Targeting the EGFR pathway in chemotherapy-resistant triple-negative breast cancer - a phase II study.

PURPOSE: Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance and inhibition of the EGFR pathway sensitizes TNBC to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175). PATIENTS AND METHODS: Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after 4 cycles of AC. were eligible for this study and received panitumumab (2.5 mg/kg IV, Q1 week x 13), paclitaxel (80mg/m2 IV Q1 week x 12), and carboplatin (AUC=4 IV, Q3 weeks x 4) as the second phase of NAT. A two-stage Gehan-type design was employed to detect an improvement in the pCR/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole exome sequencing was performed on diagnostic tumor biospecimens, where available. RESULTS: From 11/3/2016 through 8/3/2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. CONCLUSIONS: This study met its primary endpoint (pCR/RCB-I=30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of neoadjuvant therapy in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial.

Conductive Polypropylene Additive Manufacturing Feedstock: Application to Aqueous Electroanalysis and Unlocking Nonaqueous Electrochemistry and Electrosynthesis.

Additive manufacturing electrochemistry is an ever-expanding field; however, it is limited to aqueous environments due to the conductive filaments currently available. Herein, the production of a conductive poly(propylene) filament, which unlocks the door to organic electrochemistry and electrosynthesis, is reported. A filament with 40 wt % carbon black possessed enhanced thermal stability, excellent low-temperature flexibility, and high conductivity. The filament produced highly reproducible additive manufactured electrodes that were electrochemically characterized, showing a k0 of 2.00 ± 0.04 × 10-3 cm s-1. This material was then applied to three separate electrochemical applications. First, the electroanalytical sensing of colchicine within environmental waters, where a limit of detection of 10 nM was achieved before being applied to tap, bottled, and river water. Second, the electrodes were stable in organic solvents for 100 cyclic voltammograms and 15 days. Finally, these were applied toward an electrosynthetic reaction of chlorpromazine, where the electrodes were stable for 24-h experiments, outperforming a glassy carbon electrode, and were able to be reused while maintaining a good electrochemical performance. This material can revolutionize the field of additive manufacturing electrochemistry and expand research into a variety of new fields.

Insight into Predictors of Cytoreduction Score Following Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy for Gastric Peritoneal Carcinomatosis Improves Patient Selection and Prognostic Outcomes.

BACKGROUND: Peritoneal metastases due to gastric adenocarcinoma (GCPM) carry a dismal prognosis. A promising treatment strategy is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), but clear eligibility criteria for GCPM are lacking. We sought to identify factors associated with overall survival (OS) following CRS-HIPEC for GCPM to help optimize patient selection and clinical outcomes. PATIENTS AND METHODS: In this single-center retrospective cohort study, we examined CRS-HIPEC outcomes for patients with GCPM between 2001 and 2021. After analyzing patient demographic, clinicopathologic, and perioperative variables, we applied multivariable Cox hazard models to assess factors associated with OS. We then assessed associations between baseline predictors and prognostically important variables using multivariable logistic regression. RESULTS: We analyzed 55 patients with GCPM who underwent CRS-HIPEC. Median age was 54 years and 42% were female. Median peritoneal carcinomatosis index (PCI) was 8, and 75% of patients achieved a cytoreduction completeness score (CC score) of 0. Median progression-free survival (PFS) was 6.9 months, and median OS was 14.1 months. On adjusted analysis, a CC score > 0 (HR 2.3, p = 0.02) was significantly associated with worse OS. A peritoneal carcinomatosis index greater than 13 (OR 52.6, p = 0.001) and fewer lymph nodes (especially < 18) resected with the primary tumor (OR 0.86, p = 0.042) in the metachronous setting were significantly associated with incomplete macroscopic cytoreduction (CC score > 0). CONCLUSIONS: We demonstrated that PCI > 13 and primary lymph nodes harvested < 18 in metachronous tumors are associated with CC score > 0, which in turn portends a worse OS. Although these results warrant prospective validation, they provide insight into improved selection of patients with GCPM for CRS-HIPEC.

Uterine mesenchymal tumours harboring the KAT6B/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles.

Uterine mesenchymal tumours harboring KAT6B/A::KANSL1 gene fusions typically exhibit histological and immunophenotypic overlap with endometrial stromal and smooth muscle tumours. To date it remains uncertain whether such neoplasms should be regarded as variants of smooth muscle or endometrial stromal neoplasm, or if they constitute a distinct tumour type. In this study we investigated DNA methylation patterns and copy number variations (CNVs) in a series of uterine tumours harboring KAT6B/A::KANSL1 gene fusions in comparison to other mesenchymal neoplasms of the gynecological tract. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a distinct cluster for 8/13 KAT6B/A::KANSL1 tumours (herein referred to as core cluster). The other 5 tumours (herein referred to as outliers) did not assign to the core cluster but clustered near various other tumour types. CNV analysis did not identify significant alterations in the core cluster. In contrast, various alterations, including deletions at the CDKN2A/B and NF1 loci were identified in the outlier group. Analysis of the DNA methylation clusters in relation to histological features revealed that while tumours in the core KAT6B/A::KANSL1 cluster were histologically bland, outlier tumours frequently exhibited "high-grade" histologic features in the form of significant nuclear atypia, increased mitotic activity and necrosis. Three of the five patients with outlier tumours died from their disease while clinical follow-up in the remaining two patients was limited (less than 12 months). In comparison, none of the 7 out of 8 patients with tumors in the core KAT6B/A::KANSL1 sarcoma cluster, where follow-up was available, died from disease. Furthermore, only 1 out of 7 patients recurred (mean follow-up of 30 months). In conclusion, KAT6B/A::KANSL1 uterine sarcoma is a molecularly unique type of uterine tumour that should be recognized as a distinct entity. These tumors typically exhibit low-grade histologic features but are occasionally morphologically high-grade; the latter have a DNA methylation profile different from the typical low-grade neoplasms and may be associated with aggressive behaviour.

Influence of flake density and starch retrogradation on in vitro gas production kinetics, digestibility, and ruminal fermentation characteristics of steam-flaked corn.

Previous research has demonstrated that decreasing starch availability of steam-flaked corn by increasing flake density or increasing the degree of starch retrogradation influences in vitro gas production kinetics. However, it is unclear if increasing flake density or the degree of starch retrogradation influences end-products of in vitro ruminal fermentation (methane, volatile fatty acids, ammonia). The objective of this experiment was to evaluate the effects of increasing flake density and the degree of starch retrogradation on in vitro gas production kinetics, digestibility, and ruminal fermentation characteristics of steam-flaked corn. Three ruminally-cannulated steers were fed a high-concentrate diet and sampled for ruminal digesta for an in vitro fermentation experiment with a 5×2 factorial arrangement of treatments. Steam-flaked corn was produced to flake densities of 257, 296, 335, 373, and 412 g/L by adjusting the rolls of a steam-flaker. Samples were stored for 3 d at either 23°C to produce fresh steam-flaked corn or at 55°C in heat-sealed foil bags to produce retrograded steam-flaked corn. In vitro fermentation vessels were incubated for 24 h and then assessed for fermentation parameters including dry matter digestibility, volatile fatty acid concentrations, and total gas and methane production. Increasing the degree of starch retrogradation decreased (P < 0.01) the rate of gas production across all flake densities of steam-flaked corn but did not decrease the extent of gas production. In vitro methane production, dry matter digestibility, and microbial biomass concentration were not influenced by increasing flake density or starch retrogradation. Increasing the degree of starch retrogradation decreased (P = 0.03) the molar propionate proportion and increased (P < 0.06) the molar proportions of butyrate, isobutyrate, and isovalerate and the acetate:propionate ratio. Enzymatic starch availability of steam-flaked corn was positively correlated with mean propionate proportion (r2 = 0.93) and negatively correlated with the mean butyrate proportion (r2 = 0.89). Results from the current study demonstrate that increasing the degree of starch retrogradation of steam-flaked corn decreased the rate of in vitro gas production and altered volatile fatty acid profiles in the ruminal fermentation media.

Machine Learning, Deep Learning, Artificial Intelligence and Aesthetic Plastic Surgery: A Qualitative Systematic Review.

PURPOSE: This systematic review aims to assess the use of machine learning, deep learning, and artificial intelligence in aesthetic plastic surgery. METHODS: This qualitative systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. To analyze quality risk-of-bias assessment of all included articles, we used the ROBINS-I tool for non-randomized studies. We searched for studies with the following MeSH terms: Machine Learning OR Deep Learning OR Artificial intelligence AND Plastic surgery on MEDLINE/PubMed, EMBASE, and Cochrane Library, from inception until July 2024 without any filter applied. RESULTS: A total of 2,148 studies were screened and 41 were fully reviewed. We conducted article extraction, screening, and full text review using the rayyan tool. Eighteen studies were ultimately included in this review, describing the use of machine learning, deep learning and artificial intelligence in aesthetic plastic surgery. All studies were published from 2019 to 2024. Articles varied regarding the population studied, type of machine learning (ML), Deep Learning Model (DLM), Artificial Intelligence (AI) used, and aesthetic plastic surgery type. Of the eighteen studies, we included the following aesthetic plastic surgeries: augmentation mastopexy, breast augmentation, reduction mammoplasty, rhinoplasty, facial rejuvenation surgery, including facelift surgery; blepharoplasty, and body contouring. Image-based with AI, ML, and DLMs algorithms were used in these studies to improve human decision-making and identified factors associated with postoperative complications. CONCLUSION: AI, ML, and DL algorithms offer immense potential to transform the aesthetic plastic surgery field. By meticulously analyzing patient data, these technologies may, in the future, help optimize treatment plans, predict potential complications, and more clearly elucidate patient concerns, improving their ability to make informed decisions. The drawback, as with preoperative surgical simulation, is that patients may see an AI-generated image that is to their liking, but impossible to achieve; great care is needed when using such tools in order to not create unrealistic expectations. Ultimately, the old plastic surgery adage of ''under-promise and over-deliver'' will continue to hold true, at least for the foreseeable future. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Study registration A review protocol for this systematic review was registered at PROSPERO CRD42024567461.

Brown Adipose Tissue Mimicking Head and Neck Cancer on PET Scan in a Patient on GLP-1 Drug.

To report a case of a patient undergoing GLP-1 receptor agonist therapy in which increased FDG uptake in brown adipose tissue (BAT) mimicked metastatic head and neck cancer on PET/CT imaging. A 61-year-old female with Class III obesity presented with a right-sided neck mass after significant weight loss following the use of the GLP-1 receptor agonist, Semaglutide. PET/CT revealed FDG uptake in the right level II lymph node and extensive BAT uptake throughout the neck and mediastinum, complicating the diagnosis. Increased FDG uptake in the cervical and supraclavicular BAT regions led to diagnostic confusion, mimicking diffuse regional metastasis. Careful interpretation of PET/CT imaging, with fusion of anatomical and functional data, was essential to differentiate hypermetabolic BAT from malignant disease. Increased BAT FDG uptake, particularly in patients using GLP-1 receptor agonists, can complicate the evaluation of head and neck cancer. Awareness of this interaction is critical to avoid misdiagnosis and overtreatment. Laryngoscope, 2024.

α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson's disease.

BACKGROUND: Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. METHODS: aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. RESULTS: In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. CONCLUSIONS: Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and Polygenic Risk Scores to inform Colorectal Cancer screening.

INTRODUCTION: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize Colorectal Cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening to standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of "no CRC", CRC stages (A-D) and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared to SOC. The incremental cost-effectiveness ratio (ICER) was $124,415 per quality-adjusted life-year (QALY); screening had a 69% probability of being cost-effective using a willingness to pay threshold of $150,000/QALY. Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared to 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

A Global Experience of Donation after Circulatory Death for Pediatric Lung Transplantation.

OBJECTIVE: Donation after circulatory death (DCD) lung transplantation has increased, but there is limited data in children. We sought to characterize the international experience of pediatric DCD lung transplant (LT) in comparison to donation after brain death (DBD) to address extreme donor organ shortages in children needing LT. METHODS: Using the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry, 1453 children (<18yo) LT recipients from January 2004 to June 2018 were identified: 34 (3%) were DCD and 1419 (97%) were DBD recipients. Post-transplant outcomes were compared between groups. Propensity score method was used to derive matched cohorts and were compared between groups. RESULTS: DCD and DBD recipients were of similar age, with cystic fibrosis being the most frequent indication for LT in both groups (64.5% vs. 57.5%, respectively). Kaplan-Meier analysis demonstrated similar survival between DCD and DBD cohorts, whereas propensity score-matched recipients also identified similar post-transplant survival in both groups (P=0.098). Secondary analysis found that DCD LT recipients had a longer post-transplant length of hospital stay (unmatched cohorts: 36.5d vs. 20d, p=0.022; matched cohort: 26d vs. 19d, p=0.016), and shorter time to acute cellular rejection (ACR) (unmatched cohorts: 248d vs. 560d, p=0.039; matched cohorts: 248d vs. 1650d,p=0.059). CONCLUSIONS: Due to DCD being a key contributor to the increasing number of lung transplants being performed worldwide, the results of this analysis support this organ donation approach in children requiring LT, which would increase access to donor organs. The identification of a potential shorter time to ACR needs further exploration as more DCD pediatric LTs are performed.

Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis.

In murine models of visceral leishmaniasis (VL), parasitization of resident Kupffer cells (resKCs) is responsible for early growth of Leishmania infantum in the liver, which leads to granuloma formation and eventual parasite control. We employed the chronic VL model, and revealed an open niche established by KCs death and their migration outside of the sinusoids, resulting in their gradual replacement by monocyte-derived KCs (moKCs). While early granulomas were composed of resKCs, late granulomas were found outside of the sinusoids and contained resKC-derived macrophages, and monocyte-derived macrophages (momacs). ResKCs and moKCs within the sinusoids were identified as homeostatic/regulatory cells, while resKC-derived macrophages and momacs within late granulomas were pro-inflammatory. Despite the infection being largely confined to the resKC-derived macrophages, in the absence of monocyte recruitment, parasite control was strongly compromised. Macrophage heterogeneity, involving migration and reprogramming of resKCs, along with recruitment of monocyte-derived cells, is a hallmark of granuloma maturation and hepatic immunity in VL.

Multi-parametric Photoacoustic Imaging Combined with Acoustic Radiation Force Impulse Imaging for Applications in Tissue Engineering.

Tissue engineering is a dynamic field focusing on the creation of advanced scaffolds for tissue and organ regeneration. These scaffolds are customized to their specific applications and are often designed to be complex, large structures to mimic tissues and organs. This study addresses the critical challenge of effectively characterizing these thick, optically opaque scaffolds that traditional imaging methods fail to fully image due to their optical limitations. We introduce a novel multi-modal imaging approach combining ultrasound, photoacoustic, and acoustic radiation force impulse imaging. This combination leverages its acoustic-based detection to overcome the limitations posed by optical imaging techniques. Ultrasound imaging is employed to monitor the scaffold structure, photoacoustic imaging is employed to monitor cell proliferation, and acoustic radiation force impulse imaging is employed to evaluate the homogeneity of scaffold stiffness. We applied this integrated imaging system to analyze melanoma cell growth within silk fibroin protein scaffolds with varying pore sizes and therefore stiffness over different cell incubation periods. Among various materials, silk fibroin was chosen for its unique combination of features including biocompatibility, tunable mechanical properties, and structural porosity which supports extensive cell proliferation. The results provide a detailed mesoscale view of the scaffolds' internal structure, including cell penetration depth and biomechanical properties. Our findings demonstrate that the developed multimodal imaging technique offers comprehensive insights into the physical and biological dynamics of tissue-engineered scaffolds. As the field of tissue engineering continues to advance, the importance of non-ionizing and non-invasive imaging systems becomes increasingly evident, and by facilitating a deeper understanding and better characterization of scaffold architectures, such imaging systems are pivotal in driving the success of future tissue-engineering solutions.

Electrical stimulation to improve meat quality: Factors at interplay, underlying biochemical mechanisms and a second look into the molecular pathways using proteomics.

Ensuring consistent beef eating quality is paramount for meeting consumer demands and sustaining the meat industry. Electrical stimulation (ES) is a post-slaughter intervention used to accelerate post-mortem glycolysis, to avoid cold shortening, to control the tenderization rate of meat through sophisticated physical, chemical and biochemical mechanisms including proteolysis, to improve beef tenderness and to achieve normal pHu that might lead to positive impact on color. This review comprehensively examines the multifaceted effects of ES on beef quality, encompassing factors and settings influencing its efficacy and the underlying biochemical mechanisms revealed using traditional biochemistry methods. It then delves into the molecular pathways modulated by ES, as unveiled by muscle proteomics, aiming to provide a second look and an unprecedented understanding of the underlying biochemical mechanisms through an integrative proteomics analysis of low-voltage ES (LVES) proteomics studies. The proteins changing as a result of ES were gathered in a compendium of 67 proteins, from which 14 were commonly identified across studies. In-depth bioinformatics of this compendium allowed a comprehensive overview of the molecular signatures and interacting biochemical pathways behind electrically stimulated beef muscles. The proteins belong to interconnected molecular pathways including the ATP metabolic process and glycolysis, muscle structure and contraction, heat shock proteins, oxidative stress, proteolysis and apoptosis. Understanding the intricate interplay of molecular pathways behind ES could improve the efficiency of beef production, ensuring consistent meat quality and meeting consumer expectations. The integrative analysis approach performed in this study holds promise for the meat industry's sustainability and competitiveness.

Updating the no-history method in intraocular lens power calculation after myopic laser vision correction.

PURPOSE: To describe the Shammas-Cooke formula, an updated no-history (NH) formula for IOL calculation in eyes with prior myopic laser vision correction (M-LVC), and to compare the results with the Shammas PL, Haigis-L, and Barrett True-K NH formulas. SETTING: Bascom Palmer Eye Institute (BPEI), The Lennar Foundation Medical Center, University of Miami, Miami, Florida; Dean A. McGee Eye Institute (DMEI), University of Oklahoma, Oklahoma City, Oklahoma; and private practice, Lynwood, California, and St Joseph, Michigan. DESIGN: Retrospective observational study. METHODS: We analyzed 2 large series of cataractous eyes with prior M-LVC. The training set (BPEI series of 330 eyes) was used to derive the new corneal power conversion equation to be used in the new Shammas-Cooke formula and the testing set (165 eyes of 165 patients in the DMEI series) to compare the updated formula with 3 other M-LVC NH formulas on the ASCRS calculator: Shammas PL, Haigis-L, and Barrett True-K NH. RESULTS: Mean prediction error was 0.09 ± 0.56 diopters (D), -0.44 ± 0.61 D, -0.47 ± 0.59 D, and -0.18 ± 0.56 D and the mean absolute error was 0.43 D, 0.60 D, 0.61 D, and 0.45 D for the Shammas-Cooke, Shammas PL, Haigis-L, and Barrett True-K NH, respectively. The percentage of eyes within ±0.50 D was 66.7% vs 47.9%, 48.5%, and 65.5%, respectively. CONCLUSIONS: The Shammas-Cooke formula performed better than the Shammas PL and Haigis-L (P < .001 for both) and as well as the Barrett True-K NH formula (P = .923).

Primary Repair of Complete Quadriceps Tendon Rupture with Extensor Mechanism Deficit.

Background: Whereas partial quadriceps tendon ruptures may be treated nonoperatively if the extensor mechanism remains functional, complete ruptures require primary operative repair to achieve optimal functional results1,2. The 2 most common techniques are the use of transosseous tunnels and the use of suture anchors. The goal of these procedures is to reconstruct and restore mobility of the extensor mechanism of the leg. Description: The patient is positioned supine with the injured leg exposed. A midline incision to the knee is made over the quadriceps tendon defect, exposing the distal quadriceps and proximal patella. Irrigation is utilized to evacuate the residual hematoma, and the distal quadriceps and proximal patella are debrided of degenerative tissue. When utilizing transosseous tunnels, a nonabsorbable suture is passed full-thickness through the medial or lateral half of the quadriceps tendon in a locked, running pattern (i.e., Krackow). A second nonabsorbable suture is passed full-thickness through the other half of the tendon. There should then be 4 loose strands at the distal quadriceps. The anatomic insertion of the quadriceps tendon is roughened with a sharp curet to expose fresh cancellous bone. Three parallel bone tunnels are created along the longitudinal axis of the patella. The knee is placed in full extension, with a bump under the heel in order to provide slight recurvatum at the knee and to allow for a properly tensioned repair. In pairs, the free ends of the sutures are passed through the tunnels. The sutures are tensioned and tied together in pairs at the distal aspect of the patella. Alternatively, when utilizing suture anchors, Arthrex FiberTape is passed full-thickness through the medial or lateral half of the quadriceps tendon in a Krackow pattern. A second FiberTape is passed full-thickness through the other half of the tendon. There should then be 4 loose tails at the distal quadriceps. The 2 tails of the medial FiberTape are placed into a knotless Arthrex SwiveLock anchor; this step is repeated for the 2 lateral tails. The anatomic insertion of the quadriceps tendon is roughened to expose fresh cancellous bone. With use of a 3.5-mm drill, create 2 parallel drill holes along the longitudinal axis of the patella, with sufficient depth to bury the SwiveLock anchor. Unlike in the transosseous tunnel technique, these drill holes do not run the length of the patella. The holes are then tapped. Following irrigation, the anchors are tensioned into the bone tunnels, and extra tape is cut flush to the bone. For both techniques, additional tears in the medial and lateral retinacula are repaired if present. Alternatives: Alternatives include nonoperative treatment with use of a hinged knee brace; operative treatment with use of simple sutures; and augmentation with use of wire reinforcement, cancellous screws, the Scuderi technique, the Codivilla technique, tensor fasciae latae reinforcement, and/or MERSILENE tape (Ethicon). Rationale: Primary operative repair of quadriceps tendon ruptures is a well-documented, successful procedure with biomechanical, clinical, and patient-reported data to support its use3-7. However, literature comparing the 2 most common surgical techniques remains controversial. Transosseous tunnel repair is the most common technique utilized to repair quadriceps tendon ruptures, but suture anchors have become increasingly popular in the past several years1,4. Most studies have reported no significant difference in biomechanical, clinical, and patient-reported outcome measures between these 2 techniques3,4,8-10. Decreased operative time and a smaller incision have been suggested as advantages of suture anchors4,9. However, this method incurs a higher average cost of surgery and risks a more complex revision in the event of deep infection9,10. Simple suture repair is a less commonly utilized technique and is now reserved for midsubstance tendon repairs. Nonoperative treatment of complete quadriceps tendon rupture is exceedingly rare and not recommended because of the profound functional consequences. Relative indications for nonoperative treatment include a patient who is unfit for surgery, is not ambulatory at baseline, or retains full extensor mechanism function. Nonoperative treatment is typically reserved for partial quadriceps ruptures and typically involves early immobilization with a hinged knee brace. Expected Outcomes: Primary repair of quadriceps tendon ruptures, utilizing either the transosseous tunnel or suture anchor technique, yields excellent outcomes. Following surgical treatment, patients have near-full recovery in range of motion, with studies reporting a <5° deficit compared with the contralateral, uninjured limb3,4,10,11. The vast majority of patients (>90%) return to pre-injury levels of function and work3,4,7,11. The majority of patients also report satisfactory results, as assessed with use of patient-reported outcome measures3,4,10. The most commonly reported complications are knee stiffness and quadriceps muscle atrophy, which can both be treated with proper rehabilitation. Even in the event of these complications, however, patients can maintain adequate knee function2,3. More severe complications are rare (<3%) and include deep venous thrombosis and/or pulmonary embolism, superficial and/or deep infection, and tendon rerupture2-4,10-12. Delayed operative treatment is associated with worse outcomes and increased complication rates1,3,4,10,11. Important Tips: When performing the Krackow stitch, be sure to tension and remove all slack before performing another tissue pass.Surgical repair should be performed as soon as possible from the time of injury in order to minimize risks and to achieve optimal surgical outcomes.If there is concern that the primary construct would be unstable, it can be augmented with wire reinforcement, cancellous screws, the Scuderi technique, the Codivilla technique, tensor fasciae latae reinforcement, and/or MERSILENE tape.Identify and repair patellar retinaculum tears, which are common concomitant injuries in the setting of complete quadriceps rupture. Acronyms and Abbreviations: MRI = magnetic resonance imaging.

Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab.

Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.

Cytokine-mediated CAR T therapy resistance in AML.

Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123+ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5-0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07-0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).

The "Doorstop Pocket" In Thioredoxin Reductases─An Unexpected Druggable Regulator of the Catalytic Machinery.

Pyridine nucleotide-disulfide oxidoreductases are underexplored as drug targets, and thioredoxin reductases (TrxRs) stand out as compelling pharmacological targets. Selective TrxR inhibition is challenging primarily due to the reliance on covalent inhibition strategies. Recent studies identified a regulatory and druggable pocket in Schistosoma mansoni thioredoxin glutathione reductase (TGR), a TrxR-like enzyme, and an established drug target for schistosomiasis. This site is termed the "doorstop pocket" because compounds that bind there impede the movement of an aromatic side-chain necessary for the entry and exit of NADPH and NADP+ during enzymatic turnover. This discovery spearheaded the development of new TGR inhibitors with efficacies surpassing those of current schistosomiasis treatment. Targeting the "doorstop pocket" is a promising strategy, as the pocket is present in all members of the pyridine nucleotide-disulfide oxidoreductase family, opening new avenues for exploring therapeutic approaches in diseases where the importance of these enzymes is established, including cancer and inflammatory and infectious diseases.