Central Nervous System Toxicity Research Articles

SAFETY AND EFFICACY OF INTRAOSSEOUS ROPIVACAINE IN LOWER EXTREMITY (SORE) STUDY

IntroductionDay stay surgery for anterior cruciate ligament (ACL) reconstructions is an increasingly common practice and has driven clinicians to come up with postoperative pain regimes that allow same day mobilisation and a safe and timely discharge. There is a paucity of literature surrounding the use of intraosseous (IO) ropivacaine used as a Bier's block to provide both intraoperative and postoperative analgesia in lower limb surgery.MethodsThis patient blinded, pilot study randomised 15 patients undergoing ACL reconstruction to receive either IO ropivacaine 1.5 or 2.0 mg/kg; or 300 mg of ropivacaine as local infiltration (standard of care). Toxic plasma levels of ropivacaine have been defined in the literature and therefore the primary outcome for this study was arterial plasma concentration of ropivacaine as a means to determine its safety profile. Samples were taken via an arterial line at prespecified times after tourniquet deflation. Secondary outcomes that we were interested in included immediate postoperative pain scores using the visual analogue scale (VAS) and perioperative opioid equivalent consumption.ResultsParticipants had a mean age of 27.8 (SD 9.2) years and 87% (13/15) were male. All patients in the intervention group receiving IO ropivacaine had plasma concentrations well below the threshold for central nervous system (CNS) toxicity (0.60 µg/ml). The highest plasma concentration was achieved in the intervention group receiving 1.5 mg/kg dose of ropivacaine reaching 3.59 mg/ml. This would equate to 0.22 µg/ml of free plasma ropivacaine. There were no differences across the three groups regarding pain scores or perioperative opioid consumption.ConclusionsThis study demonstrates that IO administration of 0.2% ropivacaine is both safe and effective in reducing perioperative pain in patients undergoing ACL reconstruction. There may be scope to increase the IO dose further or utilise other analgesics via the IO regional route to improve perioperative pain relief.

Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

Effect of pre-incisional and peritoneal local anesthetics administration on colon anastomosis and wound healing.

Previous research has shown that levobupivacaine is as effective as bupivacaine but carries a lower risk of cardiac and central nervous system toxicity. This study explores whether levobupivacaine and bupivacaine are preferable for all patients, includ-ing those with comorbidities, particularly focusing on their effects on colonic anastomosis. The primary objective is to examine the influence of levobupivacaine and bupivacaine on colonic anastomosis. Additionally, the study will assess their impact on wound healing and their anti-adhesive properties. Conducted between July 28, 2022, to August 4, 2022, at the Hamidiye Animal Experiments Laboratory, this study was approved by the University Science Health, Hamidiye Animal Experiments Local Ethics Committee. This study was conducted using 21 male Sprague rats aged 16-20 weeks. The rats were allocated into three equal groups of seven each: Group C: pre-incisional isotonic; Group B: pre-incisional bupivacaine; and Group L: pre-incisional levobupivacaine. Macroscopic adhesion scores (MAS) were recorded during laparotomy and tissue samples were taken for histopathological examination and hydroxyproline levels measurement. Wound tensile strength along the middle incision line and anastomotic burst pressure were also assessed. MAS was statistically significantly lower in Groups B and L compared to Group C (p<0.001). The wound histopathology score (WHS) was significantly higher in Group L than in Group B (p=0.021). Colon histopathology scores (CHSs) were also signifi-cantly higher in Group L compared to Group C (p=0.011). TThe study found that bupivacaine and levobupivacaine did not significantly enhance wound healing, although le-vobupivacaine significantly improved WHS relative to bupivacaine. According to the findings of this study, levobupivacaine can enhance clinical practice by being used in patients undergoing colon anastomosis. It contributes significantly to the durability of colon anasto-mosis, has a more positive effect on wound healing compared to bupivacaine, and exhibits anti-adhesive properties. Additional clinical trials are necessary to validate these results further.

Emerging roles of long non-coding RNAs in human epilepsy.

Genome-scale biological studies conducted in the post-genomic era have revealed that two-thirds of human genes do not encode proteins. Most functional non-coding RNA transcripts in humans are products of long non-coding RNA (lncRNA) genes, an abundant but still poorly understood class of human genes. As a result of their fundamental and multitasking regulatory roles, lncRNAs are associated with a wide range of human diseases, including neurological disorders. Approximately 40% of lncRNAs are specifically expressed in the brain, and many of them exhibit distinct spatiotemporal patterns of expression. Comparative genomics approaches have determined that 65%-75% of human lncRNA genes are primate-specific and hence can be posited as a contributing potential cause of the higher-order complexity of primates, including human, brains relative to those of other mammals. Although lncRNAs present important mechanistic examples of epileptogenic functions, the human/primate specificity of lncRNAs questions their relevance in rodent models. Here, we present an in-depth review that supports the contention that human lncRNAs are direct contributors to the etiology and pathogenesis of human epilepsy, as a means to accelerate the integration of lncRNAs into clinical practice as potential diagnostic biomarkers and therapeutic targets. Meta-analytically, the major finding of our review is the commonality of lncRNAs in epilepsy and cancer pathogenesis through mitogen-activated protein kinase (MAPK)-related pathways. In addition, neuroinflammation may be a relevant part of the common pathophysiology of cancer and epilepsy. LncRNAs affect neuroinflammation-related signaling pathways such as nuclear factor kappa- light- chain- enhancer of activated B cells (NF-κB), Notch, and phosphatidylinositol 3- kinase/ protein kinase B (Akt) (PI3K/AKT), with the NF-κB pathway being the most common. Besides the controversy over lncRNA research in non-primate models, whether neuroinflammation is triggered by injury and/or central nervous system (CNS) toxicity during epilepsy modeling in animals or is a direct consequence of epilepsy pathophysiology needs to be considered meticulously in future studies.

Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.

Working with cattle slurry on farms: emission and dispersion of hydrogen sulfide gas during stirring.

Over the past 15 years, there have been numerous fatalities related to working with animal slurry. Working with cattle slurry releases toxic gases, in particular, hydrogen sulphide (H2S), which can cause acute central nervous system toxicity, breathing difficulties, and death if exposed to high concentrations. Real-time measurements of H2S gas were taken over distance and time, during the stirring of cattle slurry on farms. Gas was measured at eight slurry stores with differing typical configurations of indoor or outdoor stores and with or without slatted flooring. Highest H2S gas levels were measured from indoor stores under slatted floors, and generally at positions closest to the stirrer or the point of maximum stirring, with levels decreasing with distance from source. Most of the data indicate H2S gas levels increase very rapidly after stirring starts, and mostly decline to baseline levels within 30minpost start of stirring. There were, however, circumstances where gas levels remained high and only started to decline once the stirrer had stopped. H2S gas levels at all farms, at all positions measured were consistently below 10ppm within 30min of the stirrer being stopped. The current data highlight areas of the farm and ways of working that have the potential for workers and others to be at risk of exposure to toxic slurry gases. The area should be left to ventilate naturally for at least 30minafter the stirrer has been stopped before re-entering buildings. Influencing the design of stirring equipment and future slurry stores would likely reduce the risk of worker exposure to slurry gases.

Quantifying preferences for urea cycle disorder treatments using a discrete choice experiment

Aims: Urea cycle disorders (UCDs) can cause ammonia accumulation and central nervous system toxicity. Nitrogen-binding medications can be efficacious but certain attributes may negatively impact adherence. This study sought to quantify the administration-related attributes influencing overall prescription selection and patient adherence. Methods: A web-based, quantitative survey including discrete choice experiment (DCE) methodology captured responses from health care providers for patients with UCDs. A series of hypothetical treatment profile sets with attributes such as route of administration, taste/odor, preparation instructions, packaging, dose measurement, and weight use restrictions were presented. From 16 sets of 3 hypothetical product profiles, respondents evaluated attributes most preferred for prescription selection or patient adherence. Attributes assumed a higher overall preference if relative importance (RI) scores were >16.67% (the value if all attributes were of equal importance). Preference weight scores were assessed. A nine-point Likert scale assessed respondent attitudes, such as satisfaction. Results: A total of 51 respondents completed the survey. Respondents reported dissatisfaction with current treatments (mean [SD] = 5.4 [1.7]). For prescription selection, four attributes achieved RI >16.67%: taste/odor (24%), weight restrictions (21%), preparation instructions (18%), and route of administration (17%). For adherence, three attributes related to administration achieved RI >16.67%: taste/odor (28%), preparation instructions (21%), and route of administration (17%). Preference weights for “taste/odor masked” were higher than “not taste/odor masked” for prescription selection (mean [SD]; 1.52 [1.10] vs -1.52 [1.10]) and treatment adherence (73.8 [55.2] vs -73.8 [55.2]). Limitations: This study contained a relatively small sample size. Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases. Conclusions: Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs.

Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs.

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

Safety of blood reinfusion drains after local infiltration analgesia in total joint replacement

BackgroundLocal infiltration analgesia (LIA) is frequently administered to patient undergoing joint replacement surgical procedures. The aim of the present research was to verify the safety of collected shed blood to be reinfused postoperatively, by measuring levobupivacaine levels in drainage blood in patients undergoing LIA during knee replacement surgery.Patients and Methods24 patients who underwent total knee arthroplasty (TKA) and 12 scheduled for total hip arthroplasty (THA) who received intraoperative LIA were considered. Blood samples were collected from shed blood which was present in drainage 2 and 5 hours after surgery and serum was analysed by liquid chromatography-tandem mass spectrometry.ResultsAt 2 hours postoperatively, the median levobupivacaine serum concentration in the collected shed blood was 1.2 mg/L (SD: 4.2) for TKA and 17.13 mg/L (SD: 24.4) for THA. At 5 hours, levobupivacaine concentration was 1.84 mg/L (SD: 2.2) for TKA and 17.5 mg/L (SD: 25.2) for THA. Higher values of average serum levobupivacaine concentration were reported in drains collected from patients who had undergone THA compared to TKA (p<0.001). BMI significantly influenced levels of serum drug, that resulted to be higher in patients with BMI<25 (p= 0.01).ConclusionLevobupivacaine from collected shed blood that would have been returned to the patient, was below toxicity level at 2 and 5 hours after LIA during total joint replacement. The average serum levobupivacaine concentration was found to be higher in drains taken from THA patients than TKA patients. Patients with lower BMI demonstrated the highest levels of levobupivacaine in shed blood and a lower blood volume needed for central nervous system toxicity. Therefore, in patients with a lower BMI undergoing THA, anaesthetic dosage should be reduced or autotransfusion should be avoided to prevent potential risks of toxicity.

Comparison of clinical efficacy of hyperbaric ropivacaine with hyperbaric bupivacaine in spinal anesthesia for transurethral resection of prostate: A randomized and double-blind study

Background: Ropivacaine is an ammino-amide local anesthetic agent with properties similar to bupivacaine, but its decreased lipophilicity is associated with reduced incidence of central nervous system toxicity and cardiotoxicity. This study evaluated the safety, efficacy, effects on hemodynamics and complications of spinal anesthesia using 0.5% hyperbaric bupivacaine and 0.75% hyperbaric ropivacaine in patients undergoing transurethral resection of the prostate (TURP). Aims and Objectives: The aim was to evaluate the safety, efficacy, hemodynamic stability, and side effects of spinal anesthesia using 0.5% hyperbaric bupivacaine and 0.75% hyperbaric ropivacaine in patients undergoing TURP. Materials and Methods: Sixty adult patients with physical status classes I and II, as determined by the American Society of Anesthesiologists, scheduled to undergo elective transurethral resection of prostate, were randomly allocated to receive either hyperbaric ropivacaine 0.75% 2.8 mL plus fentanyl 15 mcg or hyperbaric bupivacaine 0.5% 2.8 mL plus fentanyl 15 mcg. The parameters, such as demographic characteristics, duration of surgery, onset of sensory and motor blockade, hemodynamic stability, and complications, were compared in both groups. Results: Hyperbaric ropivacaine exhibited significantly slower onset times for sensory and motor blockade compared to hyperbaric bupivacaine. Patients in the ropivacaine group demonstrated better hemodynamic stability and experienced less hypotension compared to those who received bupivacaine. Moreover, the sensory and motor block lasted significantly longer in the bupivacaine group. Conclusion: About 0.75% hyperbaric ropivacaine is a better choice for spinal anesthesia in elderly patients undergoing TURP as compared to 0.5% hyperbaric bupivacaine.

Metronidazole: A culprit to balance and speech

In a country like India, oral metronidazole is the commonly prescribed drug of choice for entities such as amebiasis and visceral abscesses. Oral such cases, it is usually well tolerated and safe but can cause serious neurological adverse events. Peripheral neuropathy commonly encounters in practice but central nervous system toxicity is also well documented as it crosses the blood–brain barrier easily. Neurological toxicity of metronidazole may be due to prolonged administration, high doses, or high cumulative doses. Magnetic resonance imaging (MRI) of brain is the modality of choice to evaluate brain involvement. In the brain, the splenium of the corpus callosum, dentate nucleus of the cerebellum, and posterior pons involvement are commonly seen and diagnostic. Here, we have an interesting case report of a patient who was on oral metronidazole treatment for his large liver abscess, presenting with a complaint of neurological symptoms of unsteady gait, vertigo, dysdiadochokinesia, and difficulty in speech. Moreover, thus suspected as metronidazole drug toxicity and further investigated for the same, and MRI typically shows cerebellar and posterior corpus callosal involvement.

LOCAL BIOACTIVATION AND EFFICACY OF PALI-2108: A PROMISING PDE4 INHIBITOR PRODRUG FOR ULCERATIVE COLITIS TREATMENT

Abstract Phosphodiesterase-4 (PDE4) is a key enzyme in cAMP hydrolysis and is involved in various inflammatory and fibrotic diseases, such as ulcerative colitis (UC). PDE4 inhibition elevates intracellular cAMP, downregulates inflammatory cytokines (e.g., TNFα), and reduces cell adhesion molecules, thereby preventing local infiltration of inflammatory cells. Several PDE4 inhibitors (e.g., roflumilast and apremilast) are approved for COPD and psoriasis, with others under development for diseases such as idiopathic pulmonary fibrosis (IPF). Phase 2 clinical trials have shown that oral PDE4 inhibitors enhance clinical remission in UC patients, with a 20% placebo-adjusted improvement with low-dose apremilast. However, oral administration and systemic distribution cause central nervous system (CNS) toxicity (e.g., headaches, nausea, vomiting), leading to therapy discontinuation and limiting efficacy. Targeted and better-tolerated oral treatments are needed to fully exploit PDE4 inhibitors in UC. We assessed the efficacy of PALI-2108, an oral and locally bioactivated PDE4 inhibitor prodrug for UC treatment. PALI-2108 incorporates a galactose-derived sugar moiety, making it minimally absorbed until cleaved by the colonic bacterium enzyme β-glucuronidase. In a DSS-induced UC mouse model, PALI-2108 demonstrated that at doses of 21, 4, 0.75 mg/kg BID, and 1.5 mg/kg daily, it reduced the mean disease activity index (DAI) score over time compared to the DSS control group (Fig 1). Additionally, body weight loss over time was attenuated in the 21 and 4 mg/kg BID groups (Fig 2). A tissue distribution study showed colon preference of PALI-2108 with limited plasma levels and a colon/plasma AUC ratio exceeding 200. Additionally, oxazolone colitis induced mice treated with PALI-2108 showed colon-selective bioactivation, with negligible plasma levels compared to duodenal and ileal tissue. In a target engagement study, we used a CETSA Navigate® assay to measure PALI-2108 binding to cAMP-specific 3’, 5’-cyclic PDE4D in OXZ-treated mice. Melt and shift curves showed similar changes, indicating comparable target engagement in colon tissues between PALI-2108 and apremilast. Finally, in a tolerated dose study, we showed no CNS toxicity and emesis over effective doses in dogs. In conclusion, our results demonstrate local bioactivation of a PDE4 inhibitor pro-drug, PALI-2108, and its colon-specific distribution with limited systemic exposure. PALI-2108 has similar target engagement to other PDE4 inhibitors, dose-dependent efficacy in a UC model, and no systemic toxicity. We believe PALI-2108 is a promising novel therapy for UC, with localized bioactivation, expanded therapeutic window, and potent PDE4 inhibitory activity. PALI-2108 is in development for moderate-to-severe UC and is advancing toward regulatory filing for first-in-human studies. PALI-2108 reduced DSS induced mean disease activity index score (DAI) over time compared to control. PALI-2108 attenuated DSS induced body weight loss over time compared to control.

Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment.

To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB). A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed. The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype. The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.

Acute and chronic central nervous system oxidative stress/toxicity during hyperbaric oxygen treatment of subacute and chronic neurological conditions.

Oxygen toxicity has been defined as acute central nervous system (CNS), acute pulmonary, and chronic pulmonary oxygen toxicity. This study identifies acute and chronic CNS oxygen toxicity under 2.0 atmospheres absolute (ATA) pressure of oxygen. Methods: The authors' medical records from September 29, 1989 to January 20, 2023 and correspondence to the authors (9/1994 to 1/20.2023) from patients with signs and/or symptoms historically identified as acute CNS oxygen toxicity and those with neurological deterioration receiving hyperbaric oxygen for neurological conditions were reviewed. Acute cases were those occurring with ≤5 HBOTs and chronic cases >5 HBOTs. Chronic cases were separated into those at 1.5 ATA, > 1.5 ATA, or < 1.5 ATA oxygen. Cumulative dose of oxygen in atmosphere-hours (AHs) was calculated at symptom onset. Seven acute cases, average 4.0 ± 2.7 AHs, and 52 chronic cases were identified: 31 at 1.5 ATA (average 116 ± 106 AHs), 12 at >1.5 ATA (103 ± 74 AHs), and 9 at <1.5 ATA (114 ± 116 AHs). Second episodes occurred at 81 ± 55, 67 ± 49, and 22 ± 17 AHs, and three or more episodes at 25 ± 18, 83 ± 7.5, and 5.4 ± 6.0 AHs, respectively. Most cases were reversible. There was no difference between adults and children (p = 0.72). Acute intervention in cases (<3 months) was more sensitive than delayed intervention (21.1 ± 8.8 vs. 123 ± 102 AHs, p = 0.035). Outside sources reported one acute and two chronic exposure deaths and one patient institutionalized due to chronic oxygen toxicity. A withdrawal syndrome was also identified. Hyperbaric oxygen therapy-generated acute and chronic cases of CNS oxygen toxicity in chronic neurological conditions were identified at <2.0 ATA. Chronic CNS oxygen toxicity is idiosyncratic, unpredictable, and occurred at an average threshold of 103-116 AHs with wide variability. There was no difference between adults and children, but subacute cases were more sensitive than chronic intervention cases. When identified early it was reversible and an important aid in proper dosing of HBOT. If ignored permanent morbidity and mortality resulted with continued HBOT.

Delayed lethal central nervous system toxicity induced by a low-dose intrathecal administration of bupivacaine: case report

Spinal anesthesia by intrathecal administration of local anesthetic (LA) is a routine practice. Local anesthetic system toxicity, occurring in the central nervous system (CNS) and cardiovascular system, is a common and life-threatening adverse event of LA through a variety of routes, but is rarely encountered in spinal anesthesia when a very low dose of LA is injected into the subarachnoid space. Here, we report a case with manifestations of delayed lethal CNS toxicity after spinal anesthesia. A 55-year-old man underwent elective repair surgery for a chronic ulcer after receiving 10 mg intrathecal administration of bupivacaine. He developed nausea, agitation, paresthesia and myoclonus on the arms, legs, and trunk, as well as a gradually reduced level of consciousness one hour after intrathecal administration. He was sedated, intubated, and transferred to the intensive care unit. Both CT and MRI scans of the brain and assessments of blood showed no abnormalities. The electroencephalogram showed spike waves occurring at electrodes C3, C4, P3, P4, and T5. The patient was sedated continuously and treated with valproate. These symptoms were completely resolved in the following days without residual neurological complications. No cardiovascular complications were observed during the entire process. The delayed lethal symptoms in this case were most likely to be CNS toxicity induced by intrathecal bupivacaine administration. CNS toxicity after spinal anesthesia may be underestimated and unpredictable and should be vigilantly cared for in clinical settings.

Bilateral pudendal nerve block with levobupivacaine in cats with urinary obstruction

In small animal veterinary clinics, urinary obstructions in male cats are a common occurrence and are considered emergencies due to the rapid progression and potential risk of death. Patients in this condition experience intense pain, and part of the treatment, which involves urethral unblocking through catheterization, exacerbates the pain, making adequate analgesia essential to optimize recovery and patient comfort. The use of pudendal nerve block with lidocaine has been widely adopted in urinary unblocking procedures in cats as an alternative to epidural application. The anesthetic protocol should also take into account the biochemical changes associated with this condition. Therefore, bilateral local pudendal nerve block can be considered a procedure that offers advantages in terms of pharmacological safety and ease of execution. This study reports a case where levobupivacaine was administered as a local pudendal nerve block due to its lower cardiac and central nervous system toxicity when compared to lidocaine or bupivacaine.

Anaphylactic shock secondary to topical EMLA

Abstract The eutectic mixture of local anesthetics (EMLAs) is an anesthetic cream frequently used by dermatologists for various aesthetic procedures on a daily basis. Although side effects of EMLA are usually mild local skin reactions, rare complications such as methemoglobinemia, central nervous system toxicity, and cardiotoxicity can occur. Herein, we are reporting a case of anaphylactic shock to topical application of EMLA.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

Predictors of Outcome for Allogeneic Stem Cell Transplantation with a Reduced Intensity Pentostatin/TBI Conditioning Regimen in T-Cell Lymphomas: A Single Center Experience

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative option for patients with relapsed/refractory T-cell lymphoma (TCL).A reduced intensity conditioning (RIC) regimen of infusional pentostatin and 6 Gy of total body irradiation (TBI) has been shown to be well-tolerated and to have favorable engraftment kinetics 1. We utilized this regimen for patients with aggressive TCL undergoing alloSCT due to the demonstrated activity of pentostatin as a single agent in TCL and its potential impact, along with TBI, on eradicating residual TCL. Methods: This retrospective review includes adult patients with Nodal TCL (PTCL , AITL, ALCL), rare aggressive TCL [(T-ALL, natural killer/T-cell lymphoma (NKTL), adult T-cell leukemia/lymphoma (ATLL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL)], and T-Prolymphocytic leukemia (TPLL) who underwent alloSCT between 2006 and 2021. The primary objective was to determine transplant related outcomes including grade 3-4 acute graft-versus-host disease (aGVHD), extensive chronic GVHD (cGVHD), relapse, non-relapse mortality (NRM), and overall (OS), relapse-free (RFS), and GVHD-free, relapse-free survival (GRFS) following transplant. A subgroup analysis was conducted to evaluate the impact of disease status at the time of transplant and other factors, including age and subtype of TCL. Results: We report results for 40 patients (Nodal TCL: 21, Rare aggressive TCL: 10, T-PLL: 10) with a median age of 56.6 years ( range 24-71). Seventy-five percent were in clinical CR at the time of transplant. The 1-y cumulative incidence rate (CIN) of aGVHD was 42.5%. The 3-y CIN for cGVHD was 22.9. The median OS was 3.18 years with a 3-y OS rate of 51.9%. The median RFS was 1.24 years, with a 3-year RFS rate of 41.4%. OS and RFS were significantly higher in patients &amp;lt;65 compared to ≥65 (p-value 0.050 and 0.010 respectively), with no difference between the complete response (CR) and non-CR groups or different subtypes of TCL. The median GRFS was 0.52 years, with a 3-year GRFS rate of 20%. There was no statistically significant difference in GRFS or the incidence of GVHD between groups. Renal toxicity was noted in 10 patients. No cases of pulmonary or central nervous system (CNS) toxicities were observed. By day 100, 15 patients had an infection, including 8 bacterial infections and 5 viral infections. A total of 12 patients had reactivation of cytomegalovirus. Twelve patients died within the first year: 4 from relapse, 3 from aGVHD, 3 from infection, 1 from a subdural hematoma after a fall, and 1 from bladder perforation in the setting of hemorrhagic cystitis. Of 13 patients who relapsed, all received salvage therapy and 3 received DLI. Four are alive and in remission. Conclusions: In patients with TCL, RIC for alloSCT was well tolerated and compared favorably with retrospective data from larger groups of patients from CIBMTR and EBMT who were transplanted with different regimens 2. Interestingly, transplant-related outcomes were similar for patients with CR vs partial response (PR) at the time of transplant, and outcomes were better in patients younger than 65. Relapsed patients had a poor outcome despite salvage therapy with only a 30% OS at 3 years. 1. Foss et al, Transfusion 2020 2. Hamadani et al, Blood Advances 2022

NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA

Abstract Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.