Citations

ABSTRACT Human alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme that metabolizes glyoxylate, the oxalate precursor, to glycine. AGT deficiency, due to recessive pathogenic changes in the AGXT gene, results in calcium oxalate accumulation and kidney stones, a condition known as primary hyperoxaluria type 1 (PH1). Most missense variants lead to PH1 by causing AGT misfolding, but their effects manifest differently based on the presence of two polymorphic variants, p.Pro11Leu (p.P11L) and p.Ile340Met (p.I340M), which are usually present in linkage disequilibrium and generate the minor haplotype. While the p.P11L substitution reduces AGT global stability and worsens the effects of pathogenic changes, the p.I340M exerts a stabilizing effect whose role on PH1 pathogenesis has never been elucidated. The p.Ile279Thr (p.I279T) variant is frequent in healthy populations (0.29%), mainly on the major allele, but we present data from six PH1 families (eight patients) suggesting p.I279T as a PH1 pathogenic allele. Interestingly, in these families, p.Thr279 is always associated with p.Leu11 and p.Ile340, thus with a split AGXT haplotype. Analysis of the effects of the p.I279T mutation by in silico predictions, biochemical analyses on purified proteins, and expression in two cellular models of disease ( AGXT1 ‐KO HepG2 and CHO cells) shows that it causes a folding defect that is exacerbated by p.P11L but mitigated by p.I340M, thus explaining why p.Thr279 is pathogenic just on the p.Leu11–p.Ile340 haplotype. These data indicate that genetic screenings for PH1 should document the AGXT haplotype, including its components, to obtain an accurate diagnosis and possible prognostic information.

Introduction. Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods. The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results. By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions. We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

ABSTRACTObjectivesTo achieve consensus among expert laser surgeons on standards for the prevention and management of adverse events from fully ablative laser resurfacing of the face.Materials and MethodsDelphi study with two rounds of ratings and revisions until consensus was achieved. The draft set of statements was developed by a steering committee based on expert clinical experience. This was followed by two rounds of rating and revisions completed by an expert panel, then a virtual consensus meeting. In both rounds, respondents rated the draft statements on a 9‐point Likert scale (1 = strongly disagree; 9 = strongly agree) and optionally provided comments. The consensus meeting was supplemented by the results of a systematic review of the literature (from 2000 to 2023).ResultsTwo rounds of Delphi survey were completed by 34 participants across four countries. Represented specialties were dermatology, facial plastic surgery, plastic surgery, and oculoplastic surgery. The initial 105 statements from round 1 expanded to 112 in round 2, with 96 statements achieving consensus. These included possible adverse events (11 statements); absolute and relative contraindications to treatment (5 statements); preoperative care and antimicrobial prophylaxis precautions (16 statements); intraoperative precautions (17 statements); postoperative care (21 statements); monitoring for and management of infection (16 statements); management of pigmentation changes (6 statements); and management of scarring and incipient scarring (4 statements).ConclusionAn international consensus statement was developed for the prevention and management of complications associated with fully ablative laser resurfacing of the face. While expert practices vary, key factors for optimizing outcomes include careful patient selection, counseling, and meticulous pre‐ and postoperative care. Further research will improve our understanding of this treatment technique.

ABSTRACT Introduction Improving organ preservation is essential for expanding the donor pool and enhancing outcomes for pediatric transplant recipients. This report presents three pediatric patients who received donor hearts preserved using the Organ Care System (OCS). All donor hearts were prepared, placed, and monitored on OCS according to standard protocols. Heart function and myocardial edema were visually assessed during monitoring. Case Reports Patient 1: A 17‐year‐old female patient with hypertrophic cardiomyopathy utilized OCS technology due to donor distance. She experienced an uncomplicated post‐transplant course and was discharged on post‐transplant day 10. Patient 2: A 14‐year‐old male patient with complex congenital heart disease, palliated with Fontan circulation, underwent orthotopic heart transplantation (OHT) with OCS support due to both the complexity of the procedure and donor heart distance. His post‐transplant course was complicated by a revision of the ascending aorta anastomosis and prolonged milrinone infusion for diastolic dysfunction. He was discharged on post‐transplant day 31. Patient 3: A 16‐year‐old male patient with hypoplastic left heart syndrome, also palliated with Fontan circulation, underwent OHT using OCS technology due to the complexity of the surgical procedure. His post‐transplant recovery was unremarkable, and he was discharged on post‐transplant day 15. Conclusions All three pediatric patients demonstrated favorable short‐term outcomes using OCS technology. The OCS system facilitated shorter ischemic times despite the need for extended transport distances or complex surgical procedures. However, further studies with larger patient cohorts and longer follow‐up are needed to better understand the long‐term impact of OCS on pediatric heart transplantation outcomes.

Living donor liver transplantation for oncologic indications is a complex topic that involves transplantation, oncology, and ethical considerations. The incidence of primary and secondary malignancy of the liver is growing. As transplant oncology continues to provide promising outcomes, the patient population that may benefit from transplantation will grow. In this review, we provide evidence that justify attempting transplantation for oncologic indications through the exploration of outcomes in both deceased donor and living donor liver transplants. This will focus on outcomes for patients with hepatocellular carcinoma, cholangiocarcinoma, neuroendocrine liver metastasis, and colorectal liver metastases. This review aims to summarize the current status of transplant oncology and to develop the considerations of living donor liver transplantation for these indications.

AbstractEndoscopic sleeve gastroplasty (ESG) is an effective treatment for obesity but typically is not covered by insurance. It is not known whether patients with financial investment in their endoscopic procedure are more likely to achieve and/or maintain weight loss as compared with those who have no financial buy-in. We aimed to compare treatment adherence and outcomes between patients paying out-of-pocket (OOP) and those who underwent ESG as part of any clinical trial where costs were covered by a study protocol (no payment; NP).Data were collected via retrospective chart review. One hundred sixty-four patients who had an ESG with at least 6 months of follow-up were included. Repeated measures with generalized linear model were used to evaluate weight loss at different time points after ESG and labs values at baseline and 1-year follow-up to assess for comorbidity improvement between cohorts. Compliance was evaluated by comparing exercise adherence rates.The pattern of weight loss and change in laboratory values was not different over time between the OOP group (n = 139) and NP group (n = 25). Patients lost an average of 14% (12.2–15.9) and 12.9% (9.3–16.5) of total body weight over all time points, respectively, in both groups (6, 12 and 24 months). Treatment adherence also did not differ between the groups.Having “skin in the game” by paying for ESG OOP does not correlate with better outcomes or treatment adherence, which further supports broad insurance coverage for this procedure.

A 10-year-old girl with a past medical history significant for prematurity at 29 weeks, short bowel syndrome secondary to necrotizing enterocolitis, prior episodes of small intestinal bacterial overgrowth complicated by D-lactic acidosis, and gastric tube dependence presented to an emergency department with emesis, slurred speech, somnolence, and unsteady gait. Workup was initiated, and she was started on broad-spectrum antibiotics and transferred to our pediatric intensive care unit for further evaluation and treatment. Differential diagnosis on admission was broad, and, through thorough laboratory evaluation, imaging, and multiple subspecialty inputs, an unusual diagnosis was confirmed.

Abstract Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

This phase II trial of transoral surgery (TOS) with deintensified postoperative management in human papillomavirus (HPV)–associated oropharynx cancer (OPC) enrolled patients with resectable cT1-2 stage III/IV American Joint Committee on Cancer (AJCC) seventh edition p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (arm A); those with clear margins, 2-4 + LN, or ENE ≤1 mm were randomly assigned to 50 Gy (arm B) or 60 Gy (arm C); and those with involved margins, >4 + LN, or >1 mm ENE received weekly cisplatin and 60-66 Gy (arm D). Among 359 evaluable patients, the 54-month progression-free (PFS) and overall survival (OS) were 90.6% (90% CI, 87.2% to 93.1%) and 95.3% (93.0% to 96.9%), respectively. The 54-month PFS by arm was A 93.2% (79.6% to 97.8%; all four recurrences among N1 patients), B 94.9% (89.7% to 97.5%), C 90.2% (82.7% to 94.6%), and D 85.5% (77.5% to 90.8%). The 54-month OS by arm was A 97.1% (85.7% to 99.4%), B 97.9% (93.5% to 99.3%), C 95.1% (90.1% to 97.6%), and D 92.5% (86.9% to 95.7%). PFS or OS did not differ by primary site or smoking history. TOS and neck dissection with deintensified postoperative management results in outstanding 54-month PFS and OS. Among patients with favorable pathologic characteristics, those with N1 disease are at risk of late recurrence without radiation.

Purpose of review: The purpose of this review is to provide an overview of the current clinical implications, benefits, and controversies surrounding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). This review discusses the potential risks associated with GLP-1 RA therapy, such as pulmonary aspirations, tachyphylaxis, and issues with drug efficacy over time. Furthermore, it examines the increasing ethical and medical concerns related to their off-label use, safety, and accessibility. Recent findings: Recent studies highlight significant discrepancies in the recommendations provided by different medical societies on the perioperative management of GLP-1 RAs. In addition, insurance barriers exacerbate access issues, with substantial disparities in coverage for weight loss versus diabetes management. The rise of counterfeit GLP-1 RAs, unintentional overdoses, and the growing concern about long-term health impacts are also prominent challenges in the current landscape. Summary: Despite increasing usage and the potential benefits of GLP-1 RAs, a lack of consensus on optimal perioperative management and long-term use, coupled with financial and regulatory barriers, creates significant challenges. Medical societies differ on key aspects such as fasting requirements and the risk of aspiration, and concerns about the safety of compounded and counterfeit products remain.