tbuckley/cabot-search huggingface dataset:
Glioblastoma evolution pattern under surgery and radio(chemo)therapy (RCHT) to identify novel methylome based glioma subtypes.
Authors: Maximilian Knoll, Juergen Debus, Jennifer Furkel, Rolf Warta, Nina Bougatf, Carmen Rapp, Benedikt Brors, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Amir Abdollahi
Journal: Journal of Clinical Oncology (2019)

2012 Background: Identification of isocitrate dehydrogenase mutations (IDHm) and glioma CpG island methylator phenotype (G-CIMP) as well as methylation of O6-methylguanine DNA methyltransferase (MGMT) promotor has substantially improved stratification of glioma patients into prognostic subgroups. In extension of static pre-therapy diagnostic, we sought to investigate the impact of glioblastoma evolution under selection pressure of standard therapy on methylome level. Methods: For the training cohort (T), methylome (450k Illumina) data of paired samples from 50 patients with glioblastoma (GBM, 11 G-CIMP+) were analyzed, i.e., primary (P) and at the time point of recurrence (R, re-surgery) after standard therapy at NCT. For 39 pairs matching RNASeq data was analyzed. Validation cohorts consisted of Heidelberg (V1) total n = 650, GBM (n:585, 8 G-CIMP+), grade III (n:65, CIMP+ 65), Austrian GBM (V2, n = 499, 36 IDHm, pyrosequencing data) and the TCGA (V3) Lower-grade-glioma cohort (LGG, n = 477, grade III n: 247, 178 G-CIMP+, grade II n: 228, 206 G-CIMP+). Results: Limited number of consensus differentially methylated probes (DMP) were found across all P vs. R samples (nCpG = 411 CpGs, FDR &lt; 0.05). In contrast, heterogeneity in GBM evolution was found by similarity analysis of delta-methylome data of 50 PR pairs resulting in two distinct clinical subgroups and one “intermediate” group. Intriguingly, n = 114.652 DMP (FDR &lt; 0.05) was found by comparing the evolutionary “poor” (n = 15) vs. “good” (n = 13) GBM phenotypes. A random forest classifier was built to identify the evolutionary subgroups in P samples. The performance of “good” prognosis classifier was in T cohort HR: 0.54 [0.30-0.97], p = 0.04; V1: 0.57 [0.43-0.76], p &lt; 0.001, V2: 0.62 [0.47-0.82], p &lt; 0.001, LGG: 0.16 [0.08-0.32], p &lt; 0.001. In “good” prognosis group (T), neither G-CIMP+ (n = 3) nor MGMT-STP27 (oddsratio, OR: 0.56, p = 0.47) was enriched. MGMT-STP27 OR was 0.47 (V1, p = 0.47) or 1.28 (V2, p = 0.45), respectively. The evolutionary subgroups remain prognostic independent of GCIMP status in LGG (V3). “Poor” glioma are enriched for RTKI/II methylome subtypes, and contain less frequently the mesenchymal subtype. Bevacizumab treatment showed a survival benefits only in “poor” subtype (V1+2). Conclusions: Discovery of a methylome based classifier of glioma evolution informs on “good” and “poor” prognosis subtypes and may have ramification for stratifying patients for therapy such as e.g., antiangiogenesis.
Prevalence of esophageal malignant and premalignant lesions in a Michigan cohort, 2013-2017.
Authors: Shilpa Tatineni, Divyesh Reddy Nemakayala, Ikponmwosa Enofe, Ling Wang, Heather Laird-Fick
Journal: Journal of Clinical Oncology (2019)

e15541 Background: Esophageal cancer is diagnosed in roughly 4 per 100,000 US population. Older men are most frequently affected. Adenocarcinoma is most common and incidence is increasing. EGD with biopsy is important for diagnosis. Many patients present with metastases, limiting treatment options. EGD can identify Barrett’s esophagus, a precursor lesion for adenocarcinoma, but evaluation of biopsy specimens is difficult. This study describes findings from esophageal biopsies in a large community-based Michigan cohort. Methods: Patients aged ≥18 years undergoing EGD with esophageal biopsies in Sparrow Health System were identified. Pathology reports were abstracted for sociodemographics, procedure information, and pathologic findings. Only patients with complete data were included for analysis. Statistical comparisons were assessed by chi-square tests or Fisher’s exact test in contingency tables for categorical variables, or t-tests for continuous variables as appropriate. Results: 4,471 patients were included. 3,279 (73.3%) had benign findings, 1,117 (25%) premalignant changes, 69 (1.54%) malignancy including adenocarcinoma, poorly differentiated cancer or high-grade dysplasia, 1 (0.022%) squamous cell cancer, and 5 (0.11%) neuroendocrine tumors. The latter six were excluded from analyses.Most procedures were performed for inpatients (70.5% for benign, 72.5% malignant and 76.3% pre-malignant; p&lt; 0.001 for all comparisons). Patients with malignancy were older than those with premalignancy [mean 69.8 (SD = 10.4) vs 62.6 (SD = 12.2) years; p&lt; 0.001], who were older than those with benign findings [62.6 (SD = 12.2) vs 56.2 (SD = 14.7) years; p&lt; 0.001]. Patients with premalignancy came from areas with higher average household incomes ($42,179 vs $41,247; p&lt; 0.01). There were no other socioeconomic or sex differences between groups. Conclusions: In a community sample, esophageal malignancy was uncommon but premalignant changes common. Most procedures occurred during hospitalizations. Ensuring appropriate post-discharge follow up for premalignant changes could be challenging. Association between premalignant changes and higher average household income is intriguing and merits additional study.
Muscle MASS and mortality in cancer patients.
Authors: Claudio Salas, Maria PIA De La Maza, Paula von Geldern, Claudio Silva, Pablo Alvayay, Alejandro Berkovits
Journal: Journal of Clinical Oncology (2019)

e18290 Background: Detection and prevention of cancer cachexia during oncologic treatment is an important issue in cancer patients care. AIM: To analyze the relation between overall survival and nutritional status assessed both by subjective and objective methods, in a prospective cohort of oncologic patients. Methods: Between 2012-2014 all patients under treatment in the Oncology Unit of Clinica Alemana de Santiago were invited to participate in this study, and follow-up was completed August 2018. Exclusion criteria were terminal phase patients, or those with cognitive deterioration. Apart from recording demographic, clinical and nutritional data, whenever possible, recent computed tomographic images were analyzed through Slice O Matic, at the level of the third lumbar vertebra, for measurement of abdominal fat and muscle area. Muscle Mass Index (MMI) was calculated as muscle area/squared height. The control group was composed by 130 healthy subjects 18-40 years, whose computed tomography images were obtained as part of the trauma protocol. The cutoff for sarcopenia was MMI &lt; -1 SD respect control subjects. In addition, nutritional status was assessed through anthropometric measurements and the Patient Generated Subjective Global Assessment (VGSGP). Results: We included 103 patients, predominant cancer sites were digestive, haematologic and lung; average survival was 33 ± 23 months. The sample was divided in 2 groups (TNM stages 1 and 2 versus 3 and 4). MMI in control subjects was significantly higher than values obtained from 64 oncologic patients with available CT scans, while fat area, specifically visceral, was the opposite. VGSGP scores correlated negatively and significantly with MMI (p &lt; 0.001). According to univariate analysis, survival time was inversely associated with age among male patients ( p = 0.002), cancer stage in both genders p &lt; 0.01), VGSGP (p &lt; 0.01), and positively associated with MMI, only among men (p = 004). Kaplan Meir survival estimates were significant both sarcopenia and cancer stage. According to Cox regression, both sarcopenia and cancer stage were significant predictors of mortality, without any effect of age or sex. Conclusions: Both sarcopenia and cancer stage are predictors of survival during treatment of cancer.
Immune-related adverse events (irAEs) and survival in solid tumors treated with immune checkpoint inhibitors (ICIs): A systematic review and meta-analysis.
Authors: Giulia Grizzi, Fausto Petrelli, Michele Ghidini, Antonio Ghidini, Margherita Ratti, Stefano Panni, Mary Cabiddu, Mara Ghilardi, Karen Borgonovo, Maria Chiara Parati, Sandro Barni, Gianluca Tomasello, Rodolfo Passalacqua, Alfredo Berruti, Matteo Brighenti
Journal: Journal of Clinical Oncology (2019)

e14130 Background: irAEs are autoimmune-toxic effects associated with ICIs used for treatment of advanced solid tumors. The correlation of these irAEs with survival is presently unknown. The objective of this meta-analysis is to assess the outcome of cancer patients treated with ICIs who develop irAEs. Methods: Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane library database from their inception to November 2018. Studies were selected if: 1) they reported correlation of irAEs (any) with outcome, 2) they included patients with solid tumors; 3) they included treatment with anti-PD-(L)1 or anti-CTLA-4 agents, 4) patients had no previous history of autoimmune disorders, 5) they were published in English language, and 6) they provided availability of adequate data to calculate hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs). Data were pooled using HRs for overall survival (OS) or progression-free survival (PFS) or ORs for overall response rate (ORR) of irAEs vs no irAEs according to fixed or random effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. Hazard ratio for PFS and ORs for ORR were secondary endpoints. Results: A total of 29 studies for a total of 4242 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death (HR = 0.52, p &lt; .001). Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR = 0.51, p &lt; .001). The combined odds of response was 4.87 (p &lt; .001). Conclusions: In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T cell activation. Patients showing any form of irAEs can be informed about the positive prognostic effect, and physicians can detect patients with favorable outcome to ICIs.
Role of angiogenesis factors in formation of metastatic niches.
Authors: Elena M. Frantsiyants, Oleg I. Kit, Irina V. Kaplieva, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Elena A. Dzhenkova, Nikolay S. Samoylenko, Petr N. Gabrichidze, Anton G. Milakin, Sergey I. Poluektov
Journal: Journal of Clinical Oncology (2019)

e15534 Background: A metastatic niche indicates a particular location with a specific cell type, epidermal-mesenchymal transition proteins and diffuse signals that are necessary for the growth of metastases. The purpose of the study was to determine levels of VEGFs, their receptors and TGFβ1 in tissues of gastric cancer (GC) and its metastatic niches: the peritoneum and omentum. Methods: The main group included 21 patients with metastatic GC T 3-4 а N 0-3 M 1 ; comparison group – 17 non-cancer patients. Levels of VEGFA, VEGFC, sVEGFR1, sVEGFR3 and TGFβ1 in tissues were determined by standard ELISA methods. Results: Levels of growth factors in GC tissues were higher than in controls: VEGFA in T 3-4 а N 0-3 M 1 – by 2.7 times, in T 3-4 а N 0-3 M 0 – by 2.5 times; TGFβ1 in T 3-4 а N 0-3 M 1 – by 5.6 times, in T 3-4 а N 0-3 M 0 – by 3.5 times. VEGFA levels in primary gastric tumors were similar in all patients, while TGFβ1 in T 3-4 а N 0-3 M 1 was 1.6 times (p &lt; 0.05) higher than in T 3-4 а N 0-3 M 0 . VEGFA levels in T 3-4 а N 0-3 M 1 exceeded control values: in the omentum – by 2.8, in the peritoneum – by 4.2 times. TGFβ1 in the omentum and peritoneum in T 3-4 а N 0-3 M 1 was increased by 2.5 and 3.1 times respectively, compared to controls. Statistically significant differences in VEGFA and TGFβ1 levels in the omentum and peritoneum in T3-4аN0-3M0 were not found. Conclusions: GC is characterized by equally elevated levels of VEGFA, regardless of the presence or absence of metastases. In the omentum and peritoneum with metastases, high VEGF levels can be considered as one of the primary factors for the formation of signaling pathways between metastatic tumor cells and local non-tumor cells in premetastatic niches. Levels of TGFβ1 in the omentum and peritoneum increase only in patients with metastases, and in GC tissue they are increased to a greater extent than in patients without metastases. Probably, in case of T3-4aN0-3M0, the factor produced by the primary tumor was insufficient for its paracrine induction in the metastatic niche, and scattered cells could not transit from “sleeping” to the active state.
Second cancer in Philadelphia negative myeloproliferative neoplasms (MPN-K). A nested case-control study
Authors: Tiziano Barbui, Arianna Ghirardi, Arianna Masciulli, Alessandra Carobbio, Francesca Palandri, Nicola Vianelli, Valerio De Stefano, Silvia Betti, Ambra Di Veroli, Alessandra Iurlo, Daniele Cattaneo, Federica Delaini, Massimiliano Bonifacio, Luigi Scaffidi, Andrea Patriarca, Elisa Rumi, Ilaria Carola Casetti, Clemency Stephenson, Paola Guglielmelli, Elena Maria Elli, Miroslava Palova, Laura Bertolotti, Daniel Erez, Montse Gomez, Kai Wille, Manuel Perez-Encinas, Francesca Lunghi, Anna Angona, Maria Laura Fox, Eloise Beggiato, Giulia Benevolo, Giuseppe Carli, Rossella Cacciola, Mary Frances McMullin, Alessia Tieghi, Valle Recasens, Monia Marchetti, Martin Griesshammer, Alberto Alvarez-Larran, Alessandro Maria Vannucchi, Guido Finazzi
Journal: Leukemia (2019)
Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma.
Authors: Mark R. Middleton, Neil Matthew Steven, TR Jeffry Evans, Jeffrey R. Infante, Mario Sznol, Omid Hamid, Alexander Noor Shoushtari, Alan Anthoney, Avinash Gupta, Victoria K Woodcock, Rachael Easton, Philippa Gail Corrie
Journal: Journal of Clinical Oncology (2019)

9530 Background: Bispecific antibodies have shown activity in hematologic (heme) but not solid tumors. ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeted against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma with associated immune changes. IMCgp100 causes rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. We explored clinical and biological characteristics of pts associated with treatment benefit. Methods: 84 HLA-A2 positive advanced melanoma pts received IMCgp100 on study IMCgp100-01 in 13 dose escalation cohorts. Efficacy was assessed by Kaplan–Meier survival and treatment related AEs (TRAE) reported by CTCAE v4.0. Serum samples evaluated changes in cytokines. A multivariate analysis investigated the relationship between efficacy and safety variables. Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH &gt; ULN; 25% received prior anti-PD(L)1. 83 (99%) pts had ≥1 TRAE; most commonly in skin (rash 82%, pruritus 69%) or cytokine-mediated (pyrexia 57%); the majority were Grade 1–2 and occurred and resolved within first 3 doses. The 2 most frequent Grade ≥3 TRAEs were rash (26%) and lymphopenia (13%). IMCgp100 induced transient increases in peripheral cytokines (peaking Day 1–2) that attenuated with subsequent doses; cytokine-mediated AE had similar kinetics.1-yr OS was 65% (95% CI: 48–78). In multivariate analysis, longer OS was associated with: LDH ≤ULN (p = 0.002) and any-grade rash occurring within 21 days (p = 0.003); melanoma primary site and prior anti-PD-(L)1 did not significantly affect outcome. In exploratory analyses, longer OS associated with lower baseline serum IL-6 (n = 43) or TNFα (n = 44). Conclusions: IMCgp100 is a first-in-class, TCR-based bispecific with monotherapy efficacy in advanced melanoma. AEs were manageable and consistent with MoA. Association between IMCgp100 efficacy and on-target TRAEs, previously reported for bispecifics to heme lineage antigens, is now recognized for solid tumor lineage antigens. Pivotal studies in UM are ongoing. Clinical trial information: NCT01211262.
Case 44-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Henry J. Mankin, Andrew E. Rosenberg
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 25-year-old man was admitted to the hospital because of mediastinal, hilar, and subcarinal lymphadenopathy and a pericardial effusion.He was well until six months earlier, when pain and stiffness developed in his neck and a physician prescribed a soft cervical collar. X-ray films of the cervical spine showed evidence of muscle spasm and were otherwise normal. The symptoms improved greatly, but he began to experience numbness of the left forearm and to have a nonproductive cough. Four months before entry fleeting chest pains developed, and an x-ray film of the chest, obtained elsewhere, was reported to . . .
A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with <i>KRAS</i> G12C mutation.
Authors: Kyriakos P. Papadopoulos, Sai-Hong Ignatius Ou, Melissa Lynne Johnson, James Christensen, Karen Velastegui, Diane Potvin, Demiana Faltaos, Richard C. Chao
Journal: Journal of Clinical Oncology (2019)

TPS3161 Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRAS G12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRAS G12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRAS G12C . MRTX849 inhibits KRAS G12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRAS G12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.
CellTag Indexing: genetic barcode-based sample multiplexing for single-cell genomics
Authors: Chuner Guo, Wenjun Kong, Kenji Kamimoto, Guillermo C. Rivera-Gonzalez, Xue Yang, Yuhei Kirita, Samantha A. Morris
Journal: Genome biology (2019)

High-throughput single-cell assays increasingly require special consideration in experimental design, sample multiplexing, batch effect removal, and data interpretation. Here, we describe a lentiviral barcode-based multiplexing approach, CellTag Indexing, which uses predefined genetic barcodes that are heritable, enabling cell populations to be tagged, pooled, and tracked over time in the same experimental replicate. We demonstrate the utility of CellTag Indexing by sequencing transcriptomes using a variety of cell types, including long-term tracking of cell engraftment and differentiation in vivo. Together, this presents CellTag Indexing as a broadly applicable genetic multiplexing tool that is complementary with existing single-cell technologies.
Quantifying EpCAM heterogeneity of circulating-tumor-cells (CTCs) from small cell lung cancer (SCLC) patients.
Authors: Hadas Sorotsky, Mansi Aparanthi, Daniel Zongjie Wang, Francesca McFadden, Sandra N Popescu, Reza M Mohamadi, Mark Pereira, Jessica Weiss, Devalben Patel, Safa Majeed, Michael Cabanero, Adrian G. Sacher, Penelope Ann Bradbury, Natasha B. Leighl, Frances A. Shepherd, Ming Sound Tsao, Geoffrey Liu, Shana O Kelley, Benjamin H. Lok
Journal: Journal of Clinical Oncology (2019)

e20091 Background: Tumor heterogeneity and evolution of SCLC is poorly defined. Serial longitudinal interrogation of tumor heterogeneity from CTCs detected in peripheral blood patient (pt) samples is a potential strategy to address this gap in knowledge. However, existing technology is generally limited to the capture and enumeration of CTCs, without a high-throughput method to quantify phenotypic properties. Here, we evaluated a novel nanotechnology platform – nanoparticle-mediated magnetic ranking cytometry (MagRC) to profile SCLC CTCs by EpCAM protein expression. Methods: Blood samples from 20 SCLC pts were processed through the MagRC platform. Magnetic nanoparticles conjugated with anti-EpCAM antibodies were incubated with whole blood samples then introduced into the MagRC device where CTCs are sorted by differently sized nickel micromagnets within microfluidic channels. Captured CTCs are ranked into 8 zones that correlate with EpCAM expression levels (zone 1 = highest to 8 = lowest). For 8 pts, all samples were processed at a 1mL/hr flow rate (fr), and for 12 pts, a 0.5mL/hr fr was also studied; 66% of all chips were processed at a 1ml/hr fr and 34% at a 0.5ml/hr fr. The average zone for each chip was compared to the flow rate, age, and stage (extensive-stage (ES) vs limited-stage (LS)). The differences were tested using the Wald test within the linear mixed effects model. Results: Among 20 pts, 11 were ES; 9 were LS. Median age at diagnosis was 69 years old (yo); 65% were male. We detected CTCs in 12 of 20 pts (60%), similar to other studies. When comparing the MagRC-ranked EpCAM zone, the 0.5mL/hr fr demonstrated a lower median zone (4.3 vs 6.5; p &lt; 0.001) as compared to the 1mL/hr rate. Interestingly, pts &gt; 65 yo had a higher median zone (6.2 vs. 3.5; p = 0.019) compared to those ≤65 yo. The effect remained significant after controlling for flow rate (p = 0.002). No EpCAM zone difference was detected between ES and LS. Conclusions: We demonstrate the ability of MagRC to quantify EpCAM expression levels of CTCs from SCLC pts. We observed a higher MagRC zone (i.e. lower EpCAM expression) from pts &gt; 65 yo. This observation requires validation in larger datasets along with continued investigation into the biology of SCLC CTCs.