The Role of Stem Cells in Dupuytren's Disease: A Review.

The pathogenesis of Dupuytren's disease (DD) remains unclear although there is increasing evidence supporting the role of stem cells in this and other fibrotic conditions. This review examines the role of DD tissue-associated embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs), and circulating fibrocytes and circulating MSCs, in the biology of DD. It is exciting to infer that dysfunction of an upstream ESC-like population within the affected tissue leads to the downstream development and proliferation of aberrant myofibroblasts through a putative MSC intermediate. This ESC-like population may be a potential novel therapeutic target through modulation of the renin-angiotensin system. Furthermore, circulating CD34+ fibrocytes and MSCs either derived from the bone marrow, peripheral blood cells, or DD-associated ESC-like population, may serve as potential additional extra-palmar reservoirs that undergo endothelial-to-mesenchymal transition, eventually giving rise to the aberrant myofibroblasts. Further studies examining the relative roles of these stem cells and the precise regulatory pathways that govern them may lead to novel therapy that targets these populations.

Does hypoxia play a role in infantile hemangioma?

Infantile hemangioma (IH), the most common tumor of infancy, is characterized by rapid growth during infancy, followed by spontaneous involution over 5-10 years. Certain clinical observations have led to the suggestion that IH is triggered and maintained by hypoxia. We review the literature on the possible role of hypoxia in the etiology of IH, in particular, (1) the role of hypoxia inducible factor-1α (HIF-1α) and its downstream targets including GLUT-1 and VEGF; (2) the pathophysiological link between IH and retinopathy of prematurity; (3) hypoxic events in the early life including placental insufficiency, pre-eclampsia and low birthweight that have the potential to promote hypoxic stress; and (4) the evidence supporting the development of IH independent of HIF-1α. We also discuss these observations in the context of recent evidence of the crucial role of stem cells and the cytokines niche that governs their proliferation and inevitable differentiation, offering novel insights into the biology of IH. We propose that various triggers may simultaneously up-regulate HIF-1α, which is downstream of the renin-angiotensin system, specifically angiotensin II, which promotes production of HIF-1α. These developments shed light to the understanding of this enigmatic condition.

Biology of infantile hemangioma.

Infantile hemangioma (IH), the most common tumor of infancy, is characterized by an initial proliferation during infancy followed by spontaneous involution over the next 5-10 years, often leaving a fibro-fatty residuum. IH is traditionally considered a tumor of the microvasculature. However, recent data show the critical role of stem cells in the biology of IH with emerging evidence suggesting an embryonic developmental anomaly due to aberrant proliferation and differentiation of a hemogenic endothelium with a neural crest phenotype that possesses the capacity for endothelial, hematopoietic, mesenchymal, and neuronal differentiation. Current evidence suggests a putative placental chorionic mesenchymal core cell embolic origin of IH during the first trimester. This review outlines the emerging role of stem cells and their interplay with the cytokine niche that promotes a post-natal environment conducive for vasculogenesis involving VEGFR-2 and its ligand VEGF-A and the IGF-2 ligand in promoting cellular proliferation, and the TRAIL-OPG anti-apoptotic pathway in preventing cellular apoptosis in IH. The discovery of the role of the renin-angiotensin system in the biology of IH provides a plausible explanation for the programed biologic behavior and the ß-blocker-induced accelerated involution of this enigmatic condition. This crucially involves the vasoactive peptide, angiotensin II, that promotes cellular proliferation in IH predominantly via its action on the ATIIR2 isoform. The role of the RAS in the biology of IH is further supported by the effect of captopril, an ACE inhibitor, in inducing accelerated involution of IH. The discovery of the critical role of RAS in IH represents a novel and fascinating paradigm shift in the understanding of human development, IH, and other tumors in general.

Pharmacologic therapies for infantile hemangioma: is there a rational basis?

BACKGROUND: Infantile hemangioma is the most common tumor of infancy. The majority of cases are managed conservatively, but intervention is necessary in approximately 10 percent of cases because of the threat to life or function or because of tissue distortion or destruction. The mainstay treatment for these problematic proliferating infantile hemangiomas is pharmacologic therapy, mostly discovered serendipitously. METHODS: This review examines the rational basis of the hitherto empirical pharmacologic therapies for the enigmatic infantile hemangioma, in light of new knowledge regarding its biology, including the critical roles of stem cells and the renin-angiotensin system. RESULTS: Steroids have remained the first-line therapy for problematic infantile hemangioma for over 40 years despite their known side effects and failure rates. Vincristine has emerged as an alternative to interferon for steroid-resistant cases because of interferon's adverse effects, especially neurotoxicity. ß-Blockers are now the preferred first-line therapy for problematic cases. There is increasing evidence that infantile hemangioma is a disorder of aberrant proliferation and differentiation of primitive mesoderm-derived neural crest phenotypic cells. This primitive phenotype that gives rise to a hemogenic endothelium intermediate has the ability to undergo primitive erythropoiesis and terminal mesenchymal differentiation. CONCLUSIONS: The recent discovery of the crucial role of stem cells and the inferred role of the renin-angiotensin system in the biology of infantile hemangioma underscores the possibility of even more targeted therapies, by using modulators of the renin-angiotensin system, on infantile hemangioma. The observation of the potential role of these traditional antihypertensive agents in stem cell biology may lead to better understanding of developmental biology and tumor stem cell growth.

Atypical fibroxanthoma and malignant fibrous histiocytoma.

BACKGROUND: Atypical fibroxanthoma (AFX) and malignant fibrous histiocytoma (MFH) are soft-tissue tumours with variable aggressiveness. There is considerable debate about the relationship between these lesions, as histological and immunochemical differentiation is difficult. METHODS: Current opinions and evidence for diagnostic differences between AFX and MFH were reviewed. Consecutive cases of AFX and MFH were identified from our non-melanoma skin cancer (NMSC) database 1996-2007 for the Central Region of New Zealand. RESULTS: Of the 50,411 NMSC lesions excised surgically from 26,138 patients, there were 101 AFX and 15 MFH cases. Three MFH cases were originally diagnosed as AFX. AFX and MFH share similar patient demographics, size and location and histological and immunohistochemical features. Most diagnostic biopsies of AFX were not followed by formal excision. Incomplete excision occurred in a large proportion of patients with AFX, which often did not proceed to re-excision, resulting in local recurrence. Cases of MFH generally underwent definitive treatment including re-excision if incompletely excised, and postoperative adjuvant radiotherapy. CONCLUSIONS: The failure to treat AFX adequately may have resulted from the lack of appreciation of its aggressiveness. Contrary to the literature, we found few clinical differences between AFX and MFH. AFX and MFH also share similar histologic features and there are no immunohistochemical markers that reliably distinguish them. AFX is best considered a distinct entity with MFH, now reclassified as an undifferentiated pleomorphic sarcoma.

Social media and the medical profession.

Use of social media by doctors and medical students is common and growing. Although professional standards and codes of ethics that govern the behaviour of medical practitioners in Australia and New Zealand do not currently encompass social media, these codes need to evolve, because professional standards continue to apply in this setting. Inappropriate use of social media can result in harm to patients and the profession, including breaches of confidentiality, defamation of colleagues or employers, and violation of doctor-patient boundaries. The professional integrity of doctors and medical students can also be damaged through problematic interprofessional online relationships, and unintended exposure of personal information to the public, employers or universities. Doctors need to exercise extreme care in their use of social media to ensure they maintain professional standards.