Mohs micrographic surgery for dermatofibrosarcoma protuberans: comparison of frozen and paraffin techniques.

BACKGROUND: Due to the propensity for local recurrence, Mohs micrographic surgery (MMS) has been suggested for the treatment of dermatofibrosarcoma protuberans (DFSP) and it has shown improved clinical outcomes. Recently, some authors suggested that MMS using paraffin-embedded sections (paraffin MMS) is superior in DFSP treatment compared with the conventional frozen MMS method. However, there have been no studies comparing frozen and paraffin MMS for the treatment of DFSP. OBJECTIVES: To compare the outcomes between DFSP patients who underwent frozen MMS and paraffin MMS. METHODS: Seventy-one DFSP patients treated with frozen MMS (n = 30) or paraffin MMS (n = 41) from 2003 to 2017 at a single institution were retrospectively reviewed. Recurrence rate and recurrence-free survival between frozen and paraffin MMS were assessed. RESULTS: During the mean follow-up duration of 25.4 months, four patients (frozen MMS, n = 1; and paraffin MMS, n = 3) showed recurrence after MMS. Although the local recurrence rate of the frozen MMS group (3.3%) was lower than that of the paraffin MMS group (7.3%), the difference was not statistically significant. In addition, recurrence-free survival was not significantly different between the two groups (P = 0.168). CONCLUSIONS: Frozen MMS, which has the advantages of shorter surgery time and immediate closure, is as effective as paraffin MMS in the treatment of DFSP.

Drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare disease which can cause severe morbidity and mortality. The aim of this study is to evaluate the clinical manifestation and course of DRESS syndrome. METHODS: We conducted a retrospective analysis of prospectively collected data in 45 patients with DRESS syndrome diagnosed between September 2009 and August 2011. RESULTS: The most common causative drug group was antibiotics (n=13, 28.9%), followed by anticonvulsants (n=12, 26.7%), antituberculosis drugs (n=6, 13.3%), non-steroidal anti-inflammatory drugs (n=4, 8.9%), undetermined agents (n=4, 8.9%), allopurinol (n=3, 6.7%), and others (n=3, 6.7%). The latency period ranged from 2 to 120 days, with a mean of 20.2 ± 24.3 days. The longest latency period was noted for the antituberculosis drug group, at 46.5 ± 29.9 days. Eosinophilia in peripheral blood examination was noted in 35 subjects (77.8%). Atypical lymphocytosis was noted in 16 patients (35.6%), and thrombocytopenia in seven patients (15.6%). Hepatic involvement was noted in 39 (86.7%) study patients, kidney in eight (17.8%), lung in four (8.9%), and central nervous system in one (2.3%). Systemic corticosteroids were administered to 10 patients (22.2%). Forty-three patients (95.6%) showed complete recovery, while two patients had poor outcomes. CONCLUSIONS: DRESS syndrome was not more uncommon than generally recognised. Antibiotics were the most frequently implicated drug group, followed by anticonvulsants. Most patients with this disease showed a better clinical outcome than that which had been generally expected.

FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis.

Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.

Uncertain areas in the diagnosis of allergic bronchopulmonary aspergillosis in patients with asthma.

BACKGROUND AND OBJECTIVE: The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with bronchial asthma remains unknown. We evaluated the roles of various laboratory tests in the diagnosis of ABPA, including, skin prick test (SPT) for Aspergillus fumigatus (Af), and serum Af specific IgE and IgG antibody measurement. METHODS: A total of 50 asthma patients with more than 1000cell/µL of peripheral blood eosinophils were prospectively collected between January 2007 and September 2011. Evaluations using SPT for Af, serum total IgE and specific IgE antibody to Af by CAP system, IgG antibody to Af by enzyme immunoassay (EIA) or CAP system were performed according to the essential minimal criteria for the diagnosis of ABPA - asthma, immediate cutaneous reactivity to Af, elevated total IgE, and raised Af specific IgE and IgG. RESULTS: Among 50 patients, three patients (6.0%) were diagnosed as ABPA, of whom each confirmed five items of the essential minimal diagnostic criteria for the diagnosis of ABPA. Six patients (12.0%) showed negative responses to Af in SPT, but positive responses in specific IgE by CAP system. Eight patients (16.0%) showed negative responses to IgG to Af by CAP system, but positive responses by enzyme immunoassay (EIA). CONCLUSIONS: SPT and serum IgE to Af measurement by CAP system should be performed simultaneously. It is reasonable to set up cut-off values in Af specific IgE/IgG by CAP system for the differentiation of ABPA from Af sensitised asthma patients.

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration.

There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

The impact of dermatological toxicities of anti-cancer therapy on the dermatological quality of life of cancer patients.

BACKGROUND: One of the most common side effects of anti-cancer therapies is treatment-induced skin changes, referred to as dermatological toxicities. These dermatological toxicities are noteworthy since they have a negative association with quality of life (QoL). OBJECTIVES: To evaluate the impact of dermatological toxicities on QoL of cancer patients and to identify the relationship between disease-related characteristics and QoL and changes in skin protective behaviours following anti-cancer therapy. METHODS: Cancer patients (n = 80: stage II-IV) in a longitudinal prospective study completed a battery of questionnaires at the time of enrolment and after 3 months of anti-cancer therapy. QoL, skin toxicities, smoking and drinking behaviour, sun-protective and skin care behaviour assessments were performed before and at 3 months after anti-cancer therapy. QoL was measured with the Dermatology Life Quality Index (DLQI). RESULTS: A total of 73 patients completed the study. Among them, 48 patients (65.8%) experienced at least grade 1 skin toxicity at 3 months after anti-cancer therapy. Hair loss, hyperpigmentation and dry skin were the most common dermatological toxicities. The mean baseline DLQI score changed from 1.38 to 3.49 at 3 months after anti-cancer therapy. Domain 1 (symptoms and feelings, 1.38 points) was the most greatly impacted among patients by anti-cancer treatment. Patients who experienced at least grade 1 skin toxicity (P = 0.001, 95% CI: 1.939-4.899), employed (P = 0.042, 95% CI: 0.030-1.476), more highly educated (P = 0.030, 95% CI: 0.161-3.132), and diagnosed with gastric cancer (P = 0.001, 95% CI: 2.141-8.250) or renal cell cancer (P = 0.002, 95% CI: 2.731-11.364) showed significantly higher DLQI scores. Patients showed significant change in skin protective behaviour such as use of body moisturizer (P = 0.021) and change in drinking behaviour (P = 0.006) at 3 months following anti-cancer therapy. CONCLUSION: Dermatological toxicities due to anti-cancer therapy affect the QoL of cancer patients. Therefore, health care professionals should pay attention to the psychological effects of skin problems and educate cancer patients to adapt proactive skin protective behaviours to minimize dermatological toxicities of anti-cancer therapy and maximize QoL.

The prevalence of metabolic syndrome and its association with alanine aminotransferase in clozapine-treated Korean patients with schizophrenia.

Widely ranging prevalence rates for metabolic syndrome (MetS) in patients taking clozapine have been reported on the basis of various criteria, and most studies have been carried out in non-Asian countries. Therefore, we examined the prevalence of MetS in Korean patients using three commonly applied criteria with two waist-circumference cutoff values. The indirectly standardized prevalence ratio (ISPR) was estimated using data from the Fourth Korean National Health and Nutrition Examination Survey (KNHNES, 2007) to compare the prevalence of MetS in patients with that in the general population. In addition, we also examined whether serum alanine aminotransferase (ALT) and aspartate aminotransferase levels serve as biochemical markers for the identification of MetS. We reviewed the electromedical records of patients with schizophrenia who had taken clozapine as the sole antipsychotic for 3 months or more. The prevalence of MetS ranged from 34.5 to 46.9%, and the ISPR ranged from 2.4 to 2.8, given the three definitions of MetS and the two waist-circumference cutoff points for women. The ISPR for MetS among those aged 18-30 years was the highest and decreased with age in both men and women. After adjusting for age, patients with normal serum ALT levels who were in the top third were significantly more likely to have MetS compared with those who were in the bottom third. Logistic regression analysis showed that serum ALT levels and use of antidepressants were significantly related to the presence of MetS. Korean patients with schizophrenia who were receiving clozapine as the sole antipsychotic showed a high prevalence of MetS. Although we found substantial differences in the prevalence according to criteria, the ISPR indicated significantly higher rates of MetS in this group than in the general population. In the general population, younger patients had a much higher risk for MetS than older patients. Elevated levels of serum ALT that were in the normal range were associated with the presence of MetS, which suggests the possibility of using serum ALT level as an early indicator for MetS in patients treated with clozapine.

Clinical characteristics and risk of melanoma development from giant congenital melanocytic naevi in Korea: a nationwide retrospective study.

BACKGROUND: Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated. OBJECTIVES: To evaluate the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥5% body surface area in children or measuring ≥20cm in adults. METHODS: In total, 131 patients with GCMN were enrolled, with a mean age of 10·3years (range: birth-70years). RESULTS: The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients <4years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6-year-old girl, a 14-year-old girl and a 70-year-old man), and the incidence rate was 990 per 100000 person-years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma. CONCLUSIONS: We should be aware of melanoma development from GCMN, and lifelong follow-up is required due to the risk of melanoma arising in GCMN.

Topical niacin cream-assisted 595-nm pulsed-dye laser treatment for facial flushing: retrospective analysis of 25 Korean patients.

BACKGROUND: Flushing is defined clinically as a transient reddening of the face and other areas. Due to the transient nature of flushing, a patient may not show signs of flushing during laser treatment. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of 595-nm pulsed-dye laser treatment of flushing or erythema after provocation of flushing by topical niacin cream. METHODS: We retrospectively reviewed a total of 25 Korean patients with facial flushing who were treated with three sessions of 595-nm pulsed-dye laser after the application of topical niacin cream. RESULTS: Follow-up results revealed that 12 of the 25 patients demonstrated marked (51-75%) clinical improvement of baseline facial erythema. Eight patients had moderate (26-50%) improvement and three demonstrated near total (≥ 75%) improvement. Two patients showed minimal to no (0-25%) improvement. We observed that the reactivity to topical niacin cream was markedly reduced in 64% of our patients after 595-nm pulsed-dye laser treatments. Minimal post-therapy facial oedema was noted in most of the patients, which usually resolved spontaneously within 2 days. Pronounced facial swelling was observed in four patients. CONCLUSION: We suggest that 595-nm pulsed-dye laser treatment after provocation of flushing by topical niacin cream may provide a new treatment algorithm for facial flushing in Asians.

A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53.

Human tumors are heterogeneous and evolve through a dynamic process of genetic mutation and selection. During this process, the effects of a specific mutation on the incipient cancer cell may dictate the nature of subsequent mutations that can be tolerated or selected for, affecting the rate at which subsequent mutations occur. Here we have used a new mouse model of prostate cancer that recapitulates several salient features of the human disease to examine the relative rates in which the remaining wild-type alleles of Pten and p53 tumor suppressor genes are lost. In this model, focal overexpression of c-MYC in a few prostate luminal epithelial cells provokes a mild proliferative response. In the context of compound Pten/p53 heterozygosity, c-MYC-initiated cells progress to prostatic intraepithelial neoplasia (mPIN) and adenocarcinoma lesions with marked heterogeneity within the same prostate glands. Using laser capture microdissection and gene copy number analyses, we found that the frequency of Pten loss was significantly higher than that of p53 loss in mPIN but not invasive carcinoma lesions. c-MYC overexpression, unlike Pten loss, did not activate the p53 pathway in transgenic mouse prostate cells, explaining the lack of selective pressure to lose p53 in the c-MYC-overexpressing cells. This model of heterogeneous prostate cancer based on alterations in genes relevant to the human disease may be useful for understanding pathogenesis of the disease and testing new therapeutic agents.

Pim1 kinase is required to maintain tumorigenicity in MYC-expressing prostate cancer cells.

PIM1 kinase and MYC are commonly co-expressed in human prostate cancer and synergize to induce rapidly progressing prostate cancer in mouse models. Deficiency of the Pim kinase genes is well tolerated in vivo, suggesting that PIM1 inhibition might offer an attractive therapeutic modality for prostate cancer, particularly for MYC-expressing tumors. Here we examine the molecular consequences of Pim1 and MYC overexpression in the prostate as well as the effects of depleting Pim1 in prostate carcinoma cells with high levels of MYC. Overexpression of Pim1 in the mouse prostate induces several pro-tumorigenic genetic programs including cell cycle genes and Myc-regulated genes before the induction of any discernible pathology. Pim1 depletion by RNA interference in mouse and human prostate cancer cells decreased cellular proliferation, survival, Erk signaling and tumorigenicity even when MYC levels were not significantly altered. These results indicate that PIM1 may be necessary to maintain tumorigenicity, and further support efforts aimed at developing PIM1 inhibitors for prostate cancer therapy.

Mohs' micrographic surgery for dermatofibrosarcoma protuberans.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare soft-tissue tumour with a high local recurrence rate. Recent reports indicate more favourable cure rates with Mohs' micrographic surgery (MMS). AIM: To investigate the beneficial use of MMS for DFSP in a single institution in Korea. METHODS: A retrospective review was performed of pertinent demographic data, tumour data, treatment characteristics and follow-up data of 11 patients between 1997 and 2007. A review of literature for treatment methods and recurrence rates of DFSP was also performed. RESULTS: In total, 11 patients (7 female, 4 male; mean age 26.9 years, range 3-36) with DFSP were identified and analysed. A mean number of 1.8 MMS layers were required to clear the tumour. All tumours were excised and reconstructed by the surgeon. There were no identifiable recurrences in the follow-up period of an average of 26 months. CONCLUSIONS: Treatment of primary and recurrent DFSP by MMS results in a low recurrence rate with possible benefits of smaller defects compared with wide local excision. This study provides further support for MMS as the treatment of choice for DFSP.