Office-Based Photodynamic Therapy Using Locally Applied 5-aminolevulinic Acid and 635 nm Laser for Laryngeal Leukoplakia.

OBJECTIVE: Photodynamic therapy (PDT) is a minimally invasive method with strong tissue selectivity and nonthermal effects. We aim to investigate the efficacy of an in-office method utilizing PDT with local application of 5-aminolevulinic acid (ALA) and 635 nm diode laser for treating laryngeal leukoplakia. STUDY DESIGN: Retrospective cohort study. SETTING: Outpatient clinic-tertiary medical center. METHODS: This study reviewed 32 patients with laryngeal leukoplakia, including 11 recurrent cases after surgery. All the procedures were performed in an office setting under topical anesthesia. Fifteen percent ALA solution was locally applied to the lesion through a flexible laryngoscope. Light illumination was performed using a 635 nm diode laser through a 400 µm optic fiber. The power density was 165 mW/cm2 to reach 100 J/cm2 . Results of laryngostroboscopy and voice evaluation during follow-up were collected. RESULTS: The mean follow-up was 7.91 ± 4.83 (3-18) months. Thirty-nine procedures were performed, including 1 session for 27 patients, 2 sessions for 3 patients, and 3 sessions for 2 patients. The total response rate was 96.875% (31/32), including complete responses in 26 (81.25%) patients, partial responses in 5 patients (15.625%), and no response in 1 patient (3.125%). It appeared that PDT selectively eliminated the leukoplakia without affecting lamina propria and the surrounding normal mucosa remained unharmed. Scores of Voice Handicap Index-10, jitter, shimmer, and harmonic-to-noise ratio were significantly improved after PDT. CONCLUSION: Office-based PDT is an effective, repeatable, and practical method for treating laryngeal leukoplakia. Local application of ALA is sufficient to achieve photodynamic reactions. PDT could eliminate laryngeal leukoplakia selectively while protecting the normal laryngeal structure.

[The use of photodynamic therapy in patients with severe forms of leukoplakia]. / Primenenie fotodinamicheskoi terapii u patsientov s tyazhelymi formami leikoplakii.

OBJECTIVE: The aim the study is to increase the effectiveness of the treatment of severe forms of leukoplakia with the use of photodynamic therapy. MATERIAL AND METHODS: 120 patients with severe forms of leukoplakia were examined. 30 patients were diagnosed with Cr and carcinoma in situ, and therefore they were excluded from the study. In 90 patients, the diagnosis was confirmed by histological and IHC studies. Before the use of photodynamic therapy, the degree of saturation of pathological foci with a photosensitizer was determined by the method of fluorescent diagnostics using the LED device «RFS-400¼. RESULTS: As a result of treatment with photodynamic therapy using a 2nd generation photosensitizer («Photoditazine¼ 0.5% gel penetrator), a significant improvement in the epithelization of lesion elements was observed: in 92% of patients with verrucous leukoplakia and in 83% of patients with erosive leukoplakia. CONCLUSION: The use of photodynamic therapy for the treatment of patients with complicated forms of leukoplakia is an effective method of treatment for this pathology.

Successful treatment of laryngeal leukoplakia by photodynamic therapy with local application of 5-aminolevulinic acid and 635 nm laser: A case report.

Laryngeal leukoplakia is a common disorder in otolaryngology. Presently, the most widely accepted treatment is suspension laryngoscopic surgery under general anesthesia. The high recurrence rate and hoarse voice after surgery make it an intractable disease to treat. Here we report a case of a 67-year-old man who was diagnosed of laryngeal leukoplakia 15 years ago and underwent 5 surgeries because of its repeated recurrences. Two sessions of photodynamic therapy were performed with local application of 5-aminolevulinic acid and irradiation of 635 nm diode laser. Complete response was observed and no recurrence was detected during follow-up of 6 months. Photodynamic therapy with local 5-ALA application and 635 nm laser is safe and well-tolerated. It is a promising modality for laryngeal leukoplakia.

A new approach to vocal cord leukoplakia and evaluation of proton pump inhibitor treatment.

PURPOSE: Our aim is identify a new approach to vocal cord leukoplakia treatment and detect to efficiency of proton pump inhibitors. STUDY DESIGN: Prospective, nonrandomized experimental clinical trial. METHODS: A 'First Assessment Scale' was prepared. This scale included the lesion's and the patient's characteristics. Using this scale, 24 patients included to the study. 20 mg rabeprazole twice daily was applied to all patients. At the end of 3rd month, a 'Second Assessment Scale' was used and two groups created. In group 1, 19 patients were accepted to responsive for the therapy and received the same therapy. The group 2 was included five patients that accepted unresponsive to treatment and directed to surgery. All patients received the same treatment additionally 3 months. At the end of 6th month, the Reflux Symptom Index (RSI), the Reflux Finding Score (RFS) and the Red-Green-Blue (RGB) values evaluated and comparisons were made. RESULTS: The RSI and RFS values were significantly decreased in all patients. The Red values were significantly decreased with treatment in group 1, but the Green and Blue values were not. In group 2, the RGB values were not showed the significant differences. In conclusion, seven patients (29,2%) showed complete lesion regression, 12 patients (50%) showed partial lesion regression and five patients (20,8%) showed no response to treatment. CONCLUSIONS: The proton pump inhibitor treatment may be beneficial for the selected patients. The scales that we prepared were useful for lesion assesment.

Topical Application of 5-Aminolevulinic Acid Is Sufficient for Photodynamic Therapy on Vocal Folds.

OBJECTIVES: To evaluate the feasibility of topical photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) for vocal fold leukoplakia. STUDY DESIGN: Ex vivo and in vivo. METHODS: 5-ALA was applied topically as a 20% solution to ex vivo canine vocal folds. The penetration depth and concentrations of 5-ALA in tissue were quantified using frozen sectioning and fluorescamine derivatization after 5-ALA contact incubation or topical spraying. Then, 5-ALA solution was sprayed on leporine vocal folds once, twice, or given systemically in vivo. Protoporphyrin IX (PPIX) location was visualized using fluorescence microscopy, and PPIX concentrations were measured using a fluorescent quantitative method. Hematoxylin and eosin (H&E) staining was performed to visualize the histological changes of vocal folds after PDT for each group. RESULTS: Topical incubation of 15 minutes with 5-ALA achieved a penetration depth of over 2 mm and similar concentrations within the superficial 500 µm of epithelium, compared with longer incubation times. Topical spraying of 5-ALA produced sufficient concentrations in vocal folds, but the retention time is short. An in vivo leporine model showed that laryngeal spraying of 20% 5-ALA induced similar penetration depth and concentrations of PPIX compared to systemic administration of 5-ALA. Two sprays of 20% 5-ALA solution with an interval of 30 minutes are needed to produce complete exfoliation of vocal fold epithelium. CONCLUSION: Topical PDT with laryngeal spraying of 20% 5-ALA solution achieves sufficient therapeutic effects and is potentially applicable for the treatment of vocal fold leukoplakia. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E80-E86, 2019.

[The role of NF-κB signaling pathway in laryngeal leukoplakia recurrent with laryngeal reflux].

Objective: To study the mechanism of vocal mucosal barrier damage mediated by NF-κB and NF-κB-regulated signaling pathway via probing the expression of inflammatory factors and essential proteins for node of NF-κB signaling pathway. Methods: The patients suffering from vocal leukoplakia accompanied with larygopharyngeal reflux(LPR) were treated with oral administration of proton pump inhibitor(PPI). Mucosal specimens of vocal cord were collected from all patients before PPI treatment. And the mucosal specimens of vocal cord were collected from the patients with suspected recurrence at 8 weeks after PPI treatment. HE staining was used to observe the histopathological changes of the mucosa. ELISA was utilized to detect the levels of inflammatory factors including tumor necrosis factor(TNF)-α, interleukin(IL)-1 and IL-6. Western blot was used to detect the expression of p-p65, p-IKK and p-IκB. Immunofluorescence method was adopted to detect the entrance of p65 to cell nucleus.Data was analyzed by SPSS 23.0 software. Results: In PPI untreated group, the expressions of IL-1ß, TNF-α and IL-6 in the specimens of 8 weeks after operation were not different significantly from those obtained during operation.But in the PPI-treated group, the expressions were down-regulated.The expression of p-p65 in the middle and high grade heterogenous hyperplasia group was higher than that of low level heterogenous hyperplasia group.The difference of p65 and p-p65 expression between 8 weeks after surgery and surgery in PPI-untreated group was statistically insignificant (P>0.05). The difference of p65 expression between PPI-treated group and PPI pre-treatment group was statistically insignificant (P>0.05). The expression of p-p65 in the PPI-treated group was lower than that of the PPI pre-treatment group (P<0.05). The expressions of IL-1ß, TNF-α and IL-6 were positively related with that of NF-κB-p65. Immun of luorescence method revealed the entrance of p65 to cell nucleus in PPI pre-treatment group, which meant that NF-κB was activated. In the PPI-treated group, few activated p65 could be observed in the cell nucleu. Conclusion: The possible mechanism of vocal mucosal barrier damage in vocal leukoplakia accompanied with LPR maybe the vocal mucosal inflammation mediated by NF-κB and NF-κB-regulated signaling pathway activated with refluxed materials.

A plea to provide best evidence in trials under sample-size restrictions: the example of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients.

In planning a clinical trial for demonstrating the efficacy of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients we had to discuss the need for a randomized controlled trial particularly under sample-size restrictions as very promising results were available from a single-arm clinical trial. Unfortunately, at a later stage, we had to suffer from the fact that single-arm clinical trials may sometimes mislead. When revisiting our planning at a later stage of a grant application, results of a randomized controlled trial had become available which were less impressive, but may still be of clinical interest. However, these results were perceived as disappointing in the light of previously raised hopes based on the results of the single-arm trial. We highlight some major problems when research is based on single-arm trials compared to randomized controlled trials. After debunking common arguments for the conduct of single-arm trials in rare disease we conclude that particularly in rare disease research should be based on randomized building blocks simply because more robust evidence is generated. The plea for single-arm trials should be substituted by a plea for cooperation of all stakeholders to provide best evidence for decision making under sample-size restrictions.

Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients.

OBJECTIVE: Metformin is an oral anti-hyperglycemic agent used to treat type 2 diabetes mellitus (DM). In vitro and animal models have shown that metformin can prevent the progression of oral lesions to carcinoma; however, there is conflicting data in the clinical literature regarding risk reduction for malignancy in head and neck cancer (HNC). STUDY DESIGN: Case series. METHODS: We present 3 cases in which adjuvant metformin therapy was used to treat recurrent and multifocal dysplastic lesions in previously treated nondiabetic HNC patients. RESULTS: Patients included 1 with a history of oral cavity squamous cell carcinoma (SCC) and 2 with a history of laryngeal SCC. Follow-up time ranged between 3 and 33 months. All 3 patients showed complete or partial regression of the remaining mucosal lesions and did not require any additional surgeries. CONCLUSION: We present 3 cases of nondiabetic HNC patients with field cancerization who showed a good response to adjuvant therapy with metformin. The nondiabetic population is not affected by confounding factors such as increased risk of malignancy and decreased overall survival that is itself associated with abnormal glucose metabolism and is therefore an excellent cohort in which to study the use of adjuvant metformin therapy in HNC patients.

Resolution of vocal fold leukoplakia during erlotinib treatment for lung cancer.

Treatment of vocal fold leukoplakia is complicated because it is associated with a high rate of recurrence after excision and it has the potential for progression to malignancy. Authors have presented different approaches to management, one of which is directed serial excisional biopsies. Ideally, a topical or systemic agent could be administered to eradicate this troublesome condition. We present the case of a patient with an 8-year history of vocal fold leukoplakia treated with directed serial biopsies who was subsequently diagnosed with non-small-cell lung cancer and treated with erlotinib. He experienced a complete resolution after 2 months of erlotinib therapy for his lung cancer. Immunohistochemistry confirmed that his lesion exhibited a much higher than normal expression of epidermal growth factor receptor (EGFR), which supports the idea that EGFR antagonism may combat EGFR-avid leukoplakia. However, we caution that the clinical observation made herein is an association and should not be misconstrued as a recommendation regarding the safety, efficacy, or economy of using erlotinib for the treatment of vocal fold leukoplakia.

[Application of photodynamic therapy in dentistry ­ literature review].

Photodynamic therapy (PDT) is based on the principle that the target cells are destroyed by means of toxic reactive oxygen species generated upon the interaction of a photosensitizer, light and oxygen. This method is nowadays widely applied in various branches of medicine, mainly in oncology and dermatology. It is also applied in dentistry in the treatment of oral potentially malignant disorders (like lichen planus or leukoplakia) and infectious conditions (periodontitis, herpetic cheilitis, root canal disinfection). The application of the photodynamic therapy in the abovementioned indications is worth attention, as the method is noninvasive, painless, and the results of the published studies seem promising. The present article aims at presenting the principle of the photodynamic therapy and, based on the literature, the possibilities and results of its application in dentistry.

[INFECTIONS CAUSED BY EPSTEIN-BARR VIRUS IN HIV-INFECTED PATIENTS].

The review is dedicated to features of clinical manifestations of infections caused by Epstein- Barr virus (EBV) in HIV-infected patients, problems of diagnostics and execution of antiviral therapy in the case of combination of these infections. Individuals at AIDS stage develop tumors, associated with EBV: non-Hodgkin's lymphomas, including Berkitt's,lymphoma, primary B-cell lymphoma,of CNS, nasopharyngeal carcinoma. Formation of lymphoid interstitial pneumonitis and leukoplakia is known to be associated with EBV. A large list of preparations that are inhibitors of EBV replication are currently known, however, there is no clear pathogenetically justified therapy scheme for patients with this infection against the background of HIV-infection.

Positive therapy of andrographolide in vocal fold leukoplakia.

PURPOSE: Vocal fold leukoplakia is a premalignant precursor of squamous cell carcinoma. Although many efforts have been contributed to therapy of this disease, none exhibits a satisfactory result. The aims of this study were to investigate the effectiveness and feasibility of andrographolide therapy in vocal fold leukoplakia and to explore the preliminary mechanism underlying. MATERIALS AND METHODS: Forty-one eligible patients were enrolled in the study. The patients were treated for 10-minute exposures of 5 ml (25mg/ml) andrographolide injection aerosols twice a day, and 2 weeks was considered as one treatment course. Electronic laryngoscope was used to observe the condition of vocal fold leukoplakia during the treatment. Every patient received one or two treatment courses, and the follow-up was carried out for 12 months. Toxic reactions of treatments were evaluated on the basis of the standards of the United States MD Anderson Cancer Center. Moreover, laryngeal carcinoma cell line Hep2 was applied to explore the mechanism of effect of andrographolide. Anti-proliferative effect on Hep2, cell nuclear morphology, express of mitogen-activated protein kinases (MAPK) and pro-apoptotic protein were detected after andrographolide treatment. RESULTS: We found that andrographolide exhibited significant curative effects on treatments, which were accompanied by thinning of the lesion of leukoplakia, reduction in the whitish surface area, and return of pink or red epithelium. A complete response up to 85% was observed, and no toxic side effect events occurred during the study. No patient with a complete response had a recurrence in the follow-up. Moreover, cellular experiments in Hep2 indicated that andrographolide activated MAPK pathway and caspase cascade, and finally induced apoptosis in laryngeal carcinoma cell. CONCLUSIONS: The advantages of andrographolide are connected with minimally invasive and localized character of the treatment and no damage of collagenous tissue structures, which are more convenient and less painful for patients. These results suggest that andrographolide treatment is a viable strategy for curing vocal fold leukoplakia.

Clinical classification and treatment of leukokeratosis of the vocal cords.

BACKGROUND: Leukokeratosis of the vocal cords is a clinical descriptive diagnosis, which includes a group of squamous intraepithelial lesions of the vocal cord mucosa. We investigated the clinical classification and treatment efficacy of leukokeratosis of the vocal cords. METHODS: We conducted a retrospective analysis of the medical history, laryngoscopic examinations, morphological features under a surgical microscope, and pathology results of 360 cases of leukokeratosis of the vocal cords to examine correlations among treatment modalities, therapeutic effects, and clinical features. RESULTS: All cases were divided into four types based on symptoms, examination results, and treatment efficacies as follows: 21 patients had type I inflammatory leukoplakia and their vocal cord morphology and voice quality recovered after conservative therapies; 76 patients had type II frictional polyps and received CO2 laser submucosal cordectomy; 68 patients had type III sulcus vocalis and received mucosal slicing with dredging; and 195 cases had type IV simple leukokeratosis and received partial subligamental cordectomy with CO2 lasers or transmuscular cordectomy. Our treatment achieved a surgical cure rate of 90.9% (308/339), with a recurrence rate of 9.1% (31/339) and malignant transformation rate of 6.5% (22/339). All cancerous transformations occurred in type IV patients. CONCLUSION: Choosing conservative or CO2 laser surgery based on the morphological characteristics of squamous epithelial lesions of keratinized vocal cord mucosa can maximally protect voice quality, reduce complications, and improve the cure rate.

A preliminary study of the local treatment of preneoplastic and malignant skin lesions using methyl jasmonate.

BACKGROUND: Jasmonates are plant stress hormones. These small hydrophobic compounds exhibit anti-cancer activities, in vitro and in vivo, against cancer cells of various histological origins. Moreover, they show a selective activity against transformed cells and affect drug-resistant cells as well. AIM: The aim of this study was to evaluate the activity of a powerful jasmonate derivative, that is methyl jasmonate. MATERIAL AND METHODS: Methyl jasmonate was applied topically on cancerous and pre-cancerous skin lesions from eight patients. RESULTS: Methyl jasmonate did not cause any meaningful local or systemic side effects. Three patients exhibited positive responses. Two patients had complete recovery and one had a recurrence of the lesion three months post treatment. CONCLUSIONS: Methyl jasmonate is a potentially promising novel topical treatment for prcancerous and cancerous skin lesions. Methyl jasmonate should be evaluated in a larger series of patients.

Laryngeal syphilis: a case report.

Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. The complexity of the disease gained it the moniker "the great imitator"; it was William Osler who said, "He who knows syphilis, knows medicine." In 1866, Patrick Watson of Edinburgh, Scotland, reported a case of a 36-year-old man in whom syphilis destroyed the larynx.(1) The diagnosis was made postmortem. It was once believed that this was the first reported total laryngectomy, but the credit should actually be given to Christian Albert Theodor Billroth who performed this surgery on a patient with laryngeal carcinoma in 1873.

Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis.

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer in the United States. The goal of this study was to evaluate the contribution of estrogens to the development of HNSCCs. Various cell lines derived from early- and late-stage head and neck lesions were used to characterize the expression of estrogen synthesis and metabolism genes, including cytochrome P450 (CYP) 1B1, examine the effect of estrogen on gene expression, and evaluate the role of CYP1B1 and/or estrogen in cell motility, proliferation, and apoptosis. Estrogen metabolism genes (CYP1B1, CYP1A1, catechol-o-methyltransferase, UDP-glucuronosyltransferase 1A1, and glutathione-S-transferase P1) and estrogen receptor (ER) ß were expressed in cell lines derived from both premalignant (MSK-Leuk1) and malignant (HNSCC) lesions. Exposure to estrogen induced CYP1B1 2.3- to 3.6-fold relative to vehicle-treated controls (P = 0.0004) in MSK-Leuk1 cells but not in HNSCC cells. CYP1B1 knockdown by shRNA reduced the migration and proliferation of MSK-Leuk1 cells by 57% and 45%, respectively. Exposure of MSK-Leuk1 cells to estrogen inhibited apoptosis by 26%, whereas supplementation with the antiestrogen fulvestrant restored estrogen-dependent apoptosis. Representation of the estrogen pathway in human head and neck tissues from 128 patients was examined using tissue microarrays. The majority of the samples exhibited immunohistochemical staining for ERß (91.9%), CYP1B1 (99.4%), and 17ß-estradiol (88.4%). CYP1B1 and ERß were elevated in HNSCCs relative to normal epithelium (P = 0.024 and 0.008, respectively). These data provide novel insight into the mechanisms underlying head and neck carcinogenesis and facilitate the identification of new targets for chemopreventive intervention.

Diclofenac in hyaluronic acid gel: an alternative treatment for actinic cheilitis.

OBJECTIVE: Actinic cheilitis (AC) is a precancerous lesion of the lip vermillion caused by prolonged exposure to ultraviolet light. The aim of this study was to evaluate the effect of 3% diclofenac in 2.5% hyaluronic acid gel in the treatment of AC. METHODS: Thirty-four patients with chronic AC were treated twice a day with topical diclofenac during a period of 30 to 180 days. The individuals were followed up every 15 days by means of clinical examination and digital photographic documentation. RESULTS: Of the 27 patients that completed the study, 12 (44%) showed complete remission of the whitish plaques and exfoliative areas, and 15 (56%) had partial remission of the clinical picture of cheilitis. The latter group was submitted to excision of the leukoplakic areas which diagnosis varied from mild to moderate epithelial dysplasia. CONCLUSIONS: The results suggest a promising role for diclofenac in hyaluronic acid gel in the treatment of AC. This treatment has the advantages of not being invasive and showing few side effects.

Diclofenac in hyaluronic acid gel: an alternative treatment for actinic cheilitis

OBJECTIVE: Actinic cheilitis (AC) is a precancerous lesion of the lip vermillion caused by prolonged exposure to ultraviolet light. The aim of this study was to evaluate the effect of 3 percent diclofenac in 2.5 percent hyaluronic acid gel in the treatment of AC. METHODS: Thirty-four patients with chronic AC were treated twice a day with topical diclofenac during a period of 30 to 180 days. The individuals were followed up every 15 days by means of clinical examination and digital photographic documentation. RESULTS: Of the 27 patients that completed the study, 12 (44 percent) showed complete remission of the whitish plaques and exfoliative areas, and 15 (56 percent) had partial remission of the clinical picture of cheilitis. The latter group was submitted to excision of the leukoplakic areas which diagnosis varied from mild to moderate epithelial dysplasia. CONCLUSIONS: The results suggest a promising role for diclofenac in hyaluronic acid gel in the treatment of AC. This treatment has the advantages of not being invasive and showing few side effects.

Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs.

ZengShengPing (ZSP), a mixture of six medicinal herbs, has been reported to prevent esophageal squamous cell carcinoma (SCC) in human patients with dysplasia. This study was designed to investigate the chemopreventive effects of ZSP on oral cancer in animal models and human patients. In the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model, ZSP (6g/kgBW/day by gavage for 10 weeks) significantly reduced the number of visible tumor, the tumor volume, and the incidence of SCC (P<0.01). Two biomarkers associated with cell proliferation, silver stained nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)-labeling index, were also significantly suppressed by ZSP treatment (P<0.01). In the 4-nitroquinoline 1-oxide (4NQO)-induced oro-esophageal cancer model in mice, ZSP (10% in diet) also significantly reduced the incidence of tongue SCC from 55.2% (16/29) to 22.2% (6/27) (P<0.05), and slightly reduced the incidence of esophageal SCC from 34.5% (10/29) to 22.2% (6/27). Furthermore, in a randomized clinical trial on patients with oral leukoplakia, ZSP (4 tablets, 3 times per day for 8-12months) reduced the size of oral lesion in 67.8% (40/59) patients, whereas the placebo was effective in 17% (9/53) patients (P<0.01). Such an effect was associated with significant decrease of AgNOR and PCNA-labeling index. In summary, our studies have demonstrated the chemopreventive effects of ZSP on two animal models of oral cancer, and human patients with oral leukoplakia.