Gene therapy for diabetic foot ulcers: Interim analysis of a randomised, placebo-controlled phase 3 study of VM202 (ENGENSIS), a plasmid DNA expressing two isoforms of human hepatocyte growth factor.

To evaluate the status of a 7-month phase 3 study conducted to test the effect of intramuscular injections of VM202 (ENGENSIS), a plasmid DNA encoding human hepatocyte growth factor, into the calf muscles of chronic nonhealing diabetic foot ulcers with concomitant peripheral artery disease. The phase 3 study, originally aimed to recruit 300 subjects, was discontinued because of slow patient recruitment. An unprespecified interim analysis was performed for the 44 subjects enrolled to assess the status and determine the future direction. Statistical analyses were carried out for the Intent-to-Treat (ITT) population and separately for subjects with neuroischemic ulcers, using a t-test and Fisher's exact test. A logistic regression analysis was also conducted. VM202 was safe and potentially should have benefits. In the ITT population (N = 44), there was a positive trend toward closure in the VM202 group from 3 to 6 months but with no statistical significance. Levels of ulcer volume or area were found to be highly skewed between the placebo and VM202 groups. Forty subjects, excluding four outliers in both arms, showed significant wound-closing effects at month 6 (P = .0457). In 23 patients with neuroischemic ulcers, the percentage of subjects reaching complete ulcer closure was significantly higher in the VM202 group at months 3, 4, and 5 (P = .0391, .0391, and .0361). When two outliers were excluded, a significant difference was evident in months 3, 4, 5, and 6 (P = .03 for all points). A potentially clinically meaningful 0.15 increase in Ankle-Brachial Index was observed in the VM202 group at day 210 in the ITT population (P = .0776). Intramuscular injections of VM202 plasmid DNA to calf muscle may have promise in the treatment of chronic neuroischemic diabetic foot ulcers (DFUs). Given the safety profile and potential healing effects, continuing a larger DFU study is warranted with modifications of the current protocol and expansion of enrolling sites.

An Alternative Technique for Fixation of Tongue-Type Calcaneal Fractures: The "Hurricane Strap".

Traditionally, tongue-type calcaneal fractures have been treated using screw fixation or tension band wiring. In this work, we aim to present a technique guide for an alternative approach to fixation of these fractures given the high potential for failure with traditional methods. Additionally, we present the results of 4 patients treated with this technique. A modified lateral extensile incision is made for application of a midfoot fusion plate that is pre-bent and fit to the calcaneus with 2 holes covering the superior surface of the calcaneus for bicortical interfragmentary purchase. Four screws are then placed orthogonally into the calcaneus through the plate. Typically, this allows for 2 screws to be placed in the superior fragment and 2 screws to be placed in the inferior fragment. All 4 patients went on to timely osseous union and were weightbearing in regular shoe gear at their last follow-up appointment. Average follow-up time was 16.5 (range 15 to 21) months. We believe that the "hurricane strap" provides a more mechanically sound construct than other methods. This construct may be especially useful in patients with osteoporotic bone where screws alone may not maintain adequate reduction or in neuropathic patients where noncompliance with weightbearing status may jeopardize maintenance of reduction.

Stability of Locking Plate and Compression Screws for Lapidus Arthrodesis: A Biomechanical Comparison of Plate Position.

Lapidus (first tarsometatarsal joint) arthrodesis is an established and widely used procedure for the management of moderate to severe hallux valgus, especially in cases involving hypermobility of the first tarsometatarsal joint. Multiple fixation methods are available, and several previous investigations have studied the relative strengths of these methods, including dorsomedial and plantar plating comparisons. However, these studies compared plates of varying designs and mechanical properties and used varying modes of compression and interfragmentary screw techniques. The present study mechanically investigated the resulting motion, stiffness, and strength of identical locking plate constructs fixed at various anatomic positions around the first tarsometatarsal joint. In a bench-top study, fourth-generation composite bones were divided into 3 fixation groups, each having identical interfragmentary screw applications, and randomized to 1 of 3 plate positions: dorsal, medial, or plantar. The plates applied in each case were identical locking plates, precontoured to fit the anatomy. Each construct was experimentally tested using a cantilever bending approach. The outcomes obtained were stiffness, yield force, displacement at yield, ultimate force, and displacement at ultimate force. The plantar plate position showed superior initial stiffness and force to ultimate failure. The plantar and medial plate positions exhibited superior force to yield. The medial plate position was superior regarding displacement tolerated before the yield point and catastrophic failure. The dorsal plate position was not superior for any outcome measured. Plantar and medial plating each offered biomechanical benefits. Clinical studies using similarly matched constructs are required to show whether these findings translate into improved clinical outcomes.

Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus.

Controversy remains regarding the use of arthroplasty versus arthrodesis in the surgical treatment of late-stage hallux rigidus. The purpose of our retrospective study was to report the long-term follow-up results of the metatarsal head resurfacing implant used for hemiarthroplasty. The patient assessments were conducted using the American Orthopaedic Foot and Ankle Society (AOFAS) metatarsophalangeal clinical rating system and a satisfaction questionnaire. A total of 59 consecutive implantations were performed from January 2005 to December 2009 at our institution. Of the 59 patients, 2 had died and 12 were lost to follow-up, for a 76.3% follow-up rate (45 of 59 procedures) at a mean of 117.67 (range 96 to 143) months. The mean overall AOFAS scale score was 90.6 ± 7.6. The AOFAS pain scale score was 37.78 ± 4.71. One implant was removed, and all remaining patients were happy with their outcome and would repeat the procedure on their other foot, if needed. A subset of patients from a previous mid-term study at our institution showed no significant change in the AOFAS scale scores. Of these 32 patients, 30 (93.75%) were available for follow-up examination at a mean of 122.62 (range 96 to 143) months. We were able to obtain long-term results for 32 implants (30 patients), resulting in a 10-year follow-up rate of 93.7%. With the minimal resection required for this implant, salvage arthrodesis remains a viable option if revision is needed. The surgical treatment of late-stage hallux rigidus with metatarsal head resurfacing allows for low-risk and excellent outcomes at long-term follow-up point.

Comparison of Hallux Interphalangeal Joint Arthrodesis Fixation Techniques: A Retrospective Multicenter Study.

Few studies have investigated the complications that occur after hallux interphalangeal joint arthrodesis. The present study evaluated complications in 152 patients aged 18 to 80 years from 2005 to 2012 from 4 different academic institutions after hallux interphalangeal joint arthrodesis. Overall, 65.8% of the patients had ≥1 complication. Infections occurred in 16.5%, dehiscence in 12.5%, and reoperations in 27.0%. The clinical nonunion rate was ≥17.8%, and the radiographic nonunion rate was ≥13.8%. After logistic regression analysis, only the study site and peripheral neuropathy were associated with having ≥1 complication (p < .01 and p < .05, respectively). Single screw fixation compared with other fixation did not have a statistically significant influence on the postoperative complications. However, when fixation was expanded to 4 categories, single screw fixation had lower infection and reoperation rates than either crossed Kirschner wires or other fixation category but not compared with crossed screws on multivariate logistic regression analysis. Although additional studies are warranted, the findings from the present study might aid in both the prognosis of complications and the support of the use of a single screw over crossed Kirchner wire fixation in hallux interphalangeal joint arthrodesis.

Cost-effectiveness of becaplermin gel on wound healing of diabetic foot ulcers.

We sought to determine the long-term cost effectiveness (payer's perspective) of becaplermin gel plus good wound care (BGWC) vs. good wound care (GWC) alone in terms of wound healing and risk of amputation in patients with diabetic foot ulcers (DFUs). Outcomes data were derived from a propensity score-matched cohort from the Curative Health Services database between 1998 and 2004, which was followed for 20 weeks. A four-state Markov model was used to predict costs and outcomes of wound healing and risk of amputation for BGWC vs. GWC alone over 1 year in patients with DFU. The primary outcome was closed-wound weeks. Transition probabilities for healing and amputation were derived from the aforementioned propensity score-matched cohorts. Ulcer recurrence was estimated from the medical literature. Utilization for becaplermin was calculated using the dosing algorithm in the product labeling. Of 24,898 eligible patients, 9.6% received BGWC. Based on the model, patients treated with BGWC had substantially more closed-wound weeks compared with GWC (16.1 vs. 12.5 weeks, respectively). More patients receiving BGWC had healed wounds at 1 year compared with those receiving GWC (48.1% vs. 38.3%). Risk of amputation was lower in the BGWC cohort (6.8% vs. 9.8%). Expected annual direct costs for DFU were $21,920 for BGWC and $24,640 for GWC. BGWC was economically dominant over GWC, providing better outcomes at a lower cost in patients with DFU. Compared with GWC alone, BGWC is more effective in healing wounds and lowering amputation risk, thereby decreasing long-term costs for DFU.

Rearfoot and Ankle Dislocations.

Subtalar dislocations, ankle dislocations, and total talar dislocations are high-energy injuries. As such, there may be associated osseous or soft tissue injuries that can be diagnosed with advanced imaging such as computed tomography (CT) or MRI. With closed injuries, closed reduction may require sedation or general anesthesia, flexion of the knee to release the tension of the gastrocnemius-soleus complex, distraction is applied, the deformity is accentuated, then the deformity is corrected. Open injuries are usually associated with a higher level of energy and a higher rate of infection. It is important to thoroughly irrigate and debride open dislocations both before and after reduction.

Association of hindfoot ligament tears and osteochondral lesions.

BACKGROUND: This study aimed to identify the prevalence of ligament and joint surface anatomy variants, ligament tears, and osteochondral lesions (OCLs) in the hindfoot. These data were used to identify associations between anatomic variants or ligament tears and OCLs. METHODS: Seventy-two cadaver hindfoot specimens were examined. Hindfoot ligament presence, number of ligament fascicles, variable ligament attachment sites, ligament tears, presence of joint facets, variable joint surface shape, and the location and grade of OCLs were identified in each specimen. The data were analyzed for significant associations between variables. RESULTS: Fourteen of the 30 studied ligaments were always present and 14 had variable number of fascicles. The lateral talocalcaneal and dorsolateral calcaneocuboid ligaments had varying positional attachments. Osteochondral lesions were present in 86% of specimens with the majority in the talocrural joint. Of the 235 lesions identified, 31 were grade 3 or above. Ligament tears occurred in 2% of all ligaments observed. Tears in the lateral talocalcaneal, medial calcaneocuboid, and dorsolateral calcaneocuboid ligaments were associated with an increased number of hindfoot OCLs. CONCLUSION: We demonstrated the prevalence of morphologic ligament and joint surface variants, ligament tears, and osteochondral lesions in the hindfoot. Tears in ligaments stabilizing the calcaneocuboid joint were implicated in an increase in hindfoot joint damage. CLINICAL RELEVANCE: We believe anatomic studies can be used to clarify the association between traumatic injuries and their sequelae.

Plantar Fasciitis/Fasciosis.

Many randomized controlled trials demonstrate the effectiveness of conservative treatment of plantar fasciitis. Patients with acute plantar fasciitis generally respond to treatment more rapidly and more predictably than patients with chronic plantar fasciitis. If conservative treatment fails, endoscopic plantar fasciotomy offers patients a more prompt return to activity compared with open procedures.

Follow-up Evaluation of Medial Clear Space and Talar Tilt After Bimalleolar Equivalent Fracture Fixation Without Primary Deltoid Repair.

BACKGROUND: We sought first to determine the efficacy of lateral ankle fixation alone in maintenance of medial clear space and talar valgus in bimalleolar equivalent ankle fractures not receiving primary deltoid repair, and second to assess perceived outcomes via the Foot and Ankle Outcome Score. To our knowledge, no study has quantified the reduction of medial clear space and talar valgus in bimalleolar equivalent ankle fractures receiving lateral ankle fixation alone. METHODS: We compared preoperative, initial postoperative, and greater than 1-year follow-up radiographs of medial clear space and talar valgus in individuals who received lateral ankle fixation alone in bimalleolar equivalent ankle fractures. Subjective outcomes were measured via the Foot and Ankle Outcome Score. RESULTS: Thirty-seven patients participated in the study and showed a statistically significant reduction of medial clear space and restoration of talar position, and maintenance with this fixation method during follow-up in patients with bimalleolar equivalent ankle fractures. Adjunctively, patients perceived their outcomes to be satisfactory, as demonstrated by the results of the Foot and Ankle Outcome Score. CONCLUSIONS: We aimed to assess the efficacy of lateral ankle fixation in the maintenance of medial clear space and talar valgus reduction at midterm follow-up. Although some authors contend that primary deltoid repair in bimalleolar equivalent ankle fractures is warranted, these midterm study results suggest that isolated lateral ankle fixation is adequate for medial ankle stabilization in bimalleolar equivalent fractures, and thus primary deltoid repair is not indicated.

Surgical treatment of hallux rigidus using a metatarsal head resurfacing implant: mid-term follow-up.

The treatment of advanced hallux rigidus remains controversial, with many authors discussing arthrodesis versus arthroplasty. The purpose of this study is to report mid-term outcomes after implantation of a motion-preserving metatarsal head-resurfacing prosthetic and to present our technical considerations and modifications to the published technique to further enhance the clinical benefit of the procedure. Thirty-two implantations were performed in 30 patients. Twenty-three patients were women, 9 men. The average age was 62.8 years (range, 39-86 years). Patients were graded at baseline according to Hattrup and Johnson and completed the American Orthopaedic Foot & Ankle Surgery metatarsophalangeal clinical rating system preoperatively and postoperatively and a patient satisfaction question at final follow-up. Seventy-two percent of implantations were grade III hallux rigidus and 28% were grade II. The average follow-up was 27.3 months (range, 12-43 months). The mean change score for the overall American Orthopaedic Foot & Ankle Surgery scale was 236.8% (SD = 146.62, confidence interval [CI] = 186-287.6). A similar result was achieved between grade II (250.9%, SD = 240.3, CI = 93.9-407.9) and grade III (231.3%, SD = 95.83, CI = 195.14-270.46). No implants were revised or removed, and all patients stated that they were happy with their outcome and would repeat the procedure again if needed. In conclusion, metatarsal head resurfacing in combination with joint decompression, soft tissue mobilization, and debridement can achieve excellent results in grade II and III hallux rigidus. Salvage arthrodesis remains an option if future revisions are indicated.

Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

BACKGROUND: We describe a thick fascial band arising from the medial aspect of the lateral plantar aponeurosis diving deep into the forefoot crossing over a branch of the lateral plantar nerve. Because a review of current literature resulted in limited and outdated sources, we sought to first determine the frequency of this fascial band and the location where it crosses the lateral plantar nerve and, second, discuss the clinical applications these anatomical findings could have. METHODS: 50 pairs of cadaveric feet (n = 100) were dissected to investigate for presence of the fascial band and its interaction with the lateral plantar nerve. Images were taken of each foot with the fascial band. ImageJ was used to take 2 measurements assessing the relationship of the tuberosity of the base of the fifth metatarsal to where the nerve crossed deep to the fascial band. RESULTS: Overall, 38% of the feet possessed the fascial band. It was found unilaterally in 10 pairs and bilaterally in 14 pairs. On average, the point at which the lateral plantar nerve passed deep to the fascial band was 2.0 cm medial and 1.7 cm anterior to the tuberosity of the base of the fifth metatarsal. CONCLUSION: When present, the deep band of the lateral plantar aponeurosis (PA) was consistently found to be crossing the lateral plantar nerve. The discovery of the location where this most commonly occurs has not been previously reported and adds an interesting dimension that elevates an anatomical study to one that has clinical potential. CLINICAL RELEVANCE: The established target zone gives a precise location for where the relationship between the deep band of the lateral PA and the lateral plantar nerve exists when evaluating the foot. The target zone provides a potential springboard for future investigations concerning said relationship clinically.

The role of viscosupplementation in the ankle using hylan G-F 20.

UNLABELLED: The use of intra-articular injections of high molecular weight elastoviscous solutions of hyaluronan or hylans (cross-linked derivatives of hyaluronan) to treat arthritis is termed viscosupplementation. The function of viscosupplementation is to restore the rheologic properties of synovial fluid. Although anecdotal data exist, no long-term studies regarding the use of viscosupplementation in the ankle have been published to date. The goal of this clinical trial was to compare pain reduction following ankle arthroscopy versus that following ankle arthroscopy combined with weekly intra-articular instillation of hylan G-F 20 during the first 3 postoperative weeks. In the series of patients described in this report, we found that both treatment groups experienced statistically significantly decreased pain following the intervention (P = .002 and P = .0009 for the arthroscopy alone and arthroscopy plus hylan groups, respectively), and that those who received 3 intra-articular injections of hylan G-F 20 following ankle arthroscopy improved statistically significantly (P = .0014) more than did those who underwent arthroscopy as a sole therapy. These preliminary results suggest that viscosupplementation combined with arthroscopy may be more beneficial than arthroscopy alone, and provide further insight into the role of viscosupplementation in the treatment of ankle osteoarthritis. LEVEL OF CLINICAL EVIDENCE: 4.

Clinical Outcomes for Diabetic Foot Ulcers Treated with Clostridial Collagenase Ointment or with a Product Containing Silver.

Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with clostridial collagenase ointment (CCO) or silver-containing products, both in combination with sharp debridement as needed. Approach: One hundred two subjects with qualifying DFUs were randomized to daily treatment with either CCO or a silver-containing product for 6 weeks followed by a 4 -week follow-up period. The primary outcome was the mean percent reduction in DFU area. A secondary outcome was the incidence of ulcer infections between groups. Results: At the end of treatment, the mean percent reduction in area from baseline of DFUs treated with CCO was 62% (p < 0.0001) and with silver was 40% (p < 0.0001). The difference between groups-22%-was not statistically significant (p = 0.071). Among ulcers closed by the end of treatment, the mean time to closure was 31.1 ± 9.0 days versus 37.1 ± 7.7 days, respectively (not statistically significant). There was a numerically greater incidence of target ulcer infections in the silver group (11, 21.6%) than in the CCO group (5, 9.8%; p = 0.208). No clinically relevant safety signals were identified in either group. Innovation: CCO treatment can progress a wound toward closure. Ulcer infection prophylaxis may not be sacrificed when treating DFU with CCO in lieu of silver-containing products. Conclusion: Both CCO and silver-containing products promote significant reduction in DFU area over 6 weeks of treatment with no clinically relevant safety concerns. Mean percent reduction in lesion area was numerically (22%) but not significantly greater with CCO compared to silver, as was time to ulcer closure, with an incidence of ulcer infection at least as low as for silver-containing products.

Cost-Effectiveness of Becaplermin Gel on Diabetic Foot Ulcer HealingChanges in Wound Surface Area.

BACKGROUND: A comparison of the cost-effectiveness of becaplermin plus good wound care (BGWC) versus good wound care (GWC) alone in treating patients with diabetic foot ulcers (DFUs) may enable physicians and health-care decision makers in the United States to make better-informed choices about treating DFUs, which currently contribute to a substantial portion of the economic burden of diabetes. METHODS: Data from three phase III trials were used to predict expected 1-year costs and outcomes, including the average percentage reduction from baseline in wound surface area (WSA), the direct costs of DFU therapy, and the cost per cm(2) of WSA reduction. RESULTS: At 20 weeks, the BGWC group had a statistically greater probability of complete wound closure than the GWC group (50% versus 35%; P = .015). Based on reported WSA reduction rates, DFUs in the BGWC group were predicted to close by 100% at 27 weeks, and those in the GWC group were predicted to close by 88% at 52 weeks. The GWC group had higher total estimated 1-year direct cost of DFU care ($6,809 versus $4,414) and higher cost per cm(2) of wound closure ($3,501 versus $2,006). CONCLUSIONS: Becaplermin plus good wound care demonstrated economic dominance compared with GWC by providing better clinical outcomes via faster reduction in WSA and higher rates of closure at a lower direct cost.

Comparing the Knotless Tension Band and the Traditional Stainless Steel Wire Tension Band Fixation for Medial Malleolus Fractures: A Retrospective Clinical Study.

The traditional stainless steel wire tension band (WTB) has been popularized for small avulsion fractures at the medial malleolus. Despite the tension band principle creating a stable construct, complications continue to arise utilizing the traditional stainless steel WTB with patients experiencing hardware irritation at the tension band site and subsequent hardware removal. Coupled with hardware irritation is fatigue failure with the wire. The goal of this investigation was to retrospectively compare this traditional wire technique to an innovative knotless tension band (KTB) technique in order to decrease costly complications. A total of 107 patients were reviewed with a minimum follow-up of 1 year. Outcome measures include descriptive data, fracture classification, results through economic costs, and fixation results (including hardware status, healing status, pain status, and time to healing). The KTB group had a 13% lower true cost as compared to the WTB group while the fixation results were equivocal for the measured outcomes. Our results demonstrate that the innovative KTB is comparable to the traditional WTB while offering a lower true cost, an irritation free reduction all without the frustration of returning to the operating room for additional hardware removal, which averages approximately to $8,288.

Erratum to: Cost-effectiveness of clostridial collagenase ointment on wound closure in patients with diabetic foot ulcers: economic analysis of results from a multicenter, randomized, open-label trial.

[This corrects the article DOI: 10.1186/s13047-015-0065-x.].

Bone matrix therapy for aneurysmal bone cysts.

Aneurysmal bone cysts are unique pathologic entities that cause pain and local osseous destruction. Many surgical treatment modalities have been described. This article reports on the case of a 16-year-old high school athlete with left heel pain due to an aneurysmal bone cyst in the calcaneus. Curettage of the bone cyst was performed, and the void was filled with a commercially available mixture of cancellous bone and demineralized bone matrix. Early return to athletic activity was achieved, with no recurrence noted at 3-year follow-up.

Protein C deficiency: podiatric medical relevance and case report.

We describe the management of a patient who presented to a family-practice clinic with gangrenous digits. After a thorough evaluation, she was found to have protein C deficiency, which produced a hypercoagulable state. Differential diagnosis in the evaluation of the coagulopathic patient with appropriate hematologic tests is briefly discussed.

Cost-effectiveness of clostridial collagenase ointment on wound closure in patients with diabetic foot ulcers: economic analysis of results from a multicenter, randomized, open-label trial.

BACKGROUND: Approximately 10%-15% of people with diabetes develop at least one foot ulcer during their lifetime. Treatment of diabetic foot ulcers (DFUs) represents a significant economic burden. Enzymatic debridement with clostridial collagenase ointment (CCO) can be used to remove necrotic tissue from wounds. This study examined the impact of CCO as an effective adjunct therapy to serial sharp debridement (SSD) and assessed the cost-effectiveness of CCO compared with standard DFU treatments over 1 year. METHODS: Adults 18 years or older with a diagnosis of type 1 or type 2 diabetes who had a neuropathic DFU were enrolled in a 12-week, randomized, open-label trial. Patients were randomly assigned to either treatment with CCO + SSD or to investigator-selected supportive care + SSD (Control). A 3-state Markov model with a 1-week cycle length was developed using wound-closure rates from the trial to estimate the number of healed-wound weeks and the expected DFU cost per patient. The 3 states included unhealed, healed, and death. Results were extrapolated to 1 year to estimate the number of healed-wound weeks per treatment and the average cost to achieve epithelialization. The perspective of the analysis was that of the payer, specifically, the third party payer. RESULTS: The study sample included 55 patients (28 in CCO group; 27 Control). The majority were men (74.5%) with a mean age of 57.9 years. Projected healing rates were greater for the CCO + SSD group compared to Control (89% vs. 80%, respectively). The expected number of epithelialized weeks accumulated over 1 year was 25% greater in the CCO + SSD group than for Control (35 vs. 28 weeks, respectively). Over a 1-year time horizon, the expected cost per DFU was greater in the Control group than the CCO group ($2,376 vs. $2,099, respectively). The estimated cost per ulcer-free week was 40% higher for Control ($85/closed-wound week) than for CCO + SSD ($61/closed-wound week). CONCLUSIONS: CCO + SSD therapy is a cost-effective method of debridement in the management of patients with DFUs, providing better outcomes at a lower cost. Further high quality trials are needed to confirm this finding. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov as NCT01408277.