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The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK‐positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK‐positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first‐line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor., Our case was first report to determine the excellent antitumor effect of Brigatinib on ALK positive lung SqCC. PFS was more than 11 months, and the side effects were tolerable.

Purpose of the study. There is the generalized analysis of administration of vinflunine in real clinical practice in St.Petersburg Clinical Scientific and Practical Center of Specialized medical Care (oncological).Materials and methods. This analysis gathered 27 patients with urothelial carcinoma treated using this medicine in St.Petersburg Clinical Scientific and Practical Center of Specialized medical Care (oncological). We assessed efficacy, safety profile of vinflunine in this subset of patients.Results. Clinical efficacy of vinflunine (complete response + partial response + stable disease) was 51,86 %, one patient demonstrated complete response. Median of response duration accounts for 3,4 months. Adverse events were observed in 28,4 %, most of them were 1-2 grades. 2 patients stopped therapy due to adverse events.Conclusion. In our analysis vinflunine was more effective than in randomized clinical trial and other studies from real practice in Europe. Thus, confirm expediency to administer of vinflunine for metastatic urothelial carcinoma.

Multi-phenotypic screening of zebrafish larvae, such as monitoring the heart and tail activities, is important in biological assays. Microfluidic devices have been developed for zebrafish phenotypic assays, but simultaneous lateral–dorsal screening of the same larva in a single chip is yet to be achieved. We present a multi-phenotypic microfluidic device for monitoring of tail movement and heart rate (HR) of 5–7-day postfertilization zebrafish larvae. Tail movements were stimulated using electric current and quantified in terms of response duration (RD) and tail beat frequency (TBF). The positioning of a right-angle prism provided a lateral view of the larvae and enabled HR monitoring. Investigations were performed on zebrafish larvae exposed to 3% ethanol, 250 μM 6-hydroxydopamine (6-OHDA) or 1 mM levodopa. Larvae exposed to ethanol showed a significant drop in HR, whereas electric stimulation increased the HR temporarily. Larvae experienced a significant drop in RD, TBF and HR when exposed to 6-OHDA. HR was not affected by levodopa post-treatment, whereas RD and TBF were restored to normal levels. The results showed potential for applications that involve monitoring of cardiac and behavioral parameters in zebrafish larvae. Tests can be done using the same chip, without changing the larvae’s orientation. This eliminates undue stress caused by reorientation, which may affect their behavior, and the use of separate devices to obtain dorsal and lateral views. The device can be implemented to improve multi-phenotypic and quantitative screening of zebrafish larvae in response to chemical and physical stimuli in different zebrafish disease models.

Background BRAF mutations occurring in 1%–5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSe vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%–54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8–6.8), and OS was 10 months (95% CI 6.8–15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. Trial registration ClinicalTrials.gov identifier: NCT02304809.

Botulinum toxin serotype-A (BoNT-A) preparations are widely used to improve the appearance of wrinkles. While effective and well tolerated, patients require retreatment over time to re-establish the effects. There is growing interest from patients as to whether higher doses can prolong response without significantly increasing side effects. We reviewed the efficacy and safety evidence for high-dose BoNT-A treatment of glabellar lines, by evaluating high-dose studies published since 2015. Toxins approved for glabellar line treatment in the US or Europe were considered. “High-dose” indicated doses above the licensed dose for each BoNT-A preparation. Five studies met the inclusion criteria and most were randomized, double-blind trials; designs and population sizes varied. Findings suggested that higher-dose BoNT-A treatment is feasible and may improve response duration without increased safety issues. Around 9 months’ median duration was achieved with a 2–2.5-fold increase of the abobotulinumtoxinA on-label dose, or with a 5-fold increase in incobotulinumtoxinA dose. A 2–4-fold increase of the onabotulinumtoxinA on-label dose yielded a median duration of around 6 months. Importantly, patient satisfaction and natural look remained with increasing abobotulinumtoxinA doses. While more data are needed, these findings may lead to more effective, individually tailored treatment plans to meet patient expectations.

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC)10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC10 mg/L ("stringent dFLC response"). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

PurposeFunctional imaging is often used to try to elucidate the pathophysiological mechanism of tinnitus. Residual inhibition, the temporary suppression of tinnitus after application of a masking noise, could be an interesting technique to modulate tinnitus perception in functional imaging paradigms. The purposes of this study were to primarily assess reproducibility of the (partial) positive residual inhibition response duration in patients with tinnitus and to explore its utility in experimental designs.MethodPatients with tinnitus exhibiting a (partial) positive residual inhibition response or tinnitus reduction after a 1-min white noise presentation were selected from a broad consulting tinnitus population. In 27 patients, this response was tested 4 times: twice during initial testing and twice during a retest of the psychoacoustic tinnitus measures, 4–8 weeks after initial consultation. In 17 patients with stable residual inhibition responses, reproducibility of response duration, the duration of tinnitus reduction up to pretesting state, was analyzed.ResultsInitial testing showed a residual inhibition duration of 29.5 s on average. Test–retest reproducibility of response duration was shown to be reliable with an ICC(3, 4) of .871 (95% CI [0.733, 0.948]) and a standard error of measurement of 6.64 s.ConclusionsThis study indicates the good test–retest reproducibility of residual inhibition duration in our subset of 17 patients with stable (partial) positive residual inhibition. Residual inhibition is, therefore, a technique that can potentially be used for temporary tinnitus manipulation in experimental paradigms to unravel tinnitus pathophysiology.

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

Objectives To assess the efficacy and safety of intravenous immunoglobulin (IVIG) 10% (Panzyga® ), a novel human normal IVIG 10%, in patients with chronic immune thrombocytopenia (ITP). Background First-line treatment options in ITP include IVIGs. Methods In this prospective, open-label, non-controlled, multicentre, phase III study, patients received a daily dose of IVIG 10% (1 g kg-1 body weight) for two consecutive days. The primary end point was clinical response rate; secondary end points included alternate response definitions, time to response, response duration, platelet counts, regression of bleeding and safety. Results Forty patients were enrolled (57·5% male, mean age 36·7 years); the full analysis set comprised 36 patients. A clinical response was seen for 29 of 36 patients (80·6%). Median time to response and response duration was 2 days and 14 days, respectively. IVIG 10% was well tolerated at a maximum infusion rate of 8 mg (kg min)-1 in all but one patient; adverse events were mainly mild to moderate in severity, and the most frequent was headache (42·5%). Conclusion IVIG 10% is well tolerated even at a high infusion speed and induces a rapid platelet count increase, thus decreasing the bleeding rate and the severity of bleeding events. Trial registry ClinicalTrials.gov record: NCT01349790.

Three adult patients with confirmed Erdheim-Chester disease (ECD) are followed at our department. Cladribine in monotherapy or in combination with cyclophosphamide were used for first line therapy. The median number of cycles of cladribine or cladribine and cyclophosphamide was 7 (range 6-8). In two cases complete response was achieved, in one case this therapy achieved no response. The duration of response is in one case 11 years, in second case the follow up is too short for evaluation of response duration. In case of no-response to cladribine and cyclophosphamide stabilisation of disease was achieved with anakinra. The tolerance was good without any toxicity grade II and higher. Cladribin and cyclophosphamide is one option for treatment of Erdheim-Chester disease.

We propose a Bayesian hierarchical monitoring design for single-arm phase II clinical trials of cancer treatments that incorporates the information on the duration of response into the monitoring rules. To screen a new treatment by evaluating its preliminary therapeutic effect, futility monitoring rules are commonly used in phase II clinical trials to make “go/no-go” decisions timely and efficiently. These futility monitoring rules are usually focused on a single outcome (eg, response rate), although a single outcome may not adequately determine the efficacy of the experimental treatment. For example, targeted agents with a long response duration but a similar response rate may be worth further evaluation in cancer research. To address this issue, we propose Bayesian hierarchical futility monitoring rules to consider both the response rate and duration. The first level of monitoring evaluates whether the response rate provides evidence that the experimental treatment is worthy of further evaluation. If the evidence from the response rate does not support continuing the trial, the second level monitoring rule, which is based on the duration of response, will be triggered. If both stopping rules are satisfied, the trial will be stopped for futility. We conducted simulation studies to evaluate the operating characteristics of the proposed monitoring rules and compared them to those of standard method. We illustrated the proposed design with a single arm phase II cancer clinical trial to assess the safety and efficacy of combined treatment of nivolumab and azacitidine in patients with relapsed/refractory acute myeloid leukemia. The proposed design avoids an aggressive early termination for futility when the experimental treatment substantially prolongs the duration of response but fails to improve the response rate.

Microfluidic devices have been introduced for phenotypic screening of zebrafish larvae in both fundamental and pre-clinical research. One of the remaining challenges for the broad use of microfluidic devices is their limited throughput, especially in behavioural assays. Previously, we introduced the tail locomotion of a semi-mobile zebrafish larva evoked on-demand with electric signal in a microfluidic device. Here, we report the lessons learned for increasing the number of specimens from one to four larvae in this device. Multiple parameters including loading and testing time per fish and loading and orientation efficiencies were refined to optimize the performance of modified designs. Simulations of the flow and electric field within the final device provided insight into the flow behavior and functionality of traps when compared to previous single-larva devices. Outcomes led to a new design which decreased the testing time per larva by approximately 60%. Further, loading and orientation efficiencies increased by more than 80%. Critical behavioural parameters such as response duration and tail beat frequency were similar in both single and quadruple-fish devices. The optimized microfluidic device has significant advantages for greater throughput and efficiency when behavioral phenotyping is required in various applications, including chemical testing in toxicology and gene screening.

The therapeutic targeting of the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis marked a milestone in the treatment of non-small cell lung cancer (NSCLC), leading to unprecedented response duration and long-term survival for a relevant subgroup of patients affected by non-oncogene-addicted, metastatic disease. However, the biological heterogeneity as well as the occurrence of innate/acquired resistance are well-known phenomena which significantly affect the therapeutic response to immunotherapy. To date, we are moving towards the second phase of the “immune-revolution”, characterized by the advent of new immune-checkpoint inhibitors combinations, aiming to target the main resistance pathways and ultimately increase the number of NSCLC patients who may derive long-term clinical benefit from immunotherapy. In this review, we provide an updated and comprehensive overview of the main PD-1/PD-L1 inhibitors’ combination approaches under clinical investigation in non-oncogene addicted, metastatic NSCLC patients, including checkpoints (other than CTLA-4) as well as “immune-metabolism” modulators, DNA repair pathway inhibitors, antiangiogenic agents, cytokines, and a new generation of vaccines, with the final aim of identifying the most promising options on the horizon.

Despite the promising result with FLT3 inhibitors in AML, the emergence of resistance poses a significant challenge, leading to a shorter response duration and inferior survival. This is frequently driven by on-target or parallel prosurvival mutations. The emergence of BCR-ABL1 as a mechanism of possible clonal evolution in relapsed AML has rarely been reported. Here we report our experience with three patients who had emergent BCR-ABL1 fusion at relapse after FLT3 inhibitors-based therapies. The first patient was refractory to multiple lines of therapies, including FLT3 inhibitors-based therapy. Patients 2 and 3 showed some response to combined FLT3-inhibitor and BCR-ABL targeted therapy (gilteritinib and ponatinib). The availability of effective targeted therapies for BCR-ABL1 makes this an important aberration to proactively identify and possibly target at relapse post-FLT3-inhibitor therapies.

The core region of the rodent auditory cortex has two subfields: the primary auditory area (A1) and the anterior auditory field (AAF). Although the postnatal development of A1 has been studied in several mammalian species, few studies have been conducted on the postnatal development of AAF. Using a voltage-sensitive-dye-based imaging method, we examined and compared the postnatal development of AAF and A1 in mice from postnatal day 11 (P11) to P40. We focused on the postnatal development of tonotopy, the relative position between A1 and AAF, and the properties of tone-evoked responses in the subfields. Tone-evoked responses in the mouse auditory cortex were first observed at P12, and tonotopy was found in both A1 and AAF at this age. Quantification of tonotopy using the cortical magnification factor (CMF; octave difference per unit cortical distance) revealed a rapid change from P12 to P14 in both A1 and AAF, and a stable level from P14. A similar time course of postnatal development was found for the distance between the 4 kHz site in A1 and AAF, the distance between the 16 kHz site in A1 and AAF, and the angle between the frequency axis of A1 and AAF. The maximum amplitude and rise time of tone-evoked signals in both A1 and AAF showed no significant change from P12 to P40, but the latency of the responses to both the 4 kHz and 16 kHz tones decreased during this period, with a more rapid decrease in the latency to 16 kHz tones in both subfields. The duration of responses evoked by 4 kHz tones in both A1 and AAF showed no significant postnatal change, but the duration of responses to 16 kHz tones decreased exponentially in both subfields. The cortical area activated by 4 kHz tones in AAF was always larger than that in A1 at all ages (P12-P40). Our results demonstrated that A1 and AAF developed in parallel postnatally, showing a rapid maturation of tonotopy, slow maturation of response latency and response duration, and a dorsal-to-ventral order (high-frequency site to low-frequency site) of functional maturation.

Background: Botulinum toxin-A is a well-established treatment for adult and pediatric spastic paresis and cervical dystonia. While guidelines and approved labels indicate that treatment should not occur more frequently than every 12 weeks, studies and real-world evidence show that the timing of symptom recurrence between treatments may vary. Methods: We report retreatment criteria and response duration (retreatment intervals) from four pivotal, double-blind, placebo-controlled studies with open-label extensions involving patients treated with abobotulinumtoxinA (aboBoNTA) for upper limb (NCT01313299) or lower limb (NCT01249404) spastic paresis in adults, lower limb spastic paresis in children (NCT01249417), and cervical dystonia in adults (NCT00257660). We review results in light of recently available preclinical data. Results: In spastic paresis, 24.0–36.9% of upper limb patients treated with aboBoNTA and 20.1–32.0% of lower limb patients did not require retreatment before 16 weeks. Moreover, 72.8–93.8% of aboBoNTA-treated pediatric patients with lower limb spastic paresis did not require retreatment before 16 weeks (17.7–54.0% did not require retreatment before 28 weeks). In aboBoNTA-treated patients with cervical dystonia, 72.6–81.5% did not require retreatment before 16 weeks. Conclusion: AboBoNTA, when dosed as recommended, offers symptom relief beyond 12 weeks to many patients with spastic paresis and cervical dystonia. From recently available preclinical research, the amount of active neurotoxin administered with aboBoNTA might be a factor in explaining this long duration of response.

In this paper, the novel effect of electric field (EF) on adult C. elegans egg-laying in a microchannel is discovered and correlated with neural and muscular activities. The quantitative effects of worm aging and EF strength, direction, and exposure duration on egg-laying is studied phenotypically using egg-count, body length, head movement, and transient neuronal activity readouts. Electric egg-laying rate increases significantly when worms face the anode and the response is EF-dependent, i.e. stronger (6V/cm) and longer EF (40s) exposure result in a shorter egg laying response duration. Worm aging significantly deteriorates the electric egg-laying behaviour with 88% decrease in the egg-count from Day-1 to Day-4 post young-adult stage. Fluorescent imaging of intracellular calcium dynamics in the main parts of the egg-laying neural circuit demonstrate the involvement and sensitivity of the serotonergic hermaphrodite specific neurons (HSNs), vulva muscles, and ventral cord neurons to the EF. HSN mutation also results in a reduced rate of electric egg-laying allowing the use of this technique for cellular screening and mapping of the neural basis of electrosensation in C. elegans. This novel assay can be parallelized and performed in a high-throughput manner for drug and gene screening applications.

Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of nivolumab therapy for ESCC patients. ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed. Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1–22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval [CI] 1.8–2.3) and 7.4 (95% CI 4.8–10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 [95% CI 1.8–13.1] vs. 1.9 [1.4–2.3] months, P = 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration. Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.

It is crucial for animals to discriminate between palatable (safe) and aversive (toxic) tastants. The mechanisms underlying neuronal discrimination of taste stimuli remain unclear. We examined relations between taste response properties (spike counts, response duration, and coefficient of variation [CV]) and location of taste‐sensitive neurons in the pontine parabrachial nucleus (PBN). Extracellular single units’ activity in the PBN of Wistar rats was recorded using multibarrel glass micropipettes under urethane anesthesia. Forty taste‐sensitive neurons were classified as NaCl (N)‐best (n = 15), NaCl/HCl (NH)‐best (n = 14), HCl (H)‐best (n = 8), and sucrose (S)‐best (n = 3) neurons. The net response to NaCl (15.2 ± 2.3 spikes/s) among the N‐best neurons was significantly larger than that among the NH‐best (4.5 ± 0.8 spikes/s) neurons. The response duration (4.5 ± 0.2 s) of the N‐best neurons to NaCl was significantly longer than that of the NH‐best (2.2 ± 0.3 s) neurons. These differences in the spike counts and the response durations between the two neuronal types in the PBN were similar to that previously reported in the rostral nucleus of the solitary tract (rNST). The CVs in the N‐best and the NH‐best neurons were significantly smaller in the PBN than those in the rNST. Histologically, most N‐best neurons (12/13, 92%) were localized to the medial region, while NH‐best neurons (11/13, 85%) were primarily found within the brachium conjunctivum. These results suggest that NaCl‐specific taste information is transmitted by two distinct neuronal groups (N‐best and NH‐best), with different taste properties and locations within rNST to PBN tractography. Future studies on the higher order nuclei for taste could reveal more palatable and aversive taste pathways., Topographical distribution of pontine parabrachial nucleus (PBN) neurons for each preferred stimulus category.

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.

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 center dot 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 center dot 0001). Variables predicting longer RD after first-line treatment were normal beta 2microglobulin, 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 center dot 6 and 4 center dot 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.

The aim of this study was to assess pharyngeal swallowing impairments in thyroidectomy patients and to delineate the contributory kinematic components. Forty consecutive patients (mean age = 47.33 years) and fourteen age- and sex-matched heathy adult volunteers (mean age = 42.64 years) participated in this study. A videofluoroscopic swallowing study (VFSS) was performed 1 day prior to surgery, and at 1 week and 3 months post-surgery. VFSS images were evaluated using the Modified Barium Swallowing Impairment Profile (MBSImp). Kinematic and temporal aspects of swallowing were characterized by measurement of maximum hyoid and laryngeal excursion, pharyngeal transit duration, laryngeal response duration (LRD), and laryngeal closure duration at each three time-points. At 1 week post-surgery, only pharyngeal impairment was significantly deteriorated than pre-surgery (p = 0.001). However, at 3 months, a significant improvement was observed to pre-surgery level (p = 0.01). Post-surgery, maximum hyoid excursion was significantly reduced in patients compared controls (p = 0.001). Although the maximal distance of the hyoid and the laryngeal excursion was shorter than before surgery, laryngeal excursion at all three time-points was similar to that of controls. At all three time-points, LRD was significantly longer in patients than in controls (p = 0.01). Following thyroidectomy, pharyngeal aspects of swallowing as measured by the MBSImp and kinematic aspects of swallowing were reduced with incomplete recovery at 3 months. These exploratory data may guide decision regarding management of pharyngeal swallowing impairment with patients undergoing total thyroidectomy.

KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (RECIST version 1.1), and ECOG performance status (PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary end-points were safety and overall response rate (RECIST version 1.1, central review). Secondary end-points included overall survival and response duration. Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. The median age was 62 years, 65% of patients had ECOG PS 1, and 62% had received two or more prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event of any grade, including two (8%) patients who experienced one or more events of grade 3 severity. No treatment-related deaths occurred. The overall response rate was 19% (95% confidence interval, 7%-39%). After a median follow-up of 12 months (range, 2-21 months), a median response duration was not reached (range, 6 to 17+ months); four of five responses lasted ≥6 months. Median overall survival was 11.6 months (95% confidence interval, 4.7-17.7 months). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region. (Trial registration no. NCT01848834.).

BACKGROUND Microfluidic devices are being used for phenotypic screening of zebrafish larvae in fundamental and pre-clinical research. A challenge for the broad use of these microfluidic devices is their low throughput, especially in behavioral assays. Previously, we introduced the tail locomotion of a semi-mobile zebrafish larva evoked on-demand with electric signal in a microfluidic device. Here, we report the lessons learned for increasing the number of specimens from one to four larvae in this device. METHODS AND RESULTS Multiple parameters including loading and testing time per fish and loading and orientation efficiencies were refined to optimize the performance of modified designs. Flow and electric field simulations within the final device provided insight into the flow behavior and functionality of traps when compared to previous single-larva devices. Outcomes led to a new design which decreased the testing time per larva by ≈60%. Further, loading and orientation efficiencies increased by more than 80%. Critical behavioral parameters such as response duration and tail beat frequency were similar in both single and quadruple-fish devices. CONCLUSION The developed microfluidic device has significant advantages for greater throughput and efficiency when behavioral phenotyping is required in various applications, including chemical testing in toxicology and gene screening.