In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.

Prolonged exposure to isoflurane increased neuronal apoptotic cell death in 7-day-old mice, eliminating approximately 2% of cortical neurons, of which some were identified as GABAergic interneurons. Moreover, isoflurane exposure interfered with the inhibitory nervous system by downregulating the central enzymes GAD65 and GAD67. Conversely, at this age, only a minority of degenerating cells were identified as astrocytes. The clinical relevance of these findings in animals remains to be determined.

Hyperleukocytosis in patients with acute myeloid leukemia (AML) can lead to leukostasis, which if left untreated, has a high mortality. While prompt cytoreductive chemotherapy is essential, treatment with leukapheresis is controversial. This study investigated the outcomes of patients with hyperleukocytosis who received leukapheresis. From 5596 encounters of patients with leukemia seen at Houston Methodist Hospital, we identified 26 patients who had newly diagnosed AML, WBC >50,000/μL, and received leukapheresis. We matched 26 patients who had similar baseline characteristics but did not receive leukapheresis. The primary endpoint was to compare the 28-day mortality rates between the treatment and the control groups. Secondary endpoints were 6-month, 1-year, and 2-year mortality rates. Using multivariate logistic regression analysis, leukapheresis was associated with significantly lower 28-day mortality rate (30.8% vs. 57.7%, p = .022). There was, however, no difference in long-term mortality rate. Our study demonstrates the short-term mortality benefit of using leukapheresis in AML patients presenting with hyperleukocytosis.

Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report in our case series that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.

A 55-year-old woman presented with a 3-week history of weakness. On examination, she had a heliotrope rash, V-neck and shawl signs. There was symmetric proximal muscle weakness, and 2/5 strength in upper and lower extremities. Laboratory values showed CK 5836, CRP 14.9, erythrocyte sedimentation rate 49, lactate dehydrogenase 633, negative antinuclear antibodies and anti-Jo1 antibodies. Muscle biopsy and immunohistochemistry findings were consistent with dermatomyositis. Treatment with high-dose steroids, cyclophosphamide and intravenous immunoglobulin (IVIG) was started, without improvement of symptoms. She was found to have cold agglutinins with a cold screen titre of 1:256,256. Work up for malignancy ensued. Positron emission tomography-computed tomography (PET-CT) showed increased uptake in the thyroid. Fine-needle thyroid biopsy with flow cytometry studies revealed atypical lymphocytes consistent with diffuse large B-cell lymphoma. The patient underwent R-CHOP therapy, with remarkable improvement of her symptoms. Dermatomyositis associated with primary thyroid lymphoma has not been previously reported. This case reinforces the importance of cancer screening in dermatomyositis patients.

e19355 Background: Immune checkpoint inhibitors (CIs) have been shown to improve overall survival in lung cancer and are FDA approved in multiple settings, both as single agents and in combination with chemotherapy. Immune related adverse events (irAEs) are common and frequently manifest as dermatitis, pneumonitis, colitis, and hepatitis, among others. Managing grade 2 or higher irAEs often requires multiple outpatient visits and sometimes inpatient admissions, which can significantly increase patient morbidity and healthcare cost. There is limited evidence on the safety of restarting CIs after moderate to severe irAE. Identifying high-risk factors for developing severe irAEs again after re-challenge can improve patient care and cost efficiency. Methods: We searched our electronic medical records to identify patients with NSCLC and SCLC treated with one or more PD-1, PD-L1, or CTLA-4 CIs at our institution between 2013 and 2019. We reviewed 452 patients and identified 44 patients who developed irAE requiring treatment discontinuation. Of these 44 patients, 19 were re-challenged with same or different CIs. The primary end point of this study is to assess the rate of grade 2 or higher irAE after CI re-challenge. Secondary endpoints are mortality rate, overall survival, and disease status. Results: Median follow up for the 19 patients who were re-challenged with CI was 15 months. Median duration of CI treatment after re-challenge was 6 months (range 0.5 to 25 months). 7 patients (37%) developed irAEs (grade 2 or above) again (5 pts with same irAE as prior). Multivariate logistic regression analysis revealed that age≥70 and requirement of steroid for initial irAEs were associated with a higher risk of recurrent irAEs. Median overall survival has not yet been reached; 32% of patients have died. No deaths were related to irAE. After re-challenge with CIs, 42% of the patients had partial response or stable disease, and 58% had progression of disease. Conclusions: Our study demonstrated that re-challenge with immunotherapy is feasible in some patients who had treatment held due to irAEs, though recurrent irAEs were common. Caution should be taken when restarting CIs after moderate to severe toxicities, especially in older adults.

Background Adjacent segmental intervertebral disk degeneration (ASDD) is a major complication secondary to lumbar fusion. Although ASSD pathogenesis remains unclear, the primary cause of intervertebral disk degeneration (IVDD) development is apoptosis of nucleus pulposus (NP). Raloxifene (RAL) could delay ASDD by inhibiting NP apoptosis. Methods An ASDD rat model was established by ovariectomy (OVX) and posterolateral spinal fusion (PLF) on levels 4–5 of the lumbar vertebrae. Rats in the treatment groups were administered 1 mg/kg/d RAL by gavage for 12 weeks, following which, all animals were euthanized. Lumbar fusion, apoptosis, ASDD, and vertebrae micro-architecture were evaluated. Results RAL maintained intervertebral disk height (DHI), delayed vertebral osteoporosis, reduced histological score, and inhibited apoptosis. The OVX+PLF+RAL group revealed upregulated expression of aggrecan and B-cell lymphoma-2 (bcl2), as well as significantly downregulated expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), metalloproteinase-13 (MMP-13), caspase-3, BCL2-associated X (bax), and transferase dUTP nick end labeling (TUNEL) staining. Micro-computed tomography (Micro-CT) analysis revealed higher bone volume fraction (BV/TV), bone mineral density (BMD), and trabecular number (Tb.N), and lower trabecular separation (Tb.Sp) in OVX+PLF+RAL group than in the OVX+PLF group. Conclusions RAL can postpone ASDD development in OVX rats through inhibiting extracellular matrix metabolic imbalance, NP cell apoptosis, and vertebral osteoporosis. These findings showed RAL as a potential therapeutic target for ASDD.

BackgroundThe establishment of rodent models, such as rat and mouse models, plays a critical role in the study of diabetic associated cognitive decline. With the continuous growth of relevant literature information, it is difficult for researchers to accurately and timely capture the topics in this field. Therefore, this study aims to explore the current status and frontier trends of diabetic associated cognitive decline research based on rat and mouse models through a bibliometric analysis.MethodsWe collected 701 original articles on this subject from the Science Citation Index Expanded of the Web of Science Core Collection from 2012 to 2021. Then we utilized CiteSpace and VOSviewer for plotting knowledge maps and evaluating hotpots and trends.ResultsDuring this decade, except for a slight decline in 2020, the number of annual outputs on diabetes associated cognitive decline research using rat and mouse models increased every year. China (country), China Pharmaceutical University (institution), Gao, Hongchang (the author from the School of Pharmacy of Wenzhou Medical University, China), and Metabolic Brain Disease (journal) published the most papers in this research field. The analysis results of co-cited references and co-occurrence keywords indicated that “mechanisms and prevention and treatment methods”, especially “oxidative stress”, “potential association with Alzheimer's disease” and “spatial memory” are research focuses in this subject area. The bursts detection of references and keywords implied that “cognitive impairment of type 1 diabetes” and “autophagy and diabetes associated cognitive decline” will be potential directions for future research in this subject area.ConclusionThis study systematically assessed general information, current status and emerging trends of diabetic associated cognitive decline research using rat and mouse models in the past decade based on a bibliometric analysis. The number of publications was annually increasing although a slight decline was observed in 2020. Contributions from different countries/regions, institutions, authors, co-cited authors, journals and co-cited journals were evaluated, which may also be used to guide future research. Through the analysis of references and keywords, we predicted the future research hotspots and trends in this field.