Citations

AbstractEpilepsy associated with high‐titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug‐resistant epilepsy associated with GAD65‐IgG. We retrospectively identified 15 patients with drug‐resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L−1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I–II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure‐free at last follow‐up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor–initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

Abstract Background: Circulating levels of THC and CBD may be altered when administered with medications that strongly or moderately inhibit or induce CYP450 enzymes responsible for metabolizing both substances. THC and CBD levels can also theoretically be altered in individuals who carry germline genetic variants or atypical phenotypes of CYP450 enzymes. In individuals where drug and gene interactions occur together, there could be a heightened impact on the circulating levels of THC and CBD. Materials and Methods: We conducted a retrospective chart review using a database of participants who previously completed pharmacogenomic testing and reported oral cannabis use in a medical encounter. Two pharmacogenomic-trained pharmacists reviewed medications and atypical variants in each participant to characterize the predicted effect of cannabis-drug, cannabis-gene, and cannabis-drug-gene interactions on circulating levels of THC and CBD. Results: Oral cannabis use was confirmed in 71 participants, with an average age of 68.5 years and primarily White women. Regarding THC metabolism, drug-only interactions were noted in 1 participant; both drug and gene interactions were noted in 4 participants; single- or combination-gene-only interactions were noted in 38 participants; and 28 participants had no interactions. Concerning CBD metabolism, drug-only interactions were noted in 4 participants; both drug and gene interactions were noted in 4 participants; single- or combination-gene-only interactions were noted in 36 participants; and 27 participants had no interactions. Conclusion: This study is the first, to our knowledge, to conceptualize the potential impact of drugs and atypical phenotypes on altering circulating levels of THC and CBD in a clinical sample. The absence of published clinical outcomes in this field renders it challenging to estimate clinical significance of these findings. Until such data become available, leveraging the theoretical insights into drug interactions and atypical cannabis metabolism described in our study may serve as a tool to guide clinical care.

Leptomeningeal disease (LMD) is a devastating sequelae of metastatic spread that affects approximately 5% of cancer patients. The incidence of LMD is increasing due to advancements in systemic therapy and enhanced detection methods. The purpose of this review is to provide a detailed overview of the evidence in the detection, prognostication, and treatment of LMD. A comprehensive literature search of PUBMED was conducted to identify articles reporting on LMD including existing data and ongoing clinical trials. We found a wide array of treatment options available for LMD including chemotherapy, targeted agents, and immunotherapy as well as several choices for radiotherapy including whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and craniospinal irradiation (CSI). Despite treatment, the prognosis for patients with LMD is dismal, typically 2–4 months on average. Novel therapies and combination approaches are actively under investigation with the aim of improving outcomes and quality of life for patients with LMD. Recent prospective data on the use of proton CSI for patients with LMD have demonstrated its potential survival benefit with follow-up investigations underway. There is a need for validated metrics to predict prognosis and improve patient selection for patients with LMD in order to optimize treatment approaches.

Several bacterial taxa enriched in inflammatory bowel diseases and colorectal cancer (CRC) are found in the oral cavity. We conducted a pilot study nested within a six-week aspirin intervention in a randomized placebo-controlled trial to test their response to aspirin intervention. Fifty healthy subjects, 50–75 years old, were randomized to receive 325 mg aspirin (n = 30) or placebo (n = 20) orally once daily for six weeks. Oral tongue swabs were collected at baseline and week six. We estimated the association between aspirin use and the temporal changes in the relative abundance of pre-specified genus level taxa from pre- to post-treatment. The temporal change in relative abundance differed for eight genus level taxa between the aspirin and placebo groups. In the aspirin group, there were significant increases in the relative abundances of Neisseria, Streptococcus, Actinomyces, and Rothia and significant decreases in Prevotella, Veillonella, Fusobacterium, and Porphyromonas relative to placebo. The log ratio of Neisseria to Fusobacterium declined more in the aspirin group than placebo, signaling a potential marker associated with aspirin intervention. These preliminary findings should be validated using metagenomic sequencing and may guide future studies on the role of aspirin on taxa in various oral ecological niches.

Introduction Pembrolizumab is a monoclonal PD-1 inhibitor used in the treatment of lung cancer in addition to several other malignancies. Psoriasiform dermatitis is a well-documented adverse effect. Case report We present a 68 year-old-male with a 50-year smoking history and a 30-year remote history of plaque psoriasis, limited to the knees and elbows, who presented with metastatic non-small cell lung cancer. He was started on a chemotherapy regimen of carboplatin, paclitaxel, and pembrolizumab. One month later, he presented to dermatology with diffuse erythematous scaly papules coalescing into plaques on 80% of body surface area (BSA). Management & outcome Pembrolizumab treatment was paused. The patient was prescribed triamcinolone 0.1% twice daily, but still had significant BSA at one-month and was started on an Il-17 inhibitor, ixekizumab, clearing the psoriasiform dermatitis. He was rechallenged with pembrolizumab every 3 weeks and repeat PET/CT demonstrated excellent tumor response. Discussion This case prompted a literature review to further characterize the use of IL-17 inhibitors for psoriasiform dermatitis in the setting of ICI therapy. All six cases demonstrated improvement of psoriasiform dermatitis, with two cases showing partial response and four cases showing complete resolution. In three of the six cases, the patients exhibited clinical response to the primary malignancy after rechallenging with ICI, while remaining on an IL-17 inhibitor. Our case, in conjunction with the other reported cases, seems to suggest that IL-17 blockade can maintain a fine balance in this challenging clinical scenario by treating psoriasiform dermatitis without compromising the efficacy of immunotherapy.

Objective: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. Background: The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training, considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. Methods: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. Results: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. Conclusions: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While the trainees wanted clarity on some areas, the overall opinion was in agreement with the recommendations.

Introduction: Lithium remains a gold standard treatment for bipolar disorder including during peripartum. Historically, guidelines advised against breastfeeding while taking lithium though recent data suggest it is acceptable for a healthy infant. Lack of awareness of acceptability contributes to decreased patient and clinician comfort and low breastfeeding rates. We report current breastfeeding rates, monitoring practices, and infant outcomes with lithium exposure in breastmilk at our institution. Methods: A retrospective chart review was conducted at a single academic medical center using records from 2013 to 2023. Electronic medical records were queried to identify patients prescribed lithium postpartum. Data were collected on timing of lithium initiation, lithium dose and concentration, breastfeeding status, and infant outcomes. Results: A total of 18 cases of lithium use in the postpartum period were identified. A total of 39% ( n = 7) of patients taking lithium postpartum breastfed. Most patients, 61% ( n = 11), initiated lithium prior to pregnancy, 11% ( n = 2) initiated during pregnancy and 27% ( n = 5) started postpartum. Four infant charts were reviewed with no reports of adverse events. Of these infants, average maternal lithium dose was 750 mg daily, with an average maternal serum lithium concentration of 0.62 mmol/L and average infant serum lithium concentration of 0.16 mmol/L. Conclusion: Our data demonstrate most patients using lithium postpartum have been taking lithium long-term and are not breastfeeding. Lithium exposure in breastmilk appears to be tolerated by healthy infants. There is a need for ongoing research and education on acceptability and infant monitoring recommendations to support patients who would like to breastfeed while on lithium.