Early Closure Research Articles

Early spontaneous closure of large arterial ducts in two term neonates with ebstein anomaly after failed attempts of transcatheter closure

Early spontaneous closure of large arterial ducts in two term neonates with ebstein anomaly after failed attempts of transcatheter closure

Plasma flows during the ablation stage of an over-massed pulsed-power-driven exploding planar wire array

We characterize the plasma flows generated during the ablation stage of an over-massed exploding planar wire array, fielded on the COBRA pulsed-power facility (1 MA peak current, 250 ns rise time). The planar wire array is designed to provide a driving magnetic field (80–100 T) and current per wire distribution (about 60 kA), similar to that in a 10 MA cylindrical exploding wire array fielded on the Z machine. Over-massing the arrays enables continuous plasma ablation over the duration of the experiment without implosion. The requirement to over-mass on the Z machine necessitates wires with diameters of 75–100μm, which are thicker than wires usually fielded on wire array experiments. To test ablation with thicker wires, we perform a parametric study by varying the initial wire diameter between 33 and 100 μm. The largest wire diameter (100 μm) array exhibits early closure of the cathode-wire gap, while the gap remains open over the duration of the experiment for wire diameters between 33 and 75 μm. Laser plasma interferometry and time-gated extreme-ultraviolet (XUV) imaging are used to probe the plasma flows ablating from the wires. The plasma flows from the wires converge to generate a pinch, which appears as a fast-moving (V≈100kms−1) column of increased plasma density (n¯e≈2×1018cm−3) and strong XUV emission. Finally, we compare the results with three-dimensional resistive-magnetohydrodynamic (MHD) simulations performed using the code GORGON, the results of which reproduce the dynamics of the experiment reasonably well.

Outcomes of curative laparoscopic sugery with diverting loop ileostomy in rectal cancer patients

Objective: To evaluate clinical, tests and early outcomes of curative laparoscopic sugery rectal cancer with diverting loop ileostomy and potential benifits and complications of diverting loop ileostomies after sugery rectal cancer. Materials and methods: Prospective study. From February 2020 to August 2022, there were 32 patients rectal cancer who underwent curative surgery with diverting loop ileostomies in Hue University Medical and Pharmacy Hospital and Hue Central hospital. Results: Men age was 54.7, male/female was 1.3. The most symptoms were abdominal pain and blood in stool, the rates was 68.8% and 59.4%, respectively. The rates of lower rectal cancer was 59.4%. The rates of EUS and MRI was 75% and 87.5%, respectively. The most pre- operative tumor stage was II, III with 90.6%. The most method surgery is laparoscopic low anterior resection (46.9%). The rate complicates in operative was 6.3%, post - operative was 18.9%. The incidence rates of anastomotic leakage was 6.2%. The recurrence rate was 6.2% and metastatic rates was 9.3%. The rate complications ileostomies was 12.5% include peristomal dermatitis and fluid and electrolyte imblances. The rate complications of ileostomy closure was 28.6% and there was no significant difference in postoperative complications between. Ileostomy closure before and after 8 weeks. Conclusions: The diverting loop Ileostomy is a safe procedure. A diverting stoma reduces the consequences of anastomotic leakage. Early closure of ileostomy is safe and can improve better quality of life for patiens. Key words: rectal cancer, Ileostomy.

Research Development on Management of Child-Friendly Schools (CFS) in Elementary School: A Bibliometric Analysis Using VOSviewer

The purpose of this study was to analyze the research trends development of management on child-friendly schools (CFS) management at the elementary school. The research method used is bibliometric analysis. Data was obtained from the Google Scholar database in the form of papers published in international journals from 2017-2022. Data processing was carried out in three stages, 1) data collection, 2) data selection and 3) data analysis using VOSviewer. The results showed that the trend of research development on management of child-friendly school was highest in 2013 with 162 publications. The results of the overlay analysis shown in yellow circles indicate research topics that are often used in recent research, namely young child, early childhood education, children, appropriate education, need, school closure, learning, pandemic, covid, parent and home. While topics that are rarely used are clinician, school climate, school closure, disability, anxiety, autism spectrum disorder, women. The results of this study illustrate that the research topic for management of child-friendly school can be developed towards the term model of friendly schools for women and disabilities, development of a child-friendly school climate, and friendly schools for children with special needs.

Application of Landfill Gas-Water Joint Regulation Technology in Tianjin Landfill

Landfills have long been widely used to dispose of Municipal Solid Waste (MSW). However, many landfills have faced early closure issues in recent years due to overload operations. Although in-situ aeration technology can quickly stabilize MSW, low oxygen utilization rates present a general problem that results in high energy-consuming and operating costs. This research aims to improve oxygen utilization efficiency by observing the dynamic respiratory index and the removal of contaminants. Three continuous reactors were constructed and designed with targeted aeration and re-circulation schemes for different landfill ages. The results show that a well-designed aerobic, semi-aerobic, and anaerobic reactor can fully degrade the organic components of MSW with different landfill ages, and the quantity of waste has been reduced by more than 60%. Additionally, it was disclosed that gas-water joint technology has a promotional effect on activating microorganisms.

A study of comparison between quality of life early closure of ileostomy and late closure of ileostomy

Background: In the developed countries, ileostomy is mainly constructed as a protective cover for distal colorectal or ileoanal pouch anastomosis, but in developing countries, it is still often made in emergency surgical settings where infective conditions such as enteric or tubercular perforations are common and patients present late in their course of illness which precludes primary closure. Aims and Objectives: The aim of the present study is to compare health-related quality of life at 3, 6, and 12 months comparing early versus late closure of a temporary ileostomy. Materials and Methods: The study was conducted on 50 patients, 25 patients undergoing for early stoma closure and 25 patients undergoing for late closure ileostomy each in Maharani Laxmi Bai Medical College, Jhansi, between January 2020 and June 2021. Results: The mean age of patient undergoing early closure is 36.16 and mean age of patient undergoing late closure is 40.36, out of which 80% were male patient and 20% patient were female. Using SF-36 questionnaire, out of 8 domains, quality of life of early closure of ileostomy is significantly better in respect of 3 domains and that is physical functioning – P=0.004. Mean±SD score for early stoma closure 80.6±22.495 for late closure 73.00±25.247. Social functioning P=0.05. Mean±SD score for early stoma closure, 74.00±4.243 late stoma closure 71.50 ±0.707. Role emotion P=0.04, Mean±SD score for early stoma closure 80.00±4.00 late closure 74.67±12.20. Conclusion: We concluded that quality of life in early closure of ileostomy is significantly better in respect of 3 domains (physical functioning, social functioning, and role emotion) out of 8 domains in SF-36 questionnaire than quality of life in late closure of ileostomy.

A Pilot Study Omitting Radiation in the Treatment of Children with Newly Diagnosed Wnt-Activated Medulloblastoma.

Treatment of wingless (WNT)-activated medulloblastoma (WNT+MB) with surgery, irradiation (XRT), and chemotherapy results in excellent outcomes. We studied the efficacy of therapy de-intensification by omitting XRT entirely in children with WNT+MB. Tumors were molecularly screened to confirm the diagnosis of WNT+MB. Eligible children were treated within 31 days following surgery with nine cycles of adjuvant chemotherapy per ACNS0331. No XRT was planned. The primary endpoint was the occurrence of relapse, progression, or death in the absence of XRT within the first two years after study enrollment. Four events in the first 10 evaluable patients would result in early study closure. Fourteen children were prescreened, and nine met the protocol definition of WNT+MB. Six of the nine eligible patients consented to protocol therapy, and five completed planned protocol therapy. The first two children enrolled relapsed shortly after therapy completion with local and leptomeningeal recurrences. The study was closed early due to safety concerns. Both children are surviving after XRT and additional chemotherapy. A third child relapsed at completion of therapy but died of progressive disease 35 months from diagnosis. Two children finished treatment but immediately received post-treatment XRT to guard against early relapse. The final child's treatment was aborted in favor of a high-dose therapy/stem cell rescue approach. Although OS at 5 years is 83%, no child received only planned protocol therapy, with all receiving eventual XRT and/or alternative therapy. Radiotherapy is required to effectively treat children with WNT-altered medulloblastoma. See related commentary by Gottardo and Gajjar, p. 4996.

What to do when hiccups are coming? A case report

Hiccup known as innocuous symptom and usually self-limiting within seconds or minutes. The process of hiccup related to involuntary movement, intermitent and repetitive contractions of diaphragm and lead to abrupt early closure of glottis. We report a case of 57-year-old man with 5 days chronic hiccup, following with coughing, nausea, vomiting and seizure. Patient was hospitalized 4 days and getting better after given antibiotic, proton pump inhibitor (PPI) therapy and symptomatic drug due to hiccup.

Meticulous and Early Understanding of Congenital Cranial Defects Can Save Lives.

Omitting the early closure of the cranial sutures in newly born children is not an uncommon practice. We describe the natural history of several unrelated children and adults from two unrelated families. These children were born with variable clinical manifestations: craniofacial asymmetry, ocular proptosis, floppiness, and progressive deceleration in cognitive development. None of these children underwent a cranial sutures assessment. False diagnoses of positional plagiocephaly, neonatal thyrotoxicosis, congenital muscular atrophy, and hydrocephalus were given to the parents. This sort of malpractice was the reason behind a sequence of devastating pathological events that occurred in the lifetime of these children and adults. This was a multigenerational study of two unrelated families. In total, we studied three children (aged 7-19 years) and three adults (aged 40-52 years) from two families. The children from the first family were referred to our departments because of pre-pubertal scoliosis, kyphoscoliosis, and early-onset osteoarthritis. Reading the clinical histories of these children signified apparent clinical misconceptions. For instance, craniofacial asymmetry was misinterpreted as positional plagiocephaly and treated by means of helmet molding therapy. Ocular proptosis was given the false diagnosis of neonatal thyrotoxicosis. Floppiness (hypotonia) was misdiagnosed as congenital muscular dystrophy. The index case from the second family showed progressive deceleration in his cognitive development, associated with signs of increased intracranial pressure. The only diagnosis was Dandy-Walker malformation. We documented every patient in accordance with the clinical and radiological phenotypic characterizations. The genotype characterization followed accordingly. All patients in family (I) manifested a phenotype consistent to a certain extent with the clinical phenotype of Shprintzen-Goldberg syndrome (SGS), though the intensity of spine deformities was greater than has been described in the literature. The second family showed a constellation of Marfanoid habitus, craniosynostosis, increased intracranial pressure, hydrocephalus, Dandy-Walker malformation, seizures, and intellectual disability. The overall clinical phenotype was consistent but not fully diagnostic of craniosynostosis-Dandy-Walker-malformation hydrocephalus syndrome. The early closure of the sutures was totally different from one patient to another, including the premature closure of the metopic, coronal, squamosal, and sagittal sutures. One patient from family (II) underwent the implementation of a shunt system at the age of 3 years, unfortunately passing over the pre-existing craniosynostosis. In addition to skeletal deformities, a history of seizures and severe intellectual disability was recorded. The proband underwent chromosomal karyotyping, the FISH test, and whole-exome sequencing. The purpose of this study was fivefold. Firstly, to gain a meticulous understanding in order to differentiate between positional plagiocephaly, hypotonia, and congenital exophthalmos and their connections to abnormal craniofacial contours was and still is our first and foremost concern. Secondly, we aimed to characterize craniosynostosis, seizures, intellectual disabilities, and hydrocephalus associated with Marfanoid habitus, which were clearly demonstrated in our patients. Thirdly, we aimed to address the imperative for interpretations of clinical and radiological phenotypes and relate these tools to etiological understanding, which is an essential basis for diagnosis in the majority of long-term pediatric admissions. Fourthly, we aimed to assess the impacts of the missed early closure by the pediatricians and pediatric neurologists, which added a heavy pathological burden on these patients and their families. Fifthly, we aimed to identify whether early and diligent recognition can assist in cranial vault remodeling via surgical intervention to halt premature cranial suture fusions and can possibly alter the devastating course and the complications of the synostosed sutures.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study

Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. No treatment-related deaths occurred. Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. F Hoffmann-La Roche.

Assessment of Risk Factors for Enteric Fistula and Intra-Abdominal Sepsis in Patients with Open Abdomen in Trauma: An Original Research.

In emergency surgeries, open abdomen or laparostomy, especially with perforated viscus, has been used primarily to prevent delayed ventral hernia, burst abdomen, and abdominal compartment syndrome. In the present study, the clinical and resuscitative factors that are linked with open abdomen morbidity are evaluated. A retrospective analysis was done for all the subjects who were admitted at the tertiary care center between May 2020 and May 2022 for the open abdomen surgeries. These patients were examined to see whether they needed more postoperative care than usual, including the need for resuscitative treatments and other critical clinical indicators. Patients were evaluated if they had any complications. The data that were collected were analysed for any variance using analysis of variance considering P <.05 as significant. A total of 100 subjects were analysed in this study. Forty nine patients had intra-abdominal sepsis of the 100 cases examined from historical case records and 1 had entero-cutaneous fistulas. These patients did not necessitate additional actions for intensive care unit care, resuscitation, an chest infection, extended hospital stay, or any disabilities compared to those who did not undergo laparotomy during the same period. In this group of patients with open abdomens, the immediate postoperative period was not linked to an increase in resuscitation efforts or a load on clinical staff. Once patients are stabilized, early definitive abdominal closure is advised to prevent problems associated to laparostomies. The quantity of initial fluid revival and the coagulation factors at the time of admission are not related to intra-abdominal sepsis and enteric fistula following laparostomy after significant abdominal injuries.

A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers

ObjectiveWee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases...

HIV policy legacies, pandemic preparedness and policy effort to address COVID-19.

That the world was unprepared for a major infectious disease outbreak is now readily apparent to all credible observers. However, some countries were more prepared than others and we have seen a variety of responses to COVID-19 emerge across nations. While recognizing that the sources of variation in country responses to COVID-19 are many and varied, in this study we seek to examine how policy legacies from national responses to HIV have influenced countries' responses to COVID-19. The aim of this study was to examine whether countries with a more conducive HIV policy environment were better prepared for COVID-19 and have therefore had more preemptive and rights-based responses. Using data from the Oxford Covid-19 Government Response Tracker, we develop measures of country effort to respond to COVID-19 including early containment and closure policies, prevention policies, economic policies, and health system policies. We combine this with data from the HIV Policy Lab and correlate overall and disaggregated country HIV Policy scores with COVID-19 Policy scores. We find that the COVID-19 Containment and Closure Measures Index was negatively correlated with supportive social policies related to HIV in the early stages of the pandemic, but the association did not persist as time went on. The COVID-19 Economic Support Measures had prolonged positive associations with supportive social policies related to HIV and negative association with clinical and treatment policies. Countries with stronger structural responses to HIV have been less inclined towards involuntary measures and more prepared for the social and economic elements of COVID-19 pandemic response.

Exploring Environmental Factors Associated with Child Wellbeing during COVID-19 in Australia and Germany

The COVID-19 pandemic has had a significant impact on the wellbeing of children and families globally. With extended lockdown periods, early childhood education and school closures, and remote learning, families experienced increased stress and anxiety, financial hardship, and disrupted routines. This paper aims to explore associations between children’s social-emotional wellbeing and environmental factors (including the burden of COVID-19 on the family, early learning experiences in the home and early childhood education, and parent wellbeing and mental health) during COVID-19 in Australia and Germany, two countries that experienced significant lockdown periods. Using a longitudinal online survey design, parents of young children (aged 1–6 years) in Australia (N = 66) and Germany (N = 53) completed surveys on their own wellbeing; their child’s wellbeing; the home learning environment, and their satisfaction with early childhood education and care at two time points in 2020 and 2021. The burden of COVID-19 mitigation measures on families’ everyday lives correlated with child wellbeing outcomes in both the Australian and German cohorts. Findings also provide evidence of potential protective factors of children’s social-emotional wellbeing during stressful events, such as the lockdowns experienced by families in Germany and Australia during the pandemic.

The biomechanics of chewing and suckling in the infant: A potential mechanism for physiologic metopic suture closure.

Craniosynostosis is a condition with neurologic and aesthetic sequelae requiring invasive surgery. Understanding its pathobiology requires familiarity with the processes underlying physiologic suture closure. Animal studies have shown that cyclical strain from chewing and suckling influences the closure of cranial vault sutures, especially the metopic, an important locus of craniosynostosis. However, there are no human data correlating strain patterns during chewing and suckling with the physiologically early closure pattern of the metopic suture. Furthermore, differences in craniofacial morphology make it challenging to directly extrapolate animal findings to humans. Eight finite-element analysis (FEA) models were built from craniofacial computer tomography (CT) scans at varying stages of metopic suture closure, including two with isolated non-syndromic metopic craniosynostosis. Muscle forces acting on the cranium during chewing and suckling were simulated using subject-specific jaw muscle cross-sectional areas. Chewing and suckling induced tension at the metopic and sagittal sutures, and compressed the coronal, lambdoid, and squamous sutures. Relative to other cranial vault sutures, the metopic suture experienced larger magnitudes of axial strain across the suture and a lower magnitude of shear strain. Strain across the metopic suture decreased during suture closure, but other sutures were unaffected. Strain patterns along the metopic suture mirrored the anterior to posterior sequence of closure: strain magnitudes were highest at the glabella and decreased posteriorly, with minima at the nasion and the anterior fontanelle. In models of physiologic suture closure, increased degree of metopic suture closure correlated with higher maximum principal strains across the frontal bone and mid-face, a strain regime not observed in models of severe metopic craniosynostosis. In summary, our work provides human evidence that bone strain patterns from chewing and suckling correlate with the physiologically early closure pattern of the metopic suture, and that deviations from physiologic strain regimes may contribute to clinically observed craniofacial dysmorphism.

Echocardiographic parameters predicting spontaneous closure of ductus arteriosus in preterm infants.

To evaluate the value of echocardiographic parameters in predicting early spontaneous closure of ductus arteriosus in premature infants. 222 premature infants admitted to the neonatal ward of our hospital were selected, and patent ductus arteriosus was detected by echocardiography 48 h after birth. On the 7th day, whether the ductus arteriosus was closed naturally in this cohort was observed. The infants whose ductus arteriosus were not closed were identified as the PDA group (n = 109), and the other infants were included in the control group (n = 113). The echocardiographic parameters of the two groups of premature infants at 48 h after birth were single-factor statistically and Pearson correlation analyzed, and the parameters with statistically significant differences in single-factor analyzed were selected for multivariate logistic stepwise regression analysis. The ductus arteriosus shunt velocity and the pressure difference between the descending aorta and the pulmonary artery (ΔPs) in the PDA group were lower than those in the control group (P < 0.05). The pulmonary artery pressure (PASP) in the PDA group was higher than that in the control group (P < 0.05). According to the multivariate logistic stepwise regression analysis, only the maximum shunt velocity of ductus arteriosus was correlated with early spontaneous closure of ductus arteriosus in 48 h first echocardiographic parameters (P = 0.049). The receiver operating characteristic (ROC) curve indicates the optimal critical point of echocardiographic ductus arteriosus shunt velocity in premature infants 48 h after birth was 1.165 m/s. Echocardiographic parameters are of great value in predicting the early spontaneous closure of ductus arteriosus in premature infants. In particular, the ductus arteriosus shunt velocity is correlated with the early spontaneous closure of ductus arteriosus.

THE OUTCOMES OF EARLY VERSUS LATE ILEOSTOMY CLOSURE

The best time to reverse an ileostomy is still largely unclear, however, there is growing evidence that delaying ileostomy closure may raise the risk of complications after the operation. The study's goal was to compare the outcomes of early ileostomy closure with late ileostomy closure after surgery. A prospective study was done to evaluate the results of patients who went through early ileostomy closure ( within 6 weeks) to those who had late ileostomy closure (&gt;6 weeks). All patients above 18 years old who had stoma subsequent surgery of bowel both in emergency and elective settings. In this prospective observational study, 60 patients were randomly assigned into two groups by the SNOSE method for closure of ileostomy at different intervals of time: early ileostomy closure (&lt;6 weeks), n=30, and late ileostomy closure (&gt;6 weeks), n=30. During three months, all patients were monitored for surgical complications. Early closure was performed on 30 of the 60 trial participants, with the mean time for closure in the early group being 4 weeks and 7.2 weeks in the late group. The postoperative problems and hospital stay did not vary considerably. In conclusion, based on our experience in both ileostomy closure groups at varied time intervals, the early group within 6 weeks did not increase post-operative problems and morbidity. The systematic assignment of patients with temporary loop stomas to early closure may improve patient well-being. Individualization of the usual approach of reserving patients for long-term stoma care is required, and further study is needed to compare disease-specific closure success.

Analysis of systemic immune changes in patients with advanced cancer treated with immunotoxin LMB-100 and tofacitinib.

e15017 Background: LMB-100 recombinant immunotoxin delivers a modified Pseudomonas exotoxin A payload to mesothelin-expressing tumors. Almost all patients receiving LMB-100 develop anti-drug antibodies (ADAs) after 2 cycles/ 6 doses of the drug, therefore reducing peak serum drug concentrations to near the lower limit of detection. Tofacitinib is an oral JAK inhibitor that had been shown to prevent ADA formation in pre-clinical studies. Apart from assessing safety and tolerability, this trial sought to determine whether co-administration of tofacitinib with LMB-100 delays the formation of neutralizing ADAs so more patients could achieve the peak LMB-100 concentration of &gt; 600 ng/mL during treatment cycle 2. Correlative data examining circulating immune cell subsets and cytokines pre- and on-treatment are presented here. Methods: Patients with pancreatic adenocarcinoma (n = 13) and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles (21 days) with LMB-100 given on days 4, 6, and 8 at 2 dose levels (100 and 140 mcg/kg), accompanied by oral tofacitinib for the first 10 days of the cycle (10 mg BID). Adverse events were assessed as per CTCAE 5.0. Analysis of the cytokine data was performed using a Wilcoxon signed-rank test. Results: DLTs of grade 3 cardiac toxicity (n = 1) and grade 4 hyponatremia (n = 1) were seen at the 140mcg/kg dose of LMB-100. One patient treated at 100 mcg/kg developed a grade 4 pericardial effusion, resulting in early closure of the study for safety. The two patients who experienced cardiac toxicity had lower baseline CD4+ cells and increased CD19+ cells post-LMB-100 treatment. Four out of 8 evaluable patients achieved LMB-100 concentration above the threshold during cycle 2, and 2 out of 3 did so during cycle 3. Analysis of peripheral blood cytokine levels showed sustained increases in TNF-α, IL-8, and IL-10 following LMB-100 administration through to the start of cycle 2. Percentage of Tregs increased through cycle 1 in patients who developed drug-neutralizing ADAs and was significantly higher than in patients with LMB-100 levels above threshold at the start of cycle 2. Conclusions: Combination of LMB-100 with tofacitinib is not safe. An insufficient number of patients was treated to conclusively assess the ability of tofacitinib to stop or delay ADA formation. Increases in circulating Tregs were observed in patients with early neutralizing ADA formation. Clinical trial information: NCT04034238 .

Phase II study of pembrolizumab plus mifepristone in patients with advanced HER2-negative breast cancer.

1095 Background: Metastatic breast cancer is incurable, and novel treatment (tx) strategies are needed. Single agent immune checkpoint inhibitor (ICI) tx has limited efficacy; combination approaches may yield better results. Multiple mechanisms of glucocorticoid-induced immunosuppression have been proposed, including the suppression of the cytotoxic Th1 cytokine response via glucocorticoid receptor (GR) activation. We hypothesize that pretreatment with a GR antagonist shifts the cytotoxic immune response toward Th1, thus enhancing response to ICIs. We present the safety and efficacy of the combination of pembrolizumab and mifepristone in advanced HER2-negative breast cancer. Methods: This (NCT03225547) was a phase II non-randomized study of pembrolizumab and mifepristone in patients (pts) with advanced HER2-negative breast cancer. Pts with prior ICI tx were excluded. Pts received mifepristone 300mg daily and pembrolizumab 200mg every 3 weeks; mifepristone was started 7 days prior to pembrolizumab. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety and tolerability. Results: 18 patients were enrolled from March 2018 – November 2020; 10 patients with TNBC (cohort 1) and 8 patients with HR+ BC (cohort 2). Mean age was 53 yrs (range 33-74) and 33% of patients were self-reported Black. In cohort 1, 50% of patients were tx naive in this advanced setting, and 90% of patients had &lt; 2 prior lines of tx. In cohort 2, 25% of patients had not received prior chemo in the metastatic setting. The overall ORR was 6%. One pt with TNBC had a complete response (CR). She received 36 cycles of tx; tx was discontinued due to mucositis and rash, and she remains in CR at &gt;48 mos from start of tx. No patients in cohort 2 had a partial or complete response. The most common treatment-related adverse events were rash (61%), thyroid abnormality (17%), and pruritis (17%). 45% of patients experienced a grade 3 or 4 adverse event; all except one (hypokalemia) were due to rash. Rash was described as maculopapular dermatitis. The DCR at 18 weeks was 33.3% in the overall population; it was 44.4% in cohort 1 and 16.7% in cohort 2. Overall median PFS was 1.9 months [95% CI 1.8 – 3.6]. Overall median OS was 12.9 months [95% CI 5.8 – 23.0]. Conclusions: While this regimen demonstrated efficacy in a small subset of patients, including one pt with long-term CR, given the non-randomized design, we cannot determine if mifepristone enhanced the efficacy of ICI. In addition, a higher than anticipated rate of skin toxicity, possibly related to mifepristone enhancing the activity of ICI, was observed in the study, leading to early closure. While the benefit/risk analysis of this combination does not support further evaluation, additional investigation of alternative chemotherapy-free, immunomodulatory strategies is warranted. Clinical trial information: NCT03225547 .

Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE): Trial of Fentanyl versus Fentanyl + Dexmedetomidine for Maintenance of Sedation

Abstract Objectives This article observes the mean daily dose of fentanyl required for adequate sedation in critically ill, mechanically ventilated children randomized to receive dexmedetomidine or placebo. Methods We conducted Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multicenter, double-blind, randomized, placebo-controlled, dose-escalating trial. We enrolled children aged 35 weeks postmenstrual to 17 years (inclusive) admitted across 13 pediatric multidisciplinary and cardiac intensive care units. Adequate sedation was based on a State Behavioral Score and Richmond Agitation-Sedation Scale of –1 or lower. Only the first two dexmedetomidine dosing cohorts opened for enrollment, due to early trial closure during the coronavirus 2019 pandemic. Thirty children were randomized over 13 months and included in the analyses. Results Demographic and baseline characteristics were not different between dexmedetomidine and placebo cohorts. Similarly, mean daily fentanyl use was not different, using an unadjusted mixed regression model that considered treatment, time, and a treatment-by-time interaction. Adverse events and safety events of special interest were not different between cohorts. Conclusion The DOSE trial revealed that dexmedetomidine added to fentanyl does not impact safety and may not spare fentanyl use in critically ill children, although the trial did not meet its recruitment goals, due to early closure during the coronavirus 2019 pandemic. More rigorous inpatient pediatric trials like DOSE that study critically ill, mechanically ventilated children are needed. Despite the many obstacles faced, the DOSE trial presents challenges from which the greater research community can learn and use to optimize future therapeutic trials in children.