bluuebunny/crossref_metadata_2025_split huggingface dataset:
A risk stratification model for toxicities in phase 1 immuno-oncology (P1-IO) trials.
Authors: Hernando-Calvo Alberto , Salawu Abdulazeez , Oliva Bernal Marc , Araujo Daniel Vilarim , Liu Zhihui (Amy) , Chen Rachel , Siu Lillian L. 
Published: June 2021

2648 Background: Despite an exponential increase in the number of potential targets in the immuno-oncology (IO) field, lack of risk models to predict toxicities remains a challenge in early drug development. We proposed a risk stratification strategy and investigated whether different IO classes may be associated with incremental risk of toxicities. Methods: A systematic search for IO studies from 01/2014 to 10/2020 was conducted. Among the 12053 abstracts screened, 254 reporting phase I-IO trials were selected. Type of IO treatment (IO monotherapy [mono] vs IO combination [comb]), therapeutic class (e.g. IO, molecularly targeted agents [MTA]), and dose escalation method (rule-based, model-based and model-assisted) were collected. A risk scoring model was developed after expert consensus: treatment-related deaths (1:yes, 0:no), incidence of G3/G4 treatment related adverse events (TRAE) or treatment emergent adverse events (TEAE) (0 if 1-29%,1 if ≥30-49%, 2 if ≥50%), incidence of ≥G2 cytokine release syndrome (1:yes, 0:no), incidence of ≥G2 encephalopathy (1:yes 0:no) and incidence of dose-limiting toxicity (DLT) (0:no, 1:lab, 2:clinical). Risk categories were defined by summing all points (0 = low, 1-2 = intermediate, 3+ = high) and were correlated with type of IO treatment, therapeutic class and dose escalation method. Results: Of 254 P1-IO trials reviewed, 228 (90%) were scorable, 26 were not (25 due to lack of AE data). Up to 10/26 (38%) of non-scorable studies were cell therapies. Among the 228 scorable studies, 120 (53%) scored 0, 65 (28%) scored 1-2, 43 (19%) scored 3+; 24 (11%) and 125 (55%) did not provide no. of pts with G3/G4 TRAEs or TEAEs respectively. A significant association was observed between risk categories and therapeutic class (p<0.001) (see table). Additionally, IO-MTA and IO-IO were both associated with an increased risk of toxicity as compared to IO-mono (OR=3.91 (95%CI 1.7-9.2), p=0.002) and (OR=2.79 (95%CI 1.2-6.5), p=0.02) respectively. There was no association between dose escalation method and risk of toxicity (p=0.95), but 182 (92%) used rule-based methods. Conclusions: Our results suggest that different IO classes are associated with different risks of toxicity. This risk classification strategy may guide future clinical trial design. Additionally, standards for reporting toxicities in P1-IO trials are urgently needed.[Table: see text]
Pembrolizumab patient reported benefits: A perspective based on multiple tumors.
Authors: Wu Elise , Miskala Paivi H , Siddiqui Mohd Kashif , Rai Pankaj , Hajdukova Eva , Erpelding Nathalie , Vanderpuye-Orgle Jacqueline 
Published: June 2021

2650 Background: Pembrolizumab is a programmed death ligand receptor-1 (PD-L1) treatment indicated for multiple tumors. Patient-reported outcomes (PRO) benefit has only been reported at the tumor level, while a holistic review of PRO effects across tumor types has been missing. We performed a systematic review of PRO to assess the overall health-related quality of life (HRQoL) among cancer patients treated with pembrolizumab across multiple tumors. Methods: We systematically searched PRO evidence published from January 2014 to April 2020 across approved pembrolizumab indications using Embase, MEDLINE, and CENTRAL. Eligible studies were required to assess cancer patients treated with pembrolizumab (200 mg or 2mg/kg Q3W) and report PROs and/or HRQoL. The PRO evidence was summarized into three categories: short-term (≤Week 12), mid-term (Week 13-Week 24), and long-term (Week 25-Week 52). A clinically meaningful difference in HRQoL is defined as at least a 10 points improvement or deterioration relative to baseline; a change between ± 10 points is defined as stable. Results: We screened 1,262 citations, of which 16 publications reported EORTC QLQ-C30 data; 10 (9 trial-based studies; 1 observational study) of 16 publications reported global health status (GHS) mean change from baseline (CFB) across six indications. Within trial based studies in first-line setting (n=3 studies), the short-term, mid-term, and long-term GHS changes from baseline vary from 0.5 to 2.1, 1.2 to 8.4, and 1.6 to 2.5, respectively. For second-line plus setting (n=6 studies), GHS changes vary from -3.3 to 8.6, -1.0 to 10.9, and -0.9 to 9.2, respectively. Eight trial-based publications reported EORTC QLQ-C30 domain data as CFB. Short- or mid-term mean changes in functioning domain data showed improvement or stability in emotional, cognitive, role, and social functioning. Short-term deterioration in physical functioning was observed for 1 study, whereas physical functioning remained stable for other studies. For symptom domains, deterioration was not observed in any studies; mid-term improvement was reported by one study each in fatigue, dyspnea, and appetite loss; 2 studies reported mid-term improvement in pain. Conclusions: This is the first study that presented pembrolizumab PRO evidence at the product level. This study suggests that most pembrolizumab-treated patients maintained or improved HRQoL relative to baseline at pre-defined timepoints. This review's limitations include potential publication bias and lack of meta-analytic methods in reporting results. Nevertheless, these findings provide additional information about pembrolizumab's benefits to physicians and patients from a patient-centric perspective.
Impact of multidisciplinary severe immunotherapy complication service on outcomes for cancer patients receiving immune checkpoint inhibition.
Authors: Zubiri Leyre , Molina Gabriel E. , Mooradian Meghan , Durbin Sienna , Dougan Michael , Thomas Molly , Faje Alexander , Rengarajan Michelle , Guidon Amanda C , Chen Steven T. , Nasrallah Mazen , Kohler Minna , Sise Meghan , Neilan Tomas G , Zlotoff Daniel A , Bardia Aditya , Sullivan Ryan J. , Semenov Yevgeniy R. , Villani Alexandra C , Reynolds Kerry Lynn 
Published: June 2021

2654 Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.
Concordancy of immunocytochemistry profiling of circulating tumor cells with immunohistochemistry for analysis of therapeutically relevant biomarkers.
Authors: Akolkar Dadasaheb B , Patil Darshana , Murthy Sudha S , Bendale Kiran , Patil Revati , Datta Vineet , Fulmali Pradip , Fulmali Pooja , Adhav Archana , Patel Shoeb , Chougule Rohit , Ranjan Vishal , Khan Shabista , Dhasarathan Raja , Apurwa Sachin , Schuster Stefan , Srinivasan Ajay , Datar Rajan 
Published: June 2021

3047 Background: Immunohistochemistry (IHC) profiling of tumor tissue is the present standard for evaluation of therapeutically relevant biomarkers such as ER, PR, HER2, AR, ARv7, PD-L1 and MMR for selection of targeted, endocrine and checkpoint inhibitor therapy selection. However, this critical analysis is dependent on availability of tumor tissue obtained by an invasive biopsy. Challenges to this analysis include insufficient tumor tissue and inability to perform a repeat biopsy to obtain fresh tumor tissue. We have previously described an approach for negative enrichment of Circulating Tumor Cells (CTCs) from peripheral blood and for Immunocytochemistry (ICC) profiling of these CTCs for detection of diagnostically relevant tissue of origin and subtype specific markers, concordant with tumor tissue analysis. Methods: In the present study, we determined concordance between tumor tissue (HPE) and CTCs (ICC) for ascertaining the status of therapeutically relevant markers ER, PR, HER2, AR, ARv7 PD-L1 and MMR. We evaluated 201 matched pairs of tumor tissue (FFPE blocks) and CTCs obtained from peripheral blood. Results: Among the 743 paired assays on matched tumor tissue and CTCs, concordance (positive or negative) was observed in 651 matched pairs (87.6%). The concordance was 82.9% for ER, 100% for PR, 90.2 % for Her2, 93.8% for AR, 90% for Arv7, 85.1% and 87.6% for PD-L1 clones 22c3 and 28-8, and 85.6% for MMR (MLH1, MSH2, MSH6, and PMS2). Conclusions: The study findings indicate that ICC analysis of CTCs may be able to substitute IHC analysis of tumor tissue for profiling of therapeutically relevant markers. This approach may have application in cases where tumor tissue may be limiting and / or where an invasive biopsy to obtain tumor tissue may be unviable.
Development of extracellular vesicles-based classifier for detection of early-stage bladder, ovarian, and pancreatic cancer.
Authors: Hinestrosa Juan Pablo , Kurzrock Razelle , Lewis Jean , Schork Nick , Kamat Ashish M. , Lowy Andrew M. , Eskander Ramez Nassef , Perrera Orlando , Searson David , Clark Iryna , Balcer Heath , Adler Mark J. , Lippman Scott Michael , Krishnan Rajaram 
Published: June 2021

3048 Background: Many cancers are lethal because they present with metastatic disease. Because localized/resectable tumors produce vague symptoms, diagnosis is delayed. In pancreatic cancer, only ̃10% of patients survive five years, and it will soon become the second leading cause of cancer-related deaths in the USA. For patients with metastatic disease, the 2- and 5-year survival is < 10% and ̃3%, respectively. For the few patients with local disease, 5-year survival is ̃40%. Many other cancers have comparable differences between early- and late-stage disease. It is apparent a diagnostic assay for early-stage cancers would transform the field by minimizing the need for aggressive surgeries and other harsh interventions, and by its potential to increase survival. Identifying cancer-specific aberrations in blood-based “liquid” biopsies offers a prospect for a non-invasive cancer detection tool. In the bloodstream, there are extracellular vesicles (EVs) with cargoes including membrane and cytosolic proteins, as well as RNA and lipids derived from their parent cells. Methods: We used an alternating current electrokinetics (ACE) microarray to isolate EVs from the plasma of stage I and II bladder (N = 48), ovarian (N = 42), and pancreatic cancer patients (N = 44), and healthy volunteers (N = 110). EVs were analyzed using multiplex protein immunoassays for 54 cancer-related proteins. EV protein expression patterns were analyzed using stepwise logistic regression followed by a split between training and test sets (67%/33% respectively). This process enabled biomarker selection and generation of a classifier to discriminate between cancer and healthy donors. Results: The EV protein-based classifier had an overall area under curve (AUC) of 0.95 with a sensitivity of 71.2% (69.4% – 73.0%, at 95% confidence interval) at > 99% specificity. The classifier’s performance for the pancreatic cancer cohort was very strong, with overall sensitivity of 95.7% (94.6% – 96.9%, at 95% confidence interval) at > 99% specificity. Conclusions: EV-associated proteins may enable early cancer detection where surgical resection is most likely to improve outcomes. The classifier’s performance for the initial three cancers studied showed encouraging results. Future efforts will include examining additional cancer types and evaluating the classifier performance using samples from donors with related benign conditions with the aim of a pan-cancer early detection assay.
Dermatologic adverse events of brentuximab vedotin: Characteristics, management, and their relationship with dose regimen.
Authors: Oh Yuna , Bang Alexander , Kurtansky Nicholas , Khan Niloufer , Pulitzer Melissa , Noor Sarah 
Published: June 2021

3049 Background: Owing to its high efficacy and tolerability, brentuximab vedotin (BV) is increasingly being favored over other aggressive systemic therapies for the treatment of various CD30+ Hodgkin and non-Hodgkin lymphomas, including peripheral T-cell lymphoma and cutaneous T-cell lymphomas. Dermatologic adverse events (dAE) are one of the most common toxicities associated with BV but data regarding their characteristics including correlation to dose, time to occurrence, and management is scarce. We aim to describe the clinical and pathologic characteristics of dAEs associated with BV, their relationship with administered dose regimen, and available management strategies. Methods: An IRB-approved retrospective analysis was conducted for all patients who had received at least one cycle of BV from Memorial Sloan Kettering Cancer Center in 2009-2020. Logistic regression, χ2, student’s t-test were performed for univariate analyses. Kaplan-Meier survival and multivariate Cox proportional hazard model evaluated dAE occurrence stratified by 5 major dose regimens (single cycle, 1.2mg q1w, 1.2mg q2w, 1.2mg q3w, 1.8mg q3w). Results: Of 611 patients, 201 experienced dAE with median time-to-event of 24 days and 29% experiencing > 1 dAEs. Rash was the most common (62%; 142/230), followed by alopecia (20%) and xerosis (13%). For rash, 50% reported involvement of only the extremities and/or acral sites compared to 25% who had generalized rash. Of those reported (111), 68 patients had grade 1 dAE (61%), 38 grade 2 (34%), and 5 grade 3 (5%)-all grade 3 were rash (maculopapular/morbilliform). 14 cases (7%) resulted in treatment interruptions and 6 in discontinuations due to dAEs (3%). Pathology were often nonspecific consistent with a hypersensitivity reaction: spongiotic/psoriasiform dermatitis with perivascular lymphocytic infiltrates . Patients undergoing weekly regimen were at a statistically and clinically significantly higher risk of dAE during the first 100 days of BV treatment (p = 0.001). Between the two most frequently administered dose regimens (1.8mg vs. 1.2mg, q3w), the higher dose carried 105% higher risk for dAE (HR: 2.047, p = 0.053). Those who had received a single cycle of BV had the lowest risk compared to all other regimen (1/42, p = 0.001). Topical and/or systemic steroids were most frequently prescribed (43%) with 12% of patients requiring systemic steroids. Other treatments varied ranging from antihistamines to moisturizers. Conclusions: Understanding of the detailed characteristics, management strategies, dose-dependent effects associated with BV is critical to provide clinical guidance for primary providers and minimize treatment interruptions or discontinuations. The results overall suggest that the risk for dAEs is dose-dependent with those undergoing frequent dosing regimens having a greater risk, although most dAEs remain mild or low-grade.
Sputum supernatant as a viable alternative for liquid biopsy in advanced non-small cell lung cancer.
Authors: Zhou Cheng-Zhi , Xie Xiaohong , Wu Jianhui , Guo Bingpeng , Qin Yinyin , Lin Xinqing , Liu Ming , Qiu Luting , Zou Xiao , Chen Zhange 
Published: June 2021

3053 Background: Sputum has previously attracted attention as a potential medium for detecting genetic and epigenetic alterations in early-stage lung cancer. Recent progress in advanced non-small cell lung cancer (aNSCLC) has highlighted plasma as an option in scenarios where tissue specimens are unavailable. In this study, we investigated the feasibility of mutation profiling with sputum from aNSCLC patients. Methods: Matched tissue (TIS), whole blood, and either induced or spontaneous sputum were collected from 42 prospectively enrolled, previously untreated patients with stage IIIB-IV NSCLC. Eight and two milliliters of whole blood and sputum were respectively used for preparation of plasma (PLA) and sputum supernatant (SPU). Capture-based targeted sequencing of TIS, PLA and SPU samples was performed with a panel of 520 cancer-related genes. Results: The cohort had a median age of 59 (range 26-79) with a majority of men (31/42). Thirty-five patients were diagnosed with lung adenocarcinoma (LUAD) and the remaining seven with squamous cell carcinoma (LUSC). There were more non-smokers (26/42) than smokers. Most patients (34/42) had metastatic disease. First, we assessed the performance of three sample types in terms of key quality control indices. PLA and SPU showed maximum allelic fraction that were both significantly smaller than that of TIS. Subsequently compared was positive detection rate, TIS, PLA, and SPU achieved respective rates of 92.9%, 71.4%, and 59.5%, revealing comparable levels between PLA and SPU samples (p = 0.36). Rates of detection were highly similar between induced (54.6%) and spontaneous sputum (61.3%), but were higher in LUSC (85.7%) than in LUAD patients (54.3%) although this difference was not statistically significant (p = 0.21). Furthermore, detection rates rose in smokers (81.3% for PLA and SPU, 100% for TIS). Next, using TIS as the gold standard, we compared the sensitivity of detecting eight established driver alterations in NSCLC with the two liquid biopsies. SPU and TIS achieved respective levels of 50.0% and 70.0%, which, similar to detection rate, improved to 88.9% (8/9) and 77.8% (7/9) in the smokers subgroup. Importantly, detection of altered KRAS and ALK was more sensitive with SPU (6/6, 2/3, entire cohort) than with PLA (5/6, 1/3). For EGFR mutation, which occurred mainly in nonsmokers, the sensitivity was considerably lower in SPU (4/14, entire cohort) than in PLA (12/14). Detection of mutant MET, however, appeared difficult for both biopsies (0/4). In addition, there was a high level of correlation between estimates of tumor mutational burden based on PLA and on SPU (Pearson r2 = 0.58). Conclusions: Our study demonstrated that for aNSCLC patients, sputum supernatant demonstrates comparable performance as plasma. Sputum is therefore a viable alternative for profiling for established driver alterations in aNSCLC, especially in smokers.
A phase II study investigating biological effects of maintenance usage of hydroxychloroquine on Par-4 levels in patients with resected tumors.
Authors: Wang Peng , Burikhanov Ravshan , Weiss Heidi , Jayswal Rani , Arnold Susanne M. , Villano John L. , Rangnekar Vivek 
Published: June 2021

3085 Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.