Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial.

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era.

Follicular lymphoma (FL) is an indolent disease characterized by long survival but frequent relapses. Before the introduction of rituximab, the clinical course of these patients showed a shorter response duration (RD) after each relapse. In this study, we analysed if this pattern of shortened responses remains in patients treated in the rituximab era. We selected 348 patients newly diagnosed with FL in two institutions between 2001 and 2014 that received chemoimmunotherapy. After a median follow-up of 6·3 years, 10-year progression-free and overall survivals were 53% and 72%, respectively. All patients received first-line, 111 second-line and 41 third-line treatments, with a 5-year RD of 62%, 39% and 24%, respectively (P < 0·0001). Variables predicting longer RD after first-line treatment were normal ß2microglobulin, complete remission achievement and maintenance with rituximab. Patients with longer RD after first-line showed significantly longer RD after second-line therapy. Autologous stem-cell transplantation after second-line therapy did not significantly impact RD. Median survival after first, second and third therapies was not reached, 7·6 and 4·8 years, respectively, whereas relative survival with respect to a sex- and age-matched Spanish population, the decrease in the life expectancy at 10 years was 17%, 45% and 79%, respectively. Thus, RD still shortens after each relapse in patients with FL treated in first line with rituximab combinations.

Interval timing under a behavioral microscope: Dissociating motivational and timing processes in fixed-interval performance.

The distribution of latencies and interresponse times (IRTs) of rats was compared between two fixed-interval (FI) schedules of food reinforcement (FI 30 s and FI 90 s), and between two levels of food deprivation. Computational modeling revealed that latencies and IRTs were well described by mixture probability distributions embodying two-state Markov chains. Analysis of these models revealed that only a subset of latencies is sensitive to the periodicity of reinforcement, and prefeeding only reduces the size of this subset. The distribution of IRTs suggests that behavior in FI schedules is organized in bouts that lengthen and ramp up in frequency with proximity to reinforcement. Prefeeding slowed down the lengthening of bouts and increased the time between bouts. When concatenated, latency and IRT models adequately reproduced sigmoidal FI response functions. These findings suggest that behavior in FI schedules fluctuates in and out of schedule control; an account of such fluctuation suggests that timing and motivation are dissociable components of FI performance. These mixture-distribution models also provide novel insights on the motivational, associative, and timing processes expressed in FI performance. These processes may be obscured, however, when performance in timing tasks is analyzed in terms of mean response rates.

Long-term remission in a case of plasmablastic lymphoma treated with COMP (cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) and bortezomib.

Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin lymphomas (NHL) strongly associated with HIV infection, even if cases in other immunosuppressed patients such as solid organ transplant recipients and in immunocompetent individuals have been increasingly reported. Current treatment strategy for HIV-negative patients is similar to DLBCL as first-line treatment, but durable remissions are seldom observed. Anthracycline-containing regimens could be too toxic for elderly patients and/or with cardiac failure, because a non-pegylated liposomal doxorubicin (NLD) could be used in this field. Bortezomib, a proteasome inhibitor currently approved for patients with multiple myeloma and relapsed mantle-cell lymphoma, has recently showed clinical activity in PBL patients. Herein, we report a rapid and long-term remission of a PBL patient with cardiac failure and that had previously received a double kidney transplant, treated front-line with COMP (with a NLD substituted for doxorubicin) followed by subcutaneous bortezomib consolidation. We suggest first-line treatment outcome is determinant for PBL patients. Bortezomib has a promising role and should be incorporated in future clinical trials and NLD could represent a suitable option for patients with cardiac failure or high cardiovascular risk.

Nivolumab plus ipilimumab with chemotherapy in metastatic NSCLC: minireview and a case study of a patient negative for PD-L1.

The advent of immunotherapy, and in particular the use of immune-checkpoint inhibitors, has profoundly revolutionized the treatment of different cancers, including lung cancer. The use of immune-checkpoint inhibitors has prolonged survival in lung cancer with a strong benefit in a significant percentage of patients with non-small-cell lung cancer. Here, a clinical case of a patient who, despite testing negative for PD-L1, displayed a sustained complete response to immunotherapy treatment in advanced metastatic non-small-cell lung cancer is presented. Additionally, recent findings concerning the application of immunotherapy in this context are reviewed.

Control of response duration by delayed reinforcers: A systematic replication.

Three rats responded under schedules of delayed reinforcement in which sweetened condensed milk delivery depended upon lever-press durations exceeding or falling under a programmed value. For all rats, response durations increased compared to those emitted under a fixed-ratio 1 schedule when unsignaled delayed reinforcers were programmed for lever-press durations exceeding 1 s. For two of the rats, response durations also decreased when delayed reinforcer delivery was programmed for durations less than 1 s. Extinction reduced response rate, but did not affect response duration. Data suggest that the rate decreasing effects of unsignaled delayed reinforcers may be separated from the effects those reinforcers have on a targeted continuous dimension.

Response duration is sensitive to both immediate and delayed reinforcement.

We investigated the duration of lever pressing by rats when the delivery of appetitive reinforcers was contingent upon response duration. In the first experiment, response durations increased when duration requirements were imposed, and they decreased when duration requirements were removed. This effect occurred whether reinforcers were immediate or delayed by 8 s. In order to maintain the integrity of the delay intervals, reinforcer delivery was dependent upon both lever depression and release. In a second experiment, lever depression only and a response duration of at least 4 s were required for reinforcer delivery. Compared to immediate reinforcement conditions, delayed reinforcers increased both variability and the length of the maximum response durations. In a third experiment, immediate reinforcers were delivered contingent upon lever depression and release under a variety of duration requirements. Median lever-press durations tracked the contingencies rapidly. Across all three experiments, rats emitted numerous response durations that were too short to satisfy the reinforcer requirements, and bimodal distributions similar to those produced by differential reinforcement of low rate schedules were evident for most rats. In many aspects, response duration responds to reinforcement parameters in a fashion similar to rate of discrete responding, but an examination of this continuous dimension of behavior may provide additional information about environment-behavior relationships.

Long-term study of behaviors of two cohabiting sea urchin species, Mesocentrotus nudus and Strongylocentrotus intermedius, under conditions of high food quantity and predation risk in situ.

BACKGROUND: In the predator-sea urchin-macrophyte trophic cascade, the ecological effect of sea urchins as grazers depends both on their density and the changes in foraging activity, which are influenced by various disturbing factors. However, the complete duration of the alarm reactions of echinoids has not been studied until now. Here, we tested a hypothesis that two cohabiting sea urchins, Mesocentrotus nudus and Strongylocentrotus intermedius, which differ morphologically, might display different behavioral responses to high hydrodynamic activity and predation. METHODS: We used continuous time-lapse video recording to clarify behavioral patterns of M. nudus and S. intermedius in presence of a large quantity of food (the kelp Saccharina japonica) but under different weather conditions and different types of predation threat: (1) calm weather conditions, (2) stormy weather conditions, (3) predation risk associated with the presence of several sea star species and (4) predation risk associated with an alarm stimulus (crushed conspecifics or heterospecifics). Three separate video recording experiments (134 days in total) were conducted under field conditions. Video recording analysis was performed to determine the number of specimens of each sea urchin species in the cameras' field of view, size of sea urchins' groups, movement patterns and the duration of the alarm responses of both sea urchin species. RESULTS: We showed that in the presence of kelp, M. nudus and S. intermedius exhibited both similar and different behavioral responses to hydrodynamics and predation threat. Under calm weather, movement patterns of both echinoids were similar but M. nudus exhibited the higher locomotion speed and distance traveled. Furthermore, S. intermedius but not M. nudus tended to group near the food substrate. The stormy weather caused a sharp decrease in movement activity followed by escape response in both echinoids. Six starfish species failed to predate on healthy sea urchins of either species and only a few attacks on ailing S. intermedius specimens were successful. The alarm response of S. intermedius lasted approximately 90 h and 20 h for starfish attacks on ailing conspecifics and for simulated attacks (crushed conspecifics or heterospecifics), respectively and involved several phases: (1) flight response, (2) grouping close to the food, (3) leaving the food and (4) return to the food. Phase three was the more pronounced in a case of starfish attack. M. nudus only responded to crushed conspecifics and exhibited no grouping behavior but displayed fast escape (during 4 h) and prolonged (up to 19 days) avoidance of the food source. This outcome is the longest alarm response reported for sea urchins. DISCUSSION: The most interesting finding is that two cohabiting sea urchin species, M. nudus and S. intermedius, display different alarm responses to predation threat. Both alarm responses are interpreted as defensive adaptations against visual predators.

Resurgence of response duration in human participants.

Previously reinforced responses can reappear when reinforcement is withdrawn from current responding. This is known as resurgence. Although resurgence of response topography, spacing, and patterns over time has been demonstrated, there is no evidence of resurgence of response duration. This experiment explored resurgence of response duration in humans. In Phase 1 a multiple schedule of reinforcement with two components was used. In each component a chained variable-interval 30s, variable-ratio 3 schedule was implemented. In the terminal link of the chained schedule, response durations between 0.1 and 0.5s were reinforced during one component, and between 2 and 8s in the other component. In Phase 2, response requirement during the terminal link of the chained schedule was inverted between components relative to Phase 1. In Phase 3 the chained schedule was changed to a variable-interval 30-s, extinction 30s. Resurgence of the durations trained during Phase 1 was observed. It was concluded that duration is a response dimension that reappears during extinction.

Impressive and durable response in a case of multiple relapsed mantle cell lymphoma treated with bortezomib and rituximab.

Relapsed mantle cell lymphoma (MCL) usually represents a hard challenge, especially after the failure of high-dose therapy or in elderly patients, and although new agents have been investigated, responses are often short and a significant proportion of patients finally die from progressive disease. Here, we report a case of a relapsed MCL patient that achieved durable response with bortezomib and rituximab. Treatment regimen consisted of bortezomib 1.6 mg/m(2) and rituximab 375 mg/m(2) intravenously on days 1-8-15-22 for the 1st course, followed by 2 courses of bortezomib with the same schedule. After the third course, patients in CR, PR or SD received other 3 courses. The patient achieved a CR, but because of the high risk of relapse we started a 4-week maintenance therapy with rituximab and bortezomib for 4 courses administered at six month interval. After a follow-up of 62 months, the patient maintained CR. We suggest rituximab plus bortezomib could play an important role in the treatment of patients with relapsed/refractory MCL. Maintenance therapy could be an interesting option, especially for patients with a high relapse risk rate.

Demand in rats responding under duration-based schedules of reinforcement.

In two experiments, demand curves were generated by exposing rats to a sequence of fixed-duration schedules in which the response requirement doubled each experimental session. Holding down the response lever for the requisite amount of time resulted in the delivery of sweetened condensed milk. Response durations shorter than those required for reinforcer delivery did not result in any programmed consequences, nor were cumulative durations across multiple presses applied towards the duration requirements. The number of reinforcer deliveries decreased as a function of reinforcer requirements. Reinforcer delays alone also decreased consumption, but to a lesser extent than increasing duration requirements. Results are congruent with previous research demonstrating that parameters of reinforcement schedules may have similar effects on both continuous and discrete dimensions of operant behavior. Hursh and Silberberg's (2008) exponential demand equation provided a good fit for several of the data sets.

Response characteristics of primary auditory cortex neurons underlying perceptual asymmetry of ramped and damped sounds.

Sound envelope plays a crucial role in perception: ramped sounds (slow attack and quick decay) are louder in strength and longer in subjective duration than damped sounds (quick attack and slow decay) even if they are equal in intensity and physical duration. To explain the asymmetrical perception, the perceptual constancy hypothesis supposes that the listener eliminates the slow decay of damped sounds from the judgment of perception, while the persistence of perception hypothesis supposes asymmetrical neural responses after the source has stopped. To understand neural mechanisms underlying the perceptual asymmetry, we explored response properties of the primary auditory cortex (A1) neurons during ramped and damped stimuli in awake cats. We found two distinct types of cells tuned to specific features of the sound envelope: edge cells sensitive to the temporal edge, such as quick attack and decay, while slope cells sensitive to slow attack and decay. The former needs a short (<2.5 ms) period of stimulus duration for evoking maximal peak responses, while the latter needs a long (20 ms) period, suggesting that the timescale of processing underlies differential sensitivity between the cell types. The findings suggest that perceptual constancy is not yet be executed at A1 because the specific cells distinguishing the direction of amplitude change (attack or decay) are lacking in A1. On the other hand, there is evidence of persistence of perception: overall response duration during ramped sound reached 1.4 times longer than that during damped sound, originating mainly from the response asymmetry of the edge cell (sensitive to the quick decay of ramped sounds but not to the slow decay of damped sounds), and neuronal persistence of excitation after the termination of ramped sounds was substantially longer than that of damped sounds, corresponding to the psychological evidence of persistence of perception.

The cognitive chronometric architecture of reading aloud: semantic and lexical effects on naming onset and duration.

We examined onset reaction time (RT) in a word naming task using an additive factors method (AFM). The pattern of additive and over-additive joint effects on RT among Instructions (INST: name all, name words), Word Frequency (WF: log(10) HAL), Semantic Neighborhood Density (SND: Inverse Ncount), and Word Type (WT: regular, exception) supported a cognitive chronometric architecture consisting of at least two cascaded stages of processing, with the orthographic lexical system as the locus of the INST × WF and the INST × SND interactions, and the phonological output system as the locus of the WF × WT and the SND × WT interactions. Additivity between INST and WT supports the notion that these variables affect separable systems, and a WF × SND interaction supports a common locus of their effects. These results support stage-like/cascaded processing models over parallel processing models of basic reading. We also examined response duration (RD) in these data by recording and hand-marking vocal responses, which provides evidence that basic reading processes are ongoing even after the initiation of a vocal response, and supports the notion that the more lexically a word is read, the shorter the RD. As such, the effects of WT and INST on RD were opposite to their effects on RT however the effects of WF and SND on RD were in the same direction as their effects on RT. Given the combination of consistent and dissociating effects between RT and RD, these results provide new challenges to all models of basic reading processes.

Processing order in dual-tasks when the duration of motor responses varies / Orden de ejecución de dos tareas cuando la duración de las respuestas motoras varían

Recent studies reported that central processing duration influences processing order of two tasks in the psychological refractory period (PRP) paradigm. This study examined whether the duration of response execution influences the processing of task order. For this purpose, a tone discrimination task was combined with a letter discrimination task. Both tasks were presented in random order using different stimulus onset asynchronies (SOAs). In one condition, participants responded to each stimulus with a single key press (easy response condition). In the other condition, the tone task required a single key press, whereas the letter task required a more time-consuming key press-sequence (hard response condition). The results showed that participants tend to perform the tone task first more often when the response requirement for the letter task is hard, rather than easy. This result is consistent with the notion that participants optimize response scheduling in dual-task situations.

Bajo el paradigma de periodo refractario psicológico (PRP), recientes estudios han hallado que la duración del procesamiento central influye en el orden en el que dos tareas son procesadas. En el presente trabajo se examinó si la duración de la respuesta también influye en el orden en el que dos tareas se ejecutan. Para este propósito, se utilizó una tarea de discriminación auditiva en combinación con una tarea de discriminación visual. En el experimento se varió el orden de presentación de las tareas de forma aleatoria así como se utilizaron diferentes intervalos entre estímulos (stimulus onset asynchrony; SOA) En una condición, los participantes respondieron a cada estímulo pulsando una tecla (condición de respuesta simple). En la otra condición, mientras que a la tarea auditiva se respondía de nuevo pulsando una tecla, la respuesta a la tarea visual requería pulsar una secuencia de teclas, aumentando la duración de la respuesta (condición de respuesta compleja). Los resultados mostraron que los participantes tienden a ejecutar más a menudo la tarea auditiva en primer lugar cuando la respuesta de la tarea visual es más compleja. Este resultado apoya la noción de que, en escenarios de doble tarea, los participantes pueden invertir sus respuestas si con ello optimizan su ejecución.