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PubMed2026

Serial CSF CA19-9 monitoring and CSF genomic profiling in ERBB2-mutant lung adenocarcinoma with leptomeningeal metastasis: a case report.

Leptomeningeal metastasis (LM) from ERBB2-mutant lung adenocarcinoma is difficult to treat and monitor because systemic disease and leptomeningeal disease may evolve discordantly. Evidence regarding cerebrospinal fluid (CSF) genomic profiling and serial CSF tumor marker monitoring in ERBB2-mutant non-small cell lung cancer with LM remains limited. We report a 48-year-old woman initially diagnosed with stage IB mucinous lung adenocarcinoma harboring an ERBB2 exon 20 p.G776delinsVC mutation. After surgery and adjuvant chemotherapy, she developed nodal recurrence and later presented with lower back pain and lower-limb numbness. LM was clinically diagnosed based on neurological symptoms, magnetic resonance imaging and CSF cytopathology. She received craniospinal irradiation, systemic therapy and subsequent intrathecal treatment. At month 33, CSF CA19-9 was markedly elevated despite no clear radiographic systemic progression. CSF next-generation sequencing(NGS) detected the same ERBB2 exon 20 p.G776delinsVC mutation as the primary lung tumor, with a higher variant allele fraction in CSF than in lung tissue.The patient subsequently received trastuzumab deruxtecan and sequential intrathecal therapy with pemetrexed, etoposide, cytarabine and pemetrexed rechallenge. Intrathecal treatment was adjusted according to serial CSF CA19-9 levels, neurological status, imaging findings, systemic disease activity and treatment-related toxicities. CSF CA19-9 was not used as a stand-alone criterion for progression or treatment modification.At the latest follow-up, she remained alive more than 36 months after the clinical diagnosis of LM. This case suggests that CSF NGS and serial CSF CA19-9 may provide further insights into disease activity within the integrated assessment of systemic and leptomeningeal disease. Their clinical applicability is still under investigation and necessitates future validation.

CA19-9↗

PubMed2026

Continuous Intrathecal Infusion of Nivolumab in Advanced Melanoma With Concomitant Leptomeningeal Disease: Efficacy, Safety, and Pharmacokinetics.

BACKGROUND AND OBJECTIVES: Prognosis of melanoma with leptomeningeal disease (LMD) is poor (median overall survival of 5.1 months). Intrathecal (IT) nivolumab appears safe, although its efficacy remains uncertain. We investigated the feasibility, safety, and efficacy of continuous IT nivolumab. METHODS: This was a retrospective analysis of 11 melanoma patients with progressive LMD (MelBase; NCT02828202) treated as part of the patients' care with continuous IT nivolumab administered through spinal (n = 10) or ventricular catheter (n = 1). RESULTS: Patients (5 women, median age 52) with Eastern Cooperative Oncology Group ≤1 (except for 1) and stable extracranial disease (except for 4) were treated over a median duration of 1.5 months and followed for 2.5 months. Seven presented symptomatic LMD. Primary tumors were mostly cutaneous (n = 8) and BRAF-mutated (n = 10). All patients had progressed on systemic immunotherapy; 7 had received brain radiotherapy (whole brain radiotherapy [n = 3]; stereotactic radiosurgery [n = 4]). Concomitant therapies included corticosteroids >10 mg (n = 5), intravenous nivolumab (first 3 months of IT therapy, n = 1), and targeted therapies (n = 7). The median overall survival was 2.5 months, with 3 patients surviving for more than a year. Reversible treatment-related adverse events occurred in 5 patients: meningoencephalitis (grade 3, n = 1), intracranial hemorrhage (grade 1, n = 1), intracranial hypotension (grade 2, n = 2; grade 1, n = 1). Baseline levels of nivolumab in the cerebrospinal fluid (CSF) were <2 µg/mL, even among patients with plasma detection. CSF concentrations of nivolumab at steady state varied from 36 to 97 µg/mL, with clearances of 4.3-15.7 mL/h. Next-generation sequencing identified CSF genomic profiles correlating with clinical progression in 4 patients. CONCLUSION: These findings warrant further trials on IT nivolumab.

Humans↗

PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗

PubMed2026

Ruxolitinib Penetrates Blood Brain Barrier and Reduces the Cytokine Storm in Patients With Haemophagocytic Lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis (HLH), complicated by the involvement of the central nervous system (CNS), contributes to high morbidity and mortality with rapid development and violent cytokine storms in the CNS. Consequently, intrathecal dexamethasone and methotrexate must be administered in a timely manner to treat CNS inflammation. No effective pharmacotherapy targeting cytokine pathways is available to suppress cytokine storms that occur in the CNS. Ruxolitinib, a JAK1/2 inhibitor, has been recommended for the treatment of HLH by multiple guidelines. Conventional studies have reported that ruxolitinib cannot penetrate the blood brain barrier (BBB), thereby impeding the implementation of numerous therapies. Our team previously identified the efficacy of ruxolitinib in patients with CNS-HLH. Ten patients with secondary HLH (two with CNS involvement and eight without) received ruxolitinib, and BBB permeability was evaluated. Ruxolitinib exhibited BBB penetrability, ranging from 5.31% to 18.08%, suggesting its promising potential in CNS therapy.

Humans↗

PubMed2026

The analgesic efficacy of intrathecal morphine compared to peripheral regional analgesia in total hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Following elective total hip arthroplasty, pain continues to be a significant problem. Intrathecal morphine or peripheral regional analgesia, that is local infiltration analgesia or peripheral nerve block, are common analgesic modalities, but it is still not known which is superior. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: The following electronic databases were searched from inception to 24 March 2026: CENTRAL; Ovid Embase; Ovid MEDLINE; Scopus; and Web of Science. ELIGIBILITY CRITERIA: Randomised controlled trials that compared intrathecal morphine to peripheral regional analgesia in patients scheduled for elective total hip arthroplasty under general or spinal anaesthesia. RESULTS: Eight trials and 471 patients were included. The peripheral regional analgesia was peripheral nerve block in six trials and local infiltration analgesia in two trials. No difference was demonstrated between intrathecal morphine and peripheral regional analgesia in regard to the first coprimary outcome, the pain score at rest at 24 h. The quality of evidence was moderate. Intrathecal morphine was found to be superior to peripheral regional analgesia with respect to the second coprimary outcome, the cumulative intravenous morphine equivalent consumption at 24 h. Mean difference (95% CI) was 11.38 mg (4.31-18.45; P  = 0.002, I2  = 81%). The quality of evidence was low. Intrathecal morphine was revealed to be superior to peripheral regional analgesia at 8-12 h for the pain score at rest, 1.24 (0.60-1.88); P  = 0.0001, I2  = 68%; pain score on movement, 1.15 (0.12-2.17), P  = 0.03, I2  = 65%; but the rate of in hospital pruritus was reduced with peripheral regional analgesia, 0.31 (0.17-0.58), P  = 0.0002, I2  = 0%. No differences in functional status were shown. CONCLUSIONS: We found no difference between intrathecal morphine and peripheral regional analgesia in regard to pain score at rest at 24 h. Intrathecal morphine may lead to a favourable effect on some but not all analgesic indices compared to peripheral regional analgesia in elective total hip arthroplasty. The quality of evidence for these positive effects was low. Intrathecal morphine reduced the systemic opioid consumption, but is not in itself an opioid free strategy. This notion is supported by the increased incidence of in hospital pruritus with intrathecal morphine. The quality of evidence for this was high. In view of the quality of evidence, high quality randomised controlled trials are required to substantiate these results.

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