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Journal of Cancer Research and... Apr 2024Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic...
BACKGROUND
Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA).
METHODS
A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them.
RESULTS
The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA.
CONCLUSION
Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.
Topics: Humans; Male; Female; Middle Aged; Adenocarcinoma of Lung; Retrospective Studies; Lung Neoplasms; Injections, Spinal; Prognosis; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Survival Rate; Meningeal Neoplasms; Treatment Outcome; Protein Kinase Inhibitors; Meningeal Carcinomatosis; Combined Modality Therapy; Aged, 80 and over
PubMed: 38687937
DOI: 10.4103/jcrt.jcrt_2071_23 -
BMC Cancer Apr 2024Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective...
BACKGROUND
Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration.
METHODS
The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM.
RESULTS
The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01).
CONCLUSION
The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.
Topics: Animals; Small Cell Lung Carcinoma; Mice; Humans; Lung Neoplasms; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Podophyllotoxin; Cell Line, Tumor; Mice, Nude; Meningeal Carcinomatosis; Xenograft Model Antitumor Assays; Proteolysis
PubMed: 38644473
DOI: 10.1186/s12885-024-12244-3 -
Clinical & Experimental Neuroimmunology Feb 2024We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40...
Anti-aquaporin-4 immunoglobulin G/anti-myelin oligodendrocyte glycoprotein immunoglobulin G double-positive paraneoplastic neurological syndrome in a patient with triple-negative breast cancer.
We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40 year-old woman with metastatic triple-negative breast cancer. She received multiple lines of anti-neoplastic treatment, including immunotherapy with pembrolizumab, as well as cytotoxic chemotherapy. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis followed by left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid analysis during both episodes showed normal glucose and protein, and elevated white blood cell count. Cytology was negative for malignancy. Cerebrospinal fluid was positive for neuromyelitis optica immunoglobulin G antibody anti-aquaporin-4, and autoimmune myelopathy panel was positive for myelin oligodendrocyte glycoprotein antibody. The patient had significant clinical and radiographic improvement after completion of five cycles of plasmapheresis followed by intravenous immunoglobulin. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every 6 months and daily low-dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case shows that these antibodies can occur concurrently and cause clinical features, such as both neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease, in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or cerebrospinal fluid profile negative for leptomeningeal carcinomatosis.
PubMed: 38595690
DOI: 10.1111/cen3.12767 -
World Neurosurgery Jun 2024Patients with leptomeningeal carcinomatosis (LMC) experience a poor prognosis and rapid progression, and cerebrospinal fluid drainage (CSFD) is used to manage...
BACKGROUND
Patients with leptomeningeal carcinomatosis (LMC) experience a poor prognosis and rapid progression, and cerebrospinal fluid drainage (CSFD) is used to manage intracranial hypertension and hydrocephalus in LMC patients. This study aims to describe a novel discovery of preoperative radiological features in patients who underwent CSFD for LMC.
METHODS
A retrospective review was conducted during the past 5 years of LMC patients with intracranial hypertension and hydrocephalus who underwent CSFD. We evaluated the patients' preoperative radiological features, clinical characteristics, and survival times.
RESULTS
A total of 36 patients were included. Of the 36 patients, 34 underwent ventriculoperitoneal shunting, and 2 patients underwent only external ventricular drainage due to rapid progression. The median preoperative Karnofsky performance scale score was 40.0 (interquartile range [IQR], 20.0-40.0). The median survival time after surgery was 5 months (IQR, 0.00-10.43 months). Of the 36 patients, 24 (66.7%) had supratentorial cerebral edema before surgery, including 14 patients (38.9%) with features of disproportionately enlarged subarachnoid space hydrocephalus (DESH). Four patients (11.1%) exhibited cerebellar swelling and had a median survival time of 0.27 month (IQR, 0.00-0.56 month). Nine patients (25%) have enhancement lesions on the cerebellum. The survival curve analysis shows that patients with features of cerebellar enhancement have shorter survival times than other patients. Patients with DESH features have longer survival times compared with those with global cerebral edema.
CONCLUSIONS
Patients with radiological features of cerebellar enhancement have shorter postoperative survival than other patients; however, those with supratentorial cerebral edema, especially features of DESH, could benefit from CSFD. Patients with cerebellar swelling should avoid undergoing CSFD.
Topics: Humans; Male; Meningeal Carcinomatosis; Female; Middle Aged; Retrospective Studies; Drainage; Adult; Hydrocephalus; Aged; Ventriculoperitoneal Shunt; Brain Edema; Intracranial Hypertension
PubMed: 38593911
DOI: 10.1016/j.wneu.2024.04.014 -
Journal of Veterinary Internal Medicine 2024Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in...
Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.
Topics: Dogs; Animals; Dog Diseases; Stomach Neoplasms; Meningeal Carcinomatosis; Male; Adenocarcinoma; Cell Transformation, Neoplastic
PubMed: 38587203
DOI: 10.1111/jvim.17072 -
Anti-cancer Drugs Jul 2024Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer...
Furmonertinib and intrathecal pemetrexed chemotherapy rechallenges osimertinib-refractory leptomeningeal metastasis in a non-small cell lung cancer patient harboring EGFR20 R776S, C797S, and EGFR21 L858R compound EGFR mutations: a case report.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the rarity of cases, the response of EGFR-TKIs in patients harboring uncommon compound EGFR mutations still needs to be determined. Here, we demonstrated the case of a 47-year-old smoker diagnosed with leptomeningeal metastasis from NSCLC and had EGFR20 R776S, C797S, and EGFR21 L858R compound mutations. He was treated with furmonertinib combined with intrathecal pemetrexed chemotherapy following progression on osimertinib, which led to clinical improvement and successfully prolonged his survival by 3 months. Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Pemetrexed; ErbB Receptors; Acrylamides; Lung Neoplasms; Aniline Compounds; Male; Middle Aged; Mutation; Antineoplastic Combined Chemotherapy Protocols; Injections, Spinal; Meningeal Carcinomatosis; Meningeal Neoplasms; Indoles; Pyrimidines
PubMed: 38513197
DOI: 10.1097/CAD.0000000000001593 -
Strahlentherapie Und Onkologie : Organ... Apr 2024The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of... (Review)
Review
PURPOSE
The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis.
MATERIALS AND METHODS
For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation).
CONCLUSION AND RECOMMENDATIONS
Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.
Topics: Humans; Female; Meningeal Carcinomatosis; Breast Neoplasms; Cranial Irradiation; Neoplasm Recurrence, Local; Brain Neoplasms; Radiosurgery
PubMed: 38488902
DOI: 10.1007/s00066-024-02202-0 -
Journal of Neuro-oncology May 2024Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell...
PURPOSE
Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors.
METHODS
We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival.
RESULTS
Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively.
CONCLUSIONS
CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.
Topics: Humans; Retrospective Studies; Female; Male; Prognosis; Middle Aged; Meningeal Neoplasms; Aged; Adult; Survival Rate; Follow-Up Studies; Neoplasms; Meningeal Carcinomatosis; Cell Count
PubMed: 38441840
DOI: 10.1007/s11060-024-04615-4 -
Journal of Neuro-oncology May 2024The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is...
PURPOSE
The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types.
METHODS
We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021.
RESULTS
The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results.
CONCLUSIONS
This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.
Topics: Humans; Female; Male; Retrospective Studies; Prognosis; Middle Aged; Meningeal Neoplasms; Magnetic Resonance Imaging; Aged; Adult; Survival Rate; Meningeal Carcinomatosis; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Follow-Up Studies; Neoplasms
PubMed: 38430420
DOI: 10.1007/s11060-024-04616-3 -
Acta Neurochirurgica Mar 2024This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in...
PURPOSE
This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis.
METHODS
Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate.
RESULTS
Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013).
CONCLUSION
Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.
Topics: Humans; Meningeal Carcinomatosis; Methotrexate; Nausea; Perfusion; Vomiting
PubMed: 38424255
DOI: 10.1007/s00701-024-05989-0