A descriptive cost-analysis of MYX.1/MCRN003, a phase 2 clinical trial evaluating high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma.

BACKGROUND: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. METHODS: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). RESULTS: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. CONCLUSIONS: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens.

Violations of Lab-Learned Phonological Patterns Elicit a Late Positive Component.

The experimental study of artificial language learning has become a widely used means of investigating the predictions of theories of language learning and representation. Although much is now known about the generalizations that learners make from various kinds of data, relatively little is known about how those representations affect speech processing. This paper presents an event-related potential (ERP) study of brain responses to violations of lab-learned phonotactics. Novel words that violated a learned phonotactic constraint elicited a larger Late Positive Component (LPC) than novel words that satisfied it. Similar LPCs have been found for violations of natively acquired linguistic structure, as well as for violations of other types of abstract generalizations, such as musical structure. We argue that lab-learned phonotactic generalizations are represented abstractly and affect the evaluation of speech in a manner that is similar to natively acquired syntactic and phonological rules.

Phonological Concept Learning.

Linguistic and non-linguistic pattern learning have been studied separately, but we argue for a comparative approach. Analogous inductive problems arise in phonological and visual pattern learning. Evidence from three experiments shows that human learners can solve them in analogous ways, and that human performance in both cases can be captured by the same models. We test GMECCS (Gradual Maximum Entropy with a Conjunctive Constraint Schema), an implementation of the Configural Cue Model (Gluck & Bower, ) in a Maximum Entropy phonotactic-learning framework (Goldwater & Johnson, ; Hayes & Wilson, ) with a single free parameter, against the alternative hypothesis that learners seek featurally simple algebraic rules ("rule-seeking"). We study the full typology of patterns introduced by Shepard, Hovland, and Jenkins () ("SHJ"), instantiated as both phonotactic patterns and visual analogs, using unsupervised training. Unlike SHJ, Experiments 1 and 2 found that both phonotactic and visual patterns that depended on fewer features could be more difficult than those that depended on more features, as predicted by GMECCS but not by rule-seeking. GMECCS also correctly predicted performance differences between stimulus subclasses within each pattern. A third experiment tried supervised training (which can facilitate rule-seeking in visual learning) to elicit simple rule-seeking phonotactic learning, but cue-based behavior persisted. We conclude that similar cue-based cognitive processes are available for phonological and visual concept learning, and hence that studying either kind of learning can lead to significant insights about the other.

Weighted constraints in generative linguistics.

Harmonic Grammar (HG) and Optimality Theory (OT) are closely related formal frameworks for the study of language. In both, the structure of a given language is determined by the relative strengths of a set of constraints. They differ in how these strengths are represented: as numerical weights (HG) or as ranks (OT). Weighted constraints have advantages for the construction of accounts of language learning and other cognitive processes, partly because they allow for the adaptation of connectionist and statistical models. HG has been little studied in generative linguistics, however, largely due to influential claims that weighted constraints make incorrect predictions about the typology of natural languages, predictions that are not shared by the more popular OT. This paper makes the case that HG is in fact a promising framework for typological research, and reviews and extends the existing arguments for weighted over ranked constraints.

Quality of life, mucositis, and xerostomia from radiotherapy for head and neck cancers: a report from the NCIC CTG HN2 randomized trial of an antimicrobial lozenge to prevent mucositis.

BACKGROUND: The National Cancer Institute of Canada Clinical Trials Group undertook a multicenter, randomized, double-blind controlled trial of an oral antimicrobial versus placebo to prevent and treat mucositis. We present the quality of life (QOL) analysis for this trial. METHODS: One hundred thirty-eight patients were randomly assigned. QOL data were collected every 2 weeks before, during, and after radiotherapy. The European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30) and a Trial Specific Checklist (TSC) were used. RESULTS: The antimicrobial lozenge did not impact QOL. The principal acute side effect of radiotherapy is oral pain, affecting more than 90% of patients. Role function is impacted during treatment, and patients experience fatigue. Appetite was reported to markedly increase during radiotherapy. There was a dramatic and persistent increase in dry mouth. CONCLUSIONS: This study highlights the benefits of combining the EORTC QLQ-30 with an "oral" TSC in a randomized controlled trial and provides valuable baseline data for their use with an objective mucositis scoring system.

Constraint conflict in cluster reduction.

When children reduce onset clusters to singletons, a common pattern is for the least sonorous member of the adult cluster to be produced. Within optimality theory (Prince & Smolensky, 1993), this pattern has been accounted for in terms of a fixed ranking of onset constraints that evaluate a segment's degree of sonority, whereby onset glides violate the highest ranked constraint, and onset stops the lowest. Not all children follow the sonority pattern, however. In this paper, we apply two fundamental principles of optimality theory to yield predictions about other children's cluster reduction patterns. The first principle is that of factorial typology, according to which all rankings of constraints should yield possible languages. To produce the sonority pattern, all conflicting constraints must rank beneath the onset sonority constraints. If they rank above the onset sonority constraints, these other constraints will force deviations from the sonority pattern. In this paper, we show how divergences from the sonority pattern are caused by three well-motivated conflicting constraints: *Fricative, *Dorsal, and Max-Labial. This is documented in the speech of two normally developing children (about 1;6-2;3) and a child with a phonological delay (3;8). The second principle we appeal to is that of emergent constraint activity, according to which the effects of violated constraints can be observed when higher ranked conflicting constraints are not at issue. We show that even when the onset sonority constraints are outranked by the conflicting constraints, under the right circumstances the sonority pattern does emerge in the forms produced by these children.