bluuebunny/crossref_metadata_2025_split huggingface dataset:
Herpes zoster in chronic lymphocytic leukemia: Effect of vaccination and treatment.
Authors: Antao Nirav , Chilkulwar Abhishek R. , Luo Suhong , Carson Kenneth Robert , Sanfilippo Kristen Marie , Schoen Martin W. 
Published: June 2021

7527 Background: Patients with Chronic Lymphocytic Leukemia (CLL) are susceptible to infections due to impaired humoral immunity as a complication of the disease, treatments received and age at diagnosis. Herpes zoster (HZ) is a painful, vesicular rash from reactivation of varicella-zoster virus that is common in immunocompromised patients. While HZ vaccines can reduce both varicella-zoster reactivation and post-herpetic neuralgia, vaccination rates are low. The aim of this study is to determine the effect of vaccination on rates of HZ infection in patients with CLL. Methods: We identified patients diagnosed with CLL between September 1999 and October 2015 using Veterans Administration Central Cancer Registry (VACCR). Pharmacy records were used to identify patients who received treatment for CLL and HZ. HZ events were defined as patients with International Classification of Diseases 9th Revision (ICD-9) codes for HZ infection (053) or prescriptions of acyclovir or valacyclovir at a dose of 1500 mg/day or higher or famciclovir at a dose of 1000 mg/day or higher without a diagnosis of Herpes simplex or Bell’s palsy, or an ICD-9 code and prescription above. Cox proportional hazards regression model was used to assess the association between vaccination as a time-varying exposure and developing HZ while controlling age at CLL diagnosis, co-morbidity score, and receipt of first and second line chemotherapy. The study was approved by the St. Louis VA Medical Center institutional review board. Results: A cohort of 7155 patients with CLL was identified using VACCR. 2640 patients (36.9%) and 1161 patients (16.2%) received first and second line chemotherapy respectively. Mean age at first chemotherapy was 69.5 years. We detected 1115 cases of HZ (15.6%) using ICD-9 codes, prescriptions or both. 615 patients (8.6%) received HZ vaccinations. Patients with HZ were younger (mean 68.0 vs. 69.8 years, p < 0.001), had similar co-morbidities, and were more likely to get treatment for CLL (58.1% vs. 33.0%, p < 0.001). Using a time-varying analysis, there was a trend for HZ vaccine to decrease the risk of developing HZ (HR 0.71, 95% CI 0.49-1.04, p = 0.082). When adjusting for age and co-morbidity, patients with CLL treated with first line chemotherapy had a higher risk of HZ (HR 2.34, 95% CI 2.02-2.71, p < 0.001) compared to those never receiving therapy. Second line chemotherapy increased risk of HZ (HR 1.32, 95% CI 1.13-1.55, p < 0.001) beyond first line treatment. Conclusions: HZ is prevalent in patients with CLL and affects younger patients who require chemotherapy. The risk of developing HZ increases in recipients of first and second line chemotherapy. In the time-varying analysis, there was a trend towards decreased infection in patients who received HZ vaccination. Further studies in a more modern cohort that assess infection risk using a larger vaccinated group with the newer and more effective HZ vaccine are warranted.
NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.
Authors: Granger David , Gohil Satyen , Barbarulo Alessandro , Baccaro Annalisa , Muczynski Vincent , Chester Kerry , Germaschewski Fiona , Batten Toby , Brown Kathryn , Cook Sarah , O'Donovan Kieran , Jasani Parag , Nathwani Amit C. , Phillips Peter 
Published: June 2021

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]
IL-1 receptor antagonist for prevention of severe immune effector cell-associated neurotoxicity syndrome.
Authors: Oliai Caspian , Crosetti Anna , De Vos Sven , Eradat Herbert , Mead Monica Diane , Larson Sarah Marie , Tsai Steven , Liu Annabel , Khachatrian Gina , Hannigan Christopher , Yamada Reiko E. , Rokni Neiki , Timmerman John 
Published: June 2021

7566 Background: Progress in chimeric antigen receptor (CAR) T-cell therapy has included reduction in life-threatening toxicity. Rates of severe cytokine release syndrome (CRS) have declined from 50% in early trials to 7% in the most recent real-world experience. However, rates of severe immune effector cell-associated neurotoxicity (ICANS) associated with axicabtagene ciloleucel (Axicel) remain unchanged. IL-1 is a major driver of ICANS pathophysiology that is produced upstream of IL-6. The IL-1 receptor antagonist, Anakinra, can prevent neurotoxicity in animal models when given at fever onset. We present our early experience of the first 13 participants enrolled into a phase II trial evaluating Anakinra to prevent severe ICANS (NCT4205838). Methods: This investigator-sponsored trial included adults eligible for standard-of-care Axicel for large B-cell lymphoma after ≥2 lines of intensive chemoimmunotherapy. Participants received Anakinra 100 mg SQ q6h x 12-36 doses until ICANS returned to grade ≤1. The trigger to initiate Anakinra was any grade ICANS or grade ≥3 CRS in the absence of ICANS. A protocol modification, made after the first 3 participants were treated, changed the trigger for Anakinra to grade ≥2 CRS. In addition to Anakinra, all participants received standard-of-care interventions for CRS and ICANS. The primary objective is to estimate the efficacy of Anakinra in preventing severe ICANS (grade ≥3) according to ASTCT 2018 consensus grading. Results: To date, 13 participants have been enrolled, and 7 met criteria to initiate Anakinra and received the first dose prior to severe ICANS. Median age was 56 years (range, 23-84 years). Of the 7 participants whom received Anakinra prior to severe ICANS, only 1 of 7 (14%) developed grade 3 ICANS. The most common adverse event was injection site reaction, which peaked at grade 2. There were no unexpected toxicities. Once the protocol was amended to initiate Anakinra for grade ≥2 CRS (N = 4), no participant developed severe ICANS, and only one participant met the institutional standard to receive corticosteroids (Table). Conclusions: Anakinra is feasible to initiate in the non-prophylactic setting in patients at increased risk for severe ICANS. These early results demonstrate potential to reduce severe ICANS associated with Axicel to a rate similar to other CAR T-cell products, and to reduce corticosteroid use. Further enrollment to the pre-planned sample size of N=36 is required to demonstrate statistical efficacy. Serum IL-1 analysis is also ongoing. Clinical trial information: NCT4205838. [Table: see text]
Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.
Authors: Tada Hirohito , Mitsudomi Tetsuya , Yamanaka Takeharu , Sugio Kenji , Tsuboi Masahiro , Okamoto Isamu , Iwamoto Yasuo , Sakakura Noriaki , Sugawara Shunichi , Atagi Shinji , Takahashi Toshiaki , Hayashi Hidetoshi , Okada Morihito , Yoshioka Hiroshige , Inokawa Hidetoshi , Takahashi Kazuhisa , Higashiyama Masahiko , Yoshino Ichiro , Nakagawa Kazuhiko ,   West Japan Oncology Group
Published: June 2021

8501 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.
Early detection of lung cancer using cfDNA fragmentation.
Authors: Mathios Dimitrios , Johansen Jakob Sidenius , Cristiano Stephen , Medina Jamie , Phallen Jillian , Richter Larsen Klaus , Bruhm Daniel , Niknafs Noushin , Nielsen Hans J. , Meijer Gerrit A. , Andersen Claus Lindbjerg , Bojesen Stig Egil , Scharpf Robert , Velculescu Victor E. 
Published: June 2021

8519 Background: Lung cancer incidence and mortality are increasing worldwide despite more effective treatments. This is primarily due to the late stage of diagnosis when treatments are less effective. Although large randomized trials have demonstrated a significant decrease in lung cancer mortality through screening of high-risk individuals with chest low dose computed tomography (LDCT), LDCT has made little impact in the community, mainly due to lack of accessibility. There is therefore an unmet clinical need for development of cost-effective and easily implemented tests for early lung cancer detection. Methods: We have previously shown that altered genome-wide fragmentation of cell free DNA (cfDNA) is a common characteristic of many cancers. In this study, we leverage this knowledge to increase the sensitivity of lung cancer detection by interrogating characteristics of the size distribution of cfDNA fragments across the genome using machine learning methods. The approach we present, called DELFI (DNA evaluation of fragments for early interception) generates a score that reflects the presence of tumor-derived DNA in plasma based on a multi-feature genomic analysis that assesses millions of cfDNA fragments for tumor-derived genomic and epigenomic changes in a small amount of blood (2-4 mls) via inexpensive low coverage (1-2x) whole genome sequencing. We applied this methodology in a prospectively collected cohort of 365 individuals under investigation for lung cancer and we prospectively validated it in a separate case-control cohort of patients with newly diagnosed early stage lung cancer as well as individuals without cancer (n=427). Results: These analyses revealed high performance for detection of early and late stage disease (Table). When DELFI was used as a prescreen for LDCT it increased specificity from 58% with CT imaging alone to 80% using the combined approach. The DELFI score was significantly associated with T and N stage in lung cancer cases (p<0.0001) as well as with overall survival (p=0.003). In a multivariable analysis including age, histology and stage, DELFI score was an independent prognostic factor of overall survival (HR=2.53; p=0.0003). Finally, we determined that genome-wide fragmentation profiles can be used to distinguish small cell lung cancer from non-small cell lung cancer with high accuracy (AUC 0.98). Conclusions: These findings provide key insights into cfDNA fragmentation in patients with cancer and a new and easily accessible avenue for non-invasive diagnosis and molecular profiling of lung cancer.[Table: see text]
Minimal residual disease (MRD) in patients with resected stage I NSCLC: Results of the prospective adjuvant IFCT-0703 trial.
Authors: Vasseur Damien , Jovelet Cécile , Cozic Nathalie , Mazieres Julien , Barlesi Fabrice , Bennouna Jaafar , Gervais Radj , Moreau Lionel , Berard Henri , Molinier Olivier , Moro-Sibilot Denis , Souquet Pierre Jean , Amour Elodie , Morin Franck , Zalcman Gerard , Soria Jean-Charles , Westeel Virginie , Lacroix Ludovic , Besse Benjamin 
Published: June 2021

8526 Background: MRD aims to detect circulating biomarkers of micrometastatic disease and ultimately predict recurrences. The IFCT-0703 randomized phase II trial failed to show a benefit of 6 months adjuvant pazopanib (P) vs. placebo after resection of stage I NSCLC (7th TNM edition). The outcome of pts based on their MRD status has been evaluated. Methods: Blood samples were collected in EDTA tubes (Becton Dickinson Company) after surgery (T0), after 3 months (T3) of P or placebo and at the end of treatment (T6). Plasmas were obtained after double centrifugation of total blood. Total nucleic acid was extracted using the Maxwell RSC LV plasma kit (Promega) according to the manufacturer’s protocol. Samples were quantified using the QuBit dsDNA HS Assay kit on a QuBit 3.0 flurometer (Thermo Fisher Scientific). Molecular analysis was performed by next generation sequencing using the Oncomine Lung cfDNA Assay (ThermoFisher Scientific). Two MRD definitions were tested : 1) high level of DNA in the blood or 2) any mutation detected by the standard bioinformatic pipeline was considered present, whatever the allelic fraction. Results: 143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Among the 119 pts with evaluable T0 samples, 27 pts recurred and 14 died. Median DNA concentration ([DNA]) was 6.6 ng/ml and an increase of [DNA] of 10 ng/ml was found prognostic of poor DFS and OS, HR=1.4, 95%CI [1.14-1.72], p=0.0016 and HR=1.62, 95%CI [1.15-2.30], p=0.0057 respectively. In 81 pts with available T0-T6 samples, [DNA] variation had no different impact on DFS and OS, in the P arm and the placebo arm. ctDNA mutations (ctDNA+) were detected in 31/119 pts. ctDNA+ were more frequent in samples with high DNA quantity (p=0.0002). Genes mutated at T0 were TP53 in 16, NRAS in 6, MAP2K1 in 2, KRAS in 1, EGFR in 5, BRAF in 1, ALK in 2. 29 pts had 1 mutation, 2 had 2 mutations. DFS and OS were similar between pts with or without ctDNA+ : HR= 1.038 (95%CI 0.438-2.456, p=0.93) and 1.193 (95% CI 0.367-3.882, p=0.77) respectively. Among 27 pts with ctDNA+ at T0 and available sample at T6, 23 had no more mutations at T6. Two pts had a ctDNA+ only at T6 (not at T3), one of them had a recurrence at 7 months. Conclusions: Post-operative ctDNA mutations are found in 26.0% of the pts but their positivity had no impact on DFS or OS. In contrast, DFS and OS were poorer in pts with increased plasma DNA concentration. ctDNA mutations status do not recapitulate the complexity of MRD characterization. NGS will be performed on matched tissues in order to refine MRD definition. Clinical trial information: NCT00775307.
Prognostic value of SUVmax on FDG-PET/CT before and after stereotactic body radiotherapy (SBRT) on recurrence and survival in early-stage non-small cell lung cancer (NSCLC).
Authors: Deshpande Saarang , Podder Tarun Kanti , Zhang Yuxia , Zheng Yiran , Grubb William , Kharouta Michael , Linden Philip Aaron , Biswas Tithi 
Published: June 2021

8539 Background: Stereotactic body radiotherapy (SBRT) is the standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of FDG-PET/CT before and after SBRT may stratify risk of disease recurrence and survival outcomes. Methods: Patients with T1-2N0M0 NSCLC who underwent PET/CT prior to SBRT (50-60 Gy over 3-5 fractions) between 2012 and 2019 were retrospectively identified. Pre-SBRT SUVmax and change in SUVmax at 3 and 6 months after SBRT were assessed as predictors of local control (LC), progression-free survival (PFS), and overall survival (OS). Optimal cutoff points for comparison were determined by receiver operator characteristic (ROC) analysis. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. Results: Out of 163 patients identified, 71 (43.6%) underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 – 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. Pre-SBRT SUVmax greater than 12.3 had an aHR of 2.80 (95% CI 1.3 – 6.2, p = 0.011) for PFS. A cutpoint of 12.6 for pre-SBRT SUVmax had an aHR of 3.00 (95% CI 1.6 – 5.8, p = 0.003) for OS. Pre-SBRT SUVmax did not significantly predict LC. A 3-month SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 – 0.91, p = 0.018). At 6 months following SBRT, a cutoff point of a 53% decrease in SUVmax was associated with better LC (p = 0.038). Change in SUVmax was not significantly associated with PFS or OS at either time point. Performance status significantly predicted PFS and OS in all models. No other factors were significant. Conclusions: Pre-treatment SUVmax cutoffs can predict PFS and OS in early-stage NSCLC. At both the 3- and 6-month time points following SBRT, cutoff values for change in SUVmax can stratify risk of local recurrence.[Table: see text]
Multiomics analysis reveals high-immune infiltration in tumor-adjacent lung tissues affects the prognosis of stage I NSCLC.
Authors: Ying Lisa , Su Dan , Chunliu Zhang , Tian Yiping , Bai Jing , Wang Canming , Fang Jianfei , Futreal Andrew , Zhang Jianjun 
Published: June 2021

8540 Background: Along with the wide application of low-dose spiral CT in lung cancer screening, a large number of resectable patients with lung cancer are identified, especially stage I Non-Small Cell Lung Cancer (NSCLC). However, their prognosis varies greatly and 5-year recurrence rate of stage I NSCLC is around 30%. Therefore, it is crucial to explore the potential mechanism of recurrence of early NSCLC. Methods: Eighty-seven patients with stage I NSCLC were enrolled from April 2008 to July 2015, including 79 squamous carcinoma and 28 adenocarcinoma. Frozen tumor tissues and paired tumor-adjacent lung tissues were collected to employ targeted panel sequencing, RNA sequencing and TCR repertoire sequencing. Results: Ninety-five non-silent mutations were detected in tumor-adjacent lung tissues with a median tumor mutation burden of 1.5/Mb, significantly lower than that in tumor tissues (11/Mb), p < 0.05. 42 mutations were specifically detected in the adjacent normal tissues, enriching in the immune response pathways. Comparing with paired tumors, tumor-adjacent lung tissues were found more favorable immune infiltration including higher immune cell activity like CD8+ T cell (0.50 vs 0.43, p < 0.0001), up-regulated immune-associated pathways, higher TCR clonality (0.19 vs 0.18, p < 0.05), less loss of heterozygosity (LOH) of human leukocyte antigen (HLA) (6.25% vs 50%, p < 0.0001) and observed predicted neoantigens expression (1 vs 128, p < 0.01). However, more shared viral-associated TCRs in tumor and tumor-adjacent tissues were found using the GLIPH algorithm. Prognostic analysis showed patients with higher overlap of TCR in tumors and tumor-adjacent lung tissues were prone to recur in five years. Furthermore, patients with higher immune infiltration in tumor-adjacent lung tissues had favorable outcomes than those with lower immune infiltration (HR: 0.37 for DFS, p < 0.05, HR: 0.31 for OS, p < 0.05), irrelevant of the infiltration level in tumor tissues. Conclusions: Immune microenvironment in tumor-adjacent lung tissues plays important roles in progress of stage I NSCLC.