bluuebunny/crossref_metadata_2025 huggingface dataset:
The analysis of BRAF fusions in Chinese patients with glioma.
Authors: Cheng Chuandong , Ji Ying , Han Tiantian , Guo Didi , Sun Weijie , Lu Guanghua , Bu Fanfeng
Published: June 2022

e14031

Background: KIAA1549-BRAF fusion is the most common genetic event in pilocytic astrocytoma (PA), and leads to activation of the mitogen activated protein kinase (MAPK) signaling pathway. KIAA1549-BRAF fusion has been considered to be a key variant of PA in WHO CNS5, however, fusions of BRAF with other partner genes leading to MAPK pathway activation, have been described rarely. Herein, we explore BRAF fusions profiles in Chinese glioma patients. Methods: Next generation sequencing of 131-gene profiling was performed to analyze BRAF fusions from 1955 Chinese brain tumor patients in 2019-2021. BRAF fusions were detected by following the standard operating procedure (SOP). We screened out the BRAF fusions, and calculated the mutation frequency and other rare BRAF gene fusions. Results: A total of 49 cases were detected with BRAF fusions, 36 cases were children (< 18 years old), and 13 cases were adults, with a mean age of 13 years (0-57 years). Interestingly, 39(80%) of them were KIAA1549-BRAF fusions, the most common fusion is between KIAA1549 exon 16 and BRAF exon 9 (exon 16–exon 9) followed by (exon 15–exon 9) and (exon 16–exon 11). And the other ten were rare fusions, including DENND2A-BRAF, MRPS33(Intergenic)- BRAF, BCAS1- BRAF, TMEM176B-BRAF, RNF130-BRAF, RIN2-BRAF, GNAI1-BRAF, EXOC4-BRAF, TNK2-BRAF. Most retained BRAF exons 9–18 (7/10, 70%). There was a significant statistical difference in age that the non- KIAA1549-BRAF fusions group was higher than the KIAA1549-BRAF fusions group (25 vs. 10, p < 0.005). Importantly, we identified new BRAF fusion variants resulting in RIN2-BRAF, EXOC4-BRAF, TNK2-BRAF and TMEM176B-BRAF rearrangements, which has not previously been reported in gliomas. Conclusions: We find new BRAF fusions in our 20% glioma patients. In addition, analysis of rare BRAF fusion may help guide diagnosis and develop potential targeted therapies of older PA.
A multi-modal deep learning model integrates clinical, pathomic, and radiomic features for glioma classification and grading.
Authors: Alessio Adam Michael , Khan Sameed , Patel Snehal
Published: June 2022

e14038

Background: Histopathologic glioma diagnosis relies on the interpretation of the morphologic appearance of tumor cells. This conventional approach suffers from documented inter-pathologist disagreements with minor discordances in 36% and serious discordances in 8.8% of cases (Bruner JM et al. Cancer. 1997). Machine learning applied to automatically extracted pathomic features offers the potential to reduce this inter-reader variability and improve classification accuracy. The addition of clinical history and radiomic features may further improve performance. This work compares the performance of automatic pathomic and radiomic feature analysis to human histologic impressions for glioma classification according to the 2021 WHO scheme. Methods: We developed and evaluated models for predicting the 2021 WHO Glioma class using data from The Cancer Genome Atlas and The Cancer Imaging Archive. We used a cohort of 112 glioma cases with complete data of molecular markers, digital slides, and MRI images. Using molecular markers, we divided this cohort into 2021 WHO types, including 61 glioblastomas, 38 astrocytomas, and 13 oligodendroglioma. We extracted 374 pathomic features summarizing the tumor-rich region on each digital slide. Neural network models were developed with pathomic features alone or in combination with clinical factors (sex, age, and Karnofsky index) and 670 radiomic features obtained from multi-sequence MRI exams. Accuracy was estimated with 5-fold cross validation. Feature importance analysis was carried out with recursive feature elimination to identify the top pathomic and radiomic features related to the specific glioma diagnosis. Results: In this cohort, the conventional histologic impression, reliant on pathologist interpretation, was successful in identifying the WHO glioma class with an accuracy of 0.77 +/- 0.08. The use of pathomics features alone, representing a fully automatic approach, had an accuracy of 0.83 +/- 0.08. The use of pathomics and radiomics information increased the accuracy to 0.88 +/- 0.08. Feature importance analysis revealed that the most important pathomic features were related to nuclear size, nuclear hematoxylin staining intensity, and nuclear circularity. Conclusions: In this pilot study, our machine learning model with pathomic features achieved promising performance for glioma classification. Combining clinical and radiomic features further enhanced performance. We found that the pathomic features that most correlated with the pathologic classification are the same key features that pathologists use in their diagnostic evaluation. While molecular testing is now the definitive reference information for final glioma classification, this pilot study suggests that pathomics analysis could have a valuable role during a pathologist’s initial histologic review.
Clinical characteristics and treatment outcomes in patients with intracranial germ cell tumors: A single center analysis of 1448 patients in China.
Authors: Li Bo , Qiu Xiaoguang
Published: June 2022

e14048

Background: To explore the clinical characteristics and treatment outcomes of patients with intracranial germ cell tumors (iGCTs). Methods: Clinical data of 1448 patients who were diagnosed with iGCTs based on histology and/or tumor marker elevation between 1990 and 2019 at Beijing Tiantan Hospital were studied retrospectively. Results: The median age was 12 years, and 74.3% of patients were male. In total, 32.6% of patients were of sellar origin, 32.3% were of pineal origin, 20.4% were of basal ganglia (BG) origin, and 14.7% were others. In nonmetastatic germinoma patients, multivariate analysis found that both whole-brain radiotherapy (p < 0.001) and craniospinal irradiation (p = 0.040) could significantly reduce the risk of relapse compared with focal radiotherapy. In nonmetastatic NGGCT patients, the disease control rate was similar among the above three radiation volumes. Among 87 relapsed patients, those with germinoma (n = 35) showed a significantly higher out-field relapse rate than patients with NGGCTs (54.3% vs. 32.7%, p = 0.003). In patients with NGGCTs (n = 52), the in-field (36.5%) and out-field (32.7%) relapse rates were similar. In terms of relapse sites, relapse at the parenchyma (36.4%) was documented only in patients with BG region involvement. In patients with sellar or pineal origin, > 80% of relapses were documented in ventricles and/or the spine. Conclusions: iGCT patients in our series showed unique characteristics. Considering both efficacy and potential adverse effects, the optimal radiation strategy in nonmetastatic germinoma patients should be minimum coverage of at-risk areas. In patients with nonmetastatic NGGCTs, the optimal radiation strategy needs further investigation.
Pan-cancer analysis of PBRM1 mutation and their association with immune-related biomarkers and prognosis.
Authors: He Xujun , Xin Yaqun , Yuan Hongling , Tao Houquan , Wang Qingqing , Zhu Honglin
Published: June 2022

e14536

Background: Polybromo 1 ( PBRM1), which is required for the stability of the SWI/SNF chromatin remodeling complex, is often deleted or mutated in clear cell renal cell carcinoma (ccRCC). However, the prognostic value of PBRM1 in ccRCC with immunotherapy was controversial and less explored in other cancer types. Methods: The sequencing data and clinical information of patients were obtained from The Cancer Genome Atlas (TCGA) cohort (n = 10967) and the immunotherapy MSKCC cohort (n = 387). In TCGA cohort, the expression levels of PD1 were defined as high or low using a 75% cut-off. The association of PBRM1 mutation and related immune biomarkers such as PD1, TMB and immune infiltrates CD4+ and CD8+ T cells was analyzed. Results: Loss-of-function (LOF) of PBRM1 mutation ( PBRM1LOF), including frameshift, nonsense and splice, accounted for 61.4% of all somatic mutations, with a frequency of 2.2% across all cancer types. It is most common in renal clear cell carcinoma (KIRC; 23.2%, 119/512), followed by stomach adenocarcinoma (STAD; 4.1%, 18/440), uterine corpus endometrial carcinoma (UCEC; 3.8%, 20/529), and colon adenocarcinoma (COAD; 2.5%, 11/439) in TCGA cohort. In KIRC, no differences of PD1 expression (P = 0.307) and TMB (P = 0.389) were observed between patients with PBRM1LOF and non- PBRM1LOF mutations, while in STAD, UCEC and COAD, patients with PBRM1LOF mutations had significantly higher levels of PD1 (P = 0.002 in COAD, P < 0.001 in STAD and UCEC) and TMB (all P < 0.001). As for immune infiltrates, expression levels of CD4+ (P = 0.34) and CD8+ (P = 0.18) were found no difference between patients with PBRM1LOF and non- PBRM1LOF in KIRC. However, significantly higher expression levels of CD4+ (P = 0.0014) and CD8+ (P = 0.0016) in UCEC, and CD8+ in COAD (P = 0.04) were found in patients with PBRM1LOF compared with non- PBRM1LOF mutations. Further, in MSKCC cohort, a cohort of patients who had undergone immunotherapy, PBRM1LOF was shown no significant effect on patient outcome in KIRC (P = 0.42), while in other cancer types (COAD+STAD), PBRM1LOF trended towards a promising biomarker for better survival even though the difference was not statistically significant in this small cohort (P = 0.51). Conclusions: PBRM1LOF may play different prognostic roles on immunotherapy in different cancer types. In KIRC, PBRM1LOF was not associated with immune-related biomarkers as well as prognosis of immunotherapy. In COAD, STAD and UCEC, PBRM1LOF was positively associated with immune-related biomarkers and might be a promising biomarker for immunotherapy. This result needs further validation in a lager cohort.
Biodegradable nanoparticle-induced sting pathway activation for the treatment of cancer.
Authors: Podojil Joseph , Cogswell Andrew , Chiang Ming-Yi , Eaton Valerie , Efergan Igal , Neef Tobias , Xu Dan , Meghani Khyati , Yu Yanni , Orbach Sophia , Murthy Tushar , Boyne Michael , Elhofy Adam , Shea Lonnie , Meeks Joshua J. , Miller Stephen D.
Published: June 2022

e14552

Background: Recent advances in the field of cancer immunology have highlighted the importance of the immune system for eliminating tumors. Numerous studies have shown that tumor-infiltrating immune cells such as antigen-presenting cells (APCs), T cells, and natural killer (NK) cells play critical roles in tumor control. However, the inflammatory anti-tumor immune response is counteracted by the induction of immune regulatory mechanisms within the tumor microenvironment (TME). These findings have led to the development of immune-targeted therapies, which are aimed at activating anti-tumor immune signaling pathways and enhancing anti-tumor immune function. While immunotherapies, have revolutionized the treatment of several solid tumors and leukemias, at best response rates remain low at 25%-30%, and a portion of patients eventually develop resistance to therapy leading to disease progression and mortality. Methods: We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic- co-glycolic acid) (PLGA) nanoparticles, ONP-302, free from drugs or other bioactive agents, for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302 nanoparticles, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. The efficacy of ONP-302 nanoparticles at inducing an anti-tumor immune response was evaluated using syngeneic mouse tumor models. Results: ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. Conclusions: These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.
Molecular classification for predicting the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer.
Authors: Hu Hailong , Niu Yuanjie , Wang HaiTao , Liu Huanhuan , Shen Chong , Da La , Zhao Gangjian , Wang Lili , Wu Zhouliang , Cao Shanbo , Lou Feng , Wang Huina
Published: June 2022

e14563

Background: Bladder cancer is a molecularly diverse disease with heterogeneous clinical outcomes. Transcriptome-based molecular subtypes of muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) have been shown to be both prognostic and predictive. However, its predictive role in Chinese bladder cancer remains unclear. The aim of this study was to identify the predictive role of molecular subtypes in China bladder cancer with neoadjuvant therapy. Methods: The study was conducted from May 2020 to August 2021. Patients who were age 18 years or older, were diagnosed with NMIBC or MIBC, and neoadjuvant tislelizumab combining nab-paclitaxel followed by surgery were included. Multigenomic sequencing was performed. Molecular subtypes were identified by published consensus. Results: We prospectively recruited 30 patients for neoadjuvant tislelizumab combining nab-paclitaxel, including 14 patients with NMIBC and 16 patients with MIBC. For bladder cancer, 73.3% (22/33) patients responded to neoadjuvant tislelizumab combining nab-paclitaxel. In NMIBC groups, 64.3% (9/14) patients were pCR. The objective remission rate ( ORR) was 71.4%. 4 molecular classes were identified in Chinese NMIBC, including class 1 (7.1%), class 2a (35.7%), class 2b (50%), class 3 (7.1%). Interesting, ORR was significantly higher for patients with class 2b (5/7, 71.4%) as compared to class 2a (3/5,60%) before neoadjuvant. Molecular classes changed in 35.7% (5/14) of patients before and after neoadjuvant. After neoadjuvant, 80% of class 2b patients responded to neoadjuvant, and all class 2a patients did not respond to neoadjuvant. In MIBC groups, a pPR was achieved by 37.5% patients (6/16). The ORR was 75%. We found 4 molecular classes in Chinese MIBC: basal/squamous (43.8%), luminal unstable (25%), luminal papillary (25%), and stroma-rich (6.2%). Patients with basal/squamous (85.7%) and luminal unstable (75%) had significantly higher ORR than luminal papillary (50%) before neoadjuvant. Molecular classes changed in 44.4% (4/9) of patients before and after neoadjuvant. After neoadjuvant, all patients with stroma-rich responded to neoadjuvant. Conclusions: Molecular classification could predict the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer, which may be preferable when studying biomarkers of bladder cancer in the future.
The combination timing of radio-immunotherapy determines immune microenvironment remodeling and abscopal effect through eosinophils.
Authors: Zhu Xiaoxia , Li Shangbiao
Published: June 2022

e14566

Background: Recently, several studies have confirmed the abscopal effect of tumor shrinkage outside the irradiated field induced by local radiotherapy (RT) combined with immunotherapy. The timing of the combination, including concurrent and sequential treatment, may affect the anti-tumor efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). However, the optimal timing of RT combined with immunotherapy to enhance the abscopal effect and the underlying mechanism are still unknown. Methods: The animal model of bilateral subcutaneous tumor of MC38 in C57BL/6J mice were randomly divided into four groups: PD-1 therapy (P1) group, radiotherapy (unilateral irradiation, 8Gy × 3F, the same below) concurrent with anti-PD-1 therapy (Con.) group, anti-PD-1 therapy one week after radiotherapy (Seq.1) group and anti-PD-1 therapy two weeks after radiotherapy (Seq.2) group. RNA sequencing was employed to identify differential genes. The changes of the immune microenvironment of tumor-draining lymph nodes (TDLN) and tumors were detected by flow cytometry. The expression of chemokine receptors, ligands, and cytokines was detected by qPCR, western blot, and ELISA. Results: The results showed that the survival benefit of sequential PD-1 inhibitor after RT was higher than that of the Con. group and P1 group., the survival benefited most in Seq.1 group, particularly. Similarly, tumor growth on both sides was significantly inhibited in Seq.1 group compared with the Con. group, P1 group, and Seq2. group. Furthermore, a combination of RT with anti-PD-1 inhibitor induced changes of immune microenvironment in irradiated tumor, abscopal tumor and TDLN. In the Seq.1 group, the tumor immune microenvironment was reshaped, including increased eosinophils and CD8+T cells infiltration, while decreased Treg, MDSCs, and TAMs frequency. Correspondingly, the expression of crucial chemokine receptors and ligands involved in chemotaxis of eosinophils and CTL CD8+T cells was up-regulated in tumors of mice in the Seq.1 group. After eosinophil neutralization in vivo, the survival of mice in Seq.1 group was significantly shortened. Besides, the anti-tumor effect and abscopal effect were significantly weakened, accompanied by deduction of the infiltration of T cells, especially cytotoxicity CD8+T cells in the immune microenvironment. Conclusions: Our results showed that RT combined with PD-1 inhibitors could induce a synergistic anti-tumor effect. Sequential PD-1 inhibitor one week after RT could enhance the anti-tumor effect most, including the abscopal effect. The mechanism related to eosinophils recruitment, which established a tumor-suppressive immune microenvironment mainly through enrichment of anticancer T lymphocytes in abscopal tumors. This study provides an insight for clinical precision treatment in combination of RT and immunotherapy.
The role and impact of immunotherapy in multiple malignancies in the Mexican population.
Authors: Juarez - Vignon Whaley Juan Jose , Sanchez Dominguez Gisela , Gonzalez Espinoza Iván Romarico , Garcia Montes Lizbett Vanessa , Alatorre-Alexander Jorge , Hernandez Flores Osvaldo , Garibay Diaz Julio Cesar , Rodriguez Cid Jeronimo Rafael Rafael
Published: June 2022

e14570

Background: Cancer in Mexico represents the third cause of death nationally. Immunotherapy agents have changed management and prognosis of cancer patients. Immune-checkpoint agents are now being used as both first- and second-line treatment improving cancer patient prognosis, nevertheless it is not always accessible. Methods: Retrospective review of patients diagnosed with any type of cancer that received immunotherapy during their disease course from the last 5-years. We present the most common malignancies, immunotherapeutic regimens received, population characteristics and survival analysis. Results: 130 records of patients ≥18 years that received immunotherapy were included. 52.3% female with mean age of 59 years (range, 22-89 years), 48.5% former smokers (average pack/year of 22.5) and 31.5% asbestos exposure. 53.1% were ECOG 0 and 82.3% clinical stage IV. 62.3% of cases were lung adenocarcinoma, followed by lung epidermoid carcinoma (13.1%) and 10% small-cell lung carcinoma. Immunotherapeutic agents used included nivolumab in 63.1%, pembrolizumab 12.3%, nivolumab + ipilimumab 8.5%, durvalumab 6.2%, pembrolizumab + ipilimumab 4.6%. 36.2% of patients received immunotherapy as second line treatment, 30.0% as third and 23.8% as first line treatment. The best Response Evaluation Criteria in Solid Tumors (RECIST) was RECIST 3 in 46.2% followed by RECIST 0 with 25.4%. Median progression-free survival (PFS) was 5 months (95% CI; 3.883-6.117) and median OS of 13 months (95% CI; 10.210-15.790). Analysis per immunotherapy on PFS (p = 0.0414) and OS (p = 0.0046) demonstrated pembrolizumab had the longest median PFS with 19-months and OS with 22-months. Analysis between tumor types was significant for both PFS (p = 0.0018) and OS (p = 0.0090) with melanoma having the longest median PFS (42-months) and OS (46-months). Conclusions: Immunotherapy has changed cancer management; however, its use depends on specific biomarkers and adequate patient selection. Not all patients benefit from immunotherapy, in a country like ours where resources are limited, it is of vital importance to properly select candidates for immunotherapy. Even though, all patients had an FDA-approved indication at the time of receiving immunotherapy, PFS and OS are not as significant as Phase 3 studies demonstrate, this may be due to late stages, advanced ECOG, correct biomarkers availability and adequate patient selection. It is important to mention that about 40-60% of patients with immunotherapy do not respond adequately. In our study, because there is more evidence with pembrolizumab, the patients who received it were better chosen and therefore there was an impact in PFS and OS. Immunotherapy selection also depends on physician experience to the different immunotherapy regimens.
XIRP2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Chen Hualin , Liu Meilian , Luo Yiping , Zhao Lele , Huang Lingli , Xiao Mingzhe , Qi Chuang , Yang Zhixiong
Published: June 2022

e14573

Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Xin-actin binding repeat containing 2 (XIRP2) encodes an actin-cross-linking protein that was previously reported to be significantly mutated in breast cancer metastases. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between XIRP2 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between XIRP2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with XIRP2 mutation were significantly associated with better PFS (HR = 0.4; 95% CI, 0.21-0.75; P = 0.003) after ICIs therapy, compared with those with wide-type XIRP2. XIRP2 mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between XIRP2 mutation and PFS remained significant (HR = 0.4; 95% CI, 0.20-0.81; P = 0.011). In contrast, no association between XIRP2 mutation and OS (LUAD: P = 0.43 ; LUSC: P = 0.17) or PFS (LUAD: P = 0.54; LUSC: P = 0.19) was observed in TCGA datasets, suggesting that XIRP2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, XIRP2 mutation was significantly associated with higher M1 macrophage, CD8+ T cell, as well as lower Treg cell. Moreover, XIRP2 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that XIRP2 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of XIRP2 in immunotherapy is needed to be further studied.
PD1 inhibition effect on immunization with MRNA vaccines against SARS-CoV-2.
Authors: Majer Martin , Knoefler Justin , Little Elizabeth Fauchier , Powell Megan , Ordorica Edward J. , Arakozie Roxanna , Tran Phuc , Ha Duke , Cheam Socheat , Lay Linda , Le Andrew , Park Min , Atwal Gurbir , Nguyen Hanh , Yang Mee , Ghuman Sudeep Kaur , Jones Sarah , Singh Narinder , Shannon Roy
Published: June 2022

e14594

Background: We provide care for the rural, low-income, and underserved population of Oroville. The community has a vaccination rate of 50% and booster rate of over 20% in the 3rd year of the ongoing global SARS-CoV-2 pandemic in 2022. During this period, a subset of our cancer patients benefited from the use of immune checkpoint inhibitors. Methods: This is a cross-sectional observational study of the effectiveness of a mRNA-based vaccine in medical care workers compared to patients with systemic malignancies treated with immunomodulation of PD-1 and CTLA-4 inhibitors. The study was approved by the hospital IRB. We evaluated the total anti-Spike protein antibody titer using a commercial semi-quantitative assay, Labcorp Test #164090. All subjects received 3 doses of the mRNA vaccine. We excluded anyone who was administered therapeutic monoclonal antibodies (mAb) or had a recent infection within 120 days. Results: Subjects with systemic malignancies were significantly older, p = 0.0001 by t-test: median age: 76, range: 64-82, compared to health care workers: median age: 52, range: 21-75. Accrual had to be prematurely stopped upon the arrival of Omicron wave in the community. Out of the seven subjects treated with immunomodulation, six received nivolumab, including two in combination with ipilimumab. One subject received pembrolizumab. Six of the subjects had metastatic disease: one was treated adjuvantly for locally advanced esophageal adenocarcinoma. The rest had NSCLC and one case of urothelioma. We divided the groups to those who had the highest titer of antibody versus everybody else and found a similar distribution in both groups using the Chi2 test. The vast majority of the healthcare workers, 24/27 or 89%, had above the upper limit antibody titer. Patients with systemic malignancy, 5/7 or 71%, had above the upper limit antibody titer p = N.S. Conclusions: Three doses of the mRNA vaccine provided high titers irrespective of frailty or age. We hypothesize that immunomodulation could favorably affect vaccination response.
Association of opioid use with response to immune checkpoint inhibitors.
Authors: Weinfeld Michael , Wang Heidy , Liu Li C. , Pasquinelli Mary , Huber Michael , Feldman Lawrence Eric , Weinberg Frank
Published: June 2022

e14595

Background: Management of cancer-related pain with opioids is hypothesized to decrease efficacy of immune checkpoint inhibitors (ICIs) through immunosuppressive effects of opioids, such as down-regulation of major histocompatibility complex class II. There is limited evidence on how opioids affect outcomes in patients receiving ICIs. Methods: We identified 212 patients at the University of Illinois Hospital and Health Sciences System who received an ICI between January 1, 2015 and July 31, 2021. Overall survival (OS) and progression-free survival (PFS) were compared in patients who were not treated with opioids, patients treated with low-dose opioids (defined as less than 60 morphine milliequivalents per day), and patients treated with high-dose opioids (defined as at least 60 morphine milliequivalents per day). Results: Out of 212 patients who received an ICI, 98 (46.2%) received no opioids, 69 (32.6%) received low-dose opioids, and 45 (21.2%) received high-dose opioids. Among all patients, 105 (49.5%) died during the study duration. The overall median survival time was 23 (95% CI = 16, 38) months for the entire sample. Patients who received opioids at any dose had a median OS of 17 months compared to 37 months in those who received no opioids (HR = 1.53, p = 0.0385). When patients receiving opioids were further divided by dose, survival time was highest in those receiving no opioids, next highest in those receiving low-dose opioids, and lowest in those receiving high-dose opioids (37 months vs 18 months vs 10 months, p = 0.0515). Among all 212 patients, progression of disease occurred in 84 (39.6%) patients. The overall median time-to-progression was 24 months. There was no significant difference in median PFS between those treated with opioids (36 months) versus not (23 months, p = 0.156). Conclusions: We observed an association between opioid therapy, especially at higher doses, and decreased median OS in patients receiving ICIs. On the other hand, there was no statistical association between opioid therapy and median PFS. These data highlight a potential drug interaction in oncology care, and further analysis looking at duration of opioid use and ECOG PS is planned.[Table: see text]
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.