Lucy He

Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration

A shot in the arm for damaged tissue Tissue damage can be caused by injury, disease, and even certain medical treatments. There is great interest in identifying drugs that accelerate tissue regeneration and recovery, especially drugs that might benefit multiple organ systems. Zhang et al. describe a compound with this desired activity, at least in mice (see the Perspective by FitzGerald). SW033291 promotes recovery of the hematopoietic system after bone marrow transplantation, prevents the development of ulcerative colitis in the intestine, and accelerates liver regeneration after hepatic surgery. It acts by inhibiting an enzyme that degrades prostaglandins, lipid signaling molecules that have been implicated in tissue stem cell maintenance. Science, this issue 10.1126/science.aaa2340; see also p. 1208 A compound that inhibits prostaglandin degradation enhances tissue regeneration in multiple organs in mice. [Also see Perspective by FitzGerald] INTRODUCTION Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models. RATIONALE We used 15-PGDH knockout mice to elucidate the role of 15-PGDH in regulating tissue levels of PGE2 and tissue repair capacity in multiple organs. We then developed SW033291, a potent small-molecule inhibitor of 15-PGDH with activity in vivo. We used SW033291 to investigate the therapeutic potential of 15-PGDH inhibitors in tissue regeneration and to identify a 15-PGDH–regulated hematopoietic pathway within the bone marrow niche. RESULTS We found that in comparison with wild-type mice, 15-PGDH–deficient mice display a twofold increase in PGE2 levels across multiple tissues—including bone marrow, colon, and liver—and that they show increased fitness of these tissues in response to damage. The mutant mice also show enhanced hematopoietic capacity, with increased neutrophils, increased bone marrow SKL (Sca-1+ C-kit+ Lin−) cells (enriched for stem cells), and greater capacity to generate erythroid and myeloid colonies in cell culture. The 15-PGDH–deficient mice respond to colon injury from dextran sulfate sodium (DSS) with a twofold increase in cell proliferation in colon crypts, which confers resistance to DSS-induced colitis. The mutant mice also respond to partial hepatectomy with a greater than twofold increase in hepatocyte proliferation, which leads to accelerated and more extensive liver regeneration. SW033291, a potent small-molecule inhibitor of 15-PGDH (inhibitor dissociation constant Ki ~0.1 nM), recapitulates in mice the phenotypes of 15-PGDH gene knockout, inducing increased hematopoiesis, resistance to DSS colitis, and more rapid liver regeneration after partial hepatectomy. Moreover, SW033291-treated mice show a 6-day-faster reconstitution of hematopoiesis after bone marrow transplantation, with accelerated recovery of neutrophils, platelets, and erythrocytes, and greater recovery of bone marrow SKL cells. This effect is mediated by bone marrow CD45– cells, which respond to increased PGE2 with a fourfold increase in production of CXCL12 and SCF, two cytokines that play key roles in hematopoietic stem cell homing and maintenance. CONCLUSIONS Studying mouse models, we have shown that 15-PGDH negatively regulates tissue regeneration and repair in the bone marrow, colon, and liver. Of most direct utility, our observations identify 15-PGDH as a therapeutic target and provide a chemical formulation, SW033291, that is an active 15-PGDH inhibitor in vivo and that potentiates repair in multiple tissues. SW033291 or related compounds may merit clinical investigation as a strategy to accelerate recovery after bone marrow transplantation and other tissue injuries. Inhibiting 15-PGDH accelerates tissue repair. (A) The enzyme 15-PGDH degrades and negatively regulates PGE2. (B) SW033291 inhibits 15-PGDH, increases tissue levels of PGE2, and induces CXCL12 and SCF expression from CD45– bone marrow cells. This in turn accelerates homing of transplanted hematopoietic stem cells (HSC), generation of mature blood elements, and post-transplant recovery of normal blood counts. Inhibiting 15-PGDH similarly stimulates cell proliferation after injury to colon or liver, accelerating repair of these tissues. Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

Pipeline Embolization Device for small paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic artery origin and aneurysm

OBJECTIVE Contemporary treatment for paraophthalmic artery aneurysms includes flow diversion utilizing the Pipeline Embolization Device (PED). Little is known, however, about the potential implications of the anatomical relationship of the ophthalmic artery (OA) origin and aneurysm, especially in smaller aneurysms. METHODS Four major academic institutions in the United States provided data on small paraophthalmic aneurysms (≤ 7 mm) that were treated with PED between 2009 and 2015. The anatomical relationship of OA origin and aneurysm, radiographic outcomes of aneurysm occlusion, and patency of the OA were assessed using digital subtraction angiography. OA origin was classified as follows: Type 1, OA separate from the aneurysm; Type 2, OA from the aneurysm neck; and Type 3, OA from the aneurysm dome. Clinical outcome was assessed using the modified Rankin Scale, and visual deficits were categorized as transient or permanent. RESULTS The cumulative number of small paraophthalmic aneurysms treated with PED between 2009 and 2015 at the 4 participating institutions was 69 in 52 patients (54.1 ± 13.7 years of age) with a male-to-female ratio of 1:12. The distribution of OA origin was 72.5% for Type 1, 17.4% for Type 2, and 10.1% for Type 3. Radiographic outcome at the last follow-up (median 11.5 months) was available for 54 aneurysms (78.3%) with complete, near-complete, and incomplete occlusion rates of 81.5%, 5.6%, and 12.9%, respectively. Two aneurysms (3%) resulted in transient visual deficits, and no patient experienced a permanent visual deficit. At the last follow-up, the OA was patent in 96.8% of treated aneurysms. Type 3 OA origin was associated with a lower rate of complete aneurysm occlusion (p = 0.0297), demonstrating a trend toward visual deficits (p = 0.0797) and a lower rate of OA patency (p = 0.0783). CONCLUSIONS Pipeline embolization treatment of small paraophthalmic aneurysms is safe and effective. An aneurysm where the OA arises from the aneurysm dome may be associated with lower rates of aneurysm occlusion, OA patency, and higher rates of transient visual deficits.

Minimizing bleeding complications in spinal tumor surgery with preoperative Onyx embolization via dual-lumen balloon catheter

Background Intraoperative bleeding is a significant risk in surgery for highly vascular spinal tumors, but preoperative embolization can safely decrease intraoperative blood loss in extrinsic spine tumors. Onyx, widely used for cerebrovascular embolization, has been increasingly used as an embolic agent for preoperative spinal tumor embolization. The Scepter catheter, a dual-lumen balloon catheter, may improve tumor parenchymal penetration without the danger and limitations of significant embolic reflux. This may reduce bleeding risk during spinal surgery. Methods Eleven consecutive cases of preoperative Onyx embolization of extrinsic spinal tumors were identified, all of whom had subsequent spinal surgery. Demographic data and clinical variables were collected. Patients were divided into Scepter (n=6) and non-Scepter (n=5) groups. The Mann–Whitney U test was used to compare continuous outcome variables and the Fisher exact test was used to compare categorical variables. Results Estimated blood loss in the Scepter group was significantly lower than in the non-Scepter group (584±124 vs 2400±738 mL, p=0.004). The volume of intraoperative transfusion was also significantly lower (1.2±0.4 vs 5.8±1.7 units, p=0.004). There was no significant difference in the number of vessels embolized, vials of Onyx used, use of coiling adjunct, contrast load, radiation dose, or fluoroscopy time per pedicle (p>0.05). Conclusions The addition of the Scepter catheter to preoperative Onyx embolization is safe and feasible. In this small series, the Scepter catheter was associated with a reduction of intraoperative bleeding by 76% and a 79% lower transfusion volume. This was not accompanied by any unwanted increase in vials of Onyx used, contrast load, radiation dose, or fluoroscopy time.

Documentation of Improved Outcomes for Intracranial Aneurysm Management Over a 15-Year Interval

Background and Purpose— Despite rapid advancements in intracranial aneurysm management, there is no evidence as of yet that this has translated into improvement in overall prognosis. Methods— We compared 2 periods of aneurysm management, 1998 to 2003 (n=1023 aneurysms) and 2007 to 2013 (n=1499 aneurysms), at a single, high-volume neurovascular center. Our outcome of interest was low or moderate disability (Glasgow Outcome Scale score of 4 or 5) at 6 months or more post treatment. Results— There were significant improvements in outcome for surgical, endovascular, and overall treatment of unruptured (adjusted odds ratio [OR], 2.33; P=0.0091; adjusted OR, 4.40; P=0.0271; and adjusted OR, 2.58; P=0.0008, respectively) and ruptured (adjusted OR, 3.18; P=0.0004; adjusted OR, 3.54; P=0.0001; and adjusted OR, 3.11; P<0.0001, respectively) aneurysms from the first to the second time period. In 2007 to 2013, the proportion of cases with low or moderate disability at 6 months post subarachnoid hemorrhage was 75.6% for surgical clipping and 76.6% for endovascular therapy. Conclusions— We report significantly improved outcomes over time for overall aneurysm management and for multiple patient subgroups, associated with increased usage of endovascular therapy.

Mechanical thrombectomy for acute stroke in childhood: how much does restricted diffusion matter?

Mechanical thrombectomy holds promise for children with large cerebral arterial occlusions, although there are few reports in this population. We report a case of retrievable stent-assisted mechanical thrombectomy in a 5-year-old with basilar artery occlusion, despite late presentation and extensive initial diffusion-weighted imaging (DWI) restriction. This resulted in successful Thrombolysis in Cerebral Infarction 2B reperfusion and excellent clinical outcome. At 6-week follow-up he was completely back to baseline with no residual deficits (pediatric stroke outcome measure=0, modified Rankin scale=0). At 3-month follow-up the patient has not had any recurrent stroke or concern for stroke-like symptoms. We review the literature on mechanical thrombectomy and DWI changes in acute stroke in early to middle childhood (<12 years old).

Rule of 5: angiographic diameters of cervicocerebral arteries in children and compatibility with adult neurointerventional devices

Background and purpose The safety of using adult-sized neuroendovascular devices in the smaller pediatric vasculature is not known. In this study we measure vessel diameters in the cervical and cranial circulation in children to characterize when adult-approved devices might be compatible in children. Methods For 54 children without vasculopathy (mean age 9.5±4.9 years (range 0.02–17.8), 20F/34M) undergoing catheter angiography, the diameters of the large vessels in the cervical and cranial circulation (10 locations, 611 total measurements) were assessed by three radiologists. Mean±SD diameter was calculated for the following age groups: 0–6 months, 1, 2, 3, 4, 5–9, 10–14, and 15–18 years. To compare with adult sizes, each vessel measurement was normalized to the respective region mean diameter in the oldest age group (15–18 years). Normalized measurements were compared with age and fitted to a segmented regression. Results Vessel diameters increased rapidly from 0 to 5 years of age (slope=0.069/year) but changed minimally beyond that (slope=0.005/year) (R2=0.2). The regression model calculated that, at 5 years of age, vessels would be 94% of the diameter of the oldest age group (compared with 59% at birth). In addition, most vessels in children under 5, while smaller, were still potentially large enough to be compatible with many adult devices. Conclusions The growth curve of the cervicocerebral vasculature displays rapid growth until age 5, at which point most childrens vessels are nearly adult size. By age 5, most neuroendovascular devices are size-compatible, including thrombectomy devices for stroke. Under 5 years of age, some devices might still be compatible.

Epidural Bovine Pericardium Facilitates Dissection During Cranioplasty: A Technical Note

BACKGROUND AND OBJECTIVE Adhesions and scarring of the subcutaneous tissue to the dura mater or dural substitute often complicate cranioplasty. We present our experience with epidural bovine pericardium as a barrier membrane to minimize adhesions and facilitate separation of tissue layers. METHODS A cohort of patients who underwent decompressive craniectomy and subsequent cranioplasty at a major academic institution in the United States from August 2007 to October 2013 and had epidural bovine pericardium placed as a barrier membrane was retrospectively reviewed. Medical records and imaging studies were reviewed for a number of variables including presence of adhesions, infection, contusions, and operative complications. RESULTS Twenty-nine patients (male-to-female = 1:1.1; mean age 45 ± 14.7 years) who underwent decompressive craniectomy with placement of epidural bovine pericardium with subsequent cranioplasty were identified. The median interval between craniectomy and cranioplasty was 64 days, and autologous bone was used for cranioplasty in 86.2% of cases. The average size of cranial defect was 71.2 ± 28.5 cm(2). At the time of cranioplasty, no or minimal adhesions were found between the subcutaneous tissue and the epidural bovine pericardium. There were 2 (6.9%) infections, 2 (6.9%) patients had contusion after the cranioplasty, and no patient had a complication after cranioplasty that required reoperation. CONCLUSIONS Epidural bovine pericardium at the time of decompressive craniectomy facilitates dissection at the time of cranioplasty and is not associated with any additional risks.

Initial experience with dual-lumen balloon catheter injection for preoperative Onyx embolization of skull base paragangliomas.

OBJECT Paragangliomas are highly vascular head and neck tumors for which preoperative embolization is often considered to facilitate resection. The authors evaluated their initial experience using a dual-lumen balloon to facilitate preoperative embolization in 5 consecutive patients who underwent preoperative transarterial Onyx embolization assisted by the Scepter dual-lumen balloon catheter between 2012 and 2014. OBJECT The authors reviewed the demographic and clinical records of 5 patients who underwent Scepter-assisted Onyx embolization of a paraganglioma followed by resection between 2012 and 2014. Descriptive statistics of clinical outcomes were assessed. RESULTS Five patients (4 with a jugular and 1 with a vagal paraganglioma) were identified. Three paragangliomas were embolized in a single session, and each of the other 2 were completed in 3 staged sessions. The mean volume of Onyx used was 14.3 ml (range 6-30 ml). Twenty-seven vessels were selectively catheterized for embolization. All patients required selective embolization via multiple vessels. Two patients required sacrifice of parent vessels (1 petrocavernous internal carotid artery and 1 vertebral artery) after successful balloon test occlusion. One patient underwent embolization with Onyx-18 alone, 2 with Onyx-34 alone, and 1 with Onyx-18 and -34. In each case, migration of Onyx was achieved within the tumor parenchyma. The mean time between embolization and resection was 3.8 days (range 1-8 days). Gross-total resection was achieved in 3 (60%) patients, and the other 2 patients had minimal residual tumor. The mean estimated blood loss during the resections was 556 ml (range 200-850 ml). The mean postoperative hematocrit level change was -17.3%. Two patients required blood transfusions. One patient, who underwent extensive tumor penetration with Onyx, developed a temporary partial cranial nerve VII palsy that resolved to House-Brackmann Grade I (out of VI) at the 6-month follow-up. One patient experienced improvement in existing facial nerve weakness after embolization. CONCLUSIONS Scepter catheter-based Onyx embolization seems to be safe and effective. It was associated with excellent distal tumor vasculature penetration and holds promise as an adjunct to conventional transarterial Onyx embolization of paragangliomas. However, the ease of tumor penetration should encourage caution in practitioners who may be able to effect comparable improvement in blood loss with more conservative proximal Onyx penetration.

Middle Meningeal Artery: Gateway for effective transarterial Onyx embolization of dural arteriovenous fistulas

Curative transarterial embolization of noncavernous sinus dural arteriovenous fistulas (dAVFs) is challenging. We sought to evaluate the role of the middle meningeal artery (MMA) in endovascular treatment of these lesions. We performed a retrospective cohort study on patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVFs with contribution from the MMA at a major academic institution in the United States from January 2009 to January 2015. Twenty consecutive patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVF were identified. One patient was excluded as there was no MMA contribution to the dAVF. All of the remaining 19 patients (61.3 ± 13.8 years of age) underwent transarterial embolization through the MMA. Six patients (31.6%) presented with intraparenchymal or subarachnoid hemorrhage from the dAVF. The overall angiographic cure rate was 73.7% upon last follow up. In 71.4% of successfully treated patients transarterial embolization of the MMA alone was sufficient to achieve angiographic cure. When robust MMA supply was present, MMA embolization resulted in angiographic cure even after embolization of other arterial feeders had failed in 92.9% of patients. A robust contribution of the MMA to the fistula was the single most important predictor for successful embolization (P = 0.00129). We attribute our findings to the fairly straight, non‐tortuous course of the MMA that facilitates microcatheter access, navigation, and Onyx penetration. Noncavernous sinus dAVF can be successfully embolized with transarterial Onyx through the MMA, as long as supply is robust. A transvenous approach is rarely necessary. Clin. Anat. 29:718–728, 2016.

Dual diagnostic catheter technique in the endovascular management of anterior communicating artery complex aneurysms

Background: The configuration of the anterior communicating artery (AcomA) complex is important in the endovascular treatment of AcomA complex aneurysms. In cases of codominant anterior cerebral arteries (ACA), coil embolization may result in inadvertent occlusion of the contralateral ACA due to poor visualization. A second diagnostic catheter in the contralateral carotid artery may help with visualization of this angiographic blind spot. To our knowledge, the safety and efficacy of this dual diagnostic catheter technique have never been assessed. Methods: A cohort of consecutive patients that underwent coil embolization of an AcomA complex aneurysm at a major academic institution in the United States between 2007 and 2014 were retrospectively reviewed. Results: Eighty-two patients who had an AcomA complex aneurysm treated with coil embolization were identified. The dual diagnostic catheter technique was used in 17 (20.7%) patients. Aneurysms treated with the dual diagnostic catheter technique were less frequently ruptured and had less favorable dome-to-neck ratios as well as neck width for primary coil embolization. The rate of codominant ACAs was significantly higher and stent-assisted coil embolization was performed more frequently. The rate of thromboembolic complications, angiographic outcome, and retreatment did not differ between both the groups. Conclusions: The dual diagnostic catheter technique is a safe and effective method during coil embolization of AcomA complex aneurysms and preferred for aneurysms with codominant ACAs, incorporation of either A1 or A2 segments into the aneurysm, and aneurysms with a wide neck and low dome-to-neck ratios.