Skin disorder management in oral anticancer drugs by collaboration of hospital pharmacists and community pharmacists.

BACKGROUND: In Japan, the multidisciplinary team approach in cancer chemotherapy has become quite widespread. However, patients treated with oral anticancer drugs in outpatient clinics usually receive short medical examinations from doctors without any intervention of pharmacists. To improve this medical circumstance, we made a skin disorder manual for community pharmacists and evaluated its feasibility. METHODS: Patients who underwent oral skin toxic chemotherapy from May 1, 2017, to October 31, 2017, were enrolled. The severity of skin toxicities was evaluated based on NCI-CTCAE ver4.0. Skin care and skin disorders were assessed by community pharmacists based on the assessment document arranged by the investigator. Numbers of patients who replied to the assessment, numbers of replies, numbers of assessments and instructions for skin care, and numbers of prescription proposals were evaluated to assess the value of intervention of community pharmacists. RESULTS: Sixty-two patients were enrolled in this study. Community pharmacy responded to 55 patients (88.7%), for a total of 335 replies. The data described in the replies were as follows: 317 assessments of skin disorders (94.6%), 307 assessments of skin care (91.6%), 248 instructions for skin care (74%), and 19 prescription proposals (5.7%). CONCLUSIONS: Community pharmacists have high motivation for prevention and early detection of skin disorders. Although the number of prescription proposals is small, some proposals have contributed to improving side effects. Collaboration of hospital pharmacists and community pharmacists is important for prevention, early detection, and treatment of skin disorders caused by oral anticancer drugs.

Hand Foot Syndrome Has the Strongest Impact on QOL in Skin Toxicities of Chemotherapy.

Background: Chemotherapy often results in dermatologic toxicities, which decrease quality of life (QOL) of cancer patients. These adverse skin reactions sometimes happen simultaneously. Though previous reports have demonstrated that skin reactions influence QOL, those reports were focused on only one kind of skin toxicity or on the most serious skin toxicity. The aim of this study is to demonstrate the contribution of each skin toxicity to QOL. Methods: This is a cross-sectional study at Kinki Central Hospital. Patients were enrolled who underwent skin toxic chemotherapy from April 1 to June 30, 2017. DLQI and Skindex29 were used to grade the QOL of patients. Also, the severity of skin toxicities was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE ver4.0). We investigated how QOL changed with patient demographic and clinical characteristics, the worst skin toxicity grade, and each skin toxicity using statistical analyses. Results: No significant differences were detected between QOL scores (total score of DLQI, emotions domain, symptoms domain, functioning domain and total score of Skindex29) and patient demographic and clinical characteristics (P values were 0.155, 0.086, 0.052, 0.312 and 0.114, respectively). There were statistically significant QOL differences among the grades of the worst skin toxicity (P values were <0.001). Xerosis, paronycia, pigmentation, and hand foot syndrome showed statistically significant associations with some QOL domains analyzed by multiple logistic regression analyses adjusted by demographic characteristics. When adjusted by both demographic characteristics and other skin toxicities, three of xerosis, paronycia, and pigmentation showed no statistically significant associations, but hand foot syndrome showed statistically significant associations in all subdomains and total score of Skindex29 (P values were <0.05). Conclusions: Hand foot syndrome was a stronger factor in decreasing QOL than xerosis, paronychia, pigmentation, or rash. Therefore, especially in hand foot syndrome, prevention, early detection, and daily medical care are necessary to maintain QOL.

Mesenchymal to Epithelial Transition Induced by Reprogramming Factors Attenuates the Malignancy of Cancer Cells.

Epithelial to mesenchymal transition (EMT) is a biological process of metastatic cancer. However, an effective anticancer therapy that directly targets the EMT program has not yet been discovered. Recent studies have indicated that mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is observed in fibroblasts during the generation of induced pluripotent stem cells. In the present study, we investigated the effects of reprogramming factors (RFs) on squamous cell carcinoma (SCC) cells. RFs-introduced cancer cells (RICs) demonstrated the enhanced epithelial characteristics in morphology with altered expression of mRNA and microRNAs. The motility and invasive activities of RICs in vitro were significantly reduced. Furthermore, xenografts of RICs exhibited no lymph node metastasis, whereas metastasis was detected in parental SCC-inoculated mice. Thus, we concluded that RICs regained epithelial properties through MET and showed reduced cancer malignancy in vitro and in vivo. Therefore, the understanding of the MET process in cancer cells by introduction of RFs may lead to the designing of a novel anticancer strategy.

Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation.

BACKGROUND: Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling. OBJECTIVE: The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia. METHODS: K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia. RESULTS: Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment. CONCLUSION: These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.

GPHR-dependent functions of the Golgi apparatus are essential for the formation of lamellar granules and the skin barrier.

The lumen of the Golgi apparatus is regulated to be weakly acidic, which is critical for its functions. The Golgi pH regulator (GPHR) is an anion channel essential for normal acidification of the Golgi apparatus, and is therefore required for its functions. The Golgi apparatus has been thought to be the origin of lamellar granules in the skin. To study the functional role(s) of GPHR in the skin, we established keratinocyte-specific GPHR-knockout mice using the Cre-loxP system. These mutant mice exhibited hypopigmented skin, hair loss, and scaliness. Histological examination of GPHR-knockout mice showed ballooning of the basal cells and follicular dysplasia. In addition, inflammatory cells were seen in the dermis. The expression of trans-Golgi network 46, a marker for lamellar bodies, and kallikrein 7, a protein within lamellar bodies, is diminished in GPHR-knockout mouse skin. Examination by electron microscopy revealed that keratinocytes produced aberrant lamellar bodies. The transepidermal water loss of these knockout mice was increased compared with wild-type mice. Moreover, expression of cathelicidin-related antimicrobial peptide (CRAMP) in the skin was diminished. These results suggest that GPHR is essential for the homeostasis of the epidermis including the formation of lamellar bodies and for the barrier function.

The role of pigment epithelium-derived factor as an adipokine in psoriasis.

Pigment epithelium-derived factor (PEDF), first purified from the conditioned medium of human retinal pigment epithelial cells, has been shown to be a highly effective inhibitor of angiogenesis. A recent study showed that PEDF is also a novel adipokine secreted mainly by adipocytes. Psoriasis has been shown to be associated with metabolic syndrome (MS) and some adipokines. Since PEDF levels were reported to be elevated in the serum of patients with MS, we examined PEDF levels in the serum of psoriasis patients and studied the relationships between PEDF levels and other cytokines. Circulating levels of PEDF were significantly elevated in the sera of psoriasis patients compared to normal controls. PEDF levels were highly negatively associated with TNF-α levels in normal controls. Furthermore, the association between PEDF and TNF-α had a negative correlation in psoriasis patients although not statistically significant. These data suggest that PEDF may be elevated as an anti-inflammatory system in patients with psoriasis.

Blue nevus with a starburst pattern on dermoscopy.

An 11-year-old girl presented to our department with a blue-gray papule approximately 4 mm in diameter. We suspected that it was a blue nevus or a pigmented Reed/Spitz nevus. On dermoscopic observation, the lesion showed homogeneous black-bluish pigmentation. This dermoscopic feature was suggestive of a blue nevus. However, near-circumferential streaks and a global feature of a "starburst pattern" were also observed, as is often found in a Reed/Spitz nevus. The lesion was excised and histological examination revealed spindle cells with melanin pigments diffusely present in the upper dermis and around hair follicles in the mid-dermis, but not in the epidermis. The melanocytic cells were arranged in a symmetrical wedge-shaped configuration. In addition, there was a diffuse fibrosis. Finally, we made a diagnosis of a blue nevus based on these findings.

Safety and effectiveness of a new enzyme-targeting radiosensitization treatment (KORTUC II) for intratumoral injection for low-LET radioresistant tumors.

Linear accelerator-based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and most locally-advanced neoplasms that have grown to several centimeters or more. These tumors contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low linear energy transfer radiation. Therefore, it was necessary to develop a new radiosensitizer to overcome these situations. We previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which uses 3% w/v hydrogen peroxide solution-soaked gauze. We developed a new radiosensitizer for intratumoral injection (KORTUC II), comprising a combination of hydrogen peroxide and sodium hyaluronate. After providing a fully informed written consent, 52 patients with unresectable or recurrent neoplasms (53 lesions) were enrolled in the KORTUC II trial. The present study of 52 patients with unresectable or recurrent neoplasms showed that KORTUC II is safe when injected intratumorally, well tolerated, and can efficiently exert a radiation sensitizing effect. Because this radiosensitizer is safe and less expensive than other methods, and can be applied for almost every type of low-LET radio-resistant neoplasm, it has potential for worldwide and immediate use.

Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients.

Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome (MS). Psoriasis patients have a high prevalence of the MS. In this study, we investigated the statistics of circulating Th17-related cytokines and adipokines in psoriasis patients. Our study identified the significant elevation of serum IL-6, IL-21, IL-22, and resistin levels in psoriasis patients. Increased serum levels of IL-22 and adiponectin were positively correlated with Psoriasis Area and Severity Index (PASI). In contrast, serum high molecular weight adiponectin levels were decreased in psoriasis and negatively correlated with PASI.

Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.

Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti-IL-12/23p40 or anti-IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti-IL-17A Ab was relatively less prominent. Treatment with anti-IL-12/23p40 or anti-IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), ß-defensins, and S100A family members in skin lesions. However, anti-IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A-deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate-induced lesions, which were further attenuated by anti-IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22-producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.