Outpatient surgery for tibial plateau fractures.

PURPOSE: The purpose of this study was to determine the rates of compartment syndrome and other early complications following outpatient open reduction and internal fixation (ORIF) of tibial plateau fractures. METHODS: This was a retrospective cohort at a single US level I academic trauma centre of patients with tibial plateau fractures managed operatively. Inpatients received their definitive ORIF during their index hospital stay and were admitted post-operatively following ORIF. Outpatients were scheduled for ambulatory surgery during definitive ORIF. Exclusion criteria for outpatient surgery included compartment syndrome, polytrauma, open types IIIb/IIIc, and patients who received any internal fixation during index presentation. The primary outcome measure was post-operative compartment syndrome. Secondary outcomes were return to the 90-day return to the ED, 90-day readmission, surgical wound infection, thromboembolism, and 90-day mortality. An intention-to-treat (ITT) and as-treated (AT) analyses were performed. RESULTS: Totally, 71 inpatients and 47 outpatients were included. There were no cases of post-operative compartment syndrome. In the ITT analysis, there were no differences for inpatients vs outpatients for 90-day re-admission (22.5% vs 12.8%, p = 0.275), 90-day return to the ED (35.2% vs 17.0%, p = 0.052), infection (12.7% vs 2.1%, p = 0.094), DVT (7% vs 4.3%, p = 0.819), or PE 1.4% vs 0.0%, p = 1.000). The AT analysis showed a significantly higher 90-day re-admission (26.9% vs 2.5%, p = 0.003) and 90-day ED visit (38.5% vs 7.5%, p = 0.001) rate in the inpatient group. CONCLUSIONS: Appropriately selected patients with isolated tibial plateau fractures can have non-inferior rates of compartment syndrome and post-operative complications when compared to inpatients.

Chest tube management following two row vertebral body tethering for adolescent idiopathic scoliosis.

BACKGROUND: The current gold standard of scoliosis correction procedures is still posterior spinal fusion, an extensively studied procedure. anterior vertebral body tethering is a newer surgical technique for the correction of scoliotic curves. Consequently, best practices have yet to be determined. METHODS: A single-institution, retrospective, review of all patients diagnosed with adolescent idiopathic scoliosis who underwent two row anterior vertebral body tethering between June 2020 and April 2022 was performed. RESULTS: Over the study period, 95 patients met inclusion: 79 females (83.2%) and 16 males (16.8%), age 14.4 ± 2.5 years, with a body mass index of 20.0 ± 2.9, and an average of 8.4 ± 2.1 levels treated. 28 (29.5%) procedures were for double curves and 67 (70.5%) for single curves. After tethering, a chest tube was positioned in each corrected side. A total of 123 chest tubes were analyzed, including 67 single curves and 28 double curves. The average chest tube duration was 2.5 ± 1.1 days and the average length of stay was 5.0 ± 2.0 days. The average chest tube output eight hours prior to removal was 61.1 ± 45.6 mL. There was no significant difference in average length of stay for patients who underwent correction of a single curve versus a double curve nor was there a difference in average length of stay or chest tube duration for revisions compared to primary procedures. For the entire cohort, the 30-day emergency department visit rate was 7.4% (n = 7) and the readmission rate was 4.2% (n = 4). CONCLUSIONS: This early review of a 2-year two row vertebral body tethering postoperative experience provides a report of a safe and effective approach to chest tube management at a single academic center.

Management of Diaphragm Paralysis and Eventration.

An elevated diaphragm may be due to eventration or paralysis. Diaphragm elevation is often asymptomatic and found incidentally on imaging. Fluoroscopic testing can be used to differentiate eventration (no paradoxic motion) from paralysis (paradoxic motion). Regardless of etiology, a diaphragm plication is indicated in all symptomatic patients with an elevated diaphragm. Plication can be approached either from a thoracic or abdominal approach, though most thoracic surgeons perform minimally invasive thoracoscopic plication. The goal of plication is to improve lung volumes and decrease paradoxic elevation of the hemidiaphragm. Diaphragm plication is safe, has excellent outcomes, and is associated with symptom improvement.

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

In vivo effects of cell seeding technique in an ex vivo regional gene therapy model for bone regeneration.

When delivering cells on a scaffold to treat a bone defect, the cell seeding technique determines the number and distribution of cells within a scaffold, however the optimal technique has not been established. This study investigated if human adipose-derived stem cells (ASCs) transduced with a lentiviral vector to overexpress bone morphogenetic protein 2 (BMP-2) and loaded on a scaffold using dynamic orbital shaker could reduce the total cell dose required to heal a critical sized bone defect when compared with static seeding. Human ASCs were loaded onto a collagen/biphasic ceramic scaffold using static loading and dynamic orbital shaker techniques, compared with our labs standard loading technique, and implanted into femoral defects of nude rats. Both a low dose and standard dose of transduced cells were evaluated. Outcomes investigated included BMP-2 production, radiographic healing, micro-computerized tomography, histologic assessment, and biomechanical torsional testing. BMP-2 production was higher in the orbital shaker cohort compared with the static seeding cohort. No statistically significant differences were noted in radiographic, histomorphometric, and biomechanical outcomes between the low-dose static and dynamic seeding groups, however the standard-dose static seeding cohort had superior biomechanical properties. The standard-dose 5 million cell dose standard loading cohort had superior maximum torque and torsional stiffness on biomechanical testing. The use of orbital shaker technique was labor intensive and did not provide equivalent biomechanical results with the use of fewer cells.

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs.

INTRODUCTION: Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data. METHODS: We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. RESULTS: All 22 donors progressed to cardiac arrest and underwent TA-NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was 41 years, 55% had anoxic brain injury, 45% were hypertensive, 0% were diabetic, and median kidney donor profile index was 40%. TA-NRP utilization was high across all organ types (88%-100%), with a higher percentage of kidneys procured via TA-NRP compared to tDCD (88% vs. 72%, p = .02). Recipient and graft survival ranged from 89% to 100% and were comparable to tDCD and DBD recipients (p ≥ .2). Delayed graft function was lower for kidneys procured from TA-NRP compared to tDCD donors (27% vs. 44%, p = .045). CONCLUSION: Procurement from TA-NRP donors yielded high organ utilization, with outcomes comparable to tDCD and DBD recipients across organ types. Further large-scale study of TA-NRP donors, facilitated by its capture in the national registry, will be critical to fully understand its impact as an organ procurement technique.

Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation.

Rationale: Acute cellular rejection (ACR) after lung transplant is a leading risk factor for chronic lung allograft dysfunction. Prior studies have demonstrated dynamic microbial changes occurring within the allograft and gut that influence local adaptive and innate immune responses. However, the lung microbiome's overall impact on ACR risk remains poorly understood. Objectives: To evaluate whether temporal changes in microbial signatures were associated with the development of ACR. Methods: We performed cross-sectional and longitudinal analyses (joint modeling of longitudinal and time-to-event data and trajectory comparisons) of 16S rRNA gene sequencing results derived from lung transplant recipient lower airway samples collected at multiple time points. Measurements and Main Results: Among 103 lung transplant recipients, 25 (24.3%) developed ACR. In comparing samples acquired 1 month after transplant, subjects who never developed ACR demonstrated lower airway enrichment with several oral commensals (e.g., Prevotella and Veillonella spp.) than those with current or future (beyond 1 mo) ACR. However, a subgroup analysis of those who developed ACR beyond 1 month revealed delayed enrichment with oral commensals occurring at the time of ACR diagnosis compared with baseline, when enrichment with more traditionally pathogenic taxa was present. In longitudinal models, dynamic changes in α-diversity (characterized by an initial decrease and a subsequent increase) and in the taxonomic trajectories of numerous oral commensals were more commonly observed in subjects with ACR. Conclusions: Dynamic changes in the lower airway microbiota are associated with the development of ACR, supporting its potential role as a useful biomarker or in ACR pathogenesis.

Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Applying deep learning to segmentation of murine lung tumors in pre-clinical micro-computed tomography.

Lung cancer remains a leading cause of cancer-related death, but scientists have made great strides in developing new treatments recently, partly owing to the use of genetically engineered mouse models (GEMMs). GEMM tumors represent a translational model that recapitulates human disease better than implanted models because tumors develop spontaneously in the lungs. However, detection of these tumors relies on in vivo imaging tools, specifically micro-Computed Tomography (micro-CT or µCT), and image analysis can be laborious with high inter-user variability. Here we present a deep learning model trained to perform fully automated segmentation of lung tumors without the interference of other soft tissues. Trained and tested on 100 3D µCT images (18,662 slices) that were manually segmented, the model demonstrated a high correlation to manual segmentations on the testing data (r2=0.99, DSC=0.78) and on an independent dataset (n = 12 3D scans or 2328 2D slices, r2=0.97, DSC=0.73). In a comparison against manual segmentation performed by multiple analysts, the model (r2=0.98, DSC=0.78) performed within inter-reader variability (r2=0.79, DSC=0.69) and close to intra-reader variability (r2=0.99, DSC=0.82), all while completing 5+ hours of manual segmentations in 1 minute. Finally, when applied to a real-world longitudinal study (n = 55 mice), the model successfully detected tumor progression over time and the differences in tumor burden between groups induced with different virus titers, aligning well with more traditional analysis methods. In conclusion, we have developed a deep learning model which can perform fast, accurate, and fully automated segmentation of µCT scans of murine lung tumors.

Double-Barrel Vascularized Free Fibula Flap for Reconstruction of Sternal Nonunion with Bone Defect: A Case Report.

CASE: Given the rare incidence of sternal nonunion after traumatic injury, literature describing the management of posttraumatic sternal reconstruction is limited. We present a case of a 54-year-old man with a history of traumatic chest wall injury with multiple unsuccessful attempts at sternal repair who presented with chronic sternal nonunion and persistent bone defect. Sternal reconstruction using a vascularized double-barrel free fibula flap with rigid fixation in multiple planes was performed, with confirmed bony union at 6 months. CONCLUSION: This novel approach to sternal nonunion management allowed effective bridging of posttraumatic sternal bone defects while facilitating osseous integration and long-term stabilization.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

Breastfeeding and Antepartum Breast Milk Expression (BABE): A Randomized Control Trial Utilizing an Electric Breast Pump and its Effect on Postpartum Breastfeeding.

Objective: To evaluate the effect of antenatal breast milk expression (ABE) on exclusive breastfeeding. Materials and Methods: A randomized control study was performed with the primary outcome being formula use during the postpartum hospital stay. Secondary outcomes were the exclusive breastfeeding rate at 6 months postpartum and peripartum safety outcomes. Participants included multiparous and nulliparous patients who planned to breastfeed. Exclusion criteria included exclusively breastfeeding in prior pregnancies for greater than 6 months, medical contraindications for breastfeeding, multiple gestation, history of preterm delivery, or any contraindication to vaginal delivery. ABE group participants were instructed to pump for 20 minutes, three times daily, starting at 37 weeks of gestation. Results: Three-hundred four participants from two clinics were enrolled. There was no significant difference in formula use during hospital admission (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.34-1.22) or in exclusive breastfeeding at 6 months postpartum (OR 0.66, 95% CI 0.34-1.29). Colostrum use was more prevalent in the ABE group (OR 5.31, 95% CI 2.63-10.76). ABE participants were more likely to present in spontaneous labor (OR 2.09, 95% CI 1.05-4.14). Conclusion: ABE did not significantly improve exclusive breastfeeding rates, but safely provides women opportunities to become familiar with breastfeeding before delivery and can provide readily available colostrum. There was no negative secondary safety outcome related to ABE identified. Prenatal care providers can consider recommending ABE to patients with minimal to no experience with breastfeeding.

Digital spatial profiling to predict recurrence in grade 3 stage I lung adenocarcinoma.

OBJECTIVE: Early-stage lung adenocarcinoma is treated with local therapy alone, although patients with grade 3 stage I lung adenocarcinoma have a 50% 5-year recurrence rate. Our objective is to determine if analysis of the tumor microenvironment can create a predictive model for recurrence. METHODS: Thirty-four patients with grade 3 stage I lung adenocarcinoma underwent surgical resection. Digital spatial profiling was used to perform genomic (n = 31) and proteomic (n = 34) analyses of pancytokeratin positive and negative tumor cells. K-means clustering was performed on the top 50 differential genes and top 20 differential proteins, with Kaplan-Meier recurrence curves based on patient clustering. External validation of high-expression genes was performed with Kaplan-Meier plotter. RESULTS: There were no significant clinicopathologic differences between patients who did (n = 14) and did not (n = 20) have recurrence. Median time to recurrence was 806 days; median follow-up with no recurrence was 2897 days. K-means clustering of pancytokeratin positive genes resulted in a model with a Kaplan-Meier curve with concordance index of 0.75. K-means clustering for pancytokeratin negative genes was less successful at differentiating recurrence (concordance index 0.6). Genes upregulated or downregulated for recurrence were externally validated using available public databases. Proteomic data did not reach statistical significance but did internally validate the genomic data described. CONCLUSIONS: Genomic difference in lung adenocarcinoma may be able to predict risk of recurrence. After further validation, stratifying patients by this risk may help guide who will benefit from adjuvant therapy.

Association between Endometriosis and Surgical Complications among Benign Hysterectomies.

STUDY OBJECTIVE: To investigate the effect of endometriosis on perioperative outcomes in patients undergoing hysterectomy for benign disease. DESIGN: A retrospective cohort study. SETTING: The American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: A total of 127 556 hysterectomies performed for benign gynecologic indications INTERVENTIONS: Differences in the primary outcomes were compared between patients with and without endometriosis after adjustment for group differences in covariates using inverse probability of treatment weighting approach. MEASURES AND MAIN RESULTS: Of the 127 556 hysterectomies identified, 19 618 (15.4%) had a diagnosis of endometriosis. Patients with endometriosis were younger with a lower prevalence of chronic comorbidities but had higher rates of concurrent pelvic inflammatory disease and previous abdominal operations. The incidence of postoperative complications was higher in patients with endometriosis (9.9% vs 8.1%; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.34). The incidence of 30-day mortality (0.1% vs 0.03%; OR, 1.98; 95% CI, 0.69-5.65) and reoperations (1.50% vs 1.36%; OR, 1.18; 95% CI, 0.98-1.42) were not different in patients with and without endometriosis. CONCLUSION: Postoperative complications are more likely in hysterectomies involving endometriosis than those without endometriosis, likely owing to anatomic distortion incurring increased surgical complexity. Patients and surgeons should be aware of the increased risk of complications and plan for mitigating these increased risks before and during surgery for suspected endometriosis.