Malignant mixed mullerian tumors: a SEER database review of rurality and treatment modalities on disease outcome.

Introduction: Malignant Mixed Mullerian Tumors (MMMT) are rare and poorly understood sarcomas with limited research on risk factors, pathogenesis, and optimal treatments. This study aimed to address this knowledge gap and explore the impact of community size, patient characteristics, disease characteristics, and treatment modalities on MMMT outcomes. Methods: Using the Surveillance, Epidemiology, and End Results database (SEER), the largest SEER cohort to date of 3,352 MMMT patients was analyzed for demographic factors, treatment modalities, and histologic characteristics. Data was processed, including the removal of incomplete entries, and analyzed in Python 3.1 using packages scikit-learn, lifelines, and torch; log-rank analysis and Cox proportional hazards models were used to evaluate a number of demographic characteristics and disease characteristics for significance in regard to survival. Results: Our study found adjuvant radiotherapy and chemotherapy significantly improved survival, with modest benefits from neoadjuvant chemotherapy. Our findings also suggest age at diagnosis, disease grade, and suburban versus rural geographic locations may play key roles in patient prognosis. On multivariable analysis both disease Grade and surgical treatment were significant factors. Discussion: MMMTs remain challenging, but appropriate treatment appears to enhance survival. The present findings suggest opportunities for improved outcomes and treatment strategies for patients with MMMTs.

First application of GammaTile cesium-131 brachytherapy with maximal safe resection of a glioma in a patient with limited scleroderma.

The purpose of this report is to present the first documented application of GammaTile to an intra-cranial tumor of a patient with a symptomatic radiosensitive connective tissue disorder, a case where there were significant concerns with standard oncologic strategies. We hypothesized that GammaTile® (GT Medical Technologies, Tempe, Arizona, USA) would also be advantageous in the application of intra-cranial tumors in patients with conditions of increased radiosensitivity. We generated a standard external beam radiation therapy (EBRT) plan consisting of an overall 1.5 cm expansion to 59.4 Gy in 1.8 Gy fractions. Also, we developed a CyberKnife (Accuray, Sunnyvale, CA, USA) plan with a 5 mm expansion on the surgical cavity prescribed to 60 Gy in 30 fractions, to make an EBRT comparison using the same prescription volume as GammaTile. We report the first published application of GammaTile® brachytherapy to an intra-cranial malignancy in a patient with limited scleroderma. The dose delivered by GammaTile was compared to the dose that would be delivered with both typical volumes and small volumes of EBRT. The maximum dose delivered to the scar and scalp by GammaTile was reduced to half of that from other external beam techniques (~25 Gy vs. ~55 Gy). MRI imaging at 6 months and 12 months post-resection demonstrated no evidence of disease recurrence nor radiation necrosis. At the 12-month follow-up visit, the surgical scar was well-healed with no skin changes to the surrounding scalp. Dosimetrically and clinically, this report highlights the successful application of GammaTile to an intra-cranial tumor bed in a patient with scleroderma.

Novel combination of GammaTile cesium-131 brachytherapy with 5-aminolevulinic acid fluorescence-guided resection in the re-irradiation of pediatric recurrent high-grade glioma: illustrative case.

BACKGROUND: Herein, the authors describe the successful utilization of 5-aminolevulinic acid (5-ALA) and the first case of GammaTile cesium-131 therapy in a pediatric patient with recurrent high-grade glioma. 5-ALA was utilized to optimize gross-total resection prior to GammaTile implantation. After conversion to an equivalent dose in 2-Gy fractions (EQD2), a composite was made of the GammaTile dose with the initial external beam radiotherapy. Two hypothetical plans consisting of a standard hypofractionated strategy for glioma reirradiation and a CyberKnife plan using GammaTile's planning target volume were developed and likewise underwent EQD2 conversion and composite plan generation with the initial radiotherapy. OBSERVATIONS: 5-ALA was useful in achieving gross-total resection with no acute toxicity from the surgery or GammaTile irradiation. When compared with the hypothetical composite doses, GammaTile's composite, axium point dose (D0.03cc) to the brainstem was 32.9 Gy less than the hypofractionated and the CyberKnife composite plans at 38.7 Gy and 40.2 Gy, respectively. The right hippocampus demonstrated a substantially reduced composite plan dose with GammaTile with a D0.03cc of 62.4 Gy versus 71.7 and 80.7 Gy for the hypofractionated and CyberKnife composite plans, respectively. LESSONS: Utilization of 5-ALA and GammaTile therapy yielded clinically superior tumor debulking and effective radiotherapy dose localization with sparing of organs at risk, respectively.

Does point-of-care ultrasonography improve diagnostic accuracy in emergency department patients with undifferentiated hypotension? An international randomized controlled trial from the SHOC-ED investigators.

PURPOSE: Point-of-care ultrasonography (POCUS) is an established tool in the management of hypotensive patients in the emergency department (ED). We compared the diagnostic accuracy of a POCUS protocol versus standard assessment without POCUS in patients with undifferentiated hypotension. METHODS: This was an international, multicenter randomized controlled trial included three EDs in North America and three in South Africa from September 2012 to December 2016. Hypotensive patients were randomized to early POCUS protocol plus standard care (POCUS group) or standard care without POCUS (control group). Initial and secondary diagnoses were recorded at 0 and 60 min. The main outcome was measures of diagnostic accuracy of a POCUS protocol in differentiating between cardiogenic and non-cardiogenic shock. Secondary outcomes were diagnostic performance for shock sub-types, as well as changes in perceived category of shock and overall diagnosis. RESULTS: Follow-up was completed for 270 of 273 patients. For cardiogenic shock, the POCUS-based diagnostic approach (POCUS) performed similarly to the non-POCUS approach (control) for specificity [95.5% (89.9-98.5) vs.93.8% (87.7-97.5)]; positive likelihood ratio (17.92 vs 14.80); negative likelihood ratio (0.21 vs 0.09) and diagnostic odds ratio (85.6 vs 166.57), with a similar overall diagnostic accuracy between the two approaches [93.7% (88-97.2) vs 93.6% (87.8-97.2)]. Diagnostic performance measures were similar across sub-categories of shock. CONCLUSION: This is the first randomized controlled trial to compare diagnostic performance of a POCUS protocol to standard care without POCUS in undifferentiated hypotensive ED patients. POCUS performed well diagnostically in undifferentiated hypotensive patients, especially as a rule-in test; however, performance did not differ meaningfully from standard assessment.

RéSUMé: OBJECTIF: L'échographie au point d'intervention (POCUS) est un outil bien établi dans la gestion des patients hypotendus dans le service des urgences. Nous avons comparé la précision diagnostique d'un protocole POCUS par rapport à une évaluation standard sans POCUS chez des patients présentant une hypotension indifférenciée. MéTHODES: Il s'agissait d'un essai contrôlé randomisé international multicentrique incluant 3 services d'urgence en Amérique du Nord et 3 en Afrique du Sud de septembre 2012 à décembre 2016. Les patients hypotenseurs ont été répartis par randomisation selon le protocole POCUS précoce plus les soins standard (groupe POCUS) ou les soins standard sans POCUS (groupe témoin). Les diagnostics initiaux et secondaires ont été enregistrés à 0 et 60 minutes. Le principal résultat était la mesure de la précision diagnostique d'un protocole POCUS pour différencier le choc cardiogénique du choc non cardiogénique. Les résultats secondaires étaient la performance diagnostique pour les sous-types de chocs, ainsi que les changements dans la perception de la catégorie de choc et du diagnostic global. RéSULTATS: Le suivi a été complété pour 270 des 273 patients. Pour le choc cardiogénique, l'approche diagnostique basée sur le POCUS (POCUS) a donné des résultats similaires à l'approche non-POCUS (Contrôle) pour la spécificité (95,5 % (89,9­98,5) vs 93,8 % (87,7­97,5)) ; Rapport de vraisemblance positif (17,92 vs 14,80) ; Le rapport de vraisemblance négatif (0,21 vs 0,09) et le rapport de cotes diagnostiques (85,6 vs 166,57), avec une précision diagnostique globale similaire entre les deux approches (93,7 % (88­97,2) vs 93,6 % (87,8­97,2). Les mesures de performance diagnostique étaient similaires dans toutes les sous-catégories de choc. CONCLUSION: Il s'agit du premier essai contrôlé randomisé visant à comparer la performance diagnostique d'un protocole POCUS aux soins standard sans POCUS chez des patients hypotendus indifférenciés aux urgences. La POCUS a donné de bons résultats diagnostiques chez les patients hypotendus indifférenciés, surtout en tant que test de référence ; cependant, les performances ne diffèrent pas de manière significative de l'évaluation standard.

Survival Is Worse in Patients Completing Immunotherapy Prior to SBRT/SRS Compared to Those Receiving It Concurrently or After.

Purpose/Objectives: The abscopal effect could theoretically be potentiated when combined with immunomodulating drugs through increased antigen production. The optimal dosing and schedule of radiotherapy with immunotherapy are unknown, although they are actively investigated in laboratory and clinical models. Clinical data in patients treated for metastatic disease with both modalities may guide future studies. Materials and Methods: This is a single-institution retrospective review of all patients treated with stereotactic body radiotherapy (SBRT)/stereotactic radiosurgery (SRS) and immunomodulating therapy within 6 months before or after SBRT/SRS for metastatic cancer. Clinical and tumor characteristics were recorded, as well as SBRT/SRS details, immunotherapy details, and survival. Log-rank tests on Kaplan-Meier curves for overall survival (OS) that were calculated from the end of SBRT/SRS were used in univariate analysis and Cox proportional hazards regression for multivariate analysis. Results: A total of 125 patients were identified who met the inclusion criteria; 70 received SBRT, and 57 received SRS. Eighty-three patients were treated for non-small cell lung cancer, 7 patients for small cell lung cancer, and 35 patients for other cancers, with the most common one being melanoma. Fifty-three percent of patients received nivolumab, 29% pembrolizumab, 13% atezolizumab, 5% other. Twenty percent received immunotherapy before SBRT/SRS, 39% during SBRT/SRS, 41% after. Eighty-six patients had died by the time of the analysis; the median OS for the whole cohort was 9.7 months. Patients who had completed immunotherapy prior to SBRT/SRS had worse OS than those who received concurrent therapy or immunotherapy after SBRT/SRS, with a difference in median OS of 3.6 months vs. 13.0 months (p = 0.010) that was retained on multivariate analysis (p = 0.011). There was no significant difference in OS between patients receiving SRS vs. SBRT (p = 0.20), sex (p = 0.53), age >62 years (p = 0.76), or lung primary vs. others (p = 0.73) on univariate or multivariate analysis. When comparing before/concurrent to after/concurrent administration, there is a difference in survival with after/concurrent survival of 8.181 months and before survival of 13.010 months, but this was not significant (p = 0.25). Conclusions: OS appears to be worse in patients who complete immunotherapy prior to SBRT/SRS compared to those receiving it concurrently or after. The design of this retrospective review may be prone to lead time bias, although the difference in median survival is longer than the 6-month window before SBRT/SRS and could only account for part of this difference. Further analysis into causes of death and toxicity and prospective studies are needed to confirm the results of this analysis.

Towards a multi-scale computer modeling workflow for simulation of pulmonary ventilation in advanced COVID-19.

Physics-based multi-scale in silico models offer an excellent opportunity to study the effects of heterogeneous tissue damage on airflow and pressure distributions in COVID-19-afflicted lungs. The main objective of this study is to develop a computational modeling workflow, coupling airflow and tissue mechanics as the first step towards a virtual hypothesis-testing platform for studying injury mechanics of COVID-19-afflicted lungs. We developed a CT-based modeling approach to simulate the regional changes in lung dynamics associated with heterogeneous subject-specific COVID-19-induced damage patterns in the parenchyma. Furthermore, we investigated the effect of various levels of inflammation in a meso-scale acinar mechanics model on global lung dynamics. Our simulation results showed that as the severity of damage in the patient's right lower, left lower, and to some extent in the right upper lobe increased, ventilation was redistributed to the least injured right middle and left upper lobes. Furthermore, our multi-scale model reasonably simulated a decrease in overall tidal volume as the level of tissue injury and surfactant loss in the meso-scale acinar mechanics model was increased. This study presents a major step towards multi-scale computational modeling workflows capable of simulating the effect of subject-specific heterogenous COVID-19-induced lung damage on ventilation dynamics.

Large effects of brief meditation intervention on EEG spectra in meditation novices.

This study investigated the impact of a brief meditation workshop on a sample of 223 novice meditators. Participants attended a three-day workshop comprising daily guided seated meditation sessions using music without vocals that focused on various emotional states and intentions (open focus). Based on the theory of integrative consciousness, it was hypothesized that altered states of consciousness would be experienced by participants during the meditation intervention as assessed using electroencephalogram (EEG). Brainwave power bands patterns were measured throughout the meditation training workshop, producing a total of 5616 EEG scans. Changes in conscious states were analysed using pre-meditation and post-meditation session measures of delta through to gamma oscillations. Results suggested the meditation intervention had large varying effects on EEG spectra (up to 50 % increase and 24 % decrease), and the speed of change from pre-meditation to post-meditation state of the EEG co-spectra was significant (with 0.76 probability of entering end-meditation state within the first minute). There was a main 5 % decrease in delta power (95 % HDI = [-0.07, -0.03]); a global increase in theta power of 29 % (95 % HDI = [0.27, 0.33]); a global increase of 16 % (95 % HDI = [0.13, 0.19]) in alpha power; a main effect of condition, with global beta power increasing by 17 % (95 % HDI = [0.15, 0.19]); and an 11 % increase (95 % HDI = [0.08, 0.14]) in gamma power from pre-meditation to end-meditation. Findings provided preliminary support for brief meditation in altering states of consciousness in novice meditators. Future clinical examination of meditation was recommended as an intervention for mental health conditions particularly associated with hippocampal impairments.

Spatial shifts in frame-based Gamma Knife radiosurgery: A case for cone beam CT imaging as quality assurance using the Gamma Knife® Icon™.

BACKGROUND: Cone beam CT (CBCT) imaging has been integrated into the most recent version of the Leksell Gamma Knife for the primary purpose to facilitate fractionated therapy. CASE DESCRIPTION: This case study presents three patients where the CBCT system of the Gamma Knife Icon discovered potentially clinically significant frame shifts. In each case, patients were imaged with volumetric MR prior to stereotactic frame placement. Immediately following frame placement, diagnostic stereotactic CT imaging was acquired with a stereotactic indicator box attached to the frame. Following treatment planning and immediately before radiosurgery, a CBCT was acquired using the on-board imaging functionality of the Gamma Knife Icon, which provides a registration of the patient's anatomy to stereotactic space independent of that provided by the stereotactic frame/fiducials. Co-registration of the CT and CBCT provides an estimate of the difference between these two estimates of stereotactic coordinates. The vector magnitudes of the differences measured at the center of stereotactic space were 0.93mm, 2.64mm and 2.18 mm for Case 1, Case 2 and Case 3 respectively. CONCLUSIONS: Use of the CBCT functionality of the Gamma Knife Icon to verify the consistency of frame placement can prevent clinically significant targeting errors due to frame slippage or frame adapter mounting errors, and allows any required adjustments to be made without interrupting the overall treatment workflow.

Stereotactic Shifts During Frame-Based Image-Guided Stereotactic Radiosurgery: Clinical Measurements.

PURPOSE: To determine the magnitude and reason for discrepancies between frame- and cone beam computed tomography (CBCT)-determined stereotactic coordinates, we reviewed frame-based Gamma Knife radiosurgery procedures in which CBCT was performed before treatment. METHODS AND MATERIALS: Clinical and treatment documentation was reviewed for 150 frame placements for which stereotactic coordinates were defined via both frame and fiducials on computed tomography imaging and CBCT. Treatment planning system-reported rotational and translational differences and standard deviations (SDs) between frame-based and CBCT-based stereotactic coordinates were recorded. Potential clinical predictors for increased differences were collected. Multiple linear regressions were performed to evaluate for associations with increased translations and rotations. RESULTS: The absolute mean of the measured pitch, yaw, and roll shifts was 0.14 degrees (range -0.71-0.63 degrees, SD 0.19 degrees), 0.16 degrees (range -0.50 to 0.83 degrees, SD 0.21 degrees), and 0.12 degrees (range 0.37-0.51 degrees, SD 0.15 degrees), respectively. The absolute mean of the measured shifts in the left-right, anteroposterior, and superior-inferior direction was 0.29 mm (range -1.29 to 0.82 mm, SD 0.35 mm), 0.24 mm (range -0.59 to 0.33 mm, SD 0.19 mm), and 0.24 mm (range -0.69 to 0.91 mm, SD 0.27 mm), respectively. Three cases (2.0%) exceeded 1 mm in translational difference, all in the left-right direction (1.05, 1.13, and 1.29 mm). Lower Karnofsky Performance Scale status was associated with greater translational differences (vector magnitude, P = .023) and rotation (pitch, P = .044; yaw, P = .002). Usage of longer total pin length (sum of all 4 fixation pin lengths) was associated with increased rotation but not with translation (P < .001 and P = .56, respectively). CONCLUSIONS: CBCT imaging in this cohort of frame-based cases suggests that the discrepancy in stereotactic coordinates is less than 1 mm or degree in most cases. Low Karnofsky Performance Scale status and longer total pin length correlate with larger differences between frame-defined and CBCT-defined stereotactic coordinates.

Patient-reported outcomes in head and neck cancer: prospective multi-institutional patient-reported toxicity.

PURPOSE: Head and neck cancer is occurring in an increasingly younger patient population, with treatment toxicity that can cause significant morbidity. Using a patient guided, Internet-based survivorship care plan program, we obtained and looked at patterns of patient-reported outcomes data from survivors seeking information after treatment for head and neck cancer. METHODS: The Internet-based OncoLife and LIVESTRONG Care Plan programs were employed, which design unique survivorship care plans based on patient-reported data. Care plans created for survivors of head and neck cancer were used in this evaluation. Demographics, treatment modality, and toxicity were included in this evaluation. Toxicity was further analyzed, grouped into system-based subsets. RESULTS: A total of 602 care plans were created from self-identified head and neck cancer survivors, from which patient-reported outcome data were attained. A majority of patients were Caucasian (96.2%) with median age at diagnosis of 55 years, living in suburban locations (39.9%), with ~50% receiving care within 20 miles of their residence. There was an equal distribution of education levels from high school only to graduate school. The majority of patients received care through cancer centers (96.7%), with a split between academic and non-academic centers. Ninety-three percent of patients had radiation therapy as part of their treatment modality, with 70.3% having chemotherapy and 60.1% having surgery. The most common system toxicities affected the oropharynx, followed by epithelium (skin/hair/nail), and then general global health. Specifically, the most common side effects were difficulty swallowing (61.5%) and changes in skin color/texture (49.7%). One third of patients experienced hearing/tinnitus/vertigo, xerostomia, loss of tissue flexibility, or fatigue. CONCLUSION: The current work demonstrates the ability to obtain patient-reported outcomes of head and neck cancer survivors through an Internet-based survivorship care plan program. For this group dysphagia and dermatitis were the most commonly reported toxicities, as was expected; however, global effects of therapy, such as fatigue, were also significant and should be addressed in future survivorship planning.

Endometrial cancer in an increasingly obese population: Exploring alternative options when surgery may not cut it.

OBJECTIVES: The study objectives were to describe outcomes of obese patients with early endometrial cancer following primary non-surgical treatment, assess predictors of response, and estimate the increased surgical risk for these women. METHODS: Retrospective chart review identified women with early stage endometrial cancer at a single institution with BMI ≥ 30 kg/m2 who did not undergo surgery as primary treatment modality due to obesity and medical co-morbidities. Clinicopathologic factors were abstracted, characteristics of responders vs. non-responders compared and the National Surgical Quality Improvement Program (NSQIP) surgical risk calculator utilized to quantify surgical risks. RESULTS: Fifty-one patients were identified, with a mean BMI of 49.0 kg/m2. The NSQIP calculator predicted a significantly higher complication rate for our cohort compared to the expected average risk for hysterectomy (18.8% vs 7.2%, p < .0001). The majority of patients were treated with radiation alone (49%), followed by hormone therapy (45.1%). Response rates were 38.1% for women treated with hormones and 63.6% in the radiation group (p = .063). No significant differences were identified between responders and non-responders with regard to NSQIP scores, BMI, co-morbidities or age. Among those with persistent or progressive disease, 87.5% responded to secondary treatment. Only one death was from cancer progression. Two individuals died following treatment complications (one surgical, one chemotherapy); the remaining twelve deaths were due to pre-existing co-morbidities. CONCLUSIONS: Hormone and radiation therapy are both viable options for obese patients deemed to have too significant risk of surgical complications. Pursuing surgical intervention in this population may do more harm than good.

High dose-rate tandem and ovoid brachytherapy in cervical cancer: dosimetric predictors of adverse events.

BACKGROUND: Brachytherapy (BT) is a vital component of the curative treatment of locally advanced cervical cancer. The American Brachytherapy Society has published guidelines for high dose rate (HDR) BT with recommended dose limits. However, recent reports suggest lower doses may be needed to avoid toxicity. The purpose of this study is to investigate incidence and predictive factors influencing gastrointestinal (GI) and genitourinary (GU) toxicity following HDR intracavitary brachytherapy for locally advanced cervical cancer. METHODS: We retrospectively evaluated a cohort of patients with locally advanced cervical cancer who received CT-based HDR BT. Cumulative doses were calculated using the linear-quadratic model. Statistical analyses were used to investigate clinical and dosimetric predictors of GI and GU toxicity following HDR brachytherapy according to CTCAE v4.0 grading criteria. RESULTS: Fifty-six women with FIGO IB1 - IVA cervical cancer were included. The overall rate of any GU adverse event (Grade 1+) was 23.3% (n = 13) and severe adverse events (Grade 3+) was 7.1% (n = 4). Of those, the bladder equivalent dose in 2- Gray (Gy) fractions (EQD2) D2cc was ≥80 for three of the four patients. The overall rate of any GI adverse event was 26.8% (n = 15) and the rate of severe adverse events was 14.3% (n = 8). Of those, six of the eight patients had a rectal EQD2 D2cc ≥ 65 Gy and seven patients had a sigmoid D2cc ≥ 65 Gy. Amongst clinically meaningful factors for development of adverse events (i.e. diabetes, smoking status, ovoid size, and treatment duration), there were no statistically significant prognostic factors identified. CONCLUSIONS: Severe adverse events are observed even with adherence to current ABS guidelines. In the era of recent multi-institutional study results, our data also supports more stringent dosimetric goals. We suggest cumulative D2cc dose limits of: less than 80 Gy for the bladder and less than 65 Gy for the rectum and sigmoid.

Evaluation of outcomes after stereotactic radiosurgery for pilocytic astrocytoma.

Pilocytic astrocytomas are rare intracranial gliomas that are typically treated with surgical extirpation. Our aim was to report the radiologic and clinical outcomes of patients treated with stereotactic radiosurgery (SRS) for pilocytic astrocytoma in the primary and salvage setting. Patients with pilocytic astrocytoma treated at a single institution with SRS from 1990 to 2015 were reviewed. Patient, disease, and treatment characteristics were collected and overall survival, local control, and toxicity were evaluated. Twenty-eight consecutive patients (12 females and 16 males) with a median age of 17.4 years at SRS were identified. Overall, 46% of patients were treated with SRS as part of the initial treatment course after biopsy or subtotal resection, and the remainder as a salvage therapy. The most common location was the cerebellum (28%) followed by brainstem and basal ganglia (21 and 18%, respectively). Four patients received prior external beam radiation therapy (14%). Median tumor volume was 1.84 cc (0.19-15.94 cc), and 39% had a cystic component at SRS. Prescription dose ranged from 4 to 20 Gy (median 16 Gy) to a median isodose line of 50% (range 30-100%). With a median follow-up of 5.2 years (0.3-17.1 years), all patients remained alive at last follow-up. Two patients demonstrated evidence of local radiographic progression at last follow-up (7%). No toxicity could be directly attributed to SRS. In this SRS series, durable tumor control was achieved in 93% of patients with pilocytic astrocytoma, although continued follow up will be important giving the natural history of this disease. As demonstrated, SRS is an appropriate technique in the primary and recurrent treatment of pilocytic astrocytoma that offers favorable disease control and infrequent clinical toxicity.

Engineered stem cell niche matrices for rotator cuff tendon regenerative engineering.

Rotator cuff (RC) tears represent a large proportion of musculoskeletal injuries attended to at the clinic and thereby make RC repair surgeries one of the most widely performed musculoskeletal procedures. Despite the high incidence rate of RC tears, operative treatments have provided minimal functional gains and suffer from high re-tear rates. The hypocellular nature of tendon tissue poses a limited capacity for regeneration. In recent years, great strides have been made in the area of tendonogenesis and differentiation towards tendon cells due to a greater understanding of the tendon stem cell niche, development of advanced materials, improved scaffold fabrication techniques, and delineation of the phenotype development process. Though in vitro models for tendonogenesis have shown promising results, in vivo models have been less successful. The present work investigates structured matrices mimicking the tendon microenvironment as cell delivery vehicles in a rat RC tear model. RC injuries augmented with a matrix delivering rat mesenchymal stem cells (rMSCs) showed enhanced regeneration over suture repair alone or repair with augmentation, at 6 and 12-weeks post-surgery. The local delivery of rMSCs led to increased mechanical properties and improved tissue morphology. We hypothesize that the mesenchymal stem cells function to modulate the local immune and bioactivity environment through autocrine/paracrine and/or cell homing mechanisms. This study provides evidence for improved tendon healing with biomimetic matrices and delivered MSCs with the potential for translation to larger, clinical animal models. The enhanced regenerative healing response with stem cell delivering biomimetic matrices may represent a new treatment paradigm for massive RC tendon tears.

Systematic Review of Focal Prostate Brachytherapy and the Future Implementation of Image-Guided Prostate HDR Brachytherapy Using MR-Ultrasound Fusion.

Prostate cancer is the most common malignancy found in North American and European men and the second most common cause of cancer related death. Since the practice of PSA screening has become common the disease is most often found early and can have a long indolent course. Current definitive therapy treats the whole gland but has considerable long-term side effects. Focal therapies may be able to target the cancer while decreasing dose to organs at risk. Our objective was to determine if focal prostate brachytherapy could meet target objectives while permitting a decrease in dose to organs at risk in a way that would allow future salvage treatments. Further, we wanted to determine if focal treatment results in less toxicity. Utilizing the Medline repository, dosimetric papers comparing whole gland to partial gland brachytherapy and clinical papers that reported toxicity of focal brachytherapy were selected. A total of 9 dosimetric and 6 clinical papers met these inclusion criteria. Together, these manuscripts suggest that focal brachytherapy may be employed to decrease dose to organs at risk with decreased toxicity. Of current technology, image-guided HDR brachytherapy using MRI registered to transrectal ultrasound offers the flexibility and efficiency to achieve such focal treatments.

Polyphosphazene functionalized polyester fiber matrices for tendon tissue engineering: in vitro evaluation with human mesenchymal stem cells.

Poly[(ethyl alanato)(1)(p-methyl phenoxy)(1)] phosphazene (PNEA-mPh) was used to modify the surface of electrospun poly(ε-caprolactone) (PCL) nanofiber matrices having an average fiber diameter of 3000 ± 1700 nm for the purpose of tendon tissue engineering and augmentation. This study reports the effect of polyphosphazene surface functionalization on human mesenchymal stem cell (hMSC) adhesion, cell-construct infiltration, proliferation and tendon differentiation, as well as long term cellular construct mechanical properties. PCL fiber matrices functionalized with PNEA-mPh acquired a rougher surface morphology and led to enhanced cell adhesion as well as superior cell-construct infiltration when compared to smooth PCL fiber matrices. Long-term in vitro hMSC cultures on both fiber matrices were able to produce clinically relevant moduli. Both fibrous constructs expressed scleraxis, an early tendon differentiation marker, and a bimodal peak in expression of the late tendon differentiation marker tenomodulin, a pattern that was not observed in PCL thin film controls. Functionalized matrices achieved a more prominent tenogenic differentiation, possessing greater tenomodulin expression and superior phenotypic maturity according to the ratio of collagen I to collagen III expression. These findings indicate that PNEA-mPh functionalization is an efficient method for improving cell interactions with electrospun PCL matrices for the purpose of tendon repair.

Design and optimization of polyphosphazene functionalized fiber matrices for soft tissue regeneration.

Electrospun polycaprolactone nanofiber matrices surface functionalized with poly[(ethyl alanato), (p-methyl phenoxy),] phosphazene were fabricated for the purpose of soft skeletal tissue regeneration. This preliminary study reports the effect of fiber diameter and polyphosphazene surface functionalization on significant scaffold properties such as morphology, surface hydrophilicity, porosity, tensile properties, human mesenchymal stem cell adhesion and proliferation. Six fiber matrices comprised of average fiber diameters in the range of 400-500, 900-1000, 1400-1500, 1900-2000, 2900-3000 and 3900-4000 nm were considered for primary evaluation. After achieving the greatest proliferation while maintaining moderate tensile modulus, matrices in the diameter range of 2900-3000 nm were selected to examine the effect of coating with 1%, 2% and 3% (weight/volume) polyphosphazene solutions. Polyphosphazene functionalization resulted in rougher surfaces that correlated with coating solution concentration. Analytical techniques such as energy dispersive X-ray analysis, Fourier transform infrared spectroscopy, elemental analysis, differential scanning calorimetry, water contact angle goniometry and confocal microscopy confirmed the presence of polyphosphazene and its distribution on the functionalized fiber matrices. Functionalization achieved through 2% polymer solutions did not affect average pore diameter, tensile modulus, suture retention strength or cell proliferation compared to PCL controls. Surface polyphosphazene functionalization significantly improved the matrix hydrophilicity evidenced through decreased water contact angle of PCL matrices from 130 degrees to 97 degrees. Further, enhanced total protein synthesis by cells during in vitro culture was seen on 2% PPHOS functionalized matrices over controls. Improving PCL matrix hydrophilicity via proposed surface functionalization may be an efficient method to improve cell-PCL matrix interactions.

Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours.

BACKGROUND: Dulanermin (rhApo2L/TRAIL) induces apoptosis by binding to death receptors DR4 and DR5, leading to caspase activation and subsequent cell death. A Phase1a trial evaluated the safety and tolerability of dulanermin in patients with advanced tumours. One aim was to develop and validate pharmacodynamic biomarkers to monitor dulanermin activity in patient serum. METHODS: We optimised assays to measure the cell-death markers caspase 3/7, cytokeratin 18 and genomic DNA in serum. Mice bearing Colo205 xenografts were treated with dulanermin and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored apoptotic markers in patients who received dulanermin. RESULTS: We detected transient increases in apoptotic markers in mouse sera 8-24 h after dulanermin treatment. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumours. A statistically significant increase in serum caspase 3/7 was detected in cohorts of colorectal and sarcoma patients 24 h after receiving dulanermin dosed above 4 mg kg(-1). CONCLUSION: Owing to limited responses in the Phase 1a study, the changes in circulating cell-death markers were not evaluable. Future studies with dulanermin are needed to determine the utility of these assays with respect to providing evidence of activity or predicting overall response.

Composite scaffolds: bridging nanofiber and microsphere architectures to improve bioactivity of mechanically competent constructs.

Tissue engineering often benefits from the use of composites to produce an ideal scaffold. We present the focused development of a novel structure that combines the biomimetic properties of nanofibers with the robust mechanical aspects of the sintered microsphere scaffold to produce a composite scaffold that demonstrates an ability to mimic the mechanical environment of trabecular bone while also promoting the phenotype progression of osteoblast progenitor cells. These composite nanofiber/microsphere scaffolds exhibited a mechanical modulus and compressive strength similar to trabecular bone and exhibited degradation resulting in a mass loss of 30% after 24 weeks. The nanofiber portion of these scaffolds was sufficiently porous to allow cell migration throughout the fibrous portion of the scaffold and promoted phenotype progression through focal adhesion kinase-mediated activation of the transcription factor Runx2, control scaffolds not containing nanofibers did not demonstrate extensive cell migration or phenotype progression. Ultimately, the focal adhesion kinase activity on the composite nanofiber/microsphere scaffolds demonstrated causality over the production of the mature osteoblast marker, osteocalcin, and the development of a calcified matrix.

The comparative morphology of pit organs in elasmobranchs.

The pit organs of elasmobranchs (sharks, skates and rays) are free neuromasts of the mechanosensory lateral line system. Pit organs, however, appear to have some structural differences from the free neuromasts of bony fishes and amphibians. In this study, the morphology of pit organs was investigated by scanning electron microscopy in six shark and three ray species. In each species, pit organs contained typical lateral line hair cells with apical stereovilli of different lengths arranged in an "organ-pipe" configuration. Supporting cells also bore numerous apical microvilli taller than those observed in other vertebrate lateral line organs. Pit organs were either covered by overlapping denticles, located in open grooves bordered by denticles, or in grooves without associated denticles. The possible functional implications of these morphological features, including modification of water flow and sensory filtering properties, are discussed.