Prognostic Factors for Development of Subsequent Metastases in Localized Osteosarcoma: A Systematic Review and Identification of Literature Gaps.

AIM: To investigate prognostic factors in pediatric and young adult patients with localized osteosarcoma that could predict the development of subsequent pulmonary metastases and lead to an ability to risk-stratify therapy. We performed a systematic review of the literature published since January 1990 to establish common evidence-based prognostic factors. METHODS: PubMed and Embase searches (Jan 1990-Aug 2018) were performed. Two reviewers independently selected papers for patients with localized osteosarcoma with subsequent metastatic development and then reviewed for quality of methods and prognostic factors. RESULTS: Database searches yielded 216 unique results. After screening, 27 full-text articles were studied in depth, with 9 items fulfilling predetermined inclusion and exclusion criteria. Age, tumor location, tumor size/volume, and histologic response carried independent prognostic value in the majority of the studies. CONCLUSIONS: Several prognostic factors seemed to be consistent amongst the studies, but the heterogeneity and smaller sizes of the study populations made pooling of results difficult. Standardization of larger patient populations and consistent definitions/cutoffs for prognostic factors are needed to further assess for consistent prognostic factors and potential predictive models to be developed.

The meninges enhance leukaemia survival in cerebral spinal fluid.

Central nervous system (CNS) relapse is a common cause of treatment failure in patients with acute lymphoblastic leukaemia (ALL) despite current CNS-directed therapies that are also associated with significant short- and long-term toxicities. Herein, we showed that leukaemia cells exhibit decreased proliferation, elevated reactive oxygen species (ROS) and increased cell death in cerebral spinal fluid (CSF) both in vitro and in vivo. However, interactions between leukaemia and meningeal cells mitigated these adverse effects. This work expands our understanding of the pathophysiology of CNS leukaemia and suggests novel therapeutic approaches for more effectively targeting leukaemia cells in the CNS.

Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance.

Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. In this study we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we found that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell-mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.

Ectopic banking of amputated great toe for delayed thumb reconstruction: case report.

Ectopic banking of amputated parts is a recognized technique for delayed replantation of an amputated part when the amputation stump will not permit immediate replantation. This is conventionally performed with the intent of transferring the injured part back to its anatomic position when the amputation stump is more appropriate for replantation. Current warfare conditions have led to a commonly encountered military trauma injury pattern of multiple extremity amputations with protected trunk and core structures. This pattern poses many challenges, including the limit or absence of donor sites for immediate or delayed flap reconstructive procedures. We describe a case in which we ectopically banked the great toe of an amputated lower extremity for delayed thumb reconstruction.

Use of intraoperative fluorescent angiography to assess and optimize free tissue transfer in head and neck reconstruction.

PURPOSE: Composite tissue defects in the head and neck region present unique challenges. Definitive head and neck reconstruction of these cases is often complicated by complex 3-dimensional defects that may require multiple flap or chimeric flap procedures. These advanced techniques can have serious repercussions should poor perfusion of the flap cause flap failure, which can be devastating. MATERIALS AND METHODS: A retrospective review was completed for those complex reconstructions using free tissue transfers and fluorescent indocyanine green angiography (Lifecell SPY Elite imaging, Lifecell Corporation, Bridgewater, NJ) at Walter Reed National Military Medical Center over a 24-month period. Data analyzed included flap type (myocutaneous, osteocutaneous, or fasciocutaneous), flap success and failure rates, and complications. These also were compared with data from the institution before the study period and the incorporation of SPY technology. RESULTS: Sixty-one free flaps, including 11 head and neck flaps, were performed. The head and neck flaps included 1 latissimus, 3 gracilis, 1 vastus lateralis, 4 anterior lateral thigh, and 2 fibular flaps. The overall success rate was 98.4%; 1 flap was lost (1.6%) and 2 flaps developed partial flap necrosis (3.3%). Where SPY Elite was used, there was no unpredicted partial flap necrosis. The only total flap loss was related to a hypercoagulable condition. CONCLUSIONS: Free tissue transfer can be technically challenging, especially in complex head and neck reconstruction. An algorithmic approach using SPY Elite imaging aids in pedicle location, angiosomal assessment, anastomotic flow visualization, and cutaneous and osteocutaneous flap perfusion assessment. This objective tool can assist the reconstructive surgeon in avoiding perfusion-related complications and total and partial flap losses, thus improving patient outcomes.

Soft tissue injury management with a continuous external tissue expander.

BACKGROUND: Blast exposure is a common cause of soft tissue injury within the battlefield setting, with the extremities often critically involved. The resulting injury pattern presents with massive soft tissue defects that may be further complicated by varying degrees of accompanying orthopedic and peripheral nerve damage. To address the severe soft tissue defect, various combinations of advanced reconstructive methods are typically required to achieve definitive wound coverage. Continuous external tissue expansion has been used by our institution to significantly reduce wound burden and provide for definitive wound closure in certain blast-injured patients. METHODS: The authors present an early series of 14 patients who suffered massive extremity soft tissue injuries and were treated with an external tissue expansion system (DermaClose RC). Outcome measurements included time to definitive closure and method of definitive wound closure. A 5-patient subset of this group was prospectively analyzed to determine measurements including initial wound surface area (WSA), percentage reduction in WSA, and related complications. RESULTS: Overall time to wound coverage ranged from 1 to 6 days, with mean time to wound coverage being 4.4 days. Of the 14 patients included in the series, 12 (85.7%) were able to undergo delayed primary closure, whereas 2 required split thickness skin grafting. In the 5-patient subgroup, WSA initially ranged from 20.25 to 1031.25 cm2. Mean wound size was 262.7 cm2. Decrease in WSA ranged from 44% to 93% of the initial WSA, with mean decrease being 74.3% (95% confidence interval, 57.33-91.3). CONCLUSIONS: In the management of large complex wounds, external tissue expansion has proven to be a valuable adjunct in achieving definitive wound closure. It can often aid in successful delayed primary closure of certain soft tissue wounds, has low associated morbidities, and can reduce the need for more complex or morbid procedures when used properly. The authors propose an algorithm for the use of continuous external tissue expansion system to achieve effective and successful wound closure, while potentially reducing the need for increased donor-site morbidities associated with more complex or larger reconstruction measures.

Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing.

Studies were performed evaluating the role of Smad3, a transcription factor mediating canonical TGF-ß signaling, on scarring and adhesion formation using an established flexor digitorum longus (FDL) tendon repair model. In unoperated animals the metatarsophalangeal (MTP) range of motion (ROM) was similar in Smad3(-/-) and wild-type (WT) mice while the basal tensile strength of Smad3(-/-) tendons was significantly (39%) lower than in WT controls. At 14 and 21 days following repair Smad3(-/-) MTP ROM reached approximately 50% of the basal level and was twice that observed in WT tendon repairs, consistent with reduced adhesion formation. Smad3(-/-) and WT maximal tensile repair strength on post-operative day 14 was similar. However, Smad3(-/-) tendon repairs maximal tensile strength on day 21 was 42% lower than observed in matched WT mice, mimicking the relative decrease in strength observed in Smad3(-/-) FDL tendons under basal conditions. Histology showed reduced "healing callus" in Smad3(-/-) tendons while quantitative PCR, in situ hybridization, and immunohistochemistry showed decreased col3a1 and col1a1 and increased MMP9 gene and protein expression in repaired Smad3(-/-) tendons. Thus, Smad3(-/-) mice have reduced collagen and increased MMP9 gene and protein expression and decreased scarring following tendon FDL tendon repair.

Current surgical practices in cleft care: cleft palate repair techniques and postoperative care.

BACKGROUND: The purpose of this study was to objectively report practices commonly used in cleft palate repair in the United States. This study investigates current surgical techniques, postoperative care, and complication rates for cleft palate repair surgery. METHODS: All 803 surgeon members of the American Cleft Palate-Craniofacial Association were sent online and/or paper surveys inquiring about their management of cleft palate patients. RESULTS: Three-hundred six surveys were received, a 38 percent response rate. This represented responses of surgeons from 100 percent of American Cleft Palate-Craniofacial Association registered cleft teams. Ninety-six percent of respondents perform a one-stage repair. Eighty-five percent of surgeons perform palate surgery when the patient is between 6 and 12 months of age. The most common one-stage repair techniques are the Bardach style (two flaps) with intravelar veloplasty and the Furlow palatoplasty. After surgery, 39 percent of surgeons discharge patients within 24 hours. Another 43 percent discharge patients within 48 hours. During postoperative management, 92 percent of respondents implement feeding restrictions. Eighty-five percent of physicians use arm restraints. Surgeons' self-reported complications rates are minimal: 54 percent report a fistula in less than 5 percent of cases. The reported need for secondary speech surgery varies widely. CONCLUSIONS: The majority of respondents repair clefts in one stage. The most frequently used repair techniques are the Furlow palatoplasty and the Bardach style with intravelar veloplasty. After surgery, the majority of surgeons discharge patients in 1 or 2 days, and nearly all surgeons implement feeding restrictions and the use of arm restraints. The varying feeding protocols are reviewed in this article.

Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery.

Tendon reconstruction using grafts often results in adhesions that limit joint flexion. These adhesions are precipitated by inflammation, fibrosis, and the paucity of tendon differentiation signals during healing. In order to study this problem, we developed a mouse model in which the flexor digitorum longus (FDL) tendon is reconstructed using a live autograft or a freeze-dried allograft, and identified growth and differentiation factor 5 (Gdf5) as a therapeutic target. In this study we have investigated the potential of rAAV-Gdf5 -loaded freeze-dried tendon allografts as "therapeutically endowed" tissue-engineering scaffolds to reduce adhesions. In reporter gene studies we have demonstrated that recombinant adeno-associated virus (rAAV)-loaded tendon allografts mediate efficient transduction of adjacent soft tissues, with expression peaking at 7 days. We have also demonstrated that the rAAV-Gdf5 vector significantly accelerates wound healing in an in vitro fibroblast scratch model and, when loaded onto freeze-dried FDL tendon allografts, improves the metatarsophalangeal (MTP) joint flexion to a significantly greater extent than the rAAV-lacZ controls do. Collectively, our data demonstrate the feasibility and efficacy of therapeutic tendon allograft processing as a novel paradigm in tissue engineering in order to address difficult clinical problems such as tendon adhesions.

Adhesions in a murine flexor tendon graft model: autograft versus allograft reconstruction.

Reconstruction of flexor tendons often results in adhesions that compromise joint flexion. Little is known about the factors involved in the formation of flexor tendon graft adhesions. In this study, we developed and characterized a novel mouse model of flexor digitorum longus (FDL) tendon reconstruction with live autografts or reconstituted freeze-dried allografts. Grafted tendons were evaluated at multiple time points up to 84 days post-reconstruction. To assess the flexion range of the metatarsophalangeal joint, we developed a quantitative outcome measure proportional to the resistance to tendon gliding due to adhesions, which we termed the Gliding Coefficient. At 14 days post-grafting, the Gliding Coefficient was 29- and 26-fold greater than normal FDL tendon for both autografts and allografts, respectively (p < 0.001), and subsequently doubled for 28-day autografts. Interestingly, there were no significant differences in maximum tensile force or stiffness between live autograft and freeze-dried allograft repairs over time. Histologically, autograft healing was characterized by extensive remodeling and exuberant scarring around both the ends and the body of the graft, whereas allograft scarring was abundant only near the graft-host junctions. Gene expression of GDF-5 and VEGF were significantly increased in 28-day autografts compared to allografts and to normal tendons. These results suggest that the biomechanical advantages for tendon reconstruction using live autografts over devitalized allografts are minimal. This mouse model can be useful in elucidating the molecular mechanisms in tendon repair and can aid in preliminary screening of molecular treatments of flexor tendon adhesions.

DDT and its metabolites in breast milk from two regions in Saudi Arabia.

A cross sectional study was designed to measure DDT residues and its metabolites in breast milk samples collected randomly from Saudi lactating mothers living in Al-Ehssa region; which was under leishmania control until 1995, and compare them to samples from mothers living in Riyadh region where no spraying activities was involved. p,p'-DDE, p,p'-DDD and p,p'-DDT residues were measured in 878 breast milk samples by Gas Chromatography/Electron Capture Detector (GC/ECD) and confirmed by Gas Chromatography/Mass Spectrometer Detector (GC/MSD). Variation in the DDT and its metabolites levels were investigated with respect to regional distribution. Wilcoxon rank sum tests showed that the average ranks of p,p'-DDE, p,p'-DDD, p,p'-DDT and sigma p,p'-DDT in lactating mothers from Al-Ehssa region were significantly higher than those living in Riyadh region. These differences supported our hypothesis that the implications of the spraying activities to control vector borne diseases in Al-Ehssa region are obvious. We estimated that 99.2% of infants of lactating mothers living in Al-Ehssa region had sigma p,p'-DDT daily intakes that exceeded 20 micrograms/Kg-day of body weight, the WHO/UNEP Acceptable Daily Intakes for a 5-Kg infant. Exposure of infants to these chemicals through breast-feeding is clearly a public health concern. Because the bulk of literature highlights the adverse health effects of DDT and its metabolites on children and infants, public health polices should enforce the ban of DDT use and advise pregnant and lactating women to avoid DDT containing food or any other type of exposure.