Felix Bukstein’s research while affiliated with Tel Aviv Sourasky Medical Center and other places

Real-world healthcare data sharing is instrumental in constructing broader-based and larger clinical datasets that may improve clinical decision-making research and outcomes. Stakeholders are frequently reluctant to share their data without guaranteed patient privacy, proper protection of their datasets, and control over the usage of their data. Fully homomorphic encryption (FHE) is a cryptographic capability that can address these issues by enabling computation on encrypted data without intermediate decryptions, so the analytics results are obtained without revealing the raw data. This work presents a toolset for collaborative privacy-preserving analysis of oncological data using multiparty FHE. Our toolset supports survival analysis, logistic regression training, and several common descriptive statistics. We demonstrate using oncological datasets that the toolset achieves high accuracy and practical performance, which scales well to larger datasets. As part of this work, we propose a cryptographic protocol for interactive bootstrapping in multiparty FHE, which is of independent interest. The toolset we develop is general-purpose and can be applied to other collaborative medical and healthcare application domains.

Immune check point inhibitors (ICIs) are a group of anti-cancer pharmacological agents which modify T cell activity in order to potentiate an effective immune response against tumor cells. While these drugs prove extremely potent against several types of malignancies, they may be associated with significant autoimmune adverse events. We report a patient who developed a subacute cerebellar syndrome shortly after starting treatment with nivolumab, a PD-1 inhibitor, for renal clear cell carcinoma, with detectable paraneoplastic PCA-2 antibodies. The tumor specimen stained positively for MAP1B, the antigen of PCA-2. The patient responded well to treatment with glucocorticosteroids. This is the first case to our knowledge of PCA-2 paraneoplastic cerebellar degeneration associated with ICI use, which presents in a patient with a malignancy not typically associated with neurological paraneoplastic phenomena. Treatment with immune checkpoint inhibitors (ICIs) is extremely effective in potentiating an immune response against tumor cells, but bears a substantial risk for the development of autoimmune phenomena, including paraneoplastic neurological syndromes. Increasing use of ICIs is leading to increasing numbers of patients with new-onset neurological symptoms. Awareness of these novel entities will aid in early diagnosis and proper treatment.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dosage-limited oxaliplatin-related toxicity. To date, there are no successful interventions for CIPN prevention or treatment. A therapeutic role for cannabis in diabetic and HIV-related peripheral neuropathy and a protective role in CIPN have been suggested. We examined the effect of cannabis on oncologic patients with CIPN. Methods Medical records of 768 consecutive patients treated with oxaliplatin and 5-fluorouracil-based combinations at a tertiary medical center from October 2015 to January 2018 were reviewed. Excluded patients were those with pre-existing neuropathy or patients who received fewer than two cycles of oxaliplatin treatment. CIPN grade, oxaliplatin cumulative dose, and neuropathy-free survival were evaluated. The patients were divided based upon the exposure to cannabis: prior to oxaliplatin (cannabis-first), cannabis following the initiation of oxaliplatin treatment (oxaliplatin-first), and no exposure (control). Results In total, 513 patients met the inclusion criteria, of whom 248 were treated with cannabis and 265 served as controls. The cannabis-first group included 116 (46.7%) patients and the oxaliplatin-first group included 132 (53.3%) patients. Demographic parameters were comparable between groups. There was a significant difference in CIPN grade 2–3 between cannabis-exposed patients and controls (15.3% and 27.9%, respectively, p < 0.001). The protective effect of cannabis was more pronounced among cannabis-first patients compared to oxaliplatin-first patients (75% and 46.2%, respectively, p < 0.001). The median oxaliplatin cumulative doses were higher in the cannabis-first versus the oxaliplatin-first versus the control groups (545 mg/m², 340 mg/m², and 425 mg/m² respectively, p < 0.001). Conclusion The rate of neuropathy was reduced among patients treated with cannabis and oxaliplatin. This reduction was more significant in patients who received cannabis prior to treatment with oxaliplatin, suggesting a protective effect. A large prospective trial is planned.

Background/Objectives: We have recently presented high resolution treatment response assessment maps (TRAMs) enabling efficient separation between tumor (contrast clearance >1 hr post injection, blue) and treatment-effects (TEs, contrast accumulation, red), validated histologically in 54 resected patients. Here we demonstrate potential advantages in delineating SRS dose-effects using the TRAMs. Methods: In a preliminary study on 7 brain metastases, T1-Gd and the TRAMs were co-registered to the SRS dose-plan and pixel-by-pixel analysis was performed comparing baseline T1-Gd/TRAMs and dose-plan to T1-Gd/TRAMs acquired 141±12 days (day140) post SRS. Results: T1-Gd showed that the percentage of enhancing pixels at baseline that turned non-enhancing at day140 increased moderately from 40.4% to 54.2% between 13-21.7Gy with a sharp rise to 98% above 21.7Gy. Similar analysis with the TRAMs showed linear increase in tumor-kill from 83% at 18Gy to 100% at 21.7Gy. T1-Gd also showed that the percentage of non-enhancing pixels at baseline (normal-appearing brain) that turned enhancing at day140 increased linearly to 20.2Gy, where it raised sharply to 48% followed by a sharp drop at 21.2Gy. The TRAMs showed that the linear increase to 20.2Gy may be explained by new tumor growth with a sharp drop at 20.2Gy, while the sharp rise at 20.2Gy may be explained by non-enhancing pixels that turned into red/TEs. Per-lesion analysis showed significant correlations between average treatment-dose and blue growth-rates (r2=0.78;p<0.01). Percentage of blue volumes exposed to >20Gy was found higher in solid (88%) versus cystic (54%) lesions. Conclusions: These preliminary results demonstrate the TRAMs potential advantages in delineating SRS dose effects. Efficacy at lower doses was higher when studied by the TRAMs versus T1-Gd, thresholds were depicted more sharply, and the TRAMs suggest induction of TEs in normal-appearing brain at >20Gy in agreement with significant drop in new tumor growth (may be explained by anti-tumor-infiltration effects) at this threshold.

Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.