Metastatic Skin Cancer Research Articles

Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling.

Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

Abstract 982: Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity

Abstract Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long non-coding RNAs (lncRNAs) are involved in various biological processes, and their role in cancer progression is emerging. The aim of this study was to find and characterize new biomarkers for evaluating the risk of progression and metastasis of cSCC and identify novel therapeutic targets for recurrent and metastatic cSCC. RNA-sequencing of cSCC cells (n = 8) and normal human epidermal keratinocytes (NHEKs, n = 4) revealed overexpression of a previously uncharacterized long intergenic non-coding RNA (lincRNA), LINC00162 in cSCC cells. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ MAPKs using BIRB796 or p38α and p38δ specific siRNAs. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited ERK1/2 activity and upregulated expression of dual specificity phosphatase DUSP6 in cSCC cells. Based on these observations, LINC00162 was named PICSAR (P38 Inhibited Cutaneous Squamous cell carcinoma Associated lincRNA). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of ERK1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a novel biomarker and putative therapeutic target in cSCC. Citation Format: Minna Piipponen, Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä, Atte Kivisaari, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kähäri. Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 982.

New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma.

Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing worldwide. Solar UV radiation is an important risk factor for cSCC and leads to genetic and epigenetic changes both in epidermal keratinocytes and dermal cells. Tumor cells in cutaneous cSCCs typically harbor several driver gene mutations, but epidermal keratinocytes in sun-exposed normal skin also contain mutations in these same genes. Therefore, alterations in the microenvironment of premalignant lesions are evidently required for their progression to invasive and metastatic cSCC. For example, alterations in the composition of basement membrane and dermal extracellular matrix are early events in cSCC progression. The presence of microbial structures and the influx of inflammatory cells promote the secretion of proteases, which in turn regulate the availability of growth factors, cytokines, and chemokines and thus influence the growth and invasion of cSCC. Together, these observations emphasize the role of the tumor microenvironment in the progression of cSCC and identify it as a novel therapeutic target in cSCC and other malignant tumors. Graphical abstract Tumor-stroma interactions in the progression of cutaneous squamous cell carcinoma (cSCC). Epidermal layer is separated by a well-organized basement membrane (BM) from the dermal layer. UV radiation, other environmental insults, and aging target both epidermal keratinocytes and dermal fibroblasts and lead to genetic and epigenetic changes in these cells. In addition, epidermal keratinocytes in normal sun-exposed skin harbor several mutations in the cSCC driver genes. During transition to premalignant actinic keratosis (AK), the differentiation of keratinocytes is disturbed resulting in a neoplastic epithelium with hyperplastic cells. Expression of proteinases, such as matrix metalloproteinases (MMP) by neoplastic cells and activated stromal fibroblasts and macrophages is induced in AK, and collagen XV and XVIII are lost from the dermal BM. Furthermore, inflammatory cells accumulate at the site of the hyperplastic epithelium. During a later stage of cSCC progression, the number of inflammatory cells increases, and the expression of complement components and inhibitors by tumor cells is induced (CFI complement factor I, CFH complement factor H, FHL-1 Factor H-like protein 1). In addition to MMPs, activated fibroblasts also produce growth factors and promote inflammation, growth, and invasion of tumor cells.

103 Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. Long non-coding RNAs (lncRNAs) are involved in various biological processes and their role in cancer progression is emerging. We have studied the role of lncRNAs in the progression of cSCC. Whole transcriptome analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=4) revealed marked upregulation of a specific long intergenic ncRNA, LINC00162, in cSCC cells. Expression of LINC00162 in tissue sections representing different stages of epidermal carcinogenesis, i.e. normal skin (n=9), actinic keratosis (AK) (n=26), cSCCs in situ (cSCCIS) (n=20), and invasive cSCCs (n=21) was analyzed by RNA in situ hybridization. Expression of LINC00162 was detected in tumor cells in cSCC, cSCCIS and AK, whereas no signal was detected in normal skin. Analysis of the LINC00162 positive tissue sections revealed that the number of positive sections increased with the progression from AK (23%) to cSCCIS (35%) and cSCC (43%). The expression of LINC00162 in cSCC cells was upregulated by inhibition of p38α and p38δ MAPKs. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00162 inhibited ERK1/2 activity and upregulated expression of dual specificity phosphatase DUSP6 in cSCC cells. Based on these observations, LINC00162 was named PICSAR (P38 Inhibited Cutaneous Squamous cell carcinoma Associated lincRNA). These results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of ERK1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a novel biomarker and putative therapeutic target in unresectable and metastatic cSCC.

Long Noncoding RNA PICSAR Promotes Growth of Cutaneous Squamous Cell Carcinoma by Regulating ERK1/2 Activity

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long noncoding RNAs (lncRNA) are involved in various biological processes, and their role in cancer progression is emerging. Whole transcriptome analysis of cSCC cells (n= 8) and normal human epidermal keratinocytes (n= 4) revealed overexpression of long intergenic ncRNA (LINC00162) in cSCC cells. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ mitogen-activated protein kinases. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin invivo. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth ofhuman cSCC xenografts invivo. Furthermore, knockdown of LINC00162 inhibited extracellular signal-regulated kinase 1/2 activity and upregulated expression of dual specificity phosphatase 6 (DUSP6) in cSCC cells. Based on these observations, LINC00162 was named p38 inhibited cutaneous squamous cell carcinoma associated lincRNA (PICSAR). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of extracellular signal-regulated kinase 1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a biomarker and putative therapeutic target incSCC.

Micellar electrokinetic chromatographic method for the dabrafenib determination in biological samples.

Two different micellar electrokinetic chromatographic methods to determine dabrafenib in urine and serum, both using borate buffer (pH 9.2, 20mM) and SDS as separation electrolyte, are developed and validated. The analyses were carried out in a fused-silica capillary of 75μm of internal diameter and total length of 47 and 37cm for urine and serum determination, respectively. The detection of the target compound was performed at 227nm in urine samples and at 251nm in serum samples. The linearity range was from 1 to 21mg/L of dabrafenib in urine and from 2 to 40mg/L in serum. In all cases, inter- and intraday RSDs were <4%. Sample preparation of serum samples consists of an only step of 1:1 dilution with water before its injection in the electrophoretic system. These simple, sensitive, accurate, and cost-effective methods can be used in routine clinical practice to monitor dabrafenib concentrations in urine and serum of metastatic melanoma skin cancer patients.

Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models.

Melanoma is a severe metastatic skin cancer with poor prognosis and no effective treatment. Therefore, novel therapeutic approaches using nanotechnology have been proposed to improve therapeutic effectiveness. Lipid-core nanocapsules (LNCs), prepared with poly(ε-caprolactone), capric/caprylic triglyceride, and sorbitan monostearate and stabilized by polysorbate 80, are efficient as drug delivery systems. Here, we investigated the effects of acetyleugenol-loaded LNC (AcE-LNC) on human SK-Mel-28 melanoma cells and its therapeutic efficacies on melanoma induced by B16F10 in C57B6 mice. LNC and AcE-LNC had z-average diameters and zeta potential close to 210 nm and -10.0 mV, respectively. CytoViva® microscopy images showed that LNC and AcE-LNC penetrated into SK-Mel-28 cells, and remained in the cytoplasm. AcE-LNC in vitro treatment (18–90×109 particles/mL; 1 hour) induced late apoptosis and necrosis; LNC and AcE-LNC (3–18×109 particles/mL; 48 hours) treatments reduced cell proliferation and delayed the cell cycle. Elevated levels of nitric oxide were found in supernatant of LNC and AcE-LNC, which were not dependent on nitric oxide synthase expressions. Daily intraperitoneal or oral treatment (days 3–10 after tumor injection) with LNC or AcE-LNC (1×1012 particles/day), but not with AcE (50 mg/kg/day, same dose as AcE-LNC), reduced the volume of the tumor; nevertheless, intraperitoneal treatment caused toxicity. Oral LNC treatment was more efficient than AcE-LNC treatment. Moreover, oral treatment with nonencapsulated capric/caprylic triglyceride did not inhibit tumor development, implying that nanocapsule supramolecular structure is important to the therapeutic effects. Together, data herein presented highlight the relevance of the supramolecular structure of LNCs to toxicity on SK-Mel-28 cells and to the therapeutic efficacy on melanoma development in mice, conferring novel therapeutic mechanisms to LNC further than a drug delivery system.

New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer.

Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.

Update on the Use and Treatment of Targeted Molecular Inhibitors for Locally Advanced and Metastatic Non-Melanoma Skin Cancers.

Targeting specific molecular pathway inhibitors has provided a successful approach to the management of selected patients with advanced non-melanoma skin cancer (NMSC). Clinical trials and case studies have provided a rationale for their use in clinical settings. To review the current approaches to the use of targeted molecular inhibitors for locally advanced and metastatic squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans. Literature review of the current use of molecular inhibitors in the treatment of NMSCs, including case studies, reports, and clinical trials. The development of molecular pathway inhibitors for the treatment of advanced and metastatic NMSC has increased survival rates and improved clinical outcomes in selected patients with advanced disease.

Role of the Medical Oncologist in the Management of Skin Cancer

Management of high-risk, recurrent, and metastatic skin cancers often requires a multi-modality, multi-disciplinary approach, with involvement of medical specialists in the fields of dermatology, surgical oncology, radiation oncology, and medical oncology. Medical oncologists typically treat skin cancers that have failed local therapies such as surgery or radiation and routinely manage metastatic skin cancers including melanoma, basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma. Here, we highlight the decision-making strategies employed by the medical oncologist in the management of high-risk and metastatic skin cancers and review the pertinent evidence for choice of systemic therapy.

Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas.

Refractory locally advanced or metastatic nonmelanoma skin cancer (NMSC) is a frequent therapeutic impasse. To address the question of the efficacy of induction therapy with cetuximab as neoadjuvant treatment for locally advanced NMSC. From 2008 to 2013, all patients with a diagnosis of unresectable locally advanced skin squamous cell carcinoma were treated with neoadjuvant cetuximab alone (CM) or combined with a platinum salt and 5-fluorouracil (CC). Resectability, and clinical and pathological response, as well as relapse-free and overall survival were evaluated. Thirty-four patients, with a median age of 74·5years, were evaluated. Twenty-five patients received CC. After three cycles of CC, 23 of 25 patients whose tumours were initially unresectable became amenable to surgery (92%). A complete histological response was observed in 15 (65%) patients. The mean progression-free and mean overall survival in operated patients were 8·5 and 26·0months, respectively. There was a good response in terms of resectability and tumour control in the majority of patients, with few relapses, despite the initially poor prognosis of these tumours in this elderly group of patients. However, this therapeutic strategy needs to be validated in a prospective, randomized study.

Abstract 3201: Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. We have examined the role of complement component C3 and complement factor B (CFB) in the progression of cSCC. Significantly elevated mRNA levels for C3 and CFB were detected din cSCC cell lines (n = 8) compared to normal human epidermal keratinocytes (n = 11) by quantitative real-time reverse transcriptase-PCR. Increased production of C3 and CFB by cSCC cell lines was detected by western blotting. The mRNA levels for C3 and CFB were also markedly higher in cSCC tumors (n = 6) than in normal skin (n = 10). Tumor cell specific staining for C3 and CFB was detected in cSCC tumors in vivo by immunohistochemistry and the staining intensity was stronger in invasive cSCCs (n = 71) than in cSCC in situ (n = 69), premalignant epidermal lesions (actinic keratoses, n = 65) and normal skin (n = 5). Significant upregulation of C3 and CFB mRNA expression was also noted in chemically induced mouse skin cSCCs (n = 27) compared to benign papillomas (n = 17). The expression of C3 and CFB at mRNA and protein level was markedly higher in invasive tumorigenic Ha-ras-transformed HaCaT cell line than in benign tumorigenic ras-transformed HaCaT cells and parental non-tumorigenic HaCaT cells. The expression of both C3 and CFB was significantly upregulated by IFN-γ and TNF-α in cSCC cells. Knockdown of CFB and C3 by specific siRNAs inhibited migration of cSCC cells. Knockdown of CFB inhibited proliferation of cSCC cells and this was associated with potent inhibition of ERK1/2 activation. Knockdown of C3 and CFB also significantly inhibited growth of human cSCC xenograft tumors in vivo in SCID mice. These results provide evidence for the role of C3 and CFB in progression of cSCC and identify them as specific biomarkers and putative therapeutic targets for invasive cSCC. Citation Format: Pilvi Riihila, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grenman, Ritva Heljasvaara, Taina Pihlajaniemi, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kahari. Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2015-3201

EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer.

Skin and maxillary sinus involvement of colon cancer.

Skin and maxillary sinus involvement of colon cancer.

Early Gastric Cancer with Cellulitis-like Skin Metastasis

Skin metastasis from internal carcinoma rarely occurs and it has an incidence of 0.7% to 9%. Although the prognosis of the skin metastases varies considerably depending on the type of the primary malignancy, presence of metastatic skin cancer usually implies a widespread systemic disease and a high mortality. A 50-year-old Korean male patient visited Dankook University Hospital for evaluation of skin rash on his whole abdomen of about 1 month's duration. He had undergone laparoscopy-assisted distal gastrectomy due to early gastric cancer about 3 months ago. He did not complain of any noticeable symptoms like febrile sense or pruritus. Skin biopsy was performed on the periumbilical area at previous port site and around the scar. Microscopic examination revealed multiple malignant cells in lymphatic spaces, consistent with metastatic carcinoma. He was therefore diagnosed with isolated skin metastasis from early gastric cancer. Because of patient's poor liver function, systemic chemotherapy could not be performed and only best supportive care was provided. Herein, we report a rare case of cellulitis-like skin metastasis from early gastric cancer with a brief review of the literature.

The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

Combined ipsilateral neck and axillary lymphadenectomy for metastatic skin cancers: A case series and surgical tips

In the absence of distant disease simultaneous skin cancer metastasis to neck and axillary lymph nodes necessitates both an axillary and neck en block lymphadenectomy. Acombined ipsilateral neck and axillary lymph node dissection should involve an in-continuity dissection through the cervicoaxillary canal for optimal lymphatic and oncological clearance. Review of the literature reveals little published instruction on the procedure since the radical surgery performed by Bowden over 50 years ago. We present 4 cases where ipsilateral axillary and neck lymph node dissections were performed for metastatic melanoma and a case of apical axillary node dissection via a neck incision approach. Our surgical tips include performing apical axillary node dissection via the neck incision and consideration of clavicular osteotomy or clavicular excision. A transclavicular approach was taken in one patient who had an excellent functional outcome after a plate and screw fixation. One elderly patient required a middle third claviculectomy which reduced shoulder elevation but was not associated with functional impairment. We conclude the surgery is safe and associated with the usual morbidity ascribed with either an axillary or neck dissection undertaken in isolation. However, patients have a significant risk of disease relapse as would be expected due to the duel metastatic sites, multiple lymph node and neck involvement which are known to be independent poor prognostic factors on melanoma survival and relapse.

Recent Trends (1991-2010) of Metastatic Skin Cancers in Korea

The incidence of overall cancer has increased over time. The incidence of top-ranking cancers has changed in the 1990s and the 2000s. However, few studies have evaluated the trends in metastatic skin cancers during this period. We evaluated the recent trends in incidence, peak age and location of metastatic skin cancers from 1991 to 2010. This 20-yr survey was divided into two decades to determine the trends by comparing the statistics. Out of 694,466 outpatients (1991-2010), 174 (0.025%) were diagnosed with metastatic skin cancer. The incidence of metastatic skin cancer increased significantly from 20.64 per 100,000 outpatients in the 1990s to 28.70 per 100,000 outpatients in the 2000s (P = 0.030). The peak age of skin metastasis shifted from the 40s to the 50s in women, and from the 50s to the 60s in men. The percentage of metastatic skin cancers originating from intra-abdominal organs increased from 10% in the 1990s to 23.1% in the 2000s (P = 0.027). The percentage of metastatic skin cancers located on the abdomen increased from 7.1% in the 1990s to 15.4% in the 2000s (P = 0.011). The higher proportion of metastatic skin cancers located on the abdomen may be related to the increase in skin metastases from intra-abdominal organs.

Cutaneous metastasis from carcinoma of lung

A 65-year-old male with a history of smoking since 30 years presented with breathlessness, hemoptysis, multiple swellings all over the body, and weakness in September 2010 at our hospital. Clinically, a diagnosis of chronic obstructive pulmonary disease (COPD) with cutaneous lymphoma or soft tissue tumor was made. Chest X-ray (CXR) and computed tomography (CT) scan revealed a neoplastic lesion in the right lung with secondary cavitation. Biopsy of the cutaneous nodules showed metastatic deposits from squamous cell carcinoma. Metastatic skin cancer is a relatively rare complication of internal malignancy. The clinical features of metastatic skin disease vary enormously. They may present as erysipeloid, sclerodermoid, alopecia neoplastica or in an inflammatory or bullous form or as multiple nodules as in our case. A high index of suspicion for metastatic deposits is required in an elderly male patient who is a known case of lung cancer or even one who is a chronic smoker and presents with such cutaneous lesions.

Application of Fenton, photo-Fenton, solar photo-Fenton, and UV/H2O2 to degradation of the antineoplastic agent mitoxantrone and toxicological evaluation

In the present study, selected advanced oxidation processes (AOPs)-namely, photo-Fenton (with Fe(2+), Fe(3+), and potassium ferrioxalate-FeOx-as iron sources), solar photo-Fenton, Fenton, and UV/H2O2-were investigated for degradation of the antineoplastic drug mitoxantrone (MTX), frequently used to treat metastatic breast cancer, skin cancer, and acute leukemia. The results showed that photo-Fenton processes employing Fe(III) and FeOx and the UV/H2O2 process were most efficient for mineralizing MTX, with 77, 82, and 90% of total organic carbon removal, respectively. MTX probably forms a complex with Fe(III), as demonstrated by voltammetric and spectrophotometric measurements. Spectrophotometric titrations suggested that the complex has a 2:1 Fe(3+):MTX stoichiometric ratio and a complexation constant (K) of 1.47 × 10(4) M(-1), indicating high MTX affinity for Fe(3+). Complexation partially inhibits the involvement of iron ions and hence the degradation of MTX during photo-Fenton. The UV/H2O2 process is usually slower than the photo-Fenton process, but, in this study, the UV/H2O2 process proved to be more efficient due to complexing of MTX with Fe(III). The drug exhibited no cytotoxicity against NIH/3T3 mouse embryonic fibroblast cells when oxidized by UV/H2O2 or by UV/H2O2/FeOx at the concentrations tested.