Raloxifene

Raloxifene

Raloxifene, sold under the brand name Evista among others, is a medication which is used in the prevention and treatment of osteoporosis in postmenopausal women and to reduce the risk of breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer. It is taken by mouth.


Choudhary et al., evaluated the effect of raloxifene on prolactin levels in addition to dopamine agonist (DA) therapy in patients with prolactinoma.

They conducted a retrospective chart review of 14 patients with prolactinoma on stable dose of DA for 6 months who received raloxifene 60 mg daily as Prolactin (PRL) could not be normalized despite being on fairly high doses of DA. Patients were informed that raloxifene is not FDAapproved for prolactinoma treatment. Prolactin level was measured at 1-6 months after starting raloxifene and at 1-3 months following its discontinuation. Raloxifene was stopped in 8 out of 14 after 2 (1-6) months of treatment as the absolute change in prolactin level was felt to be small. Results The median age and female/male sex ratios were 50 years (range 18-63), 6/8 respectively. The baseline DA dose was 3 mg/week (0.5-7) for cabergoline and 15 mg/day for bromocriptine. 10 patients had an absolute and percentage decrease in prolactin of 8.3 ng/ml (1.5-54.2), and 25.9% (8-55%) from baseline after 1-6 months on raloxifene treatment, respectively. Among 10 patients with a decrease in prolactin level, 2 (20%) achieved prolactin normalization. Two patients had no change in prolactin and two patients had an increase in prolactin level by 22.8 ng/ml and 8.8 ng/ml (47% and 23.6%) respectively.

Raloxifene was associated with 25.9% (8-55%) decrease in prolactin levels in 10/14 (71%) of patients with prolactinoma who were on stable doses of DA including two patients (14%) who achieved normoprolactinemia 1).


Hannen et al., analyzed the effects of fulvestrant and three Selective estrogen receptor modulators (SERMs), bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 μM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas 2).


The aim of a study was to investigate the ability of a SERM, RLX, to prevent vasospasm in a rabbit model of SAH.

Thirty-four New Zealand white rabbits were allocated into 3 groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) sham operated (no SAH [n = 12]), (2) SAH only (n = 12), and (3) SAH plus RLX (n = 10). Basilar artery lumen areas and arterial wall thickness were measured to assess vasospams in all groups.

There was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (P < .05). The difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements in the RLX-treated group was statistically significant (P < .05). The difference between the SAH group and the SAH + RLX group was also statistically significant (P < .05).

These findings demonstrate that RLX has marked vasodilatatory effect in an experimental model of SAH in rabbits. This observation may have clinical implications suggesting that this SERM drug could be used as possible anti-vasospastic agent in patients without major adverse effects 3).


The effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH) was investigated in a rat model. Seven groups of seven rats underwent no SAH, no treatment; SAH only; SAH plus vehicle; SAH plus 3 days intraperitoneal raloxifene treatment; SAH plus 4 days intraperitoneal raloxifene treatment; SAH plus 3 days intrathecal raloxifene treatment; and SAH plus 4 days intrathecal raloxifene treatment. The basilar artery cross-sectional areas were measured at 72 or 96 hours following SAH. The results showed raloxifene decreased SAH-induced cerebral vasospasm in all treatment groups, and suggested no difference between intraperitoneal and intrathecal application, or between 3 days and 4 days of raloxifene treatment. The present study demonstrates that raloxifene is a potential therapeutic agent against cerebral vasospasm after SAH 4).


To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology 5).

References

1)

Choudhary C, Hamrahian AH, Bena JF, Recinos P, Kennedy L, Dobri G. THE EFFECT OF RALOXIFENE ON SERUM PROLACTIN LEVEL IN PATIENTS WITH PROLACTINOMA. Endocr Pract. 2019 Mar 13. doi: 10.4158/EP-2018-0321. [Epub ahead of print] PubMed PMID: 30865525.
2)

Hannen R, Steffani M, Voellger B, Carl B, Wang J, Bartsch JW, Nimsky C. Effects of anti-estrogens on cell invasion and survival in pituitary adenoma cells: A systematic study. J Steroid Biochem Mol Biol. 2019 Mar;187:88-96. doi: 10.1016/j.jsbmb.2018.11.005. Epub 2018 Nov 13. PubMed PMID: 30439415.
3)

Gürses L, Seçkin H, Simşek S, Senel OO, Yigitkanli K, Oztürk E, Beşalti O, Belen D, Bavbek M. Effects of raloxifene on cerebral vasospasm after experimental Subarachnoid Hemorrhage in rabbits. Surg Neurol. 2009 Nov;72(5):490-4; discussion 494-5. doi: 10.1016/j.surneu.2008.11.007. Epub 2009 Jan 14. PubMed PMID: 19147193.
4)

Gulsen S, Inci S, Yuruk S, Yasar U, Ozgen T. Effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage in rats. Neurol Med Chir (Tokyo). 2007 Dec;47(12):537-42; discussion 542. PubMed PMID: 18159137.
5)

Lei DL, Long JM, Hengemihle J, O’Neill J, Manaye KF, Ingram DK, Mouton PR. Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice. Neuroscience. 2003;121(3):659-66. PubMed PMID: 14568026.

Cerebellar Arteriovenous Malformation Grading

Cerebellar Arteriovenous Malformation Grading

Anatomic diversity among cerebellar arteriovenous malformations (AVMs) calls for a classification that is intuitive and surgically informative. Selection tools like the Spetzler-Martin grading system are designed to work best with cerebral AVMs but have shortcomings with cerebellar AVMs 1)

The objective of a study from the Department of Neurosurgery, University of California, San FranciscoBanner-University Medical Center TucsonArizona and Barrow Neurological Institute, Phoenix, was to evaluate the existing Spetzler-Martin AVM grading system (SM), Spetzler Ponce classification (SP), and Lawton-Young Grading System (LY) for cerebellar arteriovenous malformations (AVMs) and to propose a new grading system to estimate the risks associated with these lesions.

Data for patients with cerebellar AVMs treated microsurgically in two tertiary medical centers were retrospectively reviewed. Data from patients at institution 1 were collected from September 1999 to February 2013, and at institution 2 from October 2008 to October 2015. Patient outcomes were classified as favorable (modified Rankin Scale [mRS] score 0-2) or poor (mRS score 3-6) at the time of discharge. Using chi-square and logistic regression analysis, variables associated with poor outcomes were assigned risk points to design the proposed grading system. The proposed system included neurological status prior to treatment (poor, +2 points), emergency surgery (+1 point), age > 60 years (+1 point), and deep venous drainage (deep, +1 point). Risk point totals of 0-1 comprised grade 1, 2-3 grade 2, and 4-5 grade 3.

A total of 125 cerebellar AVMs of 1328 brain AVMs were reviewed in 125 patients, 120 of which were treated microsurgically and included in the study. With our proposed grading system, we found poor outcomes differed significantly between each grade (p < 0.001), while with the SM, SP, and LY grading systems they did not (p = 0.22, p = 0.25, and p = 1, respectively). Logistic regression revealed grade 2 had 3.3 times the risk of experiencing a poor outcome (p = 0.008), while grade 3 had 9.9 times the risk (p < 0.001). The proposed grading system demonstrated a superior level of predictive accuracy (area under the receiver operating characteristic curve [AUROC] of 0.72) compared with the SM, SP, and LY grading systems (AUROC of 0.61, 0.57, and 0.51, respectively).

Nisson et al., propose a novel grading system for cerebellar AVMs based on emergency surgery, venous drainage, preoperative neurological status, and age that provides a superior prognostication power than the formerly proposed SM, SP, and LY grading systems. This grading system is clinically predictive of patient outcomes and can be used to better guide vascular neurosurgeons in clinical decision-making 2).


Rodriguez-Hernandez et al. hypothesized that the predictive capability of the supplementary grading scale was superior to that of the Spetzler Martin grading scale for assessment of outcomes following microsurgical resection of cerebellar AVMs 3).

Deep venous drainage is a better indicator of the depth of the nidus for cerebral AVMs than for cerebellar AVMs. Cerebellar anatomy is altered by AVMs in a different manner than cerebral anatomy such that the supplementary grading scale may be better than the Spetzler-Martin grade for prediction of surgical outcomes. In comparison with ruptured cerebral AVMs, which may be managed conservatively followed by radiosurgery for achievement of obliteration, ruptured cerebellar AVMs may be better treated by surgical resection, especially when the associated hemorrhage results in symptomatic compression of surrounding neural structures.

In conclusion, the surgical risk for cerebellar AVMs may be predicted by either the Spetzler-Martin or supplementary grading scales, although the supplementary scale may show better correlation with outcomes 4) 5) 6). However, neither grading system can substitute for experienced clinical and surgical judgment 7).

References

1) , 3) , 5)

Rodríguez-Hernández A, Kim H, Pourmohamad T, Young WL, Lawton MT. University of California, San Francisco Arteriovenous Malformation Study Project. Cerebellar arteriovenous malformations: Anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery. 2012 Dec;71(6):1111–1124.
2)

Nisson PL, Fard SA, Walter CM, Johnstone CM, Mooney MA, Tayebi Meybodi A, Lang M, Kim H, Jahnke H, Roe DJ, Dumont TM, Lemole GM, Spetzler RF, Lawton MT. A novel proposed grading system for cerebellar arteriovenous malformations. J Neurosurg. 2019 Mar 8:1-11. doi: 10.3171/2018.12.JNS181677. [Epub ahead of print] PubMed PMID: 30849761.
4)

Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010 Apr;66(4):702–713. discussion 713.
6)

Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986 Oct;65(4):476–483.
7)

Ding D, Liu KC. Predictive Capability of the Spetzler-Martin versus Supplementary Grading Scale for Microsurgical Outcomes of Cerebellar Arteriovenous Malformations. J Cerebrovasc Endovasc Neurosurg. 2013 Dec;15(4):307-10. doi: 10.7461/jcen.2013.15.4.307. Epub 2013 Dec 31. PubMed PMID: 24729957; PubMed Central PMCID: PMC3983531.

End to side anastomosis

End to side anastomosis

End-to-endend-to-side, and side-to-side microvascular anastomoses are the main types of vascular bypass grafting used in microsurgery and neurosurgery.

The end-to-side anastomosis is 1 of the most common anastomosis configurations used in cerebrovascular surgery.

Although several living practice models have been proposed for this technique, few involve purely arterial vessels.

Currently, there has been no animal model available for practicing all three anastomoses in one operation. The aim of a study of Yin et al., was to develop a novel animal modelthat utilizes the rat abdominal aorta (AA), common iliac artery(CIAs), and the median sacral artery (MSA) for practicing these three types of anastomosis.

Eight adult Sprague Dawley rats were anesthetized and then laparotomized. The AA, MSA, and bilateral CIAs were exposed and separated from the surrounding tissues. The length and diameter of each artery were measured. The relatively long segment of the AA without major branches was selected to perform end-to-end anastomosis. One side of the CIAs (or AA) and MSA were used for end-to-side anastomosis. The bilateral CIAs were applied to a side-to-side and another end-to-side anastomosis.

Anatomical dissection of the AA, CIAs, and MSA was successfully performed on eight Sprague-Dawley rats; four arterial-to-arterial anastomoses were possible for each animal. The AA trunk between the left renal artery and right iliolumbar arteries was 15.60 ± 0.76 mm in length, 1.59 ± 0.15 mm in diameter, for an end-to-end anastomosis. The left CIA was 1.06 ± 0.08 mm in diameter, for an end-to-side anastomosis with the right CIA. The MSA was 0.78 ± 0.07 mm in diameter, for another end-to-side anastomosis with the right CIA or AA. After finishing end-to-side anastomosis in the proximal part of bilateral CIAs, the distal portion was juxtaposed for an average length of 5.6 ± 0.25 mm, for a side-to-side anastomosis.

This model can comprehensively and effectively simulate anastomosis used in revascularization procedures and can provide more opportunities for surgical education, which may lead to more routine use in microvascular anastomosis training. 1).


The purpose of a study was to compare 2 arterial models using common carotid arteries (CCAs) and common iliac arteries (CIAs) in rats.

The CIAs and CCAs were exposed in 10 anesthetized rats, and their lengths and diameters were measured. Also, the mobilization extent of each vessel along its contralateral counterpart was measured after each artery had been transected at its proximal exposure point. We also studied the technical advantages and disadvantages of each model for practicing end-to-side anastomosis.

The average diameters of the CCA and CIA were 1.1 and 1.3 mm, respectively. The average extent of mobilization along the contralateral vessel was 13.9 mm and 10.3 mm for CCA and CIA, respectively. The CCA model had the advantages of greater arterial redundancy (allowing completion of both suture lines extraluminally) and a minimal risk of venous injury. The main disadvantage of the CCA model was the risk of cerebral ischemia. The CIA model was not limited by the ischemic time and provided the technical challenge of microsurgical dissection of the common iliac vein from the CIA, although it had limited CIA redundancy.

Both CCA and CIA models could be efficiently used for practicing the end-to-side anastomosis technique. Each model provides the trainee with a specific set of advantages and disadvantages that could help with the optimal selection of the practice model according to trainee’s skill level 2).

Case reports

A dolichoectatic intracranial vessel with multiple fusiform aneurysms on the same vessel segment is rare, and usually managed with a bypass with aneurysm trapping. This video demonstrates trapping and a double-barrel superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass to treat two fusiform aneurysms in a left dolichoectatic superior MCA trunk. A 46-year-old man with AIDS presented with aphasia and hemiparesis. IRB approval and patient consent were obtained. Both STA branches (frontal and parietal) were harvested. After widely splitting the sylvian fissure from its proximal portion to the angular gyrus, the two fusiform aneurysms on the superior MCA trunk were identified in the insular recess and the circular sulcus. The outflow artery from each aneurysm was identified and prepared for the bypass. The STA was transected, and both limbs were brought down into the fissure. After trapping the distal aneurysm, an end-to-end anastomosis of the parietal STA branch to the M2 MCA was performed. Thereafter, a second bypass was performed in an end-to-side fashion to an M2 branch from the base of the first aneurysm. The second aneurysm was then trapped. Indocyanine green angiography confirmed the patency of both bypasses. Complete aneurysm occlusion and bypass patency were also confirmed with postoperative angiography. The patient recovered from his pre-operative neurological deficits. This case demonstrates the efficacy of double-barrel STA-MCA bypass in combination with aneurysm trapping in a patient with a complex dolichoectatic superior MCA trunk aneurysm. It also highlights the advantage of using end-to-end anastomosis for deep recipients with limited access 3).


A 63-year-old man presented with repeat neurological symptoms such as dizziness, nausea, vomiting, dysarthria, left hemiparesis, and right hemianopsia. Magnetic resonance imaging revealed multiple posterior infarctions. Angiography revealed the VA to be occluded and reconstituted by collateral vessels. Considering the above results, we performed vertebral carotid artery transposition. However, several technical difficulties were encountered due to space limitations in the operative field and the limited length of the vessels to be anastomosed. To overcome such situations, we introduced a modified posterior wall end-to-side anastomosis technique 4).

Videos

In this 3-dimensional video, we perform a side-to-side and end-to-side double anastomosis using the parietal-branch of the superficial temporal artery (STA) to provide flow augmentation in a symptomatic 59-yr-old male with bilateral internal carotid artery occlusion at the origin, and left M1 segment occlusion. The patient suffered multiple left hemispheric strokes despite maximal medical therapy and was found to have poor hemodynamic reserve in the left hemisphere during evaluation with regional and global blood oxygenation level-dependent functional magnetic resonance imaging with CO2-challenge as well as quantitative magnetic resonance angiography and noninvasive optimal vessel analysis pre- and post-acetazolamide challenge. Postoperatively, the patient did very well and his hemodynamic studies improved significantly. The importance of this technique relies on the fact that we are using a single donor vessel to perform 2 anastomoses, and carries the following advantages: (1) the frontal STA branch remains intact and therefore can still be used at a later time if further revascularization is needed; (2) wound complications related to devascularizing the scalp from harvesting both STA branches are reduced; (3) 2 vascular territories are augmented (frontal and temporal) while using a single donor; (4) we are maximizing donor potential and optimizing cut flow index (CFI; total bypass flow postanastomosis divided by bypass cut flow) by flow augmenting 2 separate vascular beds therefore increasing demand. To explain that fourth point further: if the STA donor is able to carry a maximum 100 mL/min when cut, and after performing the first anastomosis bypass flow is only 37 mL/min, CFI will be 37/100 = 0.37, reflecting low demand, a poor indicator of graft patency, as previously published.1,2 By adding a second anastomosis which demands an additional 60 mL/min from the same STA donor, CFI (60 + 37)/100 improves to 1. Institutional Review Board approval was obtained for the review of patient chart and video files. Informed consent was obtained directly from the patient via telephone regarding use of media for educational and publication purposes 5).


References

1)

Yin X, Ye G, Lu J, Wang L, Qi P, Wang H, Wang J, Hu S, Yang X, Chen K, Wang D. A Novel Rat Model for Comprehensive MicrovascularTraining of End-to-EndEnd-to-Side, and Side-to-Side Anastomoses. J Reconstr Microsurg. 2019 Mar 5. doi: 10.1055/s-0039-1679957. [Epub ahead of print] PubMed PMID: 30836413.
2)

Tayebi Meybodi A, Belykh EG, Aklinski J, Kaur P, Preul MC, Lawton MT. The End-to-Side Anastomosis: A Comparative Analysis of Arterial Models in the Rat. World Neurosurg. 2018 Nov;119:e809-e817. doi: 10.1016/j.wneu.2018.07.271. Epub 2018 Aug 8. PubMed PMID: 30096493.
3)

Gandhi S, Rodriguez RL, Tabani H, Burkhardt JK, Benet A, Lawton MT. Double-Barrel Extracranial-Intracranial Bypass and Trapping of Dolichoectatic Middle Cerebral Artery Aneurysms: 3-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2019 Jan 30. doi: 10.1093/ons/opy311. [Epub ahead of print] PubMed PMID: 30715471.
4)

Seung WB. A Modified Surgical Technique for Transposition of the Vertebral Artery to the Common Carotid Artery. Case Rep Neurol. 2018 Oct 9;10(3):292-296. doi: 10.1159/000493725. eCollection 2018 Sep-Dec. PubMed PMID: 30483104; PubMed Central PMCID: PMC6244107.
5)

Arnone GD, Hage ZA, Charbel FT. Side-to-Side and End-to-Side Double Anastomosis Using the Parietal-Branch of the Superficial Temporal Artery-A Novel Technique for Extracranial to Intracranial Bypass Surgery: 3-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2019 Jan 1;16(1):112-114. doi: 10.1093/ons/opy091. PubMed PMID: 29660052.
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