EGCG inhibits growth of tumoral lesions on lip and tongue of K-Ras transgenic mice through the Notch pathway.

Epigallocatechin-3-gallate (EGCG), the main active ingredient of green tea, exhibits low toxic side effect and versatile bioactivities, and its anti-cancer effect has been extensively studied. Most of the studies used cancer cell lines and xenograft models. However, whether EGCG can prevent tumor onset after cancer-associated mutations occur is still controversial. In the present study, Krt14-cre/ERT-Kras transgenic mice were developed and the expression of K-RasG12D was induced by tamoxifen. Two weeks after induction, the K-Ras mutant mice developed exophytic tumoral lesions on the lips and tongues, with significant activation of Notch signaling pathway. Administration of EGCG effectively delayed the time of appearance, decreased the size and weight of tumoral lesions, relieved heterotypic hyperplasia of tumoral lesions, and prolonged the life of the mice. The Notch signaling pathway was significantly inhibited by EGCG in the tumoral lesions. Furthermore, EGCG significantly induced cell apoptosis and inhibited the proliferation of tongue cancer cells by blocking the activation of Notch signaling pathway. Taken together, these results indicate EGCG as an effective chemotherapeutic agent for tongue cancer by targeting Notch pathway.

Presence of Incipient Fungal Infection in Atypical Squamous Lesions of the Lip.

ABSTRACT: Epidermal barrier disruption caused by atypical squamous proliferations of the lip (SOL) creates an ideal environment for fungal growth. Histologic features of SOL include parakeratosis overlying partial- or full-thickness keratinocyte atypia with or without invasion of the dermis, dermal solar elastosis, and scattered inflammatory cells which are predominantly lymphocytes. Histologic features of SOL with fungal superinfections overlap those seen in primary fungal cheilitis with reactive atypia, creating a diagnostic challenge. One-hundred seventy SOL cases were examined for the presence of fungal elements, and the histological features associated with superinfection were identified. Cases diagnosed as actinic cheilitis with fungal superinfection were carefully examined to rule out the possibility of misdiagnosed primary fungal cheilitis with reactive atypia. Histopathological characteristics commonly present with fungal hyphae included intraepidermal or intradermal neutrophils, bacterial colonies, and erosion or ulceration. Medical record review of those patients treated conservatively with topical antifungals revealed persistent clinical neoplasm and histological evidence of residual SOL on repeat biopsy. Thus, when biopsies exhibit histological overlap between these 2 entities, clinicians should keep a high index of suspicion for underlying SOL and carefully follow these patients if conservative antifungal therapy is initially trialed.

Giant placental chorioangioma followed by circulatory failure of the newborn and infantile hemangioma: Case report.

Placental chorioangioma (CA) is a benign placental tumor. No specific treatment is required for asymptomatic cases. We report a female infant born to a mother with giant placental CA. However fetal growth was normal and, fetal hydrops was not detected by ultrasound examination until delivery, she had hydrops, subgaleal hematoma, thrombocytopenia, hemolytic anemia, respiratory distress and circulatory failure after birth. She was successfully treated without any neurological sequelae. At 2 months of age, infantile hemangioma appeared in her lower lip. The present case suggested that giant placental CA might cause postnatal problems and be associated with the development of infantile hemangioma.

Infantile hemangioma of the upper lip and enamel hypoplasia: Two case reports.

Segmental infantile hemangiomas related to PHACE syndrome have recently been associated with enamel hypoplasia. We present two cases of solitary, localized upper lip infantile hemangioma with enamel hypoplasia of deciduous teeth.

Multiple keratin granulomata: A potential histologic clue to cutaneous squamous cell carcinoma responding to programmed cell death protein 1 inhibitor therapy.

We present histologic features of a locally advanced cutaneous squamous cell carcinoma (cSCC) treated with the programmed cell death protein-1 (PD-1) antagonist, pembrolizumab, with a partial response. This contributes to a growing body of literature supporting the efficacy of pembrolizumab in treatment of surgically unresectable cSCC. We also provide a detailed description of the histologic features, particularly keratin granulomata with adjacent lymphocytic aggregates and fibrosis, observed in cSCC under treatment with a PD-1 antagonist.

Long term effectiveness of electrochemotherapy for the treatment of lower lip squamous cell carcinoma.

PURPOSE: Electrochemotherapy (ECT) is a therapeutic approach based on the local application of electrical pulses that permeabilize cell membranes to enhance the uptake of low-permeant chemotherapeutic agents, thus increasing their cytotoxic effects. MATERIALS AND METHODS: Twenty-one patients with SCC of the lower lip were treated according to the European Standard Operating Procedures of Electrochemotherapy. Bleomycin (15,000 IU/m2 body surface area) was administered intravenously over a 1-min period. Eight electrical pulses (amplitude, 1000 V/cm; duration, 100 µs) were generated and delivered at a repetition frequency of 5 kHz. Changes in tumor volume were used to assess treatment response. RESULTS: Objective response (OR), complete response (CR), and partial response (PR) rates of 100%, 71.4%, and 28.6% respectively were demonstrated following a single session of ECT. ECT was well tolerated, and no adverse events occurred. CONCLUSIONS: Intravenous bleomycin-based ECT is a safe and effective therapy for SCC of the lower lip. ECT improves the quality-of-life of patients by preserving the function and the aesthetic appearance of the affected area. ECT provides a therapeutic option for elderly and frail patients who, due to their state of health, are not suitable for, or refuse surgical interventions.

Elastosis en la queilitis actínica. Revisión de literatura / Elastosis in Actinic Cheilitis. Literature Review

Resumen La matriz extracelular (MEC) juega un papel importante en la regulación de los eventos biológicos, tales como, el desarrollo de la migración celular, proliferación y diferenciación. La exposición crónica a la luz ultravioleta (UV) provoca elastosis (en distintos grados), que corresponde a una degeneración basófila de la MEC. La queilitis actínica (QA) es una lesión potencialmente maligna del labio inducida por la exposición regular y prolongada a la luz UV, que afecta principalmente al bermellón del labio inferior. Las lesiones de QA tienen un estroma complejo, se observa siempre la presencia de elastosis, infiltrado inflamatorio crónico de distinta intensidad y la aparición de vasos sanguíneos telangiectásicos. Dentro de este infiltrado inflamatorio se ha descrito un aumento significativo de mastocitos (MCs), localizados especialmente alrededor de las zonas de elastosis y en la zona subepitelial. Se ha propuesto que la elastosis actínica se produce tanto por procesos degenerativos como de síntesis anormal de fibras elásticas por parte de fibroblastos con daño solar, lo que va acompañado de cambios morfológicos del colágeno. A pesar de que el fibroblasto tendría un rol preponderante en la formación de la elastosis actínica, diversos estudios sugieren que otros tipos celulares como el MC también contribuirían en forma significativa al daño actínico de la MEC. El propósito de esta revisión es analizar las características de la elastosis en la QA.

Abstract The extracellular matrix (ECM) plays an important role in the regulation of biological events, such as cell migration, proliferation and differentiation. Chronic exposure to ultraviolet (UV) light causes elastosis (to varying degrees), which corresponds to a basophilic degeneration of the ECM. Actinic cheilitis (AC) is a potentially malignant lip lesion induced by regular and prolonged exposure to UV light, which mainly affects the vermilion. AC lesions have a complex stroma characterized by the presence of elastosis, chronic inflammatory infiltrate of different intensity and the appearance of telangiectatic blood vessels. Within this inflammatory infiltrate a significant increase of mast cells (MCs) has been described, located especially around areas of elastosis and at the subepithelial zone. It has been proposed that actinic elastosis is produced both, by degenerative processes and by abnormal synthesis of elastic fibers by photodamaged fibroblasts, which is accompanied by morphological changes in collagen. Although the fibroblast would play a major role in actinic elastosis formation, several studies suggest that other cell types such as MCs also contribute significantly to actinic ECM damage. The purpose of this review is to discuss the characteristics of elastosis in AC.

Factors associated with delayed referral for infantile hemangioma necessitating propranolol.

BACKGROUND: Oral propranolol is the gold standard to treat infantile hemangiomas. There is better efficacy and a lower risk of sequelae if therapy is started before the end of the growth phase, but most children are referred too late. Herein, we report the first study to investigate the delay and its associated factors when referring infants with infantile hemangiomas that need propranolol therapy. OBJECTIVES: The primary objective was to determine the delay in referral (time between age at referral [first phone contact] and the optimal age for referral (fixed at 75 days). The second objective was to determine the impact of weighted factors associated with delayed referral assessed by logistic regression performed on two subgroups (referral ≤75 vs. >75 days). METHODS: Monocentric, retrospective, observational study included infants with infantile hemangiomas treated with oral propranolol between August 2014 and May 2017. RESULTS: Eighty-two children (83% females) were included. Before referral, 81 (99%) children had seen another physician (a paediatrician in 67% of cases). Median age at referral was 99 days [2-478] and 63% phoned after 75 days. Median age at the first visit was 111 days [2-515], and median age when propranolol was started was 128 days [32-541]. After adjustment, in multivariate analyses, location on the lips (OR (CI 95%): 4.21[1.19-14.89]) and superficial hemangioma (OR (CI 95%): 4.19 [1.55-11.34]) emerged as the most significant factors to influence referral before 75 days. CONCLUSIONS: This study adds to our understanding regarding delayed referral and has identified targets for future information campaigns.

Retrospective Investigation of Cutaneous Squamous Cell Carcinoma on the Lip Treated with Peplomycin Administered Through a Superficial Temporal Artery.

BACKGROUND: Continuous intra-arterial (IA) administration of peplomycin (PEP) through a tumor-feeding artery is one of the most effective treatments for cutaneous squamous cell carcinoma (cSCC) in cosmetic areas. PATIENTS AND METHODS: In order to determine the effective and safe dose of PEP and the curative rate of IA-PEP, we retrospectively investigated a case series of 24 patients with cSCC on the lips who were treated with IA-PEP. RESULTS: IA-PEP reduced the tumor mass in all 24 cases (100%). A complete response occurred in 17 patients (70.8%), and a partial response occurred in seven (29.2%). Moreover, 17 patients (70.8%) were cured, three patients developed cervical lymph node metastasis (12.5%), and four developed local recurrence (16.7%). Three out of the 24 patients developed interstitial pneumonia (12.5%). CONCLUSION: Low-dose IA-PEP administered through a superficial temporal artery was a highly effective treatment that achieved a curative response for 70.8% of patients with cSCC on the lips.

Management of actinic cheilitis using ingenol mebutate gel: A report of seven cases.

Actinic cheilitis (AC) can precede the development of squamous cell carcinoma of the lip, a location with high risk of invasiveness and metastasis. We communicate the good results that we obtained when treating seven patients suffering from AC with ingenol mebutate (IM) 0,015% concentration gel on three consecutive days. Three patients achieved complete clearance and four significant improvement. IM is a topical field treatment approved for actinic keratosis. To our knowledge, reported experience in the management of AC with IM is very limited. Local skin responses grade 3 were the main adverse event observed and they resolved in all patients without specific therapy within 1 to 2 weeks. IM is characterized by its rapid clinical effect, its favorable safety profile and its dosing period of only 3 days, shorter than with other field therapies. All these facts make it an attractive new therapy for AC, with need for further study.

Ingenol Mebutate for Recalcitrant Chronic Actinic Cheilitis.

We present the case of a healthy 76-year-old man with a whitish, hyperkeratotic lesion of the lower lip diagnosed as actinic cheilitis (AC) previously treated with classic red light photodynamic therapy 5 years ago. Initial treatment with 5% imiquimod cream - also with intensified application - failed. After 2 cycles thrice daily, consecutive applications of 150 µg/g ingenol mebutate gel at 3 weeks' interval, the lesions cleared completely. Surprisingly, no pustular or crusting reaction or other side effect occurred contrary to expectation. Remission was stable for 10 months, when recurrence occurred. Ingenol mebutate proved to be a feasible and safe treatment in this otherwise refractory case of AC.

Primary Malignant Melanoma of the Lip: A Report of 48 Cases.

PURPOSE: Lip melanoma (LM) is a rare malignant tumor and well-established treatment protocols for it are in short supply. The objective of this study was to evaluate the outcome of treatment modalities and explore the prognostic factors. PATIENTS AND METHODS: A retrospective chart review was performed on 48 patients with primary LM treated in the authors' hospital from January 1992 to November 2013. The clinical characteristics and treatment modalities were identified and correlated with the outcomes. RESULTS: The 5-year overall survival (OS) rate was 56.1%, and the rate of cervical lymph node (CLN) metastasis was 46% (22 of 48). A tumor of at least 4 cm (P = .001), nodular types (P = .003), and CLN (P < .0001) were independent prognostic factors for OS. Twenty-five patients died during follow-up, mainly from to neck recurrence (14 of 25). Chemotherapy significantly improved the 5-year OS rate in patients with stage IV LM (P = .03), but not in those with stage III (P = .8). CONCLUSIONS: LM has a lower CLN and distant metastasis rate and a better prognosis than other oral mucosal melanomas. A long history of melanin pigmentation is a dangerous sign for all patients, and smoking seems to be associated with LM in male patients. Tumor size (≥4 cm), nodular type, and CLN positivity are poor prognostic factors. A wide excision with close observation is advocated as the primary treatment for stage III LM. Adjuvant chemotherapy is useful for patients with stage IV cancer, but not for those with stage III.

Photodynamic therapy for the treatment of microinvasive squamous cell carcinoma of the lower lip: a case report.

Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) is approved in Europe for the treatment of actinic keratosis and Bowen's disease, both intraepithelial forms of squamous cell carcinoma (SCC). A therapeutic effect of MAL-PDT has been recently suggested for superficial, microinvasive and well-differentiated cutaneous SCC. We describe the successful use of MAL-PDT in a recently observed patient with microinvasive SCC of the lower lip and review published data on the use of PDT with MAL or d-aminolevulinic acid (ALA) in cutaneous microinvasive SCC. A patient with a biopsy-proven recurrent microinvasive SCC of the lower lip was treated with 2 cycles of MAL-PDT. Complete clinical, dermoscopic and histopathological clearance was obtained after 2 cycles of MAL-PDT with an excellent cosmetic result and a sustained remission after 24-month follow-up. A review of the few studies reporting on the use of MAL-PDT or ALA-PDT for cutaneous microinvasive SCCs was carried out. MAL-PDT might represent a non-invasive treatment option for microinvasive SCC of the lower lip if patients are not eligible for surgery. Post-treatment histopathological confirmation and a long-term follow-up are strictly recommended.