Central Nervous System Failure Research Articles

Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors

EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). To investigate CNS activity with lazertinib, a third-generation EGFR TKI. This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Lazertinib, 240 mg, once daily. The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. ClinicalTrials.gov Identifier: NCT05326425.

Effects of electrical and percussive stunning on neural, ventilatory and cardiac responses of rainbow trout

From an ethical standpoint, it is imperative that rainbow trout (Oncorhynchus mykiss) are humanely slaughtered, which entails that they are rendered unconscious immediately by a stunning method and remain so until death. The efficacy of electrical stunning following dewatering (i.e., in-air electrical stunning at intensities of 50 to 920 mA and durations of 5 to 30 s) and percussive stunning, both advocated as humane stunning and/or killing methods, are evaluated here for this species via the presence or absence of visually evoked responses (VERs). In addition, ventilatory and cardiac responses were evaluated to elucidate the physiological basis for the lethality of both methods. While the present study was unable to determine the capability of in-air electrical stunning to induce immediate unconsciousness, our findings revealed that irreversible stuns were induced by both in-air electrical stunning (i.e., ∼25 to 70% of individuals did not recover VERs across the various combinations of stunning intensities and/or durations) and percussive stunning (i.e., ∼100% of individuals did not recover VERs). The efficacy of in-air electrical stunning for permanently abolishing VERs was marginally, but significantly, impacted by stun intensity (i.e., explained 8% of the variation). Furthermore, due to substantial inter-specific variability and a limited sample size, significant impacts of stun intensity and/or duration on the recovery of VERs in reversibly stunned individuals were not detected in the present study (i.e., VERs recovered between <0.5 to 28.8 min). Further investigation is therefore necessary before in-air electrical stunning can be endorsed as a standalone humane slaughter method for rainbow trout. This includes determining its capacity to induce immediate unconsciousness, as well as to identify additional factors that could be modified or enhanced to improve its efficacy. Furthermore, since death following in-air electrical stunning likely entails a prolonged process involving ventilatory failure, hypoxemia, and subsequent vital organ malfunction, rather than immediate cardiac arrest or central nervous system failure, the sequential use of methods such as percussive stunning is recommended to safeguard the welfare of rainbow trout during slaughter.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1&lt;12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

Gamma knife radiosurgery following whole-brain radiation

In this study, we aimed to determine outcomes for patients requiring salvage stereotactic radiosurgery (SRS) who have progression of brain metastatic disease after initial treatment with whole-brain radiation (WBRT). This is a retrospective analysis of a prospective database of 112 patients who were treated with salvage SRS after experiencing failure following WBRT treatment with salvage SRS. Collectively, the patients had a median overall survival of 7 months after salvage SRS. Patients who had more than two brain metastases had a significantly shorter median survival but were not subjected to increased risk for distant brain failure. We also found that a short intervening time between WBRT and central nervous system (CNS) failure did not seem to worsen the nervous system control or reduce patient survival. Small cell lung cancer (SCLC) was associated with decreased overall survival and CNS control. In conclusion, SRS use following WBRT is safe and effective in the majority of patients. Patients with rapid failure after WBRT can be successfully salvaged with SRS. The findings also shed light on the overall poor outcomes, coupled with low median survival and high rates of CNS failure, in patients suffering multiple metastases stemming from SCLC.

Insights into the selective mechanism of PDE2/9a inhibitors from silico aspects

The selective design of competitive enzyme inhibitors is an extremely difficult task but necessary work for certain types of systems, such as the phosphodiesterase (PDE) system addressed in this article. In the PDE family, PDE2A and PDE9 respectively target the central nervous system and heart failure, and share many conserved amino acids at their binding sites. Therefore, gaining a deep understanding of the selective mechanisms of PDE2A/9A is crucial for designing highly selective drugs. In this study, various computer-aided drug design (CADD) methods, including molecular docking, molecular dynamics simulations (MD), and binding free energy calculations, are employed to explore the selective mechanisms of PDE2A/9A. Overall, our research results indicate a selective design strategy for PDE2A, which involves incorporating hydrophobic or aromatic moieties into the molecular structure to better accommodate the hydrophobic pocket of PDE2A. Additionally, it is recommended to introduce functional groups capable of forming connections with selective residues, such as Phe830 and Gln812 for PDE2A, or Ala452 and Tyr424 for PDE9A, to enhance the selectivity of inhibitors targeting PDE2A/9A. This achievement is anticipated to pave the way for the development of innovative and selective small molecules targeting PDE2A/9A. Communicated by Ramaswamy H. Sarma

Development and validation of a prognostic model of survival for classic heatstroke patients: a multicenter study

Classic heatstroke (CHS) is a life-threatening illness characterized by extreme hyperthermia, dysfunction of the central nervous system and multiorgan failure. Accurate predictive models are useful in the treatment decision-making process and risk stratification. This study was to develop and externally validate a prediction model of survival for hospitalized patients with CHS. In this retrospective study, we enrolled patients with CHS who were hospitalized from June 2022 to September 2022 at 3 hospitals in Southwest Sichuan (training cohort) and 1 hospital in Central Sichuan (external validation cohort). Prognostic factors were identified utilizing least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis in the training cohort. A predictive model was developed based on identified prognostic factors, and a nomogram was built for visualization. The areas under the receiver operator characteristic (ROC) curves (AUCs) and the calibration curve were utilized to assess the prognostic performance of the model in both the training and external validation cohorts. The Kaplan‒Meier method was used to calculate survival rates. A total of 225 patients (median age, 74 [68–80] years) were included. Social isolation, self-care ability, comorbidities, body temperature, heart rate, Glasgow Coma Scale (GCS), procalcitonin (PCT), aspartate aminotransferase (AST) and diarrhea were found to have a significant or near-significant association with worse prognosis among hospitalized CHS patients. The AUCs of the model in the training and validation cohorts were 0.994 (95% [CI], 0.975–0.999) and 0.901 (95% [CI], 0.769–0.968), respectively. The model's prediction and actual observation demonstrated strong concordance on the calibration curve regarding 7-day survival probability. According to K‒M survival plots, there were significant differences in survival between the low-risk and high-risk groups in the training and external validation cohorts. We designed and externally validated a prognostic prediction model for CHS. This model has promising predictive performance and could be applied in clinical practice for managing patients with CHS.

Real-world analysis of first-line afatinib in patients with EGFR-mutant non-small cell lung cancer and brain metastasis: survival and prognostic factors.

Overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) is poor. We aimed to identify prognostic factors and ascertain treatment outcomes of first-line afatinib for patients with epidermal growth factor receptor (EGFR)-mutant NSCLC with BM in a real-world setting. This retrospective observational study reviewed electronic records of patients with EGFR-mutant NSCLC who received first-line afatinib treatment between October 2014 and October 2019 in 16 hospitals across South Korea. The Kaplan-Meier method estimated time on treatment (TOT) and OS; multivariate analyses were performed using Cox proportional hazards (PH) models. Among 703 patients who received first-line afatinib, 262 (37.3%) had baseline BM. Of 441 patients without baseline BM, 92 (20.9%) developed central nervous system (CNS) failure. Compared with patients without CNS failure, those with CNS failure during afatinib treatment were younger (P=0.012), had a higher Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P<0.001), increased metastatic site involvement (P<0.001), advanced stage disease (P<0.001), with liver metastasis (P=0.008) and/or bone metastasis (P<0.001) at baseline. Cumulative incidence of CNS failure in years 1, 2 and 3 was 10.1%, 21.5% and 30.0%, respectively. In multivariate analysis, cumulative incidence was significantly higher in patients with ECOG PS ≥2 (P<0.001), uncommon EGFR mutations (P=0.001), and no baseline pleural metastasis (P=0.017). Median TOT was 16.0 months (95% CI: 14.8-17.2) and, in patients with CNS failure, without CNS failure, and with baseline BM was 12.2, 18.9, and 14.1 months, respectively (P<0.001). Median OS was 52.9 months (95% CI: 45.4-60.3) and, in patients with CNS failure, without CNS failure, and with baseline BM was 29.1, 67.3 and 48.5 months, respectively (P<0.001). First-line afatinib in the real-world setting showed clinically meaningful effectiveness in patients with EGFR-mutant NSCLC and BM. CNS failure was a poor prognostic factor for TOT and OS correlating with younger age, poor ECOG PS, higher metastatic number, advanced disease stage, uncommon EGFR mutations, and baseline liver and/or bone metastases.

CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations.

Afatinib is a potent, irreversible second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has demonstrated efficacy in advanced non-small cell lung cancer (NSCLC) patients harboring either common or uncommon EGFR mutations. However, data on its activity against brain metastases are limited. This study aimed to retrospectively evaluate the efficacy and safety of afatinib as first-line treatment for EGFR-mutant NSCLC patients with brain metastases. Treatment-naive advanced NSCLC patients harboring EGFR mutations and brain metastases treated with afatinib were retrospectively reviewed to assess the central nervous system (CNS) efficacy and also the systematic benefits. Totally 43 patients with measurable or non-measurable brain metastases were enrolled in the CNS full analysis (cFAS) set. Among them, 23 patients with measurable brain metastases were included in the CNS evaluable for response (cEFR) set. The CNS ORR was 48.8% (95% CI, 33.3 - 64.5%) in the cFAS set and 82.6% (95% CI, 61.2 - 95.0%) in the cEFR set, respectively. CNS mDoR was 8.9 months (95% CI, 4.7 - 13.1 months) and CNS mPFS was 12.7 months (95% CI, 6.9 - 18.5 months) in the cFAS set. In the subgroup analysis stratified by EGFR mutation types, CNS ORR of cEFR set in the common mutation cohort was 100% (95% CI, 75.3 - 100%) and 60% (95% CI, 26.2 - 87.8%) in the uncommon mutation cohort (p = 0.024); CNS ORR of cFAS set was 57.7% (95% CI, 36.9 - 76.6%) and 35.3% (95% CI, 14.2 - 61.7%), respectively (p = 0.151). CNS mPFS was 14.4 months in patients with common mutations and 6.1 months in patients with uncommon mutations (hazard ratio, 0.47; 95% CI, 0.22 - 1.00; p = 0.045). Patients with common mutations showed a significantly lower cumulative incidence of CNS failure than uncommon mutation cohort (p = 0.0026). Most of patients experienced grade 1/2 treatment-related adverse events. First-line afatinib demonstrated encouraging efficacy on brain metastases in NSCLC patients harboring either common or major uncommon EGFR mutations in a real-world setting, with manageable toxicities. Patients with common mutations showed better CNS outcomes than those with uncommon mutations.

Survival and Yield of Surveillance Imaging in Long-Term Survivors of Brain Metastasis Treated with Stereotactic Radiosurgery

The optimal frequency of surveillance brain magnetic resonance imaging (MRI) in long-term survivors with brain metastases after stereotactic radiosurgery (SRS) is unknown. Our aim was to identify the optimal frequency of surveillance imaging in long-term survivors with brain metastases after SRS. Eligible patients were identified from a cohort treated with SRS definitively or postoperatively at our institution from 2014 to 2019 with no central nervous system (CNS) failure within 12 months from SRS. Time to CNS disease failure diagnosis and cost per patient were estimated using theoretical MRI schedules of 2, 3, 4, and 6 months starting 1 year after SRS until CNS failure. Time to diagnosis was calculated from the date of CNS progression to the theoretical imaging date on each schedule. This cohort included 55 patients (median follow-up from SRS: 2.48 years). During the study period, 20.0% had CNS disease failure (median: 2.26 years from SRS treatment). In this cohort, a theoretical 2-month, 3-month, 4-month, and 6-month MRI brain surveillance schedule produced a respective estimated time to diagnosis of CNS disease failure of 1.11, 1.74, 1.65, and 3.65 months. The cost of expedited diagnosis for the cohort (dollars/month) for each theoretical imaging schedule compared with a 6-month surveillance schedule was $6600 for a 2-month protocol, $4496 for a 3-month protocol, and $2180 for a 4-month protocol. Based on cost-benefit, a 4-month MRI brain schedule should be considered in patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at 1 year.

Prediction of Mortality Risk After Ischemic Acute Kidney Injury With a Novel Prognostic Model: A Multivariable Prediction Model Development and Validation Study.

Background and Objectives:Acute kidney injury (AKI) that results from ischemia is a common clinical syndrome and correlates with high morbidity and mortality among hospitalized patients. However, a clinical tool to predict mortality risk of ischemic AKI is not available. In this study, we aimed to develop and validate models to predict the 30-day and 1-year mortality risk of hospitalized patients with ischemic AKI.MethodsA total of 1,836 admissions with ischemic AKI were recruited from 277,898 inpatients admitted to three affiliated tertiary general hospitals of Central South University in China between January 2015 and December 2015. Patients in the final analysis were followed up for 1 year. Study patients were randomly divided in a 7:3 ratio to form the training cohort and validation cohort. Multivariable regression analyses were used for developing mortality prediction models.ResultsHepatorenal syndrome, shock, central nervous system failure, Charlson comorbidity index (≥2 points), mechanical ventilation, renal function at discharge were independent risk factors for 30-day mortality after ischemic AKI, while malignancy, sepsis, heart failure, liver failure, Charlson comorbidity index (≥2 points), mechanical ventilation, and renal function at discharge were predictors for 1-year mortality. The area under the receiver operating characteristic curves (AUROCs) of 30-day prediction model were 0.878 (95% confidence interval (CI): 0.849-0.908) in the training cohort and 0.867 (95% CI: 0.820–0.913) in the validation cohort. The AUROCs of the 1-year mortality prediction in the training and validation cohort were 0.803 (95% CI: 0.772–0.834) and 0.788 (95% CI: 0.741–0.835), respectively.ConclusionOur easily applied prediction models can effectively identify individuals at high mortality risk within 30 days or 1 year in hospitalized patients with ischemic AKI. It can guide the optimal clinical management to minimize mortality after an episode of ischemic AKI.

DIPG-32. Paediatric histone-mutant diffuse midline glioma: real world outcomes from a low-middle income country (LMIC) setting

Abstract BACKGROUND: Histone-mutant diffuse midline glioma (H3K27M) is a distinct high-grade central nervous system (CNS) tumor arising in the midline structures of the brain and/or spinal cord in children and young adults with dismal clinical outcomes. Real world data on this entity, particularly from the low-middle income countries (LMICs) is lacking. We report outcomes of pediatric histone-mutant diffuse midline gliomas treated between 2014-2021 at our comprehensive cancer centre in India. METHODS: Children (&amp;lt;16 years) with biopsy-proven diffuse midline glioma demonstrating histone mutation (H3K27M) on gene expression profiling were identified through electronic search of neuro-pathology database. Clinico-demographic characteristics, histo-molecular features, treatment details, and survival outcomes were retrieved retrospectively from institutional records. All children had undergone biopsy and occasionally debulking surgery prior to definitive radiotherapy (RT). Upfront temozolomide (TMZ) either concurrent and/or adjuvant was at the discretion of treating oncologist. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods and expressed as point estimates with 95% confidence interval (CI). RESULTS: Median age of the study cohort (N=51) was 11 years (inter-quartile range 6-14 years) with no gender predilection. Metastatic disease (leptomeningeal dissemination, sub-ependymal spread, or distant brain involvement) was seen at presentation in 7 (13.7%) patients and at first progression after definitive RT in 10 (19.6%) patients. At a median follow up of 10.3 months, 1-year Kaplan-Meier estimates of PFS and OS were 21.5% (95%CI: 12.2-37.9%) and 45.6% (33.1-62%) yielding median PFS and OS of 7.8 months (95%CI: 5.6-11 months) and 11.3 months (95%CI: 9.4-14.9 months) respectively. CONCLUSIONS: We report aggressive biological course and dismal outcomes in pediatric histone-mutant diffuse midline gliomas (H3K27M) treated in a LMIC setting. High incidence of metastatic CNS failure in our cohort suggests a potential role for testing neuraxial irradiation and aggressive systemic therapy to improve survival.

A Middle-aged Woman Presented with Recurrent Seizure After Tricyclic Antidepressant Overdose: A Case Report

&lt;p&gt;三環抗憂鬱劑為抗憂鬱用藥之一，在過量時患者可能會出現抗膽鹼症狀、甚至是具有致死風險的中樞神經以及心血管毒性症狀。本篇案例報告介紹一位中年女性因三環抗憂鬱劑中毒而導致意識不清、呼吸衰竭以及癲癇反覆發作，接受緊急氣管內管插管以及鎮靜藥物治療後仍未見改善，但因並未出現典型的抗膽鹼症狀，在十二導程心電圖檢查以及一系列毒藥物篩檢確立診斷後，始接受碳酸氫鈉藥物治療、抗癲癇藥物的控制以及後續血管收縮藥物的支持，其後順利康復。筆者希望藉由此案例分享，以及中毒的臨床症狀、診斷和治療等介紹，能增加臨床同仁對三環抗憂鬱劑中毒的認識，也提醒同仁臨床病人藥物過量時常合併多種藥物使用，使得所謂毒性症候群表現往往不典型，因而增加臨床上診斷的困難度和挑戰性，結合病史詢問、理學檢查以及實驗室檢查仍然是早期診斷藥物中毒的不二法門&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;&lt;p&gt;Tricyclic antidepressants are a class of antidepressants, an overdose of which may cause anticholiner&amp;shy;gic syndromes. In severe cases, fatal central nervous system failure and cardiovascular toxicity may occur. This case report describes a middle-aged female patient who was suffered from unconscious&amp;shy;ness, respiratory failure, and recurrent seizures due to tricyclic antidepressant toxicity. Emergent endotracheal intubation and sedative drug treatment were failed to improve her condition. Given the absence of typical anticholinergic symptoms, the diagnosis was established followed by a 12-lead elec&amp;shy;trocardiogram examination and a series of toxic-drug screening. The patient received treatments with sodium bicarbonate, anti-epileptic drugs, and vasopressor support, which led to full recovery from the intoxication. The authors expect that by sharing this case and introducing the clinical symptoms, diagnosis, and treatment of tricyclic antidepressant-induced toxicity, clinicians could be more familiar with this syndromes. We would like to remind our peers that in clinical settings, patients presenting with drug overdose often took several drugs concomitantly. As such, the toxic syndrome is often atyp&amp;shy;ical which increases the difficulty of clinical diagnosis. The combination of medical history inquiry, physical examination, and laboratory tests remains the key for diagnosing drug toxicity at the early stage.&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;

Assessment of Cranial Radiotherapy Treatment in T-cell Lymphoblastic Lymphoma: Retrospective Study from Tertiary Care Center

Abstract Introduction Leukemia-like regimens given for acute lymphoblastic leukemia (ALL) are the cornerstone of treatment for T-cell lymphoblastic lymphoma (LBL) and can produce complete remission rates exceeding 90%. For central nervous system (CNS) prophylaxis, intrathecal chemotherapy and cranial irradiation are used to prevent future CNS recurrence. Objective The purpose of this study was to assess CNS relapse rate after cranial prophylaxis treatment given at our institute. Materials and Methods In this retrospective analysis, between July 2013 and June 2019, 149 files of lymphoblastic lymphoma were reviewed. Out of these, 53 patients received cranial irradiation. All patients were given CNS-directed therapy in the form of intrathecal methotrexate and patients with CNS-negative disease and primary tumor complete response or more than partial response after chemotherapy were given prophylactic cranial irradiation (18 Gy/10#), and in patients with upfront CNS involvement, therapeutic cranial irradiation (24 Gy/12#) was delivered. Radiotherapy was delivered as per the standard conventional protocol on a linear accelerator. Results Out of 53 patients (age range: 2–50 years, mean–16.79 years, 26 [49.1%] pediatric [&lt;14 years], 27 [50.9%] adults [&gt;14 years]), 13/53 (24.5%), and 40/53 (75.5%) patients were on MCP 841 and BFM 90 protocols, respectively. Also, 48 (90.56%) patients received prophylactic cranial irradiation (25 [52.1%] pediatric, 23 [47.9%] adults). Moreover, 3/48 (6.25%) (2 [4.16%] pediatric, 1 [2.08%] adult) patients had CNS failure after receiving prophylactic cranial irradiation. For 48 target patients, with the median follow-up of 27.27 months (26.1 months–pediatric, 28.2 months– adults), EFS (event-free survival) in the brain was 93.8% (92%: pediatric, 95.7%: adults). Also, the difference between pediatric and adult groups was not statistically significant (p-value = 0.662). Five (9.43%) patients had CNS-positive disease upfront and received therapeutic cranial irradiation. Conclusion In BFM 90/MCP 841 protocol in lymphoblastic lymphoma, prophylactic cranial irradiation and intrathecal methotrexate have been the standard of care as the CNS-directed therapy to prevent cranial infiltration. Though our results are not at par with the published world literature, further research and efforts are required to prevent CNS relapse in a selected sub-set of patients with lymphoblastic lymphoma.

Yield of Surveillance Imaging in Long-Term Survivors of Brain Metastasis Treated With Stereotactic Radiosurgery

Although patients with brain metastasis treated with stereotactic radiosurgery (SRS) in the definitive or post-operative setting have high rates of local control, surveillance imaging is necessary to assess for central nervous system (CNS) recurrence. Guidelines recommend magnetic resonance imaging (MRI) of the brain every three months for surveillance in asymptomatic patients post-SRS. However, optimal frequency and duration of surveillance imaging in long-term survivors is unknown. Our objective is to define the yield and cost of surveillance MRIs in long-term (> 1 year) survivors following SRS.We identified a cohort of patients with brain metastases treated with SRS in the definitive or postoperative setting at a single institution from 8/2014 to 9/2019. Eligible patients had at least one-year of follow-up with absence of CNS disease failure up to and including the first MRI of the brain after 12 months from SRS. Each post-treatment MRI of the brain was assessed for disease progression or new lesions. CNS disease-free survival was time from SRS to last follow-up, death or CNS failure. Delay to diagnosis and cost per patient were estimated using hypothetical MRI schedules of 2, 3, 4 and 6 months from 1-year post-treatment while CNS disease-free. Delay to diagnosis was calculated as time from actual CNS progression to hypothetical imaging date. Medicare reimbursement median cost of $498 per MRI brain with and without contrast was used for this analysis.A total of 373 patients treated with SRS for brain metastasis were identified at our institution. 61 patients met eligibility criteria for inclusion in this study (median follow-up 2.50 years, median age at treatment 60 years). The median CNS disease-free survival in this population was 2.37 years from date of SRS. 15 patients (24.6%) had CNS progression at median time of 2.26 years. Of the 15 patients, 3 patients were symptomatic at recurrence. Median frequency of MRI after one year post SRS was 5.9 months. Per patient, $1156 was spent annually on MRIs of the brain after 12 months with average annual yield of 17.0%. The cost per diagnosis of CNS progression was $6806. A 2-month, 3-month, 4-month and 6-month MRI schedule had a respective estimated delay to diagnosis of 0.69 months, 1.13 months, 1.44 months and 3.19 months. The respective mean total cost of each MRI schedule per patient from one-year post-treatment while CNS disease-free was $4662, $3053, $2229 and $1380.Patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at one year have a low rate of CNS failure and relatively good prognosis. Based strictly on limiting delay of diagnosis, a 2-month MRI Brain schedule is optimal in this population, albeit with a relatively small increase in financial cost over the patient's lifespan. We propose a multi-institutional study of long-term survivors with brain metastasis to strengthen these findings.B.J. Rich: None. D. Kwon: None. Y.S. Soni: None. D.L. John: None. J.B. Bell: None. G. Azzam: None. E.A. Mellon: None. R. Yechieli: Support and guide school in strategic and management related matters; Toras Chaim Toras Emes, Miami FL.C. Benjamin: None. R. Benveniste: None. R.J. Komotar: None. M. Ivan: None. J. Morcos: None. T. Diwanji: None.

Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia.

Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression.

Long-term neurodevelopment outcomes of hand, foot and mouth disease inpatients infected with EV-A71 or CV-A16, a retrospective cohort study

ABSTRACT Hand, foot and mouth disease (HFMD) is a common infectious disease in western Asia area and the full range of the long-term sequelae of HFMD remains poorly described. We conducted a retrospective hospital-based cohort study of HFMD patients with central nervous system (CNS) complications caused by EV-A71 or CV-A16 between 2010 and 2016. Patients were classified into three groups, including CNS only, autonomic nervous system (ANS) dysregulation, and cardiorespiratory failure. Neurologic examination, neurodevelopmental assessments, Magnetic Resonance Imaging (MRI) and lung function, were performed at follow up. Of the 176 patients followed up, 24 suffered CNS only, 133 ANS dysregulation, and 19 cardiorespiratory failure. Median follow-up period was 4.3 years (range [1.4–8.3]). The rate of neurological abnormalities was 25% (43 of 171) at discharge and 10% (17 of 171) at follow-up. The rates of poor outcome were significantly different between the three groups of complications in motor (28%, 38%, 71%) domain (p=0.020), but not for cognitive (20%, 24%, 35%), language (25%, 36%, 41%) and adaptive (24%, 16%, 26%) domains (p = 0.537, p = 0.551, p = 0.403). For children with ventilated during hospitalization, 41% patients (14 of 34) had an obstructive ventilatory defect, and one patient with scoliosis had mixed ventilatory dysfunction. Persistent abnormalities on brain MRI were 0% (0 of 7), 9% (2 of 23) and 57% (4 of 7) in CNS, ANS and cardiorespiratory failure group separately. Patients with HFMD may have abnormalities in neurological, motor, language, cognition, adaptive behaviour and respiratory function. Long-term follow-up programmes for children’s neurodevelopmental and respiratory function may be warranted.

Changes in the incidence and outcome of multiple organ failure in emergency non-cardiac surgical admissions: a 10-year retrospective observational study.

During the past decades, epidemiologic data of independent predictors of multiple organ failure (MOF), incidence, and mortality have changed. The aim of the study was to assess the potential changes in the incidence and outcomes of MOF for one decade (2008-2017). In addition, resource utilization was considered. Patients were eligible for inclusion if they were adults, admitted to the ICU between January 1, 2008 and December 31, 2017, and had complete data sets regarding MOF. MOF was defined as organ failure separately with and without central nervous system (CNS) failure. The onset of MOF was defined as being early (≤48 h of ICU admission) and late (>48 h after ICU admission). Of a total of 13,270 patients enclosed in this study, 44.6% of the patients developed MOF with and 31.4% without CNS failure. MOF-related mortality decreased in patients with (adjusted IRR 0.972 [95% CI 0.948 to 0.996], P=0.022) and without (adjusted IRR 0.957 [95% CI 0.931 to 0.983], P=0.0013) CNS failure. In addition, the incidence (adjusted IRR 0.970 [95% CI 0.950 to 0.991], P=0.006) and mortality (adjusted IRR 0.968 [95% CI 0.940 to 0.996], P=0.025) of early-onset MOF decreased, while the incidence and mortality of late-onset MOF remained constant. The length of ICU (P=0.024) and hospital (P=0.032) stays decreased while the length of mechanical ventilation remained constant (P=0.41). Despite all improvements in intensive care during the last decades, the incidence of late-onset MOF remains a resource-intensive, morbid, and lethal condition. More research on etiologies, signs of organ failure, and where and when to start treatment is needed to improve the prognosis of late-onset MOF.

Preventing Symptomatic Central Nervous System Metastasis in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Comparison of First- and Third-Generation EGFR Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Central nervous system (CNS) metastases, including brain parenchymal metastasis (BM) and leptomeningeal metastasis (LM), are common in the EGFR-TKI treatment failure. The different generation EGFR-TKIs have variant potencies of penetrating into the blood-brain-barrier. This study aims to compare the efficacy of first- and third-generation EGFR-TKIs in preventing symptomatic CNS metastases and to identify their risk factors. Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis and receiving EGFR-TKI treatment were selected. The cumulative incidence of symptomatic CNS metastasis upon treatment failure, and overall survival (OS) of patients who developed CNS metastasis, were measured from the initiation of EGFR-TKIs, using the Kaplan-Meier method. The risk factors for CNS metastasis, and predictors of OS were identified using Cox proportional hazard regression. 935 patients from two academic medical centers were enrolled, with 633, 143 and 35 receiving first-line gefitinib, erlotinib and osimertinib, respectively, the remain 124 patients received osimertinib for acquired T790M mutation. On baseline, 19del, L858R and uncommon mutations were detected in 427, 386 and 122 patients, respectively. At the median follow-up of 10 months, treatment failure was observed in 517 patients, of whom 45 developed symptomatic CNS metastasis, with 37 developing BM, 4 LM, and 4 with both BM and LM. The 1-year, 2-year and 3-year cumulative rate of symptomatic CNS metastasis, were 4.2%, 7.9% and 14.4%, respectively. There was no significant difference in symptomatic CNS metastasis among patients receiving gefitinib or erlotinib, while osimertinib treatment was found to have a lower rate compared to first-generation TKIs (HR 0.45; 95%CI 0.20-0.99, p = 0.049). However, cumulative rate of symptomatic CNS metastasis at 3-year in osimertinib group reached the similar level as the first-generation TKIs. Of interest, the curves of CNS metastasis tend to reached a plateau after three years no matter which generation was used. Patients harboring L858R mutation were at a higher risk of developing CNS metastasis, than other mutations (p = 0.003). Among the 45 patients with CNS metastasis, median OS was 22 months, and patients with single cranial lesion had a significant longer OS (p = 0.011). Compared with first-generation EGFR TKIs, osimertinib significantly delays the development of symptomatic CNS metastasis in the EGFR-mutant advanced NSCLC without baseline CNS metastasis. L858R mutation is a risk factor for CNS failure during EGFR-TKIs treatment.

Novel risk models to predict acute kidney disease and its outcomes in a Chinese hospitalized population with acute kidney injury

Acute kidney disease (AKD) is a state between acute kidney injury (AKI) and chronic kidney disease (CKD), but the prognosis of AKD is unclear and there are no risk-prediction tools to identify high-risk patients. 2,556 AKI patients were selected from 277,898 inpatients of three affiliated hospitals of Central South University from January 2015 to December 2015. The primary point was whether AKI patients developed AKD. The endpoint was death or end stage renal disease (ESRD) 90 days after AKI diagnosis. Multivariable Cox regression was used for 90-day mortality and two prediction models were established by using multivariable logistic regression. Our study found that the incidence of AKD was 53.17% (1,359/2,556), while the mortality rate and incidence of ESRD in AKD cohort was 19.13% (260/1,359) and 3.02% (41/1,359), respectively. Furthermore, adjusted hazard ratio of mortality for AKD versus no AKD was 1.980 (95% CI 1.427–2.747). In scoring model 1, age, gender, hepatorenal syndromes, organic kidney diseases, oliguria or anuria, respiratory failure, blood urea nitrogen (BUN) and acute kidney injury stage were independently associated with AKI progression into AKD. In addition, oliguria or anuria, respiratory failure, shock, central nervous system failure, malignancy, RDW-CV ≥ 13.7% were independent risk factors for death or ESRD in AKD patients in scoring model 2 (goodness-of fit, P1 = 0.930, P2 = 0.105; AUROC1 = 0.879 (95% CI 0.862–0.896), AUROC2 = 0.845 (95% CI 0.813–0.877), respectively). Thus, our study demonstrated AKD was independently associated with increased 90-day mortality in hospitalized AKI patients. A new prediction model system was able to predict AKD following AKI and 90-day prognosis of AKD patients to identify high-risk patients.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.