LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Vitamin D3 and deconvoluting a rash.

BACKGROUNDAdverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODSSkin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTSCholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSIONHigh-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATIONclinicaltrials.gov (NCT02968446).FUNDINGNIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).

Oral Vitamin D Rapidly Attenuates Inflammation from Sunburn: An Interventional Study.

The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo-controlled interventional trial, 20 healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of UVR. Compared with placebo, participants receiving vitamin D3 (200,000 international units) demonstrated reduced expression of proinflammatory mediators tumor necrosis factor-α (P = 0.04) and inducible nitric oxide synthase (P = 0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (P = 0.007) demonstrated increased skin expression of the anti-inflammatory mediator arginase-1 (P = 0.005), and a sustained reduction in skin redness (P = 0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of proinflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 upregulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans.

Does imiquimod pretreatment optimize 308-nm excimer laser (UVB) therapy in psoriasis patients?

BACKGROUND/PURPOSE: Psoriasis continues to be a debilitating skin disease affecting 1-3% of the United States population. Although the effectiveness of several current biologic therapies have described this pathology as a IL-23, TNF-a and Th17-mediated disease, less invasive approaches are still in use and in need of refinement. One of these is the usage of narrow band-UVB (NB-UVB) therapy to deplete specifically intra-epidermal CD3+, CD4+ and CD8+ cells to clear psoriatic plaques. AIMS/OBJECTIVES: In order to improve NB-UVB therapy, we sought to determine whether skin pre-treatment with the TLR7 agonist imiquimod (IMQ) would help increase the efficiency of the former at resolving psoriatic plaques. MATERIALS AND METHODS: Eucerin® Original Moisturizing Lotion (topical vehicle) or Aldara® (imiquimod 5% topical cream) were applied for 5 days once daily to a maximum contiguous area of 25 cm2 (5 cm × 5 cm area). Patients were provided with sachets containing 12.5 mg of imiquimod each and were instructed to apply imiquimod (I) to two psoriasis plaques (5 sachets of imiquimod allotted to each plaque). A PHAROS excimer Laser EX-308 (Ra Medical Systems, Inc. Carlsbad, CA, USA) with an output of monochromatic 308-nm light and pulse width of 20-50 ns was used for all patients. Punch biopsies of psoriatic lesions (6 mm) were taken at 4 and 48 h after final application of topical treatment with or without excimer laser treatment. Real-time quantitative RT-PCR was performed according to manufacturer's instructions and Inmunohistochemistry was used as described before. RESULTS: Our results suggests that although IMQ seemed to activate the type I interferon pathway as previously described, its concomitant usage with NB-UVB for clearing psoriatic skin was ineffective. Although upregulation of genes MxA, GRAMD1A and DMXL2 suggested that IMQ treatment did induce skin changes in psoriasis patients, more optimal dosing of IMQ and NB-UVB might be necessary to achieve desired treatment responses. CONCLUSION: The observation that psoriasis involvement was not aggravated by usage of topical IMQ was encouraging. Additional observational studies might be necessary to further tailor the combination of IMQ with NB-UVB therapy to reliably improve the psoriatic pathology.

Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium.

BACKGROUND: Ultraviolet light (UVL) is a long established treatment for mycosis fungoides (MF) and Sézary syndrome (SS), subtypes of cutaneous T-cell lymphoma (CTCL). Treatments have traditionally included broadband, narrowband ultraviolet B light (UVB) and psoralen plus ultraviolet A light photochemotherapy (PUVA), but more recently, treatment options have expanded to include UVA1 and excimer laser. UVL is used either as monotherapy or as an adjuvant to systemic therapy, demonstrating efficacy in many cases that equal or surpass systemic medications. Despite its utility and duration of use, the current practice of using UVL guidelines for psoriasis to treat patients with MF/SS is problematic because the goals of prolonging survival and preventing disease progression are unique to CTCL compared to psoriasis. OBJECTIVES: We sought to develop separate guidelines for phototherapy for MF/SS for both clinical practice and for clinical trials. METHODS: Literature review and cutaneous lymphoma expert consensus group recommendations. RESULTS: This paper reviews the published literature for UVB and UVA/PUVA in MF/SS and suggests practical standardized guidelines for their use. LIMITATIONS: New standardization of phototherapy. CONCLUSIONS: These guidelines should allow the comparison of results with phototherapy in MF/SS across different stages of patients, centers, and in combination with other agents in practice and in clinical trials.

Phototherapy-related ophthalmologic disorders.

Phototherapy is an effective treatment option for a variety of dermatologic disorders, and the list of indications for its use continues to grow with advances in technology and our understanding of disease processes. Commonly used types of phototherapy include PUVA, broadband UVB, narrowband UVB, photodynamic therapy, and intense pulsed light therapy. Each therapeutic modality can have adverse acute and chronic effects on periocular and ocular structures, including the conjunctiva, cornea, crystalline lens, and retina. There are many types of protective eyewear options available, including goggles and contact lenses that can be used to prevent damage to ocular structures during phototherapy, particularly if eyelid closure is incomplete.

Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches.

Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.

Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.

Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.

UVB-protective properties of contact lenses with intended use in photoresponsive eyelid dermatoses.

BACKGROUND: UV-blocking contact lenses were evaluated to determine if they could provide adequate ocular protection during narrowband UVB phototherapy treatment. Theoretical safe exposure durations for the crystalline lens, cornea and conjunctiva were determined. METHODS: A Cary 500 spectrophometer generated transmittance data for six UV-blocking and two non-UV-blocking contact lenses. An IL-1700 radiometer measured the lenses' radiation transmittance within the NB-UVB phototherapy unit. The lenses were exposed to a 1500-mJ/cm(2) dose of radiation from a 308-nm excimer laser to determine if the radiation would alter their protective properties. Theoretical safe exposure durations for eye structures were calculated using previous human and animal study data. RESULTS: All UV-blocking contact lenses showed less than 1E-7 W/cm(2) of radiation transmittance within the narrowband phototherapy unit. The excimer laser did not significantly alter the lenses' UV-blocking capabilities. The safe exposure durations for the cornea and crystalline lens were greater than 11 min with UV-blocking lenses, and that for the unprotected conjunctiva was approximately 11 s. CONCLUSION: Some UV-blocking contact lenses potentially provide sufficient ocular protection during narrowband UVB phototherapy treatment, as the crystalline lens and cornea are adequately protected should a patient open his or her eyes for a short time.

Non-sunscreen photoprotection: antioxidants add value to a sunscreen.

The association between ultraviolet radiation (UVR) exposure and both skin cancer and photo-aging is well documented. In addition to the conventional organic-chemical and physical-mineral type sunscreens, other non-sunscreen protective strategies have been developed. These include topically applied botanical extracts and other antioxidants as well as topical DNA repair enzymes. Standard terms of photoprotection such as sun protection factor (SPF) do not accurately reflect the photoprotection benefits of these materials. For example, in spite of minimal SPF, tea extract containing polyphenols such as (-)-epigallocatechin-3-gallate (EGCG) has been shown to protect against UV-induced DNA damage and immune suppression, in part through its ability to reduce oxidative stress and inhibit NF-kB. The addition of botanical antioxidants and vitamins C and E to a broad-spectrum sunscreen may further decrease UV-induced damage compared with sunscreen alone. These agents have been shown to enhance protection against UV-induced epidermal thickening, overexpression of MMP-1and MMP-9, and depletion of CD1a(+) Langerhans cells. Non-sunscreen materials such as botanical extracts, antioxidants, and DNA repair enzymes can contribute value when applied topically to human skin in vivo.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 56-59; doi:10.1038/jidsymp.2009.14.

Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin.

BACKGROUND: Tea polyphenols have been found to exert beneficial effects on the skin via their antioxidant properties. AIMS: We sought to determine whether topical application of green tea or white tea extracts would prevent simulated solar radiation-induced oxidative damages to DNA and Langerhans cells that may lead to immune suppression and carcinogenesis. METHODS: Skin samples were analysed from volunteers or skin explants treated with white tea or green tea after UV irradiation. In another group of patients, the in vivo immune protective effects of green and white tea were evaluated using contact hypersensitivity to dinitrochlorobenzene. RESULTS: Topical application of green and white tea offered protection against detrimental effects of UV on cutaneous immunity. Such protection is not because of direct UV absorption or sunscreen effects as both products showed a sun protection factor of 1. There was no significant difference in the levels of protection afforded by the two agents. Hence, both green tea and white tea are potential photoprotective agents that may be used in conjunction with established methods of sun protection.

Tranilast: a pharmaceutical candidate for reduction of adhesions using a novel approach.

Postsurgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed in hopes of reducing the tissue trauma seen with open procedures and separating tissues during the critical time of healing to reduce adhesion formation. Despite meticulous techniques by surgeons and the availability of barriers, adhesion formation remains a serious problem, with more than $1 billion spent annually on complications arising from adhesions. Our laboratories have combined a previously marketed drug, Tranilast, with a gel to provide a locally delivered medicated device that can reduce adhesion formation. This article will review the role of Tranilast in the key pathways involved in adhesion formation.

Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: the case experience with preclinical mechanistic and early clinical-translational studies.

Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

Peritransplant use of ultraviolet-B irradiation (UV-B) therapy is detrimental to allogeneic stem cell transplantation outcome.

Whole-body UV-B phototherapy has been used for the treatment of graft-versus-host disease (GVHD) of the skin and has systemic immunosuppressive and tolerogenic effects. We hypothesized that whole-body UV-B therapy would improve donor engraftment and decrease the incidence and severity of GVHD that is associated with decreased intensity allogeneic hematopoietic stem cell transplantation. This study tested the feasibility of using UV-B phototherapy that was initiated before grafting and continued until engraftment to determine its effect on transplantation outcome. Eight patients (median age, 55.5 years; range, 32-65 years) with hematologic malignancies were included. Allogeneic peripheral blood stem cells were obtained from matched related (n=5) or matched unrelated (n=3) donors. Conditioning regimen was fludarabine 30 mg/m2 intravenously for 5 days, cyclophosphamide 1 g/m2/d intravenously for 2 days, and equine antithymocyte globulin 30 mg/kg/d for 2 days. GVHD prophylaxis included cyclosporine, methylprednisolone, and escalating doses of narrowband UV-B (311 nm) according to skin tolerance, 3 days a week, from 10 days before to 28 days after transplantation. The conditioning regimen and the UV-B therapy were well tolerated. Two patients received all 14 prescribed UV-B treatments (cumulative doses of 2000 and 3260 mJ/cm2, respectively) and 6 patients received 8 to 13 treatments with a cumulative dose range of 528-3465 mJ/cm2. There was a rapid decrease in epidermal CD1a+ cells by day of transplantation. Myeloid engraftment was rapid. One patient had secondary engraftment failure at 3 months and another had mixed chimerism at day 100. Seven of 8 patients developed severe acute GVHD (grade III, n=5; grade IV, n=2). Six had skin involvement, 5 had gastrointestinal involvement, and 1 had liver involvement. Four patients died (2 from sepsis, 1 from acute GVHD, and 1 from chronic GVHD). Four patients are alive (130-287 days), 3 with extensive chronic GVHD. We conclude that extended peritransplant UV-B therapy at the standard minimally erythemogenic dose is detrimental to the outcome of allogeneic stem cell transplantation. It is unclear how UV-B at this immunsuppressive dose might have altered skin and systemic cytokine and immune cell compositions in the host and increased GVHD- and treatment-related mortalities. Different UV-B dose and schedules should be further explored. However, although other phototherapeutic modalities may be effective against GVHD, extended UV-B therapy should not be used during early phases of decreased conditioning allogeneic transplantation.

Laser-assisted penetration of allergens for patch testing.

BACKGROUND: Patch-test patients often complain of itching and inconvenience. OBJECTIVE: To demonstrate (1) the usefulness of laser-assisted alteration of the stratum corneum to enhance allergen delivery and (2) patient satisfaction with this procedure. METHODS: The LAD-01 (erbium:yttrium-aluminum-garnet) laser unit was used to alter stratum corneum from patients with known sensitivity to nickel or Kathon CG. These allergens were then applied to the laser-pretreated sites for 60 minutes. Results were observed at 24, 48, and 96 hours and at 1 week. One patient who refused conventional patch testing was tested with an entire modified North American standard series tray with the laser patch-test technique. An additional patient with previously demonstrated positive atopy patch-test reactions to environmental organisms was retested with laser pretreatment to the same antigens. RESULTS: Three of three patients known to be sensitive to Kathon CG and eight of eleven known nickel-sensitive patients had positive reactions at the laser-pretreated sites. The patient who was tested with the entire standard series demonstrated relevant positive reactions to formaldehyde and to a textile resin. One subject with known reactions to three environmental organisms reproduced patch-test responses with laser pretreatment. No irritant reactions were noted. Patients reported no pain. CONCLUSION: With further modification, laser pretreatment may improve patient convenience and decrease irritant test reactions owing to occlusion.

Outpatient endometrial ablation.

The simplicity of use and short treatment times of second-generation ablation techniques have increased the likelihood of acceptable treatment under local anaesthetic. Once treatment under local anaesthesia +/- conscious sedation has become accepted, the next step is to explore the viability of moving ablation out of theatre. Whilst there are many series reports of treatment under local anaesthetic, few well-constructed trials have evaluated acceptability and success rates. A reliable anaesthetic regime is available with low failure rates, although problems exist with unpredictable post-operative discomfort and nausea. The optimal treatment package, which will guarantee acceptable treatment with no failures and a quick recovery time allowing for early discharge, is not known. This, along with equipment requirements, safety issues and the need for well-trained support staff, will make outpatient ablation unattractive at present for all but the most determined gynaecologists who have supportive and dynamic staff.

The cost of microwave endometrial ablation under different anaesthetic and clinical settings.

OBJECTIVE: To compare the costs of microwave endometrial ablation under local anaesthetic and general anaesthetic in an operating theatre and to estimate the cost of performing treatment under local anaesthetic in a dedicated clinic setting. DESIGN: The costing study was undertaken alongside a randomised controlled trial comparing the acceptability of microwave endometrial ablation using local versus general anaesthetic in a theatre setting. SETTING: Department of Gynaecology, Aberdeen Royal Infirmary, Scotland. SAMPLES: One hundred and twenty-seven women undergoing microwave endometrial ablation who had been randomly allocated to general or local anaesthetic. METHODS: Health and non-health service resource use was recorded prospectively. Data on resource use were combined with unit costs estimated using standardised methods to determine the cost per patient for microwave endometrial ablation under local or general anaesthetic in theatre. A model was developed to estimate the health service cost of microwave endometrial ablation under local anaesthetic in a clinic setting. MAIN OUTCOME MEASURES: Health and non-health service costs. RESULTS: There was little difference in cost when treatments were performed under local or general anaesthetic in theatre. The median health and non-health cost of microwave endometrial ablation was 440 pounds and 120 pounds, respectively, under general anaesthetic and 428 pounds and 125 pounds per women under local anaesthetic. The health service cost of microwave endometrial ablation using local anaesthetic in a clinic setting was estimated to be 432 pounds per treatment; however, this varied from 389 pounds to 491 pounds in the sensitivity analysis. CONCLUSION: There are minimal cost savings to the patient or health service from using local rather than general anaesthetic for microwave endometrial ablation in a theatre setting. Cost modelling suggests that in a clinic setting microwave endometrial ablation has a similar cost to theatre based treatment once re-admissions for treatment under general anaesthetic are considered. Sensitivity analysis indicated that these findings were sensitive to assumptions in the model.