Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: A phase II randomized clinical trial.

To the editor: Hand-foot skin reaction (HFSR), characterized by skin abnormalities on palmoplantar surfaces, has an overall incidence of about 35% upon vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment.1 Zinc, which plays a role in maintaining skin health, may be implicated in the pathogenesis of HFSR.2 Zinc deficiency has been shown to associate with dermatological toxicities of epidermal growth factor receptor (EGFR)-TKI.3, 4 Regorafenib, an oral multi-kinase inhibitor targeting VEGFR 1-3, PDGFR, cKIT, BRAF, and RET1, is approved for the treatment of metastatic colorectal cancer (mCRC) but commonly causes HFSR.5 This phase II randomized trial aimed to investigate whether zinc supplementation can reduce the severity of HFSR induced by regorafenib within the first 8 weeks of treatment (NCT03898102).

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.

Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.

PURPOSE: Cutaneous toxicities are common adverse effects following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Zinc deficiency causes diverse diseases, including skin toxicities. Therefore, this study aimed to investigate the role of zinc deficiency in patients with EGFR-TKI-induced skin toxicities. EXPERIMENTAL DESIGN: This retrospective study enrolled 269 patients with diverse skin disorders who visited our hospital between January 2016 and December 2017. The skin toxicity severities and plasma zinc levels of 101 EGFR-TKI-treated cancer patients were analysed and compared with those of 43 non-EGFR-TKI-treated cancer patients and 125 patients without cancer but presenting cutaneous manifestations. Additionally, the role of zinc in erlotinib-induced skin eruptions was established in a 14-day-murine model. Clinical features were further evaluated following systemic zinc supplementation in EGFR-TKI-treated cancer patients. RESULTS: EGFR-TKI-treated patients demonstrated severe cutaneous manifestations and a significant decrease in plasma zinc levels than those of the control groups. The serum zinc level and Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading of EGFR-TKI-induced skin toxicities showed a significant negative correlation (r = -0.29; p < 0.0001). Moreover, erlotinib treatment decreased the plasma zinc levels and induced periorificial dermatitis in rats confirming zinc deficiency following EGFR-TKI treatment. Zinc supplementation to the EGFR-TKI-treated cancer patients showed a significant decrease in the CTCEA grading (p < 0.0005 for mucositis and p < 0.0.0001 for all other cases) after 8 weeks. CONCLUSIONS: Skin impairment following EGFR-TKI therapy could be ameliorated through zinc supplementation. Thus, zinc supplementation should be considered for cancer patients undergoing EGFR-TKI therapy.

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.

Electrophysiology Study for Complex Supraventricular Tachycardia in Congenital Heart Disease Patients With Single-Ventricle Physiology.

BACKGROUND: Supraventricular tachycardia (SVT) is common in complex congenital heart disease (CCHD) patients with single-ventricle physiology and may cause hemodynamic deterioration. We reported the outcomes of catheter ablation for such complex SVT in these single-ventricle CCHD patients. METHODS AND RESULTS: Patients with single-ventricle physiology (defined as CCHD patients) who received electrophysiology studies and catheter ablation between 1995 and 2015 were studied. We enrolled 30 CCHD patients (18 with right atrial isomerism, 5 with left atrial isomerism, and 7 with other CCHDs; 17 male, 13 female). The age of onset of clinical SVT was 6.7 years (±4.7 years). Electrophysiology studies and ablation were performed at age 7.1 years (±3.9 years); body weight was 20.7 kg (±10.0 kg). Twin atrioventricular nodes were present in 60% of patients (right atrial isomerism, 72.2%; left atrial isomerism, 40%; other CCHDs, 42.9%). Manifested preexcitation was noted in 10% of patients. SVT was induced in 21 patients. Twin atrioventricular nodal reentrant tachycardia was the most common (57.1%), followed by atrioventricular reentrant tachycardia (28.6%), junctional tachycardia (14.3%), and atrioventricular nodal reentrant tachycardia (9.5%). Multiple arrhythmias were common (33.3%), particularly in patients with atrioventricular reentrant tachycardia (50%). Ablation successfully eliminated SVT in 12 of 14 patients (85.7%), with a recurrence rate of 16.7% during 6 years of follow-up. CONCLUSIONS: Transcatheter ablation of complex SVT substrates, including minor atrioventricular node of twin atrioventricular nodal reentrant tachycardia, accessory pathways of atrioventricular reentrant tachycardia, and a slow pathway of atrioventricular nodal reentrant tachycardia, is effective in CCHD patients. The limitations are limited vascular access and the risk of atrioventricular block.

Pachymic acid modified carbon nanoparticles reduced angiogenesis via inhibition of MMP-3.

Angiogenesis is a process of new blood vessel generation, which is consistently and robustly correlated with tumor formation, growth, and metastasis. The disruption of angiogenesis, and the imbalanced endothelial remodeling and regression, are the main pathogenesis of malignant tumor. Recently, multi-walled nanotubes (MWNTs) have been proposed as a new tool for drug delivery in cancer treatment, which also displayed anti-angiogenic property. In the present study, we modified MWNTs with pachymic acid (PA) extracted from Heterosmilax chinensis, a traditional Chinese medicine used for cancer treatment, and compared their effects on blood vessel development. MWNTs and PA/MWNTs were evaluated for their influences on chorioallantoic membrane (CAM) vessel morphology and extracellular matrix metalloproteinase-3 (MMP-3) expression, a crucial proteinase associated with tumor metastasis. MWNTs functioned as an inhibitor of forming branch while PA was not able to promote this inhibition. Subsequently, MWNTs suppressed the endothelial cell maturation, accounting for the ceased elongation of CAM blood vessel, while PA/MWNTs increased the suppressive effect, indicating the potential roles of PA in preventing angiogenesis. PA/MWNTs also showed greater anti-angiogenic property as MMP-3 expression in CAM tissue was significantly decreased by PA/MWNTs compared to MWNTs. These results emphasize the anti-angiogenic activities of PA, supporting a new promising therapy for cancer from the perspective of traditional Chinese medicine.

National database study of survival of pediatric congenital heart disease patients in Taiwan.

BACKGROUND/PURPOSE: The incidence of congenital heart disease (CHD) and severe CHD is 13.08 and 1.51/1000 live births, respectively, in Taiwan, which has had national health insurance since 1995 and child health indices similar to those in the US. This study sought to further elucidate the fatality of CHD patients and their survival from a national database. METHODS: From the national health insurance database 2000-2010, we retrieved data from CHD patients who were diagnosed at age <6 years. The survival status at discharge was ascertained for estimation of survival. RESULTS: In total, 18,843 pediatric CHD patients were identified. The overall prevalence of CHD was 1288 per 100 000 live-births. Severe CHD (tetralogy of Fallot (4.4%), transposition of the great arteries (1.6%) and double outlet right ventricle (1.1%)) accounted for 11.5% of all cases. The 1-month/5-year survival in simple and severe CHD was 99.1%/97.5% and 90.2%/76.4%, respectively (p < 0.0001). The Kaplan-Meier survival at 5 years of age was lowest for hypoplastic left heart syndrome (19.7%), followed by transposition of the great arteries (66.7%), double outlet right ventricle (69.0%), and common ventricle (66.0%). The 5-year survival of the birth cohort in the same study period was 99.3%. CONCLUSION: This national database study revealed that the survival of children with simple CHD was still slightly lower than that of the general population and the survival of severe CHD patients, though only accounting for one-tenth of CHD cases, remained unsatisfactory. Such survival profiles are similar to those from Western reports and warrant a refined and dedicated medical care program for children with CHD.

Radiofrequency catheter ablation of supraventricular tachycardia in infants and toddlers.

BACKGROUND: The role of radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT) in infants and toddlers is still unclear. METHODS AND RESULTS: From 1993 to 2006, 27 (17 males, 10 females) of 210 patients underwent RFCA at an age less than 6 years. Indications included drug-refractory SVT or tachycardia-induced cardiomyopathy. The medical records were reviewed and the patients were interviewed regarding their current status. The 27 patients underwent RFCA at a median age of 4.4 years (8 months to 5.9 years) and a median body weight of 15 kg (6.6-30 kg). The SVT was mainly atrioventricular reentry tachycardia (15/27) and multiple mechanisms in 3. One-third of them had associated congenital heart disease, and 5 underwent RFCA using only 2-3 catheters. Immediate success rate was 92.6%, with low early (3.7%) and late recurrence (7.4%) after 5.4 +/-3.7 years follow-up. Tachycardia-induced cardiomyopathy was noted in 4 and resolved in all after RFCA. Procedure-related complications included complete atrioventricular block in 1 and Bezold-Jarisch reflex in another. No other risk factors for outcomes were noted, even with low body weight. CONCLUSIONS: The outcome of RFCA for medically refractory SVT, even associated with tachycardia-induced cardiomyopathy, in infants and toddlers is favorable.