Cutaneous reactions in children treated with MEK inhibitors, BRAF inhibitors, or combination therapy: A multicenter study.

BACKGROUND: Treatment with BRAF inhibitors (BRAFI) and MEK inhibitors (MEKI) causes cutaneous reactions in children, limiting dosing or resulting in treatment cessation. The spectrum and severity of these reactions is not defined. OBJECTIVE: To determine the frequency and spectrum of cutaneous reactions in children receiving BRAFI and MEKI and their effects on continued therapy. METHODS: A multicenter, retrospective study was conducted at 11 clinical sites in the United States and Canada enrolling 99 children treated with BRAFI and/or MEKI for any indication from January 1, 2012, to January 1, 2018. RESULTS: All children in this study had a cutaneous reaction; most had multiple, with a mean per patient of 3.5 reactions on BRAFI, 3.7 on MEKI, and 3.4 on combination BRAFI/MEKI. Three patients discontinued treatment because of a cutaneous reaction. Treatment was altered in 27% of patients on BRAFI, 39.5% on MEKI, and 33% on combination therapy. The cutaneous reactions most likely to alter treatment were dermatitis, panniculitis, and keratosis pilaris-like reactions for BRAFI and dermatitis, acneiform eruptions, and paronychia for MEKI. CONCLUSIONS: Cutaneous reactions are common in children receiving BRAFI and MEKI, and many result in alterations or interruptions in oncologic therapy. Implementing preventative strategies at the start of therapy may minimize cutaneous reactions.

PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. PATIENTS AND METHODS: PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. RESULTS: A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6-12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. CONCLUSIONS: ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

Osimertinib for Japanese patients with T790M-positive advanced non-small-cell lung cancer: A pooled subgroup analysis.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.

Overview of current systemic management of EGFR-mutant NSCLC.

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.

Evaluation of role of Candida in patients with chronic paronychia.

BACKGROUND: Chronic paronychia, earlier considered to be an infection due to Candida, is currently being considered as a dermatitis of the nail fold. Irritant, allergic and protein contact dermatitis are the suggested major pathogenic mechanisms. Hypersensitivity to Candida is more likely to be the etiology, rather than the infection itself. AIMS: To assess the clinico-etiological profiles of patients with chronic paronychia and to determine the role of contact sensitization and hypersensitivity to Candida. METHODS: All consecutive patients of chronic paronychia attending the dermatology outpatient department (OPD) were assessed for risk factors, number of nails affected, clinical presentation and presence of fungus, patch tested for contact allergy and prick tested for hypersensitivity to Candida allergen. RESULTS: A total of 80 patients of chronic paronychia were recruited into our study. There was female preponderance (66 patients, 82.5%), with the most common group affected being housewives (47 patients, 58.8%). Frequent washing of hands (64 patients, 80%) was the most common risk factor. Fungal culture was positive in 56.1% (41 patients), the predominant species cultured was Candida albicans (15 patients, 36.5%). Patch testing with Indian standard series was positive in 27.1% patients (19 out of 70 patients tested), with nickel being the most common allergen. Prick test with Candida allergen was positive in 47.6% patients (31 out of 65 patients tested). LIMITATIONS: Prick test and patch test provide indirect evidence of hypersensitivity, with inherent limitations. CONCLUSION: Our study shows that chronic paronychia is probably a form of hand dermatitis associated with prolonged wet work, and that there is a higher incidence of contact sensitization and Candida hypersensitivity in these patients.

Epidemiology of adult acute hand infections at an urban medical center.

PURPOSE: To define the current epidemiology of adult acute hand infections in an urban setting, with the aim of helping to improve empiric treatment, as hand infections represent a major source of morbidity and can result in stiffness and, possibly, amputation. METHODS: We performed an electronic medical record search to identify all patients admitted to our urban academic medical center with diagnoses related to open wounds and infections in the hand and fingers over a 6-year period (2005-2010). We recorded demographic data, location of infection, medical comorbidities, and culture data. RESULTS: Of the 2,287 patients admitted with diagnoses related to open wounds and infections in the hand and fingers, 1,507 incision and drainage procedures were performed, which resulted in 458 patients (30%) with culture-positive infections. Wound cultures identified 39 different species of bacteria. Most of these were methicillin-resistant Staphylococcus aureus, which compromised 53% of positive cultures, followed by methicillin-sensitive S aureus in 23% of positive cultures. The cultures were polymicrobial in 19%. History of intravenous drug use or diabetes mellitus was a strong predictor of polymicrobial infection. CONCLUSIONS: Methicillin-resistant Staphylococcus aureus was the most common bacteria cultured from these infections. Empiric antibiotic coverage should routinely cover methicillin-resistant S aureus. We noted a higher incidence of polymicrobial infections than previously reported, particularly with intravenous drug use, diabetes, and human bites. Volar hand infections had the highest percentage of positive cultures, whereas paronychia had the lowest percentage. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Childhood nail alterations in Polish population.

The epidemiology and nature of childhood nail apparatus pathology is not well known. The aim of our study was to investigate the frequency and nature of nail alterations in Polish pediatric patients. Among 1588 patients diagnosed and treated at our clinic due to nail alterations, 82 (5.16%) patients under age 16 were selected. The most frequent (36.59%) diagnosis were variants of normal nails, which were observed in 30 patients. The most common pathology were viral warts (19.51%). Differences in the distribution of onychomycosis and viral warts in children and adults were statistically significant. Onychomycosis was more common in adults (60.39% vs. 9.76%), whereas viral warts were more common in children (19.51% vs. 5.86%; P<0.0001). Melanonychia was diagnosed in one (1.22%) case. Benign and malignant tumors were not observed. In conclusion, distribution of nail apparatus pathology in children is different comparing with adults. In the group of children under 6 years of age, there were mainly variants of normal nails, whereas in older children viral infection and acquired structural disorders were recorded. The risk of nail apparatus malignancy in childhood seems to be extremely low.

Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte counts.

Mucocutaneous findings in 150 HIV+ve cases (F, 79; M, 71) were evaluated over a one-year period. Mucocutaneous manifestations were seen in 96% with 2.9 mean number of dermatoses and mean cluster of differentiation (CD4) count of 196.33 cells/mm(3). The highest number of mean dermatoses, 3.29, was seen in individuals with severe immunosuppression. The most common mucocutaneous manifestation seen was candidiasis (35.33%), followed by seborrhoeic dermatitis (31.33%), oral pigmentation (29.33%), xerosis/ichthyosis (22.67%), pyodermas (22%), periodontitis (17.33%) and nail pigmentation (16.67%). Patient stratification according to the WHO immunological staging, according to CD4 counts, showed a statistically significant association (P < 0.05) for candidiasis, scabies, paronychia, oral pigmentation and diffuse hair loss. Nail and oral pigmentary changes, trichomegaly and subcutaneous fungal infections caused by dermatophytes were highlights of the study. Incidences of xerosis/ichthyosis, pyodermas, scabies and molluscum contagiosum reported in our study were higher and pruritic popular eruptions was lower than those in previous Indian studies. Cutaneous neoplasms were not seen in the present study.

Foot abnormalities in Canadian Aboriginal adolescents with Type 2 diabetes.

AIMS: To determine the profile of foot abnormalities in Canadian Aboriginal adolescents with Type 2 diabetes and the risk factors associated with these abnormalities. METHODS: Aboriginal adolescents with Type 2 diabetes underwent an interview, medical record review and foot examination in a tertiary care, paediatric hospital diabetes clinic and two geographically remote outreach clinics. The notes of 110 subjects were reviewed [mean age 15 +/- 3 years; mean duration of diabetes, 30 +/- 20 months; 71 (66%) female and 39 (34%) male] and 77 (70%) of the subjects were examined. RESULTS: Foot abnormalities were identified by either interview or notes review, and included poor toenail condition in 85 (77%), paronychia in 29 (26%), ingrowing toenails in 16 (15%) and neuropathic symptoms in 13 (12%) subjects. Foot abnormalities were identified by examination in many subjects, including poor toenail condition in 38 (49%), calluses in 34 (44%) and paronychia in 13 (17%) subjects. Eighteen (24%) of 75 subjects did not have running water in the home. Factors that significantly increased the presence of foot abnormalities included: foot care provided by a person other than self; absence of running water in the home; decreased frequency of bathing; and decreased frequency of nail clipping. A greater percentage of subjects living on a reservation or rural community had specialized consultations for retinal examination, footwear, or both than of those living in an urban or unknown residence. CONCLUSIONS: A high prevalence of foot abnormalities was noted in Aboriginal adolescents with Type 2 diabetes. These findings highlight the associated comorbidities in this population, emphasizing the need for early detection and intervention.

Bacterial diseases of the skin.

When considering common bacterial diseases of the skin, rather distinct clinical responses to a variety of bacterial infections have been identified. In these cases, it is the specific site of infection and the attendant inflammatory responses that provide the characteristic clinical picture. When the pyoderma extends just below the stratum corneum, it is called impetigo. Nonbullous impetigo is the most common pediatric skin infection. It usually starts in a traumatized area. The typical lesion begins as an erythematous papule, after which it becomes a unilocular vesicle. When the subcorneal vesicle becomes pustular, it ruptures and eventually becomes a yellow, golden crust that is a hallmark of the disease process. Bullous impetigo is a less common form of impetigo, accounting for fewer than 30% of all impetigo cases. It occurs in infants and is characterized by rapid progression of vesicles to the formation of bullae measuring larger than 5 mm in diameter in previously untraumatized skin. Treatment of nonbullous impetigo must include intervention against the pathogen as well as improvements in the hygiene and living conditions of the patient. A fundamental tenet is to debride the crust (scab) from the wound surface using poloxamer 188. If the lesions are not widespread, topical mupirocin is the treatment of choice. Treatment of bullous impetigo is similar, except that the local cleansing and topical antibiotic must be complemented by systemic antibiotics if there is evidence of disseminating infections. Ecthyma is usually a consequence of failure to treat effectively impetigo. The untreated infection extends deep into the tissue in shallow ulcerations that often heal without scar. Treatment for ecthyma usually requires systemic antibiotics against either staphylococcus or streptococcus. Folliculitis is a pyoderma located within a hair follicle, secondary to follicular occlusion by keratin, overhydration, or either bacterial or fungal infection. Folliculitis may be divided into either a deep or a superficial type. In the superficial type, the pustule is located at the opening of the hair follicle. In the deep form, the infection may extend beyond the confines of the hair follicle, becoming a furuncle or boil. Carbuncles are aggregates of interconnected furuncles that drain through multiple openings of the skin. Treatment of folliculitis must include searching for and avoiding any factors predisposing to infection. If topical antibiotic therapy is ineffective in controlling the infection, surgical drainage of the infected skin abscess will be necessary. Paronychia is the most common bacterial infection of the hand, which often requires surgical incisional drainage. Similarly, a felon that is an infection of the distal pulp of a finger usually requires surgical drainage. Finally, cellulitis is an acute inflammatory reaction involving the skin and underlying subcutaneous tissue. It usually starts as erysipelas and may advance to lymphangitis, lymphadenitis, or gangrene,which will respond to life-saving interventions in the hospital that usually include systemic antibiotic treatment as well as surgical intervention.

Epidemiology of onychomycosis and paronychia in the area of ANCONA (ITALY) over a period of 5 years.

We retrospectively evaluated the epidemiology of onychomycosis and/or paronychia in 172 patients attending the Clinic of Dermatology and Venereology over a 5 year period. Although yeast isolates, belonging to the Candida species, represented the most frequent etiologic agents of these infections, an increasing prevalence of fungal infections due to emerging fungal pathogens (EFP) was noted throughout this time period. In particular, EFP as causative agents of these infections increased from 0 to 28.4% from 1998 to 2002.

Higher frequency of paronychia (nail bed infections) in pediatric and adolescent patients with type 1 diabetes mellitus than in non-diabetic peers.

OBJECTIVE: Paronychia occurs frequently in adolescents, but there are no data about its prevalence in adolescents with type 1 diabetes mellitus (DM1). We investigated the presence and characteristics of nail-bed infections in a group of adolescent patients with DM1 aged 10-20 years. METHODS: Ninety-three children and adolescents with DM1 and 100 healthy age-matched controls were studied using a structured questionnaire. Frequency, duration and treatment of paronychia and, in the DM1 group, duration of DM, mean HbA1c, frequency of hypoglycemia, footwear and foot care were evaluated. All patients with DM1 underwent a complete neurological examination including vibration perception, thermal perception, and light touch perception. RESULTS: Adolescents with DM1, particularly girls, had a higher frequency of paronychia than controls (34.4% vs 23%; p < 0.01). Diabetic patients with paronychia were older than those without and had a longer duration of DM1, while there was no difference in long-term HbA1c between the groups. Vibration perception was impaired in all regions measured, compared to healthy adolescents. Subclinical neuropathy and microalbuminuria was found to be more frequent in patients with paronychia than in those without. CONCLUSION: We conclude that foot examination is important and mandatory in adolescents with DM1.

Onychomycosis in João Pessoa City, Brazil.

Onychomycosis epidemiology is a combination of various factors which include, among others, clinical presentation, etiologic agents of the infection and the patient's history background. Out of a total of 672 nail samples examined, 460 (68.4%) were microscopy positive for fungi and 306 (66.5%) of these were culture positive, including Candida (82%), dermatophytes (13.4%), Trichosporon spp (3.6%) and nondermatophyte molds (1%). Onychomycosis was more frequent in females (79.7%) than in males (20.3%). These were more common in fingernails (96.1%) than in toenails (60%) and yeasts were the most isolated etiologic agents. Among the clinical presentations, paronychia (CP) (57.2%) and onycholysis (CO) (24.8%) were the most common, caused frequently by C. albicans in 52.6% and 60.5% of the cases, respectively. T. rubrum (44.4%) and Trichosporon spp (22.2%) were the most frequent species in the case of distal lateral subungual onychomycosis (DLSO). Fusarium spp was the agent responsible for 33.3% of the cases of proximal subungual onychomycosis (PSO) and for 14.3% of white superficial onychomycosis (WSO), whereas Acremonium spp was responsible for 14.3% of the cases of WSO.

Onychomycosis in Joõo Pessoa City, Brazil

Onychomycosis epidemiology is a combination of various factors which include, among others, clinical presentation, etiologic agents of the infection and the patients history background. Out of a total of 672 nail samples examined, 460 (68.4) were microscopy positive for fungi and 306 (66.5) of these were culture positive, including Candida (82), dermatophytes (13.4), Trichosporon spp (3.6) and nondermatophyte molds (1). Onychomycosis was more frequent in females (79.7) than in males (20.3). These were more common in fingernails (96.1) than in toenails (60) and yeasts were the most isolated etiologic agents. Among the clinical presentations, paronychia (CP) (57.2) and onycholysis (CO) (24.8) were the most common, caused frequently by C. albicans in 52.6 and 60.5 of the cases, respectively. T. rubrum (44.4) and Trichosporon spp (22.2) were the most frequent species in the case of distal lateral subungual onychomycosis (DLSO). Fusarium spp was the agent responsible for 33.3 of the cases of proximal subungual onychomycosis (PSO) and for 14.3 of white superficial onychomycosis (WSO), whereas Acremonium spp was responsible for 14.3 of the cases of WSO.(AU)

Dermatoses--an occupational hazard in the canning industry.

Despite the recognition that occupational dermatitis is extremely common, few data exist on the prevalence of skin disorders in South African industry. A cross-sectional prevalence study among 686 female workers in a canning factory in the western Cape showed high rates of dermatoses--in particular, chronic paronychia, intertrigo and dermatitis of the hands. A statistically significant association was found between exposure to 'wet work' in the industry and the prevalence of chronic paronychia and intertrigo. Age was also found to be associated with these dermatoses, irrespective of duration of service. The prevalence of dermatitis of the hands was increased among high-exposure workers, but not significantly. Dermatoses are an important occupational hazard in the canning industry, and there is a need for improved preventive measures.

Epidemiology of chronic paronychia in a skin hospital in Singapore.

A retrospective epidemiologic study of 110 patients with chronic paronychia (CP) showed a female-male ratio of 2.3:1, whereas the ratio of patients attending the same clinic was 1.1:1 (p less than 0.001). The peak age range of patients with CP (40-49 years) generally was greater than that of the general dermatologic patients (20-29 years). Seventy-seven percent of the patients with CP were "manual workers," of which 48% were homemakers. Chronic paronychia was more common on the right fingers than the left fingers. The most commonly affected fingers were the right thumb (62%), followed by the right middle finger (52%), left thumb (57.6%), and left middle finger (51.5%). Mechanical trauma appears to be an important predisposing factor in CP. Sixty-two percent of 68 patients who had nail fold smears had positive findings for budding yeast cells, suggestive of candidal infection. All of the six patients for whom nail fold bacterial cultures were performed had positive results for enteric flora.

Eponychial marsupialization and nail removal for surgical treatment of chronic paronychia.

A long-term retrospective study of patients with chronic paronychia treated by eponychial marsupialization with or without nail removal is presented. Twenty-eight consecutive fingers with chronic paronychia in twenty-five patients were surgically treated. Symptoms had been present for 28 +/- 7 weeks. Twenty-three of these had nail irregularities. Of this group, the first seven fingers were treated with marsupialization alone. Recurrences developed in two of these. The next sixteen patients with nail irregularities were treated with marsupialization plus nail removal, and there were no recurrences (p less than 0.05). Furthermore, when the two recurrent paronychia were treated with both procedures, one healed completely and the other was markedly improved. All fingers without nail irregularities healed with marsupialization alone. These results confirm that eponychial marsupialization is an effective means of treating chronic paronychia and suggest that nail removal should be done when concurrent nail irregularities are seen.