Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis.

RATIONALE: Central nervous system has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for vascular barrier in central nervous system, suppressed transcytosis in endothelial cells is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts, but its role in the maintenance of vascular barrier in central nervous system remains unknown. OBJECTIVE: To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage. METHODS AND RESULTS: We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial endothelial cells, leading to nonhemorrhagic leakage predominantly in the superficial retinal layer. Endothelial Sox17 deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Ang II (angiotensin II)-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal endothelial cells suggests that Dll4 blocking activates SREBP1 (sterol regulatory element-binding protein 1)-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF (vascular endothelial growth factor) signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 (VEGF receptor 2) signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage. CONCLUSIONS: In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.

Compact Fat Grafting: A Novel Method to Improve Graft Retention Through Modulation of Adipocyte Size.

BACKGROUND: The viable zone where adipocytes and/or adipose-derived stem cells survive is present at the surface of graft fat tissue; however, there is controversy regarding the zone thickness. Graft retention could be improved if more adipocytes are included in the zone. OBJECTIVES: We hypothesize that a temporary reduction in adipocyte size prior to grafting could increase the number of adipocytes in the viable zone. We reduced the adipocyte size by treatment with MLN4924, which controls lipid accumulation in adipocytes, and investigated the histological and microenvironmental changes in grafted fat. METHODS: Subcutaneous fat harvested from wild-type C57BL/6J mice was chopped into small pieces; treated with dimethyl sulfoxide (control group), 0.25 µM MLN4924, or 0.5 µM MLN4924 for 4 days; and grafted into recipient C57BL/6J mice at the supraperiosteal plane of the skull. RESULTS: The reduced adipocyte size in response to MLN4924 treatment was restored within 8 weeks after fat grafting. The MLN4924-treated groups exhibited substantially greater graft volume, lower tissue hypoxia, and higher production of M2 macrophages compared with the control group. CONCLUSIONS: Grafting with compact fat that had smaller adipocytes improved the microenvironment by modulating tissue hypoxia and macrophage polarization, leading to improved graft retention. Therefore, compact fat grafting may offer a new clinical strategy without the need for stem cell manipulation.

Analysis of the Molecular Signature of Breast Implant-Associated Anaplastic Large Cell Lymphoma in an Asian Patient.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)-a new category of anaplastic large cell lymphoma associated with textured breast implants-has a distinct variation in incidence and is especially rare in Asia. We report the first case of BIA-ALCL in Korea and present its histological and genetic characteristics. A 44-year-old female patient presented with a typical clinical course and symptoms, including breast augmentation with textured breast implants, late-onset peri-implant effusion, and CD30+ALK- histology, followed by bilateral implant removal and total capsulectomy. For histological analysis, we performed immunohistochemistry of the bilateral breast capsules. For transcriptome analysis, we identified highly upregulated gene sets employing RNA-sequencing and characterized the lymphoma immune cell components. In the lymphoma-associated capsule, CD30+ cells infiltrated not only the lymphoma lesion but also the peritumoral lesion. The morphologies of the myofibroblasts and vessels in the peritumoral lesion were similar to those in the tumoral lesion. We observed strong activation of the JAK/STAT3 pathway and expression of programmed death ligand-1 in the lymphoma. Unlike the molecular profiles of BIA-ALCL samples from Caucasian patients-all of which contained activated CD4+ T cells-the Asian patient's profile was characterized by more abundant CD8+ T cells. This study contributes to a better understanding of the pathogenesis and molecular mechanisms of BIA-ALCL in Asian patients that will ultimately facilitate the development of clinical therapies.

Big Data Statistical Analysis of Facial Fractures in Korea.

BACKGROUND: The big data provided by Health Insurance Review and Assessment (HIRA) contains data from nearly all Korean populations enrolled in the National Health Insurance Service. We aimed to identify the incidence of facial fractures and its trends in Korea using this big data from HIRA. METHODS: We used the Korean Standard Classification of Disease and Cause of Death 6, 7 for diagnosis codes. A total of 582,318 patients were included in the final analysis. All statistical analyses were performed using SAS software and SPSS software. RESULTS: The incidence of facial fractures consistently declined, from 107,695 cases in 2011 to 87,306 cases in 2016. The incidence of facial fractures was the highest in June 2011 (n = 26,423) and lowest in January 2014 (n = 10,282). Nasal bone fractures were the most common, followed by orbit and frontal sinus fractures. The percentage of nasal bone fractures declined, whereas those of orbital fractures increased from 2011 to 2016 (P < 0.001). Among orbital fractures, inferior wall fractures were the most common, followed by medial wall fractures. Among mandibular fractures, angle fractures were the most common, followed by condylar process and symphysis fractures. Although it was difficult to predict the most common type of zygomatic and maxilla fractures, their incidence consistently declined since 2011. CONCLUSION: We observed trends in facial fractures in Korea using big data including information for nearly all nations in Korea. Therefore, it is possible to predict the incidence of facial fractures. This study is meaningful in that it is the first study that investigated the incidence of facial fractures by specific type.

Single-stage cross-facial nerve grafting has a result equivalent to that of two-stage cross-facial nerve grafting.

BACKGROUNDS: Cross-face nerve grafting (CFNG) is an important treatment for patients with facial palsy. Currently, two-stage CFNG is frequently performed. CFNG is performed first, followed by coaptation when innervation reaches the grafted nerve ending. The present study compared single-stage CFNG with conventional two-stage CFNG. METHODS: We retrospectively reviewed data of 17 patients who underwent CFNG with zygomatic and buccal branch with hypoglossal crossover. Patients with single-stage (group 1) and two-stage (group 2) CFNG were comparatively analyzed 2 years postoperatively. There were nine and eight patients in groups 1 and 2, respectively. The patient's perioperative status was measured with imaging and animation using the Yanagihara grade, altitude, and angle differences of the oral commissure and eye closure. RESULTS: Patients in group 1 could recognize their first postoperative spontaneous movement earlier than those in group 2 (268.3 ± 25.1 days vs. 327.5 ± 51.3 days, respectively, p = 0.015). The Yanagihara grade significantly improved for patients in both groups postoperatively (group 1: 12.8 ± 5.5 to 25.3 ± 6.1, p < 0.01; group 2: 12.4 ± 5.6 to 24.3 ± 5.0, p = 0.012). Height and angle difference of the oral commissure showed a significant improvement during resting and smiling in both groups. Eye closure also showed significant improvement in both groups (group 1: 4.1 ± 0.6 to 2.6 ± 0.5, p < 0.01; group 2: 4.0 ± 0.5 to 2.8 ± 0.7, p < 0.01). There was no significant difference in the postoperative improvement rate between the groups. CONCLUSIONS: Single-stage CFNG shows results equivalent to those of two-stage CFNG. Single-stage CFNG is associated with a shorter treatment period and fewer operations.

Inhibition Mechanism of Acellular Dermal Matrix on Capsule Formation in Expander-Implant Breast Reconstruction After Postmastectomy Radiotherapy.

BACKGROUND: Capsular contracture is one of the most common complications of expander-implant breast reconstruction. Recently, clinical reports have shown that use of an acellular dermal matrix (ADM) to cover breast implants decreases incidence of capsular contracture, but the underlying mechanism is unclear. Here, we examine how ADM reduces capsular formation in expander-implant breast reconstruction and identify cellular and molecular mechanisms of ADM-mediated reduction of capsular contracture in nonirradiated and irradiated patients. METHODS: Thirty patients who underwent immediate two-stage implant-based breast reconstruction were included; 15 received radiotherapy. While the tissue expander was changed to permanent silicone implant, biopsies of the subpectoral capsule and ADM capsule were performed. Capsule thickness, immunohistochemistry of α-smooth muscle actin (αSMA), vimentin, CD31, F4/80 expression, αSMA and CD31 coexpression, and relative gene expression levels of transforming growth factor (TGF)-ß1 and platelet-derived growth factor (PDGF)-B were investigated. RESULTS: Irradiated submuscular capsules were thicker than nonirradiated submuscular capsules, but the thickness of ADM capsules did not significantly differ between nonirradiated and irradiated groups. Levels of myofibroblasts, fibroblasts, vascularity, EndoMT, and macrophages were significantly lower in ADM capsules than in submuscular capsules. With the exception of EndoMT, all others were increased in irradiated submuscular capsules compared with nonirradiated submuscular capsule, while none significantly differed between nonirradiated and irradiated ADM capsules. CONCLUSIONS: Use of ADM reduced myofibroblasts, vascularity, fibroblasts, and EndoMT in capsule tissues. Moreover, ADM use decreased macrophages, a key regulator of tissue fibrosis, as well as TGF-ß1 and PDGF-B expression. We hope that these results provide basic concepts important for prevention of capsular contracture.

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling.

RATIONALE: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. OBJECTIVE: To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling. METHODS AND RESULTS: Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF. CONCLUSIONS: Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.

Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm.

BACKGROUND: Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. METHODS AND RESULTS: The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. CONCLUSIONS: Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.

Correction of orbital wall fracture close to the optic canal using computer-assisted navigation surgery.

BACKGROUND: Repairing orbital wall fractures can result in serious complications, including enophthalmos, diplopia, or even blindness. Especially, surgeons worry about damaging the optic nerve while dissecting the optic canal area. We avoid these complications by using a navigation system that was adapted to stereotactic concept based on three-dimensional imaging of the patient's anatomy. Here, we report 5 cases of orbital wall fracture that were repaired using a navigation system. METHODS: The Navigation System II (Stryker, Freiburg, Germany) and the iNtellect Cranial Navigation (version 1.1) platform were used for each operation. A computer-assisted navigation surgery was performed according to the following procedures: (1) image set, (2) planning, (3) apparatus setup, (4) registration, and (5) intraoperative navigation. Operations were performed under general anesthesia. Dissection was performed up to the periosteum immediately anterior to the optic canal, near the fracture. Vulnerable surrounding structures were identified with the intraoperative pointer. After navigation, we inserted an implant into the defect, successfully, avoiding damage to the optic canal and optic nerve. RESULTS: None of the patients had any surgical complications. Postoperative computed tomography scans demonstrated that the fractures were corrected, and continuity was maintained without displacement. The three-dimensional image allowed us to easily visualize intraoperative anatomical structure, allowing us to avoid unnecessary procedures and to correct the orbital wall. The mean volume of fractured orbital cavity was 29.2 cm(3) (range, 28.3-30.4 cm(3)) preoperatively and 27.0 cm(3) (range, 25.9-28.5 cm(3)) postoperatively; thus, the defects were corrected by 2.2 cm(3) (range, 1.3-2.8 cm(3)) on average. CONCLUSIONS: We used a navigation system to perform accurate and safe surgery in patients with extensive orbital wall fracture, including around the optic canal. By using the functions to visualize the locations indicated by the pointer, we were able to perform successful dissections and implantations in areas adjacent to the optic canal. The good outcomes obtained here provide evidence that surgical correction of the orbital wall using a navigation system is useful in cases of deep, extensive orbital wall fracture.

Breast Reconstruction after Breast Implant-Associated Anaplastic Large Cell Lymphoma Treatment: A Case Report and Literature Review.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell non-Hodgkin's lymphoma that occurs in patients with at least one prior textured breast implant. BIA-ALCL has a relatively good prognosis when treated promptly. However, data on the methods and timing of the reconstruction process are lacking. Herein, we report the first case of BIA-ALCL in Republic of Korea in a patient who underwent breast reconstruction using implants and an acellular dermal matrix (ADM). A 47-year-old female patient was diagnosed with BIA-ALCL stage IIA (T4N0M0) and underwent bilateral breast augmentation using textured breast implants. She then underwent removal of both breast implants, total bilateral capsulectomy, adjuvant chemotherapy, and radiotherapy. There was no evidence of recurrence at 28 months postoperatively; therefore, the patient wished to undergo breast reconstruction surgery. A smooth surface implant was used to consider the patient's desired breast volume and body mass index. The right breast was reconstructed with a smooth surface implant and an ADM in the prepectoral plane. Breast augmentation was performed on the left breast using a smooth surface implant. The patient was satisfied with the results and recovered fully with no complications.

Effects of an Antiadhesive Agent on Capsule Formation in Implant-Based Breast Reconstruction: A Randomized Controlled Trial.

BACKGROUND: Although implant-based breast reconstruction is a common surgical modality, a periprosthetic capsule inevitably forms and worsens in cases of postmastectomy radiation therapy. Previous animal studies have reported that antiadhesive agents (AAAs) inhibit periprosthetic capsule formation. The authors prospectively examined the clinical effects of an AAA (Mediclore) on capsule formation in implant-based breast reconstruction. METHODS: The authors analyzed patients who underwent immediate two-stage implant-based breast reconstruction following total mastectomy for breast malignancy between November of 2018 and March of 2019. Each patient was randomly allocated to the control or AAA group. After inserting the breast expander and acellular dermal matrix, AAA was applied around the expander before skin closure. The capsule specimen was obtained during the expander-implant change; capsule thickness and immunohistochemistry were investigated. RESULTS: A total of 48 patients were enrolled and allocated to the control ( n = 22) and AAA ( n = 26) groups. There were no significant differences in patient- and operation-related characteristics. Submuscular capsule thickness was significantly reduced in the AAA group compared with the control group. The levels of pro-capsular-forming cells (myofibroblasts, fibroblasts, and M1 macrophages) in the capsule were significantly lower in the AAA group than in the control group. CONCLUSIONS: AAA reduced the thickness of periprosthetic capsules and changed the profiles of cells involved in capsule formation during the tissue expansion. These findings demonstrate the clinical value of AAA for mitigating capsule formation in implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Long-Term Ultrasonographic and Histologic Changes in Acellular Dermal Matrix in Implant-Based Breast Reconstructions.

BACKGROUND: Acellular dermal matrix (ADM) is composed of extracellular matrix (ECM) and is widely used in implant-based breast reconstructions. However, long-term changes in the ADM around implants have not been established. This study aimed to investigate long-term changes in the ADM covering breast implants using serial ultrasound and histologic evaluations. METHODS: The authors evaluated the ultrasound results of 145 patients who underwent implant-based breast reconstructions with ADM coverings. The ultrasound results obtained within 18 months of surgery and those obtained 5 years postoperatively were analyzed to determine the change in ADM thickness. For histologic analysis, the ADM was harvested from 30 patients who underwent secondary breast surgery. Histologic features of the ECM and cellular components within the ADM were compared at specific intervals from ADM implantation and the second operation (early ADM group, <18 months; late ADM group, >5 years postoperatively). RESULTS: The ADM thickness on ultrasound examination was significantly decreased in the late ADM group compared with that in the early ADM group ( P < 0.001). Histologic analyses revealed that the late ADM group had less thickness with lower ECM levels versus the early ADM group. Increased infiltration of host cells, such as vascular endothelial cells, myofibroblasts, and immune cells, occurred in the late ADM group. CONCLUSIONS: Implanted ADMs underwent gradual thinning over time, in addition to ECM reduction and infiltration of host cells. These findings are useful in understanding the natural course of ADMs currently used in implant-based breast reconstructions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Implantation and tracing of green fluorescent protein-expressing adipose-derived stem cells in peri-implant capsular fibrosis.

BACKGROUND: Adipose-derived stem cells (ASCs) have been reported to reduce fibrosis in various tissues. In this study, we investigated the inhibitory role of ASCs on capsule formation by analyzing the histologic, cellular, and molecular changes in a mouse model of peri-implant fibrosis. We also investigated the fate and distribution of ASCs in the peri-implant capsule. METHODS: To establish a peri-implant fibrosis model, customized silicone implants were inserted into the dorsal site of C57BL/6 wild-type mice. ASCs were harvested from the fat tissues of transgenic mice that express a green fluorescent protein (GFP-ASCs) and then injected into the peri-implant space of recipient mice. The peri-implant tissues were harvested from postoperative week 2 to 8. We measured the capsule thickness, distribution, and differentiation of GFP-ASCs, as well as the cellular and molecular changes in capsular tissue following ASC treatment. RESULTS: Injected GFP-ASCs were distributed within the peri-implant capsule and proliferated. Administration of ASCs reduced the capsule thickness, decreased the number of myofibroblasts and macrophages in the capsule, and decreased the mRNA level of fibrogenic genes within the peri-implant tissue. Angiogenesis was enhanced due to trans-differentiation of ASCs into vascular endothelial cells, and tissue hypoxia was relieved upon ASC treatment. CONCLUSIONS: We uncovered that implanted ASCs inhibit capsule formation around the implant by characterizing a series of biological alterations upon ASC treatment and the fate of injected ASCs. These findings highlight the value of ASCs for future clinical applications in the prevention of capsular contracture after implant-based reconstruction surgery.

Reconstruction of lower extremity complex wounds with combined free tissue transfer using the anterolateral thigh flap as a link.

In this report, the authors present the experience on the reconstruction of the totally degloved foot and extremely long soft tissue defect of a lower limb with the combined free tissue transfer using the anterolateral thigh flap as a link in two male patients between October 2009 and December 2010. The anterolateral thigh flap has been commonly used as a link between the recipient site and the distal flap. The anterolateral thigh flap and latissimus dorsi muscle flap were selected for the distal flap, according to their reconstructive needs. Two combined free flaps survived without major complication. The authors could salvage of the lower extremity through the reconstruction of complex wound with the combined free tissue transfer using the anterolateral thigh flap as a link. This combined flap may be an alternative for reconstruction of complex soft tissue defect in the lower extremity.

Surgical correction of gynecomastia with minimal scarring.

BACKGROUND: Gynecomastia is a benign, excessive development of the male breast that occurs at an overall incidence of 32-36 %. The authors effectively removed peripheral fat tissues with power-assisted liposuction (PAL) and periareolar glandular tissues with a cartilage shaver in a series of patients. The small periareolar incisions were not easily recognized. METHODS: Between February 2010 and April 2012, the charts of 15 patients (28 breasts) treated with PAL and a cartilage shaver were retrospectively reviewed. RESULTS: The mean volume of fat tissue removed with liposuction was 319 mL, and the mean volume of glandular tissue removed with the cartilage shaver was 70 mL. The mean follow-up period was 11.2 months. No infection, nipple-areola complex necrosis, nipple retraction, or saucer deformity was encountered in this series. Intraoperative bleeding occurred in one patient. Mild asymmetries developed in three patients. CONCLUSIONS: Use of PAL and a cartilage shaver for the treatment of gynecomastia allows for effective removal of both the fat and the glandular tissue of the breast through a minimal periareolar incision. This technique can achieve excellent aesthetic results with inconspicuous scarring. LEVEL OF EVIDENCE IV: 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 www.springer.com/00266 .

Prevention of Abdominal Bulging Using Onlay Dermal Autografts from Discarded Zone IV TRAM Flap Tissue.

While the transverse rectus abdominis myocutaneous (TRAM) flap is a popular option for abdominal-based breast reconstruction, abdominal wall morbidities such as bulging or hernia remain a concern. Here, we introduced a surgical technique for reinforcing the abdominal wall using an onlay autograft obtained from discarded zone IV tissue following a primary closure. We compared abdominal wall morbidities between patients receiving an onlay graft and those receiving primary closure only. We retrospectively reviewed the medical charts of patients who underwent breast reconstruction using a TRAM flap between December 2018 and May 2021. Additionally, we assessed donor-site morbidities based on physical examination. Of the 79 patients included, 38 had received a dermal graft and 41 had not. Donor-site morbidities occurred in 10 (24.5%) and 1 (2.6%) patients, and bulging occurred in 8 (19.5%) and 1 (2.6%) patients in the primary closure and dermal autograft groups, respectively. A statistically significant difference in the incidence of bulging was observed between the groups (p = 0.030). In conclusion, the introduction of a dermal autograft after primary closure can successfully ameliorate morbidities at the TRAM flap site.

Abnormal Ultrasonographic Findings of Acellular Dermal Matrix in Implant-Based Breast Reconstruction: Correlations with Histopathology.

BACKGROUND: Acellular dermal matrix (ADM) in implant-based breast reconstruction can show various ultrasound (US) findings. However, there are limited reports on the US features of the ADM. The aims of this study were to evaluate US findings of the ADM in implant-based breast reconstruction and correlate them with histopathological findings. METHODS: Between January 2015 and August 2020, 250 women who underwent implant-based breast reconstruction with ADM and a breast US examination at 6 months to 1 year after reconstruction were retrospectively analyzed. Abnormal US findings were classified as type 1 (focal thickening with decreased echogenicity), 2 (diffusely hyperechoic), or 3 (bright echogenic spots). ADM biopsy was performed in 33 patients who underwent second stage or revisional surgeries. RESULTS: In total, 176 consecutive women with 207 US findings were analyzed. The US findings were normal in 52.2% of the women. The percentages of type 1, 2, and 3 patients were 13.5%, 11.1%, and 23. 2%, respectively. These patients had microscopic findings that showed patchy areas with chronic inflammatory infiltrates, dense collagen bundles without degenerative or inflammatory changes, and empty spaces or degenerated foci unaccompanied by inflammation. CONCLUSION: Knowing the various ADM presentations on US can help avoid unnecessary invasive procedures.

Dll4 Inhibition Promotes Graft Retention in Fat Grafting Enriched with Adipose-Derived Stem Cells.

Autologous fat grafting is among the safest and most effective treatments for soft-tissue restoration and augmentation, and many efforts have been made to improve its efficiency, including adipose-derived stem cell (ASC) supplementation. Here, we investigated the role of Notch ligand Delta-like ligand 4 (Dll4) in angiogenesis within grafted fat and its effect on graft retention, as well as the effect of Dll4 inhibition on ASC supplementation. Using a murine fat graft model, we investigated the expression of Dll4 in fat grafts and assessed the graft volume, vascularity, and perfusion within the graft, and ASC differentiation patterns depending on the blockade of Dll4. The underlying mechanism of Dll4 inhibition on ASC supplemented fat grafts was investigated using transcriptome analysis. Dll4 was highly expressed in vascular endothelial cells (ECs) within grafted fat, where Dll4-blocking antibody treatment-induced angiogenesis, promoting fat graft retention. In addition, its effect on fat graft retention was synergistically improved when ASCs were concomitantly supplemented. The expression of junctional proteins was increased in ECs, and inflammatory processes were downregulated in grafted fat upon ASC supplementation and Dll4 inhibition. Dll4 inhibition induced vascularization within the grafted fat, thereby promoting graft retention and exhibiting synergistic effects with concomitant ASC supplementation. This study serves as a basis for developing new potential therapeutic approaches targeting Dll4 to improve graft retention after cell-assisted transfer.

Engineering of hybrid spheroids of mesenchymal stem cells and drug depots for immunomodulating effect in islet xenotransplantation.

Immunomodulation is an essential consideration for cell replacement procedures. Unfortunately, lifelong exposure to nonspecific systemic immunosuppression results in immunodeficiency and has toxic effects on nonimmune cells. Here, we engineered hybrid spheroids of mesenchymal stem cells (MSCs) with rapamycin-releasing poly(lactic-co-glycolic acid) microparticles (RAP-MPs) to prevent immune rejection of islet xenografts in diabetic C57BL/6 mice. Hybrid spheroids were rapidly formed by incubating cell-particle mixture in methylcellulose solution while maintaining high cell viability. RAP-MPs were uniformly distributed in hybrid spheroids and sustainably released RAP for ~3 weeks. Locoregional transplantation of hybrid spheroids containing low doses of RAP-MPs (200- to 4000-ng RAP per recipient) significantly prolonged islet survival times and promoted the generation of regional regulatory T cells. Enhanced programmed death-ligand 1 expression by MSCs was found to be responsible for the immunomodulatory performance of hybrid spheroids. Our results suggest that these hybrid spheroids offer a promising platform for the efficient use of MSCs in the transplantation field.