Citations

Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.

Background/Objectives: The growing prevalence of metabolic-associated steatotic liver disease (MASLD)/metabolic-associated steatohepatitis (MASH) is forecasted to be over 55% by 2040, representing a significant driver of cirrhosis and highlighting demand for effective therapeutic interventions. The therapeutic landscape is evolving with agents, like glucagon-like peptide-1 receptor agonists (GLP-1 RAs), under active investigation. A common concern across emerging therapies is potentially precipitating decompensation in patients with existing cirrhosis, necessitating careful consideration in this population. Case Presentation: A 46 y.o. female with obesity and cirrhosis from MASH and alcohol who underwent a deceased-donor liver transplant developed steatohepatitis within a year post-transplant after gaining 36 kg. Transient elastography revealed controlled attenuation parameter (CAP) 400 dB/m (S3 steatosis) and liver stiffness measurement (LSM) 61.2 kPa (advanced fibrosis). Follow-up biopsy confirmed severe steatohepatitis (NAS 7/8) and advanced fibrosis (F3), attributed to metabolic dysfunction without evidence of alcohol recurrence. She decompensated with ascites and varices, leading to transplant re-enlistment at MELD-Na 29. Despite two years of intensive lifestyle modification, losing 17 kg, and recompensation, her follow-up elastography showed persistent steatosis (S3) and advanced fibrosis (F4). Subsequent allograft biopsy revealed progression to cirrhosis (F4) with ongoing steatohepatitis (NAS 3/8). Tirzepatide was initiated for the development of type 2 diabetes, attributed to steroids used for immunosuppression. After 2 years on tirzepatide, she lost 43.1 kg. Shockingly, her follow-up elastography demonstrated fibrosis regression with LSM 5.5 kPa (F1) and steatohepatitis resolution with CAP 204 dB/m (S0). Follow-up liver biopsy confirmed fibrosis regression to F2-F3 and steatohepatitis resolution (NAS 1/8). Conclusions: This case challenges the widely accepted dogma that liver MASH cirrhosis is irreversible. Using multiple liver fibrosis monitoring modalities, cirrhosis reversal was demonstrated and attributed to mechanisms of GLP-1/GIP RA therapy. This study suggests that GLP-1/GIP RA may be safe in cirrhosis and may result in fibrosis regression.

Background: Motion-sparing approaches to scoliosis surgery such as vertebral body tethering (VBT) are growing in popularity. There is limited data evaluating motion preserving after the different tether approaches. We hypothesized that spinal motion would be preserved in both the sagittal and coronal planes in patients after thoracic, lumbar, and bilateral vertebral body tethering procedures. Methods: This was a retrospective comparison study of adolescent idiopathic scoliosis (AIS) patients who underwent VBT. Preoperative and postoperative coronal range of motion across the instrumented levels were compared using a standing microdose slot-scanning protocol. Flexion/extension radiographs were evaluated postoperatively to assess preserved sagittal arc of motion. Patients with known cord breakage were excluded. Results: The mean age at surgery was 12.9 years (range: 9.4 to 16.5) with mean follow-up period of 2.8 years. Skeletal maturity, defined as Risser sign ≥5, was observed in 29 patients. (26.9%). Overall, mean thoracic coronal arc of motion for postoperative VBT patients was 10 degrees in the thoracic spine and 20 degrees in the lumbar. This was a 59% (24 to 10 deg.) decrease in thoracic range of motion and a 51% (40 to 20 deg.) decrease in lumbar range of motion. Right-sided motion was greater in patients with thoracic instrumentation, whereas left-sided motion was greater in patients with lumbar instrumentation. In addition, patients also retained sagittal motion. Patients with single thoracic tethers had a total arc of motion of 22 degrees, whereas patients with single lumbar tethers had a total arc of motion of 25 degrees. It was noted that both groups had a greater degree of flexion than extension. Conclusions: Patients with single thoracic tethers saw a 60% decrease in the total coronal arc of motion. Patients with single lumbar tethers saw a 57% decrease in coronal motion. Patients had around 20 to 25-degree arc of motion preserved over the instrumented segments in the sagittal plane. Further work is needed to outline the functional benefits of motion preservation after VBT. Level of Evidence: Level III (retrospective cohort study).

Background: Pediatric orthopaedic surgery encompasses many areas of subspecialization. To improve patient care, quality improvement efforts should focus on high-volume procedures with high complication rates. This study aims to identify these procedures to better target research and quality-improvement initiatives. Methods: Patients undergoing one of the 30 most common orthopaedic procedures in NSQIP pediatric data from 2012 to 2022 were analyzed for 30-day complications, infections, unplanned reoperations, and unplanned readmissions. Multivariable models assessed associations between procedure type and adverse events, adjusted for patient characteristics. Tibial osteotomy (TO) was defined as the reference category for procedure in each model as it is a common procedure with a moderate risk profile and a similar complication rate across the cohort. Results: 191,381 patients were included in the analysis (median: 10 y, IQR: 5 to 13; 48.7% male). The 30-day overall complication rate was 2.3% (n=4401), with infections occurring in 1.6% of cases (n=3005). Unplanned reoperations occurred in 1.7% (n=3207), and the unplanned readmission rate was 2.0% per 30 person-days. The most performed procedures were posterior spine fusion (PSF; n=45,542; 23.8%), supracondylar humeral fracture (SCHfx) repair (n=45,479; 23.8%). Complication rates were highest for PSF in non-idiopathic cases (10.3%), followed by pelvic and femoral osteotomy (4.9%). Infectious complications were most frequent in PSF for non-idiopathic cases (6.1%) and tibial osteotomy (3.1%). Unplanned reoperation rates were elevated for non-idiopathic PSF (5.6%) and pelvic/femoral osteotomy (4.9%). On multivariable analysis, PSF for adolescent idiopathic scoliosis (OR=1.39; 95% CI: 1.05-1.86) and non-idiopathic causes (OR=2.16; 95% CI: 1.61-1.89) demonstrated increased odds of complications compared with TO. Factors associated with higher complication rates included BMI >95th percentile (OR=1.52; 95% CI: 1.40-1.65), developmental delay (OR=1.57; 95% CI: 1.43-1.73), seizure disorder (OR=1.41; 95% CI: 1.27-1.56), and ASA ≥2 (OR=2.14;95% CI: 1.90-2.41). Although PSF for non-idiopathic causes had the highest unplanned readmission rates (9.4% per 30 person-days), adjusted analysis showed a strong association with increased readmissions for pelvic/femoral osteotomy (HR=2.52; 95% CI: 1.58-4.03) compared with TO. SCHfx repair and calcaneal osteotomy consistently had lower rates of complications, infections, reoperations, and readmissions. Conclusions: After adjusting for covariates, PSF and tibial and femoral osteotomies, demonstrated significantly higher risks for adverse surgical outcomes compared with TO. Our findings identify SCHfx repair as a high-volume procedure with low complication, infection, reoperation, and readmission rates in contrast to PSF, one of the most common procedures with the highest complication rate.

Context.— Ensuring equitable laboratory patient care within diverse populations is a priority. The cytopathology laboratory has an important role in providing gender-inclusive care, particularly with regard to screening and prevention of human papillomavirus–related carcinoma, for individuals who are transgender, gender nonbinary, intersex, and with same-gender sexual orientation. Providing equitable care necessitates an understanding of gender-inclusive processes within the cytopathology laboratory. Many barriers to implementation exist and include sociocultural, legal, ethical, and financial hurdles. Objective.— To review the current literature regarding gender-inclusive care within a multi-institutional setting and identify challenges and opportunities for future growth in cytopathology. Specific areas of focus include appropriate terminology in laboratory information systems and requisitions, and variables affecting Papanicolaou test interpretation, human papillomavirus testing, and anal Papanicolaou test screening. Data Sources.— Primary literature was searched within the areas highlighted throughout the article. Multi-institutional experiences from the authors, in addition to editorials and expert opinion, were used. Conclusions.— The cytopathology laboratory has an important role in providing care that is inclusive and accurate for all patients. Gaps in care exist and further work is needed to address these disparities. This review attempts to increase awareness, educate, and share our own multi-institutional experiences, and calls for improvements in cytopathology to optimize quality in gender-inclusive patient care.

Abstract Aims Aortic valve-sparing root replacement is recommended over composite root replacement for aortic root aneurysms, especially in younger patients, but long-term outcomes in low-volume nationwide settings remain unclear. The objectives are to compare long-term survival, stroke, and reoperation rates between the two procedures in a low-volume national setting. Methods and results Patients were identified from the Western Danish Heart Registry and the Danish Heart Registry. Cases were validated by review of operative descriptions. The primary outcome was long-term survival from all-cause mortality; secondary outcomes included stroke, reoperation, recurrent aortic regurgitation, and aortic stenosis. Groups were balanced using propensity score matching. Echocardiographic data were provided for the matched cohort. We identified 760 patients treated with composite root replacement and 179 patients with aortic valve-sparing root replacement between January 2010 and April 2022. Mean follow-up was 6.5 years. Composite root replacement patients were younger [50.7 years (SD 14.1) vs. 55.2 (SD 13.5), P < 0.001], but more comorbid with a median EuroSCOREII of 5.5 [interquartile range (IQR): 3.3–11.7] vs. 3.4 (IQR: 2.6–5.0) (P < 0.001). After matching 157 patients per group, aortic valve-sparing root replacement showed improved 10-year survival [91.2%, 95% confidence interval (CI) 82.3–95.8 vs. 80.4%, 95% CI 70.0–87.5, log-rank P = 0.026], with lower 10-year stroke risk (4.9%, 95% CI 1.8–13.0 vs. 18.9%, 95% CI 11.7–29.9, log-rank P = 0.007). Risk of reoperation was nonsignificant (log-rank P = 0.12), which was consistent in the crude population when accounting for competing risk of death (log-rank P = 0.09). Conclusion In this nationwide study, aortic valve-sparing root replacement was associated with better long-term survival and lower stroke risk, supporting its role as a durable surgical option for selected patients.

Abstract Background The isocitrate dehydrogenase (IDH) mutation status is a key molecular marker in diagnosing and treating brain tumors. Currently, it is determined via invasive tissue biopsy. Recent advances in deep learning (DL) have offered promising non-invasive alternatives for determining IDH status. However, their clinical translation is hindered by a significant gap between DL predictions and their clinical applicability. The limited transparency of many DL-networks and inadequate evaluation metrics hinders trust and adoption, as clinicians require clear and validated insights for determining IDH status. These challenges highlight the need for robust validation and measures of predictive reliability to make DL-predictions clinically actionable. Methods We developed a unique approach for non-invasive prediction of IDH status using MRI. We combine a voxel-wise-segmentation network(MC-net) with Bayesian logistic regression (BLR) to provide an IDH status and estimate confidence scores. We utilized a comprehensive dataset of 2,481 glioma cases from eight institutions. Results Our framework(MC-net + BLR) demonstrated robust performance achieving 96.4% and 95.1% classification accuracies on diverse databases, with an AUC of 0.98. The BLR was implemented exclusively on held-out test data, ensuring that the derived confidence scores are independent of the training or validation phases. The derived confidence scores showed a low Brier score of 0.0125, highlighting its superior calibration and uncertainty quantification. Conclusion The developed framework provides an IDH status and a confidence score, offering clinicians an additional layer of assurance in prediction reliability. It bridges the gap between high-performing DL models and their clinical applicability by addressing the challenges in prediction reliability. Our framework is a significant advancement in non-invasive determination of IDH-status and confidence-informed therapeutic decision-making in neuro-oncology.

Objective: Airway management in patients with severely-narrowed tracheal lumens presents significant challenges, especially when traditional intubation methods are not feasible. In such cases, failed intubation attempts can worsen airway compromise and cause life-threatening complications. Extracorporeal membrane oxygenation (ECMO) offers an alternative approach to ensure oxygenation and ventilation during complex airway surgeries. The objective of this study was to assess the safety and feasibility of using venovenous ECMO to ensure oxygenation before attempting intubation in patients with severely-narrowed tracheal lumens undergoing head and neck surgery. Methods: This is a retrospective case series of 3 adult patients who underwent venovenous ECMO-assisted intubation for head and neck surgeries at a single institution between 2010 and 2023. The primary outcome was the successful establishment of an airway and the avoidance of respiratory failure during the surgical procedure. Results: All 3 patients successfully underwent ECMO-assisted intubation. None of the patients experienced major complications directly attributable to ECMO, and all were extubated within 24 hours postoperatively. Conclusions: Venovenous ECMO provides an effective strategy for managing difficult airways in patients with severely-narrowed tracheas, enabling safe anesthesia induction. This technique may be crucial in preventing complications associated with traditional airway management methods.