The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/ CXCR4 axis. We propose that the sus- IntroductionThe CXC chemokine stromal cell-derived factor 1 (SDF-1/ CXCL12) 1,2 is the sole natural ligand for CXCR4, 3,4 a broadly expressed G-protein-coupled receptor (GPCR). 5 The unique, nonpromiscuous interaction between CXCL12 and CXCR4 is critically involved in the organogenesis of a number of phylogenetically distant animal species. [6][7][8][9][10][11] In addition, B-cell lymphopoiesis and bone marrow (BM) myelopoiesis are regulated by the CXCL12/ CXCR4 axis during embryogenesis. [12][13][14] In postnatal life, the CXCL12/CXCR4 couple controls the BM homing of CD34 ϩ cells and lymphocyte trafficking. [15][16][17][18] Besides the regulation of homeostatic processes, CXCR4 has been implicated in the development of infectious 3,19 and inflammatory diseases as well as tumor metastasis. [20][21][22][23] Recently, inherited heterozygous autosomal dominant mutations of the CXCR4 gene, which result in the truncation of the carboxyl-terminus (C-tail) of the receptor, were found to be associated with the WHIM syndrome. 24 This rare immunodeficiency disease is characterized by disseminated human papillomavirus (HPV)-induced warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis, a form of neutropenia associated with abnormal retention of mature neutrophils in the BM. [25][26][27] Patients with WHIM also exhibit a marked T-cell lymphopenia. The disorder is clinically and genetically heterogeneous, 28 since hypogammaglobulinemia and verrucosis were absent in some cases, 29 and individuals with isolated myelokathexis were found to be wild type for the CXCR4 gene. 24 However, the altered mechanism accounting for the pathogenesis of the WHIM syndrome not associated to CXCR4 mutations remains unknown. Here, we provide original...

Daylight-mediated PDT was not inferior in efficacy to Metvix c-PDT (mild AK response rate), better tolerated, nearly painless and more convenient for patients.

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BackgroundWHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.ObjectiveThis study aims to describe the natural history of WS based on a French cohort of 8 patients.MethodsWe have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.ResultsWe identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient’s death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.ConclusionsContinuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.

Aims: The treatment of dermatofibrosarcoma protuberans (DFSP) involves wide local excision with frequent need for reconstructive surgery. A t(17;22) translocation resulting in COL1A1-PDGFB fusion is present in >95% of cases. Certain patient observations and a report on nine patients suggest that imatinib mesylate, targeting platelet-derived growth factor receptor β, has clinical potential in DFSP. The primary aim of this phase II multicenter study was to define the percentage of clinical responders (Response Evaluation Criteria in Solid Tumors) to a 2-month preoperative daily administration of 600 mg of imatinib mesylate before wide local excision. The secondary aims were to determine tolerance, objective response from imaging results (ultrasound and magnetic resonance imaging), and pathologic responses observed in sequential tissue specimens.Patients and Methods: A two-stage flexible design was used with interim analysis after the recruitment of six patients. Twenty-five adults suffering from primary or recurrent DFSP were included from July 2004 to May 2006.Results: The COL1A1-PDGFB fusion gene was detected in 21 out of 25 patients following fluorescence in situ hybridization analysis (two cases were noninformative). A clinical response was achieved in nine (36%) patients (95% confidence interval, 18.9-57.5). The median relative tumoral decrease was 20.0% (range, −12.5 to 100). Apart from expected grade 1 or 2 side effects, we observed one grade 3 neutropenia, one grade 3 maculopapular rash, and one grade 4 transient transaminitis.Conclusion: Our results support the use of imatinib in a neoadjuvant setting in nonresectable DFSP, or when surgery is difficult or mutilating. These results will be useful for setting hypotheses in the evaluation of new drugs to treat primary or secondary resistance to imatinib. Clin Cancer Res; 16(12); 3288-95. ©2010 AACR.Dermatofibrosarcoma protuberans (DFSP) is a rare soft-tissue sarcoma characterized by progressive local growth of CD34+ spindle cells with a highly infiltrative pattern (1). Approximately 85% to 90% of tumors are low-grade, whereas others contain a high-grade fibrosarcomatous component (1). Wide excision is the standard therapy, but it can be difficult and mutilating (2). In less than 2% of cases, DFSP metastasizes and becomes lifethreatening.More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to fusion of COL1A1 and PDGFB genes. Transfection studies suggest that PDGFB could act as a mitogen for tumor cells, leading to platelet-derived growth factor (PDGF) receptor activation (3), which thus constitutes a therapeutic target. Indeed, three cases of DFSP with a spectacular response to imatinib mesylate (IM) were reported in 2002 (4, 5). In approximately 5% of cases, COL1A1-PDGFB fusion was not found, suggesting that other genes might be involved in DFSP pathogenesis (6).

Exposome factors that lead to stressed skin can be defined as any disturbance to homeostasis from environmental (meteorological factors, solar radiation, pollution or tobacco smoke) and/or internal exposure (unhealthy diet, hormonal variations, lack of sleep, psychosocial stress). The clinical and biological impact of chronic exposome effects on skin functions has been extensively reviewed, whereas there is a paucity of information on the impact of short‐term acute exposure. Acute stress, which would typically last minutes to hours (and generally no more than a week), provokes a transient but robust neuroendocrine‐immune and tissue remodelling response in the skin and can alter the skin barrier. Firstly, we provide an overview of the biological effects of various acute stressors on six key skin functions, namely the skin physical barrier, pigmentation, defences (antioxidant, immune cell‐mediated, microbial and microbiome maintenance), structure (extracellular matrix and appendages), neuroendocrine and thermoregulation functions. Secondly, we describe the biological and clinical effects on adult skin from individual exposome factors that elicit an acute stress response and their consequences in skin health maintenance. Clinical manifestations of acutely stressed skin may include dry skin that might accentuate fine lines, oily skin, sensitive skin, pruritus, erythema, pale skin, sweating, oedema and flares of inflammatory skin conditions such as acne, rosacea, atopic dermatitis, pigmentation disorders and skin superinfection such as viral reactivation. Acute stresses can also induce scalp sensitivity, telogen effluvium and worsen alopecia.

It is unclear how the immune response controls human herpesvirus 8 (HHV8; also known as Kaposi sarcoma-associated herpesvirus [KSHV]) replication and thereby prevents Kaposi sarcoma (KS). We compared CD8 T-cell responses to HHV8 latent (K12) and lytic (glycoprotein B, ORF6, ORF61, and ORF65) antigens in patients who spontaneously controlled the infection and in patients with posttransplantation, AIDS-related, or classical KS. We found that anti-HHV8 responses were frequent, diverse, and strongly differentiated toward an effector phenotype in patients who controlled the infection. Conversely, HHV8-specific CD8 cells were very rare in patients who progressed to KS, and were not recruited to the tumoral tissue, as visualized by in situ tetramer staining of KS biopsies. Last, HHV8-specific CD8 T cells were observed in a seronegative recipient of an HHV8-infected graft who remained persistently aviremic and antibody negative, suggesting that specific cytotoxic T lymphocytes (CTLs) may provide protection from persistent HHV8 infection. These results support the crucial role of cellular immune responses in controlling HHV8 replication, in preventing malignancies in latently infected subjects, and in conferring genuine resistance to persistent infection. They may also have important implications for the design of prophylactic and therapeutic HHV8 vaccines, and for adoptive immunotherapy of KS. (Blood. 2006; 108:3871-3880)

Kaposi's sarcoma may develop in homosexual or bisexual men without HIV infection. This type of Kaposi's sarcoma has clinical features in common with classical Kaposi's sarcoma but occurs in younger patients. Its prognosis is good, as Kaposi's sarcoma is generally limited, but clinicians should be aware of the association with lymphoproliferative diseases, which may affect prognosis.