Reduction In Lesion Size Research Articles

Therapeutic management of lichenoid dysplasia

Lichenoid dysplasia (LD) refers to a condition that clinically resembles oral lichen planus (OLP) and/or oral lichenoid lesions (OLL), but histologically harbors epithelial dysplasia. LD has a greater tendency to acquire malignant transformation and although it resembles OLP/OLL, many authors have classified LD as a separate and distinct entity. Herein, we report a case of a 45-year-old female patient with severe burning sensation for the last 6 months. Clinically, she had lichenoid features and histologically mild epithelial dysplasia. She had extensive lesions that made surgical management complicated. Therapeutic management was instituted for her with periodic follow-up. There was adequate reduction in lesion size, burning sensation as well as in the inflammatory component of the lesion. A proper clinical and histopathological classification system is the need of the hour for OLP, OLL, and LD that will help clinicians to identify and treat the condition.

Trehalose in Machado-Joseph Disease: Safety, Tolerability, and Efficacy.

Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.

Gonadotropin-releasing hormone antagonist (linzagolix): a new therapy for uterine adenomyosis

To compare the efficacy of a selective progesterone receptor modulator, ulipristal acetate, and a gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis. Case report. Private clinic and infertility research unit. One patient born in 1981 who presented because of heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis confirmed by magnetic resonance imaging (MRI). The patient received a first treatment of 5 mg UPA daily for one course of 3 months. This therapy was discontinued because MRI revealed a worsened aspect. One year later, a once-daily dose of 200 mg linzagolix administered orally was initiated for 3 months, followed by another 3-month course of 100 mg once daily. Clinical symptoms and MRI aspect. During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms) worsened and MRI revealed aggravation of the adenomyotic lesions. During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the 100-mg linzagolix course (weeks 13-24), the patient reported continued alleviation of her symptoms. To our knowledge, this is the first reported use of linzagolix, a new oral gonadotropin-releasing hormone antagonist that significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with a selective progesterone receptor modulator, ulipristal acetate.

Mechanisms of Neuroprotective Action of Hesperetin and Carnosine in Focal Ischemia of the Brain in Rats.

We compared the direct neuroprotective effect of minor food components, antioxidants hesperetin and carnosine, and analyzed their influence on the parameters of the oxidative status of the penumbra zones in the cerebral cortex during focal ischemia (1 h) of with reperfusion in Wistar rats. The animals received hesperetin and carnosine included in the diet in daily doses of 50 and 150 mg/kg, respectively, for 7 days before ischemia induction. The neuroprotective effect of hesperetin manifested in reduction of the ischemic lesion size by 30%, which was comparable with the effect of carnosine. Both hesperetin and carnosine reduced the level of MDA in the penumbra zone of the cerebral cortex and increased the total antioxidant activity of the brain tissue. Hesperetin also increased SOD activity to a level observed in the sham-operated control group.

Novel Role for Tranilast in Regulating NLRP3 Ubiquitination, Vascular Inflammation, and Atherosclerosis.

BackgroundAberrant activation of the NLRP3 (nucleotide‐binding oligomerization domain, leucine‐rich repeat–containing receptor family pyrin domain‐containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low‐density lipoprotein receptor– or apolipoprotein E–deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models.Methods and ResultsWe provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low‐density lipoprotein receptor– and apolipoprotein E–deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low‐density lipoprotein receptor– and apolipoprotein E–deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions.ConclusionsTranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low‐density lipoprotein receptor– and apolipoprotein E–deficient mice.

Protocatechuic Acid Inhibits Vulnerable Atherosclerotic Lesion Progression in Older Apoe-/- Mice

Normalization of arterial inflammation inhibits atherosclerosis. The preventive role for protocatechuic acid (PCA) in early-stage atherosclerosis is well recognized; however, its therapeutic role in late-stage atherosclerosis remains unexplored. We investigated whether PCA inhibits vulnerable atherosclerosis progression by normalizing arterial inflammation. Thirty-wk-old male apolipoprotein E-deficient (Apoe-/-) mice with vulnerable atherosclerotic lesions in the brachiocephalic artery were fed the AIN-93G diet alone (control) or supplemented with 0.003% PCA (wt:wt) for 20 wk. Lesion size and composition, IL-1β, and NF-κB in the brachiocephalic arteries, and serum lipid profiles, oxidative status, and proinflammatory cytokines (e.g., IL-1β, monocyte chemoattractant protein-1, and serum amyloid A) were measured. Moreover, the effect of PCA on the inflammation response was evaluated in efferocytic macrophages from C57BL/6J mice. Compared with the control treatment, dietary PCA supplementation significantly reduced lesion size (27.5%; P<0.05) and also improved lesion stability (P<0.05) as evidenced by increased thin fibrous cap thickness (31.7%) and collagen accumulation (58.3%), reduced necrotic core size (37.6%) and cellular apoptosis (73.9%), reduced macrophage accumulation (45.1%), and increased vascular smooth muscle cell accumulation (51.5%). Moreover, PCA supplementation inhibited IL-1β expression (53.7%) and NF-κB activation (64.4%) in lesions. However, PCA supplementation did not change serum lipid profiles, total antioxidant capacity, and inflammatory cytokines. In efferocytic macrophages, PCA at 0.5 and 1 μmol/L inhibited Il1b/IL-1β mRNA (27.2-46.5%) and protein (29.2-49.6%) expression and NF-κB activation (67.0-80.3%) by upregulation of MER proto-oncogene tyrosine kinase (MERTK) and inhibition of mitogen-activated protein kinase 3/1 (MAPK3/1). Strikingly, the similar pattern of the MERTK and MAPK3/1 changes in lesional macrophages of mice after PCA intervention in vivo was recapitulated. PCA inhibits vulnerable lesion progression in mice, which might partially be caused by normalization of arterial inflammation by upregulation of MERTK and inhibition of MAPK3/1 in lesional macrophages.

Inhibition of choroidal neovascularization by systemic delivery of gold nanoparticles

Choroidal neovascularization (CNV) is the abnormal growth of blood vessels that sprout from the choroid vasculature and grow beneath and into the retina. The newly formed blood vessels in CNV often leak blood and fluid which deteriorates vision over time, eventually leading to blindness. In the present study, we examined the efficacy of intravenously injected gold nanoparticles in the laser-induced CNV animal model. Using optical coherence tomography (OCT) and fluorescein angiography, we evaluated CNV lesions longitudinally, over a period of 21 days, with and without nanoparticle treatment. Intravenously injected low concentration of bare gold nanoparticles showed significant anti-angiogenic properties by suppressing CNV development and progression. The treatment group showed significantly decreased fluorescein leakage at the CNV site compared to vehicle injected control mice. OCT assisted CNV volume measurement at all time points showed a significant reduction in lesion size in the treatment group compared with controls.

Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors

The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L.infantum and L.braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L.braziliensis or L.amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.

Abstract P3-09-11: Modulation of the immune microenvironment in high risk DCIS

Abstract Background. Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. Features of DCIS that are associated with a high risk of a subsequent event include large size (&amp;gt; 5 cm), high grade, comedo necrosis, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates in DCIS are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high risk DCIS could potentially alter disease progression. Objectives. The objectives of this study were: 1). to define dose limiting toxicities, tolerability, and feasibility of intralesional injection of an immune checkpoint inhibitor (pembrolizumab) into DCIS; and 2). to determine response rate as measured by an increase in total T cells or CD8+ T cells from baseline to post treatment. Methods. Study participants received 2 intralesional injections of pembrolizumab, 3 weeks apart, with surgery approximately 3 weeks after the 2nd dose. Multiplex immunofluorescence analyses were used to compare immune cell populations in pre-treatment biopsies to post-treatment surgical specimens. Tissue samples were stained with two 6-plex immune panels using Opal immunofluorescence reagents (Perkin Elmer) on a fully automated Ventana Discovery platform, imaged with a Vectra 3 system and analyzed with inForm software (Perkin Elmer). Results. The intralesional injections were well tolerated and there were no systemic toxicities observed. Multiplex immunofluorescence analyses demonstrated significant increases in total T cells, as well as cytotoxic CD8+ T cells, following therapy. We also observed a significant positive correlation between the change (pre- vs. post-therapy) in Ki67+ T cells (proliferating T cells) with the increase in total T cells, suggesting that immune checkpoint inhibition removed the “brakes” from the T cells, allowing them to proliferate. Changes in macrophage, B cell, and Treg numbers pre- vs. post-therapy were not significant. Despite an increase in T cell infiltrates, there were no measurable indicators of an anti-tumor response: no reduction in lesion size by MRI, no reduction in proliferation of DCIS cells (Ki67 staining), and no increase in cell death (cleaved caspase 3 staining). Spatial analyses indicated that in most cases the T cell expansion (both total T cells and CD8+ T cells) occurred predominantly in the stroma, not among the DCIS cells in the ducts. Conclusions. We met the objectives of our study: 1). we demonstrated the safety and feasibility of intralesional injection of an immune checkpoint inhibitor (pembrolizumab) in high risk DCIS; and 2). we demonstrated that local immunotherapy resulted in the local proliferation/expansion of T cells. However we did not observe any change in the size of the lesions by MRI. In addition, there was no evidence for T cell killing at the cellular level, suggesting that even though there was an expansion of T cells, there are other factors at play such as immune exclusion or possibly immunosuppression of their killing ability. These results suggest that combination of pembrolizumab with another agent(s) will be needed to achieve a more complete response. Citation Format: Michael Campbell, Jasmine Wong, Emma McCune, Harriet Rothschild, Tristan Loveday, Jennifer Bolen, Cliff Hoyt, Scott VandenBerg, Jo Chien, Laura Esserman. Modulation of the immune microenvironment in high risk DCIS [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-11.

First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.

1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for &gt;6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.

Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury

The lack of effective therapies for moderate-to-severe traumatic brain injuries (TBIs) leaves patients with lifelong disabilities. Neural stem cells (NSCs) have demonstrated great promise for neural repair and regeneration. However, direct evidence to support their use as a cell replacement therapy for neural injuries is currently lacking. We hypothesized that NSC-derived extracellular vesicles (NSC EVs) mediate repair indirectly after TBI by enhancing neuroprotection and therapeutic efficacy of endogenous NSCs. We evaluated the short-term effects of acute intravenous injections of NSC EVs immediately following a rat TBI. Male NSC EV-treated rats demonstrated significantly reduced lesion sizes, enhanced presence of endogenous NSCs, and attenuated motor function impairments 4 weeks post-TBI, when compared with vehicle- and TBI-only male controls. Although statistically not significant, we observed a therapeutic effect of NSC EVs on brain lesion volume, nestin expression, and behavioral recovery in female subjects. Our study demonstrates the neuroprotective and functional benefits of NSC EVs for treating TBI and points to gender-dependent effects on treatment outcomes, which requires further investigation.

Feasibility of 5-aminolevulinic acid mediated photodynamic therapy for male genital lichen sclerosus

In this report, 5-aminolevulinic acid mediated topical photodynamic therapy (ALA-PDT) was firstly used to treat 3 male patients (26-39 years old) who suffered from male genital lichen sclerosus (MGLSc), all of who had a history of circumcision. Repeated ALA-PDT treatments were performed on these patients and achieved various degrees of improvement in signs and symptoms, especially in the sclerosis and subjective symptoms. Three patients showed 30%-70% of reduction of lesion size after treatments. The side effects of ALA-PDT were irradiation site pain and swelling, which disappeared quickly after irradiation without the need of medication. There was no recurrence or aggravation with at least 6 months of follow-up. This case report demonstrates that ALA-PDT is effective and well tolerated for MGLSc patients who have a history of circumcision. The true value of ALA-PDT for MGLSc deserves further study.

Overexpression of the chitinase gene CmCH1 from Coniothyrium minitans renders enhanced resistance to Sclerotinia sclerotiorum in soybean.

Pathogenic fungi represent one of the major biotic stresses for soybean production across the world. Sclerotinia sclerotiorum, the causal agent of Sclerotinia stem rot, is a devastating fungal pathogen that is responsible for significant yield losses in soybean. In this study, the chitinase gene CmCH1, from the mycoparasitic fungus Coniothyrium minitans, which infects a range of ascomycetous sclerotia, including S. sclerotiorum and S. minor, was introduced into soybean. Transgenic plants expressing CmCH1 showed higher resistance to S. sclerotiorum infection, with significantly reduced lesion sizes in both detached stem and leaf assays, compared to the non-transformed control. Increased hydrogen peroxide content and activities of defense-responsive enzymes, such as peroxidase, superoxide dismutase, phenylalanine ammonia lyase, and polyphenoloxidase were also observed at the infection sites in the transgenic plants inoculated with S. sclerotiorum. Consistent with the role of chitinases in inducing downstream defense responses by the release of elicitors, several defense-related genes, such as GmNPR2, GmSGT-1, GmRAR1, GmPR1, GmPR3, GmPR12, GmPAL, GmAOS, GmPPO, were also significantly upregulated in the CmCH1-expressing soybean after inoculation. Collectively, our results demonstrate that overexpression of CmCH1 led to increased accumulation of H2O2 and up-regulation of defense-related genes and enzymes, and thus enhanced resistance to S. sclerotiorum infection while showing no detrimental effects on growth and development of soybean plants.

A two-arm parallel double-blind randomised controlled pilot trial of the efficacy of Omega-3 polyunsaturated fatty acids for the treatment of women with endometriosis-associated pain (PurFECT1).

BackgroundEndometriosis is defined by the presence of endometrial-like tissue (lesions) outside the uterus, commonly on the pelvic peritoneum. It affects 6–10% of women and is associated with debilitating pelvic pain. Current management options are often unsatisfactory. Omega-3 polyunsaturated fatty acids (O-PUFA) have the potential to reduce the painful symptoms associated with endometriosis, reduce lesion size, preserve the patient’s ability to conceive, and have minimal side effects. We performed a two-arm, parallel double-blinded randomised controlled trial to inform the planning of a future multicentre randomised controlled trial to evaluate the efficacy of O-PUFA for endometriosis-associated pain.ObjectivesThe primary objectives of the trial were to assess recruitment and retention rates. The secondary objectives were to determine the acceptability to women of the proposed methods of recruitment, randomisation, treatments and questionnaires, to estimate the variability in the proposed primary endpoints to inform the sample size calculation and to refine the research methodology for the future definitive trial.MethodsWe recruited women with endometriosis from June 2016 to June 2017 and randomised them to eight weeks of treatment with O-PUFA or olive oil. Pain scores and quality of life questionnaires were collected at baseline and eight weeks. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to eight weeks. Acceptability questionnaires were used to evaluate women’s experiences of the trial.ResultsThe proportion of eligible participants who were randomised was 45.2% (33/73) and 81.8% (27/33) completed the study. The majority of participants described their overall trial experience favourably and there were no adverse events in either group.ConclusionOur pilot trial supports the feasibility of a future larger trial to definitively evaluate the efficacy of O-PUFA for endometriosis-associated pain.Trial registrationThe trial was registered on the ISRCTN registry (registration number ISRCTN44202346).

Photobiomodulation therapy for the management of recurrent aphthous stomatitis in children: clinical effectiveness and parental satisfaction.

Background This study aims to evaluate the effectiveness of the photobiomodulation therapy (PBMT) in the treatment of minor recurrent aphthous stomatitis (MiRAS) in children, in terms of pain relief, lesion size reduction and the parental satisfaction of the therapy. Material and Methods This randomized controlled study was carried out on 60 children with clinical diagnosis of MiRAS. Patients were randomized into two groups: group A receiving laser therapy and group B receiving sham therapy (placebo). Laser therapy (diode laser, λ: 645 nm) was administered on day 1 (T0) for three consecutive days. Patients were evaluated also on day 4 (T1), on day 7 (T2) and on day 10 (T3). Oral aphthous lesions size was assessed through a periodontal probe to measure the diameter length (mm); pain was evaluated through the Visual Analogue Scale (VAS); parental satisfaction was assessed through a questionnaire. Results The difference in the reduction of ulcers diameters between the two groups resulted statistically significant at T1 and at T2 (p<0.05). A statistically significant difference in pain reduction between two groups was found at T1 (p<0.05). No statistically significant difference between the two groups of parents was found as concerns the parental acceptance of the procedure and the discomfort for the need of multiple appointments. Conclusions PBMT is to be considered effective in the treatment of MiRAS in children and well- accepted by the parents of the children themselves. Key words:Ulcers, children, lasers

Efficacy of the 7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline derivative against infection caused by Leishmania amazonensis.

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations.METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.

Phase 1b multicenter study of the safety and efficacy of stereotactic body radiation therapy for extracranial renal cell carcinoma metastases in combination with tyrosine kinase inhibitors or checkpoint inhibitors (VOLGA STUDY).

Background. Tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI) have been established as effective treatment for mRCC, but only a minority of patients achieves complete response and additional strategies are necessary to improve the efficacy of these agents. We have designed a prospective phase 1b «Volga» study to determine the safety and efficacy of extracranial SBRT in patients with clear-cell mRCC. Methods. Patients were included if they had stable disease for at least 4 months on TKI or CI. SBRT was delivered to an organ with multiple comparable lesions, where one lesion was in the treatment target (target lesion) and the other lesion was intentionally left untreated (control lesion). Dose of radiation and number of fractions were determined based on target lesion localization and the proximity of organs at risk. Response in both target and control lesions was scored using RECIST 1.1 criteria at least 2 months after completion of SBRT. Primary endpoint was the rate of adverse events of SBRT and secondary endpoints included the rate of reduction in target lesion size and time to progression of the first (target) and the second (control) lesions. Results. 17 patients were enrolled since November 2016 (14 men and 3 women, median age — 54,5 years old, range 32 -72), 6 of them initially were diagnosed with metastatic RCC and the reminders developed distant metastases within 6 months — 5 years since radical nephrectomy. Twelve patients received TKI and 5 received nivolumab. SBRT was delivered to lungs (n=5), bones (n=4), lymph nodes (n=4), liver (n=1), primary RCC (n=1), and locally recurrent RCC (n=2). Equivalent Dose (EQD) with alpha/beta ratio of 2.6 was 114 Gy (range, 40-276 Gy). With a median follow-up of 8 months (range, 3 -18), cumulative rate of SBRT-related toxicity (grade 1) was 12 % (n=2), consisting of esophagitis (n=1) and skin erythema (n=1). No grade 2 or higher toxicity was detected. Radiographic response in the target lesion was seen in 13 patients (76 %), with complete response in 5 (29 %) patients and partial response in 8 (47 %) including abscopal effect in 1 patient. Control lesions remained stable in 16 patients. The difference between response in target and control lesions as judged by mean sizes of these lesions before and at 2 months after SBRT was statistically significant (p&lt;0.01). Fraction size of equal to or greater than 10 Gy was associated with complete response in the target lesion (p&lt;0.01). Conclusion. Extracranial SBRT in patients with mRCC treated with TKI or CI is well tolerated and could be effective. This approach will be studied in an expanded cohort of patients.

S100 Calcium-Binding Protein A9 Knockout Contributes to Neuroprotection and Functional Improvement after Traumatic Brain Injury.

S100 calcium-binding protein A9 (S100a9), a proinflammatory protein, has been shown to be involved in the development of neuroinflammatory disorders and neurodegenerative diseases. Upregulation of S100a9 in the brain during acute brain injury has been proposed to be associated with acute neuroinflammation. However, it remains unclear whether eliminating S100a9 expression will show beneficial outcomes after traumatic brain injury (TBI). Using S100a9 knockout mice, this study has demonstrated that S100a9 deletion ameliorates post-TBI anxiety, improves TBI-impaired motor and cognitive function, reduces lesion size, prevents perilesional neuron loss and neurodegeneration, diminishes neuroinflammation and TBI-induced neurogenesis, and enhances perilesional expression of neuroplasticity protein. These findings suggest that S100a9 plays a detrimental role in TBI. Genetic deletion of S100a9 enhances neuroprotection and improves functional outcome after TBI. This study sheds light on the pathological involvement of S100a9 in TBI, which would provide a new therapeutic target to minimize TBI-induced brain damage.

Long Term Follow-up of Intralesional Laser Photocoagulation for Head and Neck Lymphatic Malformations Using Neodymium-Yttrium-Aluminium-Garnet Laser.

Lymphatic malformations remain a challenge for patients and plastic surgeons. Promising results have been reported using intralesional laser photocoagulation (ILP) for treating vascular anomalies. The objective of our study is to review the long-term results of a large series of lymphatic malformations in patients treated with ILP. A retrospective review of 190 head and neck lymphatic malformations in patients were treated by ILP with an neodymium-yttrium-aluminum-garnet (Nd:YAG) laser (1064 nm) over a period of 20 years (January 1997-January 2016). Patients' ages ranged from 10 months to 12 years and 6 months (mean, 1 year and 11 months). The patient group consisted of 98 female and 92 male patients. Patients were treated with an Nd:YAG laser (Sharplan Inc, Allendale, New Jersey) delivered through a 600-μm optical fiber. Laser power was set at 7 to 15 W and delivered with a pulse duration of 7 to 15 seconds. All patients demonstrated improvement as judged by clinical assessment of the reduction in lesion size (range, 65%-100%; mean reduction, 85%). One hundred fifty-two (80%) patients had a more than 65% reduction of the volume in lymphatic malformations at 3 months after 1 treatment, and 171 (90%) patients had a more than 85% reduction of the volume after 2 treatments. Excellent results were seen in 19 (10%) patients after 3 treatments. Postoperative complications were related to photocoagulation that was delivered too extensively or superficially, with resultant ulceration, infection, induration, and scarring. Throughout the course of our long-term study, ILP using an Nd:YAG laser is an effective treatment modality for lymphatic malformations. Complications can be avoided if the potential for harm is kept in mind.

Efficacy of non-antibiotic treatment options for digital dermatitis on an organic dairy farm

The objective of this study was to evaluate the efficacy of two non-antibiotic treatment options for digital dermatitis (DD) on an organic certified dairy farm. A randomized clinical trial was conducted using 70 multiparous Holstein cows with an early DD lesion at a USDA certified organic dairy farm in Northern Colorado, USA. Cows were enrolled in the study based on the presence of early DD lesions (scores M1 and M2) and randomly assigned to one of three treatments: (1) topical application of copper sulfate and iodine (CUI); (2) topical application of honey and iodine (HOI); and (3) control subject to no treatment (CON). Cows were evaluated at enrolment and on days 3, 12, 28, and 120 post treatment for pain and lesion size and received a locomotion and a lesion score. Cure was defined as the transition from active to non-active stages (M1/M2 to M0 or M4).The formulations had variable effects on the treatment of DD. The cure rate was numerically higher for CUI on all follow up days. The proportion of cows experiencing pain on d3 after treatment was greater in CON, followed by HOI and CUI. However, this proportion increased in HOI during the follow up period. The CUI group had a greater reduction in lesion size and larger lesions persisted in HOI. Non-antibiotic treatment formulations were partially effective in the treatment of DD in organic dairy cows: The two non-antibiotic formulations resulted in an earlier transition to mature lesions compared with the control group. The CUI combination was the most effective treatment in reducing lesion size, pain, and lameness in affected cows. However, this combination had short-term efficacy, which did not persist throughout the duration of the study. The HOI combination produced only transient reduction in lesion size.