Superselective Arterial Hyaluronidase Thrombolysis is an Effective Treatment for Hyaluronic Acid-Induced Retinal Artery Occlusion: Study in a Rabbit Model.

BACKGROUND: There are serious complications associated with hyaluronic acid (HA) facial injections, including vision impairment due to retinal artery ischemia. In this study, we put forth a clinically relevant model of retinal ischemia and reperfusion in rabbit. We used this to verify the efficacy of hyaluronidase intra-artery thrombolysis in the treatment of hyaluronic acid-induced retinal artery occlusion. METHODS: Retinal artery ischemia was induced by injecting HA into the ophthalmic artery (OA) of adult chinchilla rabbit, and reperfusion was achieved by intra-artery thrombolysis therapy with hyaluronidase following 60 min and 4 h of occlusion. Digital subtraction angiography (DSA) and fundus fluorescein angiography (FFA) were used to evaluate blood flow in the retina. Electroretinogram (ERG), hematoxylin and eosin staining and transmission electron microscope were used to evaluate the structure and function of the retina after ischemia and reperfusion following 60 min and 4 h of occlusion. RESULTS: DSA and FFA images confirmed occlusion of the ophthalmic and central retinal arteries, as well as reperfusion after hyaluronidase thrombolysis. ERG indicated retinal dysfunction following ischemia, and thrombolysis partially rescued its impairment following 4 h of occlusion. Hematoxylin and eosin staining and TUNEL staining revealed ischemia-induced histological damages in the retina at different time windows, and hyaluronidase thrombolysis partially mitigated these damages. CONCLUSIONS: We report a method to establish a HA-induced retinal artery occlusion animal model. Hyaluronidase intra-artery thrombolysis was used to recanalize the embolized OA at different time points. Using our method, we achieved retinal reperfusion, and an improvement was observed in the visual function of rabbits after hyaluronidase thrombolysis following 4 h of occlusion. We believe that hyaluronidase intra-artery thrombolysis is an effective method to treat HA-induced retinal artery occlusion in clinic. 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 www.springer.com/00266 .

A treatment algorithm for hyaluronic acid filler related complications of the face.

BACKGROUND: Throughout the last decade, a notable increase in HA-filler-related complications have been observed, owing to the increase in demand for filler injections and availability of multiple products. OBJECTIVES: The aim is to provide practical advice on the best way to prevent and treat HA-filler-related complications. METHODS: Thirty patients who experienced visible and/or symptomatic complications localized within the facial area were treated according to our algorithm. Patients with inflammatory lesions underwent antibiotic and anti-inflammatory therapy, followed by hyaluronidase injections. Patients with abscesses were treated with antibiotics, incision, and drainage. Each patient completed the dermatology-specific quality of life questionnaire (DLQI) at the first and last examinations. RESULTS: Among the 29 patients who received antibiotic therapy, 3 healed without further treatment. However, 18 received hyaluronidase injections, 9 underwent incision and drainage, and 5 presented with fistulas and developed retracted scars. Moreover, 80% of the patients were completely healed, 13% significantly improved, and 3% did not show any improvement. The DLQI scores analysis showed a notable impact of patients' diseases on their quality of life, mainly in the terms of personal relationships and symptoms, with minor impacts on intimate relationships, ability to work, and study. We demonstrated that our algorithm resulted in a significant improvement in the overall quality of life at the last follow-up (p < 0.001). CONCLUSIONS: The use of filler injections requires caution and specific training because they can lead to serious complications. If these complications are recognized promptly, healing can be optimized. Our treatment algorithm demonstrated high rate of healing and significant improvement in the patients' quality of life.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Short term treatment of secondary lymphedema with hyaluronidase injections reduces mouse hindlimb lymphedema.

Lymphedema is a common complication following breast cancer treatment with axillary lymphadenectomy and radiotherapy. Currently, there is no curative treatment for this disease, hence there is a need for new therapeutic suggestions. The aim of this study was to investigate the effect of hyaluronidase (HYAL) injections after inducing hindlimb lymphedema in 36 female C57BL/6 mice. HYAL injections were administered every second day for 14 days in three groups: (1) HYAL for 1 week followed by saline for 1 week, (2) HYAL for 2 weeks, and (3) saline injections for 2 weeks. Volume of the lymphedema limb was weekly assessed with micro-computed tomography (µ-CT) scans for a total course of 6 weeks. Lymph vessel morphometry was assessed in the end of the study after staining cross-sections of the hindlimb for anti-LYVE-1 blindly. Lymphatic function was assessed by lymphoscintigraphy to assess lymphatic clearance. There was a significant reduction of the volume of lymphedema in mice treated with HYAL-7 compared with mice treated with HYAL-14 (p < 0.05) and saline (p < 0.05). No differences were detected in lymph vessel morphometry and the lymphoscintigraphy between groups. Short-term treatment with HYAL-7 might be a potential therapeutic suggestion for secondary lymphedema induced in mouse hindlimbs. In the future, clinical studies are needed to investigate the potential of HYAL treatment in human beings.

Successful management of delayed hyaluronidase hypersensitivity after subtenon's anesthesia during the COVID-19 pandemic: A rare case report.

Subtenon's block is commonly used to achieve akinesia, analgesia, and anesthesia for ophthalmic surgeries. This case study detailed a rare hypersensitivity report in a 65-year-old female who had underwent manual small incision cataract surgery under subtenon's anesthesia (STA) in the left eye. On postoperative day 1, she presented with acute onset proptosis, periorbital edema, conjunctival chemosis, and restriction of extraocular movements. The pupillary reaction and dilated fundus examination were normal. A differential diagnosis of orbital cellulitis, Mucormycosis, and hyaluronidase hypersensitivity (HH) was considered. Since the patient was afebrile, and pupillary reactions, ENT, neurological, and fundus examination were normal, the diagnosis was narrowed down to delayed HH. The patient was managed with a 1 cc IV injection of dexamethasone once a day for 3 days, along with routine postoperative drugs. As per detailed literature review, this is probably a second case report of delayed HH post-STA.

Comparative effectiveness of medicinal interventions for oral submucous fibrosis: A network meta-analysis.

OBJECTIVES: This network meta-analysis presents an exhaustive description and comparison of the available medical interventions for the management of oral submucous fibrosis (OSMF). MATERIALS AND METHODS: A systematic review and network meta-analysis was conducted after registration with PROSPERO. (PROSPERO ID CRD42022303441). Databases (PubMed, Cochrane, EMBASE, Web of Science, and others) were searched for randomized clinical trials (RCT) trials from inception till September 2022 for the medical interventions in OSMF. The primary outcome was the improvement in mouth opening. The secondary outcomes were improvement in burning sensation, tongue protrusion, and cheek flexibility. The interventions were ranked according to their efficacy based on the surface under the cumulative ranking. RESULTS: 47 studies including 2393 patients were assessed for quantitative analysis. For mouth opening, the combined treatment with steroid, hyaluronidase, and antioxidant was most effective [MD, 7.05 (95%CI 1.76,12.34)], followed by the combination of oral antioxidants with injectable steroids, [MD, 3.80 (95%CI -0.44,8.03)]. Additionally, the combined treatment with steroid, hyaluronidase, and antioxidant was most effective in reducing the burning sensation [MD, -8.62(-10.95,-6.30)], followed by aloe vera [MD, -8.45(-10.40,-6.49)] and pentoxifylline [MD -7.57(-9.46,-5.68)]. For tongue protrusion, curcumin was most effective followed by antioxidants. Most of the drugs used were reported to cause negligible or mild adverse effects. CONCLUSION: This network meta-analysis reported the efficacy of medicinal interventions in OSMF patients compared to the placebo in the improvement of mouth opening and burning sensation, and cheek flexibility. The methodological quality of included RCTs was low. Well-designed studies are recommended to obtain strong evidence.

Hyaluronidase Availability in Emergency Rooms: A Statewide Analysis.

Objective: Authors sought to determine the immediate availability of hyaluronidase (HYAL) among emergency rooms (ERs) in California. Background: Hyaluronic acid (HA) fillers are regarded as a safe procedure; however, major ischemic complications do exist, notably blindness and tissue necrosis. The successful management of these vascular events relies on an injector's immediate HYAL, the enzymatic reversal agent for HA. Unfortunately, many barriers exist for injector sites to stock HYAL. As a result, ERs serve as unofficial safety nets in cases when providers encounter an ischemic complication and do not have HYAL in supply. Materials and Methods: Telephone survey inquiring about HYAL availability in all California ERs. Results: This study included 330 California ERs and achieved an 89.7% response rate (n = 296). 45.6% of the surveyed ERs did not have immediate access to HYAL. HYAL availability was positively associated with level I-III adult trauma center status, pediatric trauma center status, children's hospital status, higher bed counts, and regional geography (p < 0.05, all). Conclusions: HYAL availability is unreliable among Californian ERs, posing a potential risk to patient safety.

Use of the high-dose pulsed hyaluronidase protocol in the management of impending skin necrosis associated with hyaluronic acid fillers: a systematic review.

Impending skin necrosis resulting from inadvertent intravascular injection of hyaluronic acid (HA) fillers can lead to tissue loss and significant scarring. In recent years, management trends have shifted from multimodal approaches to the sole use of high doses of hyaluronidase. The aim of this systematic review was to evaluate the effectiveness of the high-dose pulsed hyaluronidase management protocol in preventing skin necrosis and possible subsequent scarring. An online search of the bibliographic databases PubMed and Embase yielded 3039 articles. A total of 72 studies reporting 186 cases were found to be eligible for inclusion. The selection and evaluation process was done according to the PRISMA criteria. Included studies were assessed using the JBI and STROBE critical appraisal tools. The analysis of treatment outcomes was done according to the timing of treatment initiation and the type of intervention used. This review found that an immediate intervention using the high-dose pulsed hyaluronidase management protocol provided predictable and satisfactory outcomes. Initiating the protocol within 24 h of filler injection halted the progression of necrosis and prevented permanent sequelae. The conclusions are limited by the lack of a high level of evidence, since the only available sources of data are case reports and case series.

The Utility of Hyaluronidase for the Free and Pedicle Flap Salvage.

Hyaluronidase is commonly used to treat swelling and hematoma for aesthetic and reconstructive purposes. It has also been reported as a stimulator of angiogenesis. The purpose of this study was to introduce the utility of hyaluronidase in patients with flap compromise after free and pedicle flap reconstructions. This study was a retrospective study of 1 case of radial forearm free flap salvage, 2 cases of keystone perforator flap salvage, and 1 case of pectoralis major myocutaneous flap salvage. A radial forearm free flap reconstruction of unilateral mouth floor and tongue defect was complicated with hematoma formation on a postoperative day 1 after taking clopidogrel due to acute-onset non-ST-elevation myocardial infarction but dramatically resolved with hyaluronidase injection into the flap and contralateral unaffected tongue. After this intervention, the flap color dramatically returned to normal and became soft without further treatments. Two keystone design perforator flaps were performed to reconstruct the sacral defect after the debridement of pressure ulcers. Two cases were related to the patients' medical conditions, such as low platelet count caused by liver cirrhosis. We also salvaged pectoralis major myocutaneous flap in a 91-year-old female patient with large breasts. This study introduced our experience of salvaging the free and pedicled flaps using hyaluronidase. Hyaluronidase is an excellent option when arterial or venous insufficiency occurs after free and perforator flap surgeries.

Pentoxifylline - A Novel Adjunct in the Management of Patients with Oral Submucous Fibrosis in Terai Population of Nepal: A Prospective Case Control Study.

Oral submucous fibrosis is a premalignant condition largely seen in the South-Asian countries mainly due to the consumption of areca nut. Pentoxifylline is a methylxanthine derivative, with vasodilating, anti-inflammatory and immune modulatory properties and is believed to increase the vascularity of the mucosal layer. The study was conducted to clinically assess the effectiveness of orally given pentoxifylline with dexamethasone (4mg/ml) given intralesionally and hyaluronidase 1500 IU with 0.5ml of 2.0% lignocaine plus multivitamins in the management of Oral submucous fibrosis patients pertaining to the Terai belt of Nepal. This study was conducted as an experimental study consisting of 70 oral submucous fibrosis patients who were divided blindly into two groups i.e. control or standard drug group (n=35) and experimental drug group (n=35). Standard drug group were given biweekly intralesional injections of dexamethasone (4mg/ml) and hyaluronidase 1500IU with 0.5ml of 2.0% lignocaine plus one capsule of multivitamins daily for a period of 12 weeks whereas experimental drug group were given pentoxifylline tablets 400mg 3 times daily for 12 weeks in addition to the drugs given to the standard drug group. Variables considered in the study were burning sensation, mouth opening, tongue protrusion and cheek flexibility using visual analog scale, vernier caliper, cheek retractor and a metric scale. On comparing, statistically significant results were seen in experimental drug group as far as reduction in burning sensation (p<0.001) and increase in mouth opening (p<0.001) was concerned. As far as improvement in tongue protrusion and cheek flexibility were concerned, the results were appreciating but statistically not significant (p=0.231) and (p=0.251) respectively. This study showed the effectiveness of pentoxifylline as an adjunct in the routine management of oral submucous fibrosis.

Muscle Activity in Pre-Treatment and Post-Treatment Oral Submucous Fibrosis Patients: Electromyography Study.

Background: Oral submucous fibrosis (OSMF) is a premalignant condition of insidious onset which affects the oral mucosa, pharynx, and esophagus. The muscles of mastication are known to be affected resulting in limited mouth opening. Electromyography (EMG) is a sophisticated method of measuring and evaluating muscle activity. Previously, EMG was primarily utilized in medical sciences, but it is currently being used extensively in both the medical and dentistry fields. Objectives: The aim of the study is to evaluate the electromyographic activity of masseter muscle in OSMF patients before and after treatment and to compare with healthy controls. Materials and Methods: This prospective case-control clinical study comprised 180 OSMF patients who were divided into four groups and 45 healthy individuals served as the control group. The OSMF individuals were injected with hyaluronidase 1,500 IU mixed in 1.5 ml of dexamethasone and 0.5 ml of lignocaine HCL intralesionally twice a week for one month along with a basic physiotherapy regimen consisting of mouth exercises two times daily. The control subjects were given placebo capsules. The treatment was carried out for a month and the electromyographic masseter muscle activity was evaluated among the OSMF patients and control group before and after treatment. Results: The results revealed that the electromyographic activity of master muscles in OSMF patients showed increased activity when compared with healthy controls. Patients with OSMF showed decreased muscle activity after treatment. Conclusion: When compared with healthy controls, OSMF patients had higher electromyographic activity of the masseter muscles and the muscle activity was decreased following treatment. In OSMF patients, EMG may help in determining the involvement of the mastication and facial expression muscles. It can also be used as a diagnostic tool to assess the treatment outcome of muscle activity in OSMF patients.

Trastuzumab and thyroid dysfunction: An association to be aware of.

The incidence of autoimmune thyroid disorders is higher among women with breast cancer (BC) than in other solid malignancies, while it has not a prognostic impact. Trastuzumab (T) is a humanized monoclonal antibody approved for human epidermal growth factor receptor 2 (HER2)-positive BC in the neoadjuvant, adjuvant, and metastatic scenarios. Since 2014, subcutaneous (SC) T has been employed with the same efficacy as the intravenous formulation together with an easier way of administration. To date, autoimmune thyroiditis has been linked rarely to the use of intravenous T, and no cases have been related to the SC presentation. We report two cases of HER2-positive early BC patients who developed hypothyroidism during maintenance therapy with SC T that required levothyroxine supplementation. SC T includes recombinant human hyaluronidase to facilitate tissue penetration of the drug. This enzyme may alter the thyroid gland stroma and facilitate the development of thyroid disorders. Thyroid function tests are recommended in patients on SC T.

Efficacy of Curcumin in Combination with Intralesional Dexamethasone with Hyaluronidase in the Treatment of Oral Submucous Fibrosis: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to determine the efficacy of curcumin in combination with  intralesional dexamethasone with hyaluronidase in the treatment of oral submucous fibrosis (OSF). METHODS: This randomized, double blind, parallel design, clinical trial was conducted at B.P. Koirala Institute of Health Sciences, Nepal. Thirty-four patients with clinically diagnosed OSF were randomized into two groups (17 participants in each) with baseline treatment of intralesional dexamethasone with hyaluronidase for 6 weeks for the both. Curcumin (2gm/day) was provided to Group A (Test) and Group B (Control) received placebo. Interincisal mouth opening, tongue protrusion, cheek flexibility and visual analogue scale (VAS) scoring of burning sensation of oral mucosa was recorded at baseline, 6, 8 and 12 weeks follow-up and independent t-test was used to compare the improvements in two groups. RESULTS: On comparing the 6 weeks and baseline values, in Group A and B the mean difference in mouth opening was 8.82±1.33 mm and 5.53±1.17 mm respectively (p<0.001), in cheek flexibility was 2.94±1.02 mm and 1.94±1.24 mm respectively (p=0.02) and in tongue protrusion was 6.23±1.48 and 3.65±1.37 mm respectively (p<0.001). The findings were consistent in the 8 weeks follow-up. In 12 weeks follow-up, on comparing with the baseline values, in Group A and B, the mean difference in mouth opening was 8.71±1.16 mm and 5.35±1.22 mm respectively (<0.001), ), in cheek flexibility was 2.81±1.01 mm and 1.76±1.35 mm respectively (p=0.02) and in tongue protrusion was 6.06±1.48 and 3.35±1.50 mm respectively (p<0.001). Both the arms showed 100% improvement in burning sensation in 6, 8 and 12 weeks follow-up. CONCLUSION: Curcumin in combination with intralesional dexamethasone with hyaluronidase is efficacious in the treatment of OSF.

Hyaluronidase responsive second near-infrared fluorescent nanocomplex for combined HER2 blockade and chemotherapy of HER2+ breast cancer.

The human epidermal growth factor receptor-2-positive (HER2+) type is aggressive and has poor prognosis. Although anti-HER2 therapy alone or in combination with other treatment regimens showed significant improvement in survival outcomes, breast cancer patients are still suffering from tumor relapse and severe dose-limiting side effects. Thus, there is still an unmet challenge to develop effective therapeutic agents for HER2+ breast cancer treatment with minimized side effects. Herein, we produced a stimuli-responsive and tumor-targeted hyaluronic acid (HA) nanocomplex that combined HER2 blockade and chemotherapy for effective HER2+ breast cancer therapy. A hydrophobic NIR-II dye, IR1048, was covalently linked with HA to form a spherical HA-IR1048 nanoparticle (HINP), with Herceptin conjugated on the surface and paclitaxel (PTX) encapsulated inside. The fluorescent signals from the yielding Her-HINP/PTX are quenched originally, but a strong NIR-II signal is generated when HINP is degraded by the hyaluronidase that is overexpressed in breast tumors, thus allowing the tracking and visualization of Herceptin and PTX accumulation. Her-HINP/PTX peaked in HER2+ tumors at 24 h post injection as imaged by NIR-II fluorescent imaging. A significantly improved tumor growth inhibition effect was observed after five systemic treatments compared to single PTX (3.71 ± 0.41 times) or Herceptin (5.98 ± 0.51 times) treatment in a HER2-overexpressed breast cancer mouse model with prolonged survival. Collectively, the designed Her-HINP/PTX presents a new hyaluronidase-responsive and HER2 blockade nanoformulation that can visualize the accumulation of nanocomplexes and release drugs inside tumors for combined HER2+ breast cancer therapy with a great promise for translational study. STATEMENT OF SIGNIFICANCE: The high expressions of a protein called human epidermal growth factor receptor 2 (HER2) in breast tumors make this subtype of cancer aggressive. Currently, chemotherapy combined with a HER2 antibody, Herceptin, is a preferred approach for HER2-positive breast cancer therapy. However, these breast cancer patients still suffer from tumor relapse and severe side effects because various therapeutic agents have inherent different biodistributions, resulting in insufficient treatment effects and unfavorable normal organ uptake of these therapeutic agents. Herein, we produced a nanocomplex carrying both Herceptin and chemotherapy drug to simultaneously deliver two drugs into tumors for efficient HER2+ tumor treatment with minimized side effects, providing new insights for designing a combined therapy strategy.

Hyaluronic Acid Basics and Rheology.

Hyaluronic acid (HA) is the most common dermal filler in use. It improves wrinkles and volume loss not only by filling and volumizing but also by hydrating the injected area with its water affinity. It is a naturally occurring component of skin, and there is a negligible risk of immunologic or allergic reaction with injection. It is rapidly degraded by the injection of hyaluronidase, thus creating an ideal injectable material that is low risk and reversible. Its duration of effect may be longer than expected based on bioavailability of the HA product due to collagen synthesis or fibroblast stimulation.

Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.

BACKGROUND & AIMS: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. METHODS: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. RESULTS: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. CONCLUSIONS: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.

PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study.

PURPOSE: PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing the delivery of therapeutic molecules. Combinations of chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by increasing tumor oxygenation by improving vascular patency and perfusion, PEGPH20 will also act as a radiosensitization agent. EXPERIMENTAL DESIGN: The effect of PEGPH20 on radiation treatment was analyzed with respect to tumor growth, survival time, p02, local blood volume, and the perfusion/permeability of blood vessels in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (HAS3). RESULTS: Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. In mice that overexpressed HAS3, EPR imaging showed an increase in local pO2 that could be linked to increases in perfusion/permeability and local blood volume immediately after PEGPH20 treatment. Hyperpolarized [1-13C] pyruvate suggested PEGPH20 caused a metabolic shift towards decreased glycolytic flux. These effects were confined to the mice overexpressing HAS3 - no effect of PEGPH20 on survival, radiation treatment, or pO2 was seen in wild type BxPC3 tumors. CONCLUSIONS: PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation. The response of the treatment may potentially be monitored by non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.

Clinical Assessment of Efficacy of Omega 3 in Oral Submucous Fibrosis Patients - A Randomized Controlled Trial.

BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic, potentially malignant condition affecting the oral cavity. Omega 3 has shown innumerable health benefits in yesteryears. So, the aim of the study was to evaluate the efficacy of Omega 3 in the medical management of this disease. METHODS: A randomized controlled trial was designed and 48 clinically confirmed patients of OSMF (24 in each group) completed the study. Patients of both the groups were given biweekly intralesional injections of dexamethasone 1.5ml, hyaluronidase 1500 IU mixed with lignocaine for 6 weeks. Additionally, group A received a placebo (lactose capsule) for 3 months while group B received 1gm of omega 3 (flaxseed oil) three times daily continuously for 3 months. Patients were followed every month for 3 months and then, after 6 months and one year. RESULTS: During the first two months, improvement was observed in both the groups independently but intergroup comparison showed no significant difference. However, after 3 months statistically significant (p<0.05) improvement among all three clinical parameters i.e. inter-incisal distance (mean improvement in group A = 3.79±1.07mm and group B = 6.58±1.24mm, p=0.019), tongue protrusion (mean improvement in group A = 1.87±1.54mm and group B = 4.62±1.78mm, p=0.044) and cheek flexibility (mean improvement in group A = 2.08±1.38mm and group B = 3.50±1.84mm, p=0.035) was observed in group B when compared to group A. In contrast, statistically significant improvement in burning sensation was observed after one month itself in group B when compared to group A (mean drop in group A = 2.5±0.78 points and group B = 6.0±1.144 points, p<0.05). CONCLUSION: Omega 3 in conjunction with intralesional injections is an effective therapy when compared to intralesional injections alone in treatment of patients with OSMF (grade II and III) with no side effects.

Cutaneous Vascular Compromise and Resolution of Skin Barrier Breakdown After Dermal Filler Occlusion-Implementation of Evidence-Based Recommendations Into Real-World Clinical Practice.

BACKGROUND: Vascular occlusions that threaten skin integrity, although not an emergency like those that threaten a patient's vision, is an urgent situation. Accurately interpreting physical examination findings is paramount. The use of high-dose, pulsed hyaluronidase is the mainstay of therapy; however, adjunctive measures that may optimize clearance of an occlusion and/or skin barrier repair such as the use of image guidance and hyperbaric oxygen should be considered. OBJECTIVE: To provide a review of the literature on the treatment of vascular occlusions threatening skin barrier integrity and develop a step-wise treatment guide. MATERIALS AND METHODS: The authors searched PubMed for peer-reviewed studies, consensus statements, case series, and case reports using a variety of keywords. RESULTS: Twenty-six articles focusing on vascular occlusions threatening the skin barrier were reviewed. The authors collectively agreed on treatments to reverse vascular occlusions and restore the skin barrier. The importance of high-dose, pulsed hyaluronidase was clear. Therapies that lacked evidence such as sodium thiosulfate were also revealed. CONCLUSION: A vascular occlusion that threatens skin integrity is an urgent matter which requires accurate interpretation of physical examination findings that will help guide intervention. High-dose, pulsed hyaluronidase along with adjunctive measures performed in a step-wise manner is key to an optimal outcome.