Detection of RAS p.Q61R by Immunohistochemistry in Practice: A Clinicopathologic Study of 217 Thyroid Nodules with Molecular Correlates.

RAS p.Q61R is the most prevalent hot-spot mutation in RAS and RAS-like mutated thyroid nodules. A few studies evaluated RAS p.Q61R by immunohistochemistry (RASQ61R-IHC). We performed a retrospective study of an institutional cohort of 150 patients with 217 thyroid lesions tested for RASQ61R-IHC, including clinical, cytologic and molecular data. RASQ61R-IHC was performed on 217 nodules (18% positive, 80% negative, and 2% equivocal). RAS p.Q61R was identified in 76% (n = 42), followed by RAS p.Q61K (15%; n = 8), and RAS p.G13R (5%; n = 3). NRAS p.Q61R isoform was the most common (44%; n = 15), followed by NRAS p.Q61K (17%; n = 6), KRAS p.Q61R (12%; n = 4), HRAS p.Q61R (12%; n = 4), HRAS p.Q61K (6%; n = 2), HRAS p.G13R (6%; n = 2), and NRAS p.G13R (3%; n = 1). RASQ61R-IHC was positive in 47% of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP; 17/36), 22% of follicular thyroid carcinomas (FTC; 5/23), 10% of follicular thyroid adenomas (FTA; 4/40), and 8% of papillary thyroid carcinomas (PTC; 9/112). Of PTC studied (n = 112), invasive encapsulated follicular variant (IEFVPTC; n = 16) was the only subtype with positive RASQ61R-IHC (56%; 9/16). Overall, 31% of RAS-mutated nodules were carcinomas (17/54); and of the carcinomas, 94% (16/17) were low-risk per American Thyroid Associated (ATA) criteria, with only a single case (6%; 1/17) considered ATA high-risk. No RAS-mutated tumors recurred, and none showed local or distant metastasis (with a follow-up of 0-10 months). We found that most RAS-mutated tumors are low-grade neoplasms. RASQ61R-IHC is a quick, cost-effective, and reliable way to detect RAS p.Q61R in follicular-patterned thyroid neoplasia and, when malignant, guide surveillance.

Supine or non-supine sleep apnea events: which can be treated better with Barbed Pharyngoplasty?

PURPOSE: Among the treatment options for Obstructive Sleep Apnea (OSA), intrapharyngeal surgery has undergone significant changes and received solid scientific support. However, it is crucial to identify the best candidate. This study aims to present the results of the modified Alianza technique in our clinic to show the differences in the impact of surgery on supine and non-supine apnea levels in moderate-severe OSA patients. METHODS: Adult patients affected by moderate-severe OSA (Apnea-Hypopnea Index (AHI) > 15), having circular palatal collapse, and candidates for modified Alianza Tecnique were retrospectively enrolled. Each subject performed polysomnography pre- and post-operatively, and the follow-up check was performed after at least six months. RESULTS: This study enrolled 24 patients who underwent the Modified Alianza technique for sleep apnea. We found significant reductions in both supine and non-supine AH) after surgery. Non-supine AHI showed a greater reduction (from 20.89 to 11.64 episodes/hour, p = 0.0001) than supine AHI (from 42.51 to 25.93, p = 0.0003). We subsequently divided the patients into two groups based on whether they were affected by positional OSA before surgery. There was a lower percentage decrease in non-supine AHI compared to supine AHI after surgery in patients who were positional before surgery, but this difference was not statistically significant. Conversely, in the non-positional patient group, there was a higher decrease in non-supine AHI compared to supine AHI, although this was not statistically significant. CONCLUSION: The Modified Alianza Tecnique leads to notable enhancement in AHI among patients with OSA. Non-supine apneas exhibit a more favorable response to the surgery than supine apneas.

Where should I search next? Messages embedded in storybooks influence children's strategic exploration in Turkey and the United States.

Despite the vital role of curiosity-driven exploration in learning, our understanding of how to enhance children's curiosity remains limited. Here, we tested whether hearing a strategic curiosity story with curiosity-promoting themes (e.g., strategically approaching uncertainty, adapting flexibly to new information) versus a control story with traditional pedagogical themes (e.g., following rules, learning from others) would influence children's strategic exploration across two cultures. Three- to 6-year-olds from the United States (N = 138) and Turkey (N = 88) were randomly assigned to hear one of these stories over Zoom, before playing a game in which they searched for sea creatures across five fish tanks. All tanks had the same number of hiding spots but varied in the number of creatures they contained. Time was limited and children could not return to prior tanks, pushing them to allocate search effort strategically. Results indicated that across both countries, children in the strategic curiosity condition explored the virtual "aquarium" more broadly; they moved through tanks more rapidly than children in the control condition and were more likely to explore all five tanks before time ran out. Children in the strategic curiosity condition also showed relatively more strategic search, adapting their search based on the likelihood of finding creatures in each tank. While further research is needed to pinpoint which elements of our stories produced differences in search behavior and whether they did so by enhancing or inhibiting children's strategic exploration, storybooks appear to be a promising method for shaping children's exploration across multiple countries. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Next generation triplex-forming PNAs for site-specific genome editing of the F508del CFTR mutation.

BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein for which there is no cure. One approach to cure CF is to correct the underlying mutations in the CFTR gene. We have used triplex-forming peptide nucleic acids (PNAs) loaded into biodegradable nanoparticles (NPs) in combination with donor DNAs as reagents for correcting mutations associated with genetic diseases including CF. Previously, we demonstrated that PNAs induce recombination between a donor DNA and the CFTR gene, correcting the F508del CFTR mutation in human cystic fibrosis bronchial epithelial cells (CFBE cells) and in a CF murine model leading to improved CFTR function with low off-target effects, however the level of correction was still below the threshold for therapeutic cure. METHODS: Here, we report the use of next generation, chemically modified gamma PNAs (γPNAs) containing a diethylene glycol substitution at the gamma position for enhanced DNA binding. These modified γPNAs yield enhanced gene correction of F508del mutation in human bronchial epithelial cells (CFBE cells) and in primary nasal epithelial cells from CF mice (NECF cells). RESULTS: Treatment of CFBE cells and NECF cells grown at air-liquid interface (ALI) by NPs containing γtcPNAs and donor DNA resulted in increased CFTR function measured by short circuit current and improved gene editing (up to 32 %) on analysis of genomic DNA. CONCLUSIONS: These findings provide the basis for further development of PNA and NP technology for editing of the CFTR gene.

Tenofovir alafenamide compared to tenofovir disoproxil fumarate, induces dysglycemia, and dyslipidemia in Wistar rats.

OBJECTIVES: To determine the metabolic effects of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) in vivo. DESIGN AND METHODS: Male Wistar rats (Rattus novergicus, 250-300 g body weight) were divided into 3 groups (n = 8) and orally treated daily with 1.0 ml distilled water (group 1), TAF (0.42 mg/kg) (group 2), or TDF (5.0 mg/kg) (group 3), respectively, for 56 days. Glucose tolerance tests were done before the animals were sacrificed by halothane overdose, and blood was collected by cardiac puncture for the analysis of plasma lipids, electrolytes, and insulin. The kidney and pancreatic tissues were excised and homogenized to measure oxidative stress. Compartmentation of TAF and TDF was determined in NRK-52 and Peripheral Blood Mononuclear Cells (PBMC). RESULTS: There were no significant differences in weight gain among controls, TAF- or TDF-treated rats. TAF-treated rats had significantly increased fasting blood glucose (FBG), fasting plasma insulin (FPI), insulin resistance, impaired glucose tolerance, and dyslipidemia compared to control or TDF-treated rats, respectively. There was increased lipid peroxidation in the pancreas of TAF-treated compared to TDF-treated or control animals, respectively. TDF- treated rats presented with symptoms of Fanconi syndrome compared to TAF-treated or control animals, respectively. Kidney homogenates from TDF-treated animals had significantly reduced antioxidant enzyme activity compared to TAF-treated animals or controls, respectively. Intracellular concentrations of TAF were significantly higher than TDF in both NRK-52E cells and PBMC, respectively. CONCLUSIONS: TAF treatment is weight-neutral and causes dysglycemia, and dyslipidemia but not Fanconi syndrome compared to TDF.

Temporal variation in the structure, abundance, and composition of Laminaria hyperborea forests and their associated understorey assemblages over an intense storm season.

Kelp species function as important foundation organisms in coastal marine ecosystems where they provide biogenic habitat and ameliorate environmental conditions, often facilitating the development of diverse understorey assemblages. The structure of kelp forests is influenced by a variety of environmental factors, changes in which can result in profound shifts in ecological structure and functioning. Intense storm-induced wave action in particular, can severely impact kelp forest ecosystems. Given that storms are anticipated to increase in frequency and intensity in response to anthropogenic climate change, it is critical to understand their potential impacts on kelp forest ecosystems. During the 2021/22 northeast Atlantic storm season, the United Kingdom (UK) was subject to several intense storms, of which the first and most severe was Storm Arwen. Due to the unusual northerly wind direction, the greatest impacts of Storm Arwen were felt along the northeast coast of the UK where wind gusts exceeded 90 km/h, and inshore significant wave heights of 7.2 m and wave periods of 9.3 s were recorded. Here, we investigated temporal and spatial variation in the structure of L. hyperborea forests and associated understorey assemblages along the northeast coast of the UK over the 2021/22 storm season. We found significant changes in the cover, density, length, biomass, and age structure of L. hyperborea populations and the composition of understorey assemblages following the storm season, particularly at our most north facing site. We suggest continuous monitoring of these systems to further our understanding of temporal variation and potential recovery trajectories, alongside enhanced management to promote resilience to future perturbations.

Precarious employment and the workplace transmission of COVID-19: evidence from workers' compensation claims in Ontario, Canada.

OBJECTIVE: To examine the association between precarious employment and risk of work-related COVID-19 infection in Ontario, Canada. METHODS: We combined data from an administrative census of workers' compensation claims with corresponding labour force statistics to estimate rates of work-related COVID-19 infection between April 2020 and April 2022. Precarious employment was imputed using a job exposure matrix capturing temporary employment, low wages, irregular hours, involuntary part-time employment and a multidimensional indicator of 'low', 'medium', 'high' and 'very high' overall exposure to precarious employment. We used negative binomial regression models to quantify associations between precarious employment and accepted compensation claims for COVID-19. RESULTS: We observed a monotonic association between precarious employment and work-related COVID-19 claims. Workers with 'very high' exposure to precarious employment presented a nearly fivefold claim risk in models controlling for age, sex and pandemic wave (rate ratio (RR): 4.90, 95% CI 4.07 to 5.89). Further controlling for occupational exposures (public facing work, working in close proximity to others, indoor work) somewhat attenuated observed associations. After accounting for these factors, workers with 'very high' exposure to precarious employment were still nearly four times as likely to file a successful claim for COVID-19 (RR: 3.78, 95% CI 3.28 to 4.36). CONCLUSIONS: During the first 2 years of the pandemic, precariously employed workers were more likely to acquire a work-related COVID-19 infection resulting in a successful lost-time compensation claim. Strategies aiming to promote an equitable and sustained recovery from the pandemic should consider and address the notable risks associated with precarious employment.

Recommendations of the DNA Commission of the International Society for Forensic Genetics (ISFG) on short tandem repeat sequence nomenclature.

The DNA Commission of the International Society for Forensic Genetics (ISFG) has developed a set of nomenclature recommendations for short tandem repeat (STR) sequences. These recommendations follow the 2016 considerations of the DNA Commission of the ISFG, incorporating the knowledge gained through research and population studies in the intervening years. While maintaining a focus on backward compatibility with the CE data that currently populate national DNA databases, this report also looks to the future with the establishment of recommended minimum sequence reporting ranges to facilitate interlaboratory comparisons, automated solutions for sequence-based allele designations, a suite of resources to support bioinformatic development, guidance for characterizing new STR loci, and considerations for incorporating STR sequences and other new markers into investigative databases.

Is precarious employment an occupational hazard? Evidence from Ontario, Canada.

OBJECTIVES: To examine the association between precarious employment and risk of occupational injury or illness in Ontario, Canada. METHODS: We combined accepted lost-time compensation claims from the Workplace Safety and Insurance Board with labour force statistics to estimate injury and illness rates between January 2016 and December 2019. Precarious employment was imputed using a job exposure matrix and operationalised in terms of temporary employment, low wages, irregular hours, involuntary part-time employment and a multidimensional measure of 'low', 'medium', 'high' and 'very high' probabilities of exposure to precarious employment. Negative binomial regression models examined exposure to precarious employment in relation to risk of occupational injury or illness. RESULTS: After adjusting for age, sex and year, all indicators of precarious employment were associated with increased risk of injury or illness. Workers with 'high' and 'very' high' exposure to precarious employment presented a nearly threefold risk of injury or illness (rate ratio (RR): 2.81, 95% CI 2.73 to 2.89; RR: 2.82, 95% CI 2.74 to 2.90). Further adjustment for physical demands and workplace hazards attenuated associations, though a statistically and substantively significant exposure-outcome relationship persisted for workers with 'high' and 'very high' exposures to precarious employment (RR: 1.65, 95% CI 1.58 to 1.72; RR: 2.00, 95% CI 1.92 to 2.08). CONCLUSIONS: Workers exposed to precarious employment are more likely to sustain a lost-time injury or illness in Ontario, Canada. Workplace health and safety strategies should consider the role of precarious employment as an occupational hazard and a marker of work injury risk.

Mixed reality technology for older adults: Evaluating the impact of a novel virtual humanoid coach in a community-based physical exercise program in the Philippines.

Physical inactivity among older adults remains a global burden, leading to a variety of health challenges and even mortality. This study evaluated the impact of a novel virtual humanoid coach-driven physical exercise program among older adults. A non-randomized (quasi) experimental research was conducted in two community senior centers. The recruited participants (n = 130) were primarily female older adults with a mean age of 66.40 and agreed to be purposively assigned either experimental or control groups. Trained healthcare providers performed health assessments in three time points using valid and reliable tools. Descriptive statistics, t-tests, and RM-ANOVA were used to quantitatively analyze the data using SPSS version 22. There are significant mean differences between the groups across all functional capacity assessments and Time 2-3 assessment of sleep quality. RM-ANOVA revealed significant differences in physical assessment over time between the two groups. The analyses of time and group interaction revealed significant improvement in health assessments among the members of the mixed reality group compared to the traditional groups. The impact of virtual coaches in community-based enhancing physical activity programs is comparable to the traditional mode and introduces a novel approach to promoting physical activity among older adults.

Malignant Epithelioid Mesenchymal Neoplasm with FUS::CREM Gene Fusion Arising in the Tongue: A Case Report Detailing Clinicopathological, Imaging, and Molecular Features.

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck.

A comparison of respiratory oscillometry and spirometry in idiopathic pulmonary fibrosis: performance time, symptom burden and test-retest reliability.

Study question: In large multinational patient surveys, spirometry (which requires repeated, reproducible maximal efforts) can be associated with cough, breathlessness and tiredness, particularly in those with idiopathic pulmonary fibrosis (IPF). Oscillometry is an effort-independent test of airways resistance and reactance. We hypothesised that oscillometry would take less time to perform and would be associated with reduced symptom burden than spirometry. Patients and methods: Spirometry and oscillometry were performed in 66 participants with IPF and repeated 2 weeks later. We compared time taken to perform tests, symptom burden and test-retest reliability with Bland-Altman plots and intraclass correlation coefficients (ICCs). Results: Oscillometry took significantly less time to perform than spirometry (mean -4.5 (99% CI -6.0 to -3.0) min) and was associated with lower symptom burden scores for cough (-1.3, 99% CI -1.7 to -0.8), breathlessness (-1.0, 99% CI -1.4 to -0.5), and tiredness (-0.5, 99% CI -0.9 to -0.2). On Bland-Altman analysis, all measures showed good agreement, with narrow limits of agreement and the mean bias lying close to 0 in all cases. The ICCs for forced expiratory volume in 1 s and forced vital capacity were 0.94 and 0.89, respectively, and ranged between 0.70 and 0.90 for oscillometry measures. Conclusion: Oscillometry is quicker to perform and provokes less symptoms than spirometry in patients with IPF.

Intermittent cluster dynamics and temporal fractional diffusion in a bulk metallic glass.

Glassy solids evolve towards lower-energy structural states by physical aging. This can be characterized by structural relaxation times, the assessment of which is essential for understanding the glass' time-dependent property changes. Conducted over short times, a continuous increase of relaxation times with time is seen, suggesting a time-dependent dissipative transport mechanism. By focusing on micro-structural rearrangements at the atomic-scale, we demonstrate the emergence of sub-diffusive anomalous transport and therefore temporal fractional diffusion in a metallic glass, which we track via coherent x-ray scattering conducted over more than 300,000 s. At the longest probed decorrelation times, a transition from classical stretched exponential to a power-law behavior occurs, which in concert with atomistic simulations reveals collective and intermittent atomic motion. Our observations give a physical basis for classical stretched exponential relaxation behavior, uncover a new power-law governed collective transport regime for metallic glasses at long and practically relevant time-scales, and demonstrate a rich and highly non-monotonous aging response in a glassy solid, thereby challenging the common framework of homogeneous aging and atomic scale diffusion.

Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with relapse being a major obstacle to successful treatment. Our understanding of the mechanisms driving chemotherapy resistance and ultimately relapse in leukemia remains incomplete. Herein, we investigate the impact of the tumor microenvironment on leukemia cell drug responses using human plasma-like media (HPLM), designed to mimic physiological conditions more accurately ex vivo. We demonstrate that while most chemotherapeutics maintain an efficacy in HPLM comparable to standard tissue culture media, the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exhibit significantly reduced potency and efficacy against both B- and T- leukemia cells in HPLM. By merging our understanding of thiopurines' mechanism of action with the metabolites supplemented in HPLM compared to standard media, we proposed and subsequently validated the hypothesis that hypoxanthine, a purine derivative, is responsible for conferring resistance to the thiopurines. Importantly, the concentration of hypoxanthine required for resistance is comparable to physiological levels found in vivo, supporting clinical relevance. Our findings demonstrate the utility of a more physiologic media in identifying and characterizing mechanisms by which the microenvironment can enable resistance. Understanding such interactions may inform strategies to overcome drug resistance and improve therapeutic outcomes in pediatric leukemia.

Return on Investment of Three-Year Accelerated Programs for Students, Medical Schools, Departments, and Community.

Building on the initial accelerated pathway programs in the 1970s to increase workforce, nearly 30 schools have launched accelerated 3-year pathways (A3YP) during the past decade. The authors based on their educational roles, experiences, and scholarship with A3YP provide this perspective of the argument for A3YP and potential disadvantages for each group-students, schools, residencies, departments, and community. When schools consider innovations, they might consider A3YPs for multiple reasons; this perspective helps provide justification for the program and broadly considers return on investment (ROI). The ROI for students includes decreased debt, reduced costs and stress associated with the fourth-year residency applications, and a directed pathway with facilitated transition into a residency program with accompanying professional identity development. Disadvantages for students include early specialty commitment, risk of deceleration, and condensed curriculum. The ROI for schools includes recruiting and retaining students, who will then transition more easily into residency and stimulating innovation. Residency programs gain residents with known skills, who have been a part of the department for 3 years. In addition, fewer residency slots for interviewing leads to saving recruitment administrative costs and time. Finally, many programs are intended to increase the workforce, since students who come to the region for medical school and transition directly into residency are likely to stay in the region. Disadvantages include increased curricular complexity for the medical school, increased administrative support, and advising resources. Finally, several of the accelerated programs attract matriculants from diverse backgrounds contributing to the diversity of the medical school, residency program, and community workforce.

The genome sequence of common knotgrass, Polygonum aviculare L. (Polygonaceae).

We present a genome assembly from an individual Polygonum aviculare (common knotgrass; Eudicot; Magnoliopsida; Caryophyllales; Polygonaceae). The genome sequence is 351.6 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules. The mitochondrial and plastid genome assemblies have lengths of 333.39 kilobases and 163.28 kilobases in length, respectively.

Optimizing isometric midthigh pull testing protocols: impact on peak force and rate of force development and their association with jump performance.

BACKGROUND: Isometric strength testing is widely applied in sports science. However, we hypothesized that traditional testing procedures with a dual focus on both peak force (PF) and rate of force development (RFD) may compromise the true assessment of early RFD measures and lower the associative value towards vertical jump performance. METHODS: Therefore, PF and RFD were assessed for 47 active participants (24 females, 23 males) with a traditional isometric midthigh pull (IMTP) protocol ("push as hard and fast as possible" over 4 s) and an RFD-specific protocol ("push as fast as possible" over 2 s). IMTP measures were compared to squat (SJ), countermovement (CMJ) and drop-jump (DJ) performance. RESULTS: The RFD-specific protocol provided higher RFD (P<0.05) for time domains up to 100 ms but lower PF (P<0.001). Independent of protocol, SJ and CMJ performance displayed significant, but low-to-moderate correlations with all RFD measures (r=0.30-0.52) as well as PF (r=0.44), whereas DJ did not show any correlation. CONCLUSIONS: In conclusion, an RFD-specific protocol appears relevant for the assessment of RFD in the time domain up to 100 ms. However, the observed associations between RFD/PF measures and vertical jump performance remained low-to-moderate independent of the IMTP test protocol.

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

PURPOSE: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND METHODS: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.