Clinical characteristics, diagnosis, and outcomes of orbital biopsies in a single Irish centre.

AIMS: To review the distribution of histopathological diagnoses and visual outcome of orbital biopsy in an Irish tertiary referral centre over a 10-year period. METHODS: This was a retrospective, clinical-histopathological case series. Clinical records of all patients who underwent orbital biopsy between January 2008 and January 2018 in the Mater Misericordiae University Hospital were reviewed using data collected from theatre logbooks and hospital-based medical records. RESULTS: A total of 83 orbital biopsies in 77 patients were included for analysis in this study. The mean age was 55.7 ± 18.41 years. The mean follow-up period was 1.87 ± 2.097 years. The most common presenting symptoms and signs were pain (22.3%) and proptosis (27.6%). Most lesions were located in the extraconal space (65%), with incisional biopsy (65%) being the most common technique used to gain a sample for histopathological diagnosis. Histopathology analysis of the biopsies revealed malignant tumours (27, 32.5%), benign tumours (7, 8.4%), inflammation (26, 31.3%), and other diagnoses (23, 27%). Excluding patients who underwent exenteration procedures, no study patients suffered visual loss following orbital biopsy. CONCLUSIONS: Orbital biopsy serves as a safe diagnostic tool in managing orbital diseases. The breakdown of diagnosis in our patients is in line with international studies. No patients in our series suffered vision loss as a result of their orbital biopsy. This emphasises its use as a safe procedure in the diagnosis and management of patients with the orbital disease. Our data provides helpful guidance to clinicians when counselling patients for orbital biopsy.

Beware the Retrobulbar Optic Neuritis Diagnosis.

A 48-year-old gentleman presented to the ophthalmology department with progressive monocular vision loss, a relative afferent-pupillary defect, decreased color perception, headache, proptosis, and retro-orbital pain. This particular patient's demographics and disease course did not suggest a "typical" retro-bulbar optic neuritis and highlights the importance of avoiding presumptive steroid treatment in such "atypical" cases. Further investigations revealed a compressive optic neuropathy secondary to an orbital tumor (B-cell non-Hodgkin's lymphoma) and were subsequently treated by a multi-disciplinary approach. Early detection and commencement of treatment is a crucial determining factor in orbital lymphoma prognosis and is therefore an important differential diagnosis for an ophthalmologist to consider when evaluating patients with "atypical" optic neuropathies.

Glomangiomatosis of the lower leg.

This paper demonstrates a case of multiple glomangiomas, or glomangiomatosis, including clinical presentation, imaging appearances, and subsequent management. Differentiating features from typical glomus tumors are described. To the best of our knowledge, this is the first reported case of a glomangioma involving the distal tibiofibular syndesmosis.

Tenosynovial chondromatosis of the flexor pollicis longus tendon: A subtype of primary synovial chondromatosis.

Primary synovial chondromatosis is a rare benign neoplastic process, in which cartilaginous nodules are produced in the subsynovial tissue. It has 3 main subtypes (intra-articular, tenosynovial and bursal). We present the case of a 61-year-old female, with a mass involving her right thumb for at least 5 years, which had recently increased in size. X-ray showed a soft tissue mass, without calcification or any underlying bony abnormality. Ultrasound and MRI showed a 6-cm mass surrounding the right flexor pollicis longus tendon of the right thumb. The patient went on to have surgical resection and was given a diagnosis of tenosynovial chondromatosis.

Multimodal imaging of Spina Ventosa (TB Dactylitis) of the foot.

We present the case of a 29-year-old male healthcare worker with a 6 month history of progressive left foot pain resulting in presentation to the emergency department on 3 occasions. He denied systemic symptoms. Multimodal imaging demonstrated an expansile erosive inflammatory lesion centered on the neck of the second metatarsal with aggressive features. CT of the thorax, abdomen, and pelvis demonstrated calcified mediastinal lymph nodes and left inguinal adenopathy. The lesion was biopsied under ultrasound guidance demonstrating a necrotizing granulomatous osteomyelitis with acid fact bacilli. This is consistent with TB dactylitis (spina ventosa). Treatment with antimycobacterial drugs was commenced.

Subperiosteal hematoma of the iliac wing presenting with leg weakness in a young adult footballer.

We present the case of a 17 year old football player with a 2 week history of left leg weakness and difficulty weight-bearing. Magnetic resonance imaging revealed a well-circumscribed lesion deep to the left iliacus muscle. The patient proceeded to computed tomography-guided biopsy. The likely diagnosis was that of a subperiosteal haematoma of the iliac wing, which was exerting mass effect upon the left femoral nerve resulting in leg pain and weakness. Imaging was repeated at an interval of 1 month, at which time the lesion had almost entirely resolved. Subperiosteal haematoma of the iliac bone is a rare entity but should be considered as a potential diagnosis in young adults, particularly where there is a history of trauma or recent sports injury.

Genomic profiling of a dedifferentiated mucosal melanoma following exposure to immunotherapy.

The treatment landscape for metastatic melanoma has been revolutionised by the introduction of immunotherapy and targeted therapies. Despite these advances, some patients exhibit primary or acquired resistance to treatment. We present the case of a resected mucosal melanoma that on relapse underwent transformation to a dedifferentiated state. The relapsed tumour was phenotypically disparate and demonstrated loss of all typical melanoma-associated immunohistochemical markers. Furthermore, it demonstrated aggressive biological behaviour and immunotherapy resistance. We performed genomic profiling of the original and relapsed tumour to further elucidate the mechanisms underlying this rare phenomenon. Mass spectrometry-based single-nucleotide polymorphism genotyping technology was used to screen for mutations in the original and recurrent tumour. Whole-exome sequencing was performed on the original tumour, recurrent tumour and blood. Both the original and recurrent tumour shared a NRAS mutation, a similar aneuploidy profile and proportion of somatic single-nucleotide variants. However, in contrast to the original tumour, the recurrent tumour demonstrated a lower mutational burden and deletions in the CDKN2A/CDKN2B and CHEK2 genes. The genomic similarity between the original and recurrent tumour attests to a common ancestry and the possible existence of nongenomic drivers inciting phenotype plasticity. In contrast, the low mutational load and potential inactivation of tumour suppressor genes in the recurrent tumour may underlie its rapid proliferative rate and immunoresistance. Dynamic treatment models are desired in the future to track the genomic and epigenetic evolution of a tumour to guide optimal therapy choice and sequencing.

Leydig Cell Hyperplasia Mimicking a Testicular Tumour in a Patient with Klinefelter Syndrome.

BACKGROUND: Klinefelter syndrome (KS) is the most common sex-chromosomal disorder in males. Frequently under-recognized, it occurs in 1 in 500-600 male births. It is caused by the inheritance of at least one additional X chromosome from either parent. Patients often have uncommon or atypical malignancies. PATIENT: We describe the case of a 35-year-old man with 47XXY KS and previous cryptorchidism, presenting with a painful testicular mass. Histology confirmed Leydig cell hyperplasia. DISCUSSION: Cryptorchidism is an established risk factor for testicular tumours and occurs six times more commonly in KS than in the general population. Despite this, large epidemiological studies have shown a reduced burden of testicular cancer in these patients. The presentation of a hypoechoic lesion on ultrasound will prompt consideration of testicular tumours, however orchalgia represents an atypical presentation. In patients with KS, Leydig cell hyperplasia is a much more common entity and should be considered early in the differential diagnosis. LEARNING POINTS: The differential diagnosis of a testicular mass in Klinefelter syndrome includes malignancy and nodular Leydig cell hyperplasia.Diagnosis can be challenging, both radiologically and histologically.Orchalgia is atypical in Leydig cell hyperplasia.

Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: a retrospective registry.

INTRODUCTION: Sudden cardiac death (SCD) in young people is a rare but devastating event for families and communities. Ireland has previously had no measure of the incidence of SCD in young people. We report the incidence and causes of SCD in persons <35 years of age. METHODS AND RESULTS: We undertook a retrospective study of SCD between 2005 and 2007 in persons aged 15-35 years in the Republic of Ireland. We identified potential cases of out of hospital SCD through the Central Statistics Office (CSO) death certificate records. Autopsy, toxicology, and inquest reports were then obtained and analysed by an expert panel who adjudicated on the cause of death. A total of 342 potential SCD cases were identified through the CSO. Fifty were younger than 15 years of age, and 86 had either incomplete or unavailable post-mortem reports. Of 206 full reports obtained, 116 were adjudicated as cases of SCD. Cases were predominantly male (75%), with a mean age of 25.8 years (standard deviation 6.3). The incidence of SCD in this age range was 2.85 per 100,000 person-years (4.36 for males and 1.30 for females) and the incidence of sudden arrhythmic death syndrome (SADS) was 0.76 per 100,000 person-years. The commonest causes were SADS, 26.7% (31 of 116), followed by coronary artery disease, 20.7% (24 of 116), hypertrophic cardiomyopathy (HCM), 14.7% (17 of 116), and idiopathic left ventricular hypertrophy not fulfilling criteria for HCM, 10.3% (12 of 116). CONCLUSIONS: The incidence of SCD in the young in Ireland was 4.96 (95% CI 3.06, 6.4) for males and 1.3 (95% CI 0.62, 2.56) for females per 100 000 person-years. Sudden arrhythmic death syndrome was the commonest cause of SCD in the young, and the incidence of SADS was more than five times that in official reports of the Irish CSO.

Cyclin E1 is amplified and overexpressed in osteosarcoma.

Osteosarcoma is a genetically complex malignancy, predominantly afflicting the adolescent population and associated still with relatively poor long-term outcomes. Although there has been some improvement in the understanding of osteosarcoma biology, this has not yet translated particularly well into therapeutic advances. By using a whole-genome tiling path array for comparative genomic hybridization analysis, we sought to evaluate DNA copy number changes in 22 osteosarcoma tumor samples. Regions of most frequent gains or losses generated by Genomic Identification of Significant Targets in Cancer analysis were evaluated for genes of interest. Correlation of the copy number data with preexisting expression data for these genes yielded not only targets known to be important in osteosarcoma but also novel targets, notably cyclin E1. Fluorescence in situ hybridization and immunohistochemical analysis confirmed the findings. Overexpression of cyclin E1 has potential prognostic and therapeutic implications that are discussed herein.

High power, low frequency ultrasound: meniscal tissue interaction and ablation characteristics.

This study evaluates high power low frequency ultrasound transmitted via a flat vibrating probe tip as an alternative technology for meniscal debridement in the bovine knee. An experimental force controlled testing rig was constructed using a 20 kHz ultrasonic probe suspended vertically from a load cell. Effect of variation in amplitude of distal tip displacement (242-494 µm peak-peak) settings and force (2.5-4.5 N) on tissue removal rate (TRR) and penetration rate (PR) for 52 bovine meniscus samples was analyzed. Temperature elevation in residual meniscus was measured by embedded thermocouples and histologic analysis. As amplitude or force increases, there is a linear increase in TRR (Mean: 0.9 to 11.2 mg/s) and PR (Mean: 0.08 to 0.73 mm/s). Maximum mean temperatures of 84.6°C and 52.3°C were recorded in residual tissue at 2 mm and 4 mm from the ultrasound probe-tissue interface. There is an inverse relationship between both amplitude and force, and temperature elevation, with higher settings resulting in less thermal damage.

2D-DIGE as a strategy to identify serum markers for the progression of prostate cancer.

Prostate cancer is the most common solid organ malignancy affecting men in the United States and Western Europe. Currently, the main diagnostic tools used to look for evidence of prostate cancer include physical examination using digital rectal exam (DRE), serum concentrations of prostate specific antigen (PSA) and biopsy. However, due to the low specificity of PSA in differentiating prostate cancer from other benign conditions, many patients undergo overtreatment for their disease. There is an urgent need for additional markers to improve the diagnostic accuracy for early stages of prostate cancer. Proteomic analysis of serum has the potential to identify such markers. An initial discovery study has been completed using 12 serum samples from patients with different grades of prostate cancer (Gleason score 5 and 7) undergoing radical prostatectomy. Serum samples were subjected to immunoaffinity depletion and protein expression analysis using 2D-DIGE. Image analysis isolated 63 spots that displayed differential expression between the Gleason score 5 and 7 cohorts (p < 0.05), 13 of which were identified as statistically significant using two independent image analysis packages. Identification of differentially expressed spots was carried out using LC-MS/MS. Because of their functional relevance and potential significance with regards to prostate cancer progression, two of these proteins, pigment epithelium-derived factor (PEDF) and zinc-alpha2-glycoprotein (ZAG), have undergone extensive validation in serum and tissue samples from the original cohort and also from a larger independent cohort of patients. These results have indicated that PEDF is a more accurate predictor of early stage prostate cancer. We are confident that proteomics-based approaches have the potential to provide more insight into the underlying molecular mechanisms of the disease and also hold great promise for biomarker discovery in prostate cancer.

Fibrogenesis in Crohn's disease.

INTRODUCTION: Over one-third of patients with Crohn's disease (CD) will develop an intestinal stricture and the great majority of these will require at least one surgical procedure. While the pathogenesis of inflammation in CD has been extensively investigated, knowledge of stricture pathogenesis remains limited. The aim of this review is to discuss the current understanding of fibrogenesis in CD and to outline potential directions in research and therapeutics. METHODS: The electronic literature (January 1966 to May 2006) on CD-associated fibrosis was reviewed. Further references were obtained by cross-referencing from key articles. RESULTS: CD-associated fibrosis results from chronic transmural inflammation and a complex interplay among intestinal mesenchymal cells, cytokines, and local inflammatory cells. The fibroblast is the key cell type mediating stricture formation. The cytoarchitecure of the bowel wall is altered with disruption of the muscularis mucosa, thickening of the muscularis propria, and deposition of collagen throughout. The cytokine TGF-beta appears critical in this process, acting to increase growth factor and extracellular matrix (ECM) production and dysregulate ECM turnover. Potential therapeutic interventions are likely to concentrate on modulating down-stream targets of TGF-beta. CONCLUSIONS: Greater understanding of the biology of fibrostenosis is likely to yield significant advances in our ability to care for patients with stricturing CD. Potential dividends of this approach include identification of novel therapeutic targets and biomarkers useful for prognostication and therapeutic monitoring.

Effects of the dual 5 alpha-reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines.

BACKGROUND: The profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 alpha-reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures. METHODS: Both human prostate androgen-sensitive cell lines (PwR-1E, PNT-2, LNCaP, and PC3[AR2]) and an androgen-independent cell line (PC-3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman alpha-methylacyl-CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 microM to 10 microM of dutasteride. RESULTS: Dutasteride induced a dose-dependent increase in apoptosis in the androgen-sensitive prostate cell lines PwR-1E, PNT-2, and LNCaP and in the androgen receptor-expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC-3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression. CONCLUSIONS: The results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells.

Neutrophil transendothelial migration potential predicts rejection severity in human cardiac transplantation.

OBJECTIVE: Transplant rejection remains a clinical problem despite therapies that focus on lymphocyte suppression, with little attention focused on the neutrophil. Neutrophils are however the first leukocyte to infiltrate the allograft, are capable of causing myocardial damage and may facilitate lymphocytes recruitment. We hypothesised that an early allograft neutrophil infiltration influences rejection severity. METHODS: Myocardial neutrophil infiltration was assessed using CD15 and myeloperoxidase immunohistochemistry of rejection surveillance endomyocardial biopsy specimens from human cardiac transplant recipients (n=18). In patients undergoing cardiac transplantation (n=10), neutrophils were isolated from multiple perioperative blood samples using a ficoll-based density gradient centrifugation method. The expression of the neutrophil adhesion protein CD11b was then assessed using flow cytometry and compared to subsequent endomyocardial biopsy rejection grades. The effects of contemporary immunosuppressive agents on human neutrophil CD11b were also assessed using healthy control volunteers. RESULTS: Myeloperoxidase staining of endomyocardial biopsies from human heart transplant recipients demonstrated a positive correlation between the degree of neutrophil infiltration and rejection severity at the first postoperative biopsy. Rejection severity was unrelated to ischaemic time. Functional assessment of neutrophils obtained from recipients was then performed. Perioperative transplant sampling demonstrated a significant correlation between the preoperative expression of CD11b and rejection grade at the first postoperative biopsy. In addition, dynamic changes in CD11b expression in the first 24 h positively correlated with subsequent rejection severity. In vitro experiments showed that transplant immunosuppression did not alter neutrophil CD11b expression. CONCLUSION: This study demonstrates a potentially greater role for neutrophils in cardiac transplantation than previously recognised, and suggests that blockade of the early allograft neutrophil infiltration might prevent subsequent lymphocyte recruitment and attenuate rejection.