bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low lymphocyte counts and association with clinical outcomes in hospitalized patients with cancer receiving immune checkpoint inhibitor therapy.
Authors: Young Richard , Panchal Hemali , Ma Weijie , Chen Shuai , Steele Aaron Paul , Iannucci Andrea A. , Li Tianhong 
Published: June 2022

e14600 Background: Immune checkpoint inhibitors (ICIs) improve survivals in a variety of cancer patients by harnessing the immune system. Pre-treatment lymphopenia as measured by absolute lymphocyte counts (ALC) was associated with decreased progression-free survival (PFS) and overall survival (OS) in patients receiving ICIs. During hospitalization ICI treatment is often deferred and efficacy in this population is unclear. Our study explores outcomes and predictive factors for hospitalized patients who received ICI therapy. Methods: Cancer patients who received inpatient ICI were identified in the institutional pharmacy database from 08/2016 to 07/2021. Data were abstracted from electronic medical records. Data were summarized according to frequency and percentage for qualitative variables, and by mean ± standard deviation, median, and range for quantitative variables. The 95% confidence interval for survival was calculated using the exact binomial distribution. PFS and OS were estimated using the Kaplan–Meier method and compared using the log-rank test between groups. Receiver-operating characteristic (ROC) analysis was used to evaluate the discrimination ability of ALC for prognosis. Statistical significance was defined as 2-sided P < 0.05. Results: Of 37 identified patients, 2 were excluded from the ALC analysis due to lack of blood counts. The most common cancer type treated was lung cancer (13, 35.1%). The majority of subjects were men (29, 78.4%) and the median age was 57 (21-79) years. Average hospital stay was 24.2 (95% CI 16.5, 31.9) days, and the most common reasons for admission were initiation of therapy (14, 37.8%) and infection (5, 13.5%). Reasons for inpatient treatment included convenience (6, 16.2%), disposition delays (6, 16.2%), initiation of therapy (13, 35.1%), and emergent or last resort measures (10, 27.0%). Most patients died during the study period, and 5 were alive at the time of data analysis. 10 patients died during the same hospitalization as treatment. Of those who followed up, 22 died within 90 days of inpatient therapy. The median PFS was 0.86 (95% CI 0.43, 1.74) months and median OS was 1.55 (95% CI 0.76, 3.72) months. Pre-treatment ALC < 600 cells/µL were associated with poor PFS (0.33 vs. 1.35 months; HR 6.9, 95% CI 10.8-25.9, P = 0.0053) and poor OS (0.33 vs. 2.34 months; HR 4.66, 95% CI 1.2-17.5, P = 0.0236), respectively. Furthermore, patients with ALC < 600 were less likely to receive a subsequent ICI dose than their counterparts. Conclusions: Administration of inpatient ICI therapy is associated with poor clinical outcomes and high rates of both inpatient mortality and death within 3 months of discharge. The presence of ALC < 600/µL in hospitalized patients was associated with poor clinical outcomes.
Ocular toxicities associated with anticancer therapies: Are we missing something in the blind spot?
Authors: Awasthy Bhawana , Maseeh Arun , Mukherji Prabhati 
Published: June 2022

e15001 Background: Ocular toxicities are common challenges associated with anticancer agents, including small molecules, antibody-drug conjugates (ADC), targeted antibodies, particularly those targeting Epidermal Growth Factor Receptor (EGFR), Mitogen-activated protein kinase (MEK) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). This subject suffers from a paucity of consensus guidelines, especially drug class versus severity of toxicity versus ocular anatomy. The aim of this paper is to examine the ocular side effects of various classes of anticancer therapies. Methods: Approved anticancer drugs known to be associated with ocular toxicity were reviewed as of Dec-2021. US FDA Labels were reviewed, as were further publications on said drugs. Ocular toxicities were then classified based on the anatomy of the eye, class of drug and drug target, severity and the recommended surveillance and management. Results: The most common ocular toxicities were mild including “visual disturbances” and conjunctivitis. Severe toxicities were reported as well, including corneal ulceration, retinal vascular occlusion, optic neuritis, and even cortical blindness. Our review clearly indicates that each class of drugs has a distinct ocular toxicity pattern, including the precise segment of the eye involved, severity and pattern of manifestation. Drug related toxicity involving the anterior segment tends to be of lesser severity, whereas posterior segment toxicity is more severe, and, as such, may result in treatment interruptions. Molecular-pathway-specific toxicity patterns were noted. EGFR inhibitors were associated with corneal-ulceration and microcysts. MEK inhibitor-associated retinopathy (MEKAR) is documented, and drugs (e.g. Trametinib) increase the risk of retinal detachment and retinal vascular occlusion. We noted a pattern of Monoclonal Antibodies (e.g. Cetuximab) having lower adverse events than the small molecule (e.g. Gefitinib) having the similar pathway of action. ADCs (12 US FDA approved) are known to affect various ocular tissues, commonly involving the ocular surface, with intra-class differences. Conclusions: Our review highlights the need for an ophthalmic referral at baseline, prior to initiating anticancer drugs known to cause ocular toxicities. Cancer patients need consensus-based multidisciplinary global standardized algorithms for surveillance, early diagnosis and management of ocular toxicities associated with anticancer therapies.
S1P/ceramides and cytokines as potential biomarkers of response following administration of bxq-350.
Authors: Tapolsky Gilles , Rixe Olivier , Morris John Charles , Wesolowski Robert , Yilmaz Emrullah , Noonan Anne M. , Villano John L. , Curry Richard Charles , Muller Carolyn , Wise-Draper Trisha Michel , Puduvalli Vinay K. , Takigiku Ray 
Published: June 2022

e15007 Background: BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 ) (safety/efficacy results reported in a separate abstract). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and elucidation of potential biomarkers. BXQ-350 is a nanovesicle of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. In nature, SapC is a protein encoded by the Psap gene, and serves as an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism, enzymes which are being investigated as novel therapeutic targets in cancers. Indeed, sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Amongst these sphingolipids, Sphingosine-1-Phosphate (S1P) induces cancer cell survival and proliferation, activates multiple oncogenic pathways, and promotes a pro-tumoral microenvironment. SapC has broad anticancer activity, lowering S1P and increasing ceramides, also inducing an anti-tumoral immune response. Methods: Lipodomic analysis (sphingolipids) and cytokines were analyzed in plasma samples of a subset of patients enrolled in this study. Results: Analysis of plasma biomarker samples, collected throughout the period patients were on study, reveals notable changes of circulating sphingolipids and cytokines. A subset of patients exhibited clinical benefits following BXQ-350 administration (see other presentation for details; ̃17% of the evaluable patients remained on study up to Cycle 6; and 8 patients (̃11%) with PFS> 6 months). Concomitant circulating changes in S1P and other ceramides may be indicative of treatment effect. Also, concurrent changes in circulating levels of pro/antitumoral cytokines were noted. Conclusions: While these results are exploratory and preliminary in nature, these initial results warrant further investigation. These observations will be further explored in specific cancer and non-cancer indications. Clinical trial information: 02859857.
Detection of molecular residual disease (MRD) for cancer management: Lessons from longitudinal profiling of NSCLC patients undergoing chemotherapy or targeted therapy.
Authors: Hsu Pei-Sung , Chen Daniel , Chien Hui-Ping , Yeh Chen , Hong Peter , Lin Shu-Ti , Lee John-See , Lai Hung-Chih 
Published: June 2022

e15020 Background: Identification of cancer patients who are at ongoing risk of relapse remains of high priority to direct effective adjuvant therapy. Plasma circulating cell-free DNA (cfDNA) analyses offer an unprecedented approach to identify patients with molecular residual disease (MRD) earlier than clinical or radiological evidence, detecting drug resistance, progression and relapse with relatively high sensitivity and specificity. Here we used longitudinal surveillance to profile cfDNA mutational landscape undergoing chemotherapy or EGFR-TKI. We demonstrated how cutting-edge NGS and digital qPCR technologies are defining new subgroups of patients with MRD for individually tailored treatment strategy. Methods: Plasma samples were collected from 8 subjects with lung adenocarcinoma, 5 patients were treated with EGFR-TKI and 3 cases by chemotherapy. Overall, 92 longitudinally collected specimens (duration of 31-143 weeks) were analyzed with a 520-gene ultra-deep NGS platform as well as a digital qPCR assay. Standard-of-care tests of CEA, CA19-9 biomarkers and CT radiography were also performed in parallel. Results: The number of somatic mutations detected ranging from 0 to 52 in a sample and correlated strongly with TMB (tumor mutational burden). The concordance of actionable EGFR mutations (L858R, T790M, Ex19Del) detected by NGS and digital qPCR assays was 100% (n = 49/49). NGS assay detected additional driver mutations in ∼20 non-EGFR genes. Majority of EGFR mutations showed directional decline in allelic fraction (AF) after treatment with EGFR-TKI. Patient progressed following EGFR-TKI were registered to undergo chemotherapy based on real-time mutational profiles and did show good responses and PFS. Longitudinal ultra-deep NGS analyses can help detect and stratify MRD, including non-druggable genetic information that could guide best clinical decision-making. Conclusions: Longitudinal ctDNA surveillance of patients treated with EGFR-TKI by a highly sensitive multi-gene NGS panel enables MRD monitoring and can potentially guide a selection of optimal adjuvant therapies earlier, and provide new surrogate endpoints for early registration of these therapies.
Molecular alterations detected on patients with glioblastoma and low-grade glioma: Review of 37 cases.
Authors: Beshiri Kristi , Epaillard Nicolas , Bayle Arnaud , Baldini Capucine , Dumont Sarah Naomie 
Published: June 2022

e15030 Background: Glioblastoma (GBM) is a short term life-threatening tumor, while lower-grade glioma (LGG) is a heterogeneous entity with longer survival due to its natural history. As few therapeutic options emerged in the past decades, innovation is lead by targetable molecular alterations such as FGFR, BRAF, NTRK... Therefore, molecular profiling access is critical for patients. Methods: We collected data from patients with GBM and LGG whose tumor sample underwent a molecular profiling with Foundation Medicine FMI testing trough clinical trials. Results: In the GBM group, we identified 26 patients, 18 males and 8 females. Medium age was 47. Median OS was 20.3 months (IC 95% 14.3-26.2). All patients were IDH wide type, one had a methylated MGMT with 13 unknown. Among them, we identified 126 alterations. The most frequent were: AKT (15.4%), BARD1 (15.4%), CDKN2A (28.5%), CDKN2B (42.3%), CKDN2C (7%), FAM (15.4%), kit (23.1%); MLL (30.7%), MTAP (loss 30.7%,) NF1 (30.7%), NOTCH (23.1%), PDGFRA (26.9%), RB1 (23.1%), tp53 (53.8%). PTEN alteration was present in 13 patients with 3 of them with 2 alterations. EGFR was found with more than 1 alteration in 5 patients: 10 amplifications, 2 rearrangements, 6 deletion and 14 other mutation. Finally, we identified also: 1 patient with a mutation of RET, 2 patients with non-actionable NTRK mutations, 3 MDM2 mutated patients. Two patients with an FGFR alteration underwent a treatment with Erdafitinib. In the LGG group we identified 11 patients, 7 females, with a medium age of 34 years old; median OS was 116.8 months/ 9.6 years (CI 95% 45.8-187.8). All patients were IDH mutated, 2 of them with a IDH2 alteration. 1p19q codeletion was detected in 3 patients with 5 unknown; 1 patent was found to have an MGMT methylation, 8 were not tested. A total of 81 mutations were identified with the most frequent: ATRX (54.5%), CDKN2A (18.1%), EGFR (36.4%) with 2 amplifications and 2 rearrangement; TERT (36.4%), tp53 (54.4%), TSC, NOTCH and PTEN loss in 27.7%. One of the patient has a TMB high (117) and he received immunotherapy in a clinical trial. Each of thr 36 patients had at least 6 mutations. We don’t know the percentage of patients who underwent a molecular profile without any alteration founded. Targetable drivers with a clinical relevance were: FGFR, NTRK, ALK, PTEN, MDM2, CDKN2A and CDKN2B. Conclusions: Molecular profiling gives an important data collection and therapeutic options on poor prognostic tumors such as GBM and LGG and may lead to explore new pathways of innovations.
Analysis of MET genetic aberrations in Chinese solid tumor patients.
Authors: Huang Guanglong , Bian Zhengying , Ma Juan , Chen Siqi , Lu Guanghua , Ding Ran , Bu Fanfeng 
Published: June 2022

e15031 Background: Mesenchymal-epithelial transition (MET) gene encodes a member of the receptor tyrosine kinase family of proteins and is a proto-oncogene. MET gene takes part in various signaling pathways such as PI3K/AKT, Ras/MAPK, and JAK/STAT which are associated with tumor development and progression. This study aimed to reveal MET aberrated characteristics in Chinese solid tumor patients and explore the occurrence of MET oncogenic variants in solid tumors. Methods: This study retrospectively analyzed MET alterations in 1856 solid tumor patients in China from laboratory of Simcere Diagnosis (Nanjing, China) during 2019-2021. Next-generation sequencing (NGS) was performed to detect gene mutations in tumor or blood samples of the patients. Results: We screened out 1856 patients with MET gene alterations from 45717 patients with solid tumor. The high frequency of MET gene alterations was lung cancer (72.8%), colorectal cancer (10.7%), gastric cancer (4.9%), and liver cancer (2.7%). MET gene variants included missense (61.7%), copy number variation (copy number≥5) (15.4%), truncation (7.9%), splicing site variant (7.2%),fusion (1.7%),and in-frame insertion/deletions (0.9%). Among them, MET amplification was detected in 285 patients, and 93 patients carried high-level MET amplification (copy number≥10). High-level MET amplification was most frequently detected in lung cancer (41, 44.1%), gastric cancer (17, 18.3%) and liver cancer (14, 15.1%). MET exon 14 skipping was detected in 287 solid tumor patients (15.5%), of which 277 patients were lung cancer, the remaining were liver cancer, colorectal cancer, gastric cancer, osteosarcoma, melanoma, bladder cancer and glioma. We analyzed MET exon 14 alterations and classified them into 4 subgroups according to the alteration types and locations. The most common alterations were at splice donor sites (215, 74.91%), followed by the splice acceptor sites (35, 12.20%), Y1003 site (5, 1.74%), and other types (32, 11.15%). Other types included insertion or deletion in MET intron 13 or 14, for example, c.3028+21_3028+65del, c.2888-20_2888-11del, c.2888-27_2888-9del, etc. 7 lung cancer patients carried MET exon 14 skipping and MET amplification simultaneously. 36 patients carried MET gene fusions, and mostly were lung cancer (22, 61.1%). The breakpoints often located in exon 2 of MET (4, 11.1%). Conclusions: We discovered MET alterations in multiple types of solid tumors in this study. We found classic MET exon 14 skipping and MET high-level amplification in solid tumors except for lung cancer. It suggested that the activation of MET-driven signaling pathway was ubiquitous in pan-cancer, which might benefit from MET inhibitors.
CtDNA dynamic detection reflects the clinical efficacy following treatment in NSCLC patients.
Authors: Feng Wei-neng , Gu Weiguang , Zhang Hua , Lu Yiyu , Gu Weiquan , Li Minjing , Yang Shuang , Ye Zhi-Jian , Liu Jian , Lin Qing , Liang Yaojun , Chen Haiming , Shi Xiaoliang , You Dong 
Published: June 2022

e15032 Background: EGFR is a major oncogene in non-small cell lung cancer (NSCLC) patients. Although EGFR tyrosine kinase inhibitors (TKIs) have effectively improved the survival of NSCLC patients, acquired drug resistance is a critical clinical challenge. Minimal residual disease (MRD) is the direct cause of tumor recurrence, and the abundance of circulating tumor DNA (ctDNA) can be used to reflect the status of MRD. We sought to identify the evaluation of effect of ctDNA on tumor therapeutic efficacy. Methods: Blood samples from 32 advanced NSCLC patients were dynamically collected at different timepoints (0, 4, 8, 12, months) with 1 sampling in 6 patients, 2 samplings in 15 patients, 3 samplings in 7 patients, 4 samplings in 3 patients, and 5 samplings in 1 patient. Targeted sequencing of 450 cancer-related genes were performed for genomic alteration identification at OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. The average variant allele frequency of each sample was used to represent ctDNA abundance. Results: A total of 32 advanced NSCLC patients harboring EGFR sensitive mutations were enrolled in the study. Patients consisted of 12 (37.5%) males and 20 (62.5%) females, with a median age of 60 years old, ranged from 38 to 82 years old. These patients were randomly divided into TKI monotherapy group (N = 11) or TKI treatment combined with pemetrexed group (N = 21). The percentage of stable disease (SD) was more pronounced in patients receiving TKI combined with chemotherapy when compared to patients treated with TKI monotherapy (47.6% [10/21] vs. 36.4% [4/11], respectively). Less patients experienced the progression of disease (PD) when they were treated with TKI combined with chemotherapy than those receiving TKI monotherapy (52.4% [11/21] vs. 63.6% [7/11], respectively). For patients with PD, ctDNA abundance was progressively increased in 55.6% (10/18) during dynamic monitoring; whereas ctDNA abundance kept stable in 44.4% (8/18) patients, while 6/8 patients did not continue to perform ctDNA detection for more than half a year. In patients experienced SD, ctDNA abundance was declined in 78.6% (11/14) during dynamic monitoring, while 21.4% (3/14) patients displayed elevated ctDNA abundance. These 3 patients did not continue to perform ctDNA detection for more than 10 months. In majority of NSCLC patients (65.6% [21/32]), variation of ctDNA abundance was correlated to the treatment-induced clinical response. Conclusions: In conclusion, our results suggested that the variation of ctDNA abundance could promptly reflect the clinical response of treatment. The dynamic variation of ctDNA/MRD can possibly be considered as a biomarker of clinical efficacy following treatment in NSCLC patients.
Evaluation of the ability of Idylla EGFR to differentiate result of ARMS EGFR in gray area and identify rare mutation variants.
Authors: Qiu Tian , Zhang Fanshuang , Zheng Bo , Junling Li , Ying Jianming 
Published: June 2022

e15033 Background: Molecular testing involving Epidermal growth factor receptor ( EGFR) mutations is recommended for patients with non-small cell lung cancer (NSCLC), especially with lung adenocarcinoma, and is nowadays an essential element of precision medicine. Although amplification-refractory mutation system (ARMS) is one of the most commonly used methods for EGFR mutation detection, it can only detect variants in known gene loci and give indistinct results in gray area occasionally, which may be caused by the input of poor DNA quality or low-abundance variants. Idylla EGFR assay can detect 51 EGFR mutations directly from formalin-fixed, paraffin-embedded (FFPE) samples within 2.5 hours with < 2 minutes of hands-on time, without manual data analysis need, whose accurate and robust have been proven among Caucasian and Chinese patients. But the assay’s ability to detect EGFR mutation in low abundance which may lead the result of ARMS EGFR in gray area or rare variants has never been evaluated. Methods: FFPE samples were retrospectively collected from 98 lung cancer patients followed by EGFR testing using the Idylla system, which were also previously assessed with ARMS-PCR. Forty-six of them were in gray area by ARMS-PCR of EGFR and need to be retested by ARMS-PCR or validated by the third method. In another 52 cases, no mutations were found by ARMS-PCR of EGFR, but mutations were found by next-generation sequencing (NGS). The ability of Idylla EGFR to detect cases with result in gray area and rare variants were analyzed. Results: In 46 cases with result in gray area by ARMS-PCR of EGFR, after retesting or validation by the third method, 37 of them had the same result with Idylla mutation test, with an overall concordance of 80.4%. Idylla EGFR test missed 8 mutational cases (22/30), identified 1 mutational case in addition (15/16). Except 2 cases with higher CQ value than 29, which means the poor DNA quality or low quantity input, low mutational abundance maybe the main reason for no mutation identified by Idylla EGFR test. In 52 cases with rare EGFR variants, Idylla EGFR test identified 9 mutational cases, while 4/9 mutational variants beyond the scope of Idylla EGFR test, 2 20ins, 1 L858R and 1 19del. Five of the 9 mutational cases, Idylla test detected 5 different 19dels. The variants of all the 52 cases beyond the scope of ARMS-PCR of EGFR, and ARMS-PCR of EGFR didn’t find mutation. Conclusions: The Idylla system provides a rapid and accurate ability to differentiate result of ARMS-PCR of EGFR in gray area and identify more rare mutation variants which may decrease the repeat testing or validation. But the ability of NGS to find more actionable variants is still important.