CNS Toxicity Research Articles

Incidence of Symptomatic Brain Injury Following Pencil Beam Scanning Proton Beam Therapy for Management of Central Nervous System Tumors

Although proton beam therapy (PBT) results in decreased dose to non-target tissue compared to modern photon therapy, there are concerns of rare CNS injury occurring following PBT due in part to RBE/LET uncertainties. Such uncertainties can be further exacerbated when delivering PBT using pencil beam scanning (PBS) technology. The primary objective of this study was to report the incidence of CNS toxicities in a large cohort of adult brain tumor patients treated with PBS at a single academic proton center. We hypothesized that PBS can be safely delivered for treatment of CNS tumors.A single-institution retrospective IRB-approved analysis was conducted of all patients with CNS tumors treated with PBT at our institution between February 2016 and April 2020. Patients were excluded if follow up was less than one month. Kaplan-Meier estimates of treatment toxicities were calculated, accounting for death and local recurrence as competing risks. Multivariate analysis (MVA) was performed using the Cox proportional hazard model to determine risk factors associated with symptomatic toxicity.A total of 283 consecutive patients with CNS toxicities (116 [41%] males, 167 [59%] females) completed a course of definitive-intent PBT; 116 patients had meningiomas/pituitary adenomas, 92 patients had gliomas/GBM, and 75 patients had other histologies (chordoma, paraganglioma, ependymoma, medulloblastoma, pineal tumor). Median age was 52 years old (range 18-91). Median dose of PBT was 51.3 Gy (RBE = 1.1, [range 20.4 - 78.8 Gy RBE]). Median dose per fraction was 1.8 Gy/fx (range 1.1-3.8 Gy/fx). Sixty patients [21%] had received some form of prior intracranial RT. Concurrent systemic therapy was delivered in 49 patients [17%]. Median follow-up time was 20 months. The 2-year incidence of symptomatic-treatment toxicity was 8.7%. Symptomatic radiation necrosis occurred in 13 patients including optic neuritis [N = 2], seizure [N = 3], neurologic deficit [N = 9], stroke [N = 1] and brainstem necrosis [N = 2]. Two patients had symptoms with no radiation-related imaging changes including stroke [N = 1] and seizure [N = 1]. MVA identified prior intracranial irradiation (HR 3.901, 95% CI 1.42, 10.73, P = 0.008) and increasing EQD2 of proton radiation (HR 1.077 per Gray, 95% CI 1.00, 1.15, P = 0.036) as predictive factors for increased incidence of adverse events including symptomatic toxicity and asymptomatic radiation necrosis. No PBT treatment planning parameters were found to correlate with toxicity risk.This is the largest series to date reporting outcomes for patients with CNS tumors treated with pencil beam scanning PBT. Our analysis indicates that pencil beam scanning PBT in this setting is well-tolerated with a toxicity profile similar to modern photon therapy. Future studies correlating toxicity-risk with LET are warranted.B. Savla: None. G.S. Alexander: None. K. Sun: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. S. Mossahebi: None. Y. Kwok: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

A prospective randomized clinical study to compare the efficacy of 0.25% bupivacaine with clonidine and 0.25% levobupivacaine with clonidine in supraclavicular brachial plexus block for upper limb surgeries

:Bupivacaine is an amide local anesthetic, available as a racemic mixture of Dextro and Levorotatory Isomers. Due to its rapid onset and longer duration of anesthesia, It is routinely preferred in various regional anesthetic techniques. However, it is associated with serious cardiovascular and neurological toxicity. Its pure S- enantiomer, Levobupivacaine having similar pharmacological profile is known to have lesser cardiovascular and CNS toxicity. Combining adjuvants like clonidine, a centrally acting partial alpha-2-adrenergic agonist to improve quality of anesthesia is common practice. Hence, the aim of our study is to compare efficacy and safety of 0.25% Levobupivacaine and 0.25% Bupivacaine when combined with clonidine in supraclavicular brachial plexus block for upper limb surgeries.Eighty patients aged between 18 to 60 years with ASA physical status I-II, scheduled for elective upper limb surgeries under were randomized into two groups. Peripheral nerve stimulator guided Supraclavicular brachial plexus block was administered. Group BC received 30ml of 0.25% Bupivacaine plus 1µg/kg Clonidine and Group LC 30ml of 0.25% Levobupivacaine plus 1µg/kg Clonidine. The time of onset of sensory and motor block, duration of sensory and motor block, perioperative hemodynamic parameters, postoperative pain for 24hours and adverse effects were studies.Group LC had faster onset of sensory block (p= 0.014) as well as faster onset of motor block (p= 0.012) compared to group BC. However, durations of sensory block and motor block were statistically not significant in both the groups (p>0.05). Perioperative hemodynamic parameters and assessment of pain during 24 hours of post operative period were comparable and statistically not significant.1mcg/kg of clonidine used as an adjuvant to 30ml of 0.25% Levobupivacaine produces faster onset of sensory and motor block compared to 0.25% Bupivacaine in supraclavicular brachial plexus block. However, similar anesthetic efficacy in terms of duration of sensory and motor block, hemodynamics and postoperative analgesia were observed.

JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.

The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.

Human-induced pluripotent stem cell-derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs.

Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome‐3 (LQTS3) is caused by mutations in the Nav1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re‐engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient‐derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on‐target) and detrimental effects (off‐target) of mexiletine and synthetic analogs, respectively. The approach combined “drug discovery” and "hit to lead” refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22. Compared to mexiletine, compound 22 showed a 1.85‐fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P‐450, as previously shown, and by the flavin‐containing monooxygenase (FMO). Deuterated‐22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.

Gemcitabine/Clofarabine/Busulfan: A New Myeloablative Reduced-Toxicity Conditioning Regimen with High Activity for Allogeneic Stem-Cell Transplant (alloSCT) in Aggressive Lymphomas

INTRODUCTION:Stem-cell transplantation (SCT) is standard treatment of relapsed lymphomas. Patients in refractory relapse or relapsed after autoSCT are often considered for an alloSCT, aiming at a graft-vs.-lymphoma (GVL) effect. While reduced intensity conditioning regimens have substantially contributed safety to alloSCT, aggressive lymphomas often progress rapidly afterwards, partly due to tumor cell growth outpacing GVL. Outcomes are particularly poor for patients with active disease at the time of alloSCT. Thus, development of more efficacious conditioning regimens for aggressive lymphomas, avoiding mucotoxic drugs (such as melphalan), is a major need. We previously showed that the combination of 2 nucleoside analogues [gemcitabine (GEM) + clofarabine (CLO)] followed by busulfan (BU) is highly synergistic against B- and T-cell lymphoma cell lines, through inhibition of DNA damage repair. Those observations led us to clinically study a novel high-dose regimen of GEM/CLO/BU with alloSCT for aggressive lymphomas.METHODS:Eligibility included age 12-65; refractory DLBCL, T-cell and Hodgkin lymphomas; acceptable end-organ function, and an 8/8 HLA-matched (A, B, C and DRB1) sibling (MSD) or unrelated donor (MUD). GEM was escalated from dose level 1 to 3; it was given on days -6 (d-6) and d-4 as a loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 40-90 min (total daily dose 475, 675 or 975 mg/m2), to be followed by CLO (40 mg/m2/day x 4, d-6 to d-3) and BU (pharmacokinetically targeted to an average daily AUC of 4,000 μMol•min x 4, d-6 to d-3). AlloSCT was on d0. Patients receiving a MUD transplant received rabbit ATG (0.5, 1.5 and 2 mg/Kg on d-3, d-2, and d-1, respectively). Patients with CD20+ tumors received rituximab (375 mg/m2) on d-14, d-7, d+1 and d+8. The GVHD prophylaxis included tacrolimus (tapered after d+100) and mycophenolate mofetil (from d0 to d+60). Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting >3 days at peak severity. Dose escalation of gemcitabine followed a Bayesian design targeting a maximal DLT probability of 25%. Non-relapse mortality (NRM), relapse incidence, G II-IV or III-IV acute GVHD or chronic GVHD were calculated with the cumulative incidence method with consideration of competing risks.RESULTS:Between 11/12 and 06/17, 48 patients were enrolled: 25 DLBCL (5 double hit), 13 T-NHL and 10 HL (Table); 27 MSD, 20 MUD.All patients received PBPC. The MTD of gemcitabine was level 3. DLT was observed at the following frequencies: level 1: 12.5% (1/8), level 2: 9% (2/9), and level 3: 25% (4/16). Regimen-related toxicities were manageable, including mucositis (47% G2, 42% G3), self-limited transaminitis (21% G2, 49% G3), hyperbilirubinemia (no cases of VOD) (30% G2, 19% G3), and dermatitis (13% G2). There were no cardiac, pulmonary, renal or CNS toxicities. Neutrophils dropped to <0.1 in all patients on median d0 (d-3 to +2), and engrafted on median d+10 (d+9 to +20). Platelets engrafted on median d+12 (d+8 to +38).All patients engrafted; full donor chimerism was established early: a median of 100% (50-100%) on d+28, and 100% (98%-100%) on d+100. The rates of G II-IV and III-IV acute GVHD were 29.8% (35% MSD, 25% MUD) and 10.6% (19% MSD, 0% MUD), respectively. The rates of moderate-severe / severe chronic GVHD were 8.5% / 6.4%. 1/3 HL pts with prior exposure to anti-PD1 developed steroid-responsive hepatic chronic GVHD.The γ-H2AX levels in PBMNC (N=19) increased throughout treatment, to a median of 8.5 fold from baseline (range, 0.4-46.3) (P=0.0001) and PARP-1 decreased to 0.45 fold (0.2-6.3) (P=0.4), indicative of activation of DNA damage response and apoptosis, respectively. The overall response rates on d+30 (in 34 patients with measurable disease) are 77% (DLBCL), 100% (T-NHL), and 75% (HL). Their respective CR rates are 69%, 100% and 75%. The d+100 / 1-year NRM rates were 6.25% / 14.5%. NRM causes were infection (6) and GVHD (1). At median follow-up of 18 months (1-53) the EFS / OS rates of the entire population are 44% / 56%. Outcomes appear especially promising in the DLBCL (EFS / OS, 54% / 54%) and the T-NHL (62% / 69%) subgroups.CONCLUSIONS:GEM/CLO/BU is a new, myeloablative, reduced-toxicity alloSCT regimen with high activity in this population of heavily pretreated and refractory aggressive lymphomas, which warrants further study in disease-specific trials [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Anti-HIV Activity of Cucurbitacin-D against Cigarette Smoke Condensate-Induced HIV Replication in the U1 Macrophages.

Chemodietary agents are emerging as promising adjuvant therapies in treating various disease conditions. However, there are no adjuvant therapies available to minimize the neurotoxicity of currently existing antiretroviral drugs (ARVs). In this study, we investigated the anti-HIV effect of a chemodietary agent, Cucurbitacin-D (Cur-D), in HIV-infected macrophages using an in-vitro blood–brain barrier (BBB) model. Since tobacco smoking is prevalent in the HIV population, and it exacerbates HIV replication, we also tested the effect of Cur-D against cigarette smoke condensate (CSC)-induced HIV replication. Our results showed that Cur-D treatment reduces the viral load in a dose-dependent (0–1 μM) manner without causing significant toxicity at <1 μM concentration. Further, a daily dose of Cur-D (0.1 μM) not only reduced p24 in control conditions, but also reduced CSC (10 μg/mL)-induced p24 in U1 cells. Similarly, Cur-D (single dose of 0.4 μM) significantly reduced the CSC (single dose of 40 μg/mL)-induced HIV replication across the BBB model. In addition, treatment with Cur-D reduced the level of pro-inflammatory cytokine IL-1β. Therefore, Cur-D, as an adjuvant therapy, may be used not only to suppress HIV in the brain, but also to reduce the CNS toxicity of currently existing ARVs.

Lithium carbonate toxicity in an elderly patient: a case report

A case report of a 73-year-old man admitted in the intensive care unit with acute renal failure and lithium toxicity is reported. Lithium is a gold standard drug for bipolar disorder. It has a narrow therapeutic index and requires blood level monitoring frequently. Hemodialysis is the last resort in management of lithium toxicity but in between high rebound levels during the dialysis result in persistent CNS toxicity.

Phase 1, 2 trial of concurrent anti-PD1 and stereotactic radiosurgery for melanoma and non-small cell lung cancer brain metastases (NCT02858869).

2022 Background: The safety and efficacy of concurrent pembrolizumab (anti-PD1) and stereotactic radiosurgery (SRS) for brain metastases (BM) is unknown. Methods: Patients with melanoma or NSCLC, 1-10 brain metastases, ≥ 1 extra-cranial lesion, age ≥ 18, and ECOG 0-1 were treated with anti-PD1 every 3 weeks. SRS was administered 1-2 days after starting anti-PD1. SRS used three different radiation arms: Arm A used 6 Gray (Gy) in 5 fractions (fx), Arm B used 9 Gy in 3 fx, and Arm C used 18-21 Gy in single fx. Primary endpoint was grade 3 CNS toxicity at 3 months (CTCAE v 4.0). Secondary endpoints were overall survival (OS), local control (LC) within the SRS field, intra-cranial progression free survival (IC-PFS), extra-cranial progression free survival (EC-PFS), rate of extra-cranial clinical benefit, and immunological changes. OS, LC, IC-PFS, and EC-PFS were estimated using the Kaplan-Meier method, and covariates were compared using log-rank tests. 95% confidence intervals for 6-month and 12-month were estimated using Greenwood’s formula. Results: 25 patients were treated from 2016 until 2020. The mean age was 61. The mean number of CNS lesions was 2.7. The mean number of extra-cranial lesions was 2.5. Six were enrolled on Arm A, 12 on Arm B, and 7 on Arm C. 21 had melanoma. 4 had NSCLC. Of the melanoma, 8 were BRAF-, 10 were BRAF+, and 3 had unknown mutation status. 12 patients (48%) had progressed on prior immunotherapy and/or other oncological therapies. The trial met its primary endpoint, with no grade 3 CNS toxicity at 3 months. Two patients (8%) experienced ≥ Grade 3 anti-PD1 related toxicity, and no grade 5 toxicity was noted. The median OS was 32.8 months. The 6 and 12 month OS were 79.1% (56.5-90.8%) and 67.8% (43.3-83.5%), respectively. The 1 year OS was similar between previously treated and treatment naïve patients (71.8% vs. 65.6%), suggesting some role for SRS in overcoming therapy resistance. However, with longer follow-up, the OS trended worse (p=0.07) for previously treated patients. LC was 95.7% (72.9-99.4%) at 6 and 12 months. IC-PFS at 6 months was 69.1% (45.8-83.9%), and at 12 months was 57.5% (33.7-75.5%). The EC-PFS at 6 and 12 month was 54.5% (32.1-72.4%) and 43.6% (22.3-63.2%), respectively. Clinical benefit, which was defined as a best overall response of stable disease or better according to RECIST 1.1, occurred in 12 patients (48%). No outcome differences were noted amongst the three different SRS arms. 70% of the patients demonstrating early activation (within 3 weeks of starting SRS/anti-PD1) of CD8+PD1+Ki67+ T cells demonstrated a clinical benefit. 100% of patients that failed to show early activation of CD8+PD1+Ki67+ T cells progressed. Conclusions: Concurrent pembrolizumab (Anti-PD-1) and SRS is safe and effective. Early activation of CD8+PD1+Ki67+ T cells correlates with improved outcome. Further trials testing pembrolizumab and SRS are justified. Clinical trial information: NCT02858869.

Pharmacogenetic Associations Between Atazanavir/UGT1A1*28 and Efavirenz/rs3745274 (CYP2B6) Account for Specific Adverse Reactions in Chilean Patients Undergoing Antiretroviral Therapy.

Background: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and atazanavir (ATV), a protease inhibitor, are drugs widely used in antiretroviral therapy (ART) for people living with HIV. These drugs have shown high interindividual variability in adverse drug reactions (ADRs). UGT1A1*28 and CYP2B6 c.516G>T have been proposed to be related with higher toxicity by ATV and EFV, respectively. Objective: To study the association between genetic polymorphisms and ADRs related to EFV or ATV in patients living with HIV treated at a public hospital in Chile. Methods: Epidemiologic, case–control, retrospective, observational study in 67 adult patients under EFV or ATV treatment was conducted, in the San Juan de Dios Hospital. Data were obtained from patients’ medical records. Genotype analyses were performed using rtPCR for rs887829 (indirect identification of UGT1A1*28 allele) and rs3745274 (CYP2B6 c.516G>T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant). Results: In ATV-treated patients, hyperbilirubinemia (total bilirubin >1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin >1.9 mg/dl) were statistically associated with UGT1A1*28 in recessive and codominant inheritance models (OR = 16.33, p = 0.028 and OR = 10.82, p = 0.036, respectively). On the other hand, in EFV-treated patients adverse reactions associated with CNS toxicity reached 34.21%. In this respect, nightmares showed significant association with CYP2B6 c.516G>T, in codominant and recessive inheritance models (OR = 12.00, p = 0.031 and OR = 7.14, p = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with CYP2B6 c.516G > T in the codominant and recessive models (OR = 30.00, p = 0.011 and OR = 14.99, p = 0.021, respectively). Conclusion: Our findings suggest that after treatment with ATV or EFV, UGT1A1*28 and CYP2B6 c.516G>T influence the appearance of moderate-to-severe hyperbilirubinemia and CNS toxicity, respectively. However, larger prospective studies will be necessary to validate these associations in our population. Without a doubt, improving adherence in patients living with HIV is a critical issue to the success of therapy. Hence, validating and applying international pharmacogenetic recommendations in Latin American countries would improve the precision of ART: a fundamental aspect to achieve the 95–95–95 treatment target proposed by UNAIDS.

Plan quality effects of maximum monitor unit constraints in pencil beam scanning proton therapy for central nervous system and skull base tumors

Purpose/objective(s)With reports of CNS toxicity in patients treated with proton therapy at doses lower than would be expected based on photon data, it has been proposed that heavy monitor unit (MU) weighting of pencil beam scanning (PBS) proton therapy spots may potentially increase the risk of toxicity. We evaluated the impact of maximum MU weighting per spot (maxMU/spot) restrictions on PBS plan quality, prior to implementing clinic-wide maxMU/spot restrictions. Materials/methodsPBS plans of 11 patients, of which 3 plans included boosts, for a total of 14 PBS sample cases were included. Per sample case, a single dosimetrist created 4 test plans, gradually reducing the maxMU/spot in the plan. Test Plan 1, unrestricted in maxMU/spot, was the reference for all restricted plan comparisons (comparison sets 2 vs. 1; 3 vs. 1; and 4 vs. 1). The impact of MU/spot restrictions on plan quality metrics were analyzed with Wilcoxon signed rank test analyses. Treatment delivery time was modeled for a representative case. ResultsA total of 14 PBS sample cases, 7 (50%) single-field optimized, 7 (50%) multi-field optimized, 9 (64%) delivering > 3500 cGy, 9 (64%) with 3 beams, and 7 (50%) without a range shifter were included. There were no differences in plan quality metrics of target coverage (V95% and V100% prescription), conformality and gradient indices, hot spot volume (V105% prescription), and dose to normal brain (V10%/30%/50%/70%/90%/100% prescription) with reductions of allowable maxMU/spot across all comparison sets (p > 0.05). Max MU/spot restrictions did not increase treatment delivery time when analyzed for a representative case. ConclusionMaxMU/spot restrictions within the thresholds evaluated in this study did not degrade overall plan quality metrics. Future studies should evaluate spot weighting with linear energy transfer/relative biologic effectiveness-informed planning to determine if spot weighting manipulation impacts clinical outcomes and mitigates toxicity.

Local Anesthetic-Induced Central Nervous System Toxicity during Interscalene Brachial Plexus Block: A Case Series Study of Three Patients.

Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.

Attenuation of ongoing neuropathic pain by peripheral acting opioid involves activation of central dopaminergic neurocircuitry

Background and purposeOngoing neuropathic pain is one of the most challenging clinical problems which have detrimental effects on a patient’s life quality. Conventional therapies for chronic neuropathic pain majorly includes centrally acting analgesics. Unfortunately, the unceasing use of these drugs results in adverse effects, such as CNS in-coordination, respiratory depression and substance use disorder. DALDA ([D-Arg2, Lys4]-Dermorphin-(1–4)-amide), a peripherally acting opioid have been shown to possess potent analgesic activity without causing CNS toxicities in nerve-injured rats. However, the mechanism(s) underpinning DALDA induced-attenuation of ongoing neuropathic pain is yet to identify [1]. Experimental designIn this study, we have measured the in–silico ligand-receptor binding affinity of DALDA against potential inflammatory targets by utilizing glide module of schrödinger software. Effect of DALDA on oxido-inflammatory stress was evaluated in LPS-induced C6 glial cells. In-vitro studies were followed by the behavioral assessments, where effect of DALDA was measured in chronic constriction injured rats. To examine the effect of DALDA on dopaminergic neurotransmission, cerebrospinal fluid of nerve-injured rats was assessed using LC-MS/QToF (Liquid Chromatography-Mass spectrometry/ Quadrapole time of flight Analyzer). ResultsDALDA has shown a good binding affinity with chemokine receptor type-2 (CCR2), chemokine CX3C receptor 1 (CX3CR1) and purinergic receptor (P2×4), major receptor subtypes involved in pain and inflammation. Findings from the in-vitro studies suggest that DALDA possesses potent anti-oxidant activity leading to inhibition of p38-MAPK pathway [1]. Moreover, the subcutaneous administration of DALDA leads to dose-dependent attenuation of thermal and mechanical hypersensitivity along with inhibition of neuroinflammatory mediators in serum and spinal cord of nerve-injured rats. Most importantly, DALDA treated neuropathic rats showed a preference for the DALDA-treated chamber, which was attenuated on pre-treatment with dopaminergic receptor antagonist, flupenthixol. LC-MS analysis further confirms the enhanced dopaminergic transmission in the brain of DALDA-treated neuropathic rats. ConclusionOur findings suggest that DALDA mediated attenuation of ongoing neuropathic pain may be associated with a decrease in spinal neuroinflammatory signalling and subsequent increase in the brain dopamine level; may serve a potential therapeutic for the treatment of ongoing neuropathic pain.

A retrospective multicenter study comparing bupivacaine and ropivacaine in endoscopic ultrasound guided celiac plexus neurolysis.

Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) is widely practiced to palliate cancer pain in patients with inoperable abdominal malignancy. During CPN, the dehydrated alcohol is injected to ablate neural tissue and local anesthetics is to minimize the discomfort from alcohol injection. This study aims to compare the efficacy and safety of bupivacaine and ropivacaine in EUS-CPN. We retrospectively pooled and analyzed two large EUS centers' 150 consecutive patients underwent EUS-CPN from January 2012 to March 2019. Patients were divided into 3 groups based on the selection of anesthetics: 0.5% ropivacaine (ROPI, n=23), 0.375% bupivacaine (0.375% BUPI, n=21), 0.75% bupivacaine (0.75% BUPI, n=106). Visual analogue scale (VAS) was used to measure pre/post-operative pain at 11 observation points. Additional data were collected from medical records. The incidence of procedure-related pain within 12 hours after CPN was significantly different among the three groups, 10.38% in 0.75% BUPI [OR =0.26 (95% CI: 0.07-0.94); P=0.04], 26.09% in ROPI and 23.81% in 0.375% BUPI group, respectively. The risk of post-procedural arrhythmia was similar between the 0.375% and 0.75% BUPI groups (19.05% versus 18.87%), while relatively lower in ROPI group (13.04%). No patients in any group developed symptoms of CNS toxicity related to anesthetics. Compared with 0.375% bupivacaine and 0.5% ropivacaine, 0.75% bupivacaine in CPN can reduce post-procedural pain. Ropivacaine shows a tendency of less arrhythmogenic effect in CPN.

Toxicity Reduction after Craniospinal Irradiation via Helical Tomotherapy in Patients with Medulloblastoma: A Unicentric Retrospective Analysis.

Simple SummaryMedulloblastoma (MB) is one of the most common pediatric brain tumors. Surgical resection, followed by radiotherapy (RT) and chemotherapy, are the standard of care for medulloblastoma patients. This retrospective analysis assesses the toxicity profile of different radiation techniques (Tomotherapy versus conventional radiotherapy technique) and estimates survival rates. Radiotherapy via Tomotherapy seems to be an efficacious treatment for patients with lower rates of acute upper gastrointestinal and central nervous system toxicities than conventional radiotherapy techniques.Objectives: Recent trials with craniospinal irradiation (CSI) via helical Tomotherapy (HT) demonstrated encouraging medulloblastoma results. In this study, we assess the toxicity profile of different radiation techniques and estimate survival rates. Materials and Methods: We reviewed the records of 46 patients who underwent irradiation for medulloblastoma between 1999 and 2019 (27 conventional radiotherapy technique (CRT) and 19 HT). Patient, tumor, and treatment characteristics, as well as treatment outcomes—local control rate (LCR), event-free survival (EFS), and overall survival (OS)—were reviewed. Acute and late adverse events (AEs) were evaluated according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Results: In total, 43 courses of CSI and three local RT were administered to the 46 patients: 30 were male, the median age was 7 years (range 1–56). A median total RT dose of 55 Gy (range 44–68) and a median CSI dose of 35 Gy (range, 23.4–40) was delivered. During follow-up (median, 99 months), six patients (13%) developed recurrence. The EFS rate after 5 years was 84%. The overall OS rates after 5 and 10 years were 95% and 88%, respectively. There were no treatment-related deaths. Following HT, a trend towards lower grade 2/3 acute upper gastrointestinal (p = 0.07) and subacute CNS (p = 0.05) toxicity rates was detected compared to CRT-group. The risk of late CNS toxicities, mainly grade 2/3, was significantly lower following HT technique (p = 0.003). Conclusion: CSI via HT is an efficacious treatment modality in medulloblastoma patients. In all, we detected a reduced rate of several acute, subacute, and chronic toxicities following HT compared to CRT.

Comparison of clinical efficacy of ropivacaine and lignocaine with adrenaline for implant surgery anesthesia: a split-mouth randomized controlled clinical trial.

BackgroundThe primary indication for using long-acting anesthetics in dentistry is extensive dental procedures that require pulpal anesthesia beyond 90 min and management of postoperative pain. Ropivacaine is an amide local anesthetic that is available at various concentrations with inherent vasoconstrictive properties at low concentrations. Ropivacaine has a 75% greater margin of safety than bupivacaine. Ropivacaine can be a good alternative to bupivacaine as a local anesthetic in dental implant surgery as it provides a longer duration of both pulpal and soft tissue anesthesia after mandibular nerve block and lowers CNS and cardiovascular toxicity. This study aimed to evaluate and compare the clinical efficacy of ropivacaine and lignocaine for implant surgery anesthesia.MethodsFifteen patients with bilateral edentulous sites indicated for implant placement were recruited for this study. Patients aged 20–60 years of both sexes were randomly recruited. Thirty implant placements were performed in the test and control groups using ropivacaine and lignocaine with adrenaline as local anesthetics, respectively.ResultsThe results were analyzed statistically. The duration of anesthesia was significantly higher in the test group than in the control group. Ropivacaine was found to be superior to lignocaine in terms of the quality of anesthesia. The comparison of mean visual analog scale scores showed ropivacaine to have better anesthetic and analgesic effects than the control group.ConclusionRopivacaine 0.75% provides a significantly longer duration of anesthesia than lignocaine 2% with adrenaline. Ropivacaine 0.75% decreased intraoperative and postoperative analgesia compared to lignocaine 2% with adrenaline. Hence, ropivacaine 0.75% can be used as an alternative to lignocaine in implant surgeries and other intraoral surgical procedures that require a longer duration of anesthesia and analgesia.

Efficacy, safety and central nervous system effects after switch from efavirenz/tenofovir/emtricitabine to doravirine/tenofovir/lamivudine.

Doravirine is an alternative treatment option for individuals who do not tolerate efavirenz. We assessed efficacy, safety, and CNS effects in adults with HIV-1 and CNS complaints who switched from an efavirenz-based regimen to a doravirine-based regimen. Multicenter, double-blind, randomized trial (NCT02652260). Virologically suppressed adults receiving efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF), or its components, with ongoing EFV-associated CNS toxicity grade 2 or higher (DAIDS criteria) were switched to doravirine/lamivudine/tenofovir (DOR/3TC/TDF) on day 1 (Immediate Switch Group [ISG]) or after 12 weeks (Deferred Switch Group [DSG]). CNS toxicity data were collected by self-administered questionnaire. The primary endpoint was the proportion of participants with any grade 2 or higher CNS toxicity at week 12. Secondary endpoints included virologic response and effect on fasting lipids. Eighty-six participants (58% men, 56% black, median age 41 years, median 4 years on prior EFV regimen) were enrolled (43 ISG, 43 DSG) and included in the analyses. At week 12, 42% of ISG and 37% of DSG had at least 1 grade 2 or higher CNS toxicity [difference 4.7%, 95% CI (-16 to 25%); P = 0.33]. At 24 weeks postswitch, HIV-1 RNA less than 50 copies/ml was maintained in 95.3% of participants, and fasting lipids were significantly decreased (LDL-cholesterol -11.0, non-HDL-cholesterol -13.2, HDL-cholesterol -7.7, total cholesterol -20.9, and triglycerides -13.0 mg/dl). In participants who had CNS complaints while receiving EFV/FTC/TDF, improvement in CNS toxicities attributable to EFV was not significantly different after switching to DOR/3TC/TDF compared with remaining on EFV/FTC/TDF. Virologic efficacy was maintained and lipid profiles improved after switching to DOR/3TC/TDF.

RADT-36. PROSPECTIVELY ASSESSED TUMOR CONTROL AND TOXICITY OF BENIGN INTRACRANIAL PATHOLOGIES TREATED WITH AUTOMATED VMAT RADIOSURGERY – INITIAL 2 YEAR EXPERIENCE WITH FIRST 100 PATIENTS

Abstract BACKGROUND HyperArc is a treatment planning technology that automates treatment planning and delivery of single-isocenter VMAT radiosurgery (SRS). The technique generates high quality, rapidly deliverable plans. It is unknown whether HyperArc is effective for commonly-encountered, benign, intracranial conditions managed with SRS. Under IRB-approved prospective registry, we collected data on treatment planning/delivery, and clinical outcomes of non-malignant conditions managed with single-fraction or fractionated SRS since deployment in October 2017. METHODS Patients received either single-fraction or fractionated SRS with HyperArc™ (Varian Medical Systems) between October 2017 &amp; October 2019. Patients with &amp;lt; 3 months follow-up were censored. All patients treated received prescription dose to ≥ 99% of gross tumor volume without PTV expansion. All treatments were delivered on Varian Edge linac with 10MV flattening-filter free beam at 2400 MU/min with high-definition (2.5mm) multi-leaf collimator. Standard pathology-specific outcomes and toxicities were assessed. Significant CNS toxicity was defined as Grade 3 or higher event by CTCAE. RESULTS Total of 100 targets (min=0.13cc, max=58.9cc) were treated. 55 received single-fraction SRS (12-22Gy), two received 2-fraction fSRS boost (12Gy) following fractionated treatment, and 43 received 5-fraction fSRS (25-30Gy). The most common pathology was meningioma (n=55), followed by AVM (n=18), non-secretory pituitary adenoma (n=12), acoustic schwannoma (n=9), secretory pituitary adenoma (n=3), glomus tumor (n=2), pineocytoma (n=1), and paraganglioma (n=1). Follow-up ranged from 1.2 to 19.5 months (median 7.2). There were three local failures, all in atypical meningiomas. One patient in the cohort experienced ≥Gr3 toxicity. Each radiosurgery session used median of 3 arcs, with median treatment and beam-on time of 12.03 and 2.3 minutes. Plan quality was excellent; median RTOG conformity was 1.15, and median Paddick GI was 3.52. CONCLUSION Although HyperArc was developed for automated multiple-metastasis radiosurgery, we found it effective and efficient for benign intracranial indications too. Early clinical outcomes appear congruent with historical controls.

Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

Background: Richter's transformation (RT) is a rare complication of Chronic Lymphocytic Leukemia (CLL), usually into clonally related diffuse large B cell lymphoma (DLBCL). Currently there is no effective therapy to RT and CLL relapse after targeted therapy. Chimeric antigen receptor-modified T (CART) cells directed to CD19+ B-cell malignancies have promising results in relapsed DLBCL. However, its effectiveness in CLL relapse after targeted therapy and RT is less clear and no systematic reports are available. Methods: From July 2019 to May 2020 we enrolled eight CLL patients with disease transformation after chemoimmunotherapy and therapy with BTK and/or BCL2 inhibitors as part of single center phase 2 CAR T-cell therapy in B-cell malignancies (NCT02772198). Following lymphodepletion consisting of cyclophosphamide and fludarabine patients received an infusion of locally produced 1x106 CD19-CART- cells/kg, which were generated by modifying autologous T cells with retroviral vector encoding a CAR comprising FMC63 anti-CD19 ScFv linked to a CD28 costimulatory domain, and CD3-zeta intracellular signaling domain. Results: All 8 patients (pts) were relatively young with median age at CLL diagnosis of 56y (47-62). Disease transformation developed after a median of 8 years (range 1-16) from CLL diagnosis. Patients treated with CD19-CAR T-cells at median age of 64 y (54-73) having median comorbidity G-CIRS score 2 (0-5), performance status ECOG 1 (0-2) and CCT 66ml/min (26-89). Pts had history of CLL with del17p/TP53 in 83%, 5/6 available, del11q 2/6 prior to transformation. Disease transformation included RT in 6 pts with DLBCL, 1 accelerated CLL and 1 prolymphocytic transformations. Among RT pts 67% (4/6) had advanced stage DLBCL, 50% (3/6) extarnodal and 33% (2/6) bulky disease. Patients received median of 3 (0-5) CLL therapies and 2 (1-3) large cell lymphoma directed therapy. CLL therapies included chemoimunotherpay: 5 Fludarabine, cyclophosphamide, rituximab/obinutuzumab (FCR/FCO), 1 bendamustin rituximab (BR); 5 dual targeted therapy (ibrutinib and Venetoclax), 2 ibrutinib only, 1 venetoclax only. Last CLL treatment was Venetoclax in 71% (5/7) and ibrutinib in 29% (2/7) with 32 (range 15-39) months duration on ibrutinib and 10 (2-17) months on venetoclax. The reason for ibrutinib discontinuation was CLL progression (PD) in 5, disease transformation in 2, and venetocalx discontinuation due to progressive disease (PD) - 4 and transformation - 2. Post transformation all RT pts were treated with R-CHOP, second line tx 2, one patient with prolymphocytic transformation was treated with alemtuzumab, allo-SCT, ibrutinib and venetoclax. All pts had PD before treatment with CAR T-cells, 63% (5/8) had elevated LDH and 5/8 evaluable PET CT before treatment had deauville score (DS) 5 with median SUVmax 8.7 (3.7-21). After infusion of CAR T-cells 7 patients had cytokine release syndrome (CRS), 4 grade 1 and 3 grade 3-4 that required tocilizumab. Three patients had CNS toxicity, two grade 3. Seventy five percent (6/8) developed neutropenia, (3/8) grade 3-4, all neutropenia resolved except in one patient that succumbed to PD, 2 pts had infections (campylobacter and H1N1 influenza, each). There were no fatalities due to CAR T-cell toxicity. There were two fatalities due to disease progression. All 71% (5/8) responders achieved complete response with DS1 in PET CT scan on day 28. After median follow up duration of 6 (4-10) months, 2 patients proceeded to allo-SCT. Conclusion: CD19-CART-cell therapy in CLL patients with disease transformation is safe and has high complete remission rate with promising clinical response. Long term remission rate after CD19-CART-cell therapy for RT needs to be further evaluated in more patients. Disclosures Benjamini: Abbvie Inc: Consultancy, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Fineman:Abbvie Inc: Consultancy, Research Funding. Jacobi:Novartis: Consultancy. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Final Report of Reduced Anthracycline Dose Intensity with the Addition of Dose Dense Rituximab in Children, Adolescents and Young Adults with De Novo Good Risk Mature B-Cell Non Hodgkin Lymphoma (B-NHL)

Background: Previous studies have demonstrated excellent results with FAB/LMB86 chemotherapy alone and in combination with rituximab in children, adolescents and young adults with mature B-NHL. (Cairo et al, JCO 2012, Goldman et al, Leukemia, 2013, Goldman et al, BJH 2014) The intermediate risk FAB/LMB Group B arm consists of 180mg/m2 of doxorubicin. This was reduced to 120mg/m2 with the addition of dose-dense rituximab. Other standard NHL regimens more commonly used in young adults with advanced stage mature B-NHL, such as R-CHOP, have a total dose doxorubicin of 360mg/m2. These approaches are associated with short term morbidities and long-term health conditions, including anthracycline induced cardiac toxicities.Dose-dense rituximab containing chemoimmunotherapy in high risk mature B-NHL has shown significant improvements in outcomes. We tested the hypothesis that rituximab can be used to even further reduce the burden of anthracycline from 120mg/m2 to 50mg/m2 in patients with good risk B-NHL. Objective: To safely reduce the burden of therapy by reducing the number of IT injections and reducing the total dose of doxorubicin from 120mg/m2 to 50mg/m2 with the addition of liposomal cytarabine and dose-dense rituximab to our prior chemotherapy backbone in children with good risk mature B-NHL. Design/Methods: Multi-institutional Phase II study (NCT01859819). Patients (3-31 years) with CD20+ B-NHL with good risk (FAB Group B GR=Stage I/II, Stage III with any LDH and Stage IV {BM tumor &amp;lt; 25%)}) were eligible. Staging was defined per the IPNHLSS as previously described. (Roselen et al, JCO 2015) All patients received FAB backbone chemotherapy with the addition of six rituximab (375mg/m2) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. Cumulative doxorubicin was reduced from 120 to 50 mg/m2 (25mg/m2 per dose) total. After systemic methotrexate clearance, patients received age-based dosing of IT liposomal cytarabine resulting in a reduction of IT injections from nine to five. The primary outcome was safety and toxic deaths with an estimated 3-year survival above 90%, monitored by an independent DSMB. Response was defined per the IPNHLRC as previously described. (Sandlund et al, JCO 2015) Results: Twenty-five FAB Group B patients were enrolled at 5 treatment centers in the United States. Histology included DLBCL in 13 patients and Burkitt in 12 patients. Table 1. All patients had at least a 20% tumor decrease after the reduction phase. Two patients were upstaged to intensified Group C therapy after residual imaging findings post first consolidation. Therefore, 23/25 patients had a cumulative doxorubicin exposure of 50 mg/m2 while the two patients who received augmented treatment had a total exposure of 170 mg/m2. There were no serious adverse events reported with rituximab administration and no reported CNS or other toxicity reported with liposomal cytarabine intrathecal prophylaxis. During the two induction cycles there were no readmissions for febrile neutropenia or other causes and no reported grade III or higher mucositis. Follow up immune globulin levels on a smaller cohort of patients revealed median IgG levels of 821 (range, 362-1172) at a median follow up of 24 months. All patients are alive and in first remission with an EFS/OS = 100% at a median follow up of 4 years (range, 2-7yr). Figure 1. Echocardiograms revealed stable left ventricular function. Rituximab CSF levels were measured as we previously described and were extremely low (&amp;lt; 10µg/ml) compared to peak serum levels (250-400µg/ml). Conclusions: Our results demonstrate the feasibility of careful reduction of anthracycline dose intensity with the addition of dose-dense rituximab immunotherapy in children, adolescents and young adults with good risk mature B-NHL. Our results demonstrate a 100% EFS/OS with a reduction to only 50mg/m2 total dose of anthracycline. This is consistent with published standard of care outcomes utilizing much higher doses of 120-550mg/m2 of doxorubicin. Our treatment strategy benefits good risk patients with mature B-NHL by using dose-dense rituximab to reduce the cumulative exposure of anthracycline associated short- and long-term toxicities as well as the number of required intrathecal injections. These excellent results require the investigation of this approach in a larger cohort in the future to confirm these preliminary findings. Disclosures Goldman: Jazz Pharmaceuticals, Inc.: Speakers Bureau. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Cairo:Miltenyi: Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Evaluating Maximum MU per Spot Thresholds on CNS Pencil Beam Proton Therapy Plan Quality

There are concerning reports of CNS toxicity in patients treated with proton therapy at doses lower than would be expected based on photon data estimates. Given the desire to mitigate risk of serious unexpected events, we propose limiting the maximum monitor unit weighting per spot (maxMU/spot) to the entire plan with the hypothesis that heavily weighted spots may pose an unforeseen risk of toxicity despite meeting objective dose constraints. This dosimetric study assesses the impact of maxMU/spot restrictions on pencil beam proton therapy (PBPT) plan quality. We hypothesize that plan quality may be preserved while still restricting the maxMU/spot, but there may be a threshold below which restrictions negatively impact plan quality. PBPT plans of 11 patients (9 consecutive, 2 additional with notably challenging plan objectives) were included, of which 3 plans included boosts, for a total of 14 nominal PBPT cases. Per nominal plan, a single dosimetrist created 4 test plans as outlined in Table 1, iteratively reducing the maxMU/spot in the plan. Test Plan 1, unrestricted in maxMU/spot, was the reference for all analyses (comparison sets 2 vs. 1; 3 vs. 1; and 4 vs. 1). The differences in each plan quality metric in each comparison set were analyzed using the Wilcoxon signed rank test, with p<0.05 significance testing. Beam-specific metrics in each comparison set were analyzed, defined by the root mean square deviation in beam metrics from the unrestricted plan. Linear regression with log transformation was performed to analyze the impact of restriction conditions on changes in the beam-specific max dose, heterogeneity, and % of target receiving the Rx/#beams. A total of 14 PBPT plans, 7 (50%) SFO, 7 (50%) MFO, 9 (64%) delivering >3500 cGy, 9 (64%) with 3 beams, 5 (36%) with 4-5 beams, and 7 (50%) without a range shifter were included. With increasing MU restriction, there were no differences in plan quality metrics of target coverage (V95% and V100%Rx), conformality and gradient indices, hot spot volume (V105%Rx), and dose to unaffected brain (V10%/30%/50%/70%/90%/100%Rx) across all comparison sets (p>0.05). However, there was a mean increase of 854 (2 vs. 1, p = 0.02), 869 (3 vs. 1, p = 0.025), and 892 (4 vs. 1, p = 0.007) total spots in the more restricted MU plans. MaxMU restriction did not significantly impact the beam-specific max dose (p = 0.259), heterogeneity (p = 0.305), and % of target receiving the Rx/#beams (p = 0.409). MaxMU/spot restriction did not negatively impact overall plan quality and beam-specific metrics within the thresholds evaluated in this study. Future studies should evaluate spot weighting with LET/RBE to determine if spot weighting manipulation may truly impact clinical outcomes and mitigate toxicity.Tabled 1Abstract 2601; Table; Iterative reduction maximum allowable MU per spot*PlanNo Range shifter (RS)2cm RS3cm RS5cm RS1No limitNo limitNo limitNo limit230405070320304060410203050∗1 MU = 1 cGY/mm2 at a 2 cm for monoenergetic proton beam Open table in a new tab