Neurosurgical Management of Patients with Alpha-Gal Syndrome.

Alpha-gal syndrome (AGS) is an immunoglobulin E-mediated hypersensitivity to galatcose-alpha-1,3-galactose (alpha-gal), a carbohydrate compound present in nonprimate mammalian products. Initial exposure to alpha-gal most often occurs through a tick bite, most commonly the lone star tick in the United States. Repeated exposure to alpha-gal may elicit severe allergic reactions, including anaphylaxis. The allergy restricts dietary intake and may significantly impact perioperative risk, as many medications, anesthetics, and intraoperative surgical products utilize bovine or porcine-derived agents, including those containing magnesium stearate, glycerol, and gelatin. Here, we review the perineurosurgical care of two individuals with AGS and highlight pertinent clinical practices and perioperative management of these patients.

PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer.

Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

Treatment of Locally Recurrent Rectal Cancer: A Review.

ABSTRACT: Up to 10% of patients with locally advanced rectal cancer will experience locoregional recurrence. In the setting of prior surgery and often radiation and chemotherapy, these represent uniquely challenging cases. When feasible, surgical resection offers the best chance for oncologic control yet risks significant morbidity. Studies have consistently indicated that a negative surgical resection margin is the strongest predictor of oncologic outcomes. Chemoradiation is often recommended to increase the chance of an R0 resection, and in cases of close/positive margins, intraoperative radiation/brachytherapy can be utilized. In patients who are not surgical candidates, radiation can provide symptomatic relief. Ongoing phase III trials are aiming to address questions regarding the role of reirradiation and induction multiagent chemotherapy regimens in this population.

MAGPIE: An interactive tool for visualizing and analyzing protein-ligand interactions.

Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutic design and aid in studying molecular evolution. Here we present Mapping Areas of Genetic Parsimony In Epitopes (MAGPIE), a publicly available software package for simultaneously visualizing and analyzing thousands of interactions between a single protein or small molecule ligand (the "target") and all of its protein binding partners ("binders"). MAGPIE generates an interactive three-dimensional visualization from a set of protein complex structures that share the target ligand, as well as sequence logo-style amino acid frequency graphs that show all the amino acids from the set of protein binders that interact with user-defined target ligand positions or chemical groups. MAGPIE highlights all the salt bridge and hydrogen bond interactions made by the target in the visualization and as separate amino acid frequency graphs. Finally, MAGPIE collates the most common target-binder interactions as a list of "hotspots," which can be used to analyze trends or guide the de novo design of protein binders. As an example of the utility of the program, we used MAGPIE to probe how different antibody fragments bind a viral antigen; how a common metabolite binds diverse protein partners; and how two ligands bind orthologs of a well-conserved glycolytic enzyme for a detailed understanding of evolutionarily conserved interactions involved in its activation and inhibition. MAGPIE is implemented in Python 3 and freely available at https://github.com/glasgowlab/MAGPIE, along with sample datasets, usage examples, and helper scripts to prepare input structures.

Endoscopic Supraorbital Translaminar Approach.

Surgical selection for third ventricle tumors demands meticulous planning, given the complex anatomic milieu. Traditional open microsurgical approaches may be limited in their access to certain tumors, prompting the exploration of alternative techniques. The endoscopic supraorbital translaminar approach (ESOTLA) has emerged as a promising alternative for managing these tumors. By combining a minimally invasive keyhole approach with endoscopic visualization, the ESOTLA provides enhanced illumination and a wider angle of view within the third ventricle. This unique advantage allows for improved access to retrochiasmatic tumors and reduces the need for frontal lobe and optic chiasm retraction required of microscopic techniques, decreasing the risk of neurocognitive and visual deficits. Complications related to the ESOTLA are rare and primarily pertain to cosmetic issues and potential compromise of the hypothalamus or optic apparatus, which can be minimized through careful subarachnoid dissection. This chapter offers a comprehensive description of the technical aspects of the ESOTLA, providing insights into its application, advantages, and potential limitations. Additionally, a case description highlights the successful surgical extirpation of an intraventricular papillary craniopharyngioma via the ESOTLA followed by targeted therapy. To better illustrate the stepwise dissection through this novel approach, a series of cadaveric and intraoperative photographs are included.

Comparison of endoscopic multiport approaches to the petrous apex: contralateral transmaxillary versus contralateral medial transorbital corridor.

OBJECTIVE: Accessing the petrous apex (PA) via an endoscopic endonasal approach (EEA) is challenging due to its posterior and lateral anatomical relationship with the paraclival carotid artery. Typically, the EEA requires the mobilization or compression of the vessel and the use of angled-lens endoscopes and instruments. A sublabial contralateral transmaxillary (CTM) corridor has been used to overcome these challenges. Still, it requires extensive osteo-meatal disruption and drilling of the medial pterygoid process, which risks the vidian nerve and increases nasal morbidity. Furthermore, the CTM corridor positions the endoscope in the same horizontal plane as the instruments passing through the nostrils, leading to fencing. The authors propose a novel minimally invasive route to the PA, the precaruncular contralateral medial transorbital (cMTO) corridor, to address these issues. This anatomical study compares the EEA+CTM and EEA+cMTO corridors in accessing the PA. METHODS: The authors dissected 14 fresh, preinjected cadaveric specimens (28 sides) using neuronavigation to complete EEA, cMTO, and CTM on each side. In addition to qualitative analysis, they measured and compared the working distance between the entry point (nose, orbit, maxilla) and the petrosal process of the sphenoid bone (PPSB), superomedial PA, and foramen lacerum (FL); angle of attack (AoA); area of surgical freedom; endoscope-instrument fencing angle; and visual angle for each approach. RESULTS: The cMTO corridor provided the shortest working distance to the petroclival region (PA = 67.4 ± 4.47 mm, PPSB = 67.57 ± 4.33 mm, and FL = 66.30 ± 4.77 mm) compared to the CTM (PA = 75.85 ± 3.63 mm, PPSB = 76 ± 3.96 mm, and FL = 74.52 ± 4.26 mm) and to the EEA (PA = 85.16 ± 3.16 mm, PPSB = 84.55 ± 3.02 mm, and FL = 83.42 ± 3.21 mm, p < 0.001). Both CTM and cMTO corridors had a similar visual angle to the PA (20.72° ± 2.16° and 21.63° ± 1.84°, respectively), offering a similar but significantly better visualization than EEA alone (44.71° ± 3.24°, p < 0.001). The cMTO corridor provided better instrument maneuverability than the CTM, as evidenced by a significantly greater fencing angle (30.9° ± 4.9°) than with the CTM (21.7° ± 4.02°, p < 0.001). The vertical AoAs for the EEA, cMTO, and CTM corridors were 9.79° ± 1.75°, 10.65° ± 0.82°, and 9.82° ± 1.43°, respectively (p = 0.009), whereas in the horizontal plane, these were 9.29° ± 1.51°, 9.10° ± 0.73°, and 10.49° ± 1.43° (p < 0.001), respectively. Both the CTM and cMTO corridors offered similar areas of surgical freedom (678.06 ± 99.5 mm2 and 673.59 ± 104.8 mm2, p = 0.986), but they were more significant than that provided by the EEA 487.29 ± 112.9 mm2 (p < 0.001). CONCLUSIONS: The EEA+cMTO multiport technique may be a better alternative than the EEA+CTM multiport approach for targeting the petroclival region. However, clinical validation is required to confirm these laboratory findings.

Phosphine versus Carbene Metal Interactions: Bond Energies.

A variety of different ground-state structures of carbene and phosphine groups 1 and 2 cationic, group 11 cationic, and group 10 neutral complexes were studied using density functional theory (DFT) and correlated molecular orbital theory (CCSD(T)) methods. Geometries of complexes with phosphines were studied and compared to available experimental data. Among the three analyzed phosphine ligands, PH3, PMe3, and PPh3, PH3 was found to have noticeably smaller ligand binding energies (LBEs, ΔH298 K). PPh3 has the greatest LBEs with group 2 dications. The difference in LBEs for PMe3 and PPh3 in complexes with group 1 monocations and transition-metal (TM) complexes was significantly less pronounced. The stability and reactivity of phosphine complexes were analyzed and compared with those of previously studied N-heterocyclic carbenes (NHC). PH3 has smaller LBEs compared to NHC carbenes. The lower LBEs correlate with the hardness for M(11)+ complexes and correlate with both the hardness and ionic radii for the M(1)+ and M(2)2+ complexes. The presence of additional PH3 substituents on the metal center makes the LBE smaller compared to their unsubstituted or less substituted analogs. The presence of NH3 in a structure causes a smaller effect on binding, and, except for carbene-PtNH3, an increase in LBE was observed. Composite-correlated molecular orbital theory (G3MP2) was used to predict the LBE of various Lewis acidic ligands with PH3 and NHCs to contrast their binding behavior. Binding either phosphine or carbene to metal diamine complexes caused ligand exchange and transfer of NH3 to an outer coordination sphere.

Intricacies of Human-AI Interaction in Dynamic Decision-Making for Precision Oncology: A Case Study in Response-Adaptive Radiotherapy.

Background: Adaptive treatment strategies that can dynamically react to individual cancer progression can provide effective personalized care. Longitudinal multi-omics information, paired with an artificially intelligent clinical decision support system (AI-CDSS) can assist clinicians in determining optimal therapeutic options and treatment adaptations. However, AI-CDSS is not perfectly accurate, as such, clinicians' over/under reliance on AI may lead to unintended consequences, ultimately failing to develop optimal strategies. To investigate such collaborative decision-making process, we conducted a Human-AI interaction case study on response-adaptive radiotherapy (RT). Methods: We designed and conducted a two-phase study for two disease sites and two treatment modalities-adaptive RT for non-small cell lung cancer (NSCLC) and adaptive stereotactic body RT for hepatocellular carcinoma (HCC)-in which clinicians were asked to consider mid-treatment modification of the dose per fraction for a number of retrospective cancer patients without AI-support (Unassisted Phase) and with AI-assistance (AI-assisted Phase). The AI-CDSS graphically presented trade-offs in tumor control and the likelihood of toxicity to organs at risk, provided an optimal recommendation, and associated model uncertainties. In addition, we asked for clinicians' decision confidence level and trust level in individual AI recommendations and encouraged them to provide written remarks. We enrolled 13 evaluators (radiation oncology physicians and residents) from two medical institutions located in two different states, out of which, 4 evaluators volunteered in both NSCLC and HCC studies, resulting in a total of 17 completed evaluations (9 NSCLC, and 8 HCC). To limit the evaluation time to under an hour, we selected 8 treated patients for NSCLC and 9 for HCC, resulting in a total of 144 sets of evaluations (72 from NSCLC and 72 from HCC). Evaluation for each patient consisted of 8 required inputs and 2 optional remarks, resulting in up to a total of 1440 data points. Results: AI-assistance did not homogeneously influence all experts and clinical decisions. From NSCLC cohort, 41 (57%) decisions and from HCC cohort, 34 (47%) decisions were adjusted after AI assistance. Two evaluations (12%) from the NSCLC cohort had zero decision adjustments, while the remaining 15 (88%) evaluations resulted in at least two decision adjustments. Decision adjustment level positively correlated with dissimilarity in decision-making with AI [NSCLC: ρ = 0.53 ( p < 0.001); HCC: ρ = 0.60 ( p < 0.001)] indicating that evaluators adjusted their decision closer towards AI recommendation. Agreement with AI-recommendation positively correlated with AI Trust Level [NSCLC: ρ = 0.59 ( p < 0.001); HCC: ρ = 0.7 ( p < 0.001)] indicating that evaluators followed AI's recommendation if they agreed with that recommendation. The correlation between decision confidence changes and decision adjustment level showed an opposite trend [NSCLC: ρ = -0.24 ( p = 0.045), HCC: ρ = 0.28 ( p = 0.017)] reflecting the difference in behavior due to underlying differences in disease type and treatment modality. Decision confidence positively correlated with the closeness of decisions to the standard of care (NSCLC: 2 Gy/fx; HCC: 10 Gy/fx) indicating that evaluators were generally more confident in prescribing dose fractionations more similar to those used in standard clinical practice. Inter-evaluator agreement increased with AI-assistance indicating that AI-assistance can decrease inter-physician variability. The majority of decisions were adjusted to achieve higher tumor control in NSCLC and lower normal tissue complications in HCC. Analysis of evaluators' remarks indicated concerns for organs at risk and RT outcome estimates as important decision-making factors. Conclusions: Human-AI interaction depends on the complex interrelationship between expert's prior knowledge and preferences, patient's state, disease site, treatment modality, model transparency, and AI's learned behavior and biases. The collaborative decision-making process can be summarized as follows: (i) some clinicians may not believe in an AI system, completely disregarding its recommendation, (ii) some clinicians may believe in the AI system but will critically analyze its recommendations on a case-by-case basis; (iii) when a clinician finds that the AI recommendation indicates the possibility for better outcomes they will adjust their decisions accordingly; and (iv) When a clinician finds that the AI recommendation indicate a worse possible outcome they will disregard it and seek their own alternative approach.

Sexual Activity in Adults with Pediatric-Onset Spinal Cord Injury: Injury, Demographic, and Lifestyle Factors.

Background: Sexual development is a complex process of understanding oneself as a sexual being. Youth with spinal cord injury (SCI) navigate the typical phases of sexual development along with the physical and psychological sequelae of an SCI. As youth with SCI progress from adolescence to emerging adulthood, sexual activity-physical intimacy and sexual intercourse-is an important milestone. Objectives: The aims of the study were to (1) describe frequency of physical intimacy among adults with pediatric-onset SCI and (2) identify injury, demographic, and lifestyle factors that predict frequency of physical intimacy. Methods: Adults with pediatric-onset SCI who were former patients within a North American pediatric hospital system (N = 277) completed a structured telephone interview that included medical and sociodemographic information and standardized measures of psychological functioning. Participants rated physical intimacy and sexual intercourse frequency on a 5-point Likert scale, with a response of monthly, weekly, or daily classified as regular frequency and never or yearly as irregular frequency. Bivariate and multivariate analyses were conducted with physical intimacy frequency as the primary outcome. Results: Of the participants, 55% engaged in physical intimacy and 49% engaged in sexual intercourse with regular frequency. In logistic regression analyses, living independently of parents, being married, and higher perceived social integration increased likelihood of regular frequency of physical intimacy. Injury severity and secondary medical complications were not significant independent predictors of frequency of physical intimacy. Conclusion: Half of adults with pediatric-onset SCI engage in regular physical intimacy; this is below the estimates for the general population. Psychosocial factors are stronger contributors to physical intimacy frequency than SCI-related factors. Health care providers and researchers should focus on barriers to social integration and development of social relationships as factors that influence physical intimacy in this population.

Iterative methods for Navier-Stokes inverse problems.

Even when the partial differential equation underlying a physical process can be evolved forward in time, the retrospective (backward in time) inverse problem often has its own challenges and applications. Direct adjoint looping (DAL) is the defacto approach for solving retrospective inverse problems, but it has not been applied to deterministic retrospective Navier-Stokes inverse problems in 2D or 3D. In this paper, we demonstrate that DAL is ill-suited for solving retrospective 2D Navier-Stokes inverse problems. Alongside DAL, we study two other iterative methods: simple backward integration (SBI) and the quasireversible method (QRM). As far as we know, our iterative SBI approach is novel, while iterative QRM has previously been used. Using these three iterative methods, we solve two retrospective inverse problems: 1D Korteweg-de Vries-Burgers (decaying nonlinear wave) and 2D Navier-Stokes (unstratified Kelvin-Helmholtz vortex). In both cases, SBI and QRM reproduce the target final states more accurately and in fewer iterations than DAL. We attribute this performance gap to additional terms present in SBI and QRM's respective backward integrations which are absent in DAL.

Immunologic Factors Associated with Differential Response to Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer.

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.

Multi-color dual wavelength vat photopolymerization 3D printing via spatially controlled acidity.

Dual wavelength vat photopolymerization (DW-VP) has emerged as a powerful approach to create multimaterial objects. However, only a limited range of properties have been showcased. In this work, we report the 3D printing (3DP) of multi-color objects from a single resin vat using DW-VP. This was accomplished by concurrently curing resin with visible light and modulating local resin color with 365-nm ultraviolet (UV) light. The key advance was to use a photoacid generator (PAG) in combination with pH responsive dyes in the 3DP resins. The specific color is dictated by the extent of reaction, or local acidity in our case, and controlled by the light dosage and pattern of UV light applied. Multi-color object formation was implemented in two-step processes involving first 3DP to set the object structure, followed by UV exposure, as well as single processes that leveraged DW-VP to create a broad range of vibrant colors and patterns.