Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study.

BACKGROUND: High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). METHODS: Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. RESULTS: Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. CONCLUSIONS: This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. CLINICAL TRIAL REGISTRATION: NCT03684980 (Registration date 26/09/2018).

Clinical trial of proton craniospinal irradiation for leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. METHODS: We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). RESULTS: We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. CONCLUSION: Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas.

PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Fertility preservation in primary brain tumor patients.

BACKGROUND: Fertility preservation (FP) is an infrequently addressed issue for young adults with primary brain tumors. Given the improved prognosis and enhanced technology in reproductive medicine, more primary brain tumor patients see procreation as feasible, making the discussion of FP increasingly important. The goals of this study were to describe patients who received FP counseling by a fertility nurse specialist (FNS) and determine which sociodemographic and disease-related factors predict acceptance of referral to a reproductive specialist. METHODS: Institutional review board-approved retrospective review of primary brain tumor patients, ages 18 to 45, who were referred for FP counseling with a FNS from 2009 to 2013. RESULTS: Seventy patients were referred for FP counseling: 38 men, 32 women, with a median age of 32 years and median KPS of 90. Eighty-nine percent had gliomas; 58% grade III, 17% grade IV. Sixty-seven percent were referred for counseling at initial diagnosis. Of those referred, 73% accepted referral to a sperm bank (87% of men) or reproductive endocrinologist (56% of women). Patients were more likely to accept referral if they had no prior children (P = .048). There was no statistically significant difference in referral acceptance by age, race/ethnicity, marital status, religion, or tumor grade. After treatment, 3 men conceived naturally, 2 men conceived using banked sperm, and 2 women conceived naturally. CONCLUSIONS: Despite the historically poor prognosis of patients with primary brain tumors, there is significant interest in FP among these patients, particularly if they have no prior children. Clinicians should develop strategies to incorporate FP counseling into practice.

Cancer-treatment-induced neurotoxicity--focus on newer treatments.

Neurotoxicity caused by traditional chemotherapy and radiotherapy is widely recognized in patients with cancer. The adverse effects of newer therapeutics, such as biological and immunotherapeutic agents, are less well established, and are associated with considerable neurotoxicity in the central and peripheral nervous systems. This Review addresses the main neurotoxicities of cancer treatment with a focus on the newer therapeutics. Recognition of these patterns of toxicity is important because drug discontinuation or dose adjustment might prevent further neurological injury. Knowledge of these toxicities also helps to differentiate treatment-related symptoms from progression of cancer or its involvement of the nervous system. Familiarity with the neurological syndromes associated with cancer treatments enables clinicians to use the appropriate treatment for the underlying malignancy while minimizing the risk of neurological damage, which might preserve patients' quality of life.

Diagnostic yield of echocardiography in cancer patients with ischemic stroke.

The yield of echocardiography in cancer patients with acute ischemic stroke is unknown. We identified adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary-care cancer center from 2005 through 2009 who underwent transthoracic (TTE) or transesophageal echocardiography (TEE). Two neurologists independently reviewed all clinical data, including TTE and TEE reports, and adjudicated whether echocardiographic studies revealed a definite or possible source of stroke according to pre-defined criteria. Patients were classified as having suspected cardioembolic strokes if imaging showed embolic-appearing infarcts in more than one vascular territory. Among 220 patients with cancer and ischemic stroke who underwent echocardiography, 216 (98%) had TTE and 37 (17%) had TEE. TTE revealed a definite source in 15 (7%, 95% CI 4-10%) patients and a possible source in 42 (19%, 95% CI 14-25%), while TEE revealed a definite source in 10 (27%, 95% CI 12-42%) patients and a possible source in 14 (38%, 95% CI 21-54%). In 92 patients with suspected cardioembolic strokes who underwent TTE, 6 (7%, 95% CI 1-12%) had a definite source, including 4 with marantic endocarditis, and 20 (22%, 95% CI 13-30%) had a possible source. Twenty-one of these patients also underwent TEE, which demonstrated a definite or possible source in 16 (76%, 95% CI 56-96%) patients, including marantic endocarditis in 4 (19%). The yield of TTE for detecting marantic endocarditis and other cardiac sources of stroke in cancer patients is low, but TEE may provide a higher yield in targeted patients.

Cryptogenic subtype predicts reduced survival among cancer patients with ischemic stroke.

BACKGROUND AND PURPOSE: Cryptogenic stroke is common in patients with cancer. Autopsy studies suggest that many of these cases may be because of marantic endocarditis, which is closely linked to cancer activity. We, therefore, hypothesized that among patients with cancer and ischemic stroke, those with cryptogenic stroke would have shorter survival. METHODS: We retrospectively analyzed all adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary care cancer center from 2005 through 2009. Two neurologists determined stroke mechanisms by consensus. Patients were diagnosed with cryptogenic stroke if no specific mechanism could be determined. The diagnosis of marantic endocarditis was restricted to patients with cardiac vegetations on echocardiography or autopsy and negative blood cultures. Patients were followed until July 31, 2012, for the primary outcome of death. Kaplan-Meier statistics and the log-rank test were used to compare survival between patients with cryptogenic stroke and patients with known stroke mechanisms. Multivariate Cox proportional hazard analysis evaluated the association between cryptogenic stroke and death after adjusting for potential confounders. RESULTS: Among 263 patients with cancer and ischemic stroke, 133 (51%) were cryptogenic. Median survival in patients with cryptogenic stroke was 55 days (interquartile range, 21-240) versus 147 days (interquartile range, 33-735) in patients with known stroke mechanisms (P<0.01). Cryptogenic stroke was independently associated with death (hazard ratio, 1.64; 95% confidence interval, 1.25-2.14) after adjusting for age, systemic metastases, adenocarcinoma histology, and functional status. CONCLUSIONS: Cryptogenic stroke is independently associated with reduced survival in patients with active cancer and ischemic stroke.

Recurrent thromboembolic events after ischemic stroke in patients with cancer.

OBJECTIVE: To determine the cumulative rate and characteristics of recurrent thromboembolic events after acute ischemic stroke in patients with cancer. METHODS: We retrospectively identified consecutive adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary-care cancer center from 2005 through 2009. Two neurologists independently reviewed all electronic records to ascertain the composite outcome of recurrent ischemic stroke, myocardial infarction, systemic embolism, TIA, or venous thromboembolism. Kaplan-Meier statistics were used to determine cumulative outcome rates. In exploratory analyses, Cox proportional hazard analysis was used to evaluate potential independent associations between a priori selected clinical factors and recurrent thromboembolic events. RESULTS: Among 263 study patients, complete follow-up until death was available in 230 (87%). Most patients had an adenocarcinoma as their underlying cancer (60%) and had systemic metastases (69%). Despite a median survival of 84 days (interquartile range 24-419 days), 90 patients (34%; 95% confidence interval 28%-40%) had 117 recurrent thromboembolic events, consisting of 57 cases of venous thromboembolism, 36 recurrent ischemic strokes, 13 myocardial infarctions, 10 cases of systemic embolism, and one TIA. Kaplan-Meier rates of recurrent thromboembolism were 21%, 31%, and 37% at 1, 3, and 6 months, respectively; cumulative rates of recurrent ischemic stroke were 7%, 13%, and 16%. Adenocarcinoma histology (hazard ratio 1.65, 95% confidence interval 1.02-2.68) was independently associated with recurrent thromboembolism. CONCLUSIONS: Patients with acute ischemic stroke in the setting of active cancer (especially adenocarcinoma) face a substantial short-term risk of recurrent ischemic stroke and other types of thromboembolism.

The type III TGF-ß receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase.

The Type III TGF-ß receptor, betaglycan, is a widely expressed proteoglycan co-receptor for TGF-ß superfamily ligands. The full-length protein undergoes ectodomain cleavage with release of a soluble ectodomain fragment. The fate of the resulting transmembrane-cytoplasmic fragment, however, has never been explored. We demonstrate here that the transmembrane-cytoplasmic fragment is stable in transfected cells and in cell lines expressing endogenous betaglycan. Production of this fragment is inhibited by the ectodomain shedding inhibitor TAPI-2. Treatment of cells with inhibitors of the intramembrane protease γ-secretase stabilizes this fragment, suggesting that it is a substrate of γ-secretase. Expression of the transmembrane-cytoplasmic fragment as well as γ-secretase inhibitor stabilization are independent of TGF-ß1 or -ß2 and are unaffected by mutation of the cytoplasmic domain serines that undergo phosphorylation. γ-Secretase inhibition or the expression of a transmembrane-cytoplasmic fragment in HepG2 cells blunted TGF-ß2 signaling. Our findings thus suggest that the transmembrane-cytoplasmic fragment remaining after betaglycan ectodomain cleavage is stable and a substrate of γ-secretase, which may have significant implications for the TGF-ß signaling response.