Intratendinous Injection of Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A 2-Year Follow-Up Study.

PURPOSE: To assess the mid-term safety and efficacy of an intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells (AD MSCs) for rotator cuff disease at 2-year follow-up. METHODS: The first part of the study consisted of 3 dose-escalation groups, with 3 patients each, for the evaluation of safety: low-dose (1.0 × 107 cells), mid-dose (5.0 × 107), and high-dose (1.0 × 108) groups. For the second part, we planned to include 9 patients receiving the high dose for the evaluation of exploratory efficacy. Clinical outcomes were assessed according to pain, range of motion, muscle strength, functional scores, overall satisfaction and function, and presence of failure. Structural outcomes included changes in volume of tendon defects measured using magnetic resonance imaging. RESULTS: This study enrolled 19 patients (9 for the first part and 10 for the second part) with partial-thickness rotator cuff tears. There were no treatment-related adverse events at minimum 2-year follow-up. Intratendinous injection of AD MSCs reduced shoulder pain by approximately 90% at 1 and 2 years in the mid- and high-dose groups. The strength of the supraspinatus, infraspinatus, and teres minor significantly increased by greater than 50% at 2 years in the high-dose group. Shoulder function measured with 6 commonly used scores improved for up to 2 years in all dose groups. Structural outcomes evaluated with magnetic resonance imaging showed that the volume of bursal-sided defects in the high-dose group nearly disappeared at 1 year and did not recur at up to 2 years. No failures-defined as the performance of any kind of shoulder surgery or return of the Shoulder Pain and Disability Index score to the preinjection level-occurred during follow-up. CONCLUSIONS: This study showed continued safety and efficacy of an intratendinous injection of AD MSCs for the treatment of partial-thickness rotator cuff tears over a 2-year period through regeneration of tendon defects. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Intratendinous Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A First-In-Human Trial.

Despite relatively good results of current symptomatic treatments for rotator cuff disease, there has been an unmet need for fundamental treatments to halt or reverse the progress of disease. The purpose of this study was to assess the safety and efficacy of intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells (AD MSCs) in patients with rotator cuff disease. The first part of the study consists of three dose-escalation cohorts; the low- (1.0 × 107 cells), mid- (5.0 × 107 ), and high-dose (1.0 × 108 ) groups with three patients each for the evaluation of the safety and tolerability. The second part included nine patients receiving the high-dose for the evaluation of the exploratory efficacy. The primary outcomes were the safety and the shoulder pain and disability index (SPADI). Secondary outcomes included clinical, radiological, and arthroscopic evaluations. Twenty patients were enrolled in the study, and two patients were excluded. Intratendinous injection of AD MSCs was not associated with adverse events. It significantly decreased the SPADI scores by 80% and 77% in the mid- and high-dose groups, respectively. Shoulder pain was significantly alleviated by 71% in the high-dose group. Magnetic resonance imaging examination showed that volume of the bursal-side defect significantly decreased by 90% in the high-dose group. Arthroscopic examination demonstrated that volume of the articular- and bursal-side defects decreased by 83% and 90% in the mid- and high-dose groups, respectively. Intratendinous injection of autologous AD MSCs in patient with a partial-thickness rotator cuff tear did not cause adverse events, but improved shoulder function, and relieved pain through regeneration of rotator cuff tendon. Stem Cells 2018;36:1441-1450.

Dermatofibrosarcoma protuberans: A retrospective study of clinicopathologic features and related Akt/mTOR, STAT3, ERK, cyclin D1, and PD-L1 expression.

BACKGROUND: Little is known regarding oncoproteins other than platelet-derived growth factor subunit B in dermatofibrosarcoma protuberans (DFSP). Moreover, the risk factors for worse prognosis are controversial. OBJECTIVE: We sought to determine the clinicopathologic features and key factors for adverse outcome in DFSP, including the implication of expression of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), extracellular signal regulated kinase (ERK), cyclin D1, and programmed death ligand 1 (PD-L1). METHODS: Clinicopathologic and immunohistochemical analyses were performed for 44 DFSPs having wide local excision and 92 dermatofibromas as controls. RESULTS: Compared with the 35 nonrecurrent DFSPs, the 9 recurrent DFSPs exhibited larger tumor size, deeper invasion beyond the subcutis, and more diverse histologic subtype. The fibrosarcomatous subtype revealed frequent mitotic figures and a high cyclin D1-positive index. The 2 metastatic DFSPs (1 each of the fibrosarcomatous and myxoid subtypes) demonstrated 4 and 11 instances of local recurrence, respectively, as well as larger tumor size, deeper invasion beyond the subcutis, and high expression of cyclin D1. Expression of Akt/mTOR, STAT3, ERK, and PD-L1 ranged from none or low in the primary skin lesions to high in the corresponding metastatic sites. Akt/mTOR and ERK were expressed more frequently in DFSP than in dermatofibroma. LIMITATIONS: Lack of information on patients before hospital evaluation. CONCLUSION: Complex factors beyond fibrosarcomatous subtype may portend local recurrence or metastasis. Akt/mTOR, STAT3, ERK, and PD-L1 may be associated with development and/or progression of DFSP.

Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A 2-Year Follow-up Study.

BACKGROUND: The intra-articular injection of mesenchymal stem cells (MSCs) into the knee has shown a potential for the treatment of generalized cartilage loss in osteoarthritis (OA). However, there have been few midterm reports with clinical and structural outcomes. PURPOSE: To assess the midterm safety and efficacy of an intra-articular injection of autologous adipose tissue-derived (AD) MSCs for knee OA at 2-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Eighteen patients with OA of the knee were enrolled (3 male, 15 female; mean age, 61.8 ± 6.6 years [range, 52-72 years]). Patients in the low-, medium-, and high-dose groups received an intra-articular injection of 1.0 × 107, 5.0 × 107, and 1.0 × 108 AD MSCs into the knee, respectively. Clinical and structural evaluations were performed with widely used methodologies including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and measurements of the size and depth of the cartilage defect, signal intensity of regenerated cartilage, and cartilage volume using magnetic resonance imaging (MRI). RESULTS: There were no treatment-related adverse events during the 2-year period. An intra-articular injection of autologous AD MSCs improved knee function, as measured with the WOMAC, Knee Society clinical rating system (KSS), and Knee injury and Osteoarthritis Outcome Score (KOOS), and reduced knee pain, as measured with the visual analog scale (VAS), for up to 2 years regardless of the cell dosage. However, statistical significance was found mainly in the high-dose group. Clinical outcomes tended to deteriorate after 1 year in the low- and medium-dose groups, whereas those in the high-dose group plateaued until 2 years. The structural outcomes evaluated with MRI also showed similar trends. CONCLUSION: This study identified the safety and efficacy of an intra-articular injection of AD MSCs into the OA knee over 2 years, encouraging a larger randomized clinical trial. However, this study also showed potential concerns about the durability of clinical and structural outcomes, suggesting the need for further studies. CLINICAL TRIAL REGISTRATION: NCT01300598.

Cosmetic Lateral Canthoplasty: Preserving the Lateral Canthal Angle.

Cosmetic lateral canthoplasty, in which the size of the eye is increased by extending the palpebral fissure and decreasing the degree of the eye slant, has become a prevalent procedure for East Asians. However, it is not uncommon for there to be complications or unfavorable results after the surgery. With this in mind, the authors have designed a surgical method to reduce complications in cosmetic lateral canthoplasty by preserving the lateral canthal angle. We discuss here the anatomy required for surgery, the surgical methods, and methods for reducing complications during cosmetic lateral canthoplasty.

Orbital Floor Fracture.

The medial wall and floor of the bony orbit are frequently fractured because of the delicate anatomy. To optimize functional and aesthetic results, reconstructive surgeons should understand the anatomy and pathophysiology of orbital fractures. Appropriate treatment involves optimal timing of intervention, proper indications for operative repair, incision and dissection, release of herniated tissue, implant material and placement, and wound closure. The following review will discuss the management of orbital floor fractures, with the operative method preferred by the author. Special considerations in operation technique and the complication are also present in this article.

Compartment syndrome due to extravasation of peripheral parenteral nutrition: extravasation injury of parenteral nutrition.

Compartment syndrome is a rare but devastating condition that can result in permanent neuromuscular or soft tissue injuries. Extravasation injuries, among the iatrogenic causes of compartment syndrome, occur under a wide variety of circumstances in the inpatient setting. Total parenteral nutrition via a peripheral route is an effective alternative for the management of critically ill children who do not obtain adequate nutrition via the oral route. However, there is an inherent risk of extravasation, which can cause compartment syndrome, especially when detected at a later stage. Herein, we report a rare case of compartment syndrome and skin necrosis due to extravasation, requiring emergency fasciotomy and skin graft in a 7-month-old boy who was treated with peripheral parenteral nutrition via a pressurized infusion pump. Although we cannot estimate the exact time at which extravasation occurred, the extent and degree of the wound suggest that the ischemic insult was prolonged, lasting for several hours. Pediatric clinicians and medical teams should carefully examine the site of insertion of the intravenous catheter, especially in patients receiving parenteral nutrition via a peripheral intravenous catheter with a pressurized infusion pump.

Medial and lateral canthal reconstruction with an orbicularis oculi myocutaneous island flap.

BACKGROUND: The eyelid and canthal areas are common locations for cutaneous tumors. The medial canthus includes, among many other apparatuses, the canthal tendon and lacrimal canaliculi, and its characteristic thin and supple skin is hard to mimic and restore using tissue from other regions. Accordingly, reconstruction of the canthal area can prove challenging for surgeons. Although various methods, such as skin grafts and local flaps from adjacent regions, have been utilized for reconstructive purposes, they present known disadvantages. However, we were able to successfully reconstruct both lateral and medial canthal area defects by using orbicularis oculi myocutaneous island flaps. METHODS: Our study included seven patients who underwent medial or lateral canthal region reconstruction, using orbicularis oculi myocutaneous island flaps, between 2011 and 2014, following either cutaneous tumor excision or traumatic avulsion injury. RESULTS: Five patients had basal cell carcinoma, one had squamous cell carcinoma of the eyelid, and one had sustained a traumatic avulsion injury of the eyelid and canthal area. Entire flap loss was not observed in any patient, but one-a heavy smoker-showed partial flap loss, which healed with secondary intention and yielded acceptable results. Donor site morbidity was not observed, and all patients were satisfied with their surgical outcomes. CONCLUSIONS: The canthal regions can be successfully reconstructed with orbicularis oculi myocutaneous island flaps. These flaps offer several key advantages, including similarity in texture, color, and thickness to the recipient site and a negligible incidence of donor site morbidity.

Three-dimensional pre-bent titanium implant for concomitant orbital floor and medial wall fractures in an East asian population.

BACKGROUND: The objective of this article is to evaluate clinical outcomes of combined orbital floor and medial wall fracture repair using a three-dimensional pre-bent titanium implant in an East Asian population. METHODS: Clinical and radiologic data were analyzed for 11 patients with concomitant orbital floor and medial wall fractures. A combined transcaruncular and inferior fornix approach with lateral canthotomy was used for the exposure of fractures. An appropriate three-dimensional preformed titanium implant was selected and inserted according to the characteristics of a given defect. RESULTS: Follow-up time ranged from 2 to 6 months (median, 4.07 months). All patients had a successful treatment outcome without any complications. Clinically significant enophthalmos was not observed after treatment. CONCLUSIONS: Three-dimensional pre-bent titanium implants are appropriate for use in the East Asian population, with a high success rate of anatomic restoration of the orbital volume and prevention of enophthalmos in combined orbital floor and medial wall fracture cases.

Modified transconjunctival lower lid approach for orbital fractures in East Asian patients: the lateral paracanthal incision revisited.

BACKGROUND: Optimal repair of an orbital fracture requires adequate exposure into the orbit. The transconjunctival approach with lateral canthotomy is a valid option in East Asian patients, who are especially sensitive to the appearance of an external skin scar, although one must also recognize the potential complications associated with eyelid aperture mechanics. The authors report the modification of the transconjunctival approach, in which a lateral paracanthal incision is made along with division of the lateral tarsal plate but not at the lateral canthus. This was developed to overcome the complications of traditional lateral cantholysis. METHODS: A retrospective chart review was performed for all patients who had received the modified transconjunctival incision. Patient demographics, injury characteristics, and surgical outcomes were evaluated. RESULTS: The baseline demographics of 30 patients in this study was typical of orbital fractures in the Korean population. A take-back operation was required in one case of preseptal hematoma. The mean follow-up period was 6 months, and no long-term functional complications were identified. Of the 30 total patients, 29 showed excellent aesthetic outcome. One patient did present with postoperative notch deformity but did not feel the need for a revision operation. CONCLUSIONS: The transconjunctival approach with a lateral paracanthal incision is an alternative approach to the orbital wall. The decoupling of the lower eyelid through the lateral portion of the tarsal plate provides excellent exposure of the orbital floor and provides a reliable and consistent landmark by which the anatomy of the eyelid can be restored. The aesthetic and functional outcomes are excellent. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 10(7) cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.

The effect of botulinum toxin A on fat graft survival.

BACKGROUND: Autologous fat grafting is a common procedure used in plastic surgery to correct soft tissue deficiency or depression deformity. However, absorption of grafted fat in the recipient area is unpredictable, and various methods for improving fat survival have been developed clinically. This study analyzed the changes and viability of injected fat in relation to the effects of botulinum neurotoxin type A (BoNTA). METHODS: Fat tissue was harvested from the pre-urinary bladder cavity of four Sprague-Dawley rats and processed using the Coleman technique. The experiment was performed on the backs of eight BALB/c-nu mice. The injection of free fat grafts was performed on the bilateral side of the back of each mouse. The one side (experimental) was treated with 0.5 ml of a free fat injection combined with 0.5 IU of BoNTA in 0.1 ml of saline. The other side (control) was treated with 0.5 ml of free fat injection combined with 0.1 ml of saline. The mice were killed after 9 weeks, and the injected fat grafts were explanted, after which the weight and volume were measured. Histologic study was performed with hematoxylin and eosin staining. Statistical analysis of the weight and volume from both sides, the histologic parameters, and cellular integrity was performed. CONCLUSION: A difference in the weight, volume, and histologic parameters of the injected fat grafts was observed. The BoNTA-treated side exhibited a significantly higher survival rate than the control side. The histologic examination of the fat grafts also demonstrated that the grade scale of cellular integrity was higher for the BoNTA-treated sides. Botulinum toxin A significantly reduces the level of fat graft resorption. Therefore, an injected fat graft can be used in conjunction with botulinum toxin A and offers better volumetric improvement. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

Correction of inverted nipple: an alternative method using two triangular areolar dermal flaps.

Inverted nipple, which is defined as a nipple located on a plane lower than the areola, presents both functional and cosmetic problems. It is a source of repeated irritation and inflammation, and interferes with nursing. In addition, its abnormal appearance may cause psychological distress. Inverted nipples are congenital or acquired, and are classified as the umbilicated and invaginated types or divided into 3 groups (grades 1, 2, and 3). With consideration of its underlying pathophysiologic components and severity, various surgical procedures have been proposed. For correcting the inverted nipple, the authors introduce an alternative, simple method using 2 triangular areolar dermal flaps. Compared with other methods using triangular areolar dermal flaps, each triangle is approximately 1 mm shorter than the diameter of the nipple, and the deepithelialized areolar dermal flaps are lodged at the slit in the bundle of the lactiferous ducts in the grade 2 inverted nipple. From August 2000 to December 2001, 11 patients (16 nipples) were treated. Five patients had bilateral inverted nipples. Patient age at operation ranged from 18 to 31 years (mean age, 27 years). All nipples were congenital and they had no previous operation. Thirteen nipples were grade 2 and 3 were grade 3 according to the classification of inverted nipple by Han and Hong. The mean follow-up period was 8.7 months (range, 3-12 months). Follow-up examinations revealed no evidence of recurrence of inversion. There was no complication associated with surgery, such as infection, hematoma, permanent sensory disturbance, or nipple necrosis. The resulting scars were minimal. All patients were satisfied with their results. The authors conclude that their procedure is reliable, preserves the lactiferous ducts in grade 2 inverted nipple, requires no special postoperative care, and leaves minimal scars and no recurrence of inversion. This technique can be applied to any type of inverted nipple as a primary surgical procedure.