Robotic Spine Surgery: Current State in Minimally Invasive Surgery.

STUDY DESIGN: Narrative review. OBJECTIVES: Robotic systems in spinal surgery may offer potential benefits for both patients and surgeons. In this article, the authors explore the future prospects and current limitations of robotic systems in minimally invasive spine surgery. METHODS: We describe recent developments in robotic spine surgery and minimally invasive spine surgery. Institutional review board approval was not needed. RESULTS: Although robotic application in spine surgery has been gradual, the past decade has seen the arrival of several novel robotic systems for spinal procedures, suggesting the evolution of technology capable of augmenting surgical ability. CONCLUSION: Spine surgery is well positioned to benefit from robotic assistance and automation. Paired with enhanced navigation technologies, robotic systems have tremendous potential to supplement the skills of spine surgeons, improving patient safety and outcomes while limiting complications and costs.

Advances in endovascular aneurysm management: flow modulation techniques with braided mesh devices.

Flow diverters and flow disruption technology, alongside nuanced endovascular techniques, have ushered in a new era of treating cerebral aneurysms. Here, we provide an overview of the latest flow modulation devices and highlight their clinical applications and outcomes.

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

Flow Diversion of Posterior Circulation Cerebral Aneurysms: A Single-Institution Series of 59 Cases.

BACKGROUND: Posterior circulation cerebral aneurysms are at higher risk of rupture and are more symptomatic than those in the anterior circulation. Existing treatments carry significant morbidity. Early reports of flow diversion for posterior circulation aneurysms have suggested high complication and low occlusion rates. OBJECTIVE: To report safety and efficacy of flow diversion with the pipeline embolization device (ev3, Medtronic Inc, Dublin, Ireland) for aneurysms located throughout the posterior circulation. METHODS: A prospective, institutional review board-approved database was analyzed for all patients with posterior circulation aneurysms treated by flow diversion at our institution. RESULTS: Fifty-nine embolization procedures were performed on 55 patients. Average aneurysm size was 9.4 mm. Morphology was saccular (45%), fusiform (29%), or dissecting/pseudo-aneurysms (25%). Sixty-two percent of aneurysms arose along the vertebral artery. There were 7 mid-basilar (13%) and 7 basilar apex (13%) aneurysms. Procedural success was 98%; 1 Pipeline embolization device was placed in 85%; and coiling was performed in 17% of cases. There were 5 major complications (8%), all strokes. Patients with major stroke had modified Rankin Scale score at last follow-up of 1, 3, 4, 6, and 6 (2 mortalities). There were zero intracerebral or subarachnoid hemorrhages. No variable predicted complications on univariate or multivariate analysis. Follow-up digital subtraction angiography was performed for 43 patients (78%). Complete occlusion was 68% at 6 mo and 78% at 12 mo. Average follow-up was 11.8 mo. Fusiform or dissecting morphology and large or giant aneurysm size were predictors of aneurysm persistence at 6 mo on multivariate logistic regression. CONCLUSION: This is a large single-institution series of Pipeline (Medtronic Inc) for posterior circulation aneurysms and demonstrates acceptable safety and effectiveness in these challenging cases.

Precision of VerifyNow P2Y12 Assessment of Clopidogrel Response in Patients Undergoing Cerebral Aneurysm Flow Diversion.

BACKGROUND: Dual antiplatelet therapy (DAT), most commonly with aspirin and Clopidogrel, is the standard of care for intracranial stenting, including flow diversion. Clopidogrel response varies by individual. OBJECTIVE: To investigate the real-world precision of VerifyNow P2Y12 assessment (Accumetrics, San Diego, California) of Clopidogrel response. METHODS: Using a prospectively-collected, IRB-approved cerebral aneurysm database 643 patients were identified who were treated with the Pipeline embolization device from 2011 to 2017. Patients with multiple P2Y12 assays drawn within a 24-h window were identified. A single patient could contribute multiple, independent sets. Levels drawn before a 5-d course of DAT and patients who received alternative antiplatelet agents were excluded. Therapeutic range was defined as platelet reaction units (PRU) 60-200. RESULTS: A total of 1586 P2Y12 measurements were recorded; 293 (46%) patients had more than one assay. One hundred forty (22%) patients had multiple P2Y12 measurements within 24 h. These patients accounted for 230 independent 24-h sets. The average P2Y12 fluctuation across all sets was 35 points; the 25th, 50th, and 75th percentiles were 12, 26, and 48 points, respectively. Of the 230 24-h sets of P2Y12 assays, 76% remained within their original therapeutic category: 100 (43%) all therapeutic, 54 (23%) all hypo-responsive, and 21 (9%) all hyper-responsive. Twenty-four percent of patients fluctuated between therapeutic categories when multiple P2Y12 assessments were drawn within a 24-h period: 29 (13%) between hypo-response and therapeutic, 23 (10%) between hyper-response and therapeutic, and 3 (1%) between hypo-response and hyper-response. CONCLUSION: Our experience suggests P2Y12 is an often-imprecise measure, and this should be considered when utilizing P2Y12 levels for clinical decisions.

Pipeline Embolization for Salvage Treatment of Previously Stented Residual and Recurrent Cerebral Aneurysms.

INTRODUCTION: This study assessed the safety and effectiveness of the Pipeline embolization device (PED) for persistent and recurrent aneurysms previously treated with either a vascular reconstruction device (VRD) or a flow diverter (FD). METHODS: A prospective, IRB-approved database was analyzed for patients treated with PED for aneurysms previously treated with a stent. RESULTS: Twenty procedures were performed on 18 patients, 11 with prior FD, 7 with VRD, and 2 previously treated with both. Overall, 15 aneurysms were saccular (75%), and size was 13.5 ± 7.6 mm. Location was internal carotid artery (ICA) in 14 cases (70%) and posterior circulation in 6 cases (30%). Average prior treatments were 1.7. Previously FD cases were re-treated at an average of 18.1 months from most recent treatment. Each case used 1 device, 82% with distal coverage and 82% with proximal coverage of prior stent. Balloon remodeling was performed in 3 cases (27%) and no in-stent thrombosis was observed. Previously VRD stent-coiled cases were re-treated at an average of 87.5 months. These cases used on average 1.9 devices, 89% with distal and 100% proximal coverage. Adjunctive coiling was performed in 1 case (11%), balloon remodeling in 5 cases (56%), and 2 cases (28%) developed thrombosis that resolved with abciximab. Re-VRD cases were longer (59.1 vs. 33.7 min, p = 0.02) than re-FD. Angiographic follow-up was available for 16 cases (80%). In re-FD, occlusion was complete in 56% and partial progressive in 33% at 17.1 months digital subtraction angiography. In re-VRD, occlusion was complete in 57% and partial progressive in 27% at 8.1 months. Two complications occurred (10%), including one asymptomatic cervical ICA occlusion and one stent occlusion with associated mortality (5%). Clinical follow-up was 17.8 months on average (range 0.5-51.9). CONCLUSIONS: Salvage flow diversion for previously stented aneurysms is technically challenging but offers good prospects of aneurysm obliteration with acceptable complication rates.

Single-stage flow diversion with adjunctive coiling for cerebral aneurysm: outcomes and technical considerations in 72 cases.

BACKGROUND: Adjunctive coiling may improve occlusion outcomes when combined in a single stage with cerebral aneurysm flow diversion. This technique has not been well described. OBJECTIVE: To present a series of aneurysm patients treated by single-stage flow diversion with adjunctive coiling, describing technical considerations and outcomes. METHODS: This was a retrospective cohort study using an IRB-approved database of procedures performed at a single institution. Treatment selection was based on large aneurysm size, morphological irregularity, branch vessel location, and wide neck. RESULTS: A total of 72 Pipeline with adjunctive coiling (PAC) procedures were performed on 69 patients. Average aneurysm size was 11.0 mm and 86% were wide-necked. Three progressively complex techniques were performed approximately equally: 27 sequential (38%), 23 jailed single-intermediate (32%), and 22 bifemoral jailed microcatheter (31%) cases. Aneurysm dome (P=0.0223) and neck size (P=0.001) increased with procedural complexity and there was a trend toward increased procedure length, radiation exposure, and stent thrombosis. A 'light' coil pack was used with an average packing density of 14% that did not vary by technique. Of the three major complications (4.2%), none were observed with the sequential approach (0%), one with the jailed single-intermediate (4.3%), and two with bifemoral cases (9.1%) (P=0.116). Complete occlusion was achieved in 85% of PAC cases at 6 months and 96% at 12-month follow-up angiography. CONCLUSIONS: There are multiple approaches to flow diversion with adjunctive coiling, each with technical challenges, suitable to different types of aneurysms. Flow diversion with coiling can expedite and improve occlusion outcomes without a significant increase in morbidity.

Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases.

To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains.