Early CT physics research at Massachusetts General Hospital.

Although CT imaging was introduced at Massachusetts General Hospital (MGH) quite early, with its first CT scanner installed in 1973, CT research at MGH started years earlier. The goal of this paper is to describe some of this innovative work and related accomplishments.

Colloid cyst curtailed: A case report of spontaneous colloid cyst regression.

BACKGROUND: Colloid cysts arise from the roof of the third ventricle and are at risk for obstructing the flow of cerebrospinal fluid (CSF) and causing increased intracranial pressure. With advancements and increased frequency of imaging, colloid cysts are sometimes discovered incidentally. In these cases, the neurosurgeon is faced with the decision of whether to intervene or manage conservatively. CASE DESCRIPTION: A 67-year-old man was discovered to have a colloid cyst when imaging was performed for transient neurologic deficits. CT and MRI brain revealed a 5mm lesion in the third ventricle with characteristics suggestive of the colloid cyst. Except for his initial presentation, the patient did not exhibit any symptoms and was followed with serial imaging. Four years after discovery, the colloid cyst regressed in size. CONCLUSION: The evolution and resolution of colloid cysts remain elusive; however, the discovery of incidental colloid cysts due to more frequent and more advanced neuroimaging emphasize the importance of this topic. The fear of conservative management is acute decompensation due to obstruction of CSF. However, surgical risks may be avoided if these asymptomatic lesions regress and resolve without intervention. Conservative management is a viable option for patients with colloid cysts, who may not only avoid surgery but who might also rarely experience cyst resolution.

A review and comparison of three neuronavigation systems for minimally invasive intracerebral hemorrhage evacuation.

Advances in stereotactic navigation technology have helped to improve the ease, reliability, and workflow of neurosurgical intraoperative navigation. These advances have also allowed novel, minimally invasive neurosurgical techniques to emerge. Minimally invasive techniques for intracerebral hemorrhage (ICH) evacuation, including endoscopic evacuation and passive catheter drainage, are notable examples, and as these gain support in the literature and their use expands, stereotactic navigation will take on an increasingly important and central role. Each neurosurgical navigation system has unique characteristics. Operators may find that certain aspects are more important than others, depending on the environment in which the evacuation is performed and operator preferences. This review will describe the characteristics of three popular stereotactic neuronavigation systems and compare their advantages and disadvantages as they relate to minimally invasive ICH evacuation.

A limit on dose reduction possible with CT reconstruction algorithms without prior knowledge of the scan subject.

PURPOSE: To find an upper bound on the maximum dose reduction possible for any reconstruction algorithm, analytic or iterative, that result from the inclusion of the data statistics. The authors do not analyze noise reduction possible from prior knowledge or assumptions about the object. METHODS: The authors examined the task of estimating the density of a circular lesion in a cross section. Raw data were simulated by forward projection of existing images and numerical phantoms. To assess an upper bound on the achievable dose reduction by any algorithm, the authors assume that both the background and the shape of the lesion are completely known. Under these conditions, the best possible estimate of the density can be determined by solving a weighted least squares problem directly in the raw data domain. Any possible reconstruction algorithm that does not use prior knowledge or make assumptions about the object, including filtered backprojection (FBP) or iterative reconstruction methods with this constraint, must be no better than this least squares solution. The authors simulated 10,000 sets of noisy data and compared the variance in density from the least squares solution with those from FBP. Density was estimated from FBP images using either averaging within a ROI, or streak-adaptive averaging with better noise performance. RESULTS: The bound on the possible dose reduction depends on the degree to which the observer can read through the possibly streaky noise. For the described low contrast detection task with the signal shape and background known exactly, the average dose reduction possible compared to FBP with streak-adaptive averaging was 42% and it was 64% if only the ROI average is used with FBP. The exact amount of dose reduction also depends on the background anatomy, with statistically inhomogeneous backgrounds showing greater benefits. CONCLUSIONS: The dose reductions from new, statistical reconstruction methods can be bounded. Larger dose reductions in the density estimation task studied here are only possible with the introduction of prior knowledge, which can introduce bias.

Initial multicenter technical experience with the Apollo device for minimally invasive intracerebral hematoma evacuation.

BACKGROUND: No conventional surgical intervention has been shown to improve outcomes for patients with spontaneous intracerebral hemorrhage (ICH) compared with medical management. OBJECTIVE: We report the initial multicenter experience with a novel technique for the minimally invasive evacuation of ICH using the Penumbra Apollo system (Penumbra Inc, Alameda, California). METHODS: Institutional databases were queried to perform a retrospective analysis of all patients who underwent ICH evacuation with the Apollo system from May 2014 to September 2014 at 4 centers (Medical University of South Carolina, Stony Brook University, University of California at San Diego, and Semmes-Murphy Clinic). Cases were performed either in the neurointerventional suite, operating room, or in a hybrid operating room/angiography suite. RESULTS: Twenty-nine patients (15 female; mean age, 62 ± 12.6 years) underwent the minimally invasive evacuation of ICH. Six of these parenchymal hemorrhages had an additional intraventricular hemorrhage component. The mean volume of ICH was 45.4 ± 30.8 mL, which decreased to 21.8 ± 23.6 mL after evacuation (mean, 54.1 ± 39.1% reduction; P < .001). Two complications directly attributed to the evacuation attempt were encountered (6.9%). The mortality rate was 13.8% (n = 4). CONCLUSION: Minimally invasive evacuation of ICH and intraventricular hemorrhage can be achieved with the Apollo system. Future work will be required to determine which subset of patients are most likely to benefit from this promising technology.

Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival.

PURPOSE: Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor-initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma. EXPERIMENTAL DESIGN: The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model. RESULTS: hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe. CONCLUSIONS: Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma.

Mesenchymal stem cells derived from adipose tissue vs bone marrow: in vitro comparison of their tropism towards gliomas.

INTRODUCTION: Glioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma. METHODS: Under an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures. RESULTS: Commercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines. CONCLUSIONS: Adipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting.

Harvey Cushing's early management of hydrocephalus: an historical picture of the conundrum of hydrocephalus until modern shunts after WWII.

PURPOSE: Throughout his early career, Cushing proposed a variety of methods for temporary and permanent drainage and diversion of CSF in his patients, and acknowledged that certain techniques were more suited to particular subsets of hydrocephalus. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records of the Johns Hopkins Hospital, from 1896 to 1912, were reviewed. Patients operated upon by Harvey Cushing were selected for further analysis. Within this cohort, we recovered all available records for a single patient with hydrocephalus and spina bifida, who was treated with a ventriculosubgaleal shunt prior to repair of the spina bifida. RESULTS: A 3 month-old infant presented with hydrocephalus associated with spina bifida. Cushing performed serial lumbar and ventricular punctures. Following this, Cushing took the patient to the operating room for placement of a ventriculosubgaleal shunt. The patient subsequently underwent excision of the myelomeningocele sac, with post-operative mortality due to unspecified causes. CONCLUSIONS: Cushing's publications document a preference for translumbar-peritoneal drainage in patients with congenital hydrocephalus, particularly those with spina bifida. Although the placement of ventriculosubgaleal shunts has become an accepted practice for contemporary neurosurgeons, this case illustrates the challenges that early neurosurgeons faced in developing operative approaches for the treatment of congenital hydrocephalus.

The potential origin of glioblastoma initiating cells.

Despite intensive clinical and laboratory research and effort, Glioblastoma remains the most common and invariably lethal primary cancer of the central nervous system. The identification of stem cell and lineage-restricted progenitor cell populations within the adult human brain in conjunction with the discovery of stem-like cells derived from gliomas which are themselves tumorigenic and have been shown to have properties of self-renewal and multipotency, has led to the hypothesis that this population of cells may represent glioma initiating cells. Extensive research characterizing the anatomic distribution and phenotype of neural stem cells in the adult brain, and the genetic underpinnings needed for malignant transformation may ultimately lead to the identification of the cellular origin for glioblastoma. Defining the cellular origin of this lethal disease may ultimately provide new therapeutic targets and modalities finally altering an otherwise bleak outcome for patients with glioblastoma.

Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives.

Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.

Early time points perfusion imaging: theoretical analysis of correction factors for relative cerebral blood flow estimation given local arterial input function.

If local arterial input function (AIF) could be identified, we present a theoretical approach to generate a correction factor based on local AIF for the estimation of relative cerebral blood flow (rCBF) under the framework of early time points perfusion imaging (ET). If C(t), the contrast agent bolus concentration signal time course, is used for rCBF estimation in ET, the correction factor for C(t) is the integral of its local AIF. The recipe to apply the correction factor is to divide C(t) by the integral of its local AIF to obtain the correct rCBF. By similar analysis, the correction factor for the maximum derivative (MD1) of C(t) is the maximum signal of AIF and the correction factor for the maximum second derivative (MD2) of C(t) is the maximum derivative of AIF. In the specific case of using normalized gamma-variate function as a model for AIF, the correction factor for C(t) (but not for MD1) at the time to reach the maximum derivative is relatively insensitive to the shape of the local AIF.

Early time points perfusion imaging.

The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.

Water- and fat-suppressed proton projection MRI (WASPI) of rat femur bone.

Investigators often study rats by microCT to investigate the pathogenesis and treatment of skeletal disorders in humans. However, microCT measurements provide information only on bone mineral content and not the solid matrix. CT scans are often carried out on cancellous bone, which contains a significant volume of marrow cells, stroma, water, and fat, and thus the apparent bone mineral density (BMD) does not reflect the mineral density within the matrix, where the mineral crystals are localized. Water- and fat-suppressed solid-state proton projection imaging (WASPI) was utilized in this study to image the solid matrix content (collagen, tightly bound water, and other immobile molecules) of rat femur specimens, and meet the challenges of small sample size and demanding submillimeter resolution. A method is introduced to recover the central region of k-space, which is always lost in the receiver dead time when free induction decays (FIDs) are acquired. With this approach, points near the k-space origin are sampled under a small number of radial projections at reduced gradient strength. The typical scan time for the current WASPI experiments was 2 hr. Proton solid-matrix images of rat femurs with 0.4-mm resolution and 12-mm field of view (FOV) were obtained. This method provides a noninvasive means of studying bone matrix in small animals.

Posttranscriptional regulation of neuronal nitric oxide synthase expression by IFN-gamma.

In this report, the mechanism through which interferon-gamma (IFN-gamma) regulates the expression of nitric oxide synthase (NOS-1) in neurons was examined. We have shown previously that IFN-gamma treatment of cells results in a two log inhibition of vesicular stomatitis virus (VSV) production. This inhibition of VSV replication is dependent both in vitro and in vivo on nitric oxide (NO) production by NOS-1. Furthermore, this effect is associated with the increased expression and activity of NOS-1 following IFN-gamma treatment. In vitro, exposure to IFN-gamma prior to infection with VSV is a prerequisite to establish an effective antiviral state, indicating the necessity for a priming event. Neuroblastoma cells (NB41A3) were treated with IFN-gamma or medium and examined for changes in NOS-1 protein and mRNA expression. NOS-1 protein expression was found to be increased after IFN-gamma treatment, and this was associated with increases in both neosynthesis and NOS-1 protein stability. NOS-1 transcription and mRNA levels were unaffected by IFN-gamma treatment. These data demonstrate that IFN-gamma regulates NOS-1 expression through posttranscriptional and posttranslational mechanisms.

Interferon-gamma-induced inhibition of neuronal vesicular stomatitis virus infection is STAT1 dependent.

In this report, the signaling pathways utilized by interferon (IFN)-gamma in neurons and their respective roles in the inhibition of vesicular stomatitis virus (VSV) replication were studied. The authors have previously shown that IFN-gamma treatment of NB41A3 neuroblastoma cells results in a 2-log inhibition of VSV production. This inhibition of VSV replication is dependent both in vitro and in vivo on nitric oxide (NO) production by NO synthase (NOS)-1. In NB41A3 neuroblastoma cells, IFN-gamma was found to induce the signal transducer and activator of transcription (STAT) STAT1 phosphorylation, interferon regulatory factor (IRF)-1 expression, and p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation; MAPK, however, was not required for inhibition of viral replication. Using olfactory bulb-enriched primary neuronal cultures, the inhibition of VSV replication was found to be STAT1 dependent, but did not require IRF-1.

Density of organic matrix of native mineralized bone measured by water- and fat-suppressed proton projection MRI.

Water- and fat-suppressed projection MR imaging (WASPI) utilizes the large difference between the proton T(2) (*)s of the solid organic matrix and the fluid constituents of bone to suppress the fluid signals while preserving solid matrix signals. The solid constituents include collagen and some molecularly immobile water and exhibit very short T(2) (*). The fluid constituents include mobile water and fat, with long T(2) (*). In WASPI, chemical shift selective low-power pi/2 pulses excite mobile water and fat magnetization which is subsequently dephased by gradient pulses, while the magnetization of collagen and immobile water remains mostly in the z-direction. Additional selective pi pulses in alternate scans further cancel the residual water and fat magnetization. Following water and fat suppression, the matrix signal is excited by a short hard pulse and the free induction decay acquired in the presence of a gradient in a 3D projection method. WASPI was implemented on a 4.7 T MR imaging system and tested on phantoms and bone specimens, enabling excellent visualization of bone matrix. The bone matrix signal per unit volume of bovine trabecular specimens was measured by this MR technique and compared with that determined by chemical analysis. This method could be used in combination with bone mineral density measurement by solid state (31)P projection MRI to determine the degree of bone mineralization.

PKR is not required for interferon-gamma inhibition of VSV replication in neurons.

In this report, the contribution of PKR to the IFN-gamma mediated inhibition of VSV replication in neurons was examined. IFN-gamma treatment of NB41A3 murine neuroblastoma cells resulted in the reduced expression of VSV protein during infection. PKR was found to be modestly upregulated in NB41A3 cells following IFN-gamma treatment. The phosphorylation state of PKR and its downstream target, eIF2alpha, were unaffected by either IFN-gamma or VSV infection. Inhibition of PKR through the use of 2-aminopurine or the expression of the Influenza A NS1 gene had no effect on the ability of IFN-gamma to inhibit the replication of VSV in vitro. These data indicate that endogenously expressed PKR is not required for the IFN-gamma mediated inhibition of VSV replication in NB41A3 neuroblastoma cells.

IL-12, while beneficial, is not essential for the host response to VSV encephalitis.

In this report, the role of STAT4 and local production of interleukin (IL)-12 in the central nervous system (CNS) were examined during experimental vesicular stomatitis virus (VSV) encephalitis. We have previously shown that IL-12 treatment is beneficial both in vitro and in vivo during experimental VSV infection. This inhibition of VSV replication was dependent on the production of nitric oxide (NO) by the neuronal isoform of nitric oxide synthase (NOS-1). In vitro, IL-12 induces the phosphorylation and nuclear localization of STAT4 in neuroblastoma cell lines. STAT4 expression was not required for host survival or clearance of virus during experimental VSV encephalitis. Taken together, these data suggest that while neurons can respond directly to IL-12 in vitro by signaling through STAT4, STAT4 is not required for survival. It is likely that redundant innate host inflammatory cytokine responses compensate for the absence of IL-12 signaling.

The role of IFN-gamma in immune responses to viral infections of the central nervous system.

Interferon (IFN)-gamma, is not only a marker of T(H)1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-gamma, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-gamma in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-gamma in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-gamma signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.