Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.

T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.

Reconstructing Failure: Assessing Surgical and Patient Reported Outcomes Following Loss of Initial Breast Reconstruction.

BACKGROUND: Breast reconstruction failure, defined as the removal of a prosthetic device or flap without immediate replacement, can be traumatic for patients. We aim to describe the progression of patients who experience tissue expander (TE), implant, or autologous breast reconstructive failure and assess the patient reported outcomes (PROs) among patients who undergo additional reconstruction. METHOD: Patients undergoing TE, implant, or autologous breast reconstruction between 2017 and 2022 were included, and patients with reconstructive failures were identified. Outcomes of interests included (1) receipt of additional reconstruction and (2) BREAST-Q scores 1-year after reconstructive failure. We also performed a propensity-matched analysis between patients who undergo secondary reconstruction and patients who had an uncomplicated reconstruction. RESULTS: 4,258 TE, 4,420 implant, and 1,545 autologous breast reconstruction patients were included. Of patients who experienced reconstructive failures, 49.5% of TE, 4.8% of implant, and 53.8% of autologous patients underwent secondary reconstruction. Age, psychiatric diagnosis, chemotherapy, radiation, and mastectomy type were associated with increased likelihood of secondary reconstruction. Between patients with and without additional reconstruction, higher Psychosocial Well-being trended towards the former cohort (61 [Interquartile Range: 56, 80] vs 50 [46, 65], p=0.085). Propensity-matched analysis demonstrated comparable PROs at 1-year after definite reconstruction. CONCLUSION: Less than half of reconstructive failure patients undergo an additional reconstruction. Patients with secondary reconstruction may have improved Psychosocial Well-being than those who do not and comparable PROs to those who had uncomplicated initial reconstruction. Surgeons should counsel patients with reconstructive failures that although traumatizing, secondary reconstruction may be beneficial.

Clinicogenetic characterization of cerebrotendinous xanthomatosis in Brazil.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

Parkinsonism Following Chimeric Antigen Receptor T Cell Therapy.

This case report describes a 67-year-old woman who had received adoptive immunotherapy with chimeric antigen receptor T cells for multiple myeloma and was experiencing parkinsonism-like symptoms.

Predicting Postoperative Satisfaction with Breasts: How Important is the Preoperative BREAST-Q Score?

BACKGROUND: The role that preoperative Satisfaction with Breast plays in a patient's postoperative course after postmastectomy breast reconstruction (PMBR) is not understood. The aim of this study is to understand the impact of the preoperative score on postoperative outcome as an independent variable. METHODS: We examined patients who underwent PMBR between 2017 and 2021 and who completed the BREAST-Q Satisfaction with Breasts at 1 year postoperatively. Two multiple linear regression models (Model 1 with the preoperative Satisfaction with Breasts score and Model 2 without the preoperative score), likelihood ratio tests, simple t-statistics, and sample patient dataset to predict the 1 year score were performed. Multiple imputation was used to account for missing preoperative scores. RESULTS: Overall, 2324 patients were included. Model 1 showed that the preoperative score is significantly associated with the postoperative score (ß = 0.09, 95% confidence interval 0.04-0.14; p < 0.001). Comparing Model 1 and Model 2 demonstrated that including preoperative Satisfaction with Breasts in a regression significantly improves model fit (test statistic = 10.04; p = 0.0021). Using the absolute value of the t-statistics as a measure of variable importance in linear regression, the importance of the preoperative score was quantified as 3.39-more important than neoadjuvant radiation, mastectomy weight, body mass index, bilateral prophylactic mastectomy, and race, but less than adjuvant radiation, reconstruction type, and psychiatric diagnoses. CONCLUSION: Preoperative Satisfaction with Breasts scores are an important independent predictor of postoperative satisfaction after PMBR. Just as vital sign and work-up are carefully documented before surgery, preoperative scores should be collected to pre-emptively gauge patients' satisfaction and optimize postoperative outcomes.

Trends and Early Complications in Direct-to-Implant Breast Reconstruction: An Updated Analysis of the ACS-NSQIP Database.

Background: Rates of direct-to-implant (DTI) breast reconstruction, in which breast implants are placed at the time of mastectomy, have been consistently rising. Advances in surgical adjuncts and technology, such as acellular dermal matrices (ADM), have made DTI reconstruction safer and more reliable. However, few studies have characterized early (30-day) postoperative complications following DTI. The aim of this study was to obtain a current understanding of early postoperative outcomes following DTI breast reconstruction. Methods: Using data from the American College of Surgeons-National Surgical Quality Improvement Program, we analyzed complications for female patients who underwent DTI reconstruction from 2017 to 2019, as well as trends in DTI reconstruction from data on mastectomy and DTI reconstruction from 2010 to 2019. We grouped complications into major surgical (including return to the operating room) or medical complications. Statistical analysis was performed using Fischer's exact test for categorical variables, Student's t-test for continuous variables, and logistic regression. Results: DTI breast reconstruction rates have increased since 2010. Among our 2017-2019 cohort of 4204 patients, the early major surgical complication rate was approximately 10% (422 patients) and the major medical complication rate was 0.83% (35 patients). Regression modeling identified body mass index, smoking status, hypertension, bleeding disorders, and intraoperative blood transfusion as having a relationship with surgical complications (P < .001). Conclusions: Despite increased use of ADM and indocyanine green angiography, compared to prior studies, early postoperative complications have remained stable. Further studies are needed to assess long-term complications and patient-reported outcomes in DTI breast reconstruction.

Historique: Le taux de reconstructions mammaires immédiates, c'est-à-dire que les implants mammaires sont installés au moment de la mastectomie, augmentent régulièrement. Grâce aux progrès des adjuvants chirurgicaux et de la technologie, tels que les matrices dermiques acellulaires (MDA), la reconstruction mammaire immédiate est désormais plus sécuritaire et plus fiable. Cependant, peu d'études ont caractérisé les complications précoces suivant une telle intervention (dans les 30 jours). La présente étude visait à comprendre les résultats postopératoires précoces actuels après une reconstruction mammaire immédiate. Méthodologie: À l'aide des données de l'American College of Surgeons-National Surgical Quality Improvement Program, les chercheurs ont analysé les complications qu'ont subies les femmes après une reconstruction mammaire immédiate entre 2017 et 2019, de même que les tendances de ce type de reconstruction à partir des données sur la mastectomie et la reconstruction mammaire immédiate entre 2010 et 2019. Ils ont divisé les complications entre les complications chirurgicales majeures (y compris le retour en salle opératoire) et les complications médicales. Ils ont effectué les analyses statistiques à l'aide de la méthode exacte de Fischer pour les variables nominales, du test de Student pour les variables continues et de la régression logistique. Résultats: Le taux de reconstructions mammaires directes a augmenté depuis 2010. Dans la cohorte de 4 204 patients de 2017 à 2019, le taux de complications chirurgicales majeures précoces s'élevait à environ 10% (422 patients) et le taux de complications médicales majeures, à 0,83% (35 patients). Selon la modélisation de régression, l'indice de masse corporelle, le tabagisme, l'hypertension, les troubles hémorragiques et la transfusion sanguine intraopératoire sont liés aux complications chirurgicales (P < 0001). Conclusions: Malgré le recours accru aux MDA et l'angiographie au vert d'indocyanine, par rapport aux études antérieures, les complications postopératoires précoces sont demeurées stables. D'autres études devront être réalisées pour évaluer les complications à long terme et les résultats cliniques déclarés par les patientes après une reconstruction mammaire immédiate.

Imaging in Autologous Breast Reconstruction.

The evolution of imaging actively shapes clinical management in the field. Ultrasonography (US), computed tomography angiography (CTA), and magnetic resonance angiography (MRA) stand out as the most extensively researched imaging modalities for ABR. Ongoing advancements include "real-time" angiography and three-dimensional (3D) surface imaging, and future prospects incorporate augmented or virtual reality (AR/VR) and artificial intelligence (AI). These technologies may further enhance perioperative efficiency, reduce donor-site morbidity, and improve surgical outcomes in ABR.

Accelerating Fourth-Generation Machine Learning Potentials Using Quasi-Linear Scaling Particle Mesh Charge Equilibration.

Machine learning potentials (MLPs) have revolutionized the field of atomistic simulations by describing atomic interactions with the accuracy of electronic structure methods at a small fraction of the cost. Most current MLPs construct the energy of a system as a sum of atomic energies, which depend on information about the atomic environments provided in the form of predefined or learnable feature vectors. If, in addition, nonlocal phenomena like long-range charge transfer are important, fourth-generation MLPs need to be used, which include a charge equilibration (Qeq) step to take the global structure of the system into account. This Qeq can significantly increase the computational cost and thus can become a computational bottleneck for large systems. In this Article, we present a highly efficient formulation of Qeq that does not require the explicit computation of the Coulomb matrix elements, resulting in a quasi-linear scaling method. Moreover, our approach also allows for the efficient calculation of energy derivatives, which explicitly consider the global structure-dependence of the atomic charges as obtained from Qeq. Due to its generality, the method is not restricted to MLPs and can also be applied within a variety of other force fields.

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.

The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.

Real-world effectiveness of first-line azacitidine or decitabine with or without venetoclax in acute myeloid leukemia patients unfit for intensive therapy.

BACKGROUND: First-line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results. METHODS: We performed a multicenter retrospective analysis of outcomes with first-line HMA-VEN versus HMA in AML patients unfit for intensive chemotherapy. RESULTS: A total of 213 patients were included from three German hospitals (125 HMA-VEN, 88 HMA). Median overall survival in the HMA-VEN cohort was 7.9 months (95% confidence interval [CI], 5.1-14.7) versus 4.9 months (3.1-7.1) with HMA. After 1 year, 42% (95% CI, 33-54) and 19% (12-30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46-0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA-VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29-0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47-0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33-0.84). DISCUSSION: These data align with findings from the pivotal VIALE-A trial and support the use of HMA-VEN in patients unfit for intensive therapy.

Osseous Maxillary Reconstruction with Immediate Dental Implant Placement: An Optimized Workflow for the Oncologic Patient.

INTRODUCTION: Maxillary reconstruction is a complex undertaking characterized by a 3-dimensional surgical site with deficiencies in multiple tissue types. Prior to virtual surgical planning(VSP), bony reconstruction was inaccurate and inefficient, thus reconstructions defaulted to soft tissue flaps or obturators. The current study describes an efficient and accurate approach to bony maxillary reconstruction with immediate dental implant placement(IDIP). METHODS: A reconstructive workflow was developed for osseous reconstruction to improve functional and aesthetic outcomes. Critical aspects include VSP, 3-D printed plates and IDIP. Review of a prospectively maintained database identified patients who underwent osseous maxillary reconstruction with a fibula flap and immediate dental implants from 2017-2022, with a focus on oncologic characteristics and reconstructive outcomes. RESULTS: During the study, 20 patients underwent maxillary reconstruction with VSP and IDIP. One dental implant out of 55 failed to osseointegrate and no flaps were lost. Three patients suffered partial loss of the fibula skin island; one required palatal closure with a radial forearm flap, and two were managed with outpatient debridement. Fifteen patients achieved either an interim or final retained dental prosthesis. All prostheses achieved acceptable aesthetic results without the instability associated with non-bone borne devices(e.g.dentures/obturators). No patients experienced delays in oncologic treatment. CONCLUSIONS: VSP technology has enabled surgeons to replace like with like to achieve better outcomes with acceptable morbidity for maxillary defects. IDIP provides all patients an opportunity for a fixed prosthesis even though not all complete the process. This maxillary reconstruction workflow can be safely accomplished in oncologic patients with promising and effective early results.

Assessing bolus peak position in CT perfusion: High variance persisting despite age-dependency in a large cohort.

PURPOSE: CT perfusion (CTP) is a valuable tool in suspected acute ischemic stroke. A substantial variability of the delay between contrast injection and bolus arrival in the brain is conceivable. We investigated the distribution of the peak positions of the concentration time curves measured in an artery (arterial input function, AIF) and - in cases with ischemia - also measured in the penumbra. METHODS: We report on 2624 perfusion scans (52 % female, mean age 72.2 ± 14.4 years) with stroke present in 1636 cases. From the attenuation time curves of the AIF and the penumbra, we calculated the respective bolus peak positions and investigated the distribution of the peak positions. Further, we analyzed the bolus peak positions for associations with age. RESULTS: The bolus peaked significantly later in older patients, both in the AIF and in the penumbra (all p < 0.001). In the whole cohort, we found a significant association of age with the bolus peak position of the AIF (ρ = 0.334; p < 0.001). In patients with stroke, age was also associated to the peak position of the AIF (ρ = 0.305; p < 0.001), and the penumbra (ρ = 0.246, p < 0.001). However, a substantial range of peak positions of the AIF and penumbra was noted across all age ranges. CONCLUSIONS: This study revealed a strong age-dependency of the contrast bolus arrival in both healthy and ischemic tissue. This variability makes non-uniform sampling schemes, which have been suggested to reduce radiation dose, problematic, as they might not always optimally capture the bolus in all cases.

Impact of Mastectomy Flap Necrosis on Patient-Reported Quality-of-Life Measures After Nipple-Sparing Mastectomy: A Preliminary Analysis.

BACKGROUND: Mastectomy skin flap necrosis (SFN) is common following nipple-sparing mastectomy (NSM), but studies on its quality-of-life (QOL) impact are limited. We examined patient-reported QOL and satisfaction after NSM with/without SFN utilizing the BREAST-Q patient-reported outcome measure (PROM) survey. PATIENTS AND METHODS: Patients undergoing NSM between April 2018 and July 2021 at our institution were examined; the BREAST-Q PROM was administered preoperatively, and at 6 months and 1 year postoperatively. SFN extent/severity was documented at 2-3 weeks postoperatively; QOL and satisfaction domains were compared between patients with/without SFN. RESULTS: A total of 573 NSMs in 333 patients were included, and 135 breasts in 82 patients developed SFN (24% superficial, 56% partial thickness, 16% full thickness). Patients with SFN reported significantly lower scores in the satisfaction with breasts (p = 0.032) and psychosocial QOL domains (p = 0.009) at 6 months versus those without SFN, with scores returning to baseline at 1 year in both domains. In the "physical well-being-of-the-chest" domain, there was an overall decline in scores among all patients; however, there were no significant differences at any time point between patients with or without SFN. Sexual well-being scores declined for patients with SFN compared with those without at 6 months and also at 1 year, but this did not reach significance (p = 0.13, p = 0.2, respectively). CONCLUSIONS: Patients undergoing NSM who developed SFN reported significantly lower satisfaction and psychosocial well-being scores at 6 months, which returned to baseline by 1 year. Physical well-being of the chest significantly declines after NSM regardless of SFN. Future studies with larger sample sizes and longer follow-up are needed to determine SFN's impact on long-term QOL.

Theoretical Studies of Anisotropic Melting of Ice Induced by Ultrafast Nonthermal Heating.

Water and ice are routinely studied with X-rays to reveal their diverse structures and anomalous properties. We employ a hybrid collisional-radiative/molecular-dynamics method to explore how femtosecond X-ray pulses interact with hexagonal ice. We find that ice makes a phase transition into a crystalline plasma where its initial structure is maintained up to tens of femtoseconds. The ultrafast melting process occurs anisotropically, where different geometric configurations of the structure melt on different time scales. The transient state and anisotropic melting of crystals can be captured by X-ray diffraction, which impacts any study of crystalline structures probed by femtosecond X-ray lasers.