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Diagnosis and classification of tumors is increasingly dependent on biomarkers. RNA expression profiling using next-generation sequencing provides reliable and reproducible information on the biology of cancer. This study investigated targeted transcriptome and artificial intelligence for differential diagnosis of hematologic and solid tumors. RNA samples from hematologic neoplasms (N = 2606), solid tumors (N = 2038), normal bone marrow (N = 782), and lymph node control (N = 24) were sequenced using next-generation sequencing using a targeted 1408-gene panel. Twenty subtypes of hematologic neoplasms and 24 subtypes of solid tumors were identified. Machine learning was used for diagnosis between two classes. Geometric mean naïve Bayesian classifier was used for differential diagnosis across 45 diagnostic entities with assigned rankings. Machine learning showed high accuracy in distinguishing between two diagnoses, with area under the curve varying between 1 and 0.841. Geometric mean naïve Bayesian algorithm was trained using 3045 samples and tested on 1415 samples, and showed correct first-choice diagnosis in 100%, 88%, 85%, 82%, 88%, 72%, and 72% of acute lymphoblastic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, colorectal cancer, lung cancer, chronic lymphocytic leukemia, and follicular lymphoma cases, respectively. The data indicate that targeted transcriptome combined with artificial intelligence are highly useful for diagnosis and classification of various cancers. Mutation profiles and clinical information can improve these algorithms and minimize errors in diagnoses.

PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10−2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294–303. ©2018 AACR.

Additional Methods: MTD determination; Biomarker analyzed Supplementary Table S1. Patient disposition by treatment group Supplementary Table S2. Treatment-related AEs reported in >10% of patients in arm A Supplementary Table S3. Treatment-related AEs reported in in {greater than or equal to}2 patients in arm B Supplementary Table S4. Treatment-related AEs reported in >20% of patients in arm C Supplementary Table S5 Median treatment duration and dose reductions/delays by treatment group Supplementary Table S6. Treatment discontinuations by treatment group Supplementary Table S7. Glasdegib pharmacokinetic parameters at the RP2D Supplementary Table S8. Best overall response in patients with AML by treatment arm Supplementary Table S9. Selected baseline characteristics including gene mutations and response to treatment Supplementary Figure S1. Potential associations of MMP-3 and SDF-1 with response in patients administered glasdegib plus cytarabine/daunorubicin

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.FUNDING: Sierra Oncology.

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

This report describes a new research resource: a searchable database of 4,700 naturally occurring instances of sluicing in English, annotated so as to shed light on the questions that have shaped research on ellipsis since the 1960s. The paper describes the data set and how it can be obtained, how it was constructed, how it is organized, and how it can be queried. It also highlights some initial empirical findings, first describing general characteristics of the data, then focusing more closely on issues concerning antecedents and possible mismatches between antecedents and ellipsis sites.

Mounting evidence suggests measurable residual disease (MRD) assessments are prognostic in acute myeloid leukemia (AML). High-risk AML encompasses a subset of AML with poor response to therapy and prognosis, with features such as therapy-related AML, an antecedent hematologic disorder, extramedullary disease (in adults), and selected mutations and cytogenetic abnormalities. Historically, few patients with high-risk AML achieved deep and durable remission with conventional chemotherapy; however, newer agents might be more effective in achieving MRD-negative remission. CPX-351 (dual-drug liposomal encapsulation of daunorubicin/cytarabine at a synergistic ratio) demonstrated MRD-negativity rates of 36–64% across retrospective studies in adults with newly diagnosed high-risk AML and 84% in pediatric patients with first-relapse AML. Venetoclax (BCL2 inhibitor) demonstrated MRD-negativity rates of 33–53% in combination with hypomethylating agents for high-risk subgroups in studies of older adults with newly diagnosed AML who were ineligible for intensive therapy and 65% in combination with chemotherapy in pediatric patients with relapsed/refractory AML. However, there is no consensus on optimal MRD methodology in AML, and the use of different techniques, sample sources, sensitivity thresholds, and the timing of assessments limit comparisons across studies. Robust MRD analyses are needed in future clinical studies, and MRD monitoring should become a routine aspect of AML management.

3047 Background: Expressed RNA can capture mutations, changes in expression levels due to methylation, and provide information on cell of origin, growth, and proliferation status. We developed an approach to isolate fragmented RNA from peripheral blood plasma and explored its potential to be used in liquid biopsy. Methods: Peripheral blood cfRNA was extracted from patients with neoplasms in B-cell (#105), T-cell (#16), Myeloid (#73), and from solid tumors (#44), Normal individuals (#51), and reactive post-transplant (#137). RNA was sequenced using a 1459-gene panel. Expression profile was generated using Cufflinks. Results: cfRNA levels of various solid tumor biomarkers (CA-125, CA-15-3, CEA 8, Keratin19, Keratin6A...) were significantly higher (P < 0.0001) in samples from solid tumors as compared with normal control. Similarly, cfRNA lymphoid markers (CD19, CD22, CD79A, and CD79B...) and cfRNA myeloid markers (CD33, CD14, CD117, CD56...) were all higher in B-cell lymphoid neoplasms and myeloid neoplasms, respectively (P < 0.0001), as compared with control. In evaluating the host immune system, cfRNA CD4:CD8B and CD3D:CD19 ratios in normal controls were as expected (median: 5.92 and 6.87, respectively) and were significantly lower in solid tumors (median 3.40 and 2.23, respectively, P < 0.0002). Solid tumor cfRNA showed CTLA4:CD8B ratio significantly higher in tumors than in normal (median 0.74 vs 0.19, P = 0.0001), while there was no difference in cfRNA PD-L1:CD8B ratio (median 1.45 vs 1.77, P = 0.96). Similar distinct patterns are noted for various cytokine and chemokines. cfRNA was highly predictive of diagnosis (AUC > 0.98) of solid tumors, B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, and myeloid neoplasms as compared with normal control. When a specific neoplastic disease was considered against all cases including control and other neoplasms, the AUC varied between 0.77 and 0.949. Conclusions: This data shows that liquid biopsy using targeted sequencing of cfRNA in patients with various types of cancer provides comprehensive and reliable information on the neoplastic disease as well as the host. [Table: see text]

3018 Background: Diagnosis and classification of tumors is becoming increasingly dependent on biological and molecular biomarkers. RNA expression profiling using next generation sequencing (NGS) provides information on various biological and molecular changes in the cancer and in the microenvironment. We explored the potential of using targeted transcriptome and artificial intelligence (AI) in the differential diagnosis and classification of various hematologic and solid tumors. Methods: RNA from hematologic neoplasms (N = 2606) and solid tumors (N = 2038) as well as normal bone marrow and lymph node control (N = 806) were sequenced by NGS using a targeted 1408-gene panel. The hematologic neoplasms included 20 different subtypes. Solid tumors included 24 different subtypes. Machine learning is used for comparing two classes at a time. Geometric Mean Naïve Bayesian (GMNB) classifier is used to provide differential diagnosis across 45 diagnostic entities with assigned ranking. Results: Machine learning showed high accuracy in distinguishing between two diagnoses with AUC varied between 1 (Sarcoma vs GIST) and 0.841 (MDS vs normal control) (examples in Table). For differential diagnosis between all 45 different diagnoses, we used 3045 samples for training the GMNB algorithm and 1415 samples for testing. Correct first choice diagnosis was obtained in 100% of ALL, 88% of AML, 85% of DLBCL, 82% of colorectal cancer, 88% of lung cancer, 72% of CLL, and 72% of follicular lymphoma. The algorithm had difficulty in typically overlapping diagnoses and diagnosed as first choice 19% of MDS, 46% of normal, and 12% of MPN. Diagnosis improved significantly when second choice was considered. Conclusions: Targeted RNA profiling with proper AI can provide highly useful tools for the pathologic diagnosis and classification of various cancers. Additional information such as mutation profile and clinical information can improve these algorithms, reduce subjectivity, and minimize errors in pathologic diagnoses. [Table: see text]

Irish Existentials in Context James McCloskey March ,  To appear in Syntax This paper grows out of NSF Research Project BCS-, Existentials at the Interface. I am grateful to my co-  on the project, Sandy Chung, for her many contributions to the research reported on here. The paper also benefitted greatly from presentations at the Maryland Mayfest, in May , at the Stanford Existentials Fest, held at Stanford University on January st , and at the Formal Approaches to Celtic Linguistics conference held at the University of Arizona, Tucson in March . I am grateful to David Beaver and to Line Mikkelsen for their help and input, to Elliott Lash for comments on an earlier version, and to Pranav Anand for a number of discussions that helped push the project towards completion at a crucial point. I am especially grateful to Lillis O Laoire for his help in sifting through some of the more subtle interpretive issues that are dealt with here. Finally, I am particularly grateful to three reviewers for Syntax whose comments led to substantial improvements.

This paper examines so-called autonomous forms of the verb in Irish in the context of ongoing work on the syntax and semantics of arbitrary pronominal subjects (on on French; man in German and so on). It argues for the syntactic presence of a phonologically null subject in such constructions and attempts to understand various characteristics of such impersonal constructions (with respect to binding and control especially) in the light of that hypothesis.

This paper reports on an eort to develop a linguistically-informed annotation scheme for sluicing (Ross, 1969), ellipsis that leaves behind a wh-phrase. We describe a scheme for annotating the elided content, both in terms of a free text representation and its degree of correspondence with its antecedent. We demonstrate that we can achieve reasonable IAA ( between .78 and .88 across eight annotation types) and describe some of the novel patterns that have arisen from this eort.

This paper will discuss the roles of electronic reserves in the digital library, focusing particularly on academic library user characteristics and how electronic reserves can be a tool in forging and expanding new ways of collaborating with faculty. Issues for implementing and managing electronic reserves operations will also be discussed.

It has been widely assumed that the preverbal particles of Irish are complementizers. Given the distribution of the particle aL, this assumption provides support for two central claims about WH-movement – that its application is successive-cyclic, and that it is driven by a morphosyntactic feature of the complementizer. However, the claim that aL is a complementizer also has been widely challenged. This paper aims to (re)confirm the original analysis. It argues that the sceptical literature (i) underestimates the morphosyntactic heterogeneity of Irish complementizers, and (ii) restricts attention to an overly narrow subset of constructions in which aL appears.

SUMMARY Operations guidelines for Ariel use among members of the Health Sciences Libraries Consortium were used as the basis for the development of the Ariel Document Delivery Protocol, or “ADDP,” which was agreed upon by many U.S. medical libraries in 1994. Each point of the protocol is noted as a way to more efficiently use the Ariel software for electronic delivery of materials to researchers.

The English of northwestern Ireland allows quantifier float of a previously undocumented kind in wh-questions. The quantifier all, though construed with a fronted wh-pronoun, may appear in a position considerably to the right of that pronoun. It is argued that all so stranded marks a position through which a wh-phrase has passed or in which a wh-phrase originates. The construction then provides visible evidence for intermediate derivational stages. This evidence is used to develop a new argument for successive cyclicity and to argue for overt object shift in English and for an origin site for subjects strictly within VP and below the object shift position.

This paper examines rightward positioning phenomena in Irish and looks particularly at their interaction with the focusing particle fein. It uses that interaction as a probe to distinguish among three theoretical options for explaining such right-edge phenomena.

In order to facilitate more effective communication between interlibrary loan users and office staff, a collaborative effort was initiated to develop a new and enhanced electronic ILL request form. Development of the Web-based form is described along with a description of HTML, the infrastructure of the Web and how Web forms collect and organize ILL requests.

(1996). Commentary: The death penalty: A personal view. Criminal Justice Ethics: Vol. 15, No. 2, pp. 2-75.

This paper presents a novel analysis of Sluicing, an ellipsis construction first described by Ross (1969) and illustrated by the bracketed portion ofI want to do something, but I'm just not sure [what _]. Starting from the assumption that a sluice consists of a displaced Wh-constituent and an empty IP, we show how simple and general LF operations fill out the empty IP and thereby provide it with an interpretable Logical Form. The LF operations we appeal to rely on the influential theory of indefinites developed by Irene Heim and Hans Kamp, and are in harmony with certain aspects of Chomsky's Minimalist Program for linguistic theory. The analysis accounts directly for the familiar properties of Sluicing, as well as some facts which have not previously been observed.

Linguistic Typology 11 (2007), 285–296 1430–0532/2007/011-0285 DOI 10.1515/LINGTY.2007.023 ©Walter de Gruyter In these remarks on the relationship between typology and theoretical (morpho)syntax, we touch briefly on three issues: what is their relationship in practice now, what relationship should one in principle expect given the founding goals of each enterprise, and what kind of research could help connect the two fields in a more productive way in the future.

Virtually no one who has thought seriously about language and its structure has been able to avoid using the terms ‘subject’ and ‘object’. This is a remarkable fact - that perceptive and knowledgeable observers have been willing to talk about ‘subjects’ and ‘objects’ in very disparate languages and feel reasonably confident that they knew what they were talking about. It is all the more remarkable, then, that in the intellectual tradition represented by the frameworks of ‘Government and Binding’, ‘Principles and Parameters’ and the ‘Minimalist Program’, the notions play no (recognized) role at all. That tradition has always insisted that talk of ‘subjects’ and ‘objects’ is either illicit or casual, and that reference to such terms is to be cashed out in terms of more primitive notions (phrase-structural measures of prominence, featural properties of heads, the theory of A-movement and so on).

The notion of “subject” is fundamental in Aristotelian logic and in almost all Western traditions of thinking about philology and grammar.* It is also fundamental to certain strands of thought within the broad tradition of generative grammar – notably Relational Grammar and Lexical Functional Grammar. However, in the tradition which extends from the “Standard Theory” through the “Extended Standard Theory” to “Principles and Parameters Theory” and then to the “Minimalist Program”, the notion of subject plays no formal role at all. Not only is “subject” not a primitive term in these theories, but in their most recent instantiations it is not even clear that there is any derived or defined notion which captures the traditional intuition of what a subject is (as there was, for instance, in the theory of Chomsky 1965). What we have seen, in a sense, is a progressive deconstruction of the traditional category “subject” so that the properties which are supposed to define it are distributed across a range of distinct (but derivationally linked) syntactic entities and positions. This theoretical eccentricity may turn out to have been foolish or wise, but it is certainly grounded in some of the deeper methodological instincts of generative grammar. My purpose in this contribution is to consider some recent proposals about the syntax of subject” nod, to try to place those proposals in a broader theoretical and historical perspective, and to evaluate their plausibility at least in a tentative way.

This paper is concerned with one aspect of the syntactic processes which derive VSO order in (Modern) Irish. Analyses which appeal to fronting of the finite verb have played an important role in recent theorizing about the VSO clausal pattern. A question which has resisted resolution, however, is the question of what the target-position for this fronting is: does the verb move as far as the C0-position, or does it remain among the inflectional projections? This paper argues that the kind of Verb Fronting found in Irish involves only fronting of V0 to I0, and that it is, as a consequence, different in important ways from Verb Fronting of the Germanic type. The analytical challenges posed by the Irish data are, however, made more interesting by the fact that the sequence of Complementizer, Inflectional element and Verb clearly forms a unit-a word at least for phonological purposes. It is an interesting issue how this conclusion is compatible with the conclusion that there is no general fronting of I0 to C0 in Irish (finite) clauses. It is argued that the Verbal Complex is formed by two movements — raising of V0 to I0 and lowering of C0 to I0. The question of how this conclusion can be compatible with current theories of movement and of locality constraints on movement is the final matter addressed.