clonotypes.
Authors: Zhou Zishan , Pu Yue , Xiao Shanshan , Wang Ping , Yu Yang , Lin Rui , Wang Tao , Jiao Shun Chang
Published: May 2020

e15021

Background: T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancers. Unlike many shared tumor-specific antigens, such as melanoma-associated antigen (MAGE)-A3, MAGE-A4, and New York esophageal squamous cell carcinoma (NY-ESO)-1, neoantigen has garnered much attention as a potential precision immunotherapy. Personalized neoantigen selection serves a broader and more precision future for cancer patients. Methods: Dendritic cells (DCs) derived from adherent monocytes were pulsed with mixed peptides during the maturation phase. CD8+ cells positively selected from PBMCs were incubated with washed DCs. After 21day culture in X-VIVO medium with IL-7 and IL-15, cells were harvested and stimulated with peptides for 6 h. CD137+ cells were sorted by flow cytometric and immediately processed using the 10x Genomic Chromium Single Cell 5' Library & Gel Bead Kit and Chromium Single Cell V(D)J Enrichment Kit. The T-cell TCR libraries were constructed and sequenced on the Illumina HiSeq X Ten platform. The sequencing reads were aligned to the hg38 human reference genome and analyzed using the 10x Genomics Cell Ranger pipeline. The paired TCR α and β chain sequence of each cell was demonstrated with V(D)J analysis. TCR-T cells were constructed using the information of neoantigen specific TCR, and infused to patients. Results: Two patients were treated with the personalized TCR-T treatment. At the first stage, specialized immune cells were harvested and proceeded to single-cell TCR profiling. Then, the single cell sequencing of the first patient's sample revealed the top five neoantigen specific TCR CDR3 clonotypes with the proportion of 25%, 7.67%, 4.81%, 2.79%, and 2.54%, respectively. Similarly, the other patient had the top five TCR CDR3 sequenced with the proportion of 13.38%, 7.04%, 4.21%, 2.83%, and 1.94%, respectively. The results demonstrated that both patients had one or two dominant CDR3 clonotypes, which might reflect the strength of neoantigen in vivo. At the third stage, TCR-T cells were constructed, and infused to the patients. The clinical outcome will be evaluated in the near future. Conclusions: We have generated a pipeline for a highly personalized cancer therapy using TCR-engineered T cells. Although some questions remain to be answered, this novel approach may result in better clinical responses in future treatment.