Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial.

BACKGROUND: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis. METHODS: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed on patients with reduced and preserved LVEF. RESULTS: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P<0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; P=0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; P<0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; P=0.0001; Pinteraction<0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF. CONCLUSIONS: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236.

An appraisal of the in vivo role of phosphate as a modulator of urinary ammonium and titratable acid excretion in the acidotic rabbit.

Previous studies have shown that the intravenous infusion of inorganic phosphate increased urinary ammonium excretion 8- to 10-fold in the acidotic rabbit. This was considered to be a very important observation at the time and to be unique to the rabbit. While investigating this finding, we discovered that the formol titration procedure, used to measure urinary ammonium by this research group, is subject to interference by phosphate, casting doubt on the validity of the urinary ammonium excretion data reported by them in the literature. In order to re-assess the importance of phosphate as a potential modulator of urinary ammonium excretion in the acidotic rabbit, renal net acid excretion studies were carried out in phosphate-loaded acidotic animals. We observed that while urinary ammonium excretion increased significantly (p < 0.05) after 50 min of phosphate infusion, the maximum concentrations excreted were substantially less than previously reported in the literature. However, through its urinary buffering capacity, we observed that inorganic phosphate, via an experimentally induced phosphaturia, could substantially enhance titratable acid excretion. Contrary to earlier reports, we demonstrated that phosphate plays a relatively minor in vivo modulator role in enhancing renal net acid excretion through the vehicle of ammonium during acute metabolic acidosis in the hyperphosphataemic rabbit. The findings reported in this study constitute an important update on ammonia metabolism in the acidotic rabbit.

Derivation of a Predictive Score for Hemorrhagic Progression of Cerebral Contusions in Moderate and Severe Traumatic Brain Injury.

BACKGROUNDS: After traumatic brain injury (TBI), hemorrhagic progression of contusions (HPCs) occurs frequently. However, there is no established predictive score to identify high-risk patients for HPC. METHODS: Consecutive patients who were hospitalized (2008-2013) with non-penetrating moderate or severe TBI were studied. The primary outcome was HPC, defined by both a relative increase in contusion volume by ≥30 % and an absolute increase by ≥10 mL on serial imaging. Logistic regression models were created to identify independent risk factors for HPC. The HPC Score was then derived based on the final model. RESULTS: Among a total of 286 eligible patients, 61 (21 %) patients developed HPC. On univariate analyses, HPC was associated with older age, higher initial blood pressure, antiplatelet medications, anticoagulants, subarachnoid hemorrhage (SAH) subdural hematoma (SDH), skull fracture, frontal contusion, larger contusion volume, and shorter interval from injury to initial CT. In the final model, SAH (OR 6.33, 95 % CI, 1.80-22.23), SDH (OR 3.46, 95 % CI, 1.39-8.63), and skull fracture (OR 2.67, 95 % CI, 1.28-5.58) were associated with HPC. Based on these factors, the HPC Score was derived (SAH = 2 points, SDH = 1 point, and skull fracture = 1 point). This score had an area under the receiver operating curve of 0.77. Patients with a score of 0-2 had a 4.0 % incidence of HPC, while patients with a score of 3-4 had a 34.6 % incidence of HPC. CONCLUSIONS: A simple HPC Score was developed for early risk stratification of HPC in patients with moderate or severe TBI.

Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a rare genetic disorder characterised by numerous renal cysts, the progressive expansion of which can impact kidney function and lead eventually to renal failure. Tolvaptan is the only disease-modifying drug approved for the treatment of ADPKD, however its poor side effect and safety profile necessitates the need for the development of new therapeutics in this area. Using a combination of transcriptomic and machine learning computational drug discovery tools, we predicted that a number of existing drugs could have utility in the treatment of ADPKD, and subsequently validated several of these drug predictions in established models of disease. We determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity. These findings demonstrate the utility of combining computational approaches to identify and understand potential new treatments for traditionally underserved rare diseases.

A novel combination treatment for fragile X syndrome predicted using computational methods.

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx's data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.

A grid-enabled web service for low-resolution crystal structure refinement.

Deformable elastic network (DEN) restraints have proved to be a powerful tool for refining structures from low-resolution X-ray crystallographic data sets. Unfortunately, optimal refinement using DEN restraints requires extensive calculations and is often hindered by a lack of access to sufficient computational resources. The DEN web service presented here intends to provide structural biologists with access to resources for running computationally intensive DEN refinements in parallel on the Open Science Grid, the US cyberinfrastructure. Access to the grid is provided through a simple and intuitive web interface integrated into the SBGrid Science Portal. Using this portal, refinements combined with full parameter optimization that would take many thousands of hours on standard computational resources can now be completed in several hours. An example of the successful application of DEN restraints to the human Notch1 transcriptional complex using the grid resource, and summaries of all submitted refinements, are presented as justification.

Cystic change in thyroid carcinoma: Prevalence and estimated volume in 360 carcinomas.

PURPOSE: The aim of this study was to determine the prevalence and amount of cystic change in thyroid cancer. This study also examined associated sonographic characteristics of cystic malignant thyroid nodules to help recognize these clinically important nodules. METHODS: This study was a retrospective review of 360 malignant thyroid nodules surgically removed at our institution between January 1, 2002 and December 31, 2004. All patients had signed research authorization. All patients had preoperative sonograms and surgical pathologic proof of their thyroid malignancy. The 360 malignant nodules were found in 307 patients. All scans were performed using 7- to 15-MHz transducers, and most studies included a digital video clip of the cancer. The preoperative ultrasound examinations were retrospectively reviewed by three radiologists and a sonographer. An estimate of cystic component percentage was derived by consensus. The presence of a mural nodule, thick irregular wall, microcalcifications, and prominent vascularity was also recorded. RESULTS: Of the 360 carcinomas, 318 (88.3%) were solid to minimally (less than 5%) cystic, 33 (9.2%) were 6-50% cystic, 9 (2.5%) were 51-100% cystic. Of the nine (2.5%) malignancies that were greater than 50% cystic, all had other suspicious findings including mural nodules, microcalcifications, increased vascularity, and/or a thick irregular wall about the cystic portion. CONCLUSION: The vast majority (88%) of thyroid cancer is uniformly solid or has minimal (1-5%) cystic change by sonography. Marked cystic change (>50% of the nodule) occurred in only 2.5% of cancers, which had other sonographic findings worrisome for malignancy.

The kinetics of inorganic phosphate excretion in the acidotic rabbit during intravenous phosphate loading: a pseudo-ruminant model.

The rabbit is a much-used experimental animal in renal tubule physiology studies. Although a monogastric mammal, the rabbit is a known hindgut fermenter. That ruminant species excrete inorganic phosphate (Pi) mainly through the digestive system while non-ruminants eliminate surplus phosphate primarily through the renal system are acknowledged facts. To understand phosphate homeostasis in the acidotic rabbit, anaesthetized animals were infused with hydrochloric acid, after which they underwent intravenous phosphate loading. Biofluids were collected during the infusion process for analysis. Plasma Pi increased (7.9 ± 1.7 mmoles.Litre-1 (N = 5) vs 2.2 ± 0.4 mmoles.Litre-1 (N = 10) pre-infusion, (p < 0.001)), while urinary phosphate excretion was also enhanced (74.4 ± 15.3 from a control value of 4.7 ± 3 µmol.min-1 (N = 9), pre-infusion, p < 0.001)) over an 82.5 minute Pi loading period. However, the fractional excretion of Pi (FePi) only increased from 14.2 ± 5.4% to a maximum of 61.7 ± 19% (N = 5) over the infusion period. Furthermore, the renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmPi/GFR) computed to 3.5 mmol.L-1, while a reading of 23.2 µmol.min-1.Kg.0.75 was obtained for the transport maximum for Pi (TmPi). The high reabsorptivity of the rabbit nephrons coupled with possibly a high secretory capacity of the salivary glands for Pi, may constitute a unique physiological mechanism that ensures the rabbit hindgut receives adequate phosphate to regulate caecal pH in favour of the resident metabolically - active microbiota. The handling of Pi by the rabbit is in keeping with the description of this animal as a monogastric, pseudo-ruminant herbivore.

Aeromedical evacuation of patients with pneumocephalus: outcomes in 21 cases.

INTRODUCTION: Aeromedical evacuation of patients with posttraumatic and/or post-surgical pneumocephalus has often been regarded with great concern. The expansion of intracranial air with increasing altitude can theoretically result in tension pneumocephalus, with potentially fatal results. This concern is primarily based on extremely rare case reports and theoretical models rather than any significant clinical experience. We report the outcomes of a series of 21 patients with posttraumatic and/or post-craniotomy pneumocephalus who underwent long-range air evacuation from a combat theater in military aircraft. METHODS: The estimated volume for each patient was calculated with a simplified method, purposely intended to err toward overestimation, based on computerized tomography scans performed within 24 h prior to air travel. RESULTS: The volumes of pneumocephalus ranged from 0.6 to 42.7 ml, with mean volume of 9.3 ml and median volume of 4.2 ml. No patient sustained a temporary or permanent neurologic decline as a result of air transportation. Three patients with continuous monitoring of intracranial pressure (ICP) were not observed to have any sustained pressure elevations during flight. DISCUSSION: We conclude that pneumocephalus in the head-injured and/or craniotomy patient is not likely by itself to be an absolute contraindication to air evacuation. The mechanism causing pneumocephalus, its time course, progression, and the rate of altitude change are likely more important factors in determining its clinical significance. More clinical experience is required to better assess the safety of aeromedical evacuation of these patients, but this small series suggests that it is not as dangerous as previously thought.

Cranial burr holes and emergency craniotomy: review of indications and technique.

Burr hole craniotomy for posttraumatic intracranial hematoma is rarely performed since the advent of computerized tomography revolutionized the treatment of these patients. It is still necessary in unique circumstances although, and the clinical urgency may require surgery by a non-neurosurgeon. This occurs rarely in rural or overseas locations in peacetime, but more commonly in combat health support operations where computed tomography and neurosurgeons are not widely available. Recent experiences in the Global War on Terrorism have prompted a detailed review of this procedure. The nonoperative care, localization of intracranial hematoma, and surgical technique are outlined here in detail, and results from the literature are reviewed. This review emphasizes that burr holes should not be performed at random on head-injured patients and should be performed only by general surgeons or other physicians who have undergone formal instruction by experienced neurosurgeons, and every reasonable attempt to contact a neurosurgeon should be made first.

Successful removal of a cerebellar hemangioblastoma in a combat support hospital.

The case of a 24-year-old male U.S. Marine Corps sergeant who presented with headache and ataxia to a combat support hospital (CSH) in Kuwait, during Operation Iraqi Freedom, is described. Imaging studies revealed a cystic brain neoplasm causing hydrocephalus and increased intracranial pressure. Because of the patient's deteriorating clinical condition and the high risk of further brain injury during a prolonged air evacuation flight, immediate surgery at the CSH was deemed the safest treatment option. The tumor was completely removed and the patient's symptoms resolved, allowing safe evacuation. A CSH is not intended to provide comprehensive neurosurgical capabilities and some equipment usually considered necessary to perform this surgery was unavailable, but field-expedient methods were devised to overcome these deficiencies. This is the first reported case of a brain tumor successfully removed in a CSH.

Collection of untainted urinary specimens from the bladder of an anesthetized rabbit.

It is difficult to collect untainted urine specimens over short intervals of time during renal studies with rabbits. This is because both the ureters and the bladder of this species are relatively friable and minor manipulation can easily cause intraluminal bleeding. We have developed and refined an effective technique and protocol for placing an indwelling urinary bladder catheter into an anesthetized rabbit. The procedure is easy to perform and completely effective and reliable, allowing high-quality urinary specimens to be collected at intervals of 15-20 min over a period of 3-4 hours during a study of acute metabolic acidosis.

Simple depressed skull fracture causing sagittal sinus stenosis and increased intracranial pressure: case report and review of the literature.

The surgical management of depressed skull fractures is determined in part by whether a fracture is open or closed. Open fractures are usually elevated surgically, but closed fractures are most often treated nonoperatively, and the only 2 indications commonly described for operative treatment of closed fractures are hematoma evacuation and correction of cosmetic deformity. There is another indication, however, that is occasionally encountered when a depressed skull fracture injures a venous sinus. This injury can result in venous sinus stenosis, leading to venous hypertension and elevated intracranial pressure (ICP). A case is presented of closed depressed fracture of the midline skull, causing compressive stenosis of the superior sagittal sinus (SSS), venous hypertension, and encephalopathy. The fracture was surgically elevated to relieve the compression of the SSS and the encephalopathy resolved. The clinical identification, the imaging, and the risks and benefits of operative repair of this condition are reviewed. Increased ICP secondary to venous sinus injury is not commonly described in association with closed depressed skull fractures, but should always be considered in patients with the appropriate clinical findings when a fracture overlies a venous sinus, even in the absence of a hematoma.

Osteoradionecrosis of the cervical spine resulting from radiotherapy for primary head and neck malignancies: operative and nonoperative management. Case report.

Osteoradionecrosis is a process of dysvascular bone necrosis and fibrous replacement following exposure to high doses of radiation. The poorly vascularized necrotic tissue may cause pain and/or instability, and it cannot resist infection well, which may result in secondary osteomyelitis. When these processes affect the cervical spine, the resulting instability and neurological deficits can be devastating, and immediate reestablishment of spinal stability is paramount. Reconstruction of the cervical spine can be particularly challenging in this subgroup of patients in whom the spine is poorly vascularized after radical surgery, high-dose irradiation, and infection. The authors report three cases of cervical spine osteoradionecrosis following radiotherapy for primary head and neck malignancies. Two patients suffered secondary osteomyelitis, severe spinal deformity, and spinal cord compression. These patients underwent surgery in which a vascularized fibular graft and instrumentation were used to reconstruct the cervical spine; subsequently hyperbaric oxygen (HBO) therapy was instituted. Fusion occurred, spinal stability was restored, and neurological dysfunction resolved at the 2- and 4-year follow-up examinations, respectively. The third patient experienced pain and dysphagia but did not have osteomyelitis, spinal instability, or neurological deficits. He underwent HBO therapy alone, with improved symptoms and imaging findings. Hyperbaric oxygen is an essential part of treatment for osteoradionecrosis and may be sufficient by itself for uncomplicated cases, but surgery is required for patients with spinal instability, spinal cord compression, and/or infection. A vascularized fibular bone graft is a very helpful adjunct in these patients because it adds little morbidity and may increase the rate of spinal fusion.

Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

Favorable outcomes for Native Hawaiians and other Pacific Islanders with severe traumatic brain injury.

Traumatic brain injury (TBI) disproportionately impacts minority racial groups. However, limited information exists on TBI outcomes among Native Hawaiians and other Pacific Islanders (NHPI). All patients with severe TBI (Glasgow Coma Scale (GCS) <9) who were hospitalized at the state-designated trauma center in Hawai'i from March 2006 to February 2011 were studied. The primary outcome measure was discharge Glasgow Outcome Scale ([GOS]: 1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; 5, good recovery), which was dichotomized to unfavorable (GOS 1-2) and favorable (GOS 3-5). Logistic regression analyses were performed to assess factors predictive of discharge functional outcome. A total of 181 patients with severe TBI (NHPI 27%, Asians 25%, Whites 30%, and others 17%) were studied. NHPI had a higher prevalence of assault-related TBI (25% vs 6.5%, P = .046), higher prevalence of chronic drug abuse (20% vs 4%, P = .02) and chronic alcohol abuse (22% vs 2%, P = .003), and longer intensive care unit length of stay (15±10 days vs 11±9 days, P < .05) compared to Asians. NHPI had lower prevalence of unfavorable functional outcomes compared to Asians (33% vs 61%, P = .006) and Whites (33% vs 56%, P = .02). Logistic regression analyses showed that Asian race (OR, 6.41; 95% CI, 1.68-24.50) and White race (OR, 4.32; 95% CI, 1.27-14.62) are independently associated with unfavorable outcome compared to NHPI. Contrary to the hypothesis, NHPI with severe TBI have better discharge functional outcomes compared to other major racial groups.

Surfers' myelopathy: a case series of 19 novice surfers with nontraumatic myelopathy.

OBJECTIVE: We report the clinical characteristics of the largest series of nontraumatic spinal cord injury in novice surfers (surfers' myelopathy). METHODS: A retrospective review of the electronic medical record was performed in patients with nontraumatic spinal cord injury associated with surfing identified upon admission to the largest tertiary referral hospital in Hawaii from June 2002 to November 2011. Classification by the American Spinal Injury Association Impairment Scale (AIS) was performed upon admission and at follow-up. Clinical management, including blood pressure measurements and optimization, use of corticosteroids, and diagnostic evaluations, were reviewed. Follow-up information was obtained by clinic visits, telephone interviews, and electronic mail up to 3 years after injury. RESULTS: In 19 patients (14 male) aged 15-46 years, all patients complained of sudden onset of low back pain while surfing, followed by bilateral leg numbness and paralysis progressing over 10-60 minutes. All patients were novice surfers; 17 of 19 were surfing for the first time. On T2-weighted MRI, all patients had hyperintensity from the lower thoracic spinal cord to the conus medullaris. Six of 10 patients who underwent spinal diffusion-weighted MRI showed restricted diffusion in this region. Patients presenting with worse AIS scores had minimal improvement at follow-up. Blood pressure, corticosteroids, and imaging results were not associated with severity of neurologic deficits at follow-up. CONCLUSIONS: Although the cause of surfers' myelopathy is unclear, the rapid onset and presence of restricted diffusion suggest ischemic injury. Admission severity appears to be most predictive of neurologic outcome.

Conformational locking upon cooperative assembly of notch transcription complexes.

The Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML). The "RAM" region of NICD recruits Notch to CSL, facilitating the binding of MAML at the interface between the ankyrin (ANK) repeat domain of NICD and CSL. Here, we report the X-ray structure of a human MAML1/RAM/ANK/CSL/DNA complex, and probe changes in component dynamics upon stepwise assembly of a MAML1/NICD/CSL complex using HX-MS. Association of CSL with NICD exerts remarkably little effect on the exchange kinetics of the ANK domain, whereas MAML1 binding greatly retards the exchange kinetics of ANK repeats 2-3. These exchange patterns identify critical features contributing to the cooperative assembly of Notch transcription complexes (NTCs), highlight the importance of MAML recruitment in rigidifying the ANK domain and stabilizing its interface with CSL, and rationalize the requirement for MAML1 in driving cooperative dimerization of NTCs on paired-site DNA.

Giant eccrine adenocarcinoma of the scalp with intracranial invasion: resection and reconstruction using a vacuum-assisted closure device: technical case report.

OBJECTIVE AND IMPORTANCE: Carcinoma of the adnexal structures of the skin is a rare malignancy, and is even more unusual in the scalp. We report an unusual case of scalp adnexal carcinoma of eccrine origin that went untreated for years, resulting in a giant tumor with extension through the cranium. The tumor resection and reconstruction of the cranium and scalp defects posed unique challenges. CLINICAL PRESENTATION: A 54-year-old woman experienced a large recurrence of her scalp adnexal carcinoma after an incomplete wide local excision, which invaded through the cranium. INTERVENTION: The entire vertex of the scalp and cranium were removed en bloc. After cranioplasty, a free vascularized muscle flap was used for soft tissue coverage, but failed owing to poor vascular inflow. A large area of dura was left open, using a vacuum-assisted wound closure device to generate granulation tissue by secondary intention. Another split thickness skin graft was used to provide a cosmetically acceptable outcome. CONCLUSION: Scalp adnexal tumors of eccrine origin rarely metastasize and can be resected for cure with complete removal. Reconstruction options for large scalp and cranial tumors may be limited, and allowing the dura to granulate by secondary intention has been very rarely described. The novel use of a vacuum-assisted wound closure device was a very useful adjunct in this situation, and may be beneficial in the reconstruction of other patients with large scalp and cranial defects after neurosurgical procedures. It should be used with caution, since it may risk injury to a major venous sinus, especially when used in the midline, or cerebrospinal fluid leakage.