Radiolabelling and preclinical characterisation of [89Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB.

PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.

Impact of emergency medicine clinical pharmacist practitioner-driven sepsis antibiotic interventions.

BACKGROUND: The 2021 Surviving Sepsis Campaign Guidelines recommend administration of antimicrobials within the first hour of recognition of sepsis. Over the last decade, several studies have demonstrated improved time-to-antibiotic administration and antibiotic appropriateness when a pharmacist was involved in the care of patients with sepsis. To our knowledge, no studies evaluating the appropriate use of antibiotics in sepsis driven entirely by an Emergency Medicine (EM) Clinical Pharmacist Practitioner (CPP) have been published. The purpose of this study is to evaluate the impact of an EM CPP-driven protocol on antimicrobial interventions in patients with sepsis in the emergency department (ED). METHODS: This was a retrospective comparison of patients with sepsis for whom antimicrobials were ordered in the ED without pharmacist intervention to patients whose antimicrobials were ordered by an EM CPP via a sepsis consult to pharmacy. An EM CPP reviewed individual patient profiles for pertinent historical admissions, culture data, and allergy profiles to guide antimicrobial selection for the suspected source of infection and entered orders under their scope of practice with formal documentation in the electronic medical record (EMR). The primary objective of this study was to compare the rates of appropriate empiric antibiotic utilization in septic patients admitted from the ED pre- and post-protocol implementation. Secondary endpoints included the following, broadening of ED-initiated empiric antibiotics on hospital admission, time-to-antibiotic administration, in-hospital mortality, Rapid Emergency Medicine Score (REMS) association with in-hospital mortality, and hospital length of stay. RESULTS: A total of 144 patients were included: 80 patients prescribed antibiotics without pharmacist intervention and 64 prescribed antibiotics by an EM CPP. Appropriate empiric antibiotic selection in the ED improved from 57.5% (46/80) to 86% (55/64) with EM CPP intervention (difference 28.5%; p < 0.01). Time-to-first antibiotic administration decreased by 64 min (p < 0.01). Administration of antibiotics within 60 min, broadening of antibiotics on admission, hospital length of stay, and in-hospital mortality did not significantly differ across groups. CONCLUSIONS: In this small, single-center study, an EM Clinical Pharmacist Practitioner-driven protocol for patients with sepsis in the emergency department improved the rate of appropriate empiric antimicrobial selection and time-to-antibiotic administration.

A Step Toward Personalized Surgical Decision Making: Machine Learning Predicts 1 Versus Numerous Melanoma Lymph Node Metastases Using RNA-sequencing.

OBJECTIVE: Develop a predictive model to identify patients with 1 pathologic lymph node (pLN) versus >1 pLN using machine learning applied to gene expression profiles and clinical data as input variables. BACKGROUND: Standard management for clinically detected melanoma lymph node metastases is complete therapeutic LN dissection (TLND). However, >40% of patients with a clinically detected melanoma lymph node will only have 1 pLN on final review. Recent data suggest that targeted excision of just the single enlarged LN may provide excellent regional control, with less morbidity than TLND. The selection of patients for less morbid surgery requires accurate identification of those with only 1 pLN. METHODS: The Cancer Genome Atlas database was used to identify patients who underwent TLND for melanoma. Pathology reports in The Cancer Genome Atlas were reviewed to identify the number of pLNs. Patients were included for machine learning analyses if RNA sequencing data were available from a pLN. After feature selection, the top 20 gene expression and clinical input features were used to train a ridge logistic regression model to predict patients with 1 pLN versus >1 pLN using 10-fold cross-validation on 80% of samples. The model was then tested on the remaining holdout samples. RESULTS: A total of 153 patients met inclusion criteria: 64 with one pLN (42%) and 89 with >1 pLNs (58%). Feature selection identified 1 clinical (extranodal extension) and 19 gene expression variables used to predict patients with 1 pLN versus >1 pLN. The ridge logistic regression model identified patient groups with an accuracy of 90% and an area under the receiver operating characteristic curve of 0.97. CONCLUSIONS: Gene expression profiles together with clinical variables can distinguish melanoma metastasis patients with 1 pLN versus >1 pLN. Future models trained using positron emission tomography/computed tomography imaging, gene expression, and relevant clinical variables may further improve accuracy and may predict patients who can be managed with a targeted LN excision rather than a complete TLND.

A non-parametric Bayesian approach for adjusting partial compliance in sequential decision making.

Existing methods for estimating the mean outcome under a given sequential treatment rule often rely on intention-to-treat analyses, which estimate the effect of following a certain treatment rule regardless of compliance behavior of patients. There are two major concerns with intention-to-treat analyses: (1) the estimated effects are often biased toward the null effect; (2) the results are not generalizable and reproducible due to the potentially differential compliance behavior. These are particularly problematic in settings with a high level of non-compliance, such as substance use disorder studies. Our work is motivated by the Adaptive Treatment for Alcohol and Cocaine Dependence study (ENGAGE), which is a multi-stage trial that aimed to construct optimal treatment strategies to engage patients in therapy. Due to the relatively low level of compliance in this trial, intention-to-treat analyses essentially estimate the effect of being randomized to a certain treatment, instead of the actual effect of the treatment. We obviate this challenge by defining the target parameter as the mean outcome under a dynamic treatment regime conditional on a potential compliance stratum. We propose a flexible non-parametric Bayesian approach based on principal stratification, which consists of a Gaussian copula model for the joint distribution of the potential compliances, and a Dirichlet process mixture model for the treatment sequence specific outcomes. We conduct extensive simulation studies which highlight the utility of our approach in the context of multi-stage randomized trials. We show robustness of our estimator to non-linear and non-Gaussian settings as well.

Associations of Race, Ethnicity, and Social Determinants of Health With Colorectal Cancer Screening.

BACKGROUND: Racial and ethnic disparities in receipt of recommended colorectal cancer screening exist; however, the impact of social determinants of health on such disparities has not been recently studied in a national cohort. OBJECTIVE: This study aimed to determine whether social determinants of health attenuate racial disparities in receipt of colorectal cancer screening. DESIGN: This was a cross-sectional telephone survey of self-reported race and ethnicity and up-to-date colorectal cancer screening. Associations between race/ethnicity and colorectal cancer screening were tested before and after adjustment for demographics, behavioral factors, and social determinants of health. SETTING: This was a nationally representative telephone survey of US residents in 2018. PATIENTS: The patients included were US residents aged 50 to 75 years. MAIN OUTCOME MEASURES: The primary outcome was up-to-date colorectal cancer screening status, according to 2008 US Preventive Services Task Force recommendations. RESULTS: This study included 226,106 respondents aged 50 to 75 years. Before adjustment, all minority racial and ethnic groups demonstrated a significantly lower odds of screening than those of non-Hispanic white respondents. After adjustment for demographics, behavioral factors, and social determinants of health, compared to non-Hispanic white respondents, odds of screening were found to be increased among non-Hispanic black respondents (OR, 1.10; p = 0.02); lower but attenuated among Hispanic respondents (OR, 0.73; p < 0.001), non-Hispanic American Indian/Alaskan Native respondents (OR, 0.85; p = 0.048), and non-Hispanic respondents of other races (OR, 0.82; p = 0.01); and lower but not attenuated among non-Hispanic Asian respondents (OR, 0.68; p < 0.001). LIMITATIONS: Recall bias, participant bias, and residual confounding. CONCLUSIONS: Adjustment for social determinants of health reduced racial and ethnic disparities in colorectal cancer screening among all minority racial and ethnic groups except non-Hispanic Asian individuals; however, other unmeasured confounders likely exist. See Video Abstract at http://links.lww.com/DCR/B977 . ASOCIACIN DE RAZA, ETNICIDAD Y DETERMINANTES SOCIALES DE LA SALUD CON LA DETECCIN DEL CNCER COLORRECTAL: ANTECEDENTES: Existen disparidades raciales y étnicas en la recepción de las pruebas recomendadas de detección de cáncer colorrectal; sin embargo, el impacto de los determinantes sociales de la salud en dichas disparidades no se ha estudiado recientemente en una cohorte nacional.OBJETIVO: El objetivo de este estudio fue determinar si los determinantes sociales de la salud atenúan las disparidades raciales en la recepción de pruebas de detección del cáncer colorrectal.DISEÑO: Encuesta telefónica transversal de raza y etnia autoinformada y detección actualizada de cáncer colorrectal. Las asociaciones entre la raza/etnicidad y la detección del cáncer colorrectal se probaron antes y después del ajuste por demografía, factores conductuales y determinantes sociales de la salud.ESCENARIO: Esta fue una encuesta telefónica representativa a nivel nacional de los residentes de EE. UU. en 2018.PACIENTES: Los pacientes eran residentes de EE. UU. de 50 a 75 años.PRINCIPALES MEDIDAS DE RESULTADO: Estado actualizado de detección de cáncer colorrectal, según las recomendaciones del Grupo de Trabajo de Servicios Preventivos de EE. UU. de 2008.RESULTADOS: Este estudio incluyó a 226.106 encuestados de 50 a 75 años. Antes del ajuste, todos los grupos étnicos y raciales minoritarios demostraron probabilidades significativamente más bajas de detección en comparación con los encuestados blancos no hispanos. Después del ajuste por demografía, factores conductuales y determinantes sociales de la salud, en comparación con los encuestados blancos no hispanos, las probabilidades de detección aumentaron entre los encuestados negros no hispanos (OR 1,10, p = 0,02); más bajo pero atenuado entre los encuestados hispanos (OR 0,73, p < 0,001), los encuestados indios americanos/nativos de Alaska no hispanos (OR 0,85, p = 0,048) y los encuestados no hispanos de otras razas (OR 0,82, p = 0,01); y menor pero no atenuado entre los encuestados asiáticos no hispanos (OR 0,68, p < 0,001).LIMITACIONES: Sesgo de recuerdo y sesgo de participante, así como confusión residual.CONCLUSIONES: El ajuste para los determinantes sociales de la salud redujo las disparidades raciales y étnicas en la detección del cáncer colorrectal entre todos los grupos étnicos y raciales minoritarios, excepto las personas asiáticas no hispanas; sin embargo, es probable que existan otros factores de confusión no medidos. Consulte Video Resumen en http://links.lww.com/DCR/B977 . (Traducción-Dr. Felipe Bellolio ).

Regional control after precision lymph node dissection for clinically evident melanoma metastasis.

INTRODUCTION: Completion lymph node dissection (CLND) for microscopic lymph node metastases has been replaced by observation; however, CLND is standard for clinically detectable nodal metastases (cLN). CLND has high morbidity, which may be reduced by excision of only the cLN (precision lymph node dissection [PLND]). We hypothesized that same-basin recurrence risk would be low after PLND. METHODS: Retrospective review at four tertiary care hospitals identified patients who underwent PLND. The primary outcome was 3-year cumulative incidence of isolated same-basin recurrence. RESULTS: Twenty-one patients underwent PLND for cLN without synchronous distant metastases. Reasons for forgoing CLND included patient preference (n = 11), comorbidities (n = 5), imaging indeterminate for distant metastases (n = 2), partial response to checkpoint blockade (n = 1), or not reported (n = 2). A median of 2 nodes (range: 1-6) were resected at PLND, and 68% contained melanoma. Recurrence was observed in 33% overall. Only 1 patient (5%) developed an isolated same-basin recurrence. Cumulative incidences at 3 years were 5.0%, 17.3%, and 49.7% for isolated same-basin recurrence, any same-basin recurrence, and any recurrence, respectively. Complications from PLND were reported in 1 patient (5%). CONCLUSIONS: These pilot data suggest that PLND may provide adequate regional disease control with less morbidity than CLND. These data justify prospective evaluation of PLND in select patients.

Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors.

Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same. We previously reported SLF1081851 as a prototype Spns2 inhibitor, which provided a scaffold to investigate the importance of the oxadiazole core and the terminal amine. In this report, we disclose a structure-activity relationship study by incorporating imidazole as both a linker and surrogate for a positive charge in SLF1081851. In vitro inhibition of Spns2-dependent S1P transport in HeLa cells identified 7b as an inhibitor with an IC50 of 1.4 ± 0.3 µM. The SAR studies reported herein indicate that imidazolium can be a substitute for the terminal amine in SLF1081851 and that Spns2 inhibition is highly dependent on the lipid alkyl tail length.

Addicted to green: priming effect of menthol cigarette packaging on brain response to smoking cues.

INTRODUCTION: Mentholated tobacco cigarettes are believed to be more addictive than non-menthol ones. Packaging of most menthol cigarette brands includes distinctive green hues, which may act as conditioned stimuli (ie, cues) and promote menthol smoking. To examine the cue properties of menthol cigarette packaging, we used a priming paradigm to assess the effect of packaging on the neural substrates of smoking cue reactivity. We hypothesised that menthol packaging will exert a specific priming effect potentiating smoking cue reactivity in menthol compared with non-menthol smokers. METHODS: Forty-two menthol and 33 non-menthol smokers underwent functional MRI while viewing smoking and neutral cues. The cues were preceded (ie, primed) by briefly presented images of menthol or non-menthol cigarette packages. Participants reported craving for cigarettes in response to each cue. RESULTS: Menthol packaging induced greater frontostriatal and occipital smoking cue reactivity in menthol smokers than in non-menthol smokers. Menthol packaging also enhanced the mediation by neural activity of the relationship between cue exposure and cigarette craving in menthol but not non-menthol smokers. Dynamic causal modelling showed stronger frontostriatal-occipital connectivity in response to menthol packaging in menthol compared with non-menthol smokers. The effects of non-menthol packaging did not differ between categories of smokers. CONCLUSIONS: Our findings demonstrate heightened motivational and perceptual salience of the green-hued menthol cigarette packaging that may exacerbate menthol smokers' susceptibility to smoking cues. These effects could contribute to the greater addiction severity among menthol smokers and could be considered in the development of science-based regulation and legal review of tobacco product marketing practices.

The Precision in Psychiatry (PIP) study: Testing an internet-based methodology for accelerating research in treatment prediction and personalisation.

BACKGROUND: Evidence-based treatments for depression exist but not all patients benefit from them. Efforts to develop predictive models that can assist clinicians in allocating treatments are ongoing, but there are major issues with acquiring the volume and breadth of data needed to train these models. We examined the feasibility, tolerability, patient characteristics, and data quality of a novel protocol for internet-based treatment research in psychiatry that may help advance this field. METHODS: A fully internet-based protocol was used to gather repeated observational data from patient cohorts receiving internet-based cognitive behavioural therapy (iCBT) (N = 600) or antidepressant medication treatment (N = 110). At baseline, participants provided > 600 data points of self-report data, spanning socio-demographics, lifestyle, physical health, clinical and other psychological variables and completed 4 cognitive tests. They were followed weekly and completed another detailed clinical and cognitive assessment at week 4. In this paper, we describe our study design, the demographic and clinical characteristics of participants, their treatment adherence, study retention and compliance, the quality of the data gathered, and qualitative feedback from patients on study design and implementation. RESULTS: Participant retention was 92% at week 3 and 84% for the final assessment. The relatively short study duration of 4 weeks was sufficient to reveal early treatment effects; there were significant reductions in 11 transdiagnostic psychiatric symptoms assessed, with the largest improvement seen for depression. Most participants (66%) reported being distracted at some point during the study, 11% failed 1 or more attention checks and 3% consumed an intoxicating substance. Data quality was nonetheless high, with near perfect 4-week test retest reliability for self-reported height (ICC = 0.97). CONCLUSIONS: An internet-based methodology can be used efficiently to gather large amounts of detailed patient data during iCBT and antidepressant treatment. Recruitment was rapid, retention was relatively high and data quality was good. This paper provides a template methodology for future internet-based treatment studies, showing that such an approach facilitates data collection at a scale required for machine learning and other data-intensive methods that hope to deliver algorithmic tools that can aid clinical decision-making in psychiatry.

Effects of current smoking severity on brain gray matter volume in opioid use disorder - a voxel-based morphometry study.

Background: Cigarette smoking (CS) and opioid use disorder (OUD) significantly alter brain structure. Although OUD and cigarette smoking are highly comorbid, most prior neuroimaging research in OUD did not control for smoking severity. Specifically, the combined effect of smoking and OUD on the brain gray matter volume (GMV) remains unknown.Objectives: We used structural magnetic resonance imaging (sMRI) to examine: (1) the GMV differences between OUD and non-OUD individuals with comparable smoking severity; and (2) the differential effect of smoking severity on the brain GMV between individuals with and without OUD.Methods: We performed a secondary analysis of existing sMRI datasets of 116 individuals who smoked cigarettes daily, among whom 60 had OUD (CS-OUD; 37 male, 23 female) and 56 did not (CS; 31 male, 25 female). Brain GMV was estimated by voxel-based morphometry analysis.Results: Compared to the CS group, the CS-OUD group had a higher GMV in the occipital cortex and lower GMV in the prefrontal and temporal cortex, striatum, and pre/postcentral gyrus (whole-brain corrected-p < .05). There was a significant interaction between group and smoking severity on GMV in the medial orbitofrontal cortex (whole-brain corrected-p < .05), such that heavier smoking was associated with lower medial orbitofrontal GMV in the CS-OUD but not CS participants (r=-0.32 vs. 0.12).Conclusions: Our findings suggest a combination of independent and interactive effects of cigarette smoking and OUD on the brain gray matter. Elucidating the neuroanatomical correlates of comorbid opioid and tobacco use may shed the light on the development of novel interventions for affected individuals.

Preoperative Identification and Management of Anemia in the Colorectal Surgery Patient.

Preoperative anemia is a common finding in patients undergoing colorectal surgery, particularly those with cancer. While often multifactorial, iron deficiency anemia remains the most common cause of anemia in this patient population. Although seemingly innocuous, preoperative anemia is associated with an increased risk of perioperative complications and need for allogenic blood transfusions, both of which may worsen cancer-specific survival. Preoperative correction of anemia and iron deficiency is thus necessary to diminish these risks. Current literature supports preoperative screening for anemia and iron deficiency in patients slated to undergo colorectal surgery for malignancy or for benign conditions with associated patient- or procedure-related risk factors. Accepted treatment regimens include iron supplementation-either oral or intravenous-as well as erythropoietin therapy. Autologous blood transfusion should not be utilized as a treatment for preoperative anemia when there is time to implement other corrective strategies. Additional study is still needed to better standardize preoperative screening and optimize treatment regimens.

A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer.

Checkpoint-blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA-A2+ or -A3+ Stage IIIC-IV CRC patients. Participants were vaccinated weekly with CEA and Her2 peptides plus tetanus peptide and GM-CSF emulsified in Montanide ISA-51 adjuvant for 3 weeks. Adverse events (AEs) were recorded per NIH Common Terminology Criteria for Adverse Events version 3. Immunogenicity was evaluated by interferon-gamma ELISpot assay of in vitro sensitized peripheral blood mononuclear cells and lymphocytes from the sentinel immunized node. Eleven participants were enrolled and treated; one was retrospectively found to be ineligible due to HLA type. All 11 participants were included in AEs and survival analyses, and the 10 eligible participants were evaluated for immunogenicity. All participants reported AEs: 82% were Grade 1-2, most commonly fatigue or injection site reactions. Two participants (18%) experienced treatment-related dose-limiting Grade 3 AEs; both were self-limiting. Immune responses to Her2 or CEA peptides were detected in 70% of participants. Median overall survival (OS) was 16 months; among those enrolled with no evidence of disease (n = 3), median OS was not reached after 10 years of follow-up. These data demonstrate that vaccination with CEA or Her2 peptides is well tolerated and immunogenic. Further study is warranted to assess potential clinical benefits of vaccination in advanced CRC either alone or in combination with CBT.

Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): a phase II, single-arm study.

BACKGROUND: Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM. METHODS: The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses. RESULTS: A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients. CONCLUSIONS: With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

An Internally Validated Prognostic Risk-Score Model for Disease-Specific Survival in Clinical Stage I and II Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined. METHODS: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables. RESULTS: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%. CONCLUSIONS: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.

A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder.

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

Bayesian set of best dynamic treatment regimes: Construction and sample size calculation for SMARTs with binary outcomes.

Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins' G-computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non-informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at https://wilart.shinyapps.io/shinysmartbayesr/.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined. METHODS: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated. RESULTS: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients. CONCLUSION: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.

A Delta-Opioid Receptor Gene Polymorphism Moderates the Therapeutic Response to Extended-Release Buprenorphine in Opioid Use Disorder.

BACKGROUND: Buprenorphine treatment is not equally effective in all patients with opioid use disorder (OUD). Two retrospective studies showed that, among African Americans (AAs), rs678849, a polymorphism in the delta-opioid receptor gene, moderated the therapeutic effect of sublingual buprenorphine. METHODS: We examined rs678849 as a moderator of the response to an extended-release subcutaneous buprenorphine formulation (BUP-XR) in a 24-week OUD treatment study of 127 AAs and 327 European Americans (EAs). Participants were randomly assigned to receive: (1) BUP-XR as 2 monthly injections of 300 mg followed by either 300 mg monthly or 100 mg monthly for 4 months, or (2) monthly volume-matched placebo injections. Generalized estimating equations logistic regression analyses tested, per population group, the main and interaction effects of treatment (BUP-XR vs placebo) and genotype group (rs678849*CC vs CT/TT) on weekly urine drug screens (UDS). RESULTS: Among AAs, the placebo group had higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.67, 95% CI = 0.36, 2.98), but no genotype by treatment effect (P = .80). Among EAs, the placebo group also showed higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.97, 95% CI = 1.14, 2.79) but a significant genotype by treatment interaction (χ 2(1) = 4.33, P = .04). CONCLUSION: We found a moderating effect of rs678849 on the response to buprenorphine treatment of OUD in EAs, but not AAs. These findings require replication in well-powered, prospective studies of both AA and EA OUD patients treated with BUP-XR and stratified on rs678849 genotype.

Childhood cancer survivors face markedly worse overall survival after diagnosis with breast cancer, melanoma, or colorectal cancer.

BACKGROUND: Childhood cancer survivors (CCS) are at elevated risk of secondary malignancies (SM). Enhanced screening for SM is recommended, but compliance is poor. We hypothesized that CCS with adult-onset SM (colorectal cancer [CRC], melanoma, or breast cancer [BC]) would present with more advanced disease and have decreased overall survival (OS). METHODS: The Surveillance, Epidemiology, and End Results Program was queried for patients diagnosed with cancer at age less than or equal to 18 also diagnosed with adult-onset CRC, melanoma, or BC. A cohort without a history of prior malignancy was likewise identified. Tumor features and clinical outcomes were compared. RESULTS: CCS with a SM (n = 224) were compared with patients without a childhood cancer history (n = 1,392,670). CCS were diagnosed younger (BC = 37.6 vs. 61.3, p < 0.01, CRC = 35.0 vs. 67.1, p < 0.01, melanoma = 29.6 vs. 61.3 years old, p < 0.01). CCS with BC were more likely to have Stage III or IV disease (25.2% vs. 16.5%, p = 0.01). Hormone-receptor expression also differed; CCS were less likely to develop Luminal A-type tumors (48.6% vs. 66.9%, p = 0.01). After age-adjustment, CCS had worse OS (Hazard ratio: CRC = 2.449, p < 0.01, melanoma = 6.503, p < 0.01, BC = 3.383, p < 0.01). CONCLUSION: CCS were younger when diagnosed with a SM. After age-adjustment, OS was diminished. Heightened surveillance may be necessary for CCS diagnosed with SM.