Supramarginal resection of skull base chordomas: proof of concept and preliminary outcomes.

OBJECTIVE: The mainstay of treatment for skull base chordoma (SBC) is maximal safe resection followed by radiotherapy. However, even after gross-total resection (GTR), the recurrence rate is high due to microscopic disease in the resection margins. Therefore, supramarginal resection (SMR) could be beneficial, as has been shown for sacral chordoma. The paradigm of postoperative radiation therapy for every patient has also begun to change, as molecular profiling has shown variability in the risk of recurrence. The aim of this study was to present the concept of SMR applied to SBC, along with an individualized decision for postoperative radiation therapy. METHODS: This is a retrospective analysis of all SBCs operated on by the senior author between 2018 and 2023. SMR was defined as negative histological margins of bone and/or dura mater, along with evidence of bone resection beyond the tumor margins in the craniocaudal and lateral planes on postoperative imaging. Tumors were classified into 3 molecular recurrence risk groups (group A, low risk; group B, intermediate risk; and group C, high risk). Postoperative radiation therapy was indicated in group C tumors, in group B chordomas without SMR, or in cases of patient preference. RESULTS: Twenty-two cases of SBC fulfilled the inclusion criteria. SMR was achieved in 12 (55%) cases, with a mean (range) amount of bone resection beyond the tumor margins of 10 (2-20) mm (+40%) in the craniocaudal axis and 6 (1-15) mm (+31%) in the lateral plane. GTR and near-total resection were each achieved in 5 (23%) cases. Three (19%) tumors were classified as group A, 12 (75%) as group B, and 1 (6%) as group C. Although nonsignificant due to the small sample size, the trends showed that patients in the SMR group had smaller tumor volumes (13.9 vs 19.6 cm3, p = 0.35), fewer previous treatments (33% vs 60% of patients, p = 0.39), and less use of postoperative radiotherapy (25% vs 60%, p = 0.19) compared to patients in the non-SMR group. There were no significant differences in postoperative CSF leak (0% vs 10%, p = 0.45), persistent cranial nerve palsy (8% vs 20%, p = 0.57), and tumor recurrence (8% vs 10%, p = 0.99; mean follow-up 15 months) rates between the SMR and non-SMR groups. CONCLUSIONS: In select cases, SMR of SBC appears to be feasible and safe. Larger cohorts and longer follow-up evaluations are necessary to explore the benefit of SMR and individualized postoperative radiation therapy on progression-free survival.

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

Endoscopic endonasal pituitary sacrifice for select tumors with retrochiasmatic and/or retrosellar extension: surgical anatomy, operative technique, and case series.

OBJECTIVE: Tumors located in the retrochiasmatic region with extension to the third ventricle might be difficult to access when the pituitary-chiasmatic corridor is narrow. Similarly, tumor extension into the interpeduncular and retrosellar space poses a major surgical challenge. Pituitary transposition techniques have been developed to gain additional access. However, when preoperative pituitary function is already impaired or the risk of postoperative panhypopituitarism (PH) is considered to be particularly high, removal of the pituitary gland (PG) might be the preferred option to increase the working corridor. The aim of this study was to describe the relevant surgical anatomy, operative steps, and clinical experience with the endoscopic endonasal pituitary sacrifice (EEPS) and transsellar approach. METHODS: This study comprised anatomical dissections to highlight the relevant surgical steps and a retrospective case series reporting clinical characteristics, indications, and outcomes of patients who underwent EEPS. The surgical technique is as follows: both lateral opticocarotid recesses are exposed laterally, the limbus sphenoidale superiorly, and the sellar floor inferiorly. After opening the dura, the PG is detached circumferentially and mobilized off the medial walls of the cavernous sinuses. The descending branches of the superior hypophyseal artery are coagulated, and the stalk is transected. After removal of the PG, drilling of the dorsum sellae and bilateral posterior clinoidectomies are performed to gain access to the hypothalamic region, interpeduncular, and prepontine cisterns. RESULTS: From 2018 to 2023, 11 patients underwent EEPS. The cohort comprised mostly tuberoinfundibular craniopharyngiomas (n = 8, 73%). Seven (64%) patients had partial or complete anterior PG dysfunction preoperatively, while 4 (36%) had preoperative diabetes insipidus. Because of the specific tumor configuration, the chance of preserving endocrine function was estimated to be very low in patients with intact function. The main reasons for pituitary sacrifice were impaired visibility and surgical accessibility to the retrochiasmatic and retrosellar spaces. Gross-total tumor resection was achieved in 10 (91%) patients and near-total resection in 1 (9%) patient. Two (18%) patients experienced a postoperative CSF leak, requiring surgical revision. CONCLUSIONS: When preoperative pituitary function is already impaired or the risk for postoperative PH is considered particularly high, the EEPS and transsellar approach appears to be a feasible surgical option to improve visibility and accessibility to the retrochiasmatic hypothalamic and retrosellar spaces, thus increasing tumor resectability.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

Eustachian tube dysfunction symptoms after endonasal skull base surgery.

KEY POINTS: ETD symptoms are present in 16% patients with underlying skull base pathology. Preoperative ETD symptoms improve following surgical treatment of skull base pathology. ETD symptoms may worsen in patients with central, posterior, or malignant skull base pathology.

Symptomatic perianeursymal cyst development 20 years after endovascular treatment of a ruptured giant aneurysm: Case report and updated review.

Perianeurysmal cysts are a rare and poorly understood finding in patients both with treated and untreated aneurysms. While the prior literature suggests that a minority of perianeurysmal cysts develop 1-4 years following endovascular aneurysm treatment, this updated review demonstrates that nearly half of perianeurysmal cysts were diagnosed following aneurysm coiling, with the other half diagnosed concurrently with an associated aneurysm prior to treatment. 64% of perianeurysmal cysts were surgically decompressed, with a 39% rate of recurrence requiring re-operation. We report a case of a 71-year-old woman who presented with vertigo and nausea and was found to have a 3.4 cm perianeurysmal cyst 20 years after initial endovascular coiling of a ruptured giant ophthalmic aneurysm. The cyst was treated with endoscopic fenestration followed by open fenestration upon recurrence. The case represents the longest latency from initial aneurysm treatment to cyst diagnosis reported in the literature and indicates that the diagnosis of perianeurysmal cyst should remain on the differential even decades after treatment. Based on a case discussion and updated literature review, this report highlights proposed etiologies of development and management strategies for a challenging lesion.

Prolonged Impact of COVID-19 on Job Prospects and Training for Pediatric Gastroenterology Fellows in North America.

As the COVID-19 pandemic persisted into the 2020 to 2021 academic year, there was a continued effect on graduate medical education trainees and graduating trainee job attainment. Our survey aims to investigate how the pandemic has continued to affect job search and attainment for pediatric gastroenterology fellows as well as to re-evaluate the pandemic's impact on pediatric gastroenterology fellow educational experiences. Methods: An anonymous survey was distributed to all North American pediatric gastroenterology fellows from May to June 2021. Survey questions included topics related to job search and fellowship training and were tailored to respondent year of training. Results: Of 453 pediatric gastroenterology fellows in the 2020 to 2021 academic year, 158 fellows (35%) responded to the survey. Of graduating fellow respondents with job contracts, 74% reported willingness to make compromises in their job search, 76% reported accepting academic positions that were primary clinical, and 42% estimated staying at their accepted job for less than 5 years. When asked about the impact of COVID-19 on various aspects of fellowship education, a negative impact was reported in the following areas: 76% in research, 94% in clinical experience, 73% in procedural skills, and 84% in didactics. Conclusion: The COVID-19 pandemic continues to make a significant impact on pediatric gastroenterology fellowship education and the job attainment process. Regarding accepted job positions, we found substantial willingness to compromise, a shorter duration to stay at the job than expected, and minimal research focus. This raises concern regarding job preparedness and satisfaction as fellows complete their medical training.

The cholestatic infant: updates on diagnosis and genetics.

PURPOSE OF REVIEW: Cholestasis in infants can indicate a serious hepatobiliary disease and requires timely assessment, diagnosis and intervention to prevent progression to serious liver decompensation. This report aims to highlight recently published studies regarding diagnosis and treatment of cholestasis in infants. RECENT FINDINGS: The evaluation of neonatal cholestasis can be challenging, requiring the assessment of a broad differential diagnosis in timely fashion. The Italian Society of pediatric gastroenterology, hepatology, and nutrition position paper on the evaluation of neonatal cholestasis is reviewed and compared to other published guidelines. In biliary atresia, the most time-sensitive of these diagnoses, serum matrix metalloproteinase-7 was studied in Japanese infants with biliary atresia with excellent diagnostic performance characteristics. Genetic testing panels are an increasingly used tool to help identify causes of cholestasis. An American experience of genetic testing in large cohort of infants identified a definite or possible genetic diagnosis in 11% of cholestatic infants. In the treatment of prutitus in Alagille syndrome and progressive familial intrahepatic cholestasis the clinical studies of two newly Food and Drug Administration approved ileal bile acid transport inhibitors are discussed. New information on the prevalence of cytomegalovirus and idiopathic cholestasis as other etiologies of infant cholestasis is also reviewed. Lastly, new insight on potential maternal microbiome regulation on biliary disease in neonates on experimental biliary atresia models is discussed. SUMMARY: Cholestasis in infants requires timely diagnosis and intervention. There are exciting new diagnostic and treatment options now being studied which could help minimize the likelihood of advanced liver disease and development of serious complications.

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study.

BACKGROUND AND AIMS: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

Development and validation of an interpretable neural network for prediction of postoperative in-hospital mortality.

While deep neural networks (DNNs) and other machine learning models often have higher accuracy than simpler models like logistic regression (LR), they are often considered to be "black box" models and this lack of interpretability and transparency is considered a challenge for clinical adoption. In healthcare, intelligible models not only help clinicians to understand the problem and create more targeted action plans, but also help to gain the clinicians' trust. One method of overcoming the limited interpretability of more complex models is to use Generalized Additive Models (GAMs). Standard GAMs simply model the target response as a sum of univariate models. Inspired by GAMs, the same idea can be applied to neural networks through an architecture referred to as Generalized Additive Models with Neural Networks (GAM-NNs). In this manuscript, we present the development and validation of a model applying the concept of GAM-NNs to allow for interpretability by visualizing the learned feature patterns related to risk of in-hospital mortality for patients undergoing surgery under general anesthesia. The data consists of 59,985 patients with a feature set of 46 features extracted at the end of surgery to which we added previously not included features: total anesthesia case time (1 feature); the time in minutes spent with mean arterial pressure (MAP) below 40, 45, 50, 55, 60, and 65 mmHg during surgery (6 features); and Healthcare Cost and Utilization Project (HCUP) Code Descriptions of the Primary current procedure terminology (CPT) codes (33 features) for a total of 86 features. All data were randomly split into 80% for training (n = 47,988) and 20% for testing (n = 11,997) prior to model development. Model performance was compared to a standard LR model using the same features as the GAM-NN. The data consisted of 59,985 surgical records, and the occurrence of in-hospital mortality was 0.81% in the training set and 0.72% in the testing set. The GAM-NN model with HCUP features had the highest area under the curve (AUC) 0.921 (0.895-0.95). Overall, both GAM-NN models had higher AUCs than LR models, however, had lower average precisions. The LR model without HCUP features had the highest average precision 0.217 (0.136-0.31). To assess the interpretability of the GAM-NNs, we then visualized the learned contributions of the GAM-NNs and compared against the learned contributions of the LRs for the models with HCUP features. Overall, we were able to demonstrate that our proposed generalized additive neural network (GAM-NN) architecture is able to (1) leverage a neural network's ability to learn nonlinear patterns in the data, which is more clinically intuitive, (2) be interpreted easily, making it more clinically useful, and (3) maintain model performance as compared to previously published DNNs.

The Impact of COVID-19 on Job Prospects and Educational Training for Pediatric Gastroenterology Fellows.

OBJECTIVES: The COVID-19 pandemic has significantly affected graduate medical education with redistribution of trainees, altered clinical care, and decreased research. For graduating trainees, there remains concern that financial stability of health systems will affect the availability of new positions and hiring practices. This survey aims to evaluate the pandemic's impact from pediatric gastroenterology fellows' perspectives. METHODS: An anonymous survey was distributed by e-mail from June 11 to July 1, 2020 to all North American pediatric gastroenterology and advanced training fellows. The survey was tailored for the fellows' year of training including questions on education, clinical experience, research, and job outlook. RESULTS: Of the 434 pediatric gastroenterology fellows, 145 completed the survey. Of all respondents, negative impact was reported in 52% on clinical training, 46% research projects, and 41% procedural confidence. A majority (93%) of third-year respondents had a job contract signed at the time of the survey; however, 18% of those contracts were subsequently altered with 5 respondents having job contracts rescinded due to hiring freezes. Fifty-four percent of first- and second-year fellow respondents reported concern regarding finding a job with the majority being second-year fellows (78%). CONCLUSIONS: The COVID-19 pandemic continues to affect the medical system and healthcare professionals. This survey identified significant impact on job acquisition for graduating pediatric gastroenterology fellows and other critical components of training, which are likely applicable to other pediatric trainees. The survey results raise questions about potential strategies to improve medical education and job search success for graduating trainees.

Nonalcoholic Fatty Liver Disease in Children.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It represents a spectrum of disease from simple hepatic steatosis to steatohepatitis that may develop into progressive hepatic fibrosis and even cirrhosis. NAFLD is the most rapidly increasing indication for liver transplantation in adults. In children, the incidence of NAFLD has also increased over the past decade. Although the majority of children with NAFLD are overweight or obese, there is an increasing subset of children with normal body mass index with so-called lean NAFLD. NAFLD in children is associated with several extrahepatic manifestations, including hyperlipidemia, insulin resistance, and obstructive sleep apnea. The pathogenesis of NAFLD in children involves a multifactorial interaction among genetics, in utero exposures, early childhood exposures, and ongoing nutritional exposures. Although there are some similarities between pediatric NAFLD and adult NAFLD, liver biopsies in children show histologic differences between the two. The current standard-of-care treatment of NAFLD in children is lifestyle change to decrease caloric intake and increase physical activity. There are no medications currently approved for the treatment of NAFLD in children. This article aims to summarize the current understanding of pediatric NAFLD and future directions for intervention and therapeutic aims.

Sirtuin activation targets IDH-mutant tumors.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. METHODS: The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. RESULTS: We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. CONCLUSIONS: Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis.

BACKGROUND AND AIMS: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma.

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma. SIGNIFICANCE: Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.

Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD+ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells.

NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation. SIGNIFICANCE: Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit.See related commentary by Pirozzi and Yan, p. 1629.This article is highlighted in the In This Issue feature, p. 1611.