The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma.

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2ß1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.

To know or not to know? Dilemmas for women receiving unknown oocyte donation.

BACKGROUND: This study aims to provide insight into the reasons for choosing an unknown oocyte donor and to explore recipients' feelings and wishes regarding donor information. METHODS: In-depth interviews were carried out with 11 women at different stages of treatment. Seven were on a waiting list and four have given birth to donor oocyte babies. The interviews were analysed using interpretative phenomenological analysis. RESULTS: The choice of unknown donor route was motivated by a wish to feel secure in the role of mother as well as to avoid possible intrusions into family relationships. The information that is available about unknown donors is often very limited. In the preconception phase of treatment, some participants wanted more information about the donor but others adopted a not-knowing stance that protected them from the emotional impact of needing a donor. In the absence of information that might normalize her, there was a tendency to imagine the donor in polarised simplistic terms, so she may be idealized or feared. Curiosity about the donor intensified once a real baby existed, and the task of telling a child was more daunting when very little was known about the donor. A strong wish for same-donor siblings was expressed by all of the participants who had given birth. CONCLUSIONS: This qualitative study throws light on the factors that influence the choice of unknown donation. It also highlights the scope for attitudes to donor information to undergo change over the course of treatment and after giving birth. The findings have implications for pretreatment counselling and raise a number of issues that merit further exploration.

The prognostic significance of delayed hypersensitivity to dinitrochlorobenzene and mechlorethamine hydrochloride in cutaneous T cell lymphoma.

Recent studies suggest that cells elaborating type 1 cytokines are important mediators of anti-tumor cell-mediated immunity in cutaneous T cell lymphoma. Type 1 cell-mediated immune responsiveness was assessed in 276 patients with cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome) using 2,4-dinitrochlorobenzene (DNCB) skin testing as part of the initial evaluation. The overall rate of sensitization after one and two DNCB challenges was 32% and 67%, respectively, which is much decreased compared with the expected rate of more than 95% for normal individuals. Moreover, the frequency of DNCB sensitization and allergic contact dermatitis to topically applied mechlorethamine decreased with advancing stage of disease. In addition to the expected strong correlation with stage, we observed that patients who were DNCB test positive were significantly less likely to experience disease progression and had a better overall prognosis compared with DNCB-negative patients. These results support the concept that cell-mediated responses are important in cutaneous T cell lymphoma, and that augmentation of these responses would be therapeutically beneficial.

Increased factor XIIIa transglutaminase expression in dermal dendrocytes after treatment with alpha-hydroxy acids: potential physiologic significance.

BACKGROUND: Topical alpha-hydroxy acids (AHAs) have been shown to improve photoaging in human skin. OBJECTIVE: We studied factor XIIIa transglutaminase expression in dermal dendrocytes (DDs) and mast cell degranulation after treatment of the skin with AHAs. METHODS: Skin biopsy specimens obtained from patients after 4 to 8 months of treatment with lotions containing 25% AHAs were evaluated for factor XIIIa transglutaminase expression with immunoperoxidase and electron microscopy. Immunoperoxidase-stained sections were studied by means of semiquantitative methods and image analysis. Mast cell degranulation was studied by image analysis. RESULTS: Increased factor XIIIa transglutaminase expression was seen after treatment with AHAs. All treated sites had increased scores compared with control sites by semiquantitative methods. Seventy-five percent of treated sites showed an increased mean area over control sites of factor XIIIa transglutaminase positivity with image analysis. These results correlated with an increased level of mast cell degranulation in treated sites and with activation of DDs as seen by electron microscopy. CONCLUSION: Treatment of the skin with AHAs leads to mast cell degranulation and increased expression of factor XIIIa transglutaminase by activated DDs. Mast cell degranulation may lead to activation of DDs and increased factor XIIIa transglutaminase expression, via the action of tumor necrosis factor-alpha. We speculate that clinical and histologic improvement in photoaged skin after treatment with AHAs may be somehow related to this process.

Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study.

BACKGROUND: alpha-Hydroxy acids (AHAs) have been reported to improve aging skin. The mechanisms of action of AHAs on epidermal and dermal compartments need clarification. OBJECTIVE: Our purpose was to determine the effects of AHAs on photoaged human skin by clinical and microanalytic means. METHODS: Patients applied a lotion containing 25% glycolic, lactic, or citric acid to one forearm and a placebo lotion to the opposite forearm for an average of 6 months. Thickness of forearm skin was measured throughout the study. Biopsy specimens from both forearms were processed for analysis at the end of the study. RESULTS: Treatment with AHAs caused an approximate 25% increase in skin thickness. The epidermis was thicker and papillary dermal changes included increased thickness, increased acid mucopolysaccharides, improved quality of elastic fibers, and increased density of collagen. No inflammation was evident. CONCLUSION: Treatment with AHAs produced significant reversal of epidermal and dermal markers of photoaging.

Use of pyruvic acid in the treatment of actinic keratoses: a clinical and histopathologic study.

Twelve patients with multiple actinic keratoses were treated with either 5-fluorouracil and pyruvic acid or pyruvic acid alone. Three patients were treated with 5 percent 5-fluorouracil cream for one to three weeks for comparison. Exposure time to alpha-hydroxy acids varied between one and ten minutes. Biopsy specimens were taken at times varying from immediately after treatment to eight weeks after treatment. The results show that the combination of 5-fluorouracil and pyruvic acid is an effective treatment for actinic keratoses. In addition, the exposure time to 5-fluorouracil is decreased and therefore this treatment is better tolerated than prolonged treatment with 5-fluorouracil alone.

A controlled clinical trial of a new formulation of betamethasone dipropionate cream in once-daily treatment of psoriasis.

In a multicenter, evaluator-blind, parallel group study of 244 patients with moderate to severe psoriasis, a once-daily application of a new formulation of beta-methasone dipropionate 0.05% cream, augmented formulation (AF), and a twice-daily application of fluocinonide 0.05% cream were compared, with respect to safety and efficacy. Results significantly favored betamethasone dipropionate AF over fluocinonide, as indicated by improvements in signs of erythema, induration, and scaling, as well as the physicians' and patients' global evaluations of response after 14 days of treatment. As a result of adverse experiences, treatment had to be discontinued in three patients on fluocinonide. No patient on betamethasone dipropionate AF had to discontinue treatment.

Risk of second malignancy after cutaneous T-cell lymphoma.

Risk of second primary malignancy was assessed in a population-based follow-up survey of all persons who developed cutaneous T-cell lymphoma (CTCL) in nine geographic areas of the United States covered by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute during the period 1973 to 1983. Among 544 patients with a first primary tumor reported as CTCL, a second cancer developed in 35 (6%), yielding a significantly elevated relative risk (RR) of 1.7, which reflects excesses for cancers of the lung and colon and non-Hodgkin's lymphoma. Although the excess of lymphoma may be related to the evolution of CTCL to less differentiated T-cell lymphoma, additional studies are needed to clarify the immunologic, genetic, viral, and environmental factors that may contribute to the development of second cancers.

Alpha hydroxy acids: procedures for use in clinical practice.

Alpha hydroxy acids and alpha keto acids applied topically in lower concentrations reduce the thickness of hyperkeratotic stratum corneum by reducing corneocyte cohesion at lower levels of the stratum corneum. This property permits efficient clinical control of dry skin, ichthyosis, follicular hyperkeratosis, and other conditions characterized by retention of stratum corneum. Applied topically in higher concentrations, these acids cause epidermolysis. This property provides a new alternative for treating seborrheic keratoses, keratoses commonly known as "age spots," actinic keratoses, and verrucae vulgares; all of which lesions involve distinct epidermal hyperplasia as well as retention of stratum corneum. Facial wrinkles can be modified with topical alpha hydroxy acids, applied in higher concentrations as office procedures, and concomitant daily home application of lower concentrations.

Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.

Complete responses lasting from 4 to 14 years were documented in 65 of 331 (20%) patients with cutaneous T cell lymphoma treated with topical mechlorethamine (HN2) between 1968 and 1982. Such long-lasting remissions occurred most often, but not invariably, in patients with patch or plaque phase mycosis fungoides without palpable lymphadenopathy (stage Ia or Ib). The likelihood of a continuous remission was enhanced by initiation of treatment before an unequivocal pathologic diagnosis. Despite the long-lasting responses in these patients, however, relapses have been documented in 11 (17%) of these patients, and all relapses occurred within 8 years of discontinuing maintenance topical chemotherapy. Thus, in our experience, a continuous remission lasting 8 or more years provides evidence that cutaneous T cell lymphoma can be eradicated by aggressive topical chemotherapy. This circumstance was observed in 35 patients, representing a cure rate of at least 11% overall. In addition, when compared with the general population of the United States, patients who received topical HN2 were at an 8.6-fold and a 1.8-fold increased risk for the development of squamous cell carcinoma and enhanced for Hodgkin's disease and colon cancer but not for systemic cancers known to be induced by systemic administration of alkylating drugs. These results compare favorably with experiences with topical HN2 chemotherapy at other centers but raise questions about the risks associated with long-term administration for maintenance of remissions.

Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids.

Hyperkeratinization is a primary or fundamental event in a majority of today's skin disorders. Hyperkeratinization is usually the result of decreased desquamation due to increased corneocyte cohesion. Strength of corneocyte cohesion is determined by strength of intercellular bonding. Intercellular bonding is weakened by water and diminished by retinoids and alpha hydroxy acids (AHAs). Conversely, bonding is strengthened or enhanced by dehydration, vitamin A deficiency, and some alpha acetoxy acids (AAAs). Agents that control or modify keratinization can be useful in treatment of many skin disorders.