bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and survival of gastrointestinal malignancies with brain metastasis: Surveillance, Epidemiology, and End Results SEER database analysis 2010-2018.
Authors: Alkrekshi Akram , Elantably Dina , Hammad Faris , Al Armashi Abdul Rahman 
Published: June 2022

e14004 Background: Gastrointestinal (GI) cancers are amongst the leading causes of cancer-related death worldwide. GI cancers with brain metastasis on presentation are rare; however, the oncologist will intermittently encounter such patients. Unfortunately, there is a paucity of data to inform the prevalence and prognosis of GI cancers with brain metastasis, especially in light of therapeutic developments in the past decade and whether that might have influenced the survival. In this study, we measured the prevalence of brain metastasis secondary to primary GI malignancies at the time of diagnosis, the observed median survival, and Kaplan-Meier 2-years overall survival. The aim is to highlight the burden and prognosis of this population. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) Program 18 registry (2010-2018) database. We identified the total number of patients and patients with brain metastasis at the time of diagnosis for the following gastrointestinal cancers: esophagus, stomach, pancreas, colon, rectum, liver, intrahepatic biliary duct, and gallbladder. We obtained the prevalence, the observed median survival, and the 2-years survival using the Kaplan-Meier method. Results: The total number of cases, prevalence, median survival, and 2-years overall survival are shown in the table. The prevalence of brain metastasis at diagnosis was highest for esophageal cancer at 1.41%, followed by stomach 0.52%, and gall bladder 0.37%. The lowest incidence was small intestinal cancers at 0.13%. The median survival was short, ranging between 2 to 4 months for all studied cancers except for the small intestine and rectum at about six months. Kaplan-Meier 2-years survival was highest for the small intestine at 17%, and the worst was gallbladder, where no one survived at the end of the 24 months. Conclusions: Brain metastasis at the time of diagnosis of GI cancer remains rare. However, its presence portends an abysmal prognosis of 2-4 months. This study helps to inform the practicing oncologist of the current prevalence and prognosis of GI malignancies with brain metastasis on presentation. In addition, these findings encourage prompt involvement of palliative care, setting realistic expectations, and discussing goals of care once such a grave diagnosis is made.[Table: see text]
Efficacy and safety study of fotemustine and bevacizumab in patients with recurrent glioblastoma.
Authors: Sánchez Escudero Laura , Amor Urbano María , Garcés María Yeray Rodríguez , Murillo Fátima Toscano 
Published: June 2022

e14041 Background: Glioblastoma (GBM) is highly vascularized tumor with elevated expression of vascular endothelial growth factor (VEGF). Bevacizumab (Bz) is a humanized monoclonal antibody against VEGF, which alone or associated with chemotherapy has obtained optimal results. However, the most suitable combination with bevacizumab is yet unknown. The objective of our study is to evaluate the efficacy and safety of Bz and fotemustine (Ft) in patients (pts) with recurrent GBM of the Huelva area and to compare our results with those published in the phase II study of the Italian Association of Neuro-oncology (AINO). Methods: Observational and descriptive study of the combination of Ft-Bz in GBM at first relapse after standard radiotherapy and TMZ concomitant in the hospital area of Huelva during the years 2010-2021. We used the same therapeutic scheme of the phase II study of AINO and the IBM SPSS Statistics 22 program to analyze the variables. Results: 42 pts were treated, 16 women and 25 men. Median age 52 years. ECOG 0-1 in 85.4%. 65.9% and 92.7% received antiepileptics and corticosteroids, respectively. In 90.2%, methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was not evaluated. Previously, 56.1% of the pts underwent total/subtotal resection, 29.3% partial and 14.6% were not resected, followed by concomitant radiotherapy and temozolamide in 100% of cases. 35.7% relapsed in less than 3 months after adjuvant treatment. 61% presented unifocal relapse and 39% multifocal. 46.3% of the pts had stable disease, 24.4% partial response and 2.4% complete response. 22% presented grade 3-4 toxicity. The most frequent toxicities are listed in the table. The median progression-free survival (PFS) was 6 months (95% CI 4.18-7.82) and the median overall survival (OS) was 7 months (95% CI 4.22-9.77). Conclusions: The results obtained in our study were similar to those of other previously published studies of Bz in combination with Ft. Although PFS was slightly higher than the phase II study AINO, OS was lower, probably due to the inclusion of a high rate of rapid progressors pts. Treatment tolerance was similar to that in the phase II study AINO. An increase in hematologic adverse events stands out in our pts. Therefore, this scheme can be a valid alternative in the management of recurrent GBM.[Table: see text]
The use of a transient transfected expression system to deliver high quality bispecific T-cell engager drug product, NVG-111, to the clinic for a fraction of the cost and time associated with the development and use of a producer cell line.
Authors: O'Donovan Kieran , Bhatt Shivam , Baccaro Annalisa , Fernando Dinusha , Smith Angel , Gbajumo Ephraim , Bobrzynski Tomasz , McIntosh Jenny , Gore Jasmine , Nathwani Amit C. , Chester Kerry , Granger David 
Published: June 2022

e14506 Background: Bispecific antibodies provide an opportunity to treat a diverse range of disorders because of their ability to simultaneously attenuate several different pathways precisely and effectively, thus overcoming many of the limitations of monoclonal antibodies. The adaptability of bispecifics has facilitated the generation of compelling preclinical data covering a range of malignant and non-malignant disorders. Proof-of-concept early phase clinical trials with bispecific antibodies, including bispecific T-cell engagers (TCE) have been hindered by manufacturing challenges, including a heavy burden in terms of time, quality and costs associated with generating a stable producer cell line. We took a more agile approach, using transient transfection to manufacture a ROR1×CD3 bispecific TCE drug product (DP [NVG-111]) for a first in human, Phase I/II clinical trial. Methods: A HEK293T cell line was expanded into 10-layer cell factories. The cells were transfected with a ROR1xCD3 scFv bispecific antibody (NVG-111) plasmid and incubated. Post incubation, the supernatant containing NVG-111 was clarified by filtration and subjected to solvent/detergent viral inactivation. This was followed by a concentration/buffer exchange step and subsequent DNA reduction using an endonuclease. NVG-111 was captured using a bind/elute Protein A column and the eluate polished on a multimodal anion exchange column in flow through mode to remove residual impurities. The eluate was formulated and concentrated to the target protein concentration, viral and sterile filtered and QC tested. The bulk drug substance was 0.2 µm filtered into Din 2R vials and the DP stored at ≤-65°C pending release. Results: The transient transfection approach resulted in the rapid tech transfer and GMP manufacture of clinical NVG-111 DP. Two batches of DP were manufactured producing 1,971 vials of NVG-111, sufficient to support the Phase I/II clinical trial in patients with advanced Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma (Clinical Trial.gov NCT04763083). Both batches met the approved specifications for identity, potency, purity/impurities, strength and safety. The exercise took less than 7 months from contract signature to DP in the freezer and cost ̃50% of the more traditional producer cell line approach. Conclusions: We established a novel GMP process in 7 months, using transient transfection to manufacture NVG-111 for Phase I/II trials. The process costed less than the more conventional manufacturing approach of using a producer cell line. The strategy offers a rapid, and very efficient way of reaching a first in human study without a trade-off between time, quality and cost.
Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: Evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications.
Authors: Akoulitchev Alexandre , Hunter Ewan , Santos Francisco C. , Dezfouli Mehrnoush , Koutsothanasi Christina , Salter Matthew , Powell Ryan , Dring Ann , Egan Benedict , Parnall Matthew , Thacker Morgan , Green Jayne , Ramadass Aroul , Ng Serene , Lim Chun Ren , Guiel Thomas , Heaton Robert , Levine Jedd 
Published: June 2022

e14525 Background: Unprecedented advantages in cancer treatments with immune checkpoint inhibitors (ICI) remain limited to a subset of patients, with high demands for development of better biomarkers to access likely clinical response in advance of ICI therapeutic interventions. 3D genomics has emerged as a novel molecular biomarker modality with strong functional correlation to clinical outcomes (1). The last few years have seen rapid emergence of 3D genomics applications in clinical stratifications. They have demonstrated high sensitivity and specificity in patient stratifications, offered solutions in symptomatic and pre-symptomatic diagnosis, in prognosis, residual disease monitoring, and prediction of response to therapeutic interventions (2-8). EpiSwitch is a 3D genomic platform that has been reduced to practice for the discovery of 3D genomic blood-based biomarkers in a variety of immune-related and oncological diseases (7,8). Methods: A clinical blood assay based on 8 markers - Checkpoint Inhibitor Response Test (CiRT) - has been developed to predict response to PD-(L)1 immune checkpoint inhibition from over 30 million data points, with validations on several independent cancer patient cohorts. The predictive 8 biomarker set is based on an observational clinical trial and several retrospective cohorts, representing all together 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in over 15 diverse oncological indications, i.e. melanoma, lung, urethral, hepatocellular, bladder, prostate, head and neck, colon, breast, bone, brain, lymphoma, larynx. Results: CiRT has demonstrated high accuracy up to 85%, sensitivity of 93% and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach could be successfully utilized for development of a non-invasive predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients. CiRT can assist in treatment decisions, help improve patient selection for optimized treatment, utilize alternative effective treatments, minimize unnecessary toxicity, and efficiently manage the costs.
A novel virus-like drug conjugate (VDC) in combination with immune checkpoint inhibitors for the treatment of primary tumors and distant metastasis.
Authors: Huis in 't Veld Ruben Victor , Ma Sen , Kines Rhonda , Savinainen Anneli , Rich Cadmus Collins , Ossendorp Ferry , Jager Martine 
Published: June 2022

e14544 Background: Although there has been great progress in the early diagnosis of choroidal melanoma, metastases remain the leading cause of cancer-related death. Therefore, improving the treatment efficacy against metastases is essential to enhance patient survival. A new targeted therapy, the virus-like drug conjugate (VDC) AU-011 (belzupacap sarotalocan), is currently in clinical development to treat early-stage choroidal melanoma with an intra-ocular administration followed by near-infrared (NIR) light activation using a photodynamic therapy (PDT) laser. Murine experiments have shown that AU-011 enhances immune checkpoint inhibition (ICI) and protects against tumor rechallenge. Methods: We investigated whether this combination therapy had an effect not only on primary tumors but also on distant, untreated tumors, as a model for treating metastatic cancer by abscopal immune effects and compared the efficacy of combining AU-011 with several ICI antibodies. Results: In vitro, AU-011 treatment induced a preferential cytotoxicity in cancer over antigen presenting cells, confirming the tumor-targeting of AU-011. AU-011 treatment induced immunogenic cell death in several murine cancer cell lines through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells. Furthermore, AU-011 in combination with ICI antibodies demonstrated greater efficacy than AU-011 alone, or ICI antibodies alone against established MC38 tumors in mice, resulting in complete tumor response in all treated animals for specific combinations. Finally, AU-011 and anti-PD-L1/ anti-LAG-3 antibody treatment was an optimal combination in an abscopal model of metastatic disease, inducing complete cures in approximately 75 % of animals. Conclusions: Based on our observations, we conclude that AU-011 treatment combined with immune checkpoint inhibition is effective against both primary tumors and distant metastases, and identify anti-PD-L1/ anti-LAG-3 as the most potent combination with AU-011. These data may support an investigation of AU-011 in this combination in future clinical trials.[Table: see text]
The Hu2G10 mAb targets the cleaved-activated form of Trop-2 and exploits vulnerability of multiple human cancers.
Authors: Alberti Saverio , Trerotola Marco , Guerra Emanuela 
Published: June 2022

e14548 Background: FDA granted accelerated approval to the anti-Trop-2 sacituzumab govitecan-hziy (TRODELVY) antibody-drug conjugate (ADC), for patients with metastatic triple-negative breast cancer. Skin rash and mucosal inflammation were, though, dose-limiting toxicities of other high-effectiveness anti-Trop-2 antibodies, and impeded their development. These adverse events appeared as on-target/off-cancer effects, related to the expression of Trop-2 by normal tissues. Trop-2 is a transmembrane glycoprotein (E. Guerra et al., The Trop-2 signalling network in cancer growth. Oncogene 32, 1594-1600 (2013)), that is cleaved and activated by ADAM10 to induce cancer growth and metastatic diffusion (M. Trerotola et al., Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23, 415-428 (2021); E. Guerra et al., Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer. Neoplasia 23, 898-911 (2021)). This cleavage causes a spatial rearrangement of the extracellular portion of Trop-2 and exposes hidden, activation-specific epitopes. We succeeded in generating monoclonal antibodies (mAbs) capable of recognizing these cancer-exposed sites. Methods: Most Trop-2-targeted approaches are based on anti-Trop-2 mAbs that recognize a single immunodominant epitope. Such mAbs have limited therapeutic index. We removed the immunodominant epitope by deletion mutagenesis, and optimized breadth of immune response, by immunizing mice with recombinant proteins with diverse end-glycosylation patterns. Screening for cancer-specific mAbs was performed on mutagenized Trop-2, by cell-based ELISA assays, bio-layer interferometry, flow cytometry and fluorescence microscopy. Results: mAbs were obtained that efficiently bound Trop-2 expressing cancer cells and were able to inhibit cell growth in vitro. We humanized the 2G10 mAb into the Hu2G10 IgG1, with an affinity for recombinant, cancer-specific, cleaved Trop-2 that is several orders of magnitude higher than existing competitor mAbs. In vivo the naked Hu2G10 antibody was effective at inhibiting the growth of breast, colon, ovary and prostate cancers. In the ADC setting Hu2G10 drove high anticancer specificity and effectiveness. Conclusions: Hu2G10 shows unprecedented specificity and efficacy, for best-in-class anti-Trop-2 anticancer therapy.
Irradiation combined with PD-1 inhibitor aggravates immune-related pneumonitis of the non-irradiated lung in a preclinical model.
Authors: Zhu Xiaoxia , Qiao Simiao , Liao Xuejiao 
Published: June 2022

e14569 Background: The combination of radiation with PD-1 inhibitors for lung cancer is a trend. However, the combination is limited by immune-related adverse effects, particularly checkpoint inhibitor pneumonitis (CIP). The incidence and the mechanism of CIP of the non-irradiated lung caused by radiation plus PD-1 inhibitors remain unknown. This study was designed to evaluate the incidence of CIP and lung tissue morphology in the preclinical model induced by radiation combined with a PD-1 inhibitor (αPD-1). Methods: Fifty-four C57BL/6 mice were divided randomly into the normal group, the irradiation combined with the αPD-1 group (RT + αPD-1 group), and the single irradiation group (RT group). Mice in the RT + αPD-1 group were treated with right lung irradiation (8 Gy once) on day1 and anti-mouse PD-1 monoclonal antibody three times a week. Mice in the RT group received right lung irradiation alone. The mice were euthanized on day10, day15, and day20 after the end RT. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining. Lung fibrosis was evaluated by Masson staining and analysis of hydroxyproline. Results: Histopathological examination revealed that the inflammation in the irradiated lung is more severe than the unirradiated site. With the extension of time, the lung inflammation of mice in the RT group and RT + αPD-1 group was significantly aggravated, and the whole lung fibrosis appeared on day20. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions, and hydroxyproline contents in lung tissues were all significantly higher in mice administered αPD-1 plus irradiation than in the other groups. In particular, the inflammation is significantly worse in the unirradiated site of the mice administered PD-1 inhibitor plus irradiation than in the RT group on day15 and day20. Conclusions: Radiotherapy combined with PD-1 inhibitors could aggravate CIP on both sides. Further studies on the mechanism are under investigation. Our findings highlight the potential risk of CIP in non-irradiated lung in patients treated with radiotherapy and PD-1 inhibitors. Research Sponsor: This work was supported by the National Natural Science Foundation of China [No. 81972853, No. 81572279] and Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2019ZD009).
NPAP1 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Yang Nuo , Huang Liwen , Liu Jun , Guo Jianji , Zhao Lele , Chai Huizi , Xiao Mingzhe , Qi Chuang 
Published: June 2022

e14574 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. Nuclear pore associated protein 1 ( NPAP1) encodes an protein is associated with the nuclear pore complex and has been previously reported as a potential prognostic biomarker for laryngeal, colorectal and lung cancers. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between NPAP1 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 NPAP1 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 NPAP1 mutation were significantly associated with better PFS (HR = 0.37; 95% CI, 0.19-0.71; P = 0.002), objective response rate (ORR, 54.2% vs 28.4%; P = 0.048) and durable clinical benefit (DCB, 75.0% vs 42.6%; P= 0.003) after ICIs therapy, compared with those with wide-type NPAP1. NPAP1 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 NPAP1 mutation and PFS remained significant (HR = 0.46; 95% CI, 0.23-0.92; P = 0.028). In contrast, no association between NPAP1 mutation and OS (LUAD: P = 0.24 ; LUSC: P = 0.94) or PFS (LUAD: P = 0.3; LUSC: P = 0.72) was observed in TCGA datasets, suggesting that NPAP1 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, NPAP1 mutation was significantly associated with higher activated memory CD4+ T cell and CD8+ T cell. Moreover, NPAP1 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that NPAP1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of NPAP1 in immunotherapy is needed to be further studied.
Rechallenge with immune checkpoint inhibitors beyond severe toxicities, an utopia?
Authors: Medina Rodriguez Laura , Jimenez-Rodriguez Begona , Llácer Casilda , Trigo Perez Jose Manuel Manuel 
Published: June 2022

e14601 Background: Immunotherapy (IO) has substantially improved clinical outcomes in different types of tumours. Its use has been associated with so-called immune-related adverse effects (IrAEs), some of them, potentially severe and/or fatal. Current guidelines recommend discontinuation of IO in severe IrAEs (grades 3/4). Therefore, there is very limited evidence about the safety of “rechallenge” or re-treatment with IO in patients who have experienced severe toxicities. The objective of this study is to describe the toxicities experienced by patients treated with IOs in our unit and identify the recurrence rate of these rEAIs in those patients in whom immunotherapy is re-administered. Methods: We carried out a retrospective analysis of patients treated with IO from January 2015 to April 2021. As inclusion criteria, we selected the condition that the patients have had at least one tumour reevaluation after the IO was started. We have collected clinical and epidemiological variables, efficacy (mesured by RECIST 1.1 and iRECIST criteria) and, as well as recorded toxicity data (mesured by CTCAE V4.3). Results: 220 patients have received some IO drug between the indicated periods. The characteristics of the patients are shown in the attached table. 66% of patients treated with IO have received anti-PD-1/PD-L1 therapy as monotherapy. 60% (134/220) of patients experienced at least 1 IrAE. Of the IrAEs, only 20% were grade 3/4. Only 34 (25%) of the 134 patients who experienced any toxicity required IO stop. Of these 34, only 17 patients achieved retreatment with IO after resolution of initial toxicity. In 14 of the 17 patients who underwent rechallenge, IO was permanently discontinued due to recurrence of the same IrAEs. The IrAE that recurs most frequently after rechallenge was colitis (35% of cases), followed by nephritis (28%). 41% of the patients who experienced toxicity had an objective response to their disease, compared to only 9% in those who did not present any IrAE, which was statistically significant (p<0.05%). Conclusions: In our serie, rechallange with IO after toxicity was associated with the appearance of the same IrAE, which is consistent with what has been published in other series. We are doing further analyses in order to explore IO toxicity deeply, increasing the number of patients which have received immune checkpoint inhibitors.[Table: see text]