The evolving landscape in the therapy of acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of myeloid precursors arrested in their maturation, creating a diverse disease entity with a wide range of responses to historically standard treatment approaches. While significant progress has been made in characterizing and individualizing the disease at diagnosis to optimally inform those affected, progress in treatment to reduce relapse and induce remission has been limited thus far. In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies. With these, and undoubtedly many others in the future, it is the hope that by combining more accurate prognostication with more effective therapies, patients will begin to have a different, and more complete, outlook on their disease that allows for safer and more successful treatment strategies.

A preliminary study on clinical diagnostic value of plasma elafin in skin acute graft-versus-host disease / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the specificity, sensitivity and receiver operating characteristic (ROC) curve of plasma elafin for diagnosis of skin acute graft-versus-host disease (aGVHD), and to explore its clinical diagnostic value.</p><p><b>METHODS</b>Incidence of skin aGVHD from fifty-three patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were observed prospectively in Guangdong General Hospital from Apr 2010 to Aug 2011. The plasma concentrations of elafin were detected by enzyme-linked immunosorbent assay (ELISA). Skin biopsies were taken from 28 patients with skin rash, and elafin expression in the skin was detected by immunohistochemistry. Positive expression was defined as significant staining of at 50% of the depth of the epidermis, excluding the granular cell layer and the acrosyringium.</p><p><b>RESULTS</b>Among 28 patients with skin rash, twenty-five were considered as skin aGVHD by clinical diagnosis, seventeen were confirmed as skin aGVHD by pathological biopsy. 11 cases were elafin positive by immunohistochemical staining. Elafin protein was overexpressed in aGVHD skin tissue (P = 0.001). Plasma concentrations of elafin were significantly higher in patients with skin aGVHD (positive) group than in those without skin aGVHD (negative) group (P = 0.005), among which there being no statistically significant difference in plasma elafin level between patients with grade I skin aGVHD group and negative group(P = 0.971), but being statistically significant difference compared patients with grade II-IV skin aGVHD group with those with grade I skin aGVHD group (P = 0.02) and with negative group (P = 0.008). Using the pathological diagnosis as the gold standard, the estimated specificity and the sensitivity of clinical diagnosis criteria were 27.3% and 100%, respectively, and those of tissue elafin protein level were 100% and 64.7%, respectively. The area under the ROC curve was 0.909 (0.797 - 1.021) when plasma concentrations of elafin was used in diagnosis of skin aGVHD. The sensitivity was 82.4% and the specificity was 81.8 % when the critical value was set at 1456.043 µg/L.</p><p><b>CONCLUSION</b>Plasma concentration of elafin is significantly higher at the onset of skin aGVHD. It can be used as biochemical marker of skin aGVHD and has higher value in diagnosis of skin aGVHD.</p>

Elafin Expression in Oral Lichen Planus

BACKGROUND: Elafin is a potent anti-elastase in human saliva, and is supposed to play a role in preventing oral ulceration. The expression of elafin was observed in the oral lichen planus (OLP), one of the most common noninfectious oral mucosal diseases, which frequently manifests as extensive ulceration on the involved oral mucosa. METHODS: 50 OLP, 10 oral leuko-plakia, 3 inflammatory oral ulcers, and 3 normal oral mucosa cases were fixed with 10% buffered formalin, and immunohistochemically stained with monoclonal elafin antibody. Representative specimens were fixed with 4% paraformaldehyde, and RNA in situ hybridization, with an elafin RNA probe, was performed. RESULTS: With both the immunohistochemistry and RNA in situ hybridization the expression of elafin was more decreased in the OLP compared to the normal mucosa, while in the hyperplastic epithelium of the leukoplakia and inflammatory ulcers the expressions of elafin was more intense. In the thin epithelia of the reticular and atrophic OLPs the expressions of elafin were reduced compared to the normal mucosa, and became almost negative in the epithelium of the erosive OLP. CONCLUSIONS: These data suggested that the extensive ulceration of the OLP was closely relevant to the reduced expression of elafin in the involved epithelium

The Expression of Elafin and Its Implication in the Inflammatory and Keratinizing Disorders of the Skin / 대한피부과학회지

BACKGROUND: Elafin is a serine proteinase inhibitor first discovered in keratinocytes from psoriatic epidermis. The molecular structure of elafin contains two different functional domains; one for the proteinase inhibitor, which is directed against elastase and proteinase-3, and the other for transglutaminase substrate. As this unique structural characteristic implies, elafin would be expected to have two distinct biologic functions in tissues. But, the roles and biological features of elafin have not been extensively studied in the skin. OBJECTIVES: This study was designed to demonstrate the immunohistochemical localization of elafin in inflammatory and keratinizing skin disorders, and to elucidate its biological functions. MATERIALS AND METHODS: The pre-elafin sequence was amplified by PCR using a human epidermal cDNA library and expression construct which was ligated into an expression vector. Then, the expressed proelafin sequence was purified and injected intradermally into rabbits to raise a polyclonal antibody. The skin biopsy samples of various skin diseases and normal controls were used for immunohistochemical staining to detect elafin expression. RESULTS: 1)Expression of elafin was observed in infected epidermis, and is believed to be involved in the defense mechanism of the skin. 2)In dermal and subcutaneous inflammatory diseases, epidermal elafin expression was influenced by the location of the inflammation. 3)Elafin was expressed in bullous dermatoses accompanied by acantholysis or spongiosis of epidermal cells. 4)Expression of elafin was upregulated in papulosquamous skin diseases which was characterized by epidermal hyperplasia and abnormal differentiation. 5)Elafin was expressed in keratinizing skin diseases that was accompanied by abnormal differentiation of epidermal cells. 6)Expression of elafin was demonstrated in skin tumors that showed proliferation of suprabasal cells. The intensity of expression is not related to the degree of malignancy, but to the degree of differentiation of tumor cells. CONCLUSION: Induction of elafin expression may play an important role in protecting the skin components against tissue damage. Elafin expression is related to the abnormal proliferation and differentiation of suprabasal cells. This means that elafin may be used as a marker of these conditions.

Expression of Elafin in the Epidermis of Cutaneous Fungal Infection / 감염

BACKGROUND: Elafin is a serine proteinase inhibitor first discovered in keratinocytes from hyperproliferative human epidermis. In addition to the proteinase inhibiting domain, elafin contains multiple transglutaminase substrate domains which enable cross-linking to extracellular and cell envelope proteins. Several characteristics of elafin suggest potential anti-microbial activity. Elafin is absent in normal skin at protein level, but is induced in inflammatory and infectious dermatoses which threat the epidermal integrity by vesicopustule formation and neutrophilic cell infiltration. Cutaneous fungal infection is one of the well-known examples of diseases characterized by such condition. The purpose of this study was to check out the possibility that elafin may be involved in the pathomechanism of fungal infection. METHODS: The biopsy samples taken from 10 cases of superficial fungal infections, 10 cases of deep and systemic mycoses, 2 cases of slide culture specimens of Candida species, were used for the immunohistochemical tissue staining for elafin expression. Polyclonal anti-elafin was used in 1:300 dilution. As control, biopsy smaples of normal skin, ichthyosis, psoriasis were used for the staining for elafin expression. RESULTS: In the normal and ichthyotic epidermis, elafin expression was virtually negative. In superficial mycoses except candidiasis, elafin was expressed in the spinous layer of infected epidermis, and fungal structures in the stratum corneum were stained with elafin antisera. In the cases of dermatophytosis of ichthyosis patients, while fungal hyphae were stained with elafin antisera, epidermal cell did not express elafin. In candidial esophagitis, elafin was expressed in the esophgeal mucosa, but spores were not stained with elafin anti-sera. In slide culture of Candida species, spores were not stained with elafin antisera, also. In cases of systemic and deep mycoses, fungal hyphae and spores were stained with elafin antisera and epidermis adjacent to severe dermal inflammatory reaction showed elafin expression. CONCLUSION: Elafin may have certain role in systemic and cutaneous fungal infection to contribute to high resistance of the epidermis against proteolysis and fungal infections, and it is shown that elafin or elafin-like protein may also be produced and utilized by fungi themselves.