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.

Phenytoin (diphenylhydantoin) is a widely prescribed antiepileptic drug and remains the most frequently used first-line antiepileptic drug in hospitalized patients.^1,2 Although effective for treating neurological diseases, phenytoin can cause cutaneous adverse reactions ranging from mild rash (maculopapular exanthema) to life-threatening severe cutaneous adverse reactions.^3-6 Phenytoin-related severe cutaneous adverse reactions include drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).^4-6 Stevens-Johnson syndrome and TEN are variants of the same mucocutaneous blistering reaction disease and carry high morbidity and mortality (10%-50%).^4-6 DRESS, also known as drug-induced hypersensitivity syndrome, is characterized by generalized maculopapular eruptions, high fever, eosinophilia, atypical lymphocytes, and visceral involvement and has a mortality rate of approximately 10%.^6,7 Phenytoin-related severe cutaneous adverse reactions frequently impair the internal organs, leading to the highest mortality among the different antiepileptic drug–related cutaneous reactions.⁵

Objective Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. Methods We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. Results In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). Conclusions Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

To assess the diagnostic accuracy of fused T2-weighted and high-b-value diffusion-weighted (DW) magnetic resonance (MR) images at 3 T for evaluation of myometrial invasion in patients with endometrial cancer. Institutional review board approval and informed consent were obtained. From May 2006 to October 2007, 48 consecutive patients aged 25-80 years (mean age, 57 years) who had endometrial cancer were prospectively enrolled for preoperative evaluation by using a 3-T MR unit. Two radiologists interpreted the depth of myometrial invasion on T2-weighted images, dynamic contrast material-enhanced MR images, and fused T2-weighted and DW MR images (b = 1000 sec/mm(2)). Statistical methods included kappa statistics for reader agreement, Pearson analysis for pathologic correlation, accuracy assessment, and receiver operating characteristic analysis for diagnostic performance comparison. Surgical pathologic findings were the reference standard. Reader agreement was excellent for fused T2-weighted and DW images (weighted kappa, 0.79), with a significant pathologic correlation regarding the depth of myometrial invasion (r = 0.94, P < .0001). For assessing any myometrial involvement, addition of fused T2-weighted and DW imaging to dynamic contrast-enhanced or dynamic contrast-enhanced and T2-weighted imaging was significantly better compared with dynamic contrast-enhanced imaging alone (P < .001) or dynamic contrast-enhanced and T2-weighted (P = .001) imaging; T2-weighted imaging combined with fused T2-weighted and DW imaging also was better than dynamic contrast-enhanced and T2-weighted imaging (P = .001). Tumor apparent diffusion coefficients were 0.60-1.32 x 10(-3) mm(2)/sec (median, 0.75 x 10(-3) mm(2)/sec), with no significant correlation with the depth of myometrial invasion (P = .31, r = -0.15). Fused T2-weighted and high-b-value DW images at 3 T can provide accurate information for preoperative evaluation of myometrial invasion.

This study was the result of a constant evaluation of surgical techniques and results to obtain excellence in primary cleft rhinoplasty. This was a retrospective study from 1992 to 2003 comparing the long-term outcomes of four techniques of nasal reconstruction. There were 76 patients divided into four groups: group I (n = 23 patients), primary rhinoplasty alone; group II (n = 16 patients), nasoalveolar molding alone; group III (n = 14 patients), nasoalveolar molding plus primary rhinoplasty; and group IV (n = 23 patients), nasoalveolar molding plus primary rhinoplasty plus overcorrection. The surgical results were analyzed using photographic records obtained at 5 years of age. A ratio of six measurements was obtained comparing the cleft and noncleft sides. A panel assessment was obtained to grade the appearance of the surgical results. All surgery was performed by the senior author (P.K.T.C.). The results are given for groups I to IV, respectively. The nostril height ratio was 0.73, 0.77, 0.81, and 0.95. The nostril width ratio was 1.23, 1.36, 1.23, and 1.21. The one-fourth medial part of nostril height ratio was 0.70, 0.87, 0.92, and 1.00. The nasal sill height ratio was 0.75, 1.02, 1.07, and 1.07. The nostril area ratio was 0.86, 0.89, 0.95, and 1.08. The nostril height-to-width ratio was 0.58, 0.58, 0.71, and 0.92. Finally, group IV had the best panel assessment. The results revealed that group IV had the best overall result. Overcorrection of 20 percent was necessary to maintain the nostril height. Further technical modifications are necessary to minimize widening of the nostril width.