A high-mass X-ray binary descended from an ultra-stripped supernova.

Ultra-stripped supernovae are different from other terminal explosions of massive stars, as they show little or no ejecta from the actual supernova event1,2. They are thought to occur in massive binary systems after the exploding star has lost its surface through interactions with its companion2. Such supernovae produce little to no kick, leading to the formation of a neutron star without loss of the binary companion, which itself may also evolve into another neutron star2. Here we show that a recently discovered high-mass X-ray binary, CPD -29 2176 (CD -29 5159; SGR 0755-2933)3-6, has an evolutionary history that shows the neutron star component formed during an ultra-stripped supernova. The binary has orbital elements that are similar both in period and in eccentricity to 1 of 14 Be X-ray binaries that have known orbital periods and eccentricities7. The identification of the progenitors systems for ultra-stripped supernovae is necessary as their evolution pathways lead to the formation of binary neutron star systems. Binary neutron stars, such as the system that produced the kilonova GW170817 that was observed with both electromagnetic and gravitational energy8, are known to produce a large quantity of heavy elements9,10.

Retrospective experience of children with relapsed brain tumors treated with oral combination of axitinib and metronomic etoposide.

Metronomic chemotherapy-based combinations have received interest for relapsed/refractory malignancies. Preclinical and clinical studies showed activity of metronomic etoposide and axitinib. We report our retrospective experience in six children treated with axitinib and metronomic etoposide for refractory/relapsed brain tumors as an "off-label" combination. Three patients with medulloblastoma experienced partial response; one patient with atypical teratoid rhabdoid tumor (ATRT) displays an ongoing stable disease (12 months); two patients with medulloblastoma had progressive disease. Grade 3-4 toxicities were observed in two patients (thrombocytopenia, anemia, diarrhea, fatigue). The axitinib-etoposide combination shows signals of efficacy in heavily pretreated patients with relapsed/refractory brain tumors. These results were based on real-world observation and will need formal evaluation in a phase I/II trial.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Facial vs Non-facial Molluscum Contagiosum Infection in Children: A Cross-sectional Study.

Molluscum contagiosum is a common skin infection affecting different body areas, including the face. Previous data have shown cases of atypical lesions, notably on the face, and it was thought relevant to further examine differences between facial and non-facial lesions. All cases of children (0-18) diagnosed with molluscum contagiosum from 2013-2022 at the paediatric dermatology clinic of Soroka University Medical Center were retrospectively reviewed, and 615 children were included in the study. Facial lesions tended to be found in younger children (p = 0.018). Non-facial lesions were more erythematous (p < 0.001), itchier (p < 0.001), and showed similar patterns of ulceration (p = 0.078) and purulence (p = 0.779). The average lesion diameter was similar in patients with or without facial lesions (p = 1). Children with facial lesions were treated differently from patients without facial lesions (p < 0.001); however, there were no differences in treatment response. This research challenges assumptions concerning the severity of facial lesions, including eyelid lesions, by revealing that, overall, they exhibit less inflammation than non-facial lesions. Despite the potential for greater psychosocial burdens and impacts on self-esteem associated with lesions on the sensitive facial area, this study provides evidence that they are not inherently more worrisome and can be managed similarly to lesions found elsewhere in the body.

Does Molluscum Contagiosum Need to be Managed Differently in Atopic Children?

The association between molluscum contagiosum and concomitant atopic dermatitis and its impact on clinical features and treatment outcomes remains unclear. This retrospective study, conducted in the paediatric dermatology clinic of a tertiary medical centre, aimed to compare molluscum patients with and without atopic dermatitis. A total of 615 children with molluscum were included, 13.17% of whom had atopic dermatitis. While the latter group exhibited higher lesion count and itchiness (p=0.026 and p=0.044, respectively), no significant differences were observed in average lesion diameter, ulceration, purulence, and erythema (p=0.239, p=0.730, p=0.682, and p=0.296, respectively). Both groups showed comparable responses to molluscum-specific and supportive treatments, with no distinct difference in outcomes or recurrence of visits. It was concluded that atopic dermatitis does not exacerbate molluscum morbidity, inflammation markers, treatment outcomes or recurrence rates.

Mammary-analog secretory carcinoma in children: Surgery or TRK inhibitors first?

We report two cases of pediatric mammary-analog secretory carcinoma (MASC), a male operated on at age 8 and a female operated on at 12, who are in remission 2 years after surgery. The diagnosis of MASC was challenging and established by identifying the ETV6::NTRK3 fusion transcript in both cases. Given the excellent results of TRK inhibitor treatments in adult MASC and pediatric tumors expressing an ETV6::NTRK3 fusion, they should probably be prescribed as first-line treatment in cases requiring surgery with foreseeable serious sequelae or metastatic disease.

Forecasting Heliospheric CME Solar-Wind Parameters Using the UCSD Time-Dependent Tomography and ISEE Interplanetary Scintillation Data: The 10 March 2022 CME.

Remotely sensed interplanetary scintillation (IPS) data from the Institute for Space-Earth Environmental Research (ISEE), Japan, allows a determination of solar-wind parameters throughout the inner heliosphere. We show the 3D analysis technique developed for these data sets that forecast plasma velocity, density, and component magnetic fields at Earth, as well at the other inner heliospheric planets and spacecraft. One excellent coronal mass ejection (CME) example that occurred on the 10 March 2022 was viewed not only in the ISEE IPS analyses, but also by the spacecraft near Earth that measured the CME arrival at one AU. Solar Orbiter, that was nearly aligned along the Earth radial at 0.45 AU, also measured the CME in plasma density, velocity, and magnetic field. BepiColombo at 0.42 AU was also aligned with the STEREO A spacecraft, and viewed this CME. The instruments used here from BepiColombo include: 1) the European-Space-Agency Mercury-Planetary-Orbiter magnetic field measurements; 2) the Japan Aerospace Exploration Agency Mio spacecraft Solar Particle Monitor that viewed the CME Forbush decrease, and the Mercury Plasma Experiment/Mercury Electron Analyzer instruments that measured particles and solar-wind density from below the spacecraft protective sunshield covering. This article summarizes the analysis using ISEE, Japan real-time data for these forecasts: it provides a synopsis of the results and confirmation of the CME event morphology after its arrival, and discusses how future IPS analyses can augment these results.

Metastatic Melanoma in Young Child.

Pediatric melanoma is a rare cancer, especially in young children, and it remains a diagnostic challenge. We report a case of massively metastatic melanoma in young patient with an atypical clinical and biological presentation and with no risk factors.

Pediatricians' confidence level in diagnosing and treating children with atopic dermatitis in Israel, based on a self-efficacy survey.

Atopic dermatitis (AD) is one of childhood's most common skin conditions. Although pediatricians often diagnose and manage it, more than half refer even mild cases to dermatologists. In this study, we aimed to evaluate pediatric residents' and pediatricians' self-confidence regarding their ability to diagnose and manage AD. A cross-sectional questionnaire study was conducted with Israeli pediatric residents and pediatricians in 2022. The questionnaire was designed to distinguish participants with high vs. low self-confidence characteristics regarding their ability to diagnose and treat AD. In total, 171 participants completed the questionnaire (59.4% women; age, 41.1 ± 10.6 years); 39.1% of the participants were residents, while 60.9% were board-certified pediatricians. Overall, 64.4% of the responders reported below or average confidence (score ≤ 3, on a scale of 1-5) in diagnosing and treating AD in children. The group with higher self-confidence was significantly older (44.39 vs. 39.14 years, P = 0.003), had more years of experience in evaluating pediatric AD (P = 0.004), had trained in dermatology during their residency (P = 0.02) with a longer training period (P = 0.01), and with more than three training methods (P = 0.009). Multivariable logistic regression analysis showed that high self-confidence was associated with age older than 40 years and training in dermatology during residency (odds ratios = 5.63 [P = 0.04] and 3.36 [P = 0.05], respectively).  Conclusion: Most pediatric residents and pediatricians were not particularly confident in treating children with AD. Those with high self-confidence were older, had been exposed to more patients, and had been trained in dermatology during their residency with various methods and for longer periods. Therefore, we encourage the implementation of a training program in dermatology during pediatric residency programs. What is Known: • Atopic dermatitis (AD) is one of childhood's most common skin conditions and often presents to pediatricians for diagnosis and management. • Many pediatricians refer children with even mild cases of AD to dermatologists. What is New: • Most pediatric residents and pediatricians report low confidence in diagnosing and treating pediatric AD. • Physicians with high self- confidence were older, exposed to more AD patients, and had been trained in dermatology during their residency with various methods and for longer periods. Therefore, the implementation of a training program in dermatology during pediatric residency programs is warranted.

The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients.

INTRODUCTION: At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. METHODS: We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. RESULTS: 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. CONCLUSIONS: Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children.

Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low-grade glioma.

AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS: A multicentre, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumours, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS: PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg m-2 dose level, were 472 L h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (P = .004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION: Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among paediatric patients.

The French FRACTURE database: A way to improve knowledge on management of children with very rare tumors.

INTRODUCTION: Very rare pediatric tumors (VRTs), defined by an annual incidence ≤2 per million inhabitants, represent a heterogeneous group of cancers. Due to their extremely low incidence, knowledge on these tumors is scant. Since 2012, the French Very Rare Tumors Committee (FRACTURE) database has recorded clinical data about VRTs in France. This study aims: (a) to describe the tumors registered in the FRACTURE database; and (b) to compare these data with those registered in the French National Registry of Childhood Cancer (RNCE). METHODS: Data recorded in the FRACTURE database between January 1, 2012 and December 31, 2018 were analyzed. In addition, these data were compared with those of the RNCE database between 2012 and 2015 to evaluate the completeness of the documentation and understand any discrepancies. RESULTS: A total of 477 patients with VRTs were registered in the FRACTURE database, representing 97 histological types. Of the 14 most common tumors registered in the RNCE (772 patients), only 19% were also registered in the FRACTURE database. Total 39% of children and adolescent VRTs registered in the RNCE and/or FRACTURE database (323 of a total of 828 patients) were not treated in or linked to a specialized pediatric oncology unit. CONCLUSION: VRTs represent many different heterogenous entities, which nevertheless account for 10% of all pediatric cancers diagnosed each year. Sustainability in the collection of these rare tumor cases is therefore important, and a regular systematic collaboration between the FRACTURE database and the RNCE register helps to provide a more exhaustive picture of these VRTs and allow research completeness for some peculiar groups of patients.

Metronomic Maintenance With Weekly Vinblastine After Induction With Bevacizumab-Irinotecan in Children With Low-grade Glioma Prevents Early Relapse.

BACKGROUND: Pediatric low-grade glioma (pLGG) represents the most common brain tumor in childhood. Previous studies have reported that a therapeutic strategy on the basis of the association of bevacizumab alone (B) or in combination with irinotecan (BI) could produce rapid tumor response and clinical improvement in children with pLGG. Nevertheless, a majority of patients relapses shortly (median, 5 mo) after stopping B or BI treatment. We proposed metronomic maintenance with weekly vinblastine added after a 6 months induction of B/BI to prevent early relapse. PATIENTS AND METHODS: Monocentric retrospective analysis of a patient with pLGG treated with B or BI for 6 months followed by a 12-month maintenance with weekly vinblastine (6 mg/m²) from October 2012 to September 2019 in a single institution. RESULTS: In total, 18 patients (7 males and 11 females) were identified. Because of progression during the B or BI induction 2/18 children were excluded. In total, 16 patients were analyzed with a median age of 10 years (range, 4 to 16 y). A total of 13 patients received BI and 3 patients received B alone. The mean duration of induction was 6.2 months (range, 2 to 12 mo). After induction 5/16 patients had a partial radiologic response, 11/16 patients had stable disease. All patients started maintenance (median duration, 12 mo; range, 3 to 12 mo). With a median follow-up of 3.9 years after the end of B or BI (range, 11 mo to 7.2 y), 15/16 patients were alive and 9/16 patients were progression-free. Seven of 16 children progressed with a median time to progression of 23 months (ranges, 5 to 39 mo). Three of 16 (18%) children progressed during vinblastine maintenance and 4/16 (25%) patients after the end of maintenance. After the total duration of treatment, clinical improvement was noted in 4 patients, 9 patients had stable symptoms, and only 3 patients progressed. One and 2-year event-free survival were, respectively, 81.2% and 56.2%. Two-year overall survival was 93.7%. CONCLUSIONS: We report here, the potential benefit and the improvement of progression-free survival by adding metronomic maintenance with weekly vinblastine after initial induction with B or BI in children with low-grade glioma.

Description of a giant hypothalamic hamartoma associated with an immature ruptured giant sacrococcygeal teratoma: a case report.

Giant hypothalamic hamartomas (GHH) are rare neonatal intracerebral congenital malformations responsible for gelastic epilepsy and/or endocrine disturbances. Sacrococcygeal teratomas (SCT) are fetal neoplasms associated with perinatal morbidity and mortality, especially hemorrhagic complications in giant examples (GSCT). Here, we describe an immature ruptured GSCT complicated by hemorrhagic shock at 32-week gestation boy requiring an emergency delivery, followed immediately by urgent surgical removal. A brain lesion resembling a GHH was also present on the antenatal MRI. In order to exclude metastatic immature teratoma or glioma, a biopsy was performed by a retro-sigmoidal approach, which confirmed the nature of the hamartoma. Here, we describe for the first time the association of a ruptured immature GSCT associated with a GHH.

Multicystic and diffuse malignant peritoneal mesothelioma in children.

BACKGROUND: Malignant and multicystic peritoneal mesotheliomas are extremely rare tumors in children, developing from mesothelial cells. No specific guidelines are available at this age. METHODS: We performed a retrospective analysis of all identified children (< 18-year-old) treated in France from 1987 to 2017 for a diffuse malignant peritoneal mesothelioma (DMPM) or a multicystic peritoneal mesothelioma (MCPM). RESULTS: Fourteen patients (5 males and nine females), aged 2.2 to 17.5 years, were included. The most frequent presenting symptoms were abdominal pain, ascitis, and alteration in the general condition. Eight patients had epithelioid mesothelioma, three had biphasic mesothelioma, and three had MCPM. Eight patients with DMPM diagnosis received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Among them, six patients had neoadjuvant systemic chemotherapy, one patient, post-operative chemotherapy, and one patient CRS and HIPEC only. Three patients received only systemic chemotherapy. All patients with MCPM had only surgery. After a median follow-up of seven years (2-15), six patients (6/11; one death) with DMPM and two patients (two/three) with MCPM had a local and distant recurrences. CONCLUSION: Peritoneal mesothelioma in children is a rare condition with difficult diagnosis and high risk of recurrence. Worldwide interdisciplinary collaboration and networking are mandatory to help diagnosis and provide harmonious treatment guidelines.

Pulmonary giant chondromatous hamartoma with multifocal evolution in an infant.

Hamartoma is the most common benign pulmonary tumor in adults, but is rarely described in the pediatric population. Giant chondromatous and progressive forms are even rarer. We report the novel case of a 13-month-old infant hospitalized for giant pulmonary chondromatous hamartoma discovered during a septic episode, rapidly progressive, with severe multifocal lesions, without clear response to several cytotoxic therapies. No predisposition syndrome was identified.

Metro-SMHOP 01: Metronomics combination with cyclophosphamide-etoposide and valproic acid for refractory and relapsing pediatric malignancies.

BACKGROUND: In low- and middle-income countries, therapeutic options for advanced, refractory, or relapsing malignancies are limited due to local constraints such as cost of drugs, distance from oncology centers, and lack of availability of new anticancer drugs. Metronomics, which combines metronomic chemotherapy (MC) and drug repositioning, allows for the provision of new therapeutic options for patients in this setting. AIM OF THE STUDY: To evaluate the activity and toxicity of a metronomic regimen in Moroccan pediatric patients with refractory or relapsing malignancies. PATIENTS AND METHODS: From July 2014 to January 2018, patients with refractory/relapsing solid tumors treated in five pediatric oncology centers were consecutively enrolled. The metronomic regimen consisted of 28-day cycles with daily oral administration of cyclophosphamide (30 mg/m2 ) from days 1 to 21, together with oral etoposide (25 mg/m2 ) from days 1 to 21 followed by break of one week and daily valproic acid (20 mg/kg) from days 1 to 28. RESULTS: Ninety-eight children (median age, 8 years) were included. Underlying malignancies were neuroblastoma (24 patients), Ewing sarcoma (18), osteosarcoma (14), rhabdomyosarcoma (14), and miscellaneous tumors (28). A total of 557 cycles were given (median: 6; range, 1-18 cycles). One-year progression-free survival of our patients was 19%, and one-year overall survival was 22%. Complete response was obtained in three cases (3%), partial response in 11 cases (11%), and tumor stabilization for more than six months in 28 cases (28%). CONCLUSION: This three-drug metronomic combination was well tolerated and associated with tumor response and disease stabilization in 42 patients even for a long period.

Impact of hydrogen dopant incorporation on InGaZnO, ZnO and In2O3 thin film transistors.

In this work, hydrogen (H) plasma treatment is implemented to dope indium gallium zinc oxide (InGaZnO), zinc oxide (ZnO), and indium oxide (In2O3) thin-film transistors (TFTs). We systematically analyze the active defect states inside these n-type metal oxides and reveal how they are impacted by H dopant incorporation, combining the device transfer characteristics (including the threshold voltage, subthreshold slope, and carrier mobility), the X-ray photoelectron spectra, and numerical and theoretical investigations. An increase of the field-effect mobility of these TFTs is mainly attributed to the decreased interface and bulk tail-distributed traps, after an appropriate amount of H dopants is incorporated. In ZnO, hydrogen exclusively acts as a shallow donor during the plasma treatment, while the zinc vacancies Zn(Vac) cannot be passivated by the H dopants as no improvement of the subthreshold slope (SS) is observed in the hydrogenated ZnO TFT. The H interstitials (Hi) incorporated into In2O3 are stable in the + charge state at equilibrium, then change into the - charge state as the Fermi level energy EF gets closer to the bottom of the conduction band. Due to the H insertion into an oxygen vacancy VO, the VOH complex (acting as an acceptor) is formed in InGaZnO with increased H plasma treatment duration, leading to the degraded SS. This paper clarifies the H dopants' role and the different dominant defects inside the three types of TFTs, which may benefit systematic understanding and exploration of H dopant incorporation into InGaZnO, ZnO and In2O3 films for TFT improvement and optimization.

High-intensity end-of-life care among children, adolescents, and young adults with cancer who die in the hospital: A population-based study from the French national hospital database.

BACKGROUND: Efforts to improve the quality of end-of-life (EOL) care depend on better knowledge of the care that children, adolescents, and young adults with cancer receive, including high-intensity EOL (HI-EOL) care. The objective was to assess the rates of HI-EOL care in this population and to determine patient- and hospital-related predictors of HI-EOL from the French national hospital database. METHODS: This was a population-based, retrospective study of a cohort of patients aged 0 to 25 years at the time of death who died at hospital as a result of cancer in France between 2014 and 2016. The primary outcome was HI-EOL care, defined as the occurrence of ≥1 chemotherapy session <14 days from death, receiving care in an intensive care unit ≥1 time, >1 emergency room admission, and >1 hospitalization in an acute care unit in the last 30 days of life. RESULTS: The study included 1899 individuals from 345 hospitals; 61.4% experienced HI-EOL care. HI-EOL was increased with social disadvantage (adjusted odds ratio [AOR], 1.30; 95% confidence interval [CI], 1.03-1.65; P = .028), hematological malignancies (AOR, 2.09; 95% CI, 1.57-2.77; P < .001), complex chronic conditions (AOR, 1.60; 95% CI, 1.23-2.09; P = .001) and care delivered in a specialty center (AOR, 1.70; 95% CI, 1.22-2.36; P = .001). HI-EOL was reduced in cases of palliative care (AOR, 0.31; 95% CI, 0.24-0.41; P < .001). CONCLUSION: A majority of children, adolescents, and young adults experience HI-EOL care. Several features (eg, social disadvantage, cancer diagnosis, complex chronic conditions, and specialty center care) were associated with HI-EOL care. These findings should now be discussed with patients, families, and professionals to define the optimal EOL.

Pharmacodynamic Therapeutic Drug Monitoring for Cancer: Challenges, Advances, and Future Opportunities.

In the modern era of cancer treatment, with targeted agents superseding more traditional cytotoxic chemotherapeutics, it is becoming increasingly important to use stratified medicine approaches to ensure that patients receive the most appropriate drugs and treatment schedules. In this context, there is significant potential for the use of pharmacodynamic biomarkers to provide pharmacological information, which could be used in a therapeutic drug monitoring setting. This review focuses on discussing some of the challenges faced to date in translating preclinical pharmacodynamic biomarker approaches to a clinical setting. Recent advances in important areas including circulating biomarkers and pharmacokinetic/pharmacodynamic modeling approaches are discussed, and selected examples of anticancer drugs where there is existing evidence to potentially advance pharmacodynamic therapeutic drug monitoring approaches to deliver more effective treatment are discussed. Although we may not yet be in a position to systematically implement therapeutic drug monitoring approaches based on pharmacodynamic information in a cancer patient setting, such approaches are likely to become more commonplace in the coming years. Based on ever-increasing levels of pharmacodynamic information being generated on newer anticancer drugs, facilitated by increasingly advanced and accessible experimental approaches available to researchers to collect these data, we can now look forward optimistically to significant advances being made in this area.