Cell therapies and its derivatives as immunomodulators in vascularized composite allotransplantation.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs.

Adipose-derived stem cell modulate tolerogenic dendritic cell-induced T cell regulation is correlated with activation of Notch-NFκB signaling.

BACKGROUND: Adipose-derived stem cells (ASCs) are recognized for their potential immunomodulatory properties. In the immune system, tolerogenic dendritic cells (DCs), characterized by an immature phenotype, play a crucial role in inducing regulatory T cells (Tregs) and promoting immune tolerance. Notch1 signaling has been identified as a key regulator in the development and function of DCs. However, the precise involvement of Notch1 pathway in ASC-mediated modulation of tolerogenic DCs and its impact on immune modulation remain to be fully elucidated. This study aims to investigate the interplay between ASCs and DCs, focusing the role of Notch1 signaling and downstream pathways in ASC-modulated tolerogenic DCs. METHODS: Rat bone marrow-derived myeloid DCs were directly co-cultured with ASCs to generate ASC-treated DCs (ASC-DCs). Notch signaling was inhibited using DAPT, while NFκB pathways were inhibited by NEMO binding domain peptide and si-NIK. Flow cytometry assessed DC phenotypes. Real-time quantitative PCR, Western blotting and immunofluorescence determined the expression of Notch1, Jagged1 and the p52/RelB complex in ASC- DCs. RESULTS: Notch1 and Jagged1 were highly expressed on both DCs and ASCs. ASC-DCs displayed significantly reduced levels of CD80, CD86 and MHC II compared to mature DCs. Inhibiting the Notch pathway with DAPT reversed the dedifferentiation effects. The percentage of induced CD25+/FOXP3+/CD4+ Tregs decreased when ASC-DCs were treated with DAPT (inhibition of the Notch pathway) and si-NIK (inhibition of the non-canonical NFκB pathway). CONCLUSIONS: ASCs induce DC tolerogenicity by inhibiting maturation and promoting downstream Treg generation, involving the Notch and NFκB pathways. ASC-induced tolerogenic DCs can be a potential immunomodulatory tool for clinical application.

A novel biodegradable magnesium skin staple: A safety and functional evaluation.

BACKGROUND: The potential of biodegradable magnesium (Mg) skin staple has recently garnered widespread attention due to their biodegradability and biocompatibility rather than traditional stainless steel staples, the most commonly used in current clinical practice. The aim of this study is to evaluate the safety and mechanical properties of a novel biodegradable Mg skin staple. METHODS: A prototype of Mg skin staple was designed using a novel ZK60 Mg alloy. The mechanical properties of the staple were evaluated using a universal testing machine. The cytotoxicity of the staple was examined in vitro and the efficacy of the staple in wound closure was assessed in New Zealand rabbits for one and three weeks, respectively. RESULTS: The tensile strength of this Mg alloy is 258.4 MPa with 6.9% elongation. The treatment of HaCaT and L929 cells with the staple extract resulted in over 95% cell viability, indicating no cytotoxicity. In vivo, no tissue irritation was observed. No difference was found in wound healing between the Mg skin staple and the stainless steel staple after one and three weeks in the cutting wound on the back of rabbits. Some Mg skin staples spontaneously dislodged from the skin within three weeks, while others were easily removed. CONCLUSION: Our results confirm the safety, biocompatibility, and functionality of the novel Mg skin staple in wound closure. The efficacy of the staple in wound closure was demonstrated to be as effectively as conventional staples, with the added benefit of decreased long-term retention of skin staples in the wounds.

Accreditation of the handheld 3-dimensional scanner and conventional photo images for area measurement.

Accurate assessment of wound areas is crucial in making therapeutic decisions, as the prognosis and changes in the size of the wound over time play a significant role. An ideal assessment method should possess qualities such as speed, affordability, accuracy, user-friendliness for both patients and healthcare professionals, and suitability for daily clinical practice. This study aims to introduce a handheld 3-dimensional (3D) scanner and evaluate its accuracy in measuring wound areas. Engineers from the Industrial Technology Research Institute in Taiwan developed a handheld 3D scanner with the intention of extending its application to the medical field. A project was conducted to validate the accuracy of this 3D scanner. We utilized a smartphone (Asus ZenFone 2 with a 13-million-pixel rear camera), a digital single-lens reflex digital camera (Nikon, D5000, Tokyo, Japan), and the 3D scanner to repeatedly measure square papers of known size that were affixed to the curved surface of life-size facial mask or medical teaching breast models. The "Image J" software was employed for 2-dimensional image measurements, while the "3D Edit" software was used to assess the "area of interest" on 3D objects. By using square papers with predetermined dimensions, the measurement-associated error rate (ER) could be calculated for each image. Three repeated measurements were performed using the "Image J" software for each square paper. The ERs of the 3D scan images were all below 3%, with an average ER of 1.64% in this study. The close-up mode of the smartphone exhibited the highest ER. It was observed that as the area increased, the ER also increased in the digital single-lens reflex camera group. The extension distortion effect caused by the wide-angle lens on the smartphone may increase the ER. However, the definition of a healthy skin edge may vary, and different algorithms for calculating the measurement area are employed in various 3D measurement software. Therefore, further validation of their accuracy for medical purposes is necessary. Effective communication with software engineers and discussions on meeting clinical requirements are crucial steps in enhancing the functionality of the 3D scanner.

Turbocharging as a strategy to boost extended perforator flap vascularity in head and neck reconstruction-A report of two cases.

Perforator flap has been applied as the most common flap for soft tissue defect reconstruction. Here, we presented two cases using turbocharging procedure of perforator to perforator as a salvage strategy. The first case was a 54-year-old male with recurrent squamous cell carcinoma (SCC) in the left buccal area and mouth floor. A 6 × 22 cm posteromedial thigh (PMT) flap was designed for reconstruction. The two eccentric perforators of the PMT flap could not conjoin together during dissection nearby the main pedicle of profunda femoral artery (PFA) resulting in inadequate perfusion. Side branched stump before clipped the branch of distal perforator was preserved, then the proximal perforator was divided and end-to-end anastomosis of side branch of distal perforator was done successfully. The second case was a 52-year-old male underwent wide composite excision of right tongue SCC. After excision, anterolateral thigh (ALT) flap around 7 × 15 cm was harvested from left thigh and two perforators were included which one tiny perforator supplied by the descending branch (DB) and the other major perforator originated from oblique branch (OB) of lateral circumflex femoral artery (LCFA). However, the OB main perforator injury showed inadequate perfusion of flap. We trimmed the injury zone of OB perforator, and shift to re-anastomosis of OB perforators to side branch of DB of LCFA directly. The flap demonstrated excellent perfusion immediately after the operation, and it exhibited complete survival 2 weeks postoperatively. These results indicated that the turbocharging procedure, from perforator to perforator, could serve as a strategy for salvaging perfusion-compromised flaps, especially in cases of eccentric perforators or perforator injury resulting in inadequate perfusion.

The niche of dermal graft to reconstruct a complex pressure injury wound in sacral region: A case report.

RATIONALE: Pressure ulcers are a common health issue, particularly among elderly and bedridden patients who are vulnerable to pressure injuries in the sacral region. Currently, free flap and local flap surgeries are the gold standard procedures for the reconstruction of such injuries. However, the recurrence rate of flap surgery appears to be high. In this context, we presented a case involving a sacral pressure ulcer reconstructed with dermal grafting. PATIENT CONCERNS: A 59-year-old male with a medical history of hepatitis C, brain hemorrhage, hydrocephalus, and multiple fractures presented with a sacral ulcer. Owing to the patient's history of recurrent pressure injuries and the challenges associated with postoperative wound care, the patient and his family were hesitant to proceed with flap surgery. DIAGNOSES: The patient was diagnosed with a stage IV pressure ulcer measuring 4 cm × 4 cm in size in the sacral region, according to the National Pressure Ulcer Advisory Panel staging system. INTERVENTIONS: Before surgery, the patient received standard wound care with dressing for 4 months, along with short-term oral antibiotics due to a positive wound culture for Pseudomonas aeruginosa. During the surgery, a dermal graft with a size of 35 cm2 and a thickness of 0.014 inches was harvested from the patient's left thigh. The graft was then secured to the wound bed. OUTCOMES: Although the dermal graft failed with sloughing after 1 week, the wound bed showed improvement with granulation. After 1.5 months, the wound area had decreased to half of its original size, and the wound eventually healed after 3.5 months. LESSONS: Dermal grafts have a niche in reconstructing pressure injury wounds in the sacral region, because of the relative ease of wound care and additional benefits even in cases where the graft fails.

Healing of a bone-exposed soft tissue defect after surgical correction of traumatic patellar dislocation: A case report.

RATIONALE: Reconstructive surgery is widely considered the primary treatment for soft tissue defects around the knee owing to its high flexibility. However, in our recent case study, we explored an alternative approach using decellularized collagen dressings, which proved highly effective in healing a soft tissue defect involving bone exposure following surgical correction of a traumatic patellar dislocation. PATIENT CONCERNS: A 65-year-old male with a traumatic patellar dislocation in the lower extremity failed to approximate the wound after surgical correction. The patient refused additional surgical reconstruction because of the potential risks of multiple operative complications. DIAGNOSES: Traumatic patellar dislocation complicated by exposed bone following surgical treatment was made. INTERVENTIONS: The procedure was performed using ABCcolla® Collagen Matrix (ACRO Biomedical, Taiwan), an acellular dermal matrix made from a decellularized native porcine collagen scaffold dressing. Collagen dressings were applied to the soft tissue defect, and biointegration was observed in the wound area of bone exposure. OUTCOMES: Through the application of ABCcolla® Collagen Matrix (ACRO Biomedical, Taiwan) and diligent wound care for a total of 105 days, the patient healed successfully and achieved partial functional recovery after undergoing rehabilitation. During recent outpatient clinic visits, the patient is now able to ambulate independently with the aid of crutches. LESSONS: Collagen dressings circumvent the potential risks and complications associated with multiple surgical procedures. We believe that the utilization of collagen dressings, combined with careful wound management, could serve as a promising alternative treatment option for patients with soft tissue defects around the knee in the future.

Extended frontalis orbicularis oculi muscle flap shortening for treating refractory apraxia of eyelid opening associated with blepharospasm.

BACKGROUND: Refractory apraxia of eyelid opening (AEO) is mostly unresponsive to botulinum toxin (BTx) and inevitably leads to functional blindness. To treat this challenging condition, an innovative surgical technique was proposed. METHODS: The extended frontalis orbicularis oculi muscle (FOOM) flap shortening consisting of frontalis suspension, partial myectomy, and myotomy in situ of eyelid protractors was applied to treat refractory AEO associated with blepharospasm. The postoperative outcomes and patient satisfaction were evaluated. RESULTS: Seven patients (mean ages 64.1 ± 3.9 years) of 14 eyelids in total had an average flap shortening distance of 24.4 ± 1.3 mm. During a mean follow-up of 31.6 ± 11.4 months, the average BTx dosage reduced from 58.6 ± 12. 1 units to 30.0 ± 8.2 units, with a mean injection interval decreasing from 2.3 ± 0.5 months to 4.1 ± 0.9 months (p < 0.05). Palpebral fissure height increased from 1.4 ± 0.5 mm to 7.9 ± 0.7 mm, and the disability scale decreased from 78.8% ± 7.2% to 12.6% ± 7.0% (p < 0.05). The postoperative BTx dosage and frequency were significantly reduced. All patients restored voluntary eyelid opening and reported high postoperative satisfaction (average Likert scale 4.6 ± 0.5). CONCLUSION: Extended FOOM flap shortening is an effective treatment to solve refractory AEO associated with blepharospasm.

The synergistic effect of full-spectrum light therapy and transient immunosuppressants prolonged allotransplant survival.

BACKGROUND: The lifelong administration of immunosuppressants remains its largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term anti-lymphocyte serum and cyclosporine-A. Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared to the control (group 1). However, group 4 with FBLT combined with short-term ALS/CsA significantly prolonged median composite tissue allograft survival time (266 days) compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (p<0.01). Group 4 also showed a significant increase in Treg cells (p = 0.04) and TGF-ß1 levels (p = 0.02), and a trend toward a decrease in IL-1ß levels (p = 0.03) at 16 weeks after transplantation as compared to control Group 1. CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and anti-inflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

Compare the effectiveness of extracorporeal shockwave and hyperbaric oxygen therapy on enhancing wound healing in a streptozotocin-induced diabetic rodent model.

Studies have revealed that both extracorporeal shock-wave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) can accelerate wound healing. This study aimed to compare the effectiveness of ESWT and HBOT in enhancing diabetic wound healing. A dorsal skin defect in a streptozotocin-induced diabetes rodent model was used. Postoperative wound healing was assessed once every 3 days. Histologic examination was performed with hematoxylin and eosin staining. Proliferation marker protein Ki-67 (Ki-67), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and 8-hydroxy-2-deoxyguanosine (8-OHdG) were evaluated with immunohistochemical (IHC) staining. The wound area was significantly reduced in the ESWT and HBOT groups compared to that in the diabetic controls. However, the wound healing time was significantly increased in the HBOT group compared to the ESWT group. Histological findings showed a statistical increase in neovascularization and suppression of the inflammatory response by both HBOT and ESWT compared to the controls. IHC staining revealed a significant increase in Ki-67, VEGF, and eNOS but suppressed 8-OHdG expression in the ESWT group compared to the HBOT group. ESWT facilitated diabetic wound healing more effectively than HBOT by suppressing the inflammatory response and enhancing cellular proliferation and neovascularization and tissue regeneration.

Heterotopic intestine and abdominal wall transplantation in a miniature swine: A model for graft immunology.

In order to accurately monitor graft immunology, we have developed a method for performing intestine and abdominal wall transplantation heterotopically in miniature swine. The procedure consisted of simultaneous segmental terminal ileum and full-thickness abdominal wall transplantation in Lanyu miniature swine, with the intestinal and the abdominal wall grafts being placed on the recipient's bilateral rear flank. Five transplantations were technically successful. One animal died on the first post-transplant day due to anesthesia-related issues, three abdominal wall and four intestinal grafts survived, while one abdominal wall graft failed due to vascular thrombosis. Acute cellular rejection (ACR) of the intestinal graft could occur preceding, simultaneously with or following ACR of the abdominal wall graft. Our experimental model demonstrates the technical feasibility of heterotopic intestine and abdominal wall transplantation in miniature swine without grafting in gastrointestinal continuity. This model could be suitable for further studies of graft immunology.

A Multifunctional Polyethylene Glycol/Triethoxysilane-Modified Polyurethane Foam Dressing with High Absorbency and Antiadhesion Properties Promotes Diabetic Wound Healing.

The delayed healing of chronic wounds, such as diabetic foot ulcers (DFUs), is a clinical problem. Few dressings can promote wound healing by satisfying the demands of chronic wound exudate management and tissue granulation. Therefore, the aim of this study was to prepare a high-absorption polyurethane (PU) foam dressing modified by polyethylene glycol (PEG) and triethoxysilane (APTES) to promote wound healing. PEG-modified (PUE) and PEG/APTES-modified (PUESi) dressings were prepared by self-foaming reactions. Gauze and PolyMem were used as controls. Next, Fourier transform-infrared spectroscopy, thermomechanical analyses, scanning electron microscopy and tensile strength, water absorption, anti-protein absorption, surface dryness and biocompatibility tests were performed for in vitro characterization. Wound healing effects were further investigated in nondiabetic (non-DM) and diabetes mellitus (DM) rat models. The PUE and PUESi groups exhibited better physicochemical properties than the gauze and PolyMem groups. Moreover, PUESi dressing showed better anti-adhesion properties and absorption capacity with deformation. Furthermore, the PUESi dressing shortened the inflammatory phase and enhanced collagen deposition in both the non-DM and DM animal models. To conclude, the PUESi dressing not only was fabricated with a simple and effective strategy but also enhanced wound healing via micronegative-pressure generation by its high absorption compacity with deformation.

The Bridging Effect of Artificial Dermis on Reconstruction of Skin Avulsion Injury.

Skin avulsion wounds are expected to be swollen and tense after trauma, and skin perfusion can be compromised after primary closure, resulting in wound dehiscence and poor healing. The artificial dermis (AD) serves as a dermal regeneration template that is used to heal skin defects with secondary intention. Therefore, the aim of this study is to evaluate the effect of AD application on traumatic skin avulsion injuries compared to conventional primary closure. A retrospective cohort of 20 patients with skin avulsion injuries were included the study: ten patients were treated with AD and ten patients were managed with primary closure. When compared to the primary closure group, AD group had a shorter average healing time (58.40 ± 26.94 days V 65.50 ± 46.45 days) and significantly higher flap viability (92.00 ± 13.17% V 78.00 ± 13.98%; p = .03). In conclusion, AD is a promising material for the treatment of skin avulsion injury and produces better clinical results.

Lesion Site Is the Key Prognostic Factor for Keloid Patients Receiving Surgery With Adjuvant Radiotherapy.

BACKGROUND: Keloid is a benign tumor with high recurrence rate; accordingly, complete surgical excision with adjuvant radiotherapy is one of the most effective treatments. This study reviewed outcomes of keloid patients receiving surgery and adjuvant radiotherapy in Kaohsiung Medical University Hospital. MATERIALS AND METHODS: All patients received radiation dose with 15 Gy, with their first radiotherapy within 24 hours after surgical excision. The end points were recurrence rate and local recurrence-free interval (LRFI), defined clinically as palpable gross tumor over the treatment site and duration from the last day of radiotherapy to disease recurrence. RESULTS: From May 2017 to July 2020, 32 patients with 40 keloid lesions were included. The mean age for these patients was 37.6 years, and the median follow-up time was 15.3 months. The overall recurrence rate was 52.5%, and the median LRFI was 9.7 months. Recurrence rates for males and females were 46.7% and 56% ( P = 0.567), respectively; for head and ear, chest, shoulder and upper extremities, and abdomen and back were 12.5%, 61.5%, 63.6%, and 62.5% ( P = 0.093); for lesions over 20 cm 2 and below 20 cm 2 were 62.5% and 50% ( P = 0.527); and for megavoltage electron beam and kilovoltage photon beam were 56.7% and 40% ( P = 0.361), respectively. Patients were further classified into 2 groups by lesion sites, which showed lower recurrence rate ( P = 0.011) and longer LRFI ( P = 0.028) with lesions over the head and ear than other sites. CONCLUSIONS: We found that lesion site might be a prognostic factor for keloid recurrence. Adjuvant radiation dose escalation for high-recurrence risk areas (other than the head and ear) might be required.

Stem Cell-Based Therapeutic Strategies in Diabetic Wound Healing.

Impaired wound healing and especially the "all-too-common" occurrence of associated diabetic foot ulcers (DFU) are becoming an increasingly urgent and deteriorating healthcare issue, which drastically impact the quality of life and further heighten the risks of infection and amputation in patients with diabetes mellitus. Amongst the multifactorial wound healing determinants, glycemic dysregulation has been identified to be the primary casual factor of poor wound healing. Unfortunately, current therapeutic modalities merely serve as moderate symptomatic relieves but often fail to completely restore the wound site to its pre-injury state and prevent further recurrence. Stem cell-based therapeutics have been employed for its promising potential to address the root of the problem as they not only exhibit the capacity for self-renewal and differentiation towards multiple lineages, but also have been disclosed to participate in mediating variant growth factors and cytokines. Herein we review the current literatures on the therapeutic benefits of using various kinds of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and adipose-derived stem cells (ASCs) in diabetic wound healing by searching on the PubMed® Database for publications. This study shall serve as an overview of the current body of research with particular focus on autologous ASCs and the laboratory expandable iPSCs in hope of shedding more light on this attractive therapy so as to elevate the efficacy of wound healing that is almost always compromised in diabetic patients.

Synchronous surgery and immediate reconstruction of double primary cancers of the ovary and breast.

INTRODUCTION: There has been an ongoing debate about the benefits and risks between synchronous surgery and two independent surgery of ovary tumor removal and breast reconstruction. Here we report a synchronous oncological surgery and immediate postmastectomy reconstruction of double primary cancers of the ovary and breast. PATIENT CONCERNS: A 58-year-old woman presented with a right breast lump and ascites. DIAGNOSIS: Computed tomography (CT) indicated synchronous breast and ovarian cancer with multiple metastases. Double primary mammary and ovarian cancer was confirmed after a series of evaluations, such as core needle biopsy of the breast tumor. INTERVENTIONS AND OUTCOMES: Synchronous surgery and immediate reconstruction of double primary cancers of the ovary and breast were performed. Post-operative results showed complete resection of ovarian tumor, no post-operative complication, and excellent life quality. CONCLUSION: Synchronous surgery is warranted as a treatment option for selected cases of double primary cancer. The surgery not only achieved complete removal of one cancer and reduction of the other but also reached excellent breast reconstruction and body shape recovery.

Foraging for the Optimal Dressing Scaffold to Carry Adipose-Derived Stromal/Progenitor Cells for Cell Therapy.

In our daily plastic surgery practice, we have seen many chronic wounds that need new biotechnology to help and improve wound healing. Stem cells play a crucial role in regenerative medicine. Many pre-clinical researches had reported the beneficial paracrine effects of stem cell therapy for chronic wounds. Cell-friendly scaffolds may provide the protection and three-dimensional space required for adherence of stem cells, thus allowing these stem cells to proliferate and differentiate for treatment purpose. A successful scaffold may enhance the effects of stem cell therapy. In this presented series, the authors attempted to identify the most suitable scaffolds from several commercially available wound dressings that could sustain adipose-derived stromal/progenitor cells (ADSCs) survival. Therefore, we isolated ADSCs containing the green fluorescent protein (GFP) from GFP transgenic rats. The GFP (+) ADSCs and their progenies could be easily observed using a fluorescence microscope. Moreover, we analyzed the cytokines secreted in condition medium (CM) to understand the activities of ADSCs in various dressings. Our results showed that the foam dressings, hydrofiber, chitosan, and alginate plus carboxymethylcellulose were identified as the most suitable dressing materials. Higher concentrations of transforming growth factor beta (TGF-ß) and vascular endothelial growth factor (VEGF) were observed 48 h after loading them with GFP (+) ADSCs. Therefore, multiple topical cell therapy using ADSCs can be performed by applying suitable dressing scaffolds without repeated needle injections to deliver the stem cells into the wound bed. Based on their fluorescence property, the GFP (+) ADSCs can also possibly be used for testing biocompatibility of medical materials in the future.

The Potential Application and Promising Role of Targeted Therapy in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare yet serious progressive disorder that is currently incurable. This female-predominant disease unfolds as a pan-vasculopathy that affects all layers of the vessel wall. Five classes of pharmacological agents currently exist to target the three major cellular signaling pathways identified in PAH but are incapable of effectively reversing the disease progression. While several targets have been identified for therapy, none of the current PAH specific therapies are curative and cost-effective as they fail to reverse vascular remodeling and do not address the cancer-like features of PAH. Our purpose is to review the current literature on the therapeutic management of PAH, as well as the molecular targets under consideration for therapy so as to shed light on the potential role and future promise of novel strategies in treating this high-mortality disease. This review study summarizes and discusses the potential therapeutic targets to be employed against PAH. In addition to the three major conventional pathways already used in PAH therapy, targeting PDGF/PDGFR signaling, regulators in glycolytic metabolism, PI3K/AKT pathways, mitochondrial heat shock protein 90 (HSP90), high-mobility group box-1 (HMGB1), and bromodomain and extra-terminal (BET) proteins by using their specific inhibitors, or a pharmacological induction of the p53 expression, could be attractive strategies for treating PAH.

Treatment algorithm for Kimura's disease: A systematic review and meta-analysis of treatment modalities and prognostic predictors.

BACKGROUND: Kimura's disease is a rare, chronic inflammatory condition that usually manifests as highly recurrent head and neck tumors. OBJECTIVE: Systematic review of recurrence predictors following surgical excision. MATERIALS AND METHODS: The pathologically confirmed cases at the tertiary medical center were reviewed. PubMed, Medline, the Cochrane Library, Web of Science, Airiti Library containing grey literature were searched through August 31st, 2019. RESULTS: A total of 31 articles were included for meta-analysis which revealed that surgical excision resulted in a lower recurrence rate (pooled odds ratio [POR] = 3.15, 95% confidence interval [CI] = 1.12-8.82; p = 0.03) than conservative measures. Surgery was an effective single treatment modality for patients with tumors smaller than 3 cm (POR = 2.89, 95% CI: 1.20-6.95; p = 0.02), symptom duration shorter than 5 years (POR = 3.11, 95% CI, 1.03-9.38; p = 0.04), peripheral blood eosinophilia less than 20% (POR = 4.49, 95% CI: 1.46-13.84; p = 0.009) or serum IgE level less than 10000 IU/ml (POR = 8.30, 95% CI: 1.05-65.34; p = 0.04). CONCLUSIONS: Directing patients with Kimura's disease through the treatment algorithm will reduce the recurrence rate. Combination adjuvant therapy with surgery is recommended for the following conditions -- a tumor greater than or equal to 3 cm in size, symptom duration longer than or equal to 5 years, peripheral blood eosinophilia greater than or equal to 20%, or serum IgE greater than or equal to 10000 IU/ml to achieve the optimal therapeutic outcome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020173258 (http://www.crd.york.ac.uk/PROSPERO).