The utilization of sodium fluorescein in pediatric brain stem gliomas: a case report and review of the literature.

INTRODUCTION: A major challenge in the surgical resection of brainstem tumors is distinguishing tumor from normal tissue. One approach for addressing this problem is the use of fluorescent tracers such as sodium fluorescein (NaFl). NaFl disseminates through a disruption in the blood-brain barrier (BBB) and accumulates in the extracellular space of brain tumors. Intraoperative fluorescence microscopy can be performed to identify tumor tissue and avoid damage to adjacent, normal tissue. Here, we present the case of a 16-year-old male who underwent a left retrosigmoid craniotomy with splitting of the tentorium to remove a large exophytic brainstem tumor involving the cerebellar peduncle and with superior extension into the midbrain and thalamus. OBJECTIVES: The primary objective of this study was to investigate the effectiveness of sodium fluorescein as an intraoperative technique and evaluate its potential benefit for resection of tumors in eloquent regions in the pediatric population. To do so, we focused on a case study approach; however, we also performed a literature review and evaluated different intraoperative fluorescent techniques and their benefits for tumor resection. METHODS: We performed a literature search using PubMed and Google Scholar by the key words "sodium fluorescein," "brain stem tumor," and "central nervous system neoplasms." Twenty-nine articles including both pediatric and adult populations were selected for analysis and qualitative review. RESULTS: In this case study, sodium fluorescein helped the surgeons to identify and obtain a gross total resection of a large brainstem tumor. The marker was especially helpful for discerning the inferior pole of the tumor buried inconspicuously in cerebellar tissue. We evaluate different fluorescent tracers, 5-ALA and ICG, and discuss their application and benefits in tumor resection surgery. We present different cases that found sodium fluorescein to be helpful in achieving a gross total resection. CONCLUSION: The application of sodium fluorescein proved to be a safe and effective technique for the resection of brain stem tumors as shown in this case study. It helped to expose concealed areas and illuminate the tumor capsule. Further studies should test the clinical use of sodium fluorescein on brain stem tumor resection.

Treatment options and long-term outcomes in pediatric spinal cord vascular malformations: a case report and review of the literature.

A 16-month-old female was admitted for prolonged fever, gait ataxia, and neurogenic bowel and bladder. Neurological exam was significant for decreased sensory and motor functions in bilateral lower extremities. Initial MRI showed a thoracic spine hematoma and diagnostic angiogram revealed a large AVM and aneurysm. The patient underwent surgical resection of the hematoma and AVM, as well as clipping and later endovascular coiling of the aneurysm. Due to significant hemorrhage perioperatively, she developed spastic paraplegia improved by baclofen and onabotulinumtoxin A injections. The aims of this paper were to conduct a systematic review of the literature on pediatric spinal cord vascular malformations and analyze trends in treatment options and long-term neurological outcomes. PubMed searches were conducted using keywords "pediatric spinal vascular malformation" and "pediatric spinal AVM", yielding 34 results after abstract screening and cross-reference. Endovascular embolization was determined to have better long-term outcomes, with 10/19 (52.6%) patients with postoperative complications associated with open vascular surgeries. Open versus endovascular surgical decisions can be difficult with unique spinal AVM pathologies in pediatric patients. Important considerations such as size, location, neurological deficits, and risk of rupture are important factors to consider in treating these patients. We recommend endovascular treatment as a first-line approach due to lower risk of hemorrhage and postoperative deficits.

Enhancing the effects of chemotherapy by combined macrophage-mediated photothermal therapy (PTT) and photochemical internalization (PCI).

Light-based treatment modalities such as photothermal therapy (PTT) or photochemical internalization (PCI) have been well documented both experimentally and clinically to enhance the efficacy of chemotherapy. The main purpose of this study was to examine the cytotoxic effects of silica-gold nanoshell (AuNS)-loaded macrophage-mediated (MaNS) PTT and bleomycin BLM-PCI on monolayers of squamous cell carcinoma cells. The two modalities were applied separately and in simultaneous combination. Two different wavelengths of light were employed simultaneously, one to activate a highly efficient PCI photosensitizer, AlPcS2a (670 nm) and the other for the MaNS-mediated PTT (810 nm), to evaluate the combined effects of these modalities. The results clearly demonstrated that macrophages could ingest sufficient numbers of silica-gold nanoshells for efficient near infrared (NIR) activated PTT. A significant synergistic effect of simultaneously applied combined PTT and PCI, compared to each modality applied separately, was achieved. Light-driven therapies have the advantage of site specificity, non-invasive and non-toxic application, require inexpensive equipment and can be given as repetitive treatment protocols.

Nanoparticle-loaded macrophage-mediated photothermal therapy: potential for glioma treatment.

Gold-based nanoparticles have been used in a number of therapeutic and diagnostic applications. The purpose of this study was to investigate the efficacy of gold-silica nanoshells (AuNS) in photothermal therapy (PTT) of rat gliomas. Rat alveolar macrophages (Ma) were used as nanoparticle delivery vectors. Uptake of AuNS (bare and PEGylated) was investigated in Ma. AuNS were incubated with Ma for 24 h. Phase contrast microscopy was used to visualize the distribution of loaded Ma in three-dimensional glioma spheroids. PTT efficacy was evaluated for both empty (Ma) and AuNS-loaded Ma (Ma(NS)) in both monolayers and spheroids consisting of C6 rat glioma cells and Ma. Monolayers/spheroids were irradiated for 5 min with light from an 810-nm diode laser at irradiances ranging from 7 to 28 W cm(-2). Monolayer survival was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay while PTT efficacy in spheroids was determined from growth kinetics and live/dead fluorescence microscopy. PTT efficacy was investigated in vivo using a Sprague-Dawley rat glioma model. Five rats received direct intracranial injection of a mixture of 10(4) C6 glioma cells and, 2 days later, an equal number of Ma(NS). Three rats received laser treatment (810 nm; 10 min; 1 W) while the remaining two served as controls (no laser treatment). The uptake ratio of bare to PEGylated AuNS by Ma was 4:1. A significant photothermal effect was observed in vitro, albeit at relatively high radiant exposures (2.1-4.2 kJ cm(-2)). PTT proved effective in vivo in preventing or delaying tumor development in the PTT-treated animals.

Macrophages as a photosensitizer delivery system for photodynamic therapy: Potential for the local treatment of resected glioblastoma.

BACKGROUND: Photodynamic therapy (PDT) efficacy is determined in part by the concentration of photosensitizer (PS) at the treatment site. The blood-brain barrier (BBB) poses a significant limitation on the transport of PS into the post-operative resection region where brain tumors most often recur. Macrophages (Ma), as opposed to free or nanoparticle bound agents, are known to actively migrate to and around tumors, and can therefore be used as delivery vectors for both drugs and photosensitizers. METHODS: Mouse Ma (RAW264.7) and F98 rat glioma cells were used in all experiments along with the photosensitizer AlPcS2a. Mitomycin-treated Ma were loaded with photosensitizer (PS) and mixed with glioma cells, forming hybrid spheroids. F98 spheroids were incubated with supernatants derived from PS-loaded Ma (MaPS). Light treatment (PDT) was administered at various radiant exposures from a 670 nm diode laser. The growth of both types of spheroids was evaluated by measurement of spheroid volume after 14 days in culture. RESULTS: PDT on F98 cell spheroid cultures, mediated by either free or PS-released from Ma, demonstrated a significant growth inhibition with supernatants harvested after 4 and 24 h. A significant PDT-induced growth inhibition was demonstrated in the MaPS/F98 hybrid spheroid experiments. CONCLUSION: Since the efficacy of PDT, mediated by either free or released photosensitizer was comparable, the uptake and released photosensitizer was not degraded. MaPS, incorporated in hybrid tumor spheroids also mediated effective PDT. These results indicate that Ma have potential as an effective vector for photosensitizer delivery to resected brain tumors.

Complete Genome Sequences of Rhizobium leguminosarum bv. phaseoli BT01, Rhizobium sp. Strain BT03, and Rhizobium sp. Strain BT04, Isolated from Black Turtle Bean Nodules in Ontario, Canada.

We report the complete genome sequences of three Rhizobium strains isolated from nodules of heritage black turtle bean (Phaseolus vulgaris) plants grown in a community garden in Ontario, Canada. The genomes are between 6.91 Mb and 7.98 Mb long and consist of five to seven DNA replicons.

Gross Total Resection of a Ruptured Micro-arteriovenous Malformation within the Cerebellar Peduncle: A Case Report and Qualitative Review of the Literature.

Deep-seated micro-arteriovenous malformations (micro-AVMs) may pose a challenge for complete yet safe resection. We propose the strategic placement of two to three microaneurysm clips throughout the hemorrhage cavity to successfully localize the micro-AVM nidus via digital subtraction angiography (DSA). We successfully demonstrate this novel method in a 15-year-old adolescent boy with cerebellar intraparenchymal hemorrhage who underwent hematoma evacuation and expansile duraplasty. He was found to have a 1-cm nidus of a micro-AVM with early venous drainage located in the right middle cerebellar peduncle. Five days later, we proceeded to resect the micro-AVM; however, a clear nidus or bleeding source was unable to be localized intraoperatively despite the use of stereotactic neuronavigation. In turn, we placed two mini-aneurysm clips superiorly and inferiorly within the hematoma cavity, which led to successful localization via DSA and complete resection. No surgical complications occurred. The patient completely recovered from right-sided weakness and dysarthria 6 to 12 months postoperatively. Our technique allows for the rapid localization and complete resection of micro-AVM nidi when stereotactic neuronavigation is inadequate.

Inhibition of glioma development by doxorubicin-photochemical internalization generated macrophage vaccine: A survival study in rats.

BACKGROUND: The process known as immunogenic cell death (ICD) is characterized by dead and dying cancer cells exposing and releasing so-called damage associated molecular patterns (DAMPs). ICD has been shown to enhance the efficacy of antigen presenting cell (APC) immunotherapy. Both anthracycline drugs such as doxorubicin (DOX), and photodynamic therapy (PDT) have been shown to be inducers of ICD. It was therefore hypothesized that combined PDT and DOX i.e. photochemical internalization of DOX (DOX-PCI) would increase ICD compared to DOX acting as a single agent. MATERIALS AND METHODS: F98 glioma cells were treated with DOX-PCI in vitro and the ICD markers HMGB1, HSP70, and HSP90 were determined by ELISA assay. Peritoneal macrophages (Ma), obtained from Fisher rats acting as APCs, were co-incubated with dead F98 glioma cells killed via DOX or DOX-PCI treatment ex vivo. The pulsed Ma (Ma DOX or Ma DOX-PCI) were used to inoculate the animals either before (preventive) or after (curative) intra-cranially implantation of the glioma cells. RESULTS: F98 cells, treated with DOX-PCI in vitro, induced a significantly higher level of HGMB1, HSP70, and HSP90 than DOX acting alone. Ma DOX-PCI inoculated animals, in both preventive and curative protocols, had a pronounced survival benefit compared to either the non-treatment or MaDOX control groups. In the curative protocol, a second booster inoculation significantly improved survival, with 60% of the animals alive at day 60. CONCLUSION: Macrophages primed with DOX-PCI treated glioma cells appeared to be highly effective as APCs and, when injected into host animals, could delay and, in some cases, prevent tumor development.

Maintaining a heart-healthy diet most of the time.

Changing dietary behavior is inherently difficult and even more so given the current obesity-promoting environment. Health professionals may facilitate this process for patients by assessing readiness to change, identifying personal priorities and barriers, and providing personalized knowledge, while increasing healthy-eating skills, motivation, and self-efficacy. It is also important to address the obesity-promoting environment through pubic policy as well as individual dietary change. Implementation of the American Heart Association diet and lifestyle recommendations is discussed along with barriers and recent assessment data. Patients may require assistance with interpretation of recommendations to their specific situations and practical application strategies considering their barriers and needs. One concept that may be helpful is a discussion that dietary change is not an end point but a process. Introducing patients to the 90-10 rule applied to food choices may help them conceptualize this process more easily. This idea revolves around the principle that what an individual does 90% of the time is most critical, and allowing some flexibility can make changing any lifestyle behavior more palatable and achievable.

Relationship between body image and body mass index in college men.

OBJECTIVE AND PARTICIPANTS: The authors examined cognitive and affective dimensions of body image of a randomized sample of 188 college men on the basis of body mass index (BMI). METHODS: They conducted chi-square tests and ANOVAs to determine differences between 4 BMI groups (underweight, normal weight, overweight, and obese) on demographics and body image measures. RESULTS: The authors found significant differences in regard to total body image (p < .001), weight or shape concern (p < .001), and body dissatisfaction (p < .001). BMI was significantly correlated with negative body image. Overweight and obese participants reported significantly higher levels of negative body image than did normal- and underweight participants. Overweight participants reported significantly higher weight and shape concerns than did underweight, normal-weight, and obese participants. In regard to body dissatisfaction, underweight, overweight, and obese participants reported significantly higher levels of body dissatisfaction than that reported by normal-weight participants. CONCLUSIONS: BMI may be an important factor in identifying potential body image disorders in college-aged men.

Vasospasm in the setting of traumatic bilateral carotid-cavernous fistulas and its effect on treatment.

BACKGROUND: Direct, Type A, cavernous-carotid fistulas (CCFs) are predominantly caused by head trauma, especially when basilar skull fractures are present. Transarterial endovascular treatment of direct CCFs is the preferred method of treatment. Bilateral CCFs are estimated to be present in 1-2% of the cases. The treatment of bilateral CCFs is difficult often requiring a combination of endovascular and open surgical approaches. CASE DESCRIPTION: We present a case of traumatic bilateral CCFs presenting with vasospasm of the anterior circulation seen on the initial angiogram on day 1 and our treatment paradigm. CONCLUSION: This case illustrates the challenges in managing bilateral CCFs as well as the changes in collateral circulation because of cerebral vasospasm which affected our treatment paradigm.

Limiting glioma development by photodynamic therapy-generated macrophage vaccine and allo-stimulation: an in vivo histological study in rats.

Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage (MaF98) vaccines can be increased by: (1) photodynamic therapy (PDT) of the priming tumor cells and (2) intracranial injection of allogeneic glioma cells directly into the tumor site. Experiments were conducted in an in vivo brain tumor development model using Fischer rats and F98 (syngeneic) and BT4C (allogeneic) glioma cells. The results showed that immunization with Ma (acting as antigen-presenting cells), primed with PDT-treated tumor cells (MaF98), significantly slowed but did not prevent the growth of F98-induced tumors in the brain. Complete suppression of tumor development was obtained via MaF98 inoculation combined with direct intracranial injection of allogeneic glioma cells. No deleterious effects were noted in any of the animals during the 14-day observation period.

Photochemical internalization enhanced macrophage delivered chemotherapy.

BACKGROUND: Macrophage (Ma) vectorization of chemotherapeutic drugs has the advantage for cancer therapy in that it can actively target and maintain an elevated concentration of drugs at the tumor site, preventing their spread into healthy tissue. A potential drawback is the inability to deliver a sufficient number of drug-loaded Ma into the tumor, thus limiting the amount of active drug delivered. This study examined the ability of photochemical internalization (PCI) to enhance the efficacy of released drug by Ma transport. METHODS: Tumor spheroids consisting of either F98 rat glioma cells or F98 cells combined with a subpopulation of empty or doxorubicin (DOX)-loaded mouse Ma (RAW264.7) were used as in vitro tumor models. PCI was performed with the photosensitizer AlPcS2a and laser irradiation at 670 nm. RESULTS: RAW264.7 Ma pulsed with DOX released the majority of the incorporated DOX within two hours of incubation. PCI significantly increased the toxicity of DOX either as pure drug or derived from monolayers of DOX-loaded Ma. Significant growth inhibition of hybrid spheroids was also observed with PCI even at subpopulations of DOX-loaded Ma as low as 11% of the total initial hybrid spheroid cell number. CONCLUSION: Results show that RAW264.7 Ma, pulsed with DOX, could effectively incorporate and release DOX. PCI significantly increased the ability of both free and Ma-released DOX to inhibit the growth of tumor spheroids in vitro. The growth of F98 + DOX loaded Ma hybrid spheroids were synergistically reduced by PCI, compared to either photodynamic therapy or released DOX acting alone.

Transdisciplinary assignments in graduate health education as a model for future collaboration.

Transdisciplinary health care continues to be at the forefront of patient treatment in the medical arena, in part due to escalating health care costs, an increasing aging population, and the development of multiple chronic diseases. Gaining the knowledge, experience, and principles associated with transdisciplinary teamwork to successfully prepare for modern-day practice is therefore essential for individuals of various health care professions. This report describes an assignment developed and implemented to facilitate professional interaction between graduate physical therapy, nutrition, and nursing students. The objectives of this assignment were to determine through student evaluation the effects of a transdisciplinary experience on students' understanding of the role of another discipline and students' communication skills across disciplines. When evaluating the assignment, students most often remarked that they developed a greater understanding of the roles of the included disciplines and reported a significant increase in communication skills. However, some students did not concur that this assignment was effective due to the scheduling conflicts and lack of teamwork that can occur during a collaborative project. The students' reports of their experiences in completing the assignment provide valuable insights for implementing and/or updating a preparatory transdisciplinary education component in other settings. Additional research can focus on the challenges faced by the majority of the students venturing into actual health care or "real-world" settings for comparative studies.

Photothermal Therapy Employing Gold Nanoparticle- Loaded Macrophages as Delivery Vehicles: Comparing the Efficiency of Nanoshells Versus Nanorods.

Macrophages (Ma) loaded with gold based nanoparticles, which convert near infrared light to heat, have been studied as targeted transport vectors for photothermal therapy (PTT) of tumors. The purpose of the experiments reported here was to compare the efficacy of gold-silica nanoshells (AuNS) and gold nanorods (AuNR) in macrophage mediated PTT. PTT efficacy was evaluated in hybrid glioma spheroids consisting of human glioma cells and either AuNS or AuNR loaded Ma, designated MaNS and MaNR respectivly. Spheroids were irradiated for 10 min. with light from an 810 nm diode laser at irradiances ranging from 0 to 28 W/cm2. PTT efficacy was determined from spheroid growth over a 14-day period. The uptake by Ma of pegylated AuNR (3.9 ± 0.9 %) was twice that of pegylated AuNS, (7.9 ± 0.7 %). Hybrid spheroids consisting of a 5:1 ratio of glioma cells to loaded Ma exhibited significant growth inhibition with MaNS when subjected to irradiances of 7 W/cm2 or greater. In contrast, no significant growth inhibition was observed for the MaNR hybrid spheroids at this 5:1 ratio, even at the highest irradiance investigated (28 W/cm2). Although AuNR were taken up by Ma in larger numbers then AuNS, MaNS were shown to have greater PTT efficacy compared to MaNR for equivalent numbers of loaded Ma.

Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy.

INTRODUCTION: Gene-directed enzyme prodrug therapy (GDEPT) employing the cytosine deaminase (CD) gene, which encodes an enzyme that converts the nontoxic agent 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU), has shown promise both in experimental animals and in clinical trials. Nevertheless, with the transfection systems available presently the percentage of tumor cells incorporating the desired gene is usually too low for successful therapy. We have examined the ability of photodynamic therapy (PDT) to enhance the efficacy of the metabolites, converted from 5-FC by CD gene transfected rat glioma cells. METHODS: Hybrid tumor cell spheroids consisting of CD poitive and CD negative F98 glioma cells in varying ratios were used as in vitro tumor models. PDT was performed with the photosensitizer AlPcS2a and λ=670nm laser irradiance, both before and after confrontation with 5-FC. RESULTS: PDT increased the toxicity of 5-FU either as pure drug or derived from monolayers of CD positive cells chalanged with 5-FC. PDT in combination with 5-FC resulted in a significantly enhanced inhibition of hybrid spheroid growth compared to non light treated controls. This was the case even at tumor to producer cell ratios as high as 40:1. CONCLUSION: The results of the present study show that GDEPT and PDT interact in a synergistic manner over a range of prodrug concentration and tumor to transfected cell ratios. The degree of synergy was significant regardless if PDT treatment was given before or after 5-FC administration. The highest degree of interaction was observed though, when PDT was delivered prior to prodrug exposure.

Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization.

Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm(-2) using an irradiance of 5 mW cm(-2). Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C.

Macrophages as nanoparticle delivery vectors for photothermal therapy of brain tumors.

Certain types of stem and immune cells, which have an innate ability to target and infiltrate tumors, can be utilized as vectors to deliver several types of anticancer agents. In particular monocytes have the advantage of carrying relatively large payloads of therapeutic nanomaterials, can be patient derived in large numbers and are able to actively infiltrate tumors despite many barriers often present in the microenvironment. Monocytes can selectively cross the compromised blood-brain barrier surrounding brain tumors and are known to actively migrate to hypoxic tumor regions. Of particular interest is the observation that, following near-infrared exposure of tumors containing gold-nanoshell-loaded macrophages, sufficient hyperthermia can be generated to suppress tumor growth. Collectively, these findings demonstrate the potential of monocytes as nanoparticle delivery vectors for several types of site specific light-based cancer therapies.