bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain metastases as a first site of recurrence in patients on chemotherapy with controlled systemic cancers: An increasingly urgent clinical scenario.
Authors: O'Connell Kaelin , Romo Carlos G , Grossman Stuart A. 
Published: May 2019

e13590 Background: As the treatment of non-central nervous system (CNS) malignancies improves, brain metastases (BM) are occurring more often in patients with controlled primary disease. In a retrospective analysis of 1953 patients with BM, 44.7% had a controlled primary tumor at the time of BM diagnosis. Given that prognosis after BM remains dismal, it is necessary to identify groups who might benefit from improved delivery of initial systemic therapy across the blood brain barrier (BBB). Methods: A retrospective literature review was conducted to estimate the proportion of patients with non-small cell lung cancer (NSCLC), breast cancer, and melanoma treated with chemotherapy in whom BM was the initial site of recurrence. Only studies explicitly reporting CNS metastasis with controlled extra-cranial (EC) disease on chemotherapy or reporting the first site of recurrence after chemotherapy were included. Results: Four studies of advanced NSCLC reported an average of 23% of patients who developed BM as an initial site of recurrence. Breast cancer cases varied by subtype with a range of 4 - 19%. In four papers reporting HER-2 status, an average of 14% of patients treated with traztuzumab had CNS metastasis with controlled EC disease. In three papers assessing patients with metastatic melanoma on chemotherapy, 4 – 25% initially progressed in the CNS. Conclusions: Of the 1024 patients treated with chemotherapy and achieving controlled systemic disease in this retrospective review, first recurrence in the brain was common: 23% in NSCLC, 12% in breast cancer, and 12% in melanoma. While chemotherapy controlled non-CNS disease, concentrations of these drugs were clearly subtherapeutic in the CNS. Preventing BM in patients with NSCLC, breast cancer, and melanoma will require novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in the treatment of the primary tumor. [Table: see text]
Risk factors for synchronous brain metastases: A National Cancer Database analysis.
Authors: Garcia Catherine R. , Slone Stacey A. , St Clair William H. , Durbin Eric B. , Pittman Thomas , Lightner Donita D. , Villano John L. 
Published: May 2019

e13591 Background: Brain metastases (BM) are a significant source of disability and mortality in cancer patients. Investigations on the risk factors for their development are limited. We provide risk factors assessment using the largest cancer database. Methods: We analyzed the National Cancer Database from 2010-2014, for risk factors and survival outcomes in all patients with BM. Results: 4,650,963 tumor records were analyzed of which 88,274 were BM. Lung cancer accounted for 82.2%, breast cancer for 4.2%, melanoma for 3.5%, and urinary system tumors for 3.1% of cases. The majority of patients were males (51.6%), and whites (84.2%) with a median age of 65 years. A high index of comorbidities [Charlson-Deyo score (CDS) ≥3] was reported in 3.5% of patients. Lung primaries had the highest risk of BM (OR of 17.867), followed by melanoma (OR 1.946). Patients diagnosed at 70 years or older were less likely to present with BM, while patients diagnosed between 40 and 60 years were at increased risk. Other and unknown race were associated with an increased risk of BM compared to whites. Patients with a CDS of one or two had a decreased risk of presenting with BM compared to patients with scores greater or equal to three. Median overall survival was 5 months, with a 5-year survival rate of 5.2%. There was a decreasing risk of mortality, and increasing risk of receiving surgery, radiation, or chemotherapy per advancing year of diagnosis. Older age, white race, Hispanic origin, and higher CDS were risk factors for mortality. Conclusions: Higher number of comorbidities, younger age at diagnosis, and other races were associated with an higher risk of synchronous BM. The risk of mortality is decreasing, with a higher risk of receiving radiation, surgery, and/or chemotherapy. Median overall survival has increased in comparison to the Radiation Therapy Oncology Group Recursive Partitioning Analysis RPA studies (4.4 months).
Intraventricular radioimmunotherapy targeting B7H3 for CNS malignancies.
Authors: Kramer Kim , Pandit-Taskar Neeta , Donzelli Maria , Wolden Suzanne L. , Zanzonico Pat , Humm John , Haque Sofia , Souweidane Mark M. , Lewis Jason , Lyashchenko Serge K. , Larson Steven M. , Cheung Nai-Kong V. 
Published: May 2019

e13592 Background: Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with primary or metastatic CNS tumors. Methods: Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. Results: 57 patients (ages 2 – 54 years, median age 11.7 years) received 158 injections Primary CNS diagnoses included medulloblastoma (n = 23), ependymoma (N = 8), chordoma (n = 1), rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 3), ETMR (n = 3), glioblastoma multiforme (n = 1) , PXA (n = 1); metastatic tumors included sarcoma (n = 9), melanoma (n = 4), retinoblastoma (n = 2), and ovarian carcinoma (n = 1). Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting; 3 injections were associated with grade 3 toxicities requiring discontinuation of therapy including chemical meningitis (n = 2),and increasing communicating hydrocephalus (n = 1), Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (≥60 mCi). 16 patients remain alive including patients with high-risk malignancies including choroid plexus carcinoma, ETMR, recurrent ependymoma and recurrent medulloblastoma. Conclusions: We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and may have clinical utility in the treatment of primary and metastatic CNS tumors. Clinical trial information: NCT00089245.
Comparison of in vitro antitumor activity between SB3 (trastuzumab biosimilar, Ontruzant) and Herceptin combined with an antibody for subdomain II of HER2 in HER2-positive cancer cells.
Authors: Lee Jae Hee , Paek Kyungyeol , Kim Eunji , Kim Inhee , Jeong Juyeon , Kim Seokkyun 
Published: May 2019

e14001 Background: The human epidermal growth factor receptor (HER) family plays a critical role in proliferation and survival of cancer cells. Trastuzumab is a recombinant humanized monoclonal antibody that blocks signaling pathways of HER2 tyrosine kinase receptor via binding to subdomain IV of HER2 extracellular domain. A subdomain II targeting therapeutic antibody (DII antibody, pertuzumab) binds to a different region on the same protein. A combination of the two different antibodies might provide a more effective antitumor activity without binding interference [1] . In this study, we evaluate in vitro antitumor activity of SB3 used in the same manner as Herceptin, in combination with a DII antibody that complements the mechanism of action of trastuzumab. [1] Nahta et al, [CANCER RESEARCH 64, 2343–2346, April 1, 2004]. Methods: Similarity assessment of in vitro antitumor activity between SB3 and Herceptin was performed on HER2-overexpressing breast and gastric cancer cells through analyzing HER2 dimerization, cell proliferation and survival activities, and antibody-dependent cellular cytotoxicity (ADCC) in the presence of a DII antibody. Combination index was calculated to evaluate the synergistic effect. Results: SB3 and Herceptin in combination with a DII antibody, showed similar in vitro inhibition rate for HER2/HER3 heterodimerization. The HER2-overexpressing breast and gastric cancer cells growth inhibition rate was similar whether SB3 or Herceptin was used in combination with a DII antibody. This effect was also shown in apoptosis activity by measuring caspase 3/7 expression. In terms of biological effect via Fc function, cell killing activity was assessed by ADCC assay in the presence of a DII antibody, and non-synergistic effect was shown with both SB3 and Herceptin. Conclusions: This study has concluded that SB3, as a trastuzumab biosimilar, demonstrates highly similar in vitro antitumor activity in experimental conditions when combined with a DII antibody, resulting in enhanced cell growth inhibition and apoptosis activities by inhibiting HER2 dimerization in HER2-positive cancer cells.
Safety and efficacy of repeated intra-hepatic artery and intravenous infusion of ET140202, a novel anti-AFP/MHC complex T-cell, in advanced hepatocellular carcinoma.
Authors: Peng Min , Li Na , Chang Chelsea , Yao Yi , Xu Bin , Zhang Yu , Liu Hong , Nejadnik Bijan , Song Qibin , Liu Cheng 
Published: May 2019

e14013 Background: Despite the success in hematological malignancies, immunotherapy of solid tumors using redirected T cells such as CAR-T remains challenging due to the lack of a unique tumor antigen, inefficient trafficking of CAR T cells to tumor sites and the presence of immunosuppressive tumor microenvironment. ET140202 is a novel T-cell platform that targets AFP/MHC complex with GPC3-guided co-stimulation aiming to improve the specificity and efficacy. Herein we report a case study of ET140202 for a subject with AFP+ recurrent HCC previous treated with surgery and 2 TACE therapies. Baseline imaging showed multiple nodules on segment 7 of right lobe with enlarged lymph nodes in hepatic hilar region. Methods: From 9/25/18 to 1/29/19 the subject first received 2 intra-hepatic artery infusions (i.a.) of ET140202 T cells at the dose of 3×106 cells/kg followed by 4 i.v. infusions at the dose of 6×106 cells/kg. No lymphodepleting chemotherapy was given prior to T-cell infusion. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 2, 3, 4, 6, 9, 12 and 24. Results: Vital signs are normal after each infusion. No treatment-related Grade 2 or higher AEs observed. Grade 1 events that were possibly attributable to therapy included transient elevation of AST and bilirubin 58 days post the 1st infusion. Both events resolved in 4 days without treatment. The subject did not experience any clinical signs of CRS or neurotoxicity. Month 1, 2, and 3 follow-ups showed that the number and size of the liver nodules slowly increased overtime. Month 4 follow-up showed that the size of liver nodules decreased more than 50% of baseline and resulted in PR based on RECIST criteria. The AFP level elevated in the subject after infusion and reached the peak of 2097 ng/mL 55 days post 1st infusion, gradually dropped to 905 ng/mL on day 67, elevated to the 2nd peak of 2660 ng/mL and gradually decreased to 1235 ng/mL at the last follow-up on day 130. Conclusions: Repeated infusion of ET140202 T cells via i.a. and i.v. routes is safe and shows early sign of efficacy 4 months post initiation of the treatment in AFP+/HLA-A2+ HCC subject.
Effect on anti-tumor immunity and long-term memory CD8+ T-cell generation with a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine.
Authors: Hutchins Jeff , Tahiliani Vikas , Miriyala Jayalakshmi , Rose Jason , Dillon Patrick , Seavey Matthew M 
Published: May 2019

e14016 Background: We are focused on developing and optimizing a next generation cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), into a single tumor cell line overexpressing a host of cancer associated neoantigens. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma cell line, stably transfected to express gp96-Ig, is being tested in a phase 1/2 clinical trial (NCT#02439450) for NSCLC. A similar line was generated that complements HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). Methods: To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines (mHS-110 and mHS-130) to activate and expand adoptively transferred ovalbumin specific T cells (OT-1) responding to tumor challenge with ovalbumin over-expressing, B16F10. To identify the best ratio of mHS-110 to mHS-130; multiple dose ratio and dose escalation studies were performed to measure T cell expansion (peripheral and intratumoral) in the context of tumor challenge. Results: CD8+ T-cell expansion was observed on day-7, post-priming, with greatest expansion seen for the 1 to 0.5 ratio. Animals were subsequently boosted 14-days post-priming; the 1 to 0.5 ratio combination gave the most consistent and robust expansion, peaking on day-21. Animals were then challenged with tumors s.c. and growth delay was monitored. Only the 1 to 0.5 and 1 to 4.5 ratio dose groups showed significant delay in tumor growth and weight. Spleen CD4+ and CD8+ T-cells, and CD8+ TILs all increased significantly, as compared to mHS-110 vaccination alone, for the 1 to 0.5 and 1 to 4.5 ratio dose groups. Conclusions: Only the 1 to 0.5 ratio dose group showed any long-term OT-1 expansion or longevity over all other dose ratios, strongly suggesting this is the best combination of gp96-Ig and OX40L-Ig expression for long-term anti-tumor memory generation. These results support the clinical translation of this approach of combining a T cell activation platform with costimulation.
Characteristics of POLE and POLD1 gene variations in Chinese cancer patients.
Authors: Yao Jianfei , Dang Shiying , Li Lifeng , Liu Xinyi , Liu Guifeng , Chen Shifu , Song Lele 
Published: May 2019

e14031 Background: POLE and POLD1 gene variations have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutation burden (TMB), an effective indicator for response prediction in immunotherapy. Methods: In this study, we systematically studied the spectrum and characteristics of POLE and POLD1 gene variations from 1,392 Chinese cancer patients, and their correlation with existing immunotherapeutic markers and cancer associated genes. Results: We found that the frequency of POLE variations was not statistically different from that in COSMIC database, while the frequency of POLD1 variations in Chinese lung cancer patients was significantly higher than that in COSMIC database. Variations frequency analysis showed that c.857C > G and c.2091dupC were potential high frequency variations in Chinese cancer patients. Patients carrying POLE damaging variations were significantly younger, and patients carrying POLD1 damaging variations exhibited significantly higher frequency of MSI than POLE/POLD1 WT patients. Further studies found that patients carrying POLE exonuclease domain damaging variations, POLD1 exonuclease and non-exonuclease domain damaging variations exhibited significantly higher TMB than POLE/POLD1 WT patients, while no such difference was found in patients carrying POLE and POLD1 neutral variations. Moreover, patients with POLE exonuclease domain damaging variations showed significantly higher frequency of MMR gene and driver gene variations than POLE/POLD1 WT patients, including genes associated with RTK/RAS/RAF pathway. Patients with damaging POLD1 variations also exhibited higher frequency of MMR gene variations than POLE/POLD1 WT patients. The high frequency variant genes in patients with POLE exonuclease domain damaging variations or POLD1 damaging variations were associated with MMR, RTK/RAS/RAF, TGFβ, WNT, PI3K-Akt and TP53 pathways. Conclusions: This study identified key characteristics and domains of POLE and POLD1 gene variations that related to TMB, MSI, MMR gene variations and key driver gene variations, and provided theoretical and practical basis for patient selection based on POLE or POLD1 gene status in immunotherapy.
Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.
Authors: Berg Stephanie A. , Wesolowski Michael , Burke Brianna , Wagner Courtney Regan , Clark Joseph I , Guevara Jose 
Published: May 2019

e14037 Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.
Correlation between peripheral CD8+PD-1+ T cells diversity, tumor mutation burden (TMB) and T cell clones with anti-PD-1 antibody treatment of lung cancer patients: TCR repertoire as a novel predictive biomarker.
Authors: Matsumoto Seiji , Matsutani Takaji , Fujita Yoshiko , Kitaura Kazutaka , Nakamura Yukio , Nakamichi Toru , Nakamura Akifumi , Kuroda Ayumi , Hashimoto Masaki , Kondo Nobuyuki , Shini Tadasu , Suzuki Ryuji , Hasegawa Seiki 
Published: May 2019

e14041 Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers. There is a demand for less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells, tumor mutation burden and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P < 0.05, P < 0.05, P < 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P < 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. TCR repertoire was proportional to TMB. Clones found in multiple patients were more frequent in indel than in SNP. Conclusions: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy.