FOxTROT2: innovative trial design to evaluate the role of neoadjuvant chemotherapy for treating locally advanced colon cancer in older adults or those with frailty.

Treating older adults with cancer is increasingly important in modern oncology practice. However, we currently lack the high-quality evidence needed to guide optimal management of this heterogeneous group. Principally, historic under-recruitment of older adults to clinical trials limits our understanding of how existing evidence can be applied to this group. Such uncertainty is particularly prevalent in the management of colon cancer (CC). With CC being most common in older adults, many patients also suffer from frailty, which is recognised as being strongly associated with poor clinical outcomes. Conducting clinical trials in older adults presents several major challenges, many of which impact the clinical relevance of results to a real-world population. When considering this heterogeneous group, it may be difficult to define the target population, recruit participants effectively, choose an appropriate trial design, and ensure participants remain engaged with the trial during follow-up. Furthermore, after overcoming these challenges, clinical trials tend to enrol highly selected patient cohorts that comprise only the fittest older patients, which are not representative of the wider population. FOxTROT1 was the first phase III randomised controlled trial to illustrate the benefit of neoadjuvant chemotherapy (NAC) in the treatment of CC. Patients receiving NAC had greater 2-year disease-free survival compared to those proceeding straight to surgery. Outcomes for older adults in FOxTROT1 were similarly impressive when compared to their younger counterparts. Yet, this group inevitably represents a fitter subgroup of the older patient population. FOxTROT2 has been designed to investigate NAC in a full range of older adults with CC, including those with frailty. In this review, we describe the key challenges to conducting a robust clinical trial in this heterogeneous patient group, highlight our strategies for overcoming these challenges in FOxTROT2, and explain how we hope to provide clarity on the optimal treatment of CC in older adults.

Parametric manipulation of interresponse-time contingency independent of reinforcement rate.

Pecking of pigeons was reinforced under a modified interval-percentile procedure that allowed independent manipulation of overall reinforcement rate and the degree to which reinforcement depended on interresponse-time duration. Increasing the contingency, as measured by the phi coefficient, between reinforcement and long interresponse times while controlling the overall rate of reinforcement systematically increased the frequency of those interresponse times and decreased response rate under both of the reinforcement rates studied. Increasing reinforcement rate also generally increased response rate, particularly under weaker interresponse-time contingencies. Random-interval schedules with comparable reinforcement rates generated response rates and interresponse-time distributions similar to those obtained with moderate-to-high interresponse-time reinforcement contingencies. These results suggest that interresponse-time reinforcement contingencies inherent in random-interval and constant-probability variable-interval schedules exercise substantial control over responding independent of overall reinforcement rate effects. The interresponse-time reinforcement contingencies inherent in these schedules may actually mask the effects of overall reinforcement rate; thus differences in response rate as a function of reinforcement rate when interresponse-time reinforcement is eliminated may be underestimated.

Bisection of temporal intervals by pigeons.

Two experiments investigated temporal bisection in pigeons using a procedure similar to that of Stubbs (1976). This procedure measures the point in time at which the bird switches from the shorter to the longer valued of two fixed-interval reinforcement schedules with a common starting point. The first experiment substantiated previous findings of switching at the geometric mean of the two interval values and strengthened identification of this switching with bisection by eliminating the possibility that the birds simply switched to the longer interval when the shorter one was perceived to have expired. The experiment also extended the range of values for which temporal intervals have been found to be bisected at their geometric mean. A second experiment demonstrated that the usefulness of the present procedure for determining temporal bisection points is limited to cases in which the longer interval is no more than four times the duration of the shorter interval. Greater separation of the two interval durations produced a period of nonresponding during which the location of the switching or bisection point was totally ambiguous.

Perceived pitch class of isolated musical triads.

A paired-comparisons task was used to determine which note of a pure-tone triad sounded most similar to the triad. Musically inexperienced Ss showed no systematic preference, experienced Ss consistently preferred the highest note in the triad, and professional musicians split equally between preferring the highest note and the root note. Preference for the root note shifted to preference for the highest note as the triad type became increasingly inharmonic, suggesting that the former depended on inference of a missing fundamental. When Ss were asked to vocally reproduce the pitch they heard when listening to a triad, similar results were obtained, except that a root-note preference was not detectable in Ss with less musical experience. Preference for the root note was also facilitated by use of octave-replicated tones, and this increase was shown to be due to obscuring of pitch-height cues, rather than harmonic complexity.

Interresponse-time shaping by variable-interval-like interresponse-time reinforcement contingencies.

The interresponse-time reinforcement contingencies and distributions of interreinforcement intervals characteristic of certain variable-interval schedules were mimicked by reinforcing each key peck with a probability equal to the duration of the interresponse time it terminated, divided by the scheduled mean interreinforcement interval. The interresponse-time reinforcement contingency was then eliminated by basing the probability of reinforcement on the fifth interresponse time preceding the key peck. Even though distributions of interreinforcement intervals were unaffected by this manipulation, response rates consistently increased. A second experiment replicated this effect and showed it to combine additively with that of mean reinforcement rate. These results provide strong support for the contention that current analyses of variable-interval response rates that ignore the inherent interresponse-time reinforcement contingency may be seriously in error.

Reinforcement rate and interresponse time differentiation.

Reinforcement rate and differential reinforcement of IRTs were independently manipulated to assess their relative contribution to the control of interresponse times (IRTs). Modified percentile reinforcement schedules (Platt, 1973) allowed control of reinforcement rate while longest or shortest IRTs were selectively reinforced. In the absence of differential IRT reinforcement, mean IRT decreased with increasing reinforcement rate. Compared to this small effect of reinforcement rate, reinforcement of long IRTs produced large changes in mean IRT at constant reinforcement rates. No interaction of reinforcement rate and IRT reinforcement was detected. The demonstration of large IRT changes in the absence of reinforcement-rate changes indicates the precedence of IRT reinforcement over molar reinforcement-rate correlations in the determination of IRTs in these procedures.

Response-reinforcer contingency and spatially defined operants: testing an invariance property of phi.

A chamber containing 72 response keys defining the circumference of a circle 1 m in diameter was used to examine the relation between differentiation of response location and a measure of response-reinforcer contingency known as the phi coefficient. A different target key was specified in each successive phase, and response location was differentiated with respect to the target. Criterional and noncriterional responses (i.e., responses "near" and "far" from the target) were defined using targeted percentile schedules to control the overall probability of each response class. By manipulating criterional (and, hence, noncriterional) response probability and the reinforcement probabilities conditional on each, a mathematical invariance property peculiar to phi in contingency analysis was examined. Specifically, diagonally interchanging cell frequencies in a 2 x 2 table relating criterional/noncriterional responses to reinforcement/nonreinforcement leaves phi unchanged. Hence, the degree of response differentiation predicted by phi remains unchanged under the four permutations implied by the various diagonal interchanges. This predicted invariance was examined under values of phi equal to .33, .58, and .82. Increasing phi generally increased the stereotypy of response location. Three of the permutations generated almost interchangeable performance at different phi values. The remaining permutation, however, generated functions relating response concentration to phi with slopes shallower than those obtained under the other permutations. This resulted from relatively higher levels of differentiation, compared to the other permutations, at low phi values. These data strongly suggest boundary conditions on the ability of phi to reflect completely the local processes that are indexed by phi at a molar level.

Interresponse-time punishment: a basis for shock-maintained behavior.

Lever pressing of squirrel monkeys postponed brief electric shock according to a free-operant shock-postponement procedure. Pressing also produced shock with a probability proportional to the duration of the current interresponse time in some conditions, or to the fifth ordinally-preceding interresponse time in others. These conditions provided equal frequencies and temporal distributions of response-produced shocks either contingent on or independent of the current interresponse-time duration, respectively. Shock delivered contingent on the current interresponse-time duration resulted in shorter mean interresponse times and higher overall response rates that shock delivered independent of the current interresponse time. In subsequent conditions, response-produced shocks were sufficient to maintain responding following suspension of the postponement procedure only when those shocks were contingent on the current interresponse time. Presenting shock independent of the current interresponse time, conversely, suppressed response rate and ultimately led to cessation of responding in the absence of a conjoint shock-postponement procedure. These results demonstrate interresponse-time punishment in the absence of any indirect avoidance contingencies based on overall shock-frequency reduction, and strongly support similar interpretation at the more local level of shock-frequency reduction correlated with particular interresponse times. Differential punishment of long interresponse times also provides both an a priori basis for predicting whether a schedule of shock presentation will maintain or suppress responding and a framework for interpreting many of the functional relations between overall response rate and parameters of consequent shock presentation. Finally, these results and others indicate the importance of response-consequence contiguity above and beyong any notion of noncontiguous contingency in the control of behavior.

Rats' lever-press durations as psychophysical judgements of time.

Hungry rats received food following lever-press durations exceeding a minimum value, which ranged from 0 to 6.4 sec. When no intertrial intervals separated successive presses, modal press durations remained at very short values as the minimum value required for food was increased. This was particularly true immediately after a food presentation. When an 8-sec intertrial interval followed each lever release, modal press durations were always at or beyond the minimum value required for food, and outcome of the preceding press had no effect on press duration. Possible reasons for the effects of intertrial intervals included punishment of short presses, increased delay of reinforcement of short presses, and reduced density of reinforcement. In addition, functions relating discrete-trials lever-press duration to minimum duration required for food were found to be qualitatively and quantitatively similar to the power functions recently proposed by Catania (1970) for interresponse time and response latency. This similarity was taken as support for a general psychophysical law of temporal judgments.

Radon: its impact on the community and the role of the nurse.

1. Radon contamination is of growing concern in many industries and communities, but it need not remain a hazard. Testing can be inexpensive and mitigation may be as simple as opening a window. 2. High risk areas are known. For more information on radon one may contact the local EPA office. The address is found in the government section of the white pages of the telephone directory. 3. Occupational health nurses are uniquely positioned to gather and disseminate much needed information on the effects of radon.

Harmonic accents in inference of metrical structure and perception of rhythm patterns.

Research on rhythmic structure is somewhat fragmented, due in part to differential use of terminology and a lack of research on the timing of harmonic accents. In this study, a harmonic and a temporal accent were pitted against each other in such a way as to form different rhythm patterns. In addition, two harmonic conditions that varied in the frequency of chord presentations (i.e., the composite rhythm) but not in the frequency of chord changes (i.e., the harmonic rhythm) were presented. Musicians and nonmusicians were requested to report perceived rhythm patterns in an attempt to determine the relative salience of the harmonic and temporal accents. In addition, a behavioral measure of the perceived meter was taken. Results indicated that the location of chord changes was the main determinant of subjects' rhythmic perceptions and the perceived onset of a measure. Furthermore, although subjects primarily inferred different meters based on the composite rhythm, an interaction of metrical and rhythmic choices was found, indicating that perception of rhythm patterns and inference of metrical structure may not always be independent.

Rhythm perception and differences in accent weights for musicians and nonmusicians.

In order to investigate the contribution of harmonic-temporal and structural features to the perception of musical rhythm, three experiments were conducted in which a harmonic and a temporal accent were pitted against each other in such a way as to form five possible patterns. In three experiments, the temporal structure of various chord progressions was manipulated in an effort to determine the harmonic contributions to the inference of meter. The final experiment differed from the first two in the use of nondiatonic progressions that implied an unlikely key modulation. In all experiments, musicians and nonmusicians were requested to report perceived rhythm patterns in an attempt to determine the relative salience of various accents. Results indicated that changes in the temporal structure led to predictable change in an inferred meter, and that all diatonic chord progressions led to similar patterns of responses in which coincidences of harmonic, temporal, and metrical accents were perceptually salient events. Unusual progressions implying key modulations resulted in a qualitatively distinct pattern of results, and, in all experiments, amount of formal musical training was found to be a good predictor of the use of harmonic cues.