Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion.

Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene.

Pulmonary hypertensive vasculopathy in parenchymal lung diseases and/or hypoxia: Number 1 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.

Pulmonary hypertension (PH) with complicating chronic lung diseases and/or hypoxia falls into group 3 of the updated classification of PH. Patients with chronic obstructive lung disease (COPD), diffuse lung disease (such as idiopathic pulmonary fibrosis (IPF)) and with sleep disordered breathing are particularly exposed to the risk of developing PH. Although PH in such a context is usually mild, a minority of patients exhibit severe haemodynamic impairment, defined by a mean pulmonary arterial pressure (mPAP) of ≥35 mmHg or mPAP values ranging between 25 mmHg and 35 mmHg with a low cardiac index (<2 L·min·m).

Increasing time trends of thin melanomas in The Netherlands: What are the explanations of recent accelerations?

Background: A disproportional increase in in situ or thin melanomas may point at underlying causes such as increased melanoma awareness, as well as 'overdiagnosis' of melanoma in diagnostically equivocal small lesions.

Objectives: The purposes of this study were to estimate trends in melanoma incidence by sex, Breslow thickness (thin melanomas subdivided into four subgroups: <0.25 mm, 0.

"Lentiginous melanoma": full-fledged melanoma or melanoma precursor?

On the basis of a critical review of published literature, it is concluded that there is as yet insufficient evidence to conclude that the melanocytic lesion, which is currently known as "lentiginous melanoma," is a full-fledged melanoma, with the capacity to metastasize to distant sites and to cause the demise of the patient. It is proposed that this lesion is better designated as "lentiginous SAMPUS," that is, a superficial atypical melanocytic proliferation of uncertain significance, with a lentiginous, or predominantly lentiginous, arrangement of the junctional component. As there is uncertainty regarding its actual metastatic potential or the likelihood of progression to melanoma NOS, the lesion should be removed completely, with free surgical margins.

Nitric oxide donors augment interleukin-1β-induced vascular endothelial growth factor in airway smooth muscle cells.

Angiogenesis and microvascular leakage are features of chronic inflammatory diseases of which molecular mechanisms are poorly understood. We investigated the effects of interleukin-1β (IL-1β) on the expression and secretion of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in porcine airway smooth muscle cells (PASMC) in relation to a nitric oxide (NO) pathway. Serum-deprived (48 h) PASMC were stimulated with IL-1β alone or with NO donor, L-arginine and/or NO synthase inhibitor L-NAME for 4 and 24 h.

Angiogenesis and vascular remodeling in chronic airway diseases.

Asthma and chronic obstructive pulmonary disease remain a global health problem, with increasing morbidity and mortality. Despite differences in the causal agents, both diseases exhibit various degrees of inflammatory changes, structural alterations of the airways leading to airflow limitation. The existence of transient disease phenotypes which overlap both diseases and which progressively decline the lung function has complicated the search for an effective therapy.

Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation.

Background: Lifetime melanoma risk of mutation carriers from families with a germline mutation in the CDKN2A gene is estimated to be 67%. The necessity to include family members in a melanoma surveillance program is widely endorsed, but there is no consensus on which family members should be invited.

Methods: In a retrospective follow-up study, we investigated the yield of surveillance of first- and second-degree relatives of melanoma and pancreatic cancer patients from 21 families with the "p16-Leiden" CDKN2A mutation.

DNA microarray and quantitative analysis reveal enhanced myocardial VEGF expression with stunted angiogenesis in human tetralogy of Fallot.

Tetralogy of Fallot (ToF) is a cyanotic congenital heart disease with prominent right ventricular hypertrophy (RVH) associated with impaired myocardial oxygen and nutrient supply. Consequently, the right ventricle may manifest in altered molecular phenotype with a number of adaptive and inherited gene profiles which are largely unknown. The aim of the present study was to investigate the myocardial differential gene expression profile and to assess myocardial vascularisation in patients with ToF.

[Revision of the national guideline 'Melanoma'].

Melanoma is in the top ten of the most common types of cancer in the Netherlands. Incidence is increasing steadily by about 4% every year. The relative 5-year survival rate for patients with a melanoma with Breslow thickness < 1mm is about 98%.

Targeting BRAFV600E in an inducible murine model of melanoma.

The MAP kinase and PI3 kinase pathways have been identified as the most common pathways that mediate oncogenic transformation in melanoma, and the majority of compounds developed for melanoma treatment target one or the other of these pathways. In addition to such targeted therapies, immunotherapeutic approaches have shown promising results. A combination of these two treatment modalities could potentially result in further improvement of treatment outcome.

Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis.

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear.

Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells.

The airways in asthma and COPD are characterized by an increase in airway smooth muscle (ASM) mass and bronchial vascular changes associated with increased expression of pro-angiogenic growth factors, such as fibroblast growth factors (FGF-1 and FGF-2) and vascular endothelial growth factor (VEGF). We investigated the contribution of FGF-1/-2 in VEGF production in ASM cells and assessed the influence of azithromycin and dexamethasone and their underlying signaling mechanisms. Growth-synchronized human ASM cells were pre-treated with MAPK inhibitors, U0126 for ERK1/2(MAPK) and SB239063 for p38(MAPK) as well as with dexamethasone or azithromycin, 30 min before incubation with FGF-1 or FGF-2.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.

Background: Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors.

Transforming growth factor-beta 1 induces angiogenesis in vitro via VEGF production in human airway smooth muscle cells.

Increase in size and number of bronchial blood vessels as well as hyperaemia are factors that contribute to airway wall remodelling in patients with chronic airway diseases, such as asthma and chronic obstructive pulmonary diseases (COPD). Expression of transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine as well as vascular endothelial growth factor (VEGF), a key angiogenic molecule, has been shown in the inflammed airways in patients with chronic airway diseases. TGF-beta 1 has been implicated in the regulation of extracellular matrix, leading to airway remodelling in patients with chronic airway diseases.

Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families.

Background: For more than 25 years families with an increased susceptibility to melanoma have been under surveillance at our institution.

Objective: We sought to investigate the effectiveness of surveillance for CDKN2A-mutated families and causes for failure of the program in patients with more advanced tumors.

Methods: In a retrospective case-control study, Breslow thickness of melanomas diagnosed in relatives enrolled in the surveillance program were compared with melanomas of unscreened index patients.

Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study.

Introduction: Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH.

Nevus versus melanoma: to FISH, or not to FISH.

Fluorescence in-situ hybridization (FISH) has arisen as a novel ancillary test for the pathological diagnosis of melanoma. It is an outgrowth of studies using comparative genomic hybridization, a technique capable of surveying the entire genome for DNA copy number changes. An original report published in 2009 showed high sensitivity (87%) and specificity (95%) for diagnosing melanoma, using a combination of 4 FISH probes that target 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and chromosome 6 centromere.

[Modern education in histopathology and radiology].

Radiological and pathological imaging constitute an essential part of modern medicine. Furthermore, by showing microscopic and radiological images many pathological processes can be made clearer and easier to understand. This has consequences for education.

The essence of senescence.

Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of "cellular senescence" in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression.

HRAS-mutated Spitz tumors: A subtype of Spitz tumors with distinct features.

It is often very difficult to confidently distinguish benign and malignant Spitz lesions, and a diagnosis of Spitz tumor of unknown malignant potential (STUMP) is rendered. To address this problem, we performed molecular genetic analysis in a large group of Spitz tumors (93 Spitz nevi and 77 STUMPs) and identified a subgroup of 24 lesions harboring a HRAS mutation. This subgroup lay predominantly in the dermis, had a relatively low cellularity, showed desmoplasia (with single cells interspersed between the collagen bundles), and had an infiltrating base.

Pulmonary vascular remodeling in congenital heart disease: enhanced expression of heat shock proteins.

In congenital heart disease (CHD), mechanical wall stress by increased pulmonary artery pressure and pulmonary blood flow is believed to play a pivotal role in the pathogenesis of pulmonary plexogenic arteriopathy (PPA). The pathogenesis of this disease that involves significant pulmonary arterial remodelling, is, however, largely unknown. In the systemic circulation, upregulation of HSP-70 and HSP-27 in the arterial wall occurs in response to acute hypertension, whereas HSP-60 and increased titres of anti-HSP-60 antibodies are associated with atherosclerotic vessel disease.

State of the art, nomenclature, and points of consensus and controversy concerning benign melanocytic lesions: outcome of an international workshop.

The following communication summarizes the proceedings of a one-day International Workshop focusing on the histology of benign melanocytic nevi. Areas of controversy identified in 6 focus sessions were the nomenclature and relationships among common nevi including nevi with halo reactions, traumatized nevi, "dysplastic" nevi, and nevi from particular anatomic sites; developmental biology and frequency of malignant transformation associated with congenital nevi; the characterization and biologic nature of atypical spitzoid neoplasms; the basic definition of particular melanocytic cellular phenotypes, and the nomenclature and biologic nature of many candidate blue nevi, combined nevi, and other controversial lesions such as deep penetrating nevus and pigmented epithelioid melanocytoma. Concentrated data collection and follow-up, molecular characterization, and future consensus Workshops may facilitate the resolution of some of these problems.

[Improved compliance with the 'Melanoma' treatment guideline].

Objective: To evaluate the level of compliance with the revised treatment guideline for melanoma (2005) and the extent to which the points of concern from the previous guideline evaluation in 2001 had been implemented.

Design: Retrospective observational cohort study.

Method: The evaluation was performed using data from the pathology reports of patients diagnosed with melanoma of the skin between 1 April and 30 September 2007 at hospitals that fall under the Comprehensive Cancer Centres for the South and West of the Netherlands.

Oncogene-induced cellular senescence.

Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response brought about by oncogenic signaling resulting from an activating mutation of an oncogene, or the inactivation of a tumor-suppressor gene. The pathways mediating OIS are complex and incompletely elucidated but, the proliferative arrest involves activation of both the RB and p53 pathways. In addition, whereas there are indications that at least in some situations, negative feedback loops abolish the increased mitogenic signaling resulting from the oncogenic mutations, also an unexpected contribution of interleukin-mediated signaling has recently been found.