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MRI of a 43-year-old woman with leptomeningeal metastases from breast cancer. Diagnostic MRI showed on T1- weighted images the typical intense contrast enhancement of cerebellar folia ( a , b , and c ). After treatment with oral capecitabine (2500 mg/m 2 per day) and intrathecal methotrexate (12 mg) administered during 6 months, she achieved a complete neuroimaging and cerebrospinal fluid response associated with neurological clinical improvement ( e , f , and g ). FLAIR- weighted imaging obtained at diagnosis ( d ) and 6 months after initiating treatment showed subclinical chemotherapy-induced leukoencephalopathy ( h ).
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Opinion statement:
Leptomeningeal cancer dissemination is a metastatic complication with growing impact in clinical oncology. Advances in treatment have been hampered by difficulties in diagnosis and response assessment, and nihilistic attitudes of physicians due to the poor prognosis, even when treating patients. However, relevant advances in the...
Context in source publication
Context 1
... biggest limitation of systemic chemotherapy for the treatment of LM is CNS penetration with acceptable systemic toxicity when used at standard doses. However, the blood – brain barrier may be disrupted in patients with LM, and empiric data support the potential benefit of conventional systemic treatment alone or in combination with ITC (Fig. 2). Systemic treatment has several advantages, including the possibility of treating patients with altered CSF flow and bulky LM, and the simultaneous treatment of systemic disease. Two provocative ...
Citations
... Focal radiotherapy can help alleviate pain by reducing the bulky masses that cause radiculopathies and can be useful in the case of obstructive lesions that cause hydrocephalus and increased intracranial pressure. By clearing obstructive lesions, RT helps increase chemotherapeutic and targeted agents' penetration through the BBB and is, therefore, useful before systemic therapy [37,45]. ...
... The median OS time in this study was nearly one year. All these new trials demonstrate that oral treatment with small molecules of TKI and anti-drug conjugates showed penetrance through the Blood-Brain Barrier (BBB) and may be a solution for these subjects [45,61,62], Table 3. Our cohort obtained the best PFS using Tucatinib + Capecitabine + Trastuzumab (18 months) compared to Pertuzumab + Trastuzumab or T-DM1 or Lapatinib + Capecitabine, even if patients receiving Tucatinib were heavily treated and received multiple lines of chemotherapy and anti-HER2 therapy. ...
Leptomeningeal metastases (LM) are a rare but rapidly fatal complication defined by the spread of tumor cells within the leptomeninges and the subarachnoid space, found in approximately 10% of patients with HER2-positive breast cancers. This pilot study evaluated the efficacy of local treatment with intrathecal Trastuzumab (IT) added to systemic treatment. The oncologic outcome of 14 patients with HER2-positive LM is reported. Seven received IT, and seven received standard of care (SOC). The mean number of IT cycles administered was 12.14 ± 4.00. The response rate to CNS after IT treatment + SOC was 71.4%, and three patients (42.8%) obtained durable responses lasting more than 12 months. The median progression-free survival (mPFS) after LM diagnosis was six months, and the median overall survival (mOS) was ten months. The mean values of the PFS in favor of IT therapy (10.6 mo vs. 6.6 mo) and OS (13.7 vs. 9.3 mo) suggest a non-negligible investigation direction in the sense of exploiting intrathecal administration as a possible treatment modality in these patients. Adverse events reported were local pain related to intrathecal administration and one case of arachnoiditis, hematoma, and CSF fistulae. Intrathecal administration of Trastuzumab, alongside systemic treatment and radiotherapy, might improve oncologic outcomes in LM HER2-positive breast cancer with manageable toxicity.
... The patient's treatment differed in that the dose volume included a significant amount of the ventricular system, while other studies report irradiating the pineal region, but none have specifically mentioned expanding the volume into the ventricles to prevent leptomeningeal spread. In other tumors with common leptomeningeal spread, whole brain radiation therapy (WBRT) has been shown to improve survival [7][8][9]. Alternatively, whole ventricular irradiation has shown success in tumors such as germinomas in limiting disease to common areas of spread while maintaining reduced levels of cerebral toxicity and better cognitive function [10,11]. ...
We present an updated case report of a patient with glioblastoma isolated to the pineal gland with an overall survival greater than five years and no progression of focal central nervous system (CNS) deficits since initial presentation. The patient underwent radiotherapy up to 60 Gy with concurrent and adjuvant temozolomide with the use of non-standard treatment volumes that included the ventricular system. The utilization of ventricular irradiation as well as the addition of bevacizumab at disease recurrence may have encouraged this unusually long survival by preventing/delaying leptomeningeal spread. We also present an updated review of the literature, which shows a median survival of six months, reinforcing the patients atypical disease trajectory. Finally, we utilize OpenAI's language model ChatGPT to aid in synthesizing this manuscript. In doing so, we demonstrate that ChatGPT is apt at creating concise summaries of relevant literature and topic subjects, however its output is often repetitive with similar sentence/paragraph structure, less than ideal grammar and poor syntax requiring editing. Thus, in its current iteration, ChatGPT is a helpful aid that cuts down on the time spent in data acquisition and processing but is not a replacement for human input in the creation of quality medical literature.
... The incidence of LMC is increasing as patient survival improves with advances in the management of metastatic solid tumors and as magnetic resonance imaging (MRI) becomes more widely utilized (5,6). LMC occurs in approximately 4%-15% of patients with malignant solid tumors, most commonly melanomas and malignancies of the breast, lung, and gastrointestinal organs (7)(8)(9)(10)(11). Signs and symptoms of LMC include headaches, vomiting, seizures, focal neurologic deficits, radicular neck and back pain, cerebellar dysfunction, altered mental status, cauda equina syndrome, dizziness, or syncope (12)(13)(14). ...
Objective:
Leptomeningeal carcinomatosis (LMC), a common complication of advanced malignancies, is associated with high morbidity and mortality, yet diagnosis and treatment decisions remain challenging. This study describes the diagnostic and treatment modalities for LMC and identifies factors associated with overall survival (OS).
Materials and methods:
We performed a single-institution retrospective study (registration #: OSU2016C0053) of 153 patients diagnosed with LMC treated at The Ohio State University, Comprehensive Cancer Center, (OSUCCC)-James between January 1, 2010 and December 31, 2015.
Results:
Median age at diagnosis was 55.7 years, and 61% had Eastern Cooperative Oncology Group baseline performance status ≤1. Most common primary tumors were breast (43%), lung (26%), and cutaneous melanoma (10%). At presentation, most patients were stage III-IV (71%) with higher grade tumors (grade III: 46%). Metastases to bone (36%), brain (33%), and lung (12%) were the most common sites with a median of 0.5 years (range, 0-14.9 years) between the diagnosis of first metastasis and of LMC. 153 (100%) patients had MRI evidence of LMC. Of the 67 (44%) who underwent lumbar puncture (LP), 33 (22%) had positive cerebrospinal fluid (CSF) cytology. Most patients received radiotherapy for LMC (60%) and chemotherapy (93%) for either the primary disease or LMC. 28 patients received intrathecal chemotherapy, 22 of whom had a primary diagnosis of breast cancer. 98% died with median OS of all patients was 1.9 months (95% CI: 1.3-2.5 months).
Conclusion:
Despite improved treatments and targeted therapies, outcomes of LMC remain extremely poor. Positive CSF cytology was associated with lower OS in patients who had cytology assessed and specifically in patients with breast cancer. CSF cytology serves as an important indicator for prognosis and helps aid in developing individualized therapeutic strategies for patients with LMC.
... LMD is associated with a poor prognosis, with a median survival of 4-6 wks without treatment and 4-6 mos with treatment. 1 The incidence of LMD is believed to be increasing because of earlier detection and cancer treatments that are able to prolong survival while allowing cancer progression in sanctuary sites such as behind the blood-brain barrier. [2][3][4] Although CSF cytology is the gold standard for LMD diagnosis, it has a high false-negative rate of up to 50%. 5 Magnetic resonance imaging false-negative rates are between 30% and 70%. ...
The incidence of leptomeningeal disease (LMD) is believed to be increasing in part because of more effective chemotherapy treatments allowing cancer progression behind the blood-brain barrier. However, little has been published about the rehabilitation of this growing patient population. In this study, impairments and rehabilitation utilization by cytology-proven LMD patients receiving intrathecal chemotherapy at a cancer center are described. A total of 109 consecutive patients with pathology-confirmed LMD who received an intrathecal chemotherapy infusion from January 1, 2017, through October 31, 2017, were retrospectively reviewed. Of the 109 patients, 103 (95%) had impairments described in their medical record that could impact physical function, including 74 of 109 (68%) who had deconditioning or fatigue. Kaplan-Meier median survival from initial LMD diagnosis was 13.1 mos. The median number of hospital admissions and intrathecal chemotherapy administrations was both 8. Of the 109 patients, 43 (39%) had magnetic resonance imaging radiology interpreted LMD. Most LMD patients used rehabilitation services (95/109, 87%) and most were able to forego post-acute inpatient rehabilitation facilities (96/109, 88%). Additional research and education for rehabilitation professionals about this increasingly common syndrome are needed.
... Radiation is usually administered at a dose of 3 Gy for 10 days, but can vary between 20-40 Gy as patients with better prognosis tend to receive more sessions. However, there has not been a documented benefit in survival from WBRT [4,[56][57][58]. Furthermore, WBRT can cause transient somnolence and cognitive decline. ...
... On the other hand, focal radiotherapy is well-proven in providing palliative relief, such as reduction of radiculopathies, bulky disease, or obstructive lesions causing hydrocephalus [59]. Resolution of obstructive lesions also increases penetrance and distribution of intra-thecal chemotherapeutics, and so may precede chemotherapy [58]. ...
Leptomeningeal disease has become increasingly prevalent as novel therapeutic interventions extend the survival of cancer patients. Although a majority of leptomeningeal spread occurs secondary to breast cancer, lung cancer, and melanoma, a wide variety of malignancies have been reported as primary sources. Symptoms on presentation are equally diverse, often involving a combination of neurological deficits with the possibility of obstructive hydrocephalus. Diagnosis is definitively made via cerebrospinal fluid cytology for malignant cells, but neuro-imaging with high quality T1-weighted magnetic resonance imaging can aid diagnosis and localization. While leptomeningeal disease is still a terminal, late-stage complication, a variety of treatment modalities, such as intrathecal chemotherapeutics and radiation therapy, have improved median survival from 4–6 weeks to 3–6 months. Positive prognosticative factors for survival include younger age, high performance scores, and controlled systemic disease. In looking to the future, diagnostics that improve early detection and chemotherapeutics tailored to the primary malignancy will likely be the most significant advances in improving survival.
... Once clinical symptoms appear, the diagnosis of neoplastic meningitis relies on the cytological identification of malignant cells in the CSF, and/or compatible magnetic resonance imaging (MRI) findings and/or suggestive biochemical CSF findings [3]. However, the sensitivity of cytology and the specificity of MRI are not optimal [1,2,4,5]. Moreover, incidental MRI features suggestive of meningeal dissemination can be found in asymptomatic and paucysymptomatic patients, increasing the diagnostic challenge. ...
... However, using FCI to analyze the CSF did not eliminate the false negative cases. It is likely that some of the reasons given to explain negative cytology results may also justify negative FCI results: negative or transient seeding in the CSF and suboptimal collection with samples obtained far from the site of origin of clinical symptoms [1,2,4,5]. In addition, down regulation of EpCAM expression described in some aggressive tumors [27] and epithelial-mesenchymal-transition should also be considered [28]. ...
... In the meantime, the inclusion of FCI among the LC diagnostic procedures adds specificity to MRI data, and, combined with CSF cytology, significantly decreases the number of undiagnosed cases. Regarding the prognostic study, and in keeping with previous reports, our series also confirmed that a good performance status remains as an independent factor associated with better survival [1,2,4,5,[29][30][31][32]. The levels of glucose in the CSF showed a trend towards significance [17], and receiving only whole brain RDT was the only therapeutic choice associated with a bad prognosis. ...
Some patients with epithelial-cell cancers develop leptomeningeal carcinomatosis (LC), a severe complication difficult to diagnose and with an adverse prognosis. This study explores the contribution of flow cytometry immunophenotyping (FCI) to the diagnosis and prognosis of LC. Cerebrospinal fluid (CSF) samples from patients diagnosed with LC were studied using FCI. Expression of the epithelial-cell adhesion molecule (EpCAM) was the criterion used to identify the epithelial cells. To test the diagnostic precision, 144 patients (94 diagnosed with LC) were included. The prognostic value of FCI was evaluated in 72 patients diagnosed with LC and eligible for therapy. Compared with cytology, FCI showed greater sensitivity and negative predictive value (79.79 vs. 50 %; 68.85 vs. 51.55 %, respectively), but lower specificity and positive predictive value (84 vs. 100 %; 90.36 vs. 100 %, respectively). The multivariate analysis revealed that the percentage of CSF EpCAM+ cells predicted an increased risk of death (HR: 1.012, 95 % CI 1.000-1.023; p = 0.041). A cut-off value of 8 % EpCAM+ cells in the CSF distinguished two groups of patients with statistically significant differences in overall survival (OS) (p = 0.018). This cut-off value kept its statistical significance regardless of the absolute CSF cell-count. The FCI study of the CSF improved the sensitivity for diagnosing LC, but refinement of the technique is needed to improve specificity. Furthermore, quantification of CSF EpCAM+ cells was revealed to be an independent prognostic factor for OS in patients with LC eligible for therapy. An 8 % cut-off value contributed to predicting clinical evolution before initiation of therapy.
... Magnetic resonance imaging (MRI) of the brain and/or spine is widely used to detect LMD, and cerebrospinal fluid (CSF) analysis confirms the diagnosis. The presence of LMD indicates a very advanced stage of cancer with a grave prognosis; the median survival time of patients with LMD is 4-6 weeks without treatment but may be increased to 4-6 months with treatment in patients with breast cancer [4]. However, the survival of patients with LMD from melanoma is more dismal. ...
We present a patient with metastatic BRAF-mutated melanoma who achieved long-term stabilization of leptomeningeal disease (LMD) with sequential whole-brain radiation therapy and vemurafenib. A 53-year-old woman with melanoma that harbored the BRAF V600E mutation and had that metastasized to multiple lymph nodes, lungs, breast, and subcutaneous tissue had developed symptomatic LMD 16 months after starting vemurafenib treatment despite achieving a substantial response at the existing metastatic sites. Vemurafenib was discontinued for 7 days, she received whole-brain radiation therapy (30 Gy in 10 fractions), and 7 days after completing the radiation therapy, she resumed vemurafenib therapy. The neurologic symptoms improved significantly, and a cerebrospinal fluid examination revealed disappearance of melanoma cells. She remained alive with radiologically stable LMD for at least 18 months after the whole-brain radiation therapy.
Leptomeningeal spread of cancer is rare, difficult to both diagnostically confirm and treat, and associated with a poor prognosis. The blood–brain barrier largely prevents sufficient penetration of systemic therapy to be effective. Direct administration of intrathecal therapy has thus been used as an alternative treatment option. We present a case of breast cancer complicated by leptomeningeal spread. Intrathecal methotrexate was initiated, and the manifestation of systemic side effects suggested systemic absorption. This was subsequently confirmed by blood work showing detectable methotrexate levels following intrathecal administration as well as resolution of symptoms with reduction in the dose of methotrexate administered.
Background
Cerebrospinal fluid (CSF) cytology remains the gold standard approach for diagnosing of leptomeningeal metastases (LM), but has clinical problems due to its low sensitivity. This systemic review and meta-analysis evaluated the diagnostic accuracy of the novel CSF biomarkers of liquid biopsy and magnetic resonance imaging (MRI) for detecting LM in patients with solid cancers.
Methods
A systematic search of electronic databases was conducted to identify all published diagnostic accuracy studies on CSF liquid biopsies and MRI since January 2000 with registration for PROSPERO (#CRD42022301988). Articles were selected based on pre-defined inclusion and exclusion criteria following the PRISMA 2020 statement.
Results
The search yielded 3790 citations, and 10 studies with 668 patients were included in the final analysis. The pooled prevalence of LM was 50.9% (340/668). The respective sensitivity and specificity for index tests were as follows: circulating tumor cells (CTC), 87.0% (95% confidence interval [CI] 77.9–92.6%) and 93.8% (86.9–97.2%); cell-free tumor DNA, 97.9% (19.3–100%) and 89.0% (25.3–99.5%); MRI 59.4% (60.7–76.9%) and 97.6% (77.3–99.8%); cytology, 71.9% (54.7–82.9%) and 100%. The diagnostic odds ratio was 100.6 (29.38–344.09) for CTC and 93.3 (88.42–1034.05) for MRI.
Conclusion
Novel CSF liquid biopsies and MRI may offer improved diagnostic accuracy for LM from solid cancers; however, further research is required to specify the threshold values and to construct standards for individual primary cancers.
Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the pleura and pulmonary mesenchyme, associated with pathogenic germline DICER1 mutations. Although the most common site of metastasis is the central nervous system (CNS), patients with CNS metastasis have dismal outcome. We report a case of a patient presenting with type II PPB and intracranial and bone metastases. We describe a multimodal therapy approach and highlight the use of intraventricular topotecan for isolated CNS recurrence. In addition, a new pathogenic germline mutation heterozygous for the c.1234delT of DICER1 was identified. Patient remains in remission 3 years after recurrence.
