Central Nervous System Involvement Research Articles

Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: a case report

BackgroundWe describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL) with central nervous system (CNS) involvement.Case presentationA 65-year-old Asian female with Ph+-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph+-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased.ConclusionsTo the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse.

#2456 Real world outcomes of Fabry disease in Italian excellence centers: the ground study

Abstract Background and Aims Fabry disease (FD) is an X-linked lysosomal storage disorder with an estimated prevalence from 1:1368 to 1:8882, caused by galactosidase alpha gene (GLA) mutations, resulting in renal, cardiac and central nervous system involvement with significant morbidity and mortality in both sexes. Treatment includes enzyme replacement therapies (ERTs) and chaperone therapy. A better understanding of this disorder from its diagnostic journey, along with the impact of patient characteristics and available treatments on disease prognosis are relevant topics for physicians dealing with FD. The Global buRden and treatment trajectOries in Italian patients with Fabry disease: a retrospective longitUdinal and cross-sectioNal study–GROUND describes a cohort of FD Italian patients, addressing the unmet needs arising from this condition while providing a real-world picture from which further research insights can be derived. Methods This was a retrospective, longitudinal and cross-sectional study. Data about adult patients of either sex living or deceased with a documented FD diagnosis and at least 3 years of follow-up or early occurrence of severe/fatal outcomes were collected. Occurrence of severe/fatal events (renal, cardiac, cerebral events, death) from birth to last follow-up visit was the composite primary outcome. Other outcomes assessed were disease progression measured by FAbry STabilization indEX (FASTEX), occurrence of clinically significant events/FD related symptoms (i.e., renal function decline, detection/worsening of left ventricular hypertrophy (LVH), lysoGb3 increase, new FD symptoms), time from first manifestation to diagnosis, treatment trajectories. Results From June 2021 to June 2022, 199 patients, 73 males and 126 females, including 169 classic and 30 late-onset phenotypes, were enrolled at 8 Italian centers. Median time from onset of FD symptoms to diagnosis was 60.3 months [95% confidence interval (IC) 38.8-89.7], with a median of 0.64 years (range 0-19.29) from diagnosis to beginning of treatment. Chronic pain and angiokeratomas were the most common initial symptoms (18.1% and 13.1% of patients respectively); acroparesthesia and abdominal pain were reported in 12.5% of patients and LVH in 8.5%. Among the 143 missense/nonsense mutations identified, 14 were Variants of Uncertain Significance (VUS). Overall, 82% of patients were treated with 1 FD specific therapy, of whom 24% switched at least one treatment, while 5% definitively stopped. The composite primary outcome was experienced by 31.7% of patients for a total of 85 severe/fatal events. Specifically, 7.5% (n = 15, all treated) patients experienced a renal event; 20.6% of patients had a cardiac event (n = 41, 38/41 treated); 11.1% (n = 22, all but 1 treated) of subjects experienced a cerebral event; fatal events occurred in 7 patients of whom 1 was untreated. In addition, 88.9% of patients reported at least one clinically significant event, among which detection/worsening of LVH was the most common (41.2%). Estimated Glomerular Filtration rate (eGFR) slopes in the last 1-3 years of follow up were −2.07 [Standard Error (SE): 1.38] and −0.76 (SE: 1.75) in classic males and females, respectively. Long-term (i.e., from diagnosis to last available measure) FASTEX identified 31.1% of patients as being unstable. Conclusions In this real-world Italian FD cohort, patients were promptly treated after diagnosis according to existing guidelines, following expert evaluation. Nevertheless, severe clinical events occurred in about 30% of the cohort, mainly among classic treated males, revealing persistent unmet needs such as a better assessment of determinants of disease progression and outcomes, as well as response to treatment and further insights on the potential benefit of new therapeutic options.

#99 Clinical characteristics and outcomes of PTLD after kidney transplant: a single center experience

Abstract Background and Aims Post-Transplant Lymphoproliferative Disorder (PTLD) is a serious and potentially fatal complication of immunosuppression in kidney transplantation. Given the rarity of this entity, a high index of suspicion is necessary. We aimed to review the incidence, clinical presentation, histological subtypes, treatment, patient and graft survival of PTLD in kidney transplant patients in our unit. Methods Observational retrospective study, including adults diagnosed with PTLD between 1998 and 2023 in a Kidney Transplantation Center. Results Of 1390 kidney transplant recipients, 4 (0.3%) developed PTLD with a mean age of 52 ± 12.5 years. All cases were late-onset, occurring one year after transplantation with a median time from transplantation to diagnosis of 16.7 ± 7.3 years (range: 5-22 years). Of these, none had EBV donor/recipient mismatch. Two patients had prior rejection episodes (one patient, acute T cell-mediated rejection and the other patient, acute T cell-mediated rejection and active antibody mediated rejection). Clinical presentation was variable. Non-specific constitutional symptoms such as fever, fatigue and night sweats were present in all patients. Organ-specific symptoms were also present: lumbar pain in one patient with bone involvement, and delirium and lethargy in two patients with central nervous system involvement. Laboratory analyses revealed an increase in serum LDH in all patients. The primary sites of involvement were central nervous system (50%), lymph nodes (25%) and bone (25%). At PTLD diagnosis, immunosuppression included: tacrolimus (100%), mycophenolate mofetil (75%), low-dose of steroids (50%) and everolimus (25%). Regarding histologic classification, 75% were monomorphic and 25% polymorphic. In the monomorphic group, all patients had Diffuse Large B Cell Lymphoma (CD20 positive). In the polymorphic group, the patient had a Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative). Immunosuppression therapy was reduced in all patients with discontinuation of mycophenolate mofetil and tacrolimus. In the patient who was taking everolimus, the dose was increased due to the potential clinical antitumor effects of mTOR inhibition. Additional therapies included, rituximab in monotherapy or in combination with chemotherapy (R-CHOP) in the monomorphic group. Palliative measures were selected for one patient of this group due to advanced disease. The patient with Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative) did chemotherapy with ABVD. None of the patients underwent surgery or radiation therapy. Two patients needed dialysis. Three patients died in the first four weeks after PTLD diagnosis, all due to infectious complications. Patient survival was 25% one year after diagnosis. Conclusions Although the incidence of PTLD was low following kidney transplantation, its impact was significant in kidney graft and overall patient survival. Given the poor prognosis, new therapies combining high efficacy and low toxicity are an urgent unmet medical need in this field.

#896 Long-term renal outcome in childhood-onset lupus nephritis

Abstract Background and Aims Lupus nephritis (LN) is a common and severe complication of childhood-onset SLE. Little is known about the long-term renal outcome of childhood-onset LN. We investigated predictive factors of end-stage kidney disease (ESKD) and chronic kidney disease (CKD) in a paediatric cohort of patients with LN. Method This is a retrospective multicentre study including patients with childhood-onset (<18 years) biopsy-proven LN. Clinical features were analysed at disease onset, time of kidney biopsy, 12 and 24 months after biopsy, and last follow-up. We investigated the prognostic significance of clinical, laboratory and histologic characteristics on the incidence of ESKD and CKD stage 3-5. Results We included 73 patients with a median age of 14 years (IQR 11.5-17) . At the time of kidney biopsy, most subjects displayed an aggressive disease: 2 (3%) children required haemodialysis, 27 (38%) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. The overall median eGFR was 70 mL/min/1.73 m2 (IQR 43-96) . Moreover, the median proteinuria was 4 g/24 h (IQR 1.35-7.41) , with 41 (59%) children displaying a nephrotic range proteinuria (i.e., >3 g/24 h) . The median follow-up was 13.3 years (IQR 4.7-25.4) . A total of 10 patients (13.7%) reached ESKD, the majority of whom (12%) within 10 years from kidney biopsy; during the subsequent follow-up the incidence of ESKD stabilised (Fig. 1). At last follow-up, around 50% of patients displayed an eGFR <90 mL/min/1.73 m2. A younger age at LN onset, a lower eGFR and central nervous system involvement at the time of kidney biopsy were identified as predictors of ESKD by a univariable Cox regression model (Table 1). The same features were significantly associated with the occurrence of CKD stage 3-5 at last follow-up at a univariable logistic regression analysis. Conclusion LN often presents with severe kidney function impairment and aggressive systemic involvement in children. In our cohort, whose follow-up was among the longest reported in the literature, 12% of patients reached ESKD within 10 years from kidney biopsy. Significant predictors of poor kidney outcome in the long term were a younger age at LN onset, a lower eGFR and the presence of neurological manifestations at the time of kidney biopsy.

Radiological features of patients with headache as a presenting symptom of neurosarcoidosis.

To describe the radiological features of patients with headache as a presenting symptom of neurosarcoidosis. Neurologic complications occur in approximately 5%-10% of patients with sarcoidosis, and approximately 50% of these patients have neurologic deficits at the time sarcoidosis is first diagnosed. A wide spectrum of central and peripheral nervous system clinical manifestations may be observed, including cranial nerve palsies, sensory and/or motor deficits, and headache. Magnetic resonance imaging (MRI) results in patients with neurosarcoidosis may include abnormal contrast enhancement, structural masses, and demyelinating lesions. This single-center retrospective cohort study assessed patients who were diagnosed with neurosarcoidosis in an urban tertiary care center between 1995 and 2016. We included patients who had MRI results at the time of diagnosis. Patients were divided into two groups based on the presence or absence of headache as a presenting symptom. The MRI result of meningeal contrast enhancement was reviewed. Of the 110 patients analyzed, 30 (27.3%) had an initial presenting symptom of headache while 80 (72.7%) did not. Patients with headache had a higher proportion of meningeal contrast enhancement on MRI (66.7% [20/30] vs. 25.0% [20/80]; p < 0.001) and leptomeningeal involvement (53.3% [16/30] vs. 7.5% [6/80], p < 0.001) compared to patients with no headache. However, those with headache had a lower proportion of spinal cord localization (13.8% [4/29] vs. 34.2% [26/76], p = 0.038) and intraparenchymal central nervous system involvement (16.7% [5/30] vs. 51.3% [41/80], p = 0.001) compared to patients with no headache. Patients with neurosarcoidosis who presented with headache as an initial symptom had a higher proportion of meningeal contrast enhancement seen by MRI than patients who presented with other neurological symptoms. This suggests a clinico-radiologic link between headache and meningeal disruption in patients with neurosarcoidosis.

The effectiveness of the doxorubicin-etoposide-methylprednisolone regimen for adult HLH secondary to rheumatic disease.

To investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects.

Neurological involvement in hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT). The understanding of TA-TMA pathophysiology has expanded in recent years. Dysregulation of the complement system is thought to cause endothelial injury and, consequently, microvascular thrombosis and tissue damage. TA-TMA can affect multiple organs, and each organ exhibits specific features of injury. Central nervous system (CNS) manifestations of TA-TMA include posterior reversible encephalopathy syndrome, seizures, and encephalopathy. The development of neurological dysfunction is associated with a significantly lower overall survival in patients with TA-TMA. However, there are currently no established histopathological or radiological criteria for the diagnosis of CNS TMA. Patients who receive total body irradiation (TBI), calcineurin inhibitors (CNI), and severe acute and chronic graft-versus-host disease (GVHD) are at a high risk of experiencing neurological complications related to TA-TMA and should be considered for directed TA-TMA therapy. However, the incidence and clinical manifestations of TA-TMA neurotoxicity remain unclear. Studies specifically examining the involvement of CNS in TMA syndromes are limited. In this review, we discuss clinical manifestations and imaging abnormalities in patients with nervous system involvement in TA-TMA. We summarize the mechanisms underlying TA-TMA and its neurological complications, including endothelial injury, evidence of complement activation, and treatment options for TA-TMA.

Eosinophilic granulomatous polyangiitis with central nervous system involvement in children: a case report and literature review

ObjectiveTo explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).MethodsA child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.ResultsA ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.ConclusionThe diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.

Concomitant Central and Peripheral Nervous System Involvement Associated With Mycoplasma pneumoniae Infection in Pediatric Patients: Two Case Reports and Literature Review.

Mycoplasma pneumoniae (M. pneumoniae) is a common pathogen for community-acquired pneumonia and is also implicated in a broad array of extra-pulmonary manifestations. M. pneumoniae infection is rarely associated with concurrent central nervous system (CNS) and peripheral nervous system (PNS) involvement in children. We report 2 patients who presented with acute encephalitis and polyradiculitis due to M. pneumoniae infection and review the literature to discuss the pathogenesis and treatment of concomitant CNS and PNS involvement associated with M. pneumoniae infection. We report two 6-year-old boys with M. pneumoniae antecedent infection who presented initially with impaired consciousness followed by limb weakness, limb pain and urinary retention, and responded well to immunotherapy. We described 2 patients who presented symptomatic combined CNS and PNS involvement with persistent urinary retention associated with M. pneumoniae infection. We found autoimmunity plays an important role and recommend that antibiotics and immunomodulators should be administered with concurrent CNS and PNS involvement associated with M. pneumoniae.

Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2

COVID-19, caused by SARS-CoV-2, affects neuronal cells, causing several symptoms such as memory loss, anosmia and brain inflammation. Curcuminoids (Me08 e Me23) and curcumin (CUR) are derived from Curcuma Longa extract (EXT). Many therapeutic actions have been linked to these compounds, including antiviral action. Given the severe implications of COVID-19, especially within the central nervous system, our study aims to shed light on the therapeutic potential of curcuminoids against SARS-CoV-2 infection, particularly in neuronal cells. Here, we investigated the effects of CUR, EXT, Me08 and Me23 in human neuroblastoma SH-SY5Y. We observed that Me23 significantly decreased the expression of plasma membrane-associated transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D, consequently mitigating the elevated ROS levels induced by SARS-CoV-2. Furthermore, Me23 exhibited antioxidative properties by increasing NRF2 gene expression and restoring NQO1 activity following SARS-CoV-2 infection. Both Me08 and Me23 effectively reduced SARS-CoV-2 replication in SH-SY5Y cells overexpressing ACE2 (SH-ACE2). Additionally, all of these compounds demonstrated the ability to decrease proinflammatory cytokines such as IL-6, TNF-α, and IL-17, while Me08 specifically reduced INF-γ levels. Our findings suggest that curcuminoid Me23 could serve as a potential agent for mitigating the impact of COVID-19, particularly within the context of central nervous system involvement.

CNS involvement in myotonic dystrophy type 1: does sex play a role?

Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient's and disease-transmitting parent's sex) with a focus on CNS outcomes. Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions. Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion. This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinic-molecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis.

Treatment-related mortality among children with cancer in Denmark during 2001-2021.

Survival of children with cancer has markedly improved over recent decades, largely due to intensified treatment regimes. The intensive treatment may, however, result in fatal complications. In this retrospective cohort study, we assessed temporal variation in the incidence of treatment-related death and associated risk factors among children diagnosed with cancer in Denmark during 2001-2021. Among all children diagnosed with first incident cancer before age 15 years recorded in the Danish Childhood Cancer Register (n = 3,255), we estimated cumulative incidence of treatment-related death (death in the absence of progressive cancer) within 5 years from diagnosis using Aalen-Johansen estimators and assessed associated risk factors using Cox regression. Among all 3,255 children with cancer, 93 (20% of all 459 deaths) died from treatment. Of these treatment-related deaths, 39 (42%) occurred within 3 months of diagnosis. The 5-year cumulative incidences of treatment-related death were 3.3% during 2001-2010 and 2.5% during 2011-2021 (p = 0.20). During 2011-2021, treatment-related deaths accounted for more than half of all deaths among children with haematological cancers. Risk factors varied according to cancer group and included female sex, age below 1 year at diagnosis, disease relapse, stem cell transplantation, central nervous system involvement, and metastasis at diagnosis. Despite increasing treatment intensities, the incidence of treatment-related death has remained stable during the past 20 years in Denmark. Still, clinical attention is warranted to prevent treatment-related deaths, particularly among children with haematological cancers. Patient characteristics associated with increased treatment-related death risk support patient-specific treatment approaches to avoid these fatalities.

Persistence of Treponema pallidum IgM antibodies in serum: What is their meaning?

We studied the detection of Treponema pallidum (TP)-IgM antibodies in the serum of 69 patients treated for syphilis. The persistence of TP-IgM antibodies in serum for more than 3 years was the only clue to suspect an active infection and, therefore, to investigate a central nervous system involvement.

CAR T-cell therapy in mantle cell lymphoma with secondary CNS involvement: a multicenter experience

Secondary central nervous system (CNS) involvement in Mantle cell lymphoma has poor outcomes, with limited data for efficacy of CAR-T therapy. This study reports encouraging response with reasonable safety profile, but risk of CNS relapse remains high in such patients.

Abstract PS11-02: Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer

Abstract Background: Central nervous system (CNS) relapse represents a challenge in the management of patients with HER2-positive (+) metastatic breast cancer. Data regarding the impact of brain metastases (BrM) and CNS involvement on mortality are sparse. In this study we sought to determine the proportion of HER2+ MBC patients in which CNS disease is the cause of death and identify risk factors associated with CNS-related mortality. Methods: We reviewed medical records of 294 consecutive patients with HER2+ MBC and diagnosis of CNS disease including parenchymal BrM, leptomeningeal disease (LMD) or dural metastases (DM), treated at Memorial Sloan Kettering Cancer Center between August 2010 and April 2022. HER2-positivity was assessed at the first diagnosis of metastatic disease (any site). Clinicopathologic characteristics including disease burden at presentation, timing of CNS disease and extracranial metastases (ECM), neurologic complications, and local and systemic treatments were collected. CNS-related death was defined as any death caused by BrM or LMD or DM progression or CNS treatment-associated complications. CNS-related death was estimated using cumulative incidence in the competing risks setting (with death due to other causes as a competing event) and overall survival (OS) was estimated using Kaplan Meier methodology. Risk factors associated with CNS-related death were assessed using sub-distribution hazards regression modeling. Treatments given after CNS disease diagnosis were treated as time-varying variables. Tests were two-sided with statistical significance &amp;lt; 0.05. Results: After excluding 19 patients (11 for discordant HER2 status, 5 for concomitant second solid tumor, and 3 for missing data), 275 patients were included in these analyses (258 patients with parenchymal BrM +/- LMD, 8 patients with DM only, 2 patients with DM concomitantly with LMD, and 6 patients with LMD only). Overall, 63/275 (23%) presented with CNS as first and only site of metastasis, 210 (76%) patients developed CNS disease synchronously with or following ECM, and 2 had unknown timing. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS local therapies (92% ≥1 radiation treatment and 28% underwent ≥1 BrM resection). The median number of lines of systemic therapy after CNS disease diagnosis was 1 (range: 0-14); 105/275 (38%) patients received a HER2 tyrosine kinase inhibitor (lapatinib: 21%, neratinib: 4.4%, and tucatinib: 12%). The median follow-up was 3.6 years for survivors (range: 0.22 years-12 years). 193/275 (70%) patients died, of whom 105 (54%) died of CNS-related cause. The 3-year OS rate was 40% (95% CI=34%-46%), which varied for patients with BrM only at the diagnosis of metastatic disease [56% (95% CI=43%-69%] compared to patients with ECM +/- BrM [35% (95% CI=28%-42%] (p=0.05). The cumulative incidence of CNS-related death at 3 years was 33% (95% CI=27%-39%). Upon univariable modeling, LMD and CNS radiation treatment (RT) were associated with CNS-related death, and these associations remained statistically significant in a multivariable model [LMD: HR=2.49 (95% CI=1.62-3.83), p&amp;lt; 0.0001, and RT: HR=2.91 (95% CI=1.27-6.64), p=0.01]. Conclusions: Greater than half of patients with HER2+ with CNS involvement suffered of CNS-related death, with greatest risk among patients with LMD. We hypothesize that the association between radiotherapy and CNS-related death may reflect upfront response to systemic cancer-directed treatments of those in patients with DM only or limited CNS disease extension. CNS-only relapse at metastatic presentation portended improved survival than intra- plus extracranial progression, supporting an approach of aggressive local therapy for selected patients. Multimodality approaches using HER2-directed agents effective against parenchymal BrM, LMD along with extracranial metastases, in combination with local CNS-directed therapies need to be optimized. Citation Format: Emanuela Ferraro, Rabih Bou Nassif, Anne Reiner, Samantha Brown, Umberto Tosi, Katherine Panageas, Chau Dang, Andrew D Seidman, Nelson Moss. Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-02.

Abstract PS11-05: Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study

Abstract Background: Leptomeningeal carcinomatosis (LMC) occurs in approximately 5-15% of patients (pts) with advanced breast cancer (ABC) and is associated with poor survival and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity, leading to its widespread clinical use. DEBBRAH is evaluating the efficacy and safety of T-DXd in pts with HER2[+] and HER2-low ABC with a history of brain metastases (BM) and/or LMC. Here, we report results from cohort 5 that included pts with pathologically confirmed LMC. Methods: DEBBRAH (NCT04420598) is a single-arm, open-label, five-cohort, phase 2 study conducted across 18 sites in Spain and Portugal. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC and LMC with positive cerebrospinal fluid cytology. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response, clinical benefit rate (CBR) according to RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions); and safety and tolerability as per NCI-CTCAE v.5.0. OS was tested with the maximum likelihood exponential method (H0: median OS ≤2 months; H1: median OS≥6 months). We estimate that 7 pts are needed to attain an 80% power at the nominal level of one-sided α of 0.05. Results: Between Apr 14, 2021, and Apr 5, 2022, 7 pts were allocated into cohort 5. Median age was 57 (range, 42–69) years, 3 (42.9%) pts were HER2[+], 6 (85.7%) pts had synchronous extracranial metastases, 2 of whom (28.6%) also presented BM, and 3 (42.9%) pts had measurable disease. Median number of previous lines of therapy for advanced disease was 4 (range, 1-8) and no patient received prior local treatment for central nervous system involvement. At data cut-off (Apr 4, 2023), median follow-up was 12 months (range, 2.5-18.6). Median duration of treatment was 9.0 months (range, 2.1-18.6). Two (28.6%) pts remained on treatment: 1 HER2[+] and 1 HER2-low, after 18.6 and 12.0 months, respectively. Median OS rate was 13.3 months (95% CI, 5.7-NA, p&amp;lt; 0.001) meeting the primary endpoint. Among 5 pts with disease progression, none had intracranial progression. A total of 4 (57.1%) pts presented extracranial progression and 1 (14.3%) patient had clinical worsening. No objective responses were observed, but 5 out of 7 pts had prolonged stabilization (≥24 weeks) for an overall CBR of 71.4% (95% CI, 29.0-96.3) and a median PFS of 8.9 months (95% CI, 4.9-NA) according to RECIST v.1.1. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were nausea (57.1%; 14.3% G3), fatigue (42.9%; 0% G3), vomiting (42.9%; 0% G3), headache (42.9%; 0% G3), and urinary tract infection (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most frequent hematological TEAEs. No cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 4 (57.1%) of 7 pts, and 1 patient experienced a related serious TEAE (nausea G3). No treatment-related deaths were reported. Conclusions: T-DXd showed promising activity with no new safety concerns in HER2[+] and HER2-low pts with previously untreated, pathologically confirmed LMC. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. Citation Format: Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez-Castedo, Fabriccio Racca, Salvador Blanch, Manuel Ruíz - Borrego, Adela Fernández, María Fernández-Abad, Vega Iranzo, Maria Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofía Braga, Javier Cortés. Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-05.

Effects of total body irradiation on hematopoietic cell transplantation outcomes in pediatric acute myeloid leukemia with prior central nervous system involvement

BackgroundThe implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post HCT. ObjectiveWe analyzed a publicly available dataset derived from the Center of International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. MethodsThe study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplant and non-calcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. Cox regression model and Fine Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. ResultsThe study cohort comprised 550 pediatric AML patients, of which 25% (n =136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0-3 years, patients who were in the second complete remission, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio [HR]: 0.50, 95% confidence interval: 0.33-0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (p =0.10 and 0.20, respectively) in the two cohorts. The entire TBI treated cohort showed an association with increased risks of Grade 2-4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of non-relapse mortality and a trend of higher grade 3-4 acute GVHD. ConclusionIn this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

A rare presentation of Rosai-Dorfman-Destombes disease with central nervous system involvement and cutaneous wounds.

The aim of this case report is to investigate an uncommon presentation of Rosai-Dorfman-Destombes (RDD) disease, and discuss possible differential diagnoses and treatment options for this pathology. RDD is a rare disorder of histiocytes that typically presents in patients as painless cervical lymphadenopathy. However, this case involves a patient with the central nervous system (CNS) type of RDD who later developed cutaneous lesions. Several differential diagnoses were examined, including hidradenitis suppurativa, pilonidal cyst and pressure ulcers. It is important to be able to exclude these diagnoses based on the presentation, patient demographic and wound location. Biopsies verified the presence of RDD in the patient's suprasellar hypothalamic mass and skin lesions, confirming the patient had both CNS-RDD and cutaneous-RDD in the absence of lymphadenopathy. Recognising the unique manifestations of rare diseases such as RDD prevents delay of proper intervention and treatment.

Cryptococcal meningitis patients associated with HIV co-infection admitted in tertiary care hospital–A Case Series

Meningitis is a significant infection of the central nervous system that is followed by inflammation of the meninges, resulting in catastrophic neurologic consequences. The inflammation may be caused by infection with viruses, bacteria, fungi, or other microorganisms and less commonly by certain drugs. Meningitis can be life-threatening because of the inflammation’s proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency. In the present case series, we encompass patient demographics, initial clinical symptoms, physical examinations, laboratory results, cerebrospinal fluid examination findings, treatment side effects, the occurrence of complications, and hospital outcomes. Furthermore, documented were any instances of recurrent cryptococcal meningitis (CM) during follow-up, along with the potential causes of recurrence, the treatment modalities administered, any complications that arose, and the ultimate outcomes. This series reveals CM can manifest alongside HIV co-infection in male patients. Therefore, it is essential to consider the possibility of CM when an immune-compromised patient presents with symptoms such as headaches and other indications of central nervous system involvement. These cases reveal cryptococcosis with HIV-infected patients for rapid and early diagnosis and appropriate treatment of opportunistic infections.

Intra- and Extra-Medullary Tuberculoma: Case Report and Review of the Literature

Spinal cord tuberculoma is an extremely rare presentation of human tuberculosis in general, and of central nervous system involvement in particular. Only a dozen cases have been described in the literature. We report the case of a 62-year-old man who initially presented with neurological deficit in a context of febrile altered general condition. Diagnosis was made on MRI, which revealed necrotic lesions with medullary contrast.