Diagnosis Of Central Nervous System Disease Research Articles

Central nervous system metastases in breast cancer patients with germline BRCA pathogenic variants compared to non-carriers: a matched-pair analysis

BackgroundBreast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA1/2 genes.MethodsA retrospective cohort of 75 breast cancer patients with known BRCA1/2 mutation status, who were diagnosed with CNS metastases in 2006–2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA1/2 carriers (n = 25) and non-carriers (n = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses.ResultsPatients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P = 0.026) and leptomeningeal spread (40% vs. 20%, P = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival.ConclusionPatients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA1/2 mutations in CNS metastatic breast cancer.

Voiding Dysfunction Due to Urethral Sphincter Dysfunction Might Be an Early Neurological Presentation of Central Nervous System Disorders in Aged Patients.

To investigate the incidence of central nervous system (CNS) diseases in adult patients with voiding dysfunction and videourodynamics (VUDS) proven urethral sphincter dysfunction. This retrospective analysis reviewed the medical charts of patients aged > 60 years who underwent VUDS for non-prostatic voiding dysfunction from 2006 to 2021. A chart review was performed to search for the occurrence and treatment of CNS diseases after the VUDS examination up to 2022. The diagnosis of CNS disease, such as cerebrovascular accidents (CVA), Parkinson's disease (PD), and dementia, by neurologists was also retrieved from the charts. Based on the VUDS findings, patients were divided into the following subgroups: dysfunctional voiding (DV), poor relaxation of the external sphincter (PRES), and hypersensitive bladder (HSB) and coordinated sphincter subgroups. The incidence of CVA, PD, and dementia in each subgroup was recorded and compared among them using one-way analysis of variance (ANOVA). A total of 306 patients were included. VUDS examinations revealed DV in 87 patients, PRES in 108, and HSB in 111. Among them, 36 (11.8%) patients had CNS disease, including CVA in 23 (7.5%), PD in 4 (1.3%), and dementia in 9 (2.9%). Among the three subgroups, the DV group had the highest incidence rate of CNS disease (n = 16, 18.4%), followed by PRES (n = 12, 11.1%) and HSB (n = 8, 7.2%). However, no significant difference was noted in the incidence of CNS disease across the three subgroups. Nevertheless, the incidence of CNS disease was higher in patients with DV and PRES than that in the general population. The incidence of CNS diseases was high in patients aged > 60 years with voiding dysfunction due to urethral sphincter dysfunction. Patients with VUDS-confirmed DV had the highest incidence of CNS disease among the three subgroups.

Characteristics of Central Nervous System (CNS) Involvement in Children With Non-Hodgkin's Lymphoma (NHL) and the Diagnostic Value of CSF Flow Cytometry in CNS Positive Disease.

Objective:To investigate the characteristics of central nervous system (CNS) involvement in children with non-Hodgkin’s lymphoma (NHL) and the value of flow cytometry (FC) in the diagnosis of CNS disease in pediatric NHL.Methods:The data of 56 newly diagnosed pediatric NHL patients with CNS involvement (CNS+/mass, CNS+/palsy, CNS+/CSF) were analyzed. The proportions and formats of CNS disease in different pathological types were compared. In addition, FC and conventional cytology (CC) of cerebrospinal fluid (CSF) were carried out in 383 newly diagnosed NHL cases.Results:A total of 383 children with NHL were enrolled. Among these patients, 56 (14.6%) were diagnosed with positive CNS involvement (CNS+), 33 had bulky disease (tumor diameter >10 cm), 32 had bone marrow invasion, 32 had lactate dehydrogenase levels >1000 U/L, and 25 had invasion of more than 4 organs at the time of diagnosis. There were 14 patients with T lymphoblastic lymphoma (T-LBL), 9 with B lymphoblastic lymphoma (B-LBL), 26 with Burkitt’s lymphoma (BL), and 2 with Epstein-Barr virus-positive diffuse large B cell lymphoma (EBV + DLBCL). Among the 56 CNS+ patients, 35 were CSF-positive (CSF+); there were 2 patients who were CSF+ via CC detection and 35 who were CSF+ via FC detection. The difference between CC and FC was statistically significant (P < 0.01). In the T-LBL group, 14 patients were CNS+/CSF, and in the B-LBL group, 8 were CNS+/mass. In the BL group, 22 patients were CNS+/mass and 15 were CNS+/CSF. In the anaplastic large-cell lymphoma group, 5 patients were CNS+/mass. Nine of the 56 CNS+ patients had events. The 2-year overall survival rate was 87% ± 0.046%, and the 2-year event-free survival rate was 76.2% ± 0.07%.Conclusion:CNS+ diagnoses were more common in pediatric NHL patients with bulky disease and/or bone marrow involvement and/or involvement of more than 4 organs at the time of diagnosis, and they were also common in the EBV + DLBCL and BL groups. FC of CSF showed important clinical significance in the diagnosis of CNS disease in pediatric NHL patients, and it can be used to significantly improve the CNS+ detection rate.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45years old and 109 patients > 45years old. The younger group was characterized by longer median overall survival (117.1months vs 88months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4months vs 75.9months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7months vs 11.1months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Abstract P3-08-41: Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome

Abstract Background: Breast cancer is the second most common cause of central nervous system (CNS) metastasis, leading to a significant decrease in survival rate. High risk groups for CNS involvement include younger age, human epidermal growth factor 2 (HER2) over-expression, estrogen receptor (ER) and progesterone receptor (PR) negativity, high histologic grade, and presence of systemic metastases. Young age at diagnosis of breast cancer is associated with more aggressive biological behavior and worse prognosis than in the elderly. However, data are limited regarding CNS involvement in this group of patients. Although it could be expected that younger patients would also have a poor prognosis after the diagnosis of CNS metastases, earlier studies have demonstrated conflicting results, some with favorable outcomes for this unique group. In this study we aimed to explore the differences in the patterns and outcome of CNS involvement according to age at diagnosis of breast cancer (≤45 years vs. &amp;gt;45 years). Methods: A retrospective database of consecutive breast cancer patients who were treated in our institute and were diagnosed with CNS metastases during 2006-2019 was generated. Data analyzed included age at diagnosis of breast cancer, age at diagnosis of CNS involvement, histopathological factors (histology, grade, hormone receptor and HER2 status), treatments given before and after CNS involvement, characteristics of CNS involvement (location, number of brain deposits, clinical manifestations), overall survival, time to CNS progression, and survival after diagnosis of CNS disease. Results: Study cohort was comprised of 174 patients: 65 patients were age≤45 and 109 patients were older than 45 at breast cancer diagnosis. The percentage of patients with triple-negative breast cancer was higher among the younger age group (24.6% vs. 14.7%). Median overall survival from breast cancer diagnosis was significantly longer for younger patients [117.1 months (95% CI 67.2-167) vs. 88 months (95% CI 65.6-110.4), p=0.017]. Median time from breast cancer diagnosis to development of CNS metastases was also significantly longer in the younger age group [58.1 months (95% CI 46.5-69.6) vs. 37.5 months (95% CI 22.9-52.2), p=0.021]. Median survival as measured from time of CNS involvement was 18.7 months (95% CI 10.8-26.6) in the younger group vs. 11.1 months (95% CI 7.8-14.5) in the older patients (p=0.341). Survival of patients with triple-negative breast cancer from time of CNS metastases diagnosis was significantly longer for the younger age group [22.5 months (95% CI 1.2-43.8) vs. 7.9 months (95% CI .77-15.1), p=0.033]. The number, location and clinical presentation of CNS metastases were not statistically different between the two groups. Systemic and CNS-directed treatment approaches were also similar. Conclusion: While the presentation of CNS metastasis was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival. Numerically, after diagnosis of CNS involvement younger patients had longer survival, but the difference was statistically significant only for patients with triple-negative disease. Citation Format: Matan Ben-Zion Berliner, Shlomit Yust-Katz, Inbar Lavie, Alexandra Amiel, Dalia Zoref, Daniel Hendler, Hadar Goldvaser, Michal Sarfaty, Ofer Rotem, Olga Ulitsky, Tali Siegal, Victoria Neiman, Rinat Yerushalmi. Central nervous system metastases in breast cancer: The impact of age on patterns of development and outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-41.

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice.

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy-related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575-580, 2016. © 2016 Wiley Periodicals, Inc.

Central Nervous System Metastases in Patients with HER2-Positive Metastatic Breast Cancer: Incidence, Treatment, and Survival in Patients from registHER

registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients. Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated. Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor-negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P < 0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively). For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival.

Central nervous system metastases in women with HER‐2 positive metastatic breast cancer after treatment with trastuzumab

Abstract Background: Historically, central nervous system (CNS) metastases have been reported to occur in 10–16% of women with metastatic breast cancer (MBC) with a median survival of less than 1 year after diagnosis of CNS disease. A higher rate of CNS metastases has been described in women with metastatic breast cancer (MBC) over‐expressing HER‐2 who receive trastuzumab therapy. Aims: The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with trastuzumab, CNS metastases occurred (i) more frequently than historical controls, and (ii) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 consecutive patients with MBC over‐expressing HER‐2 and treated with trastuzumab and chemotherapy was performed. Results: A total of 22/25 (88%) patients who initially responded to trastuzumab had progressed within a median of 11.2 months after starting trastuzumab therapy. Central nervous system metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) had controlled systemic disease (CR = 2, PR = 6, SD = 1). There were trends for patients with CNS metastases to have greater than one site of metastatic disease at the commencement of trastuzumab therapy (P = 0.06), and to be hormone receptor negative at initial diagnosis (P = 0.14). The median time to diagnosis of CNS metastases after the commencement of trastuzumab therapy was 12 months (range 6–19 months). The median survival after diagnosis of CNS metastases was 12 months (range 2–22 months). Conclusions: This study demonstrates a high rate of CNS metastases (39%) in HER‐2 positive MBC patients treated with trastuzumab. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was 1 year. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration.

High dose therapy (HDT) and autologous stem cell transplantation (ASCT) in diffuse large B cell lymphoma (DLBL) patients with secondary central nervous system (CNS) involvement

6658 Background: The prognosis of patients with secondary CNS involvement in DLBL is universally poor. Although randomized studies have shown that ASCT improves survival in relapsed DLBL patients, limited data is available to ascertain its role in those with secondary CNS disease. In this single institution experience, we evaluated whether HDT with ASCT improved outcomes in DLBL patients with secondary CNS involvement. Methods: Our institutional database was searched for all cases of DLBL with pathologic confirmation of secondary CNS involvement diagnosed over the last 10 years. Patients receiving ASCT subsequent to CNS diagnosis were identified and a comprehensive chart review was done to obtain information regarding clinical characteristics, prognostic variables, treatment and outcomes. Similar information was also collected for the remaining DLBL patients with secondary CNS disease who did not receive ASCT. Results: 21 patients with DLBL and secondary CNS disease were identified. Of these, 6 patients received HDT with ASCT. The median age at diagnosis was 44 years (range 22–52 years) and 4 were male. 2 had International Prognostic Index (IPI) scores of 2, while 4 had IPI scores of 3 at diagnosis. 3 received directed CNS radiation therapy and 4 received intrathecal chemotherapy. The median time to CNS involvement from diagnosis was 3.5 months (range 0–11 months). Two patients had died at 7 and 10 months after the diagnosis of CNS disease while 4 (67%) patients are alive at 50 48, 46, and 22 months following diagnosis of CNS disease. One year survival from the time of CNS diagnosis was 67%. This compares favorably to the remaining 15 patients with DLBL and CNS involvement (0 % one year survival) and historic controls (mean survival 3.5 months)1. Conclusions: HDT with ASCT can potentially improve the long-term survival in DLBL patients with secondary CNS involvement and warrants further studies. 1Hoerni-Simon G. Oncology. 1987; 44(2):98–101. No significant financial relationships to disclose.

Contrast enhancement issues in the MR evaluation of the central nervous system.

Because of its high intrinsic contrast resolution, magnetic resonance imaging (MRI) has largely replaced computed tomography (CT) in the diagnosis of central nervous system (CNS) diseases, and the use of contrast media in MRI of the CNS has increased progressively, gadolinium chelates being, by far, the most used ones. Our paper will focus on the current indications for contrast-enhanced MR imaging of the CNS and will outline the current role and the future trends in contrast medium (CM) administration in the diagnosis of CNS disease. Gadolinium chelates are now routinely employed in MRI of the brain and spine and have been shown to be relatively safe and well tolerated at standard doses of 0.1 mmol/kg b. w. Although there is general consensus on the usefulness of CM administration in MRI of the CNS, some controversy still persists on the type of CM to be used, on the administration scheme, and on the imaging protocol. The current trend is toward selective employment of CM, the effect of which can be enhanced by Magnetization Transfer (MT) techniques, to increase the sensitivity of the procedure. Double or triple doses of CM can be useful in the detection of small parenchymal lesions with faint enhancement, in functional/dynamic studies of the brain parenchyma and in MR angiography. Gadoteridol (ProHance(R)) closely resembles the features of an optimal CM, because it is non-ionic, has a low osmolality and a low viscosity, and may be particularly efficacious when high doses are required.

Central nervous system metastases from non-hodgkin's lymphoma: Treatment and prophylaxis

Central nervous system (CNS) lymphoma was identified in 96 patients treated for non-Hodgkin's lymphoma at Memorial Sloan-Kettering Cancer Center between 1975 and 1981. During the same period, 68 other patients with non-Hodgkin's lymphoma but no CNS disease received prophylactic CNS chemotherapy. In the 156 total patients, the lymphomas were diffuse in 96 percent, and 67 percent were stage IV at diagnosis. CNS involvement was present at initial diagnosis in 27 percent, at relapse in 26 percent, and during the course of progressive systemic disease in 47 percent. CNS involvement was asymptomatic in 10 percent. Cytologic study of the cerebrospinal fluid was the most sensitive and specific laboratory test, but often (22 percent) more than one lumbar puncture was required to identify malignant cells. CNS lymphoma was treated in 85 patients, 46 by intracerebroventricular cannulae; 81 percent improved. Although median survival after the diagnosis of CNS disease was four months, there were seven longterm disease-free survivors and the CNS disease contributed to death in only 14 percent. In 52 percent of treated patients, there was no CNS lymphoma at autopsy. CNS prophylaxis was with methotrexate or cytosine arabinoside, usually by lumbar puncture; an intraventricular cannula was used in seven patients. Although this group of high-risk patients with non-Hodgkin's lymphoma had a high systemic response rate and the median projected survival was greater than five years, CNS lymphoma developed in eight patients (12 percent). In five, CNS lymphoma occurred as an apparently isolated relapse site. The role of CNS chemoprophylaxis in high-risk patients with non-Hodgkin's lymphoma is still uncertain.