Efficacy of Hydromechanical Therapy in Nonhealing, Chronic Wounds as a Cost- and Clinically Effective Wound Care Modality.

INTRODUCTION: Chronic wounds pose a widespread challenge to health care, with many new, costly wound care modalities introduced in recent years with varying degrees of success. Bacterial biofilms have been postulated as one of the main culprits of the stagnation of chronic wound healing. For years, surgical fields have used pressurized irrigation for cleansing surgical wounds, but its utility in managing nonhealing chronic wounds has often been overlooked. OBJECTIVE: In this case series, the authors aimed to demonstrate that hydromechanical therapy with pressurized irrigation can be a cost-effective and clinically effective wound care modality. MATERIALS AND METHODS: The authors present 6 clinical cases of difficult nonhealing wounds managed with hydromechanical therapy with pressurized irrigation, a follow-up from the initial case report. Other, often more expensive modalities, had previously failed. In all 6 cases, irrigation was performed using tap water or saline either at home or long-term care facilities. Literature that focused on the mechanism of healing from hydromechanical therapy was reviewed. RESULTS: All chronic wounds in the series reached stable healing. The authors speculate that such healing was achieved through biofilm disruption and tissue stimulation with a mechanical impact. Literature supporting this hypothesis is presented. CONCLUSIONS: The current clinical results offer a new perspective on the role of a traditional surgical modality of hydromechanical therapy in chronic wound care and on the associated opportunity of potential cost savings.

Anterograde injection of low-dose urokinase salvages free anterolateral thigh flap: A case report of safe and effective treatment.

RATIONALE: A 54-year-old Taiwanese male came to our hospital presented with right retromolar mucoepidermoid carcinoma. Composite resection and right modified radical neck dissection were performed. We then use free anteral lateral thigh flap to reconstruct the defect. However, venous congestion was found 32 h after the surgery. PATIENT CONCERNS: The main concerns of the patient is complete salvage of the free flap, and avoiding the secondary free flap harvesting and reconstruction surgeries. DIAGNOSES: Right retromolar mucoepidermoid carcinoma. INTERVENTIONS: We report the case of a patient with an anterolateral thigh flap with venous perianastomosis thrombosis and intraflap microvascular thrombosis successfully salvaged using anterograde intra-arterial injection of low-dose urokinase (60,000 U), without administering intravenous anticoagulation heparin during the postoperative period. OUTCOMES: The flap was completely salvaged 3 days after treatment. No other flap-associated or bleeding complications were noted. The intra-oral wounds around the flap completely healed without any post-ischemic complications. LESSONS SUBSECTIONS: Although the ideal urokinase doses and delivery procedures for free flap salvage have not been developed thus far, our method maximizes the urokinase gradient in the flap, minimizes the total dose required for flap salvage, and ensures no systemic spread. Thus, compared with other thrombolytic agents, urokinase may be more effective and safe for free flap salvage. With more experience, a standardized dosage and procedure can be developed.

Use of the Ipsilateral Anteromedial Thigh Flap for Immediate Rescue of Nonviable Anterolateral Thigh Flaps in Head and Neck Cancer Reconstruction.

BACKGROUND: It is not always possible to use the anatomically variable free anterolateral thigh (ALT) flap for reconstructive surgery. An anteromedial thigh (AMT) flap serves as a good alternative, and shares the same vascular pedicle as the ALT flap. METHODS: Of 698 reconstructions performed in 2006 to 2013 following head and neck tumor ablation surgery, ALT flaps were used in 653 patients. Eighteen free AMT flaps were harvested to replace variant nonviable ALT flaps. RESULTS: The lack of a sizable perforator in the ALT flap territory was the main reason for changing the reconstruction plan. Anteromedial thigh flap size ranged from 10 × 4 to 30 × 8 cm. The flap survival rate was 100%. The follow-up period ranged from 3 to 56 months. CONCLUSION: During head and neck reconstruction, when no sizable perforator is available during harvest of the ALT flap, successful reconstruction can be achieved using the ipsilateral AMT flap without additional donor-site morbidity.

A 'silent' skull metastatic follicular thyroid carcinoma mimicking as a benign scalp tumor in a pregnant woman.

Thyroid cancer with cranial metastasis in a pregnant woman is very rare. In the literature, most cases are diagnosed early from neurogenic signs or symptomatic thyroid gland. Pregnancy also contributes to a hesitation toward early surgical and medical treatments. We reported a scalp tumor in a physically healthy 37-year-old pregnant female with a follicular thyroid carcinoma (FTC) with lung, bone and cranial metastasis in initial presentation. Silent neurogenic and physical examinations make an early diagnosis very challenging. Resection of scalp and intracranial tumor, a thyroidectomy, post-operative radioactive iodine therapy and tyrosine kinase inhibitors were employed as treatment. The scalp tumor was confirmed as a metastatic follicular thyroid carcinoma via positive immunoreactivity for thyroglobulin and thyroid transcription factor 1 in tumor cells. Blood examination revealed an elevated thyroglobulin level (>5335 ng/mL). The patient was discharged without any neurological deficit. An asymptomatic scalp tumor in a pregnant woman with a normal thyroid disease history needs differential diagnosis from intracranial origin. Rapid progression and an elevated thyroglobulin level are the indicators that further image study is needed. Aggressive surgical excision of resectable thyroid gland and metastatic tumor are essential for a longer survival rate. There is nothing to indicate that a post-partum operation will worsen prognosis. LEARNING POINTS: Follicular thyroid cancer with cranial metastasis in initial presentation can be asymptomatic.Follicular thyroid cancer with cranial metastasis in a pregnant woman can be treated after delivery.Rapid enlargement of scalp tumor is indicated for further image study even in a patient without any neurological deficit.

Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation.

The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC50 ~ 5 nM). Moreover, kinase profiling and cell-line profiling revealed BPR1K871 to be a potential multi-kinase inhibitor. Functional studies using western blot and DNA content analysis in MV4-11 and HCT-116 cell lines revealed FLT3 and AURKA/B target modulation inside the cells. In vivo efficacy in AML xenograft models (MOLM-13 and MV4-11), as well as in solid tumor models (COLO205 and Mia-PaCa2), led to the selection of BPR1K871 as a preclinical development candidate for anti-cancer therapy. Further detailed studies could help to investigate the full potential of BPR1K871 as a multi-kinase inhibitor.

Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification.

The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 µM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.

Functional Outcome Analysis After Anterolateral Thigh Flap Reconstruction of Pharyngoesophageal Defect.

BACKGROUND: Pharyngoesophageal defects are traditionally reconstructed with jejunal or radial forearm flaps. Recently, anterolateral thigh flaps have served for pharyngoesophageal reconstruction. We tell of our experience with anterolateral thigh flap for the reconstruction of pharyngoesophageal defect for the past 5 years. This study presents another modified flap design and refinement of surgical techniques. METHODS: In all, 45 pharyngoesophageal reconstructions were performed during 2006 to 2011, namely patch (n = 18), near-circumferential (n = 8), and circumferential defect (n = 19) reconstructed by 2 plastic surgeons with the same trapezoid anterolateral thigh flap design. RESULTS: Total flap loss occurred in 2 patients (4%). Two patients experienced partial flap necrosis. Fistulas occurred in 8 patients, but only 5 of these needed further suture ligation or local flap treatment. Postoperative strictures without tumor recurrence were identified in 4 patients (9%). Forty patients (88.9%) could tolerate oral diet; 34 of these ate soft or solid food. CONCLUSIONS: Anterolateral thigh flap offers good coverage and swallowing function in the reconstruction of hypopharyngeal defect. Trapezoid drawing of anterolateral thigh flap makes the design simplified, with an accepted complication rate.

Efficacy and safety of negative pressure wound therapy for Szilagyi grade III peripheral vascular graft infection.

A best evidence topic in vascular surgery was written according to a structured protocol. The question addressed was whether it is safe and effective to use negative pressure wound therapy (NPWT) for Szilagyi grade III (i.e. the arterial implant proper involved in the infection) peripheral vascular graft infection. Altogether, 69 papers were found using the reported search. From the search results, reference lists of potentially eligible studies and related citations in PubMed, seven papers represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. In the only randomized, controlled trial that compared NPWT (n = 10) and alginate dressing change (n = 10), the NPWT group demonstrated shorter time to full skin epithelialization (median 57 vs 104 days; P = 0.026). In the other six case series, the recruited case number ranged from 12 to 72. The mode of NPWT varied among the included studies, with the majority using a continuous negative pressure of 125 mmHg. One study combined NPWT and sartorius myoplasty, another used sartorius myoplasty in selected cases and others did not. The mean duration of using NPWT ranged from 14.2 to 43 days. The mean duration to achieve complete wound healing ranged from 24 (the study with sartorius myoplasty) to 51 days. The NPWT treatment failure rate ranged from 0 (the study with sartorius myoplasty) to 25%. The major complication of NPWT was bleeding and the incidence rate was reported to be <10%. We conclude that the amount of evidence for recommending NPWT alone as the first-line treatment for Szilagyi grade III peripheral vascular graft infection is small with only one small-sized randomized controlled trial demonstrating that NPWT alone is superior to alginate dressing change in shortening the time to complete wound healing by 2 months. Limited evidence (case series with >1 year of follow-up) showed that NPWT with a continuous negative pressure of 125 mmHg, or combined NPWT and sartorius myoplasty, may shorten the time to complete wound healing by 2 months, have a >70% success rate, and have a <10% NPWT-related complication rate.

3D-QSAR-assisted drug design: identification of a potent quinazoline-based Aurora kinase inhibitor.

We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC(50) values toward Aurora kinase A ranging from 33 nM to 10.5 µM. The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r(2) (CV) =0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R(2) (pred) =0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC(50) =43 nM; HCT-116 IC(50) =400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC(50) =25 nM; HCT-116 IC(50) =23 nM). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.

Treatment of temporomandibular joint ganglion cyst.

Ganglion cysts of the temporomandibular joint are very rare and always misdiagnosed as synovial cyst, parotid gland tumor, or other cystic lesions. They present with pain, swelling, or dysfunction. Image studies could facilitate to identify the tumor mass from the adjacent soft tissue, but a definitive diagnosis could be made from the pathologic report.A 59-year-old woman presented to the clinics with a chief complaint of a painless swelling mass in the right preauricular region of 3-month duration. Computed tomography was performed, which showed a small radiolucent lesion adjacent to the right condyle. Local excision was performed, and the specimen was sent for histologic examination.Microscopic examination showed a cystic space walled by dense fibrous connective tissue without epithelial or endothelial lining. Immunohistochemical staining of these lining cells showed positivity for vimentin and negativity for cytokeratin. These findings were consistent with the diagnosis of ganglion cyst.Ganglion cysts present as unilobulate or multilobulate cysts that arise from the collagenous tissue and is filled with highly viscous fluid. It does not communicate with the joint cavity. In contrast, synovial cyst is a true cyst lined by cuboidal or flattened cells from the synoviocytes and is filled with gelatinous fluid. It may or may not communicate with the joint cavity. Excision is the treatment of choice of symptomatic cystic lesions. Incomplete excision of these lesions may cause further recurrence or infection. Thus, injection of hydrocortisone or aspiration may be considered as an alternative management.

The conditioned enhancement of neutrophil activity is catecholamine dependent.

Neutrophil activity was elevated in the conditioned mice for the first time through an established conditioned training process. Catecholamines were proved to be important in the regulation of this conditioned innate immunity. In the study, the camphor odor (as the conditioned stimulus, CS) and poly I: C (as the unconditioned stimulus, US) was used to conditionally elevate the activity of the splenic neutrophils. The mechanism(s) responsible for the conditioned enhancement of neutrophil activity was further investigated using the neurochemical blocking assay and immunohistochemical analysis. Results showed that the neutrophil activity was significantly enhanced through the conditioned training process; both reserpine and 6-hydroxydopamine (6-OHDA) significantly blocked this conditioned innate immunity at the conditioned recall stage. Dexamethasone (Dex), however, showed no effect on the conditioned neutrophil response. Tyrosine hydroxylase (TH)-positive cells significantly increased in the locus coeruleus (LC), hypothalamus, and cortex but not in the spleen of the conditioned animals. These results indicate that during the conditioned recall stage, the brain signals the splenic neutrophils via the sympathetic nervous system (SNS) by releasing the peripheral catecholamines in spleen. The activation of the SNS, on the other hand, is also under the influence of catecholamines released in the LC. The hypothalamic pituitary (HP) axis, on the other hand, plays no role in the regulation of the conditioned neutrophil response.