Photodynamic therapy for squamous cell carcinoma of the head and neck: narrative review focusing on photosensitizers.

This narrative review aimed to evaluate the effectiveness of PDT in early or advanced squamous cell carcinoma of the head and neck (SCCHN). Scopus, MEDLINE/PubMed, and Embase were searched electronically following the PRISMA protocol. Quality assessment was performed according to JBI, NIH, and AMSTAR protocols. The main outcomes evaluated were treatment response, recurrence, survival, and adverse effects. A total of 49 articles met the search criteria: 43 case series, two cohort studies, two prospective before-after clinical trials, one systematic review, and one meta-analysis. Data from 2121 SCCHN patients were included. The response to PDT was variable according to the type of photosensitizer, tumor location, and tumor stage. In general, higher complete responses rated were observed in T1/T2 SCCHN, mainly with mTHPC-mediated PDT. With regard to T3/T4 or advanced SCCHN tumors, there is no compelling evidence suggesting the effectiveness of PDT. Any adverse effects reported were well tolerated by patients. The present review suggests that PDT is a promising treatment modality for early-stage SCCHN. Although there are limitations due to the low level of evidence of the included studies, we believe that the present review could help to design robust clinical trials to determine the efficacy of PDT in SCCHN.

Analysis of the psychopathological profile, quality of life, and cost-effectiveness of oral lichen planus patients treated with photobiomodulation.

OBJECTIVES: To evaluate the effect of PBM on the psychological profile and quality of life of patients with oral lichen planus (OLP) in comparison to corticoid and to investigate the cost-effectiveness of both treatments. MATERIALS AND METHODS: Patients were randomized into two groups: Control (clobetasol propionate 0.05%) and Photobiomodulation (660 nm, 100mW, 177 J/cm2, 5 s, 0.5 J) twice a week for 30 days. The Hospital Anxiety and Depression Scale (HADS) and OHIP-14 were used in different treatment time points and at follow-up. The cost-effectiveness was calculated using the improvement in OHIP-14 after treatment. RESULTS: OLP patients showed detected levels of anxiety, depression, and poor quality of life at baseline. No improvement in anxiety and depression was noticed after treatments. However, PBM and corticoid significantly improved the quality of life of OLP patients, considering the OHIP-14-T and the physical pain domain. The treatment with corticoid was more cost-effective than PBM. CONCLUSIONS: Psychological distress was not improved after both treatments and PBM is as effective as corticoids in promoting a better quality of life in OLP patients, despite its higher cost. CLINICAL RELEVANCE: This study highlights the need for additional therapeutic interventions in OLP patients, to early recognize and to manage the alterations in their psychological profile. Moreover, PBM is an effective therapy in OLP patient's quality of live and although it was a more expensive, the advantage of being a minimally invasive therapy associated with no side effects must be considered in clinical practice, especially in those patients with refractory disease. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov; the registration number is NCT03320460, registered in 17/10/2017.

Effects of the phenotypic polarization state of human leukocytes on the optical absorbance spectrum.

This study evaluated the optical absorbance spectrum of human monocytes, neutrophils and lymphocytes polarized, or not, to the inflammatory or immunoregulatory phenotypes. Peripheral human blood leukocytes were isolated and polarized (10 ng/mL) with LPS or IL-4 + LPS for 2 hours. After polarization, cells were washed and incubated for an additional 24 hours (monocytes and lymphocytes) or 12 hours (neutrophils). Next, cells were collected to evaluate the optical absorbance spectrum. The three types of leukocytes exhibited absorbance in the region from 450 to 900 nm, with greater absorbance at wavelengths lower than 570 nm. Lymphocytes had a second region of greater absorbance between 770 and 900 nm. Inflammatory monocytes and lymphocytes showed increased absorbance of blue, green and yellow wavelengths (monocytes), as well as red and infrared wavelengths (monocytes and lymphocytes). Immunoregulatory polarization altered the absorbance of monocytes and lymphocytes very little. Neutrophils treated with LPS or LPS + IL-4 exhibited lower absorbance at wavelengths higher than 575 nm compared to untreated cells. The present findings showed that leukocytes exhibit greater absorbance in regions of the spectrum that have not been much used in photobiomodulation (PBM), and the polarization of these cells can affect their capacity to absorb light. Taken together, these results suggest new perspectives in the use of PBM in the clinical setting depending on the wavelengths and the stage of the inflammatory process.

Effects of photobiomodulation on cellular viability and cancer stem cell phenotype in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy; it has been shown that cancer stem cells (CSC) are present in OSCC and associated with tumor growth, invasion, metastasis, and therapeutic resistance. Photobiomodulation (PBM) is an alternative tool for oncologic treatment adverse effects such as oral mucositis (OM); however, controversy exists regarding the undesirable effects of PBM on tumor or CSC. This study aimed to evaluate in vitro, the effects of PBM, with the same dosimetric parameters as those used in the clinic for OM prevention and treatment, on OSCC cellular viability, as well as PBM's effect on CSC properties and its phenotype. OSCC cell lines were submitted to single or daily PBM with 3 J/cm2 and 6 J/cm2 and then the cellular viability was evaluated by MTT, NRU (neutral red uptake), and CVS (crystal violet staining). The CSC populations were evaluated by clonogenic formation assay, flow cytometry, and RT-qPCR. The single PBM with the 3 J/cm2 group was associated with increased cellular viability. Daily PBM with 3 J/cm2 and 6 J/cm2 was associated with a significant decrease in cellular viability. Additionally, daily PBM was not able to promote CSC self-renewal or the CD44high/ESAlow and CD44high/ESAhigh cellular phenotypes. Moreover, a decrease in the number of spheres and in the expression of the CSC related gene BMI1 was observed after daily PBM with 6 J/cm2. Daily PBM with 3 J/cm2 and 6 J/cm2 showed an inhibitory effect on cellular viability and was not able to promote the CSC self-renewal or phenotype.

Photobiomodulation is effective in oral lichen planus: A randomized, controlled, double-blind study.

OBJECTIVES: To compare the efficacy of photobiomodulation to that of topical clobetasol 0.05% in patients with symptomatic oral lichen planus (OLP). SUBJECTS: Thirty-four patients with symptomatic OLP were randomly allocated into two groups: (a) the Control group (n = 17), application of topical clobetasol propionate 0.05% three times a day for 30 consecutive days with laser placebo applied twice a week to mask the treatment, and (b) the photobiomodulation group (n = 17), laser application twice a week, totalling 8 sessions, and gel placebo for 30 consecutive days to mask the treatment. Evaluations were performed once a week during treatment and 30, 60 and 90 days after treatment. The following parameters were evaluated: pain, clinical scores, clinical resolution and recurrence rate. RESULTS: Photobiomodulation and propionate clobetasol 0.05% were able to significantly decrease pain in oral lichen planus patients and improve clinical scores during treatment and follow-up. Both the Control and photobiomodulation groups presented similar clinical resolution and recurrence rates. Most importantly, no difference was observed between treatments during treatment and follow-up. CONCLUSIONS: These findings indicate that photobiomodulation twice a week is as effective as corticoid therapy in treating oral lichen planus. Moreover, photobiomodulation is a safe and non-invasive therapy with the remarkable advantage of no adverse effects.

Evaluation of photobiomodulation in salivary production of patients with xerostomy induced by anti-hypertensive drugs: Study protocol clinical trial (SPIRIT compliant).

INTRODUCTION: Hypertension (systemic arterial hypertension [SAH]) is a systemic condition that affects about 30% of the world population, according to data from the World Health Organization (WHO). Drugs used to control this disease have the potential to induce xerostomia, an oral condition in which the decrease of the salivary flow is observed and whose presence leads to the increase of the index of caries, periodontal disease, loss of the teeth, dysgeusia, difficulty of mastication, dysphagia, bad breath and oral burning and impairment of prothesis installed in the buccal cavity, including retention of removable and total dentures. METHODS: This is a randomized, placebo-controlled, blind clinical protocol that aims to analyze the impact of phobiomodulation (PBM) on salivary glands of patients with antihypertensive drug induced xerostomia. Patients will be divided into 2 groups: G1: older adults with xerostomia induced by antihypertensive drugs and treatment with PBM (n = 30); G2: placebo PBM (n = 30). The irradiation will be made using a diode laser emitting at 808 nm with 100 mW and 40 seconds of exposure per site at the salivary glands. Twenty sites will be irradiated weekly for 4 weeks. Non-stimulated and stimulated salivary flow will be analyzed before and after the treatment. RESULTS: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. CONCLUSION: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. TRIAL REGISTRATION: Clinicaltrials.gov - NCT03632096.

The effects of photodynamic therapy with blue light and papain-based gel associated with Urucum, on collagen and fibroblasts: a spectroscopic and cytotoxicity analysis.

Papacarie Duo™ is clinically used and has proven effectiveness; however, it is necessary to improve its antimicrobial action. The combined treatment of Papacarie Duo™ with Urucum (Bixa Orellana) could create a potential tool for dental caries treatment; its extract obtained from the seeds' pericarp contains a water-soluble primary pigment (cis-bixin) with smaller amounts of other carotenoids. The dicarboxylic acid salts of cis-norbixin and trans-norbixin occur in heated alkaline solutions. To analyze the absorption spectra and cytotoxicity (with human dermal fibroblasts) in different concentrations of Urucum, associated or not with Papacarie Duo™, we performed this in vitro study. The effects of pure Urucum, Papacarie Duo™, and PapaUrucum™ on the microstructure of collagen were also analyzed. The application of papain-based gel with Urucum did not present cytotoxicity, its exhibit UV absorption spectrum peak around 460 ± 20 nm. Also, it showed that the compound used did not alter the chemical structure of collagen. Consequently, this product could be used as a chemomechanical method to remove dentin caries as well as being a potential product for antimicrobial photodynamic therapy (aPDT) application.

Differential expression of inflammatory and anti-inflammatory mediators by M1 and M2 macrophages after photobiomodulation with red or infrared lasers.

In response to stimuli in the microenvironment, macrophages adopt either the M1 or M2 phenotype to coordinate the tissue repair process. Photobiomodulation (PBM) plays an important role in the modulation of acute inflammation, including cellular influx, macrophage polarization, and the release of inflammatory mediators. The aim of the present study was to evaluate the effects of red and infrared PBM on the mRNA expression of cytokines and chemokines in macrophages polarized to the M1 and M2 phenotypes. J774 macrophages activated to induce M1 (lipopolysaccharide + interferon gamma) or M2 (interleukin-4) phenotypes were irradiated with red or infrared PBM (1 J). After 4 and 24 h, gene expression was analyzed by qPCR. PBM at 660 nm decreased the mRNA expression of CCL3, CXCL2, and TNF-α in M1 macrophages and CXCL2 in M2 macrophages 4 h after irradiation. Similarly, PBM at 780 nm decreased mRNA expression levels of CCL3 and IL-6 by M1 macrophages 24 h after irradiation. Moreover, PBM at 780 nm increased the mRNA expression of TGFß1 4 h after irradiation and decreased the expression of this gene after 24 h in M2 macrophages. Although red and infrared PBM were able to modulate and reduce M1/M2a-related markers, infrared laser irradiation promoted a temporal increase in the expression of TGFß1 in M2 macrophages. Thus, depending on the time PBM is used on injured tissue, different parameters can promote optimal results by modulating specific macrophage phenotypes.

Influence of Nd:YAG laser on the penetration of a bioceramic root canal sealer into dentinal tubules: A confocal analysis.

OBJECTIVE: The aim of this in vitro study, is to evaluate the penetration of a bioceramic root canal sealer into dentinal tubules at 3 mm and 5 mm from the apex after Nd:YAG laser irradiation. METHODS: Forty freshly extracted human mandibular premolars were prepared using Reciproc® and irrigated with 17% ethylenediaminetetraacetic acid (EDTA). Teeth were divided into 4 groups: group 1, obturated with control sealer (AH Plus®); group 2, obturated with bioceramic sealer (Endosequence BC Sealer®); group 3, Nd:YAG laser + control sealer (AH Plus®); and group 4, Nd:YAG laser + bioceramic sealer (Endosequence BC Sealer®). The samples were transversely sectioned 3 mm and 5 mm from the apex and examined using confocal laser scanning microscopy. Two parameters were measured: 1) sealer penetration into dentinal tubules of the root canal and 2) sealer penetration into the perimeter of the root canal walls. RESULTS: Penetration analysis showed that bioceramic sealer had a higher penetration at depths of 3 and 5 mm than that of the control sealer, regardless of laser use (p <0.05). Perimeter analysis showed that there was no difference between both sealers at a depth of 3 mm (p <0.05), regardless of laser use. At a depth of 5 mm, bioceramic sealer and laser showed a greater perimeter of penetration (p <0.05) than the control sealer. CONCLUSION: The use of Nd:YAG laser did not compromise the penetration of bioceramic sealer into dentinal tubules of root canals at 3 mm and 5 mm from the apex.

Effects of formaldehyde exposure on the development of pulmonary fibrosis induced by bleomycin in mice.

Environmental and Occupational pollution has been extensively studied because of its serious implications on the human health. Formaldehyde (FA) is a pollutant widely employed in several industries and also in anatomy, pathology and histology laboratories. Studies have shown the correlation between FA exposure and development or worsening of asthma. However, the effect of FA exposure on the pulmonary fibrosis (PF) is unknown. PF is a progressive and chronic lung disease with high incidence and considerable morbidity and mortality. Few studies have shown a worsening of PF after pollutants exposure such as ozone and nitrogen dioxide. Therefore, our objective was to assess the effects of FA on the PF. Male mice C57BL6 were treated or not with bleomycin (1,5 U/kg) and exposed or not to FA inhalation (0.92 mg/m3, 1 h/day, 5 days/week during 2 weeks). Non-manipulated mice were used as control. Our data showed that FA exposure in fibrotic mice increased the number of granulocytes in the bronchoalveolar lavage followed by elevated levels of interleukin 1 beta and interleukin 17. In addition, FA exposure in fibrotic mice enhanced the gene expression of C-X-C motif chemokine ligand 1 (CXCL1) and tumor necrosis factor alpha (TNF-α) in the lung. We also showed an increase in the collagen production, while lung elastance was reduced. No differences were found in the mucus production, oedema and interstitial thickening in the lung tissue of fibrotic mice after FA exposure. In conclusion our study showed that FA exposure aggravates the lung neutrophils influx and collagen production, but did not alter the lung elastance, mucus production, oedema and interstitial tickening. This work contributes to understand the effects of pollution in the development of PF.

Vitamin D treatment abrogates the inflammatory response in paraquat-induced lung fibrosis.

A high incidence of intentional or accidental paraquat (PQ) ingestion is related to irreversible lung fibrosis and no effective therapy is currently available. Vitamin D has emerged with promising results as an immunomodulatory molecule when abrogating the inflammatory responses of lung diseases. Therefore, we have investigated the role of vitamin D treatments on PQ-induced lung fibrosis in male C57/BL6 mice. Lung fibrosis was induced by a single injection of PQ (10 mg/kg; i.p.). The control group received PQ vehicle. Seven days later, after the PQ injection or the vehicle injection, the mice received vitamin D (5 µg/kg, i.p., once a day) or vehicle, for a further 7 days. Twenty-four hours after the last dose of vitamin D or the vehicle, the analysis were performed. The vitamin D treatments reduced the number of leukocytes in their BALF and they decreased the IL-6, IL-17, TGF-beta and MMP-9 levels and the abrogated collagenase deposits in their lung tissues. Conversely, the vitamin D treatments increased the resolvin D levels in their BALF. Moreover, their tracheal contractility was also significantly reduced by the vitamin D treatments. Altogether, the data that was obtained showed a promising use of vitamin D, in treating the lung fibrosis that had been induced by the PQ intoxications. This may improve its prognostic use for a non-invasive and low cost therapy.

Photobiomodulation improves motor response in patients with spinal cord injury submitted to electromyographic evaluation: randomized clinical trial.

Photobiomodulation is a treatment that has been widely used in neurotrauma and neurodegenerative diseases. In the present study, low-level laser therapy was administered to patients with spinal cord injury. Twenty-five individuals were divided into two groups: placebo photobiomodulation plus physiotherapy and active photobiomodulation plus physiotherapy. Electromyographic evaluations were performed before and after 12 sessions of phototherapy as well as 30 days after the end of treatment. In the active phototherapy group, median frequency values of the brachial biceps and femoral quadriceps muscles were higher at rest and during isotonic contraction 30 days after photobiomodulation (p = 0.0258). No significant results were found regarding the rest and isotonic conditions in the pre-photobiomodulation period (p = 0.950) or immediately following photobiomodulation (p = 0.262). The data provide evidence that phototherapy improves motor responses in individuals with spinal cord injury, as demonstrated by differences in the EMG signal before and after treatment. TRIAL REGISTRATION: NCT 03031223.

Infrared Laser Improves Collagen Organization in Muscle and Tendon Tissue During the Process of Compensatory Overload.

BACKGROUND: The photobiomodulation using the low-level laser therapy (LLLT) exerts a positive modulating effect on the synthesis of collagen in skeletal muscles and tendons. However, few studies have addressed this effect during the compensatory overload. OBJECTIVE: Evaluate the effect of infrared laser on the deposition and organization of collagen fibers in muscle and tendon tissue during compensatory overload of the plantar muscle in rats. MATERIALS AND METHODS: Wistar rats were submitted to bilateral ablation of the synergist muscles of the hind paws and divided in groups: Control, Hypertrophy, and Hypertrophy (H)+LLLT (780 nm, 40 mW, 9.6 J/cm2 and 10 s/point, 8 points, total energy 3.2 J, daily), evaluated at 7 and 14 days. Muscle cuts were stained with Picrosirius-Red and hematoxylin-eosin and tendon cuts were submitted to birefringence for determination of collagen distribution and organization. RESULTS: After 7 days an increase was observed in the area between beam muscles in H+LLLT (25.45% ± 2.56) in comparison to H (20.3% ± 3.31), in mature fibers and fibrilis in H+LLLT (29346.88 µm2 ± 2182.56; 47602.8 µm2 ± 2201.86 respectively) in comparison to H (26656.5 µm2 ± 1880.46; 45630.34 µm2 ± 2805.82 respectively) and in the collagen area in H+LLLT (2.25% ± 0.19) in comparison to H (2.0% ± 0.15). However, after 14 days a reduction was observed in the area between beam muscles in H+LLLT (13.88% ± 2.54) in comparison to H (19.1% ± 2.61), in fibrils and mature fibers in H+LLLT (17174.1 µm2 ± 2563.82; 32634.04 µm2 ± 1689.38 respectively) in comparison to H (55249.86 µm2 ± 1992.65; 44318.36 µm2 ± 1759.57) and in the collagen area in H+LLLT (1.76% ± 0.16) in comparison to H (2.09 ± 0.27). A greater organization of collagen fibers in the tendon was observed after 7 and 14 days in H+LLLT groups. CONCLUSIONS: Infrared laser irradiation induces an improvement in collagen organization in tendons and a reduction in the total area of collagen in muscles during compensatory atrophy following the ablation of synergist muscles.

Pilot study on laser propagation in maxillary and mandibular bone: Grey level image analysis for optical measurements.

BACKGROUND: Bone tissue anatomy, density and porosity vary among subjects in different phases of life and even within areas of a single specimen. The optical characteristics of changes in bone tissue are analyzed based on these properties. Photobiomodulation has been used to improve bone healing after surgery or fractures. Thus, knowledge on light propagation is of considerable importance to the obtainment of successful clinical outcomes. OBJECTIVE: This study determines light penetration and distribution in human maxillary and mandibular bones in three different regions (anterior, middle, and posterior). METHODS: A HeNe laser (633nm) irradiated maxillary and mandibular bones in the cervical-apical direction. The light propagation and scattering pattern were acquired and the grey level of the images was analyzed. Three-dimensional plots of the intensity profile and attenuation profiles were created. RESULTS: Differences in optical properties were found between the mandibular and maxillary bones. The maxilla attenuated more light than the mandible at all sites, leading to a shallower penetration depth. CONCLUSION: Our results provide initial information on the behavior of the propagation of red laser on alveolar bone using an optical method.

The effect of low-level laser therapy (LLLT) applied prior to muscle injury.

AIM: To evaluate the effect of LLLT (780 nm; 10 J/cm2 , 40 mW, 3.2 J) prior to injury on the morphological analysis, collagen deposition, and activity of matrix metalloproteinase-2 (MMP-2). METHODS: Wistar rats were divided into groups: control; sham; only LLLT; only muscle injury and LLLT + injury. The rats were euthanized at 1, 3, and 7 days following cryoinjury to muscle that was removed for analysis. RESULTS: LLLT applied prior to muscle injury led to a reduction in myonecrosis and inflammatory cells, an increase of blood vessels and immature muscle fibers. An increase in MMP-2 activity and a decrease in collagen deposition were also found, with a better collagen organization and distribution. CONCLUSION: LLLT applied immediately prior to injury had positive effects during the muscle regeneration process. Therefore, this resource may have considerable therapeutic value, especially for athletes who practice sports in which there is a constant risk of muscle injury. Lasers Surg. Med. 47:571-578, 2015. © 2015 Wiley Periodicals, Inc.

Effect of laser therapy on skeletal muscle repair process in diabetic rats.

Skeletal muscle myopathy is a common source of disability in diabetic patients. This study evaluated whether low-level laser therapy (LLLT) influences the healing morphology of injured skeletal muscle. Sixty-five male Wistar rats were divided as follows: (1) sham; (2) control; (3) diabetic; (4) diabetic sham; (5) nondiabetic cryoinjured submitted to LLLT (LLLT); (6) diabetic cryoinjured submitted to LLLT (D-LLLT); and (7) diabetic cryoinjured non-treated (D). Diabetes was induced with streptozotocin. Anterior tibialis muscle was cryoinjured and received LLLT daily (780 nm, 5 J/cm(2), 10 s per point; 0.2 J; total treatment, 1.6 J). Euthanasia occurred on day 1 in groups 1, 2, 3, and 4 and on days 1, 7, and 14 in groups 5, 6, and 7. Muscle samples were processed for H&E and Picrosirius Red and photographed. Leukocytes, myonecrosis, fibrosis, and immature fibers were manually quantified using the ImageJ software. On day 1, all cryoinjured groups were in the inflammatory phase. The D group exhibited more myonecrosis than LLLT group (p < 0.05). On day 14, the LLLT group was in the remodeling phase; the D group was still in the proliferative phase, with fibrosis, chronic inflammation, and granulation tissue; and the D-LLLT group was in an intermediary state in relation to the two previous groups. Under polarized light, on day 14, the LLLT and D-LLLT groups had organized collagen bundles in the perimysium, whereas the diabetic groups exhibited fibrosis. LLLT can have a positive effect on the morphology of skeletal muscle during the tissue repair process by enhancing the reorganization of myofibers and the perimysium, reducing fibrosis.