Oral Intake of Combined Natural Immunostimulants Suppresses the 7,12-DMBA/ Croton Oil Induced Two-step Skin Carcinogenesis in Swiss Albino Mice.

BACKGROUND: The immune system is critical in fighting cancer, so is it possible that the natural stimulation of this system can slow down or stop the evolution of cancer? Our in vivo study aimed to evaluate the protective effect of the combination of five types of immunostimulants, which are Beta-glucan and Arabinogalactan as polysaccharides and three mushroom extracts (Reishi, Maitake, and Shiitake), on 7,12-Dimethyl Benz[a]anthracene (DMBA)/ Croton oil-induced papilloma in Swiss albino mice. METHODOLOGY: We used blood count analyses to estimate broadly the immunological reaction and biochemical techniques to determine the oxidative stress variations in the enzymatic activity of Superoxide dismutase (SOD), Catalase (CAT), and Glutathion peroxidase (GPx), which could have a preventive function against cancer development. RESULTS: The cutaneous application of the DMBA/Croton oil caused precancerous hyperplasia in squamous cells (papilloma) on the back of the mice. Tumor development was accompanied by a decrease in SOD and GPx activities. The treatment with the immunostimulants led to the total disappearance of the incidence of skin papillomas and also showed a nearly back to normal SOD activity but not CAT and GPx activities. The increase in the level of immune cells (lymphocytes, monocytes, and white blood cells) reflected a clear enhancement of the immune system activity. DISCUSSION: The healthy epidermis observed with treated mice simultaneously subjected to the cancerogenosis protocol suggests the inhibition of spinous cell proliferation leading to the total suppression of the hyperplasia. Moreover, the increase in the level of immune cells in this batch reflects an inflammatory reaction. Indeed, previous studies reported that immunostimulants, including Betaglucan involve a release of some inflammatory mediators who would be at the origin of its anticancer activity. Cancerogenesis has clearly disrupted the activities of the antioxidant enzymes, but the relationship between the two process is often complex. Bibliographic data led us to suggest that low catalytic activities of CAT and GPx observed in treated mice simultaneously subjected to the cancerogenesis protocol, would have induce an accumulation of H2O2 which has often been described as an inducer of cancer cells apoptosis. CONCLUSION: Immunostimulants used in our study could have an effective protective effect against skin carcinogenesis via the enhancement of the global function of the immune system and modulation of the antioxidant defense. KEYWORDS: Immunostimulants, Beta-glucan, Arabinogalactan, Reishi, Maitake, Shiitake, DMBA, Croton oil, Oxidative stress, Carcinogenesis. ABBREVIATIONS: C, control group; Dc, drug control group; Pc, positive control group; St, sick treated group;DMBA, 7,12 Dimethyl Benz[a]anthracene; NK, natural killer; CAT, catalase; SOD, superoxide dismutase, GPx, glutathione peroxidase; IS, immunostimulants; WBC, White blood cells; LY, Lymphocytes; MO, Monocytes; ROS, Reactive oxygen species; ONAB, Office national des aliments de bétail.

A prospective randomized controlled study of Mycobacterium Indicus Pranii vaccine, Measles Mumps Rubella vaccine and Vitamin D3 in extragenital cutaneous warts.

DESIGN: Interventional, prospective, four arm randomized control. SETTING: Outpatient department, Department of Dermatology, Venereology and Leprology, AIIMS Jodhpur (Rajasthan), India. PARTICIPANTS: Two hundred patients. METHODS: The intervention administered in the groups were normal saline (A), vitamin D3 (B), MIP (C), and MMR (D). The injections were given into the largest wart at 2-weekly intervals until complete clearance or for a maximum of seven sittings. Post-treatment clearance of the injected wart and the distant wart was compared on the basis of change in wart number, percentage clearance, and mean time to complete clearance. Side effects were recorded. RESULTS: A total of 197 patients were recruited. The mean percentage improvement in the injected and non-injected warts was 68.4% and 66.8%, respectively. Intention to treat analysis (ITT) showed that complete clearance of lesions in injected wart occurred in placebo, vit D3 , MMR, and MIP arms in 64%, 66%, 58%, and 55% patients, respectively (p > 0.05), while in the non-injected warts in 62%, 64%, 52%, and 53%, respectively (p > 0.05). The mean time to achieve complete clearance of wart was fastest in MIP at 7.1 weeks followed by MMR at 7.2 weeks, VIT D3 at 7.4 weeks and in placebo group 7.8 weeks (p > 0.05). Side effects noted were fever, pain, erythema, and swelling which was highest in VIT D3 group (p < 0.05). CONCLUSION: The efficacy of immunotherapies was comparable to placebo with minimal side effects.

Efficacy of photodynamic therapy for warts induced by human papilloma virus infection: A systematic review and meta-analysis.

BACKGROUND: The incidence of warts caused by human papilloma virus (HPV) infection is very high in the population. Photodynamic therapy (PDT), as an emerging method for wart treatment, has been demonstrated to be effective and safe by an increasing number of studies. This meta-analysis of previous literature aimed to investigate the potential of PDT as a first-line treatment for warts. METHODS: To acquire proper and accurate information from relevant literature, the four databases PubMed, Embase, Web of Science and the Cochrane Library were searched. The wart clearance rate and patient cure rate were analysed as the primary outcomes. The recurrence rate, patient satisfaction and adverse reactions were also recorded. RESULTS: A total of 19 randomized controlled trials (RCTs) were included based on our search strategy. In the hand and foot wart group, PDT showed a statistically significant improvement in the wart clearance rate compared with placebo (P = 0.02), other lasers (P < 0.0001), and cryotherapy (P < 0.009). PDT use in the condyloma acuminatum group was not superior in terms of the wart clearance rate, with a value lower than that of the carbon dioxide (CO2) laser (P = 0.003) and electrosurgical generator (P < 0.00001). However, all studies mentioned a significant decrease in the recurrence rate after PDT. In the plane wart group, PDT demonstrated its superiority over placebo (P = 0.003) and cryotherapy (P = 0.007) in terms of the cure rate. CONCLUSION: Our study demonstrated that PDT provided several benefits, including but not limited to positive clinical outcomes, low recurrence rates and minor adverse reactions. The use of PDT as first-line therapy can be recommended.

Oral florid papillomatosis: Topical treatment with 5% imiquimod in orabase.

BACKGROUND: Florid oral papillomatosis is characterized by its tendency to local recurrence that requires multiple treatments, leading to important functional sequelae. METHODS: We present 74-year-old woman with oral florid papillomatosis (OFP) who refused a new surgical treatment, and was treated with imiquimod 5% in orabase on alternate days for 16 weeks. Treatment was complemented with application of hyaluronic acid gel. RESULTS: There were no side effects to the treatment, nor signs of local recurrence, in the treated area at 2 years of follow-up. CONCLUSIONS: After reviewing the literature and according to our knowledge, this is the first published case of oral florid papillomatosis treated topically with imiquimod 5% successfully. Topical treatment with imiquimod 5% in orabase may be a valid alternative for patients with recurrent OFP located in the anterior area of the oral cavity who refuse surgical treatment, although we must closely monitor the patient for the possibility of recurrence or malignant degeneration.

Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized, double-blind, placebo-controlled pilot study.

OBJECTIVES: After surgical resection of papilloma, adjuvant therapy may be recommended for the control of recurrent respiratory papillomatosis (RRP). As the efficacy of adjuvant therapy remains unproven, the aim of this study was to compare the efficacy of cidofovir versus bevacizumab used as adjuvant therapies for the control of RRP. METHODS: This randomized, double-blind, placebo-controlled pilot study was performed in a national respiratory disease referral centre. Patients with RRP were recruited prospectively and were divided into juvenile or adult RRP. Participants were randomly assigned to receive adjuvant therapy with cidofovir, bevacizumab or placebo. The study drug or placebo was administered after direct microlaryngoscopy with papilloma resection using cold instruments. The Derkay severity score and the Voice Handicap Index (VHI) were assessed at 3-6-week intervals, for a total of 3 visits. Follow-up included VHI and Derkay score assessments at 2-month intervals over the course of one year. Annual rates before and after surgical treatment were compared. RESULTS: Five children and 11 adults were enrolled in the study. After one year, the group treated with cidofovir had a significant decrease in Derkay score (p=.027). No difference between treatment arms was observed in the annual surgery rate. There was a significant decrease in the VHI score in all treatment groups (p<.001), and no significant difference was observed between groups (p=.32). CONCLUSION: While we observed a significant decrease in RRP severity with intralesional cidofovir, we were unable to provide proof of efficacy of intralesional bevacizumab. CLINICALTRIALS: gov Identifier: NCT02555800.

Treatment with Angiotensin-(1-7) Prevents Development of Oral Papilloma Induced in K-ras Transgenic Mice.

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting the oral cavity. It is characterized by high morbidity and very few therapeutic options. Angiotensin (Ang)-(1-7) is a biologically active heptapeptide, generated predominantly from AngII (Ang-(1-8)) by the enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown that Ang-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings, exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailing effects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used an inducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase (CreERtam), which is under the control of the cytokeratin 14 promoter (K14-CreERtam), induces the expression of the K-ras oncogenic variant KrasG12D (LSLK-rasG12D). These mice develop highly proliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosa within one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papilloma development accompanied by a significant reduction in cell proliferation and a decrease in pS6 positivity, the most downstream target of the PI3K/Akt/mTOR signaling route in oral papilloma. These results suggest that Ang-(1-7) may be a novel therapeutic target for OSCC.

Retrospective review of confluent and reticulated papillomatosis in pediatric patients.

BACKGROUND/OBJECTIVES: Confluent and reticulated papillomatosis is a skin condition with unclear etiology and limited understanding of risk factors, comorbidities, and treatment strategies in the pediatric population. This study aims to describe the varied presentations and outcomes of confluent and reticulated papillomatosis and report associated comorbidities in pediatric patients. METHODS: In this retrospective single-institution case-control study, pediatric patients with a diagnosis of confluent and reticulated papillomatosis seen between 2012 and 2020 were matched approximately 1:5 with an acne vulgaris cohort based on diagnosis, setting, and time period when seen. The primary measures were the clinical features, demographics, comorbidities, treatment, and outcomes of patients with confluent and reticulated papillomatosis. Univariate and multivariable analyses were conducted to describe the association of confluent and reticulated papillomatosis with several potential risk factors and comorbidities. RESULTS: Patients with confluent and reticulated papillomatosis typically presented in adolescence with a median age of 14 years and female predominance. In a multivariable analysis, patients with confluent and reticulated papillomatosis were significantly more likely to identify as Black, be overweight or obese, and have concurrent acanthosis nigricans compared to control patients. Most of the confluent and reticulated papillomatosis patients were treated with oral minocycline or doxycycline. Although all patients who received antibiotics responded to treatment, approximately half presented with recurrence, typically within 1-2 years of first treatment. CONCLUSIONS: Confluent and reticulated papillomatosis is a disorder that presents in adolescence and appears to be more frequent in patients who are Black, obese, or overweight, and also have acanthosis nigricans. Clinicians should assess patients with confluent and reticulated papillomatosis for comorbidities, particularly those associated with insulin resistance, which may help reduce long-term disease burden.

Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types. METHODS: We conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison. RESULTS: Dual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject's own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas. CONCLUSIONS: Intact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP. TRIAL REGISTRATION NUMBERS: NCT03707587 and NCT02859454.

Canine pedal papilloma identification and management: a retrospective series of 44 cases.

BACKGROUND: Papillomavirus infections in dogs have a variety of manifestations and involve multiple viral genera. Canine pedal papillomas have been infrequently studied and reported in the literature. OBJECTIVE: To report the signalment, history, treatment and outcome of biopsy-confirmed cases of canine pedal papillomatosis, collected from veterinarians across the United States and Canada ANIMALS: Medical records from 44 dogs were submitted by North American veterinarians. METHODS AND MATERIALS: Surveys were submitted through the Veterinary Information Network for biopsy-confirmed cases of canine pedal papillomatosis. Submissions included information on patient signalment, history, biopsy report, treatment and outcome. RESULTS: Forty-four cases were reviewed. The median age of presentation was four years old. Dogs most commonly presented with lameness and/or paw licking/chewing. Only one paw was affected in 35 cases, and front paws were more often affected than back paws. Twenty-eight dogs presented with one mass. Histopathological evaluation documented 33 cases of noninverted papillomas and 11 cases of inverted papillomas. Thirty-four papillomas resolved in total; 25 resolved within three weeks after biopsy collection. Twenty-one dogs received no additional treatment and 15 of those cases resolved. Azithromycin was the most commonly reported treatment initiated after biopsy was collected. CONCLUSIONS AND CLINICAL IMPORTANCE: The biological behaviour of canine pedal papillomas in this case series was similar to oral papillomas, and most lesions resolved with or without additional treatment. Further research is needed to better characterise the causative papillomavirus types and genera involved in the development of canine pedal papillomas.

Panchvalkala, a traditional Ayurvedic formulation, exhibits antineoplastic and immunomodulatory activity in cervical cancer cells and C57BL/6 mouse papilloma model.

ETHNOPHARMACOLOGICAL RELEVANCE: Panchvalkala, an Ayurvedic traditional formulation has references in Charak Samhita and Bhavaprakasha Nighantu for the treatment of women with endometriosis-related problems, leucorrhea and vaginal ailments. The formulation comprises of equal ratios of the barks from Ficus glomerata, Ficus virens, Ficus religiosa, Ficus benghalensis, and Thespesia populnea. AIM OF THE STUDY: The present study aimed to evaluate the anticancer and immunomodulatory activity of aqueous extract of Panchvalkala (PVaq) against cervical cancer in vitro and in vivo. MATERIALS AND METHODS: The effect of PVaq on disruption of mitochondrial membrane potential in cervical cancer cell lines, SiHa and HeLa, was studied by using JC1 dye. The expression of generic caspases in the cells after treatment with PVaq was evaluated by ELISA kit. The expression of pRb, p53, E6 and E7 proteins were evaluated by western blotting. Acute oral toxicity and DRF studies were performed in Swiss albino mice by following OECD guidelines 423 and 407, respectively. Tumor retardation study was done in C57BL/6 mouse papilloma model. The mice were divided into six groups: No tumor control (NTC), Tumor control (TC), Cisplatin (Cis) (4 mg/kg b.w.), PVaq 100, 200 mg/kg b.w and combination of PVaq (200 mg/kg b.w.) and Cisplatin (4 mg/kg b.w.). The mice were orally gavaged with PVaq daily for 14 days and cisplatin was given intravenously on every 1st, 5th and 9th day. Hematological and biochemical parameters were studied by using hematology analyzer and kits, respectively. E6 and E7 gene expression in the tumor samples was determined by qPCR. Th1 and Th2 cytokine levels were determined by ELISA. RESULTS: PVaq induced mitochondrial depolarization in SiHa and HeLa, and increased the expression of generic caspases, resulting into apoptosis. PVaq upregulated the expression of tumor suppressor proteins (p53 and pRb) and reduced the expression of viral oncoproteins (E6 and E7). Acute toxicity study displayed non-toxicity of PVaq while DRF study ensured its safe dose for further efficacy studies. PVaq reduced tumor volume and weight in mouse papilloma model and induced immunomodulation in the animals. It increased serum levels of IL-2 (Th1) with a concomitant decrease in IL-10 (Th2) cytokines. The drug did not affect body weight, food consumption and organ histopathology of the animals. CONCLUSIONS: PVaq exhibited anticancer and immunomodulatory activities against cervical cancer cells and female mouse papilloma model.

Antitumor Effect of Inula viscosa Extracts on DMBA-Induced Skin Carcinoma Are Mediated by Proteasome Inhibition.

The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of Inula viscosa extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of Inula viscosa treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of Inula viscosa on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that Inula viscosa extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of Inula viscosa was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts Inula viscosa delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure-activity relationship information obtained from component of Inula viscosa particularly tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in ß 1, ß 2, and ß 5 subunits determine its selectivity and potent inhibition for ß 5 subunit.

Resolution of confluent and reticulated papillomatosis after bariatric surgery.

Confluent and reticulated papillomatosis (CARP), a rare dermatologic disorder characterized by hyperpigmented papules that subsequently develop into plaques with reticulated margins, is frequently confused with acanthosis nigricans. The aetiology and pathogenesis of CARP is not yet fully understood, but it is often present in individuals with obesity and PCOS. This case report describes an African American adolescent female with obesity with a rash diagnosed as CARP after unsuccessful treatment with antifungals and corticosteroids. Her dermatosis proved recalcitrant to antibiotics and metformin but started to resolve immediately after bariatric surgery. This case report supports insulin resistance as a contributor to CARP's pathogenesis and as well as its association with obesity. Clinically significant weight reduction should be considered in the management of this challenging skin condition.

Prolapsed tongue papilloma cured by administration of the traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin: A case report.

Squamous papilloma is a benign mass lesion of the oral mucosa. For papillomas of the tongue, surgery is recommended owing to their malignant potential; however, certain complications may be associated with surgery. A traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin (KBGY), has been used to treat viral warts and various skin diseases in Japan. Therefore, the effect of KBGY on papillomas is promising. A 49-year-old Japanese man presented with a wart on his tongue that was about 3 months old. He smoked 5 cigarettes per day. He did not drink alcohol. He had no history of malignant illnesses. He was taking alprazolam for panic disorder. The patient was diagnosed with a suspected papilloma of the tongue at the Department of Otolaryngology and was advised to undergo an excision biopsy to exclude malignancy. However, he refused owing to the fear of an invasive procedure. After informed consent was obtained from the patient, KBGY was prescribed. Three months later, the wart on his tongue spontaneously prolapsed. The histopathological diagnosis was squamous papilloma. There was no indication of malignancy, and the patient discontinued Kampo treatment. He has had no recurrence in the past 3 years. KBGY is a combination of Keishibukuryogan and yokuinin (adlay seeds). Keishibukuryogan may be beneficial for skin or oral mucosal remodeling, and yokuinin may have antiviral properties. The present case report suggests the use of KBGY as an appropriate complementary therapy for squamous papilloma.