Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

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Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation-treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated.

Importance: Tumor Treating Fields (TTFields) are an anti-mitotic treatment approved for treating newly diagnosed and recurrent glioblastoma, and mesothelioma. TTFields in glioblastoma comprise alternating electric fields (200 kHz) delivered continuously, ideally for ≥18 h/day, to the tumor bed via transducer arrays placed on the shaved scalp. When applied locoregionally to the tumor bed and combined with systemic temozolomide chemotherapy, TTFields improved overall survival vs. temozolomide alone in patients with newly diagnosed glioblastoma. Improved efficacy outcomes with TTFields were demonstrated, while maintaining a well-tolerated and manageable safety profile. The most commonly-reported TTFields-associated adverse events (AEs) are beneath-array dermatologic events. Since survival benefit from TTFields increases with duration-of-use, prevention and management of skin AEs are critical to maximize adherence. This paper describes TTFields-associated dermatological AEs and recommends prevention and management strategies based on clinical trial evidence and real-world clinical experience. Observations: TTFields-associated skin reactions include contact dermatitis (irritant/allergic), hyperhidrosis, xerosis or pruritus, and more rarely, skin erosions/ulcers and infections. Skin AEs may be prevented through skin-care and shifting (∼2 cm) of array position during changes. TTFields-related skin AE management should be based on clinical phenotype and severity. Depending on diagnosis, recommended treatments include antibiotics, skin barrier films, moisturizers, topical corticosteroids, and antiperspirants. Water-based lotions, soaps, foams, and solutions with minimal impact on electrical impedance are preferred with TTFields use over petroleum-based ointments, which increase impedance. Conclusions: Early identification, prophylactic measures, and symptomatic skin AE management help patients maximize TTFields usage, while maintaining quality-of-life and optimizing therapeutic benefit. Lacouture et al. Managing TTFields-Associated Skin Adverse Events Implications for practice: TTFields confer a survival benefit in patients with glioblastoma that correlates positively with duration of daily use. Skin events (rash) are the primary treatment-related AE that can limit duration of use. The recommendations described here will help healthcare professionals to recognize, prevent, and manage dermatologic AEs associated with TTFields treatment. These recommendations may improve cutaneous health and support adherence to therapy, both of which would maximize treatment outcomes.

Purpose The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration. Methods CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response. Results Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0-200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2-3 months prior to changes seen on MRI, and while CSF cytology remained negative. Conclusion Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology. Trial Registration: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

BACKGROUND: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. METHODS: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). RESULTS: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. CONCLUSIONS: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone. Cancer 2019;125:3790-3800.We thank the patients who participated in this clinical trial and their families. We also thank the study investigators for their contributions.

Background Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive LMD. Methods This multicenter study enrolled 34 LMD patients in a combined Phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the Phase I; the Phase II was limited to HER2-positive breast cancer. Results Intrathecal trastuzumab was well tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended Phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for Phase 2 dose treated patients was 8.3 months (95% CI 5.2 to 19.6). The Phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2 to 20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable CSF concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. Conclusion This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.