Significant morphological change in osteoarthritic hips identified over 6-12 months using statistical shape modelling.

OBJECTIVE: Predicting who will develop osteoarthritis, assessing how rapidly their disease will progress and monitoring early responses to treatment are key to the development of therapeutic agents able to treat this crippling disease and to their future clinical use. Statistical Shape Modelling (SSM) enables quantification of variations in multiple geometric measures describing the whole hip joint to be considered in concert. This prospective study evaluates the responsiveness of SSM to changes in hip-shape within 1 year. METHODS: Sixty-two people, mean age 67.1 yrs, were recruited. Dual-energy X-ray Absorptiometry images were taken at three timepoints (baseline, 6 and 12 months). Based on Kellgren-Lawrence grading (KLG) of their baseline images, subjects were classified into control/doubtful OA: KLG < 1 in both hips; moderate OA: KLG = 2; and severe OA: KLG ≥ 3 in their most severe hip. Morphology was quantified using SSM and changes in shape were assessed using generalised estimating equations. Standardized response means (SRMs) were calculated for the first and second 6 month periods, then the full 12 months. RESULTS: Disease severity ranged from KLG0-KLG4 in the 124 hips assessed at baseline. Three SSM modes (Modes 1, 3 and 4) were associated with OA severity. Across the whole cohort, SRM magnitudes ranged from 0.16 to 0.63. The greatest subgroup SRM (magnitude 0.91) was observed over 12 months in those subjects with moderate OA (KLG2). CONCLUSIONS: We have demonstrated that SSM can capture changes in hip shape over 6 and 12 months across the entire hip joint providing a sensitive measure of hip OA progression.

DXA-derived hip shape is related to osteoarthritis: findings from in the MrOS cohort.

OBJECTIVE: Statistical shape modelling (SSM) of radiographs has been used to explore relationships between altered joint shape and hip osteoarthritis (OA). We aimed to apply SSM to Dual-energy X-ray Absorptiometry (DXA) hip scans, and examine associations between resultant hip shape modes (HSMs), radiographic hip OA (RHOA), and hip pain, in a large population based cohort. METHOD: SSM was performed on baseline hip DXA scans from the Osteoporotic Fractures in Men (MrOS) Study. Associations between the top ten HSMs, and prevalent RHOA from pelvic radiographs obtained 4.6 years later, were analysed in 4100 participants. RHOA was defined as Croft score ≥2. Hip pain was based on pain on walking, hip pain on examination, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). RESULTS: The five HSMs associated with RHOA showed features of either pincer- or cam-type deformities. HSM 1 (increased pincer-type deformity) was positively associated with RHOA [1.23 (1.09, 1.39)] [odds ratio (OR) and 95% CI]. HSM 8 (reduced pincer-type deformity) was inversely associated with RHOA [0.79 (0.70, 0.89)]. HSM 10 (increased cam-type deformity) was positively associated with RHOA [1.21 (1.07, 1.37)]. HSM 3 and HSM 4 (reduced cam-type deformity) were inversely associated with RHOA [0.73 (0.65, 0.83) and 0.82 (0.73, 0.93), respectively]. HSM 3 was inversely related to pain on examination [0.84 (0.76, 0.92)] and walking [0.88, (0.81, 0.95)], and to WOMAC score [0.87 (0.80, 0.93)]. CONCLUSIONS: DXA-derived measures of hip shape are associated with RHOA, and to a lesser extent hip pain, possibly reflecting their role in the pathogenesis of hip OA.

Can we improve the prediction of hip fracture by assessing bone structure using shape and appearance modelling?

PURPOSE: There is a continuing need to improve the prediction of hip fractures to identify those at highest risk, enabling cost-effective use of preventative therapies. METHODS: The aim of this work was to validate an innovative imaging biomarker for hip fracture by modelling the shape and texture of the proximal femur assessed from dual energy X-ray absorptiometry (DXA) scans. Scans used were acquired at baseline from elderly patients participating in a prospective, placebo-controlled fracture prevention study of the bisphosphonate, clodronate. 182 subjects who subsequently suffered a hip fracture were age, weight and height matched with two controls who did not suffer a fracture during a median 4-year follow-up period. Logistic regression was used to test if variables were good predictors of fracture and adjust for bone mineral density (BMD). RESULTS: Shape mode 2, reflecting variability in neck-shaft angle, neck width and the size of both trochanters (0.81 (OR), 0.68-0.97 (CI), 0.024 (P)), and appearance mode 6, recording grey-level contrast (1.33, 1.11-1.59, 0.002), were significant predictors of hip fracture and remained so after adjustment for BMD (shape mode 2 (0.77, 0.64-0.93, 0.006), appearance mode 6 (1.32, 1.10-1.59, 0.003)). Receiver Operating Curve analysis showed the combination of shape mode 2, appearance mode 6 and BMD was 3% better than any single predictor. CONCLUSION: Variables derived from shape and appearance models gave a prediction of fracture comparable to BMD and in combination with BMD gave an improvement in the prediction of hip fracture that could predict an additional 2000 hip fracture cases per year in the UK, potentially saving more than £20 million per year and 10,000 cases in the US.

Population screening for osteoporosis risk: a randomised control trial of medication use and fracture risk.

UNLABELLED: Randomised control trial of osteoporosis screening in 4,800 women aged 45-54 years was carried out. Screened group observed an increase of 7.9% in hormone replacement therapy (HRT) use (p < 0.001), 15% in other osteoporosis treatments (p < 0.001) and a 25.9% reduction in fracture risk compared with control. Screening for osteoporosis significantly increases treatment use and reduces fracture incidence. INTRODUCTION: Population screening programmes can identify menopausal women with low bone mineral density (BMD) and elevated risk of future fracture but require to be proven effective by a randomised control trial. METHODS: A total of 4,800 women, 45-54 years, were randomised in equal numbers to screening or no screening (control) groups. Following screening, those in the lowest quartile of BMD were advised to consider HRT. Nine years later, the effect of screening on the uptake of treatment and the incidence of fractures were assessed by postal questionnaire. Categorical differences were assessed using chi(2) test. Cox regression was used to assess hazard ratio (HR). RESULTS: Of the screened and the control groups, 52.4% vs 44.5%, respectively, reported taking HRT (p < 0.001). In addition, 36.6% of the screened vs 21.6% of the control groups reported the use of vitamin D, calcium, alendronate, etidronate or raloxifene (p < 0.001). In a per protocol analysis of verified incident fractures, a 25.9% reduction in risk of fractures (of any site) in the screened group was observed (HR = 0.741, 95% CI = 0.551-0.998 adjusted age, weight and height). CONCLUSIONS: Screening for osteoporosis as assessed by low bone density significantly increases the use of HRT and other treatments for osteoporosis and reduces fracture incidence.

Screening elderly women for risk of future fractures--participation rates and impact on incidence of falls and fractures.

We have assessed the acceptability of a method for screening for risk of future hip fracture in elderly women. After receipt of an initial response to a mailed risk-factor questionnaire sent out to 5,306 women, women were randomly assigned to active or control groups. The active group was invited to participate in a screening visit that comprised a life-style questionnaire and a quantitative ultrasound heel scan. General practitioners (GPs) of women who were found to be in the lowest quartile of broadband ultrasound attenuation and/or who had two or more risk factors for hip fracture were advised to prescribe a calcium and vitamin D supplement. A second mailed questionnaire was sent to both groups 1 to 3 years later. Compared with the control group, the active group had a 56% lower risk of fracture (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24-0.81 adjusted age, weight, and treatment status). At follow-up, the proportion of fallers in the active group (25.3%) was lower than that in the control group (29.6%) (P = 0.064). The control group was found to have a higher rate of falls at follow-up than the active group (95% CI, 0.02-0.22); no difference was found at baseline (95% CI, -0.08 to +0.14). The screening method used was found to be acceptable to the majority of elderly women in this study. Screening the elderly in this way together with simple advice on treatment appears to reduce the age-associated increase in fall rates and the number of subsequent fractures. This form of screening may provide a cost-effective method to reduce falls and fractures in free-living elderly women. However, no such cost-effectiveness analysis has been performed to date.

Can peripheral DXA measurements be used to predict fractures in elderly women living in the community?

While axial dual energy X-ray absorptiometry (DXA) is the accepted "gold standard" method both for diagnosing osteoporosis and predicting fractures, appropriate equipment is not universally available. Peripheral bone mass measurements may have the potential to identify patients at risk of fracture and to be used to target appropriate treatment. We assessed the effectiveness of peripheral DXA (PIXI, GELunar) in the assessment of risk and targeting treatment to prevent future fracture in 7,604 women aged 60-80 from five centres across Britain. At enrolment women completed a lifestyle and risk factor questionnaire and had a PIXI DXA scan of the heel. Women were categorised by PIXI DXA bone mineral density (BMD) into high, medium or low risk of future osteoporotic fracture. Treatment was recommended to those at highest risk. Follow-up was by simple questionnaire 18-24 months after baseline assessment. Seventy-four percent returned the follow-up questionnaire. The area under the receiver operator characteristic (ROC) curves for any fracture and osteoporotic fracture were comparable to those published using other sites and technologies. A 1-SD decrease in PIXI BMD was associated with an 86% increase in risk of osteoporotic fracture. Of the women identified as high risk, 74% had started treatment following their heel scan and 84.7% continued to take treatment at follow-up. No significant difference was noted in fracture rates in those who started treatment after assessment compared to those who did not. While peripheral DXA is highly effective for predicting older women who are at increased risk of future fracture, it has yet to be established as an effective method for targeting bisphosphonate or other therapy.

The nongenotropic synthetic ligand 4-estren-3alpha17beta-diol is a high-affinity genotropic androgen receptor agonist.

The nongenotropic ligand estren (Science 298:843-846, 2002) was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate two known target genes of AR in androgen-responsive cell lines. Estren binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-alpha or ERbeta. Estren-bound AR can translocate AR to the nucleus and stimulate the androgen response element-luciferase reporter activity with an efficacy similar to that of androgen. Estren also increased the expression of prostate-specific antigen (PSA) in a dose-dependent manner in human LnCaP cells. Using chromatin immunoprecipitation analysis, we show that the estren-bound AR coimmunoprecipitates with a region of the PSA gene promoter. Therefore, cotreatment with an AR antagonist, bicalutamide, blocked the estren-induced increase in PSA expression. In contrast, phosphoinositol 3-kinase inhibitor wortmannin, or extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male-orchidectomized ICR mice revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Taken together, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen-responsive cells and tissues.

p16 expression in psoriatic lesions following therapy with propylthiouracil, an antithyroid thioureylene.

Plaque formation is a characteristic finding in patients with psoriasis and reflects cytokine-induced keratinocyte proliferation and/or impaired apoptosis of keratinocytes. Antithyroid thioureylenes such as propylthiouracil (PTU) and methimazole (MMI) are effective in the treatment of plaque psoriasis. Following PTU and MMI treatment, proliferative cell nuclear antigen (PCNA) expression is significantly reduced, suggesting that these medications have an antiproliferative effect. p16 is an antiapoptotic protein that is present in relative abundance in psoriatic plaques and is believed to play a potential role in the persistent senescence and impaired apoptosis of the keratinocytes in the plaque. This study examined p16 expression in biopsy samples of eight patients with plaque psoriasis given 300 mg of propylthiouracil in divided doses for 3 months. Despite significant clinical and histological improvement with PTU treatment, p16 expression was essentially unchanged, suggesting that the beneficial effect of PTU in psoriasis is not mediated through a decrease in p16 expression. The effect of PTU on other antiapoptotic proteins such as bcl-xL remains to be determined.

Wnt ligand expression in malignant melanoma: pilot study indicating correlation with histopathological features.

AIMS: Secreted Wnt ligands are key proteins regulating cell-cell interactions and cell growth and differentiation. These proteins, along with other components of the Wnt signalling pathway, are involved in the malignant transformation of various human cancers, including malignant melanoma. This study defines the expression of several members of the Wnt ligand family and correlates their expression with histological characteristics. METHODS: The expression of Wnt2, Wnt5a, Wnt5b, Wnt7b, and Wnt10b was defined by in situ, antisense RNA hybridisation of paraffin wax embedded sections of benign naevi and malignant melanoma. Immunoperoxidase based antibody staining was used to define the expression of frizzled (Fz) receptors. RESULTS: All naevi tested strongly expressed Wnt2, Wnt5a, Wnt7b, and Wnt10b. Melanomas characterised by small, uniform cells expressed each of the Wnts in a pattern similar to that seen for benign naevi. In contrast, melanomas characterised by large, pleomorphic cells expressed Wnt10b but did not express Wnt2 and had low levels of expression of Wnt5a. Expression of Wnt7b was variable in these melanomas. Fz receptor expression was present at a low level in normal epithelium and all naevi and melanomas. CONCLUSIONS: The expression pattern of Wnt ligands in malignant melanoma correlates with histopathological features and may provide a basis for the molecular classification of this disease.

The early management of severe tibial pilon fractures using a temporary ring fixator.

BACKGROUND: The management of pilon fractures of the distal tibia is fraught with complications. Poor initial management leads to a poorer outcome. Protection of the soft tissue envelope is paramount and to achieve this objective early fracture reduction, restoration of leg length and elevation are important principles in the management of severe injuries. Reduction and restoration of length can be achieved through ligamentotaxis by various methods but the most commonly employed are calcaneal traction or bridging external fixation. OBJECTIVE: We describe our method for the early management of these injuries using a simple semicircular bridging frame.

Minimal deviation melanoma.

Minimal deviation melanomas (MDM) are poorly characterized, uncommon naevomelanocytic tumours that are thought to represent part of the continuum from benign atypical naevi to frank malignant melanomas. Exactly where on that continuum they stand and who is most affected remains controversial. The few studies classifying MDM pointed to a less aggressive nature. Furthermore, it is thought that MDM affects patients in the fourth and fifth decades of life. In a recent review conducted at our institution, medical records of all patients with melanoma diagnosed at a tertiary care university medical center between January 1997 and May 2000 were reviewed to identify those with MDM. Those with MDM were examined to determine subtype, age and sex distributions, and location of tumour and findings were compared to those in the published literature. Unlike previous studies, the mean age of patients with MDM was 27 years with 20/31 being under 30 years old. Our results support prior findings that MDM is less aggressive than typical malignant melanomas in that only 1/5 undergoing lymphatic mapping had a positive node. Despite its description more than 30 years ago, MDM remains a poorly understood pathologic entity. Further study in such techniques as sentinel lymph node mapping and determination of angiogenesis factors is warranted to give insight as to what features predict an aggressive nature and to identify prognostic factors.

Basal cell carcinoma of the buccal mucosa.

True basal cell carcinoma (BCC) involving the oral mucous membranes is extraordinarily rare. Most of those described as occurring in the oral cavity usually involve the gingiva and are not true BCCs but peripheral ameloblastomas. A true BCC, which arose on the buccal mucosa of a 69-year old man, is reported. It presented as a 1.3 cm ulcerated plaque without gingival connection. Histologically, the lesion exhibited classic features of BCC with palisading and retraction spaces, and focally communicated with the overlying squamous epithelium. Although it is possible that this lesion also arose from a heterotopic odontogenic rest, the anatomical location, focal squamous (metatypical) features, and positive staining for Ber-EP4 support an origin from the basal cell layer of stratified squamous mucosa.

Testicular choriocarcinoma metastatic to the skin: an additional case and literature review.

Choriocarcinoma, a malignancy of trophoblastic cells, is characterized by the secretion of human chorionic gonadotropin (hCG). Choriocarcinoma primarily arises from the fetal (placental) trophoblasts in the setting of a molar pregnancy. Nongestational choriocarcinoma from the ovary or testis is much rarer. Testicular choriocarcinoma is a malignant tumor with great propensity for distant metastasis. The primary sites of metastasis are the lungs, liver, and brain. Skin metastasis is very rare but portends a grave prognosis when diagnosed. We present the case of a 24-year-old white male with a testicular mixed germ-cell tumor with skin metastases of choriocarcinoma.

Rippled-pattern sebaceous trichoblastoma.

BACKGROUND: There is a large spectrum trichoblastoma; of which, several histologic variants have been described including a rippled-pattern variant. Three cases of rippled-pattern trichoblastoma are described which also exhibited definitive foci of sebaceous differentiation. METHODS: Three cases were retrieved from the archives of the Dermatopathology Laboratory at the University of California Irvine (Orange, CA, USA). All specimens were stained with hematoxylin and eosin (H&E). In addition, sections were submitted for immunohistochemical studies with epithelial membrane antigen (EMA). RESULTS: All three biopsies were composed of well-circumscribed multiple variously sized tumor lobules present in the upper to deep dermis comprised of with rounded or slightly elongated basaloid cells with scant eosinophilic cytoplasm. The lobules were separated by a slightly hyalinized stroma. The unique finding present in all three specimens was a peculiar arrangement of the basaloid cells in linear rows parallel to one another. This gave the tumors a rippled pattern similar to the palisading of nuclei of Verocay bodies seen in schwannomas. In addition all three biopsies showed definite sebaceous differentiation. CONCLUSIONS: Three additional cases of rippled-pattern trichoblastoma are presented. All three were located on the scalp and showed additional features of foci of sebaceous differentiation. No associations with Muir-Torre Syndrome were found in these patients. Because this appears to be a distinct variant within the large spectrum of trichoblastoma, the term rippled-pattern sebaceous trichoblastoma is suggested.

Benign atypical junctional melanocytic hyperplasia associated with intradermal nevi: a common finding that may be confused with melanoma in situ.

Over the past few years, consultation cases thought to represent melanoma in situ have been received that consisted of otherwise normal intradermal nevi with an abnormal but benign junctional proliferation of melanocytes that we have termed benign atypical junctional melanocytic hyperplasia. In order to evaluate the incidence of this feature, 400 cases of intradermal nevi were reviewed. Of these, 25 (6.2%) qualified for inclusion, making this a rather common phenomenon. Clinically, patient ages ranged from 18 to 64 years (mean, 35 years), with a male to female ratio of 1:1. Face (40%) and back (32%) were the most common locations. Histologically, the lesions were predominantly dome-shaped with an intradermal component consisting of conventional nevus cells. Most importantly, each lesion exhibited prominent individual nevomelanocytic cells dispersed at uneven intervals along the dermoepidermal junction in insufficient numbers to be considered compound nevi. The cells exhibited abundant pale to clear cytoplasm, an increased nuclear:cytoplasmic ratio, and often exhibited prominent nucleoli. However, these lesions could be distinguished from melanoma in situ by the lack of several features including lateral spread, upward epidermal migration, marked cytologic atypia, finely granular "smoky" melanin pigment, mitotic figures, and a subjacent host inflammatory response. All cases behaved in a benign fashion. Although benign atypical junctional melanocytic hyperplasia is a relatively common histological curiosity, it is a potential pitfall in the diagnosis of pigmented lesions.

Epithelioid blue nevus occurring in children with no evidence of Carney complex.

We report two pediatric patients who had biopsies of solitary lesions diagnosed as epithelioid blue nevi. Histologically these lesions had wedge-shaped, heavily pigmented infiltrates extending to the subcutaneous fat. The infiltrate was composed of spindled and polyhedral cells that were nevomelanocytic cells with nuclear pleomorphism. Also noted were pigmented globular cells interpreted as melanophages. These lesions have the same characteristics as those blue nevi occurring in patients with Carney complex. More recently, adult patients have been identified with similar nevi, but without evidence of Carney complex. To our knowledge, pediatric patients with epithelioid blue nevi, but no evidence of Carney complex have not been described previously.

Ectopic breast tissue and breast-like sweat gland metaplasias: an overlapping spectrum of lesions.

There are many similarities in the morphology of benign and malignant lesions of the sweat glands and the breasts. The recently described cutaneous mammary-like sweat glands, also known as mixed sweat glands or apoeccrine glands, are also a likely source of selected proliferations that closely mimic those of the breast. We present three cases of breast-like lesions arising in the skin that demonstrate the ways in which the morphologic and pathologic continuum of the mammary glands, cutaneous mammary-like glands, and sweat glands can produce difficulties in precise diagnosis. The examples demonstrate that an anatomic location outside the milk line does not preclude the diagnosis of ectopic mammary tissue, and that lesions closely resembling those of the breast may also arise outside the milk line from conventional sweat glands or mixed sweat glands. The concept of homologous lesions of the breast, breast-like glands and sweat glands, in which morphology is partially mirrored by biochemical similarities, provides a perspective for classification of problematic cases of breast-like cutaneous lesions.