Progressive Ratio Research Articles

Neutrophil‑to‑lymphocyte ratio and risk of disease progression in patients with nivolumab‑treated unresectable or recurrent gastric cancer

Neutrophil‑to‑lymphocyte ratio and risk of disease progression in patients with nivolumab‑treated unresectable or recurrent gastric cancer

Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma

BackgroundIncorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin’s lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin’s lymphoma, including in preliminary studies involving previously untreated patients.MethodsWe conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin’s lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.ResultsOf 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P=0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.ConclusionsN+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin’s lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.)

Catalase, superoxide dismutase and butylated hydroxytoluene benefit mid-term storage of red-legged partridge sperm (Alectoris rufa)

ABSTRACT 1. The present study assessed the effect of different antioxidants on the quality of chilled/frozen-thawed sperm of red-legged partridge. 2. Sperm samples from 40 red-legged partridges were collected and extended 1:1 (v:v) with Lake and Ravie 84, supplemented with ascorbic acid or butylated hydroxytoluene (BHT) at 0, 0.2, 0.4, 0.8 mM and catalase (CAT) or superoxide dismutase (SOD) at 0, 100, 200 and 300 IU/ml. Ten sperm samples were used per concentration. Motility and viability were evaluated in fresh and after 6 h of chilling at 5°C or after freezing-thawing. 3. For chilled sperm, the presence of ascorbic acid decreased viability and several motility variables; BHT 0.8 mM increased non-progressive motility (NPM, 26.7 ± 1.99 vs. 20.7 ± 2.12); CAT 200 IU/ml improved the rectilinear velocity (40.4 ± 4.63 μ/s vs. 29.9 ± 4.62 μ/s) and linear progression ratio (52.8 ± 3.11% vs. 45.4 ± 2.98%); SOD 100 IU/ml increased NPM (24.5 ± 1.21% vs. 19.3 ± 1.75%) and tended to improve total progressive motility (42.7 ± 3.33% vs. 33.2 ± 3.26%, p = 0.07). Using an extender supplemented with CAT 200 or SOD 100 did not improve the post-thawed sperm quality. 4. The present work provides an advance in the optimisation of chilling and freezing protocols for red-legged partridge sperm.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

Chronic inflammatory pain reduces fentanyl intake during early acquisition of fentanyl self-administration, but does not change motivation to take fentanyl in male and female rats

The co-occurrence of chronic pain and opioid misuse has led to numerous preclinical investigations of pain-opioid interactions to examine how pain manipulations alter the reinforcing properties of opioids. However, preclinical investigations of chronic pain effects on opioid drug self-administration have produced inconsistent results. Our previous work demonstrated that established fentanyl self-administration is resistant to change by induction of chronic inflammatory pain (Complete Freund's Adjuvant; CFA) in male and female rats, while other laboratories have shown that CFA increased fentanyl self-administration in male but not female rats when pain induction precedes self-administration, which may be a critical factor in determining the effects of chronic pain on self-administration. The present study was designed similarly to Higginbotham et al. (2022) to test the effects of CFA on fentanyl self-administration in rats that underwent pain prior to acquisition of fentanyl self-administration. Male and female rats treated with hindpaw CFA or saline were trained to intravenously self-administer (IVSA) fentanyl for 3 weeks under limited access to fentanyl (2 h per day) conditions. After 3 weeks of fentanyl IVSA acquisition, we tested motivation to take fentanyl using progressive ratio testing and dose-response testing. CFA male and female rats self-administered less fentanyl than saline-treated controls during week 1 of acquisition, but not during weeks 2–3 of acquisition. Intra-session analysis of week 1 data demonstrated that chronic inflammatory pain suppressed fentanyl intake towards the end of week 1 and at the end of each operant session. We also report no effects of chronic inflammatory pain on motivation to take fentanyl. We discuss potential methodological explanations for differences between these results and prior reports. Our findings demonstrate that CFA temporarily suppresses fentanyl IVSA in animals without changing motivation to take fentanyl or promoting escalation of opioid use, suggesting that chronic inflammatory pain is unlikely to promote long-term risk of opioid misuse.

Anticipated buffer time – An evasive surrogate safety indicator for risk assessment of unsignalized intersections under heterogeneous traffic and aggressive driving conditions

Risk assessment of unsignalized intersections is particularly challenging when confronted with a combination of factors such as heavy traffic, diverse vehicle types, lane indiscipline, aggressive driving, and evasive manoeuvres. Understanding how people drive in these situations is crucial for accurately assessing the risks at unsignalized intersections. This study introduces a novel surrogate safety indicator, i.e. Anticipated Buffer Time (ABT), designed to account for these various factors. Additionally, three new indicators derived from ABT are introduced, namely ABT Negation Ratio, ABT Extremity Ratio, and ABT Progression Ratio. A risk assessment measure, denoted as UnSigRisk Score, is formulated using these three indicators for unsignalized intersections. Three intersections in Ahmedabad, India, were selected for the study due to their manifestation of these challenging conditions. Spearman Rank Correlation Coefficient was estimated to find out how well can UnSigRisk Score measure is able to quantify evasive behaviour. The results indicate that this score proficiently measures evasive behaviour, exhibiting coefficients exceeding 0.6 in all cases—significantly outperforming the current evasive indicators, Yaw Rate Ratio and Jerk. The proposed risk assessment score could serve as a practical tool for transportation authorities, enabling them to identify the most vulnerable intersections and allocate resources for targeted safety interventions wisely. The study unequivocally demonstrates that the use of ABT paves the way for a thorough examination of safety at unsignalized intersections, regardless of driving behaviour and traffic conditions.

Basal cortisol level modulates stress-induced opioid-seeking behavior

In preclinical studies and our human laboratory, the α2-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; t = 0 min) then hydrocortisone (0, 20, 40-mg; t = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.

Incentive motivation for palatable food blocked by intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonist in female rats

Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females.

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model

There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals’ break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.

Sex Differences in Home-Cage Ethanol Drinking and Operant Self-Administration in C57BL/6J Mice but Equivalent Regulation by Glutamate AMPAR Activity.

Considering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice. C57BL/6J mice (male and female) were assessed for EtOH intake under continuous and limited access conditions in the home cage. Acute sensitivity to EtOH sedation and blood clearance were evaluated as potential modifying factors. Motivation to consume EtOH was measured using operant self-administration procedures. Sex-specific differences in neural regulation of EtOH reinforcement were examined by testing the effects of a glutamate AMPA receptor antagonist on operant EtOH self-administration. Female C57BL/6J mice exhibited a time-dependent escalation in EtOH intake under both continuous and limited access conditions. They were less sensitive to EtOH sedation and had lower blood levels post-EtOH administration (4 g/kg) despite similar clearance rates. Females also showed increased operant EtOH self-administration and progressive ratio performance over a 30-day baseline period compared to males. The AMPAR antagonist GYKI 52466 (0 - 10 mg/kg, IP) dose-dependently reduced EtOH-reinforced lever pressing in both sexes, with no differences in potency or efficacy. These findings confirm that female C57BL/6J mice consume more EtOH than males in home-cage conditions and exhibit reduced acute sedation, potentially contributing to higher EtOH intake. Females demonstrated increased operant EtOH self-administration and motivation, indicating higher reinforcing efficacy. The lack of sex differences in the relative effects of GYKI 52466 suggests that AMPAR activity is equally required for EtOH reinforcement in both sexes.

Role of serotonin neurons in the dorsal raphe nucleus in heroin self-administration and punishment.

One hallmark of substance use disorder is continued drug use despite negative consequences. When drug-taking behavior is punished with aversive stimuli, i.e. footshock, rats can also be categorized into punishment-resistant or compulsive vs. punishment-sensitive or non-compulsive phenotypes. The serotonin (5-hydroxytryptamine, 5-HT) system modulates responses to both reward and punishment. The goal of the current study was to examine punishment phenotypes in heroin self-administration and to determine the role of dorsal raphe nucleus (DRN) 5-HT neurons in both basal and punished heroin self-administration. First, rats were exposed to punished heroin self-administration and neuronal excitability of DRN 5-HT neuronswas compared between punishment-resistant and punishment-sensitive phenotypes using ex vivo electrophysiology. Second, DRN 5-HT neuronal activity was manipulated in vivo during basal and punished heroin self-administration using chemogenetic tools in a Tph2-iCre rat line. While rats separated into punishment-resistant and punishment-sensitive phenotypes for punished heroin self-administration, DRN 5-HT neuronal excitability did not differ between the phenotypes. While chemogenetic inhibition of DRN 5-HT neurons was without effect, chemogenetic activation of DRN 5-HT neurons increased both basal and punished heroin self-administration selectively in punishment-resistant animals. Additionally, the responsiveness to chemogenetic activation of DRN 5-HT neurons in basal self-administration and motivation for heroin in progressive ratio each predicted resistance to punishment. Therefore, our data support the role for the DRN 5-HT system in compulsive heroin self-administration.

The Relative Reinforcing Value of Menthol Among Young Adult Cigarette Smokers: Results From a Behavioral Choice Task.

Menthol cigarettes are associated with experimentation and progression to regular use. Although reinforcement processes likely underlie menthol's appeal, the reinforcing value of menthol cigarettes remains unknown. This study examined the relative reinforcing value (RRV) of menthol versus nonmenthol cigarettes in young adult menthol (n = 54) and nonmenthol (n = 53) smokers, and differences in menthol's RRV by race, ethnicity, and sexual orientation. Overnight abstinent participants completed a choice task assessing willingness to "work" to click targets on a computer screen to earn menthol or nonmenthol cigarette puffs. A progressive ratio schedule was used where the menthol target had to be clicked progressively more times, over 10 trials, to earn a menthol cigarette puff, while clicks for the nonmenthol target were fixed across trials. RRV for menthol was defined by the breakpoint, or the highest trial (out of to 10) completed for a menthol cigarette puff. Number of clicks for menthol and nonmenthol puffs were also examined. Menthol smokers worked harder for menthol versus nonmenthol cigarette puffs (breakpoint = 9.17; ~1236 clicks vs. 24 clicks). Breakpoint was higher among Hispanic (6.49) versus NH White (4.83) and NH non-White smokers (4.43). In exploratory analyses of interactions of menthol preference with race and ethnicity, nonmenthol Hispanic smokers worked harder for menthol cigarette puffs versus NH non-White and NH White nonmenthol smokers. Menthol cigarettes are highly reinforcing for young adult menthol and Hispanic smokers. A menthol ban may reduce addiction risk among younger individuals and some minoritized groups of smokers. This study provides evidence of the greater relative reinforcing value of menthol compared to nonmenthol cigarettes among young adults who had a cigarette flavor preference, suggesting increased addiction risk of menthol cigarettes. Young adult menthol smokers and Hispanic (vs. non-Hispanic) smokers worked harder to earn menthol (vs. nonmenthol) cigarette puffs. Findings add to the evidence base supporting the U.S. Food and Drug Administration's (FDA) intent to ban menthol in cigarettes. Further, prevention messaging campaigns and cessation programs should take into account the reinforcing value of menthol in cigarettes, especially in vulnerable and at-risk populations.

Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats

Ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) are important for nicotine reinforcement. To determine whether and to what extent these receptors are sufficient for nicotine reinforcement, we expressed β2Leu9′Ser (i.e. sensitized) nAChR subunits in the VTA of adult male rats and assessed the nicotine dose-response relationship in intravenous self-administration (SA). β2Leu9′Ser rats self-administered nicotine doses 50–100 fold lower than the lowest doses that control rats would respond for. Expression of WT β2 subunits confirmed that this enhanced sensitivity to nicotine was due to the Leu9′Ser mutation in β2. Higher unit doses were associated with strong escalation in β2Leu9′Ser rats over 17 fixed ratio sessions. Escalation was minimal or absent in control rats at the same unit doses. In progressive ratio SA, β2Leu9′Ser rats exhibited higher breakpoints than control rats when the nicotine unit dose was 1.5 μg/kg/inf or higher. In intermittent access SA, β2Leu9′Ser rats exhibited response patterns very similar to control rats. By adding nicotine dose-response data, progressive ratio assays, and intermittent access results that rule out stereotypy, these data significantly extend our previous finding that nicotine activation of the mesolimbic dopamine pathway is sufficient for nicotine reinforcement.

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear. We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety. In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

Relationship between hypertransmission defect size and progression in eyes with intermediate age-related macular degeneration.

To determine the associations between the presence of various-sized hypertransmission defects (hyperTDs) and progression to incomplete retinal pigment epithelial (RPE) and outer retinal atrophy (iRORA) and complete RORA (cRORA) in eyes with intermediate age-related macular degeneration (iAMD). Optical coherence tomography (OCT) data from consecutive iAMD patients, were retrospectively reviewed. All of iAMD eyes with or without iRORA (but not cRORA) at baseline were included. Graders evaluated the presence of hyperTDs at baseline (small: 63-124 µm; medium: 125-249 µm; large: ≥250 µm in diameter on choroidal en face OCT) and the progression two years later. Of the 145 eyes that not developed neovascular AMD at two years, the eyes that progressed to or developed iRORA or cRORA included 13 eyes (10.7%), 5 eyes (83.3%), 9 eyes (81.8%), and 6 eyes (85.7%) in the groups with no, small, medium, and large hyperTDs at baseline, respectively (P-value < 0.001). The odds ratios (95% CI) for progression were 41.6 (4.5-383.6), 37.4 (7.3-192.0), and 49.9 (5.6-447.1) in the small, medium, and large hyperTDs groups, compared to no hyperTDs (P-value ≤ 0.001). Eyes with ≥2 hyperTDs also showed more frequent progression than eyes with one or no hyperTDs (100% vs. 16.4%; P-value < 0.001). While most iAMD eyes with no hyperTDs remained stable on OCT over two years, eyes with hyperTDs of any size appeared to be at a higher risk for progression. HyperTDs may provide an important OCT biomarker for identifying high-risk iAMD patients.

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.

Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.).

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.

Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown. In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation. A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).

Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.

There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m2) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.

Radiotherapy vs Surgery for Survival and Locoregional Control of Head and Neck Extramedullary Plasmacytoma

There are significant gaps in the literature pertaining to the locoregional control and survival rates of extramedullary plasmacytoma (EMP) with respect to various treatment approaches. To systematically evaluate the differences in radiotherapy and surgical outcomes in EMP. Databases including PubMed, Scopus, Web of Science, Embase, and ScienceDirect were systematically searched from their inception up to November 2023. Articles reporting radiotherapy and surgical outcomes of head and neck EMP were included. A random-effects model for meta-analysis was used to obtain pooled estimates and calculate hazard ratios for survival and odds ratios for recurrence and progression of EMP. Survival, tumor control, and progression rates to multiple myeloma (MM) between radiation therapy and surgery for EMP of the head and neck. Of 742 included patients from 12 studies, 527 (71.0%) were male, and the median (IQR) age was 59.1 (53-62) years. A total of 505 patients (68.1%) received radiotherapy only, while 237 (31.9%) underwent surgery-only treatment for EMP. All included patients had an initial diagnosis of EMP without MM. Comparable trends were observed in overall survival and disease-free survival (DFS) rates at 2, 3, 5, and 10 years between patients with EMP treated with radiotherapy only and surgery only. Notably, there were no significant differences in recurrence rate (odds ratio, 0.65; 95% CI, 0.20-2.06) between radiotherapy-only and surgery-only treatment. However, radiotherapy-only treatment of EMP was associated with decreased odds of progression to MM compared with surgery (odds ratio, 0.4; 95% CI, 0.1-0.9). Sensitivity analysis revealed that the radiotherapy-only population had significantly better 5-year DFS (hazard ratio, 0.55; 95% CI, 0.31-0.96) compared with surgery-only treatment. This systematic review and meta-analysis provides evidence that patients with EMP receiving radiotherapy had significantly lower chances of progression to MM compared with surgery-only therapy. Additionally, radiotherapy had better 5-year DFS outcomes compared with surgery. Comparable outcomes in terms of overall survival rates, recurrence, and mortality rates were noted between radiotherapy-only and surgery-only EMP treatment groups.