Orangutans and the evolution of sharp stone tools.

Orangutans use stone tools in a variety of modes, including cutting. This behavior appears to be learned from trusted social partners.

Metabolic acceleration and the evolution of human brain size and life history.

Humans are distinguished from the other living apes in having larger brains and an unusual life history that combines high reproductive output with slow childhood growth and exceptional longevity. This suite of derived traits suggests major changes in energy expenditure and allocation in the human lineage, but direct measures of human and ape metabolism are needed to compare evolved energy strategies among hominoids. Here we used doubly labelled water measurements of total energy expenditure (TEE; kcal day(-1)) in humans, chimpanzees, bonobos, gorillas and orangutans to test the hypothesis that the human lineage has experienced an acceleration in metabolic rate, providing energy for larger brains and faster reproduction without sacrificing maintenance and longevity. In multivariate regressions including body size and physical activity, human TEE exceeded that of chimpanzees and bonobos, gorillas and orangutans by approximately 400, 635 and 820 kcal day(-1), respectively, readily accommodating the cost of humans' greater brain size and reproductive output. Much of the increase in TEE is attributable to humans' greater basal metabolic rate (kcal day(-1)), indicating increased organ metabolic activity. Humans also had the greatest body fat percentage. An increased metabolic rate, along with changes in energy allocation, was crucial in the evolution of human brain size and life history.

Orangutan strategies for solving a visuospatial memory task.

The popular game known as Concentration (also commonly referred to as Memory), in which players search for matching pairs among a grid of face-down cards, provides a robust platform for examining visuospatial memory in a simple and nonverbal way. Five orangutans (Pongo ssp.) at the Indianapolis Zoo were given a modified version of the Concentration Game in which three cards were shown face-down on a computer screen, two of which matched each other while the third was a foil. Subjects overturned two cards at a time by touching them, with trials terminating in a food reward if the overturned cards matched, or reverting to their face-down position if they did not. A constraint was experimentally imposed on the game whereby the first two cards touched would never match, resulting in an optimal strategy composed of touching the first two cards, followed by the third, followed by the card among the first two cards that matched the third. We aimed to measure the extent to which orangutans would memorize and utilize visuospatial cues to solve the task in the optimal manner. Findings showed that three of five subjects utilized an optimal strategy more often than would be expected by chance, but also over utilized specific patterns of choices instead of adjusting their strategies to minimize the overall number of card flips. Visuospatial recall played a role in several of the participants' strategies for completing the task, but not to an extent that was necessary to achieve optimal gameplay.

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. METHODS: In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096. FINDINGS: Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7-20·1). 21 (39·6% [95% CI 26·5-54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. INTERPRETATION: Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study. FUNDING: Eisai and Merck.

Primate energy expenditure and life history.

Humans and other primates are distinct among placental mammals in having exceptionally slow rates of growth, reproduction, and aging. Primates' slow life history schedules are generally thought to reflect an evolved strategy of allocating energy away from growth and reproduction and toward somatic investment, particularly to the development and maintenance of large brains. Here we examine an alternative explanation: that primates' slow life histories reflect low total energy expenditure (TEE) (kilocalories per day) relative to other placental mammals. We compared doubly labeled water measurements of TEE among 17 primate species with similar measures for other placental mammals. We found that primates use remarkably little energy each day, expending on average only 50% of the energy expected for a placental mammal of similar mass. Such large differences in TEE are not easily explained by differences in physical activity, and instead appear to reflect systemic metabolic adaptation for low energy expenditures in primates. Indeed, comparisons of wild and captive primate populations indicate similar levels of energy expenditure. Broad interspecific comparisons of growth, reproduction, and maximum life span indicate that primates' slow metabolic rates contribute to their characteristically slow life histories.

Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison.

Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate. The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 µCi) oral dose of (14)C-lenvatinib. Metabolites of (14)C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and comprised 0.38 and 2.5 % of the administered dose excreted in urine and feces, respectively. The primary biotransformation pathways of lenvatinib were hydrolysis, oxidation and hydroxylation, N-oxidation, dealkylation and glucuronidation. Various combinations of these conversions with modifications, including hydrolysis, gluthathione/cysteine conjugation, intramolecular rearrangement and dimerization, were observed. Some metabolites seem to be unique to the investigated species (human, rat, monkey). Because all lenvatinib metabolites in human plasma were at very low levels compared to lenvatinib, only lenvatinib is expected to contribute to the pharmacological effects in humans.

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer.

AIMS: Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODS: This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTS: The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONS: The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.

Pharmacokinetics and excretion of (14)C-lenvatinib in patients with advanced solid tumors or lymphomas.

Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 µCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

Orangutans (Pongo spp.) have deeper, more efficient sleep than baboons (Papio papio) in captivity.

The nightly construction of arboreal sleeping platforms or "nests" has been observed among every great ape population studied to date. However, this behavior has never been reported in any other nonhuman primate and comparisons between ape and monkey sleep illuminate the link between sleeping substrates, positional behavior, and sleep efficiency. Here, we compare sleep depth and efficiency and night-time positional behavior between a large-bodied cercopithecoid (Papio papio) and a large-bodied hominoid (Pongo spp.) at the Indianapolis Zoo. We used infrared videography to assess nightly sleep and awake behavioral states, gross body movements, and postures in baboons (N = 45 nights) and orangutans (N = 128 nights). We calculated the total waking time, total sleep time, sleep fragmentation (the number of brief awakenings ≥2 min/h), sleep motor activity (number of motor activity bouts per hour), sleep efficiency (sleep duration/time in bed), and percentage of time spent in each posture. By every measure, orangutans experienced overall deeper, more efficient sleep. Baboons were more likely to sleep in guarded, upright positions (weight bearing on their ischial callosities) and never opted to use additional materials to augment sleep environments, whereas orangutans slept in insouciant, relaxed positions on constructed sleeping materials. Our results suggest that relaxed sleeping postures may have been enabled by sleeping platforms as a behavioral facilitator to sleep, which could have allowed for greater sleep depth and next-day cognitive capacities in both great apes and hominins.

Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers.

OBJECTIVE: To evaluate the effect of formulation and a high-fat meal on the pharmacokinetics of orally administered lenvatinib (E7080). MATERIALS: Lenvatinib 10-mg capsule and tablet. METHODS: Pharmacokinetics and safety of a single 10-mg lenvatinib dose were evaluated in healthy subjects in two randomized, two-period, crossover, phase 1, bioavailability trials. The first compared a new capsule formulation with an older tablet formulation (n = 20 subjects); the second evaluated the influence of a standard high-fat meal on the relative bioavailability of the capsule formulation (n = 16 subjects). Geometric least squares mean ratios of AUC0-∞, maximum observed concentration (Cmax), and AUC0-t were determined. tmax, tlag (food effect only), and t1/2,z were also calculated, and descriptive statistics were provided. RESULTS: A total of 36 healthy volunteers were enrolled in the two studies (mean ages 29 and 33 years). In the formulation study, AUC0-∞ and AUC0-t of the capsule formulation were ~ 10% less than the tablet formulation, and Cmax for the capsule formulation was ~ 14% lower. 90% Confidence intervals (CIs) for both AUCs were within the 80 - 125% CI, which is generally considered to denote bioequivalence, while the lower bound of the interval for Cmax was 79.8%. tmax and t1/2,z were comparable. For the capsule formulation, the mean (%CV) t1/2,z was 27.6 hours (27.3) and the median (range) tmax was 2.0 hours (2 - 4). In the food effect study, lenvatinib's AUC0-∞ and AUC0-t increased ~ 6% and 4% with the high-fat meal. Cmax following a high-fat meal was 5% lower than following administration in the fasted state. Administration with food delayed lenvatinib's tmax (2 vs. 4 hours). 90% CIs for AUCs were within the 80 - 125% CI, while the CI for Cmax was 72.1 - 126.4%. The single 10-mg dose demonstrated an acceptable tolerability profile; treatment-emergent adverse events occurred in 9 subjects (25%) overall and were typically mild in severity. CONCLUSIONS: These studies show that a new capsule formulation produces slightly lower exposure (~10 - 14%) to lenvatinib compared with the original tablet formulation, and that oral administration with a high-fat meal does not significantly affect exposure, although absorption is delayed. Thus, lenvatinib can be administered without regard to the timing of meals.

Metabolic adaptation for low energy throughput in orangutans.

Energy is the fundamental currency of life--needed for growth, repair, and reproduction--but little is known about the metabolic physiology and evolved energy use strategies of the great apes, our closest evolutionary relatives. Here we report daily energy use in free-living orangutans (Pongo spp.) and test whether observed differences in energy expenditure among orangutans, humans, and other mammals reflect known differences in life history. Using the doubly labeled water method, we measured daily energy expenditure (kCal/d) in orangutans living in a large indoor/outdoor habitat at the Great Ape Trust. Despite activity levels similar to orangutans in the wild, Great Ape Trust orangutans used less energy, relative to body mass, than nearly any eutherian mammal ever measured, including sedentary humans. Such an extremely low rate of energy use has not been observed previously in primates, but is consistent with the slow growth and low rate of reproduction in orangutans, and may be an evolutionary response to severe food shortages in their native Southeast Asian rainforests. These results hold important implications for the management of orangutan populations in captivity and in the wild, and underscore the flexibility and interdependence of physiological, behavioral, and life history strategies in the evolution of apes and humans.

Orangutan (Pongo spp.) whistling and implications for the emergence of an open-ended call repertoire: a replication and extension.

One of the most apparent discontinuities between non-human primate (primate) call communication and human speech concerns repertoire size. The former is essentially fixed to a limited number of innate calls, while the latter essentially consists of numerous learned components. Consequently, primates are thought to lack laryngeal control required to produce learned voiced calls. However, whether they may produce learned voiceless calls awaits investigation. Here, a case of voiceless call learning in primates is investigated--orangutan (Pongo spp.) whistling. In this study, all known whistling orangutans are inventoried, whistling-matching tests (previously conducted with one individual) are replicated with another individual using original test paradigms, and articulatory and acoustic whistle characteristics are compared between three orangutans. Results show that whistling has been reported for ten captive orangutans. The test orangutan correctly matched human whistles with significantly high levels of performance. Whistle variation between individuals indicated voluntary control over the upper lip, lower lip, and respiratory musculature, allowing individuals to produce learned voiceless calls. Results are consistent with inter- and intra-specific social transmission in whistling orangutans. Voiceless call learning in orangutans implies that some important components of human speech learning and control were in place before the homininae-ponginae evolutionary split.

Model-based treatment optimization of a novel VEGFR inhibitor.

AIM: To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment. METHODS: A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred. RESULTS: Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%). CONCLUSIONS: The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Evolution of water conservation in humans.

To sustain life, humans and other terrestrial animals must maintain a tight balance of water gain and water loss each day.1-3 However, the evolution of human water balance physiology is poorly understood due to the absence of comparative measures from other hominoids. While humans drink daily to maintain water balance, rainforest-living great apes typically obtain adequate water from their food and can go days or weeks without drinking4-6. Here, we compare isotope-depletion measures of water turnover (L/d) in zoo- and rainforest-sanctuary-housed apes (chimpanzees, bonobos, gorillas, and orangutans) with 5 diverse human populations, including a hunter-gatherer community in a semi-arid savannah. Across the entire sample, water turnover was strongly related to total energy expenditure (TEE, kcal/d), physical activity, climate (ambient temperature and humidity), and fat free mass. In analyses controlling for those factors, water turnover was 30% to 50% lower in humans than in other apes despite humans' greater sweating capacity. Water turnover in zoo and sanctuary apes was similar to estimated turnover in wild populations, as was the ratio of water intake to dietary energy intake (∼2.8 mL/kcal). However, zoo and sanctuary apes ingested a greater ratio of water to dry matter of food, which might contribute to digestive problems in captivity. Compared to apes, humans appear to target a lower ratio of water/energy intake (∼1.5 mL/kcal). Water stress due to changes in climate, diet, and behavior apparently led to previously unknown water conservation adaptations in hominin physiology.

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors.

BACKGROUND AND OBJECTIVE: Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib. METHODS: This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available. RESULTS: Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%). CONCLUSIONS: Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. CLINICALTRIALS. GOV IDENTIFIER: NCT02686164.

Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.

PURPOSE: Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors. METHODS: Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORRweek 24) at the recommended phase II dose. RESULTS: Overall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose-de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORRweek24 was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%). CONCLUSION: Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.

Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer.

PURPOSE: Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. METHODS: Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. RESULTS: At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. CONCLUSION: Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.

Does early care affect joint attention in great apes (Pan troglodytes, Pan paniscus, Pongo abelii, Pongo pygmaeus, Gorilla gorilla)?

The ability to share attention with another is the foundation on which other theory of mind skills are formed. The quality of care received during infancy has been correlated with increased joint attention in humans. The purpose of this study was to assess the effects of care style (responsive or basic) and caregiver type (ape or human) during the first 6 months on joint attention in 4 great ape species (Pan troglodytes, Gorilla gorilla, Pongo spp., and Pan pansicus). Great apes engaged in joint attention with conspecifics and humans regardless of the style of early care they experienced from either a great ape mother or human caregiver. This finding suggests that joint attention is a robust ability in great apes that is resilient against at least some differences in early care. Future studies using additional measures of early care quality are recommended.

A case of spontaneous acquisition of a human sound by an orangutan.

The capacity of nonhuman primates to actively modify the acoustic structure of existing sounds or vocalizations in their repertoire appears limited. Several studies have reported population or community differences in the acoustical structure of nonhuman primate long distance calls and have suggested vocal learning as a mechanism for explaining such variation. In addition, recent studies on great apes have indicated that there are repertoire differences between populations. Some populations have sounds in their repertoire that others have not. These differences have also been suggested to be the result of vocal learning. On yet another level great apes can, after extensive human training, also learn some species atypical vocalizations. Here we show a new aspect of great ape vocal learning by providing data that an orangutan has spontaneously (without any training) acquired a human whistle and can modulate the duration and number of whistles to copy a human model. This might indicate that the learning capacities of great apes in the auditory domain might be more flexible than hitherto assumed.

Orangutans show active voicing through a membranophone.

Active voicing - voluntary control over vocal fold oscillation - is essential for speech. Nonhuman great apes can learn new consonant- and vowel-like calls, but active voicing by our closest relatives has historically been the hardest evidence to concede to. To resolve this controversy, a diagnostic test for active voicing is reached here through the use of a membranophone: a musical instrument where a player's voice flares a membrane's vibration through oscillating air pressure. We gave the opportunity to use a membranophone to six orangutans (with no effective training), three of whom produced a priori novel (species-atypical) individual-specific vocalizations. After 11 and 34 min, two subjects were successful by producing their novel vocalizations into the instrument, hence, confirming active voicing. Beyond expectation, however, within <1 hour, both subjects found opposite strategies to significantly alter their voice duration and frequency to better activate the membranophone, further demonstrating plastic voice control as a result of experience with the instrument. Results highlight how individual differences in vocal proficiency between great apes may affect performance in experimental tests. Failing to adjust a test's difficulty level to individuals' vocal skill may lead to false negatives, which may have largely been the case in past studies now used as "textbook fact" for great ape "missing" vocal capacities. Results qualitatively differ from small changes that can be caused in innate monkey calls by intensive months-long conditional training. Our findings verify that active voicing beyond the typical range of the species' repertoire, which in our species underpins the acquisition of new voiced speech sounds, is not uniquely human among great apes.