Psoriasiform drug eruption secondary to sorafenib: case series and review of the literature.

The expanding use of novel targeted anticancer agents such as sorafenib has led to an increasing number of dermatologic adverse events. Although cutaneous adverse events are commonly described in patients taking sorafenib, there are few reports describing psoriasis secondary to this medication. In this report, we describe 3 patients with sorafenib-induced psoriasiform drug eruption and review the available literature of similar patient cases. Our findings highlight shared characteristics among affected patients and potential treatment options for patients in whom sorafenib cannot be discontinued. Increased awareness of such drug eruptions and management options is critical to prevent suboptimal dosing and decreased quality of life.

Treatment Outcomes of Immune-Related Cutaneous Adverse Events.

PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics. METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed. RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043). CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

The Medication Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Asians: The Major Drug Causality and Comparison With the US FDA Label.

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.

Clear cell acanthoma (CCA)-like lesions of the nipple/areola: A clinicopathological study of 12 cases supporting a nonneoplastic eczematous disease.

BACKGROUND: Clear cell acanthoma (CCA) of the nipple/areola has been reported. The CCA-like histology more likely represents a feature of eczematous dermatitis of the nipple/areola. OBJECTIVE: We reviewed cases of CCA-like lesions of the nipple/areola and compared them with classic CCA to clarify their relationship. METHODS: The clinicopathological features of 12 cases of CCA-like lesions of the nipple/areola were compared with classic CCA. The literature on this condition was reviewed, and the results of various treatments were analyzed. RESULTS: CCA-like lesions of the nipple/areola were clinically different from those of classic CCA. Although they shared the glycogen-rich clear epidermal cells with neutrophilic exocytosis, dermal eosinophils appeared to be a distinctive feature. The anatomic site and association with atopic dermatitis suggested that CCA-like lesions of nipple/areola might represent a manifestation of atopic eczema involving nipple/areola. Topical steroids could be effective. LIMITATIONS: This was a retrospective study with limited cases. CONCLUSIONS: Although CCA-like lesions of the nipple/areola shared histopathological features with classic CCA, their clinical changes were consistent with dermatitis. We propose to name this condition CCA-like eczematous dermatitis of the nipple/areola.

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies.

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5-91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.

Anticancer Drugs Induced Severe Adverse Cutaneous Drug Reactions: An Updated Review on the Risks Associated with Anticancer Targeted Therapy or Immunotherapies.

Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite). Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

BACKGROUND: Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. METHODS: We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. RESULTS: Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS: The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01276314. FUNDING: Ministry of Science and Technology of Taiwan.

In vivo detection of UV-induced acute skin effects using optical coherence tomography.

Ultraviolet (UV) rays have been identified as a carcinogen with long-term irradiation and are an important risk factor for skin cancer. Here, we report the use of optical coherence tomography/optical coherence tomography angiography (OCT/OCTA) to study acute UV-induced effects on skin in vivo. To understand the relationship between the acute effects and irradiated UV power density, three groups were irradiated with different power densities in our experiments. Furthermore, the same skin area was repeatedly scanned with OCT during UV irradiation to investigate the progress of the induced acute effects and after irradiation for observation of skin recovery. Subsequently, the OCT/OCTA results were quantitatively analyzed to acquire skin thickness and blood-vessel density for comparison. UV-induced acute effects on morphology and microcirculation can be identified from OCT/OCTA results, which showed the increases in the skin thickness and blood-vessel density and even severe damage types such as blisters. The results of quantitative analyses also illustrated that the severity of damage induced by UV irradiation can be distinguished and the skin recovery can be monitored with OCT. Our results indicate that OCT can be a promising tool for early detection of UV-induced acute skin damage.

Novel Patched 1 Mutations in Patients with Gorlin-Goltz Syndrome Strategic Treated by Smoothened Inhibitor.

We studied a family with Gorlin-Goltz syndrome. The novel mutations of our cases were located on the 21st exon of the PTCH1 gene (c.3450C>G). The father, who received a strategic 56-day vismodegib treatment for disease control, was the first patient with Gorlin syndrome treated with the hedgehog inhibitor in Taiwan. The lesions regressed gradually, with scar formation, and were subsequently removed via a wide excision. Further details are provided below.

Quantitative Analysis of Face and Neck Skin Tightening by Microfocused Ultrasound With Visualization in Asians.

BACKGROUND: Previous studies of microfocused ultrasound with visualization (MFU-V) on facial and neck laxity were largely based on masked physician assessments, histological analysis, and safety profile. More quantitative studies are needed. OBJECTIVE: To evaluate the 800 treatment lines of MFU-V on skin tightening effect of face and neck in Asians using 2 quantitative analysis systems at 0, 90, and 180 days after treatment. MATERIALS AND METHODS: Total 25 subjects were recruited in this prospective study. Subjects were treated with MFU-V to the face and neck using 2 different transducers: 4 MHz, 4.5-mm focal depth and 7 MHz, 3.0-mm focal depth with total 800 lines. The subjects were evaluated by skin complexion analysis and 3-dimensional imaging system at 0, 90, and 180 days. Mean brow height lift and submental lift were calculated. RESULTS: All 25 subjects completed treatment and received the follow-up examinations at 90 and 180 days. Two of the 25 subjects were male. Mean patient age was 53.3 years (range: 39.8-61.1 years). Wrinkles, texture, and pores were 3 variables relevant to analysis of skin laxity. Only mean wrinkles score reduction at 90 days was statistically significant (p = .0222). There was a mean 0.47 mm brow lift at 90 days (p = .0165), but there was a 0.12 mm decrease in brow height compared to baseline at 180 days (p = .6494). At 90 days, a mean 26.44 mm submental lift was noted (p = .0217). And at 180 days, a mean 13.76 mm submental lift was noted (p = .243). CONCLUSION: This study showed that the most prominent change after the 800-line MFU-V treatments in Asians was the significant submental lift at 90 days. Other noninvasive or minimally invasive treatment modalities can be considered to combine with MFU-V for the optimal treatment response. Additional MFU-V treatments can be considered 3 months after the first treatment.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.

Postcesarean section wound infection caused by Mycobacterium massiliense.

BACKGROUND/PURPOSE: Mycobacterium abscessus subsp. massiliense (a subspecies of the M. abscessus complex) is a rare causative agent of surgical site infection after cesarean section (C section). We tried to seek the common source of infection and unravel the optimal treatment modalities. METHODS: From September 2009 to October 2012, four postpartum women developed C-section wound infections caused by M. massiliense. Speciation of the four isolates was identified using of hsp65, rpoB, and secA1 partial gene sequencing and the Basic Local Alignment Search Tool. The erm(41) and rrl genes were detected for the possibility of inducible macrolide resistance. Pulsed-field gel electrophoresis was used as a tool of molecular epidemiology. All patients underwent intensive intravenous and oral antimycobacterial regimens. Of these patients, three underwent debridement at least once. RESULTS: All four isolates were identified as M. abscessus subsp. massiliense. All of the isolates harbored a truncated erm(41) gene without rrl gene mutations, which explains the susceptibility to clarithromycin and azithromycin. Three isolates were indistinguishable by DNA strain typing, and the fourth strain was clonal with the other three strains. Their infections were not improved in spite of teicoplanin treatment initially. These patients underwent antimycobacterial regimens with/without surgery and were all cured. DISCUSSION: Teicoplanin treatment failure, painful cutaneous nodules, and persistent wound drainage alerted us to the possibility of nontuberculous mycobacterial skin and soft tissue infection. Accurate identification of subspecies, detection of drug resistance genes, susceptibility testing, and optimal antimycobacterial agents with/without surgical debridement are warranted for successful treatment.

Optical coherence tomography-guided laser microsurgery for blood coagulation with continuous-wave laser diode.

Blood coagulation is the clotting and subsequent dissolution of the clot following repair to the damaged tissue. However, inducing blood coagulation is difficult for some patients with homeostasis dysfunction or during surgery. In this study, we proposed a method to develop an integrated system that combines optical coherence tomography (OCT) and laser microsurgery for blood coagulation. Also, an algorithm for positioning of the treatment location from OCT images was developed. With OCT scanning, 2D/3D OCT images and angiography of tissue can be obtained simultaneously, enabling to noninvasively reconstruct the morphological and microvascular structures for real-time monitoring of changes in biological tissues during laser microsurgery. Instead of high-cost pulsed lasers, continuous-wave laser diodes (CW-LDs) with the central wavelengths of 450 nm and 532 nm are used for blood coagulation, corresponding to higher absorption coefficients of oxyhemoglobin and deoxyhemoglobin. Experimental results showed that the location of laser exposure can be accurately controlled with the proposed approach of imaging-based feedback positioning. Moreover, blood coagulation can be efficiently induced by CW-LDs and the coagulation process can be monitored in real-time with OCT. This technology enables to potentially provide accurate positioning for laser microsurgery and control the laser exposure to avoid extra damage by real-time OCT imaging.

Cutaneous plasmacytosis: a clinicopathologic study of 12 cases in Taiwan revealing heterogeneous underlying causes.

BACKGROUND: Cutaneous plasmacytosis is clinically characterized by multiple pigmented papules and plaques that occur mainly on the trunk and many plasma cells in the lesional skin. Most of the cases reported have occurred in Japan. Whether cutaneous plasmacytosis is a unique reactive disease or a neoplastic condition has not been established. METHODS: We collected 12 cases fulfilling the criteria for a diagnosis of cutaneous plasmacytosis at our institution from 2001 to 2013. We analyzed clinicopathologic features and performed immunohistochemical and immunoglobulin gene rearrangement studies. RESULTS: All 12 patients presented with characteristic cutaneous lesions mainly on the trunk and proximal extremities. Many plasma cells were observed in the lesional skin, and the basal layer was hyperpigmented. Four patients had numerous plasma cells in lymph nodes, and one patient also had increased plasma cells in bone marrow. One patient fulfilled the criteria for immunoglobulin G4 (IgG4)-related lymphadenopathy. Elevated serum IgG and IgG4 concentrations were found in seven patients. Monoclonal immunoglobulin gene rearrangements were detected in four patients. The median duration of follow-up was four years. One patient was lost from follow-up. Partial remission of the cutaneous lesions was observed in five patients, and progressive disease was noted in five patients. One patient died of respiratory failure. CONCLUSIONS: Our study suggests that the so-called "cutaneous plasmacytosis" has heterogeneous underlying causes with or without systemic involvement and may be associated with clonal immunoglobulin gene rearrangements and IgG4-related lymphadenopathy. No effective treatment is available for this condition.