Outcomes of apexification in immature traumatised necrotic teeth and risk factors for premature tooth loss: A 20-year longitudinal study.

BACKGROUND/AIM: To evaluate the long-term survival of immature traumatized incisors with pulp necrosis and apical periodontitis after endodontic treatment with two apexification techniques (calcium hydroxide apexification and MTA-apical plug) and to identify major factors affecting the survival of these teeth. MATERIALS AND METHODS: Records of 2400 children and adolescents were screened for presence of traumatic dental injuries to immature incisors where endodontic treatment with the two apexification techniques was performed during January 2003 and December 2022, compared to a control group of mature teeth treated with conventional endodontic techniques. The studied variables were age; sex; apexification technique, presence of luxation and hard tissue injuries; preoperative root development stage (RDS), preoperative and postoperative periapical index (PAI), the time-point for tooth loss, and overall survival time in years. Kaplan-Meier estimates were used to graphically present the survival functions and Cox proportional hazard model to calculate hazard ratios (HR, 95% CI). RESULTS: The median survival time was 10 years for calcium hydroxide apexification, 16.1 for MTA-apexification, for luxation injuries other than intrusions and avulsions 15.5 years, for intrusions 12.5 years and for avulsions 6.8 years. The variables with significant negative impact on tooth survival were calcium hydroxide apexification, avulsion and postoperative PAI 3-5. No significant relationships were found for the variables MTA apexification, concussion; subluxation; lateral luxation; extrusion, intrusion, hard tissue injuries, preoperative RDS and PAI scores and postoperative PAI 1-2. After adjustment, the risk for premature tooth loss was 13.5 times higher in calcium hydroxide apexification, approximately 2 to 4 times higher in PAI 3-5, and 5.6 times higher in avulsions. CONCLUSIONS: Calcium hydroxide apexification, avulsion, and postoperative PAI 3-5 were identified as prognostic variables with significant negative impact on the risk for premature tooth loss.

Extended caries prevention programme with biannual application of fluoride varnish for toddlers: prevalence of dental fluorosis at ages 7-9 years and associated factors.

OBJECTIVE: To investigate the prevalence of and factors associated with dental fluorosis in children living in areas of high caries risk in Stockholm and who had participated in a prospective, parallel, cluster-randomized, controlled caries prevention trial between ages 1 and 3 years. MATERIALS AND METHODS: The study group comprised a random sample of the children who had completed the 2-year prevention trial (n = 2536) in 2011-2014. All children were instructed to use fluoride toothpaste; the test group received fluoride varnish applications twice a year. Dental fluorosis prevalences in the reference (n = 220) and the test (n = 234) groups were compared. Presence of fluorosis was determined using the Thylsturp & Fejerskov (TF) index on photos of the permanent maxillary incisors. RESULTS: No significant difference in dental fluorosis was observed between the two groups. Nearly one-third (29.7%) of the children in the study cohort exhibited dental fluorosis (TF index ≥ 1). Associations with use of fluoride toothpaste at age 1 year and with socioeconomic status factors were found. CONCLUSIONS: Biannual applications of fluoride varnish in toddlers was not associated with dental fluorosis, which when found was rarely of aesthetic concern. Parental education in tooth-brushing routines is recommended.

Dental trauma in toddlers 1-3 years of age living in multicultural areas of Stockholm, Sweden: A retrospective cohort study.

BACKGROUND/AIM: Traumatic dental injuries are common and affect many children. The aim of this retrospective study was to investigate the prevalence and characteristics of dental trauma as well as the costs and resource use in a cohort of children aged 1-3 years in low socioeconomic areas (low income and educational level) of Stockholm. MATERIALS AND METHODS: Data were extracted from a larger intervention trial and analyzed for the prevalence and other characteristics of dental trauma as well as patient characteristics of children (n = 1346) from six dental clinics in low-income, multicultural areas. Variables describing the trauma, socioeconomic status, direct and indirect costs, and time spent at the emergency visit for the dental trauma were retrieved from the dental records. The study also recorded which healthcare profession handled the first and follow-up visits. RESULTS: The prevalence of dental trauma in the study cohort was 8.2%, and higher among boys (n = 71) than girls (n = 39). Boys exhibited a significantly higher risk for dental trauma (OR, 1.76; 95% CI = 1.17-2.65). Maxillary incisors were the teeth most often traumatized, and lateral luxation was the most common diagnosis. The mean time spent per child during the first year following the dental trauma was 36 min, and the mean costs per child were EUR 878. The total average per-child cost (direct and indirect costs) for dental trauma was EUR 2107. Dental visits due to traumatic injuries were significantly less common among children with an immigrant background and in families with an income ≤EUR 2000 per month. CONCLUSIONS: Toddlers in families who have a low socioeconomic status, a foreign background, and live in multicultural areas of Stockholm visit dental clinics for traumatic dental injuries less often than non-immigrant children living in families with a high socioeconomic status.

Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model.

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer's disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions.

Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy.

BACKGROUND: Cardiovascular exercise (CVE) has been shown to be protective against cognitive decline in aging and the risk for dementias, including Alzheimer's Disease (AD). CVE has also been shown to have several beneficial effects on brain pathology and behavioral impairments in mouse models of AD; however, no studies have specifically examined the effects of CVE on cerebral amyloid angiopathy (CAA), which is the accumulation of amyloid-beta (Aß) in the cerebral vasculature. CAA may be uniquely susceptible to beneficial effects of CVE interventions due to the location and nature of the pathology. Alternatively, CVE may exacerbate CAA pathology, due to added stress on already compromised cerebral vasculature. METHODS: In the current study, we examined the effects of CVE over many months in mice, thereby modeling a lifelong commitment to CVE in humans. We assessed this voluntary CVE in Tg-SwDI mice, a transgenic mouse model of CAA that exhibits behavioral deficits, fibrillar vascular Aß pathology, and significant perivascular neuroinflammation. Various "doses" of exercise intervention (0 h ("Sedentary"), 1 h, 3 h, 12 h access to running wheel) were assessed from ~ 4 to 12 months of age for effects on physiology, behavior/cognitive performance, and pathology. RESULTS: The 12 h group performed the greatest volume of exercise, whereas the 1 h and 3 h groups showed high levels of exercise intensity, as defined by more frequent and longer duration running bouts. Tg-SwDI mice exhibited significant cerebral vascular Aß pathology and increased expression of pro-inflammatory cytokines as compared to WT controls. Tg-SwDI mice did not show motor dysfunction or altered levels of anxiety or sociability compared to WT controls, though Tg-SwDI animals did appear to exhibit a reduced tendency to explore novel environments. At all running levels, CAA pathology in Tg-SwDI mice was not significantly altered, but 12-h high-volume exercise showed increased insoluble Aß burden. However, CVE attenuated the expression of pro-inflammatory cytokines TNF-α and IL-6 and was generally effective at enhancing motor function and reducing anxiety-like behavior in Tg-SwDI mice, though alterations in learning and memory tasks were varied. CONCLUSIONS: Taken together, these results suggest that CAA can still develop regardless of a lifespan of substantial CVE, although downstream effects on neuroinflammation may be reduced and functional outcomes improved.

Economic evaluation of an expanded caries-preventive program targeting toddlers in high-risk areas in Sweden.

OBJECTIVE: To economically evaluate a caries-preventive program "Stop Caries Stockholm" (SCS) where a standard program is supplemented with biannual applications of fluoride varnish in toddlers and compared it with the standard preventive program. MATERIAL AND METHODS: Data from the cluster randomized controlled field trial SCS including 3403 children, conducted in multicultural areas with low socioeconomic status was used. The difference in mean caries increment between the examinations; when the toddlers were 1 and 3 years old, was outcome measure of the intervention. The program was evaluated from a societal as well as a dental health care perspective. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental cost for each defs prevented. RESULTS: Average dental health care costs per child at age 3 years were EUR 95.77 for the supplemental intervention and EUR 70.52 for the standard intervention. The ICER was EUR 280.56 from a dental health care perspective and EUR 468.67 and considered high. CONCLUSIONS: The supplemental caries intervention program was not found to be cost-effective. The program raised costs without significantly reducing caries development. A better alternative use of the resources is recommended. TRIAL REGISTRATION: www.controlled-trials.com (ISRCTN35086887).

Approaching Spirituality Using the Patient-Centered Clinical Method.

Although the scientific literature already suggests the importance of spiritual care in clinical practice, this topic has been apart from the routine of many practitioners, and many physicians still have difficulties in how to carry out such approaches in the clinical setting. This article reflects on the importance of spirituality in the health-disease process and provides an approach to the biopsychosocial-spiritual care in the practice of primary care. In addition, the aim of the authors is to propose a spiritual approach based on the patient-centered clinical method. This method has been used for clinical communication and can be powerful for exploring spiritual history. Thus, using a fictional case scenario as a practical example, the authors guide readers to understand the patient-centered approach they propose.

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer.

LESSONS LEARNED: The lack of efficacy associated with anti-EGFL7 combined with standard bevacizumab and chemotherapy in this phase II trial in non-small cell lung carcinoma is consistent with the lack of benefit observed in colorectal carcinoma, highlighting the challenge of enhancing the efficacy of VEGF inhibition in unselected populations.Future efforts with agents like anti-EGFL7 should be guided by advances in pharmacodynamic and predictive biomarker development for antiangiogenic agents. BACKGROUND: Epidermal growth factor-like domain 7 (EGFL7) is an extracellular matrix-associated protein that is upregulated during angiogenesis and supports endothelial cell survival. This phase II trial evaluated the efficacy of the anti-EGFL7 antibody, parsatuzumab, in combination with bevacizumab plus platinum-based therapy for advanced or recurrent nonsquamous non-small cell lung cancer (NS-NSCLC). METHODS: Patients (n = 104) were randomized to either placebo or parsatuzumab (600 mg) in combination with bevacizumab (15 mg/kg) and carboplatin/paclitaxel, administered on day 1 of each 21-day cycle. Carboplatin and paclitaxel were administered for up to six cycles. Bevacizumab and parsatuzumab/placebo were administered for a maximum of 24 months. RESULTS: The progression-free survival (PFS) hazard ratio (HR) was 1.7 (95% confidence interval [CI], 1.0-2.8; p = .047). The median PFS was 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm. The hazard ratio for overall survival (OS) was 1.1 (95% CI, 0.5-2.2; p = .847). The objective response rate (ORR) was 29% in the parsatuzumab arm and 56% in the placebo arm. Overall safety and tolerability were consistent with the established toxicity profile of bevacizumab. CONCLUSION: There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line NS-NSCLC.

[Expansion of family medicine in Latin America: challenges and lines of actionExpansão da medicina familiar na América Latina: desafios e linhas de ação]. / Expansión de la medicina familiar en América Latina: desafíos y líneas de acción.

This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer.

LESSONS LEARNED: These negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses.Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents. BACKGROUND: EGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5-fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC). METHODS: One-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles. RESULTS: The progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71-1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46-2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms. CONCLUSIONS: There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC. The Oncologist 2017;22:375-e30.

Dynamic microglial modulation of spatial learning and social behavior.

Microglia are active players in inflammation, but also have important supporting roles in CNS maintenance and function, including modulation of neuronal activity. We previously observed an increase in the frequency of excitatory postsynaptic current in organotypic brain slices after depletion of microglia using clodronate. Here, we describe that local hippocampal depletion of microglia by clodronate alters performance in tests of spatial memory and sociability. Global depletion of microglia by high-dose oral administration of a Csf1R inhibitor transiently altered spatial memory but produced no change in sociability behavior. Microglia depletion and behavior effects were both reversible, consistent with a dynamic role for microglia in the regulation of such behaviors.

Effectiveness of Early Preventive Intervention with Semiannual Fluoride Varnish Application in Toddlers Living in High-Risk Areas: A Stratified Cluster-Randomized Controlled Trial.

This study evaluated whether toddlers in an extended preventive program of semiannual fluoride varnish applications from 1 year of age had a lower incidence of caries than those undergoing a standard program. A cohort of 1-year-old children (n = 3,403) living in multicultural areas of low socioeconomic standing in Stockholm participated in a cluster-randomized controlled field trial with two parallel arms. The children attended 23 dental clinics. Using the ICDAS II criteria, the examiners recorded caries at baseline and after 1 and 2 years. The children in the reference group received a standardized oral health program once yearly between 1 and 3 years of age. The children in the test group received the same standard program supplemented with topical applications of fluoride varnish every 6 months. We compared the test group and the reference group for the prevalence and increment of caries. At baseline, 5% of the children had already developed caries (ICDAS II 1-6). We reexamined the children after 1 year (n = 2,675) and after 2 years (n = 2,536). Neither prevalence nor caries increment differed between the groups. At 3 years of age, 12% of the children had developed moderate and severe carious lesions (ICDAS II 3-6), with a mean increment of 0.5 (SD 2.4) in the test group and 0.6 (SD 2.2) in the reference group. In conclusion, semiannual professional applications of fluoride varnish, as a supplement to a standard oral health program, failed to reduce caries development in toddlers from high-risk communities.

Oral microflora in preschool children attending a fluoride varnish program: a cross-sectional study.

BACKGROUND: To compare the oral microflora in preschool children attending a fluoride varnish program with a reference group receiving a standard oral health program without fluoride varnish applications. A second aim was to relate the microbial composition to the caries prevalence. METHODS: Five hundred seven 3-year-old children were enrolled from a cohort of 3403 preschool children taking part in a community based oral health project. Two hundred sixty-three of them had attended caries-preventive program with semi-annual applications of a fluoride varnish since the age of 1 year (test group) while 237 had received standard preventive care (reference group). Oral samples were collected with a sterile swab and analysed with checkerboard DNA-DNA hybridization using 12 pre-determined bacterial probes. Caries and background data were collected from clinical examinations and questionnaires. RESULTS: Gram-positive streptococci (S. intermedius, S. salivarius, S. oralis) were most frequently detected and displayed the highest counts in both groups. There were no significant differences between the groups concerning prevalence of any of the selected bacterial strains except for S. oralis that occurred less frequently in the reference group. In children with caries, V. parvula were significantly more common (p < 0.05) while strains of Lactobacillus, Bifidobacterium and Neisseria were more prevalent among the caries-free children (p < 0.05). CONCLUSIONS: A 2-year community program with semi-annual fluoride varnish applications did not seem to significantly influence the oral microflora in preschool children. TRIAL REGISTRATION: www.controlled-trials.com (ISRCTN35086887) 20131216 'retrospectively registered'.

Particle- and Gaseous Emissions from an LNG Powered Ship.

Measurements of particle number and mass concentrations and number size distribution of particles from a ship running on liquefied natural gas (LNG) were made on-board a ship with dual-fuel engines installed. Today there is a large interest in LNG as a marine fuel, as a means to comply with sulfur and NOX regulations. Particles were studied in a wide size range together with measurements of other exhaust gases under different engine loads and different mixtures of LNG and marine gas oil. Results from these measurements show that emissions of particles, NOX, and CO2 are considerably lower for LNG compared to present marine fuel oils. Emitted particles were mainly of volatile character and mainly had diameters below 50 nm. Number size distribution for LNG showed a distinct peak at 9-10 nm and a part of a peak at diameter 6 nm and below. Emissions of total hydrocarbons and carbon monoxide are higher for LNG compared to present marine fuel oils, which points to the importance of considering the methane slip from combustion of LNG.

Exploring the neuroprotective role of physical activity in cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a common neurological finding characterized by abnormalities of the small blood vessels in the brain. Previous research has established a strong connection between cSVD and stroke, as well as neurodegenerative disorders, notably Alzheimer's disease (AD) and other dementias. As the search for effective interventions continues, physical activity (PA) has emerged as a potential preventative and therapeutic avenue. This review synthesizes the human and animal literature on the influence of PA on cSVD, highlighting the importance of determining optimal exercise protocols, considering aspects such as intensity, duration, timing, and exercise type. Furthermore, the necessity of widening the age bracket in research samples is discussed, ensuring a holistic understanding of the interventions across varying pathological stages of the disease. The review also suggests the potential of exploring diverse biomarkers and risk profiles associated with clinically significant outcomes. Moreover, we review findings demonstrating the beneficial effects of PA in various rodent models of cSVD, which have uncovered numerous mechanisms of neuroprotection, including increases in neuroplasticity and integrity of the vasculature and white matter; decreases in inflammation, oxidative stress, and mitochondrial dysfunction; and alterations in amyloid processing and neurotransmitter signaling. In conclusion, this review highlights the potential of physical activity as a preventive strategy for addressing cSVD, offering insights into the need for refining exercise parameters, diversifying research populations, and exploring novel biomarkers, while shedding light on the intricate mechanisms through which exercise confers neuroprotection in both humans and animal models.

Material-Sparing Feasibility Screening for Hot Melt Extrusion.

Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations in generating a successful amorphous solid dispersion by HME. This work aims to develop a material-sparing approach for screening manufacturability of a given pharmaceutical API by HME using physically relevant time, temperature, and shear. Piroxicam, ritonavir, and phenytoin were used as model APIs with PVP VA64 as the dispersion polymer. We present a screening flowchart, aided by a simple custom device, that allows rapid formulation screening to predict both achievable API loadings and expected degradation from an HME process. This method has good correlation to processing with a micro compounder, a common HME screening industry standard, but only requires 200 mg of API or less.

PRESTO: Promoting Engagement for the Safe Tapering of Opioids.

ABSTRACT: Twenty-four percent of all U.S. opioid overdose deaths involve a prescription opioid. Changing prescribing practices is considered a key step in reducing opioid overdoses. Primary care providers (PCPs) commonly lack the patient engagement skills needed to address patient resistance to taper or end opioid prescriptions. We developed and evaluated a protocol aimed at improving PCP opioid-prescribing patterns and modeled on the evidence-based Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach. We conducted a time series trial comparing provider opioid prescribing 8 months before and 8 months after training with the PRomoting Engagement for Safe Tapering of Opioids (PRESTO) protocol. The 148 Ohio PCPs who completed PRESTO training gained confidence in their ability to engage their patients on the topics of opioid overdose risk and potential opioid tapering. Promoting Engagement for Safe Tapering of Opioids participants had decreased opioid-prescribing over time, but this was not significantly different from Ohio PCPs who had not received PRESTO training. Participants completing PRESTO training had small, but significant increased buprenorphine prescribing over time compared with Ohio PCPs who had not received PRESTO training. The PRESTO approach and opioid risk pyramid warrant further study and validation.

First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors.

PURPOSE: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. PATIENTS AND METHODS: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. RESULTS: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. CONCLUSIONS: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.