tbuckley/cabot-search huggingface dataset:
Study of microsatellite instability in neuroendocrine tumors of pancreas and colon.
Authors: Vladimir S. Trifanov, Natalya N. Timoshkina, Dmitry Yu. Gvaldin, Milana Yu. Mesheryakova, Evgeniy N. Kolesnikov, Umar M. Gaziev, Sergey V. Sanamyants, Stanislav S. Mezentsev, Maksim N. Duritskiy, Petr N. Gabrichidze, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e16196 Background: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in NET samples of different localizations. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3) and NET of colon (G2-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 25.8% cases of the NET of colon and in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), while in the case of NET of colon, most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%), unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusions: Thus, MSI-positive NET of colon resembles MSI-positive adenocarcinomas of colon in frequency and pathogenetic mechanisms, while in terms of the identified frequency of MSI in pancreatic NET resembles the NET of the small intestine.
EMBR-21. CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY
Authors: Alberto Delaidelli, Christopher Dunham, Maria Rita Santi, Gian Luca Negri, Joanna Triscott, Olga Zheludkova, Andrey Golanov, Marina Ryzhova, Konstantin Okonechnikov, Daniel Schrimpf, Damian Stichel, Andreas von Deimling, Marcel Kool, Stefan Pfister, Vijay Ramaswamy, Andrey Korshunov, Michael Taylor, Poul Sorensen
Journal: Neuro-Oncology (2021)

Abstract Background International consensus and the 2021 WHO classification recognize eight molecular subtypes among Group 3/4 medulloblastoma (representing ~60% of tumors). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. Patients and Methods We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. Results TPD52 IHC positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67–26.7 [95% CIs between 1.00–706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53–45.40], p &amp;lt; 0.0001), suggesting important implication for therapeutic choices. Conclusion The current study redefines the approach to risk-stratification in Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
Trabectedin (T) in desmoplastic small round cell tumor (DSRCT): Report of its effect in 3 relapsed patients (pts) and the comparison of different regimens in a patient-derived xenograft (PDX) model.
Authors: Silvia Stacchiotti, Anna Maria Frezza, Alessandro Gronchi, Sandro Pasquali, Stefano Radaelli, Marco Fiore, Carlo Morosi, Paola Collini, Gianpaolo Dagrada, Paolo Giovanni Casali, Monica Tortoreto, Valentina Zuco, Nadia Zaffaroni
Journal: Journal of Clinical Oncology (2021)

e23553 Background: DSRCT is an ultra-rare soft tissue sarcoma marked by the presence of the EWS-WT1 translocation and a dismal prognosis. Anecdotal activity of T in DSRCT pts was reported. We describe herein three advanced DSRCT pts treated with T and a comparative assessment of doxorubicin (D), pazopanib (P) and T in a patient-derived xenograft (PDX) model of DSRCT. Methods: Three pts (#1, #2 and #3) suffering from progressive, metastatic, unresectable relapsing disease from a primary peritoneal DSRCT previously treated with 8 cycles of anthracycline-based neoadjuvant chemo and complete surgical resection, were started on T (1.3 mcg/sqm every 3-4 weeks). A PDX model was generated by subcutaneously implanting small tumor fragments obtained at surgery from a treatment-naïve DSRCT patient into the right flank of SCID mice. Consistency of PDX and the originating tumor was confirmed in terms of histomorphology and presence of the EWS-WT1 gene fusion. Mice were randomized to receive D, P and T, administered as single agents at optimal doses and schedules. Drug activity was assessed in terms of tumor volume inhibition (TVI) percentage in treated versus control mice. An orthotopic xenograft model was also generated by injecting DSRCT cells into the peritoneal cavity of SCID mice. Results: At the time of this report, pt #1 and #2 are on therapy with T, with a partial response by RECIST maintained after 48 and 36 months from treatment start, respectively, while #3 progressed after 4 months. In the DSRCT PDX model, T was the most effective drug, with a maximum TVI of 82%, while D and P showed lower, comparable activity (maximum TVI: 59% and 66%, respectively). In the orthotopic DSRCT PDX, DSRCT cells spreading in the abdominal cavity generated different tumor masses, properly recapitulating the dissemination pattern in patients, confirming the reliability of this preclinical model. Conclusions: Both our preliminary model and our further clinical observations support the potential of T in DSRCT. A confirmatory prospective clinical study is now warranted.
The effect of different types of allogeneic hematopoietic stem cell transplantation donors in Philadelphia chromosome-positive acute lymphoblastic leukemia during tyrosine kinase inhibitors era: A systematic review and meta-analysis.
Authors: Ben Ponvilawan, Smith Kungwankiattichai, Nipith Charoenngam, Weerapat Owattanapanich
Journal: Journal of Clinical Oncology (2021)

e19022 Background: Matched donor (MD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the preferred choice of treatment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) who achieve complete remission. However, the unavailability of the appropriate donor remains a problem for a large group of patients. This systematic review and meta-analysis were conducted to investigate the effect of allo-HSCT from different types of the donor in Ph + ALL patients who received tyrosine kinase inhibitors (TKIs). Methods: Studies from EMBASE and MEDLINE databases were identified from inception to December 2020 using search terms related to “Ph + ALL” and “HSCT.” Eligible studies must be either randomized controlled trials or cohort studies with Ph + ALL patients who received a TKI and allo-HSCT. The primary outcome of interest, consisting of overall survival (OS) or relapse-free survival (RFS), must be reported as the number of patients in each donor type. The Hantel-Maenszel method was implemented for combining effect estimates and associated 95% confidence interval (CI) from each. Results: Thirteen cohort studies were included for the meta-analysis. Haploidentical (HID)-HSCT for Ph + ALL patients resulted in superior RFS than MD-HSCT with pooled odds ratio (OR) 1.64 (95%CI, 1.07–2.53; I 2 =0%) while had comparable OS (pooled OR 1.11 (95%CI, 0.74–1.69; I 2 =0%). Although HID-HSCT had significantly less relapse rate compared to the other group (pooled OR 0.53; 95%CI, 0.33–0.86; I 2 =0%), it also carried increased risks of graft-versus-host disease (GVHD) (pooled OR of acute GVHD rate 2.12; 95%CI, 1.05–4.31; I 2 =0% and chronic GVHD rate 1.63; 95%CI, 1.01–2.62; I 2 =0%). Matched sibling-HSCT, matched unrelated-HSCT, and cord blood-HSCT had the comparable OS and RFS to HID-HSCT. Conclusions: This systematic review and meta-analysis showed that HID-HSCT is as effective as MD-HSCT, and appears to be safe to implement in Ph + ALL patients which could become useful in the case where there was no available donor.
IMMU-17. USE OF MRNA FOR SAFE AND EFFECTIVE GD2-DIRECTED CAR T CELLS TO TREAT DIFFUSE MIDLINE GLIOMAS
Authors: Jessica Foster, Crystal Griffin, Allison Stern, Cameron Brimley, Phillip Storm, David Barrett, Adam Resnick
Journal: Neuro-Oncology (2021)

Abstract Chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 have garnered interest as an effective therapeutic for treating diffuse midline glioma (DMG). However, prior studies raised significant concerns of neurotoxicity and fatality when using virally transduced CAR T cells against these midline tumors. Building upon our prior work optimizing mRNA for use in CAR T cells (Hum Gen Ther, 2019), we hypothesized transient GD2-directed mRNA CAR T cells could be successfully employed for safe and effective treatment of DMG. GD2-directed CAR T cells were created using mRNA encoding the 14G2a single chain variable fragment paired with 41BB and CD3-zeta co-stimulatory domains and transfected into human T cells. GD2-directed CAR T cells were tested against a panel of DMG cell lines and two murine xenograft models of DMG: 7316-6349 and SU-DIPG13P*. In all DMG cellular models, GD2-directed mRNA CAR T cells induced significant tumor cell death compared to CD19-directed mRNA CAR T cell controls. In vivo, mRNA CAR T cells were delivered locoregionally using an indwelling infusion catheter to allow for repeated dosing. Four intratumoral doses of 5 x 106 GD2-directed mRNA CAR T cells induced significant tumor regression measured by bioluminescence in DMG model 7316-6349 (p&amp;lt;0.0001). In addition, GD2-directed mRNA CAR T cells prolonged survival of mice harboring the aggressive DMG model SU-DIPG13P* by 61% (mean survival 29 days versus 18 days, p&amp;lt;0.01) following four intratumoral doses of 4 x 106 CAR T cells. No GD2-directed CAR T cell treatment-related deaths or toxicities were observed. These data highlight the utility of using mRNA to titrate CAR T cell therapy in the brain, and establish GD2-directed mRNA CAR T cells as a safe and effective method for treating DMG.
Co-occurring alteration of NOTCH and DDR pathways serve as novel predictor to efficacious immunotherapy in NSCLC.
Authors: Zhimin Zhang, Yanyan Gu, Xiaona Su, Jing Bai, Wei Guan, Jungang Ma, Jia Luo, Juan He, Bicheng Zhang, Mingying Geng, Xuefeng Xia, Yan-Fang Guan, Cheng Shen, Chuan Chen
Journal: Journal of Clinical Oncology (2021)

e21106 Background: Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the majority produce an ultra-rapid progressive disease. Methods: Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. 106 NSCLC patients treated with immunotherapy were combined from Rizvi et. al and Hellman et. al studies (whole exon sequencing) as the discovery dataset. Two independent validation datasets were comprised of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. Results: In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [ 22.1 vs 3.6 months, p &lt; 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [ Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96 ; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1 ]. By analyzing TCGA cohort, we found patients with coexisting NOTCH and co-DDR pathway had a higher TMB, more infiltration of CD4+T cells. Conclusions: Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis
Authors: Yannick van Sleen, William F. Jiemy, Sarah Pringle, Kornelis S. M. van der Geest, Wayel H. Abdulahad, Maria Sandovici, Elisabeth Brouwer, Peter Heeringa, Annemieke M. H. Boots
Journal: Arthritis & Rheumatology (2021)

Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA.Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation.In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.
Phase 1 trial of the adenosine A<sub>2A</sub> receptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A<sub>2A</sub> receptor within the tumor.
Authors: Laurence Buisseret, Sylvie Rottey, Johann S. De Bono, Ariane Migeotte, Brant Delafontaine, Thubeena Manickavasagar, Chiara Martinoli, Noémie Wald, Maura Rossetti, Esha A. Gangolli, Erol Wiegert, Nicola McIntyre, Joanne J. Lager, Jean-Pascal H. Machiels
Journal: Journal of Clinical Oncology (2021)

2562 Background: Tumors produce high levels of extracellular adenosine which suppress anti-tumor immune responses. Blocking A 2A receptors, predominantly expressed on tumor-infiltrating immune cells, can reverse the immunosuppressive effect of adenosine. Inupadenant is a non brain-penetrant, potent and highly selective small molecule antagonist of the A 2A receptor that remains active even at the high adenosine concentrations found in tumors. Methods: This is the phase I portion of an ongoing first-in-human, clinical trial (NCT02740985) to evaluate safety/tolerability, pharmacokinetic, pharmacodynamic and anti-tumor activity of inupadenant in adult patients with solid tumors who have exhausted standard treatment options. In addition, tumor biomarkers, including adenosine-pathway markers by immunohistochemistry (IHC), are being evaluated. We present updated results of the dose escalation, new results from the monotherapy expansion and new analysis of tumor biomarkers. Results: Overall, 42 patients (21 patients in the dose escalation and an additional 21 patients in a monotherapy expansion) with a median of 3 prior regimens were treated as of the data cut off (DCO, 30Nov20).The dose levels investigated, along with the most frequent (&gt;20%) treatment-emergent adverse events (TEAEs) across all dose levels are presented in the table. 7 AEs led to discontinuation; 2 (atrial fibrillation and myocardial infarction) were considered possibly study drug-related by the investigator. No dose reductions were required. Two partial responses (PRs) were reported: melanoma (NRAS-mutant; received prior immunotherapy), and prostate cancer (received antiandrogen and chemotherapy). At the DCO, both PRs were ongoing with a duration of response &gt;230 days. 12 patients had stable disease (SD) as best response and SD &gt;6 months was observed in 3 patients. Response and stable disease were associated with a higher number of cells expressing the A 2A receptor within the tumor at baseline, as measured by IHC. Conclusions: Inupadenant monotherapy was generally well-tolerated as of the DCO at a dose of 80 mg twice daily with initial evidence of clinical benefit, including 2 durable PRs in patients who have exhausted standard treatment options. Analysis of pre-treatment tumor biopsies has identified the A 2A receptor as a biomarker which may be associated with clinical benefit. Clinical trial information: NCT03873883. [Table: see text]
Suppression of tumor development by another tumor in primary immunodeficiency in experiment.
Authors: Ekaterina I. Surikova, Elena M. Frantsiyants, Irina V. Kaplieva, Valeria A. Bandovkina, Lidia K. Trepitaki, Irina V. Neskubina, Inga Movlievna Kotieva, Konstantin A. Shumarin, Galina V. Zhukova
Journal: Journal of Clinical Oncology (2021)

e21583 Background: Multiple primary malignant tumors (MPMTs) are characterized by the presence of several primary neoplasms in one patient. The purpose of the study was to create an experimental model of MPMTs with one dominating tumor. Methods: The study included 21 female BALB/c Nude mice. The main group included mice with simultaneous subcutaneous inoculation of tumors: Guerin's carcinoma (0.5 million tumor cells in 0.5 ml of saline solution) under the right scapula and B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline solution) under the left scapula. Control groups included females with melanoma or carcinoma inoculated at the same dosage and volume as in the main group. Results: In a MPMT model, tumors appeared 3 times faster than in controls and demonstrated larger volumes: melanoma – by 7.5 times, carcinoma – by 2.2 times; the survival of mice with MPMTs decreased. Carcinoma in a MPMT model metastasized to melanoma and almost completely suppressed its growth. Melanoma was represented by a small “island” of tumor tissue 3-4 mm in diameter and was located just under the skin at the site of injection of melanoma cells. The light part of the same loose pasty consistency as the dark part, with a diameter of 6-7 mm, was located around the dark “center” of melanoma. The rest part of the tumor located under the left scapula looked like an elongated grayish-pink node of a dense elastic consistency - just like the tumor located under the right scapula, which was much larger in volume. The right and left tumors did not merge with each other; there was a small distance of about 2-3 mm between them. A small lesion of caseous necrosis, 6–7 mm in diameter, was recorded in the center of the right tumor node of Guerin's carcinoma; there was no necrosis in the left tumor. Smaller size, the absence of necrosis and visually more “young” carcinoma tissue on the left indicated its later appearance than that on the right, which, in combination with the remnants of melanoma fused to the left tumor and the absence of “contact” between the left tumor and the right one, indicated the metastatic nature of Guerin’s carcinoma on the left. B16/F10 melanoma did not metastasize. Conclusions: In simultaneous subcutaneous inoculation of murine B16/F10 melanoma and rat Guerin’s carcinoma to female BALB/c Nude mice, carcinoma cells metastasized to melanoma and suppressed its growth.