Oleg E. Akilov

Diagnostic Inaccuracy of Smartphone Applications for Melanoma Detection

OBJECTIVE To measure the performance of smartphone applications that evaluate photographs of skin lesions and provide the user with feedback about the likelihood of malignancy. DESIGN Case-control diagnostic accuracy study. SETTING Academic dermatology department. PARTICIPANTS AND MATERIALS: Digital clinical images of pigmented cutaneous lesions (60 melanoma and 128 benign control lesions) with a histologic diagnosis rendered by a board-certified dermatopathologist, obtained before biopsy from patients undergoing lesion removal as a part of routine care. MAIN OUTCOME MEASURES Sensitivity, specificity, and positive and negative predictive values of 4 smartphone applications designed to aid nonclinician users in determining whether their skin lesion is benign or malignant. RESULTS Sensitivity of the 4 tested applications ranged from 6.8% to 98.1%; specificity, 30.4% to 93.7%; positive predictive value, 33.3% to 42.1%; and negative predictive value, 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis; the lowest, for applications that use automated algorithms to analyze images. CONCLUSIONS The performance of smartphone applications in assessing melanoma risk is highly variable, and 3 of 4 smartphone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation can delay the diagnosis of melanoma and harm users.

The potential for photodynamic therapy in the treatment of localized infections

At the present time photodynamic therapy (PDT) is receiving considerable interest for its potential as an antimicrobial therapy. This treatment may be a valuable tool in achieving a rapid reduction of the microbial burden perhaps even in the management of localized infections that are resistant to standard antibiotic regimens. A variety of photosensitizers from different groups including porphyrins, chlorophyll derivatives, phthalocyanines and azines have been effective in the photokilling of many Gram-positive and Gram-negative bacterial pathogens in addition to parasites, fungi, and viruses. Much of the suggested antimicrobial uses of this therapy are based on results from in vitro studies. Only a limited number of animal models of infection or clinical studies have been employed to assess the effectiveness of PDT. These studies have reported moderate successes that have not quite achieved the expectations projected from the in vitro results. In order to fully validate the potential of PDT as an antimicrobial therapy considerably more effort is required in the area of appropriate experimental models to better understand the mechanisms of photodynamic destruction of bacteria.

Parasiticidal effect of δ‐aminolevulinic acid‐based photodynamic therapy for cutaneous leishmaniasis is indirect and mediated through the killing of the host cells

Abstract:  Several clinical reports have shown promising, but not optimal, results from photodynamic therapy with δ‐aminolevulinic acid‐derived protoporphyrin IX, termed ALA‐PDT, as a treatment for cutaneous leishmaniasis (CL). Therefore, understanding the basis of the phototoxic response of Leishmania parasites to ALA‐PDT may be critical for optimization. We report here both in vitro and in vivo mechanistic studies of ALA‐PDT against CL. Following in vitro co‐incubation of Leishmania major with 0.1 μm ALA, the PpIX concentration remained at the basal level, whereas after co‐incubation with 0.1 μm exogenous PpIX, the PpIX level was 100‐fold higher. No differences in ALA‐derived PpIX levels were detected between Leishmania‐infected and non‐infected J774.2 cells, and PDT did not demonstrate any parasiticidal effects on amastigotes. In contrast, in vivo topical ALA‐PDT, performed on a murine CL model, resulted in significant reductions of the parasite loads and vigorous tissue destruction. After ALA‐PDT, a dramatically decreased percentage of macrophages and increased levels of interleukin‐6 were observed in the infected skin. The clinical outcome observed with ALA‐PDT is likely the result of unspecific tissue destruction accompanied by depopulation of macrophages rather than direct killing of parasites.

Clinical manifestations and classification of Old World cutaneous leishmaniasis

With the migratory trends amongst populations during the last decade (urbanization, political conflicts, etc.), there has been an increase in the incidence of Old World cutaneous leishmaniasis (CL). In endemic zones (Afghanistan, Pakistan, Iran, and Iraq), the incidence of CL is estimated to be approximately 2–3%. 1–4 Armed operations in Asia and the Middle East have given rise to a significant number of CL cases. Current World Health Organization (WHO) reports estimate the annual incidence of CL cases to be 1–1.5 million. 5,6

The role of mannose receptor during experimental leishmaniasis

The primary host cells for Leishmania replication are macrophages (MP). Several molecules on the surface of professional phagocytic cells have been implicated in the initial process of parasite internalization and initiation of signaling pathways. These pattern recognition receptors distinguish molecular patterns on pathogen surfaces. Mannose receptor (MR), specifically, recognizes mannose residues on the surface of Leishmania parasites. We studied the role of MR in the pathogenesis of experimental cutaneous and visceral leishmaniasis using MR‐deficient [MR‐knockout (KO)] C57BL/6 mice. MR‐deficient MP exhibied a comparable infection rate and cytokine production. In the absence of MR, the clinical course of Leishmania major and Leishmania donovani infections was similar in MR‐KO and wild‐type mice (MR‐WT). Furthermore, immunohistochemistry of cutaneous lesions from MR‐KO and MR‐WT mice revealed no differences in lesion architecture or cell components. Inhibition of MP responses is a hallmark of Leishmania infection; our data demonstrate further that host MR is not essential for blocking IFN‐γ/LPS‐induced IL‐12 production and MAPK activation by Leishmania. Thus, we conclude that the MR is not essential for host defense against Leishmania infection or regulation of IL‐12 production.

Photodynamic therapy for cutaneous leishmaniasis: the effectiveness of topical phenothiaziniums in parasite eradication and Th1 immune response stimulation

Photodynamic therapy (PDT) is emerging as a therapeutic modality in the clinical management of cutaneous leishmaniasis (CL). The efficacy of PDT against CL has been demonstrated previously with aminolevulinic acid, although the prolonged terms of therapy were less than ideal, and the search for new photosensitizers (PS) is ongoing. However, phenothiaziniums have demonstrated high parasiticidal effects in vitro. The subject of our investigation is the in vivo activity of two PS, 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium chloride (EtNBSe) and (3,7-Bis(N,N-dibutylamino) phenothiazinium bromide (PPA904). The results of our comparative analysis of the efficacy of these two phenothiazinium analogues demonstrated a high antiparasitic activity of EtNBSe in vitro, and the higher efficacy of PPA904 in a mouse model of CL. The kinetics of photodestruction are different in parasite and mammalian cells, and with both dyes, the macrophages are more susceptible to photodynamic effects than L. major parasites. As the number of parasites in the lesions undergoes a biphasic change, temporarily increasing on days 2-4 and decreasing on days 5-7, more than one treatment is required within an interval of 5 to 7 days. We have also shown that PPA904-PDT can provide an immunomodulating, dose-dependent efflux on IL-12p70 production. This mechanism could be responsible for promoting a more rapid healing in PPA904-PDT treated mice. Our initial data indicate that phenothiaziniums exhibit a high parasiticidal effect in vivo against CL; this finding may be of use in establishing curative PDT regimens for future clinical trials.

Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial

BACKGROUND Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. METHODS In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physicians choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. FINDINGS Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physicians choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physicians choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physicians choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physicians choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physicians choice group. INTERPRETATION Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physicians choice of methotrexate or bexarotene. FUNDING Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Photoinactivation of Mycobacteria In Vitro and in a New Murine Model of Localized Mycobacterium bovis BCG-Induced Granulomatous Infection

ABSTRACT Treatment of tuberculosis is currently hindered by prolonged antibiotic regimens and the emergence of significant drug resistance. Alternatives and adjuncts to standard antimycobacterial agents are needed. We propose that a direct attack utilizing photosensitizers and light-based treatments may be effective in curtailing Mycobacterium tuberculosis in discrete anatomical sites in the most infectious phase of pulmonary tuberculosis. To demonstrate experimental proof of principle, we have applied established photodynamic therapy (PDT) technology to in vitro cultures and an in vivo mouse model using Mycobacterium bovis BCG. We report here in vitro and in vivo PDT efficacy studies and the use of a three-dimensional collagen gel as a delivery vehicle for BCG, subcutaneously inserted, to induce specifically localized granuloma-like lesions in mice. When a benzoporphyrin derivative was utilized as the photosensitive agent, exposure to light killed extracellular and intracellular BCG in significant numbers. Collagen scaffolds containing BCG inserted in situ in BALB/c mice for 3 months mimicked granulomatous lesions and demonstrated a marked cellular infiltration upon histological examination, with evidence of caseating necrosis and fibrous capsule formation. When 105 BCG were present in the in vivo-induced granulomas, a significant reduction in viable mycobacterial cells was demonstrated in PDT-treated granulomas compared to those of controls. We conclude that PDT has potential in the treatment of localized mycobacterial infections, such as pulmonary granulomas and cavities.

Comparative split-face study of 5-aminolevulinic acid photodynamic therapy with intense pulsed light for photorejuvenation of Asian skin.

Photodynamic therapy (PDT) with 5‐aminolevulinic acid (ALA) (ALA‐PDT) using intense pulsed light (IPL) as a light source (IPL‐ALA‐PDT) has been used for photorejuvenation, but it is unclear if this protocol can be applied to darker skin types. We performed this study to assess our IPL‐ALA‐PDT protocol for photorejuvenation in Asian skin. To determine an appropriate dose, ALA ointment (0–20%) was applied to the upper arm of five healthy volunteers and the fluorescence intensity (FI) was measured using a spectrofluorometer. Non‐linear regression analysis of FI 2 h after ALA application with global fitting gave a typical sigmoid dose–response curve with R2 = 0.9705 and saturation after 5% ALA. The entire faces of 16 Japanese women with photodamage were then treated with IPL (500–670 and 870–1400 nm, 23–30 J/cm2) 2 h after application of 5% ALA to one side of the face. Three treatments were delivered at 4‐week intervals with follow‐up visits. Comparative analysis of photorejuvenation showed noticeable improvements on both sides of the face, although the reduction in the photoaging score from baseline did not differ significantly between the two sides in all subjects. Despite this finding, 75% of the patients felt that the IPL‐ALA‐PDT‐treated side of the face showed greater improvement than the IPL‐treated side. However, all IPL‐ALA‐PDT‐treated sides showed adverse effects such as erythema and pain. Therefore, we conclude that the IPL‐ALA‐PDT protocol requires optimization for photorejuvenation in Asians.

Targeting of sebaceous glands by δ‐aminolevulinic acid‐based photodynamic therapy: An in vivo study

Wide application of ALA‐PDT for acne is limited due to relative strong side effects, such as pain and erythema. The objective of this study was to establish a protocol for ALA‐PDT that would provide specific destruction of sebaceous glands at the lowest concentrations and shortest contact times of ALA.