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.

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.

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.

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.

Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma.

The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer.

Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis.

Recent studies suggest that some serous ovarian carcinomas (SOCs) arise from the fallopian tube (FT) epithelium rather than the ovarian surface epithelium. This hypothesis places emphasis on the FT secretory epithelial cell as a cell-of-origin. Herein, we report the development of a novel ex vivo primary human FT epithelium culture system that faithfully recapitulates the in vivo epithelium, as shown by morphological, ultrastructural and immunophenotypic analyses. Mass spectrometry-based proteomics reveal that these cultures secrete proteins previously identified as biomarkers for ovarian cancer. We also use this culture system to study the response of the FT epithelium to genotoxic stress and find that the secretory cells exhibit a distinct response to DNA damage when compared with neighboring ciliated cells. The secretory cells show a limited ability to resolve the damage over time, potentially leaving them more susceptible to accumulation of additional mutagenic injury. This divergent response is confirmed with in situ studies using tissue samples, further supporting the use of this ex vivo culture system to investigate FT epithelial pathobiology. We anticipate that this novel culture system will facilitate the study of SOC pathogenesis, and propose that similar culture systems could be developed for other organ site-specific epithelia.

Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model.

Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.

Use of human amniotic membrane wrap in reducing perineural adhesions in a rabbit model of ulnar nerve neurorrhaphy.

The object of this experimental study was to assess the effect of wrapping human amniotic membrane around a repaired ulnar nerve in a rabbit model of perineural adhesion. Ulnar nerves from 10 white New Zealand rabbits were exposed bilaterally, dissected and repaired. Human amniotic membrane was then wrapped around the repair site in one limb with no such wrap in the neurorrhaphy of the contralateral limb. Three months later, the same nerves were re-explored and removed using microsurgical external neurolysis. Perineural adhesion around the ulnar nerve was evaluated by blinded surgical dissection and scored using a visual 4-point qualitative scale. Extent and grade of fibrosis around repair sites were measured microscopically (x 200) after Masson trichrome staining using measure of the depth of fibrosis and the grading criteria of adhesion. Quantitative morphometric analysis was also performed under light microscopy (x 200) with the aid of a digital counter and virtual slide imaging software (ScanScope T2, Vista, CA, USA). Human amniotic membrane wrapped nerves showed significantly less perineural adhesion and fibrosis than controls (P < 0.05). No nerve healing problems were encountered. This study suggests that human amniotic membrane application can reduce fibrosis and adhesion around neurorrhaphy sites in this animal model.

Syndecan-1 expression in gallbladder cancer and its prognostic significance.

AIM: To determine whether the immunohistochemical detection of syndecan-1 could provide useful information as a novel therapeutic or prognostic factor in primary gallbladder (GB) cancer. MATERIALS AND METHODS: Forty-three GB cancer tissues were evaluated by immunohistochemistry for syndecan-1 expression. The relationship between syndecan-1 expression and clinicopathological characteristics, and the univariate survival analysis for the influence of the syndecan-1 expression on the overall survival were analysed. RESULTS: Epithelial syndecan-1 immunoreactivity was observed in 25 (58.1%) of the 43 GB cancer cases. The tumors with a positive syndecan-1 expression more frequently showed lymph node metastasis (p = 0.037). Although there was no statistically significant association, the tumors with a positive syndecan-1 expression tended to show a deeper invasion depth (p = 0.087) and more frequent lymphovascular invasion (p = 0.064). The Kaplan-Meier survival curves demonstrated that patients with positive syndecan-1 expression had a significantly shorter survival time than those patients with negative syndecan-1 expression (p = 0.05). CONCLUSIONS: A subset of GB cancers revealed an epithelial overexpression of syndecan-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, epithelial syndecan-1 expression may be a predictor for a poor prognosis in patients with GB cancer.

Acute generalized exanthematous pustulosis as a manifestation of carbamazepine hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome (AHS) is a multisystemic disorder involving cutaneous changes and typical blood abnormalities that can be triggered by aromatic anticonvulsant drugs.The syndrome is commonly associated with a macular or papular rash or erythroderma. Acute generalized exanthematous pustulosis is a very rare cutaneous manifestation of AHS. A 41-year-old man was referred to our hospital for evaluation of a 3-day history of fever, leukocytosis, and generalized skin eruption. The patient had been taking carbamazepine for 1 month to treat hand tremor following surgery for intracerebral hemorrhage. Physical examination revealed facial edema and a large number of variable-sized pustules covering the body. Initial laboratory testing showed peripheral blood eosinophilia and abnormal liver function.A biopsy of pustular lesions revealed intraepidermal pustules, with perivascular lymphocytic infiltration. The skin lesions and laboratory results improved after withdrawal of carbamazepine and treatment with oral corticosteroids.