Ab Initio Molecular Dynamics Simulations of Phosphocholine Interactions with a Calcium Oxalate Dihydrate (110) Surface.

We use ab initio modeling (CASTEP) to help elucidate the crystallization phenomena and chemistry behind kidney stone composition and formation. To explore the stone formation process, we have constructed a surface model of calcium oxalate dihydrate-the mineral most commonly found in patients with hypercalciuria and modeled stone growth, by simulating further calcium oxalate adsorption onto the surface (-7.446 eV, -0.065 eV/atom). Furthermore, urine analysis of kidney stone patients has previously revealed that their urine contains higher concentrations of phospholipids compared to healthy individuals. Therefore, to investigate the interactions between urinary macromolecules and the growing crystal surfaces at an atomic level, we have performed ab initio molecular dynamics simulations of phosphocholine adsorption on calcium oxalate surfaces. We have shown that the phosphocholine headgroups become entrapped within the growing crystal and the lowest energy structures (-18.008 eV, -0.0396 eV/atom) are those where the calcium oxalate dihydrate surfaces have become disrupted, with reorganization of their crystallographic structure. Urinary calculi (kidney stones) are a common ailment affecting around 10% of the world's population and resulting in nearly 90,000 finished consultant episodes (FCE) each year in the United Kingdom [Hospital Episode Statistics, Admitted Patient Care-England, 2011-12 NHS Digital, 2021-2022. https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/hospital-episode-statistics-admitted-patient-care-england-2011-12].

Cost Analysis of Avoiding Gastrostomy Tube in Robin Sequence Neonates that Undergo Mandibular Distraction.

OBJECTIVES/HYPOTHESIS: To evaluate costs associated with perioperative gastrostomy tube (G-tube) placement for neonates with Robin sequence (PRS) that undergo mandibular distraction osteogenesis (MDO). METHODS: Retrospective chart review was performed to examine the medical records of neonates with RS who received treatment at our institution between 2012 and 2021. Patients under 6 months of age that underwent MDO for RS were included. Billing records of hospital costs over a 2-year period were analyzed. RESULTS: The study included 26 total patients with 11 in the MDO-only group, 9 in G-tube after MDO group, and 6 in G-tube before MDO group. There was a significant difference (p < 0.001) in total hospital costs between groups with MDO-only group averaging $119,532 (SD ± $$ \pm $$ 33,503), the G-tube after MDO group averaging $245,315 (SD ± $$ \pm $$ 102,327), and G-tube before MDO group averaging $252,300 (SD ± $$ \pm $$ 84,990). Multiple linear regression was performed controlling for genetic syndrome and birth weight, which still showed a statistically significant difference in total cost between the MDO-only group and G-tube after MDO (p = 0.006), and between the MDO-only group and G-tube prior to MDO (p = 0.01). There was a significant difference in costs between all three groups for total inpatient/outpatient costs with MDO-only group averaging $78,502 (SD ± $$ \pm $$ 30,953), the G-tube after MDO group averaging $176,125 (SD ± $$ \pm $$ 84,315), and the G-tube prior to MDO group averaging $156,309 (SD ± $$ \pm $$ 95,746). CONCLUSIONS: MDO performed without perioperative G-tube placement may reduce charges by >$100,000. The associated improvement of dysphagia after MDO surgery and potential for avoiding a G-tube has tremendous downstream cost and social benefits for families. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Quality of Life and Psychosocial Outcomes Among Children With Cleft Differences.

Introduction Velopharyngeal insufficiency (VPI) and craniofacial differences can lead to diminished speech and swallowing function resulting in communication and social challenges throughout childhood. To monitor changes in patients' psychosocial health and velopharyngeal function, the Pediatric Symptom Checklist (PSC) and Velopharyngeal Insufficiency Effects on Life Outcomes (VELO) survey tools can be utilized. This study aimed to investigate the relationship between VPI quality-of-life outcomes and psychosocial disturbances through a comparative analysis of PSC and VELO parental surveys among children followed by a craniofacial team. Methods A retrospective chart review was completed using data from a single, multidisciplinary cleft and craniofacial team. Previously completed parental survey responses between 2010 and 2022 were collated and results were analyzed using a Spearman's rank correlation test (rs). Results There were 89 subjects who completed both surveys on the same day (n = 148 survey pairs (s)). Patients aged three to five years old (s = 88) had a mean VELO of 17.9 (0-65) and a mean PSC of 7.9 (0-27), while patients aged six to eight years old (s = 60) had a mean VELO of 16.6 (0-74) and a mean PSC of 12.0 (0-37). The strongest correlation observed for both age groups was between the total PSC and VELO Speech Limitations sub-scores (three to five years old: rs = 0.537, p < 0.001; six to eight years old: rs = 0.330, p = 0.010). Similarly, children in the six- to eight-year-old group with cleft lip and palate showed a correlation between the total PSC and VELO Speech Limitations (rs = 0.583, p < 0.001). Conclusion This study suggests a relationship between PSC and VELO scores among children ages three to eight years old with cleft differences and demonstrates that specific domains within the VELO questionnaire should be considered as being associated with a higher risk for psychosocial impairment. Specifically, higher VELO Speech Limitations sub-scores may portend a greater risk for poor psychosocial outcomes supporting the importance of early interventions in this group.

Characterization of dynamic changes in cardiac microstructure after reperfused ST-elevation myocardial infarction by biphasic diffusion tensor cardiovascular magnetic resonance.

BACKGROUND AND AIMS: Microstructural disturbances underlie dysfunctional contraction and adverse left ventricular (LV) remodelling after ST-elevation myocardial infarction (STEMI). Biphasic diffusion tensor cardiovascular magnetic resonance (DT-CMR) quantifies dynamic reorientation of sheetlets (E2A) from diastole to systole during myocardial thickening, and markers of tissue integrity [mean diffusivity (MD) and fractional anisotropy (FA)]. This study investigated whether microstructural alterations identified by biphasic DT-CMR: (i) enable contrast-free detection of acute myocardial infarction (MI); (ii) associate with severity of myocardial injury and contractile dysfunction; and (iii) predict adverse LV remodelling. METHODS: Biphasic DT-CMR was acquired 4 days (n = 70) and 4 months (n = 66) after reperfused STEMI and in healthy volunteers (HVOLs) (n = 22). Adverse LV remodelling was defined as an increase in LV end-diastolic volume ≥ 20% at 4 months. MD and FA maps were compared with late gadolinium enhancement images. RESULTS: Widespread microstructural disturbances were detected post-STEMI. In the acute MI zone, diastolic E2A was raised and systolic E2A reduced, resulting in reduced E2A mobility (all P < .001 vs. adjacent and remote zones and HVOLs). Acute global E2A mobility was the only independent predictor of adverse LV remodelling (odds ratio .77; 95% confidence interval .63-.94; P = .010). MD and FA maps had excellent sensitivity and specificity (all > 90%) and interobserver agreement for detecting MI presence and location. CONCLUSIONS: Biphasic DT-CMR identifies microstructural alterations in both diastole and systole after STEMI, enabling detection of MI presence and location as well as predicting adverse LV remodelling. DT-CMR has potential to provide a single contrast-free modality for MI detection and prognostication of patients after acute STEMI.

18F-FDG PET/CT biomarkers as predictors of long term outcomes and survival rates in patients with high risk malignant pulmonary masses/nodules treated with stereotactic ablative radiotherapy.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) is a standard treatment option for patients with malignant pulmonary masses (including primary and metastatic lesions) who are unfit for surgery or who are medically operable but refuse surgery. Flourine-18 flurodeoxyglucose positron emission tomography (18F-FDG PET) volumetric metabolic parameters, i.e., metabolic tumour volume (MTV) and total lesion glycolysis (TLG) play an important role in assessing the biological characteristics of some tumours and its role as potential prognostic factors has also been introduced. OBJECTIVES: The aim of this retrospective study is to assess the value of baseline metabolic volumetric parameters as prognostic imaging biomarkers in patients with pulmonary masses/nodules treated with SABR. METHODS: 70 patients were included in this retrospective study (39 male and 31 female, age range 47-91 years, mean 76 years). Standardized uptake value (SUVmax), SUVmean, MTV and TLG for all the patients were calculated on baseline 18F-FDG PET/CT. Patient outcome was divided into 3 categories free of disease, stable disease and disease progression. RESULTS: There was no significant statistical difference in the SUVmax and SUVmean in all the three categories. Mean SUVmax ranges from 7.13 to 8.08 with its highest value in the stable disease and lowest value in the progressive disease categories. Similarly, the average SUVmean was 4.9 in the free of disease category and 4.68 in the progressive disease category. MTV and TLG were low in the free of disease and the highest in progressive disease. MTV increased from 2.25 cm3 in free of disease category to 3.23 cm3 and 7.29 cm3 in stable disease and progressive disease, respectively. TLG has increased from 11.7 in the disease-free survival category to 18.77 and 40.39 in the stable and progressive disease, respectively. Patients with low MTV had longer overall survival (OS) than patients with high MTV (37 months versus 27 months, p value = 0. 0018). In addition, OS was longer in patients with low TLG (36 months versus 24 months, p value = 0.016). CONCLUSIONS: TLG and MTV are more useful than SUVmax and SUVmean for predicting outcome, OS and progression-free survival (PFS) in patients receiving SABR. The TLG and MTV measurement on 18F-FDG PET imaging may be routinely recommended in baseline 18F-FDG PET/CT prior to SABR.

G-tube placement in patients with robin sequence undergoing mandibular distraction osteogenesis: A multi-institutional review.

The goal of this study was to investigate the relationship between mandibular distraction osteogenesis (MDO) and rates of postoperative gastrostomy tube (G-tube) placement among patients with isolated and syndromic Robin sequence (RS). This study was a multi-institutional retrospective chart review of patients with RS who underwent MDO at one of three different pediatric tertiary medical centers. The primary aim of the study was to compare rates of G-tube placement following MDO among the three institutions. The primary outcome was analyzed using Fischer's exact test. The secondary aim of the study was to assess for other contributing factors to G-tube placement such as demographic differences, length of hospital stay, and age at MDO. Analysis of secondary outcomes was assessed using multiple logistic regression models. A total of 125 patients met the inclusion criteria, which required RS diagnosis, completion of MDO between 2004 and 2019, and adequate medical record availability. Sixty percent (n = 75) of subjects were categorized as isolated RS (iRS) and forty percent (n = 50) as syndromic RS (sRS). After MDO, 20% (n = 25) of all patients had G-tubes placed. Of the iRS group, 14.7% (n = 11) required a G-tube, while 28% (n = 14) of the sRS group required a G-tube. The post-operative G-tube rate was similar between institutions when considering all patients. When considering only those patients with iRS, the post-MDO G-tube rate at one center was significantly higher than the other two. Overall, most patients with RS did not require a G-tube after MDO, regardless of diagnosis. However, the significant differences in rates of G-tube placement among patients with iRS may indicate differing practice philosophies, surgical protocols, thresholds for G-tube placement, or regional influences between institutions.

AB036. Targeting glioblastoma de-novo purine metabolism to overcome chemoradiation resistance: an interim result of phase 0/1 clinical trial in newly diagnosed and recurrent glioblastoma.

BACKGROUND: Glioblastoma cells preferentially use de-novo purine synthesis pathway, whereas normal brain prefers salvage pathway. Mycophenolate mofetil (MMF), a commonly used oral immunosuppressant that inhibits inosine-5'-monophosphate dehydrogenase (IMPDH), a key enzyme in the de-novo purine pathway. Pre-clinical suggested MMF can improve radiation and temozolomide efficacy in glioblastoma which led to this phase 0/1 trial (NCT04477200) to assess MMF's tolerability with chemoradiation in glioblastoma, mycophenolic acid accumulation, and purine synthesis inhibition in tumor. METHODS: In the phase 0 study, eight recurrent glioblastoma patients received MMF at doses ranging 500-2,000 mg BID for 1-week before surgery. The tissues were analyzed using mass spectrometry for drug accumulation and purine synthesis inhibition. In the phase 1 study, adult patients were given MMF starting at 1,000 mg orally (PO) twice daily (BID), with the possible dose ranging 500-2,000 PO BID. Nineteen recurrent glioblastoma patients (target N=30) received MMF 1-week prior to and concurrently with re-irradiation (40.5 Gy). Thirty newly diagnosed glioblastoma patients received MMF 1-week prior to and concurrently with chemoradiation, followed by MMF 1-day before and during 5 days of each adjuvant temozolomide cycle. RESULTS: Both enhancing and non-enhancing tumors from phase 0 subjects yielded >1 µM active drug metabolite, and the guanosine triphosphate: inosine monophosphate ratio was decreased by 75% in enhancing tumors in MMF-treated patients compared to untreated controls (P=0.009), indicating effective target engagement and inhibition of purine synthesis. In the phase 1 study, no dose-limiting toxicities (DLTs) were observed at the interim analysis at MMF 1,000-1,500 mg BID combined with chemoradiation. At 2,000 mg BID, there was no DLT combined with temozolomide alone, however, there were four DLTs noted (hemiparesis, cognitive disturbance, fatigue, thrombocytopenia) when combined with radiotherapy and temozolomide together, though all were reversible. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSIONS: MMF with chemoradiation has been reasonably well tolerated and showed promising evidence of brain tumor target engagement and drug accumulation. This study led to a recommended phase 2 dose of MMF 1,500 mg BID and will provide a preliminary efficacy estimate for a randomized phase 2/3 trial through the Alliance for Clinical Trials in Oncology.

Diagnostic Accuracy of [18F]FDG PET/MRI in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Metaanalysis.

This study evaluates the diagnostic utility of PET/MRI for primary, locoregional, and nodal head and neck squamous cell carcinoma (HNSCC) through systematic review and metaanalysis. Methods: A systematic search was conducted using PubMed and Scopus to identify studies on the diagnostic accuracy of PET/MRI for HNSCC. The search included specific terms and excluded nonhybrid PET/MRI studies, and those with a sample size of fewer than 10 patients were excluded. Results: In total, 15 studies encompassing 638 patients were found addressing the diagnostic test accuracy for PET/MRI within the chosen subject domain. Squamous cell carcinoma of the nasopharynx was the most observed HNSCC subtype (n = 198). The metaanalysis included 12 studies, with pooled sensitivity and specificity values of 93% and 95% per patient for primary disease evaluation, 93% and 96% for locoregional evaluation, and 89% and 98% per lesion for nodal disease detection, respectively. An examination of a subset of studies comparing PET/MRI against PET/CT or MRI alone for evaluating nodal and locoregional HNSCC found that PET/MRI may offer slightly higher accuracy than other modalities. However, this difference was not statistically significant. Conclusion: PET/MRI has excellent potential for identifying primary, locoregional, and nodal HNSCC.

[89Zr]Zr-girentuximab for PET-CT imaging of clear-cell renal cell carcinoma: a prospective, open-label, multicentre, phase 3 trial.

BACKGROUND: With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89Zr-labelled monoclonal antibody ([89Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [89Zr]Zr-girentuximab PET-CT imaging for detection and characterisation of clear-cell renal cell carcinoma. METHODS: ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET-CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET-CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET-CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment. FINDINGS: Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5-89·6) and mean specificity was 87·0% (81·0-93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths. INTERPRETATION: Our results suggest that [89Zr]Zr-girentuximab PET-CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing. FUNDING: Telix Pharmaceuticals.

Deep learning method with integrated invertible wavelet scattering for improving the quality ofin vivocardiac DTI.

Objective.Respiratory motion, cardiac motion and inherently low signal-to-noise ratio (SNR) are major limitations ofin vivocardiac diffusion tensor imaging (DTI). We propose a novel enhancement method that uses unsupervised learning based invertible wavelet scattering (IWS) to improve the quality ofin vivocardiac DTI.Approach.Our method starts by extracting nearly transformation-invariant features from multiple cardiac diffusion-weighted (DW) image acquisitions using multi-scale wavelet scattering (WS). Then, the relationship between the WS coefficients and DW images is learned through a multi-scale encoder and a decoder network. Using the trained encoder, the deep features of WS coefficients of multiple DW image acquisitions are further extracted and then fused using an average rule. Finally, using the fused WS features and trained decoder, the enhanced DW images are derived.Main result.We evaluate the performance of the proposed method by comparing it with several methods on threein vivocardiac DTI datasets in terms of SNR, contrast to noise ratio (CNR), fractional anisotropy (FA), mean diffusivity (MD) and helix angle (HA). Comparing against the best comparison method, SNR/CNR of diastolic, gastric peristalsis influenced, and end-systolic DW images were improved by 1%/16%, 5%/6%, and 56%/30%, respectively. The approach also yielded consistent FA and MD values and more coherent helical fiber structures than the comparison methods used in this work.Significance.The ablation results verify that using the transformation-invariant and noise-robust wavelet scattering features enables us to effectively explore the useful information from the limited data, providing a potential mean to alleviate the dependence of the fusion results on the number of repeated acquisitions, which is beneficial for dealing with the issues of noise and residual motion simultaneously and therefore improving the quality ofinvivocardiac DTI. Code can be found inhttps://github.com/strawberry1996/WS-MCNN.

Recovery from social isolation requires dopamine in males, but not the autism-related gene nlg3 in either sex.

Social isolation causes profound changes in social behaviour in a variety of species. However, the genetic and molecular mechanisms modulating behavioural responses to social isolation and social recovery remain to be elucidated. Here, we quantified the behavioural response of vinegar flies to social isolation using two distinct protocols (social space preference and sociability, the spontaneous tendencies to form groups). We found that social isolation increased social space and reduced sociability. These effects of social isolation were reversible and could be reduced after 3 days of group housing. Flies with a loss of function of neuroligin3 (orthologue of autism-related neuroligin genes) with known increased social space in a socially enriched environment were still able to recover from social isolation. We also show that dopamine (DA) is needed for a response to social isolation and recovery in males but not in females. Furthermore, only in males, DA levels are reduced after isolation and are not recovered after group housing. Finally, in socially enriched flies mutant for neuroligin3, DA levels are reduced in males, but not in females. We propose a model to explain how DA and neuroligin3 are involved in the behavioural response to social isolation and its recovery in a dynamic and sex-specific manner.

Characterization of an Estrogen Receptor α-Selective 18 F-Estradiol PET Tracer.

Objective Conventional imaging of cancer with modalities such as computed tomography or magnetic resonance imaging provides little information about the underlying biology of the cancer and consequently little guidance for systemic treatment choices. Accurate identification of aggressive cancers or those that are likely to respond to specific treatment regimens would allow more precisely tailored treatments to be used. The expression of the estrogen receptor α subunit is associated with a more aggressive phenotype, with a greater propensity to metastasize. We aimed to characterize the binding properties of an 18 F-estradiol positron emission tomography (PET) tracer in its ability to bind to the α and ß forms of estrogen receptors in vitro and confirmed its binding to estrogen receptor α in vivo. Methods The 18 F-estradiol PET tracer was synthesized and its quality confirmed by high-performance liquid chromatography. Binding of the tracer was assessed in vitro by saturation and competitive binding studies to HEK293T cells transfected with estrogen receptor α ( ESR1 ) and/or estrogen receptor ß ( ESR2 ). Binding of the tracer to estrogen receptor α in vivo was assessed by imaging of uptake of the tracer into MCF7 xenografts in BALB/c nu/nu mice. Results The 18 F-estradiol PET tracer bound with high affinity (94 nM) to estrogen receptor α, with negligible binding to estrogen receptor ß. Uptake of the tracer was observed in MCF7 xenografts, which almost exclusively express estrogen receptor α. Conclusion 18 F-estradiol PET tracer binds in vitro with high specificity to the estrogen receptor α isoform, with minimal binding to estrogen receptor ß. This may help distinguish human cancers with biological dependence on estrogen receptor subtypes.

Radiolabeling and Preclinical Evaluation of Therapeutic Efficacy of 225Ac-ch806 in Glioblastoma and Colorectal Cancer Xenograft Models.

The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with 225Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: 225Ac-ch806 was prepared using different chelators, yielding [225Ac]Ac-macropa-tzPEG3Sq-ch806 and [225Ac]Ac-DOTA-dhPzPEG4-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of 225Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of 225Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [225Ac]Ac-macropa-tzPEG3Sq-ch806 surpassed [225Ac]Ac-DOTA-dhPzPEG4-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [225Ac]Ac-macropa-tzPEG3Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. 225Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. 225Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in 225Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all 225Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with 225Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, 225Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of 225Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.

The Role of Preoperative Imaging for Midline Congenital Upper Lip Sinus Tracts.

OBJECTIVE: To describe 3 cases of midline congenital upper lip sinus (MCULS) and review current literature to inform risk of intracranial involvement in the context of this rare congenital facial anomaly. MATERIALS AND METHODS: A limited case series with chart review is presented. A literature search was conducted to review proposed theories of the embryology of MCULS and to determine the relative frequency of cephalic extension. RESULTS: Including the 3 new cases presented herein, there have been 42 cases of MCULS described in the literature over the past 53 years. Thirty-nine cases (93%) underwent surgical excision, with 2 of these cases (4.7%) demonstrating cephalic extension of the fistula tract beyond the maxillary crest with termination at the anterior skull base. However, 95% (37/39) of surgically excised MCULS cases demonstrated a more limited depth of extension, with termination of the tract at or below the anterior nasal spine. CONCLUSIONS: The MCULS anomaly is rare, with fewer than 50 cases reported in the literature. Only 2 cases have been described with extension of the MCULS superior to the anterior nasal spine and into the nasal septum. It is the authors' opinion that preoperative neuroimaging is not routinely required for MCULS. However, if extension of the sinus tract beyond the anterior nasal spine is noted intraoperatively, the surgeon should consider aborting the case and obtaining appropriate neuroimaging.

Targeting Fn14 as a therapeutic target for cachexia reprograms the glycolytic pathway in tumour and brain in mice.

PURPOSE: Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia. METHODS: [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software. RESULTS: [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14. CONCLUSION: Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.

Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with 89Zr-labelled CI-8993.

BACKGROUND: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. METHODS: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. RESULTS: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. CONCLUSIONS: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials.

Regional differences in admissions and surgical management of pediatric nontuberculous mycobacterial cervicofacial lymphadenitis.

OBJECTIVES: This study aims to determine the overall incidence of medical and surgical admissions related to non-tuberculous mycobacterial cervicofacial lymphadenitis (NTMCL) and determine if rates vary by geographic region in the US. It also aims to assess if the relative frequency of varying treatment modalities for NTMCL differ among geographic regions. STUDY DESIGN: Population-based inpatient registry analysis. SETTING: Academic medical center. METHODS: The Kids' Inpatient Database (2016 and 2019) was used to determine NTMCL-related admissions and common head and neck procedures performed during these admissions were identified. Analysis was performed on regional differences in demographic factors and procedures performed during NTMCL-related admissions. RESULTS: There were 159 weighted admissions (1.31 per 100,000) for NTMCL in 2016 and 2019 in the US, with the Midwest having the highest proportion of NTML-related admissions (1.59:100,000). NTMCL-related admissions were 2.21 times as likely to be elective rather than non-elective in the Midwest when compared to all other geographic regions (p = 0.038). The Midwest was 2.83 times as likely to treat with surgery (p = 0.011), while the Northeast was negatively associated with performing procedures (OR 0.38; p = 0.026). In the Midwest, significantly more excisional surgeries were preformed when compared to other regions, with an OR of 2.98 (p = 0.003). CONCLUSION: The Midwest had the highest incidence of pediatric NTMCL-related admissions and was more likely to perform excisional surgery as primary NTMCL treatment. Regions that rarely see pediatric NTMCL have a more inconsistent approach to management.