PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE (PPNAD) PRESENTING AS CUSHING SYNDROME IN A CHILD AND REVIEW OF LITERATURE.

Cushing syndrome in the paediatric age group is very difficult to diagnose due to atypical presenting features in children. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome in children and it has characteristic gross and microscopic pathologic features. We report a case of PPNAD in a 16-year-old boy who was evaluated in our hospital with chief complaints of poor height velocity and rapid weight gain for 2-3 years before presentation. Proper evaluation showed ACTH-independent Cushing syndrome with normal imaging. Total bilateral adrenalectomy was performed followed by hormones replacement. 6 months after surgery, significant acceleration of height velocity was noticed. Patient also lost body weight and developed secondary sexual characteristics.

Copy number differences of Y chromosomal genes between superior and inferior quality semen producing crossbred (Bos taurus × Bos indicus) bulls.

The removal of crossbred bulls from semen collection programs due to the production of poor quality semen causes substantial monetary losses to the dairy industry. Seminal quality, a quantitative trait, is greatly influenced by genome level variations. Deletion and/or duplication of Y chromosomal genes and subsequent changes in gene copy number have a major role in determining spermatogenic efficiency and, therefore, seminal quality. In this study, copy numbers of three Y chromosomal genes TSPY, DDX3Y, and USP9Y in genomic DNA were estimated and compared in two groups of crossbred (Bos taurus × Bos indicus) bulls of ten each, superior and inferior quality semen producing bulls, which were classified based on their seminal quality parameters. For TSPY gene, the inferior quality semen donor group has significantly lower copy number than superior quality semen donor group (p < 0.05). No significant difference was found in DDX3Y and USP9Y gene copy numbers between two groups (p > 0.05). In conclusion, this study demonstrates that the copy number of TSPY, a Y chromosomal spermatogenesis related gene, may be an important determinant to predict the quality of bull semen, facilitating better selection of bulls in a herd for semen collection program.

Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma.

DNA methylation plays an important role in cancer biology and methylation events are important prognostic and predictive markers in many tumor types. We have used methylation-specific multiplex ligation-dependent probe amplification to survey the methylation status of MGMT and 25 tumor suppressor genes in 73 glioblastoma cases. The data obtained was correlated with overall survival and response to treatment. The study revealed that methylation of promoter regions in TP73 (seven patients), THBS1 (eight patients) and PYCARD (nine patients) was associated with improved outcome, whereas GATA5 (21 patients) and WT1 (24 patients) promoter methylation were associated with poor outcome. In patients treated with temozolomide and radiation MGMT and PYCARD promoter methylation events remained associated with improved survival whereas GATA5 was associated with a poor outcome. The identification of GATA5 promoter methylation in glioblastoma has not previously been reported. Furthermore, a cumulative methylation score separated patients into survival groups better than any single methylation event. In conclusion, we have identified specific methylation events associated with patient outcome and treatment response in glioblastoma, and these may be of functional and predictive/prognostic significance. This study therefore provides novel candidates and approaches for future prospective validation.

Occurrence and distribution of pilomyxoid astrocytoma.

PURPOSE: To know the occurrence and distribution of Pilomyxoid Astrocytomas amongst tumours previously diagnosed histologically as Pilocytic Astrocytoma and to assess the clinical impact of this new entity. METHODS: Retrospective Diagnostic review of all cases histologically diagnosed as WHO Grade I Astrocytoma at a single Neurosurgical unit between 1990 and 2003. RESULTS: Of a total of 91 cases identified, 9 were found to have Pilomyxoid histology. Of these, 8 were children (mean age 3.33 years) and 1 adult. 6 tumours were hypothalamochiasmatic in location. The clinical course of Pilomyxoid tumours was aggressive marked by maturation, multiple recurrences and disease control was rarely achieved with single treatment modality as opposed to typical pilocytics. The overall survival of the pilomyxoid group was not statistically different from the pilocytic tumours. CONCLUSIONS: Encompassing all age-groups and locations, Pilomyxoid Astrocytomas constitute about 10% of all tumours previously diagnosed as Pilocytic Astrocytoma. Nearly two-thirds are hypothalamo-chiasmatic in location. Knowledge of this entity is essential for appropriate aggressive treatment and follow-up.

H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3.

Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K, but not E545K PI3K, markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors.

Metastatic malignant melanoma within meningioma with intratumoral infarct: report of an unusual case and literature review.

We report an unusual case of a patient with a sphenoid wing meningioma that after a few years of static radiological appearance presented with sudden deterioration following rapid growth of tumor with intratumoral infarct. The patient underwent surgery and malignant melanoma deposits within the meningioma were demonstrated on histopathological examination. She had a history of a malignant melanoma (MM) excised from the left forearm 10 months ago with no evidence of recurrence. Although metastasis to meningioma has been widely reported, this is only the second report where the primary tumor is MM. In addition, to the best of our knowledge, intratumoral hypodensity from metastasis is unusual. The tumor-to-tumor phenomenon is discussed and the literature is reviewed.

Distribution of uranium in drinking water and associated age-dependent radiation dose in India.

Exposure due to natural radiation is of particular importance because it accounts for the largest contribution (nearly 85 %) to the total collective dose of the world population. An attempt has been made to present the feasibility of uranium occurrence in drinking water samples from different states of India, by laser-induced fluorimetry. The associated age-dependent radiation dose was estimated by taking the prescribed water intake values of different age groups. The concentration of uranium obtained, i.e. 0.1 +/- 0.01 to 19.6 +/- 1.8 microg l(-1), is well below the drinking water guideline value of 30 microg l(-1). The annual ingestion dose due to uranium in drinking water for various age groups is found to vary from 0.14 to 48 microSv y(-1).

Primitive neuroectodermal tumour arising within low grade astrocytoma: transformation, de novo or radiation induced? Report of three cases and review of literature.

The transformation from low grade to aggressive astrocytoma is well known. However, the development of a completely different tumour such as a primitive neuroectodermal tumour (PNET) within a low grade astrocytoma (LGA) is rare. Only two cases have been reported to date. We present three cases and review the literature. One case was identified at presentation. A subsequent review of our histopathology database revealed two further cases. All three patients had histologically proven low-grade astrocytoma and received radiotherapy following biopsy. The tumour location was infratentorial in one and supratentorial in two. The mean age at presentation with initial tumour was 20 years. Two patients underwent partial resection for recurrence, one at five and the other ten years later with histological confirmation of low-grade astrocytoma. At subsequent recurrence eight and thirty years following original presentation and eleven years later for the third patient, further tumour debulking was performed. Histology now revealed high grade PNET. Cytogenetics showed a complex karyotype with multiple chromosomal abnormalities in all three patients. All patients died within 1 year of final surgery. Among the six reported cases of PNET arising following prophylactic radiation therapy to low grade astrocytomas, only two occurred within the original tumour. Whether these cases represent transformation of low-grade astrocytoma, de novo formation of new tumour or radiation induced neoplasm is uncertain.

Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis.

The iron chelator, Desferal, suppressed disease activity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and it has been tested in pilot trials for MS. The administration regimen of Desferal is cumbersome and prone to complications. Orally-deliverable, iron chelators have been developed that circumvent these difficulties, and the objective of this study was to test an oral chelator in EAE. SJL mice with active EAE were randomly assigned to receive deferiprone (150 mg/kg) or vehicle (water) 2x/day via gavage. EAE mice given deferiprone had significantly less disease activity and lower levels of inflammatory cell infiltrates (revealed by H&E staining) than EAE mice administered vehicle. T-cell infiltration, assessed by anti-CD3 immunohistochemical staining, also was reduced, although not significantly. Splenocytes cultured from naïve SJL mice were stimulated with anti-CD3 and anti-CD28 with or without 250 microM deferiprone. While approximately 39% of costimulated splenocytes without deferiprone underwent division, only approximately 2.8% of costimulated splenocytes with deferiprone divided and the latter cells were only 53% as viable as the former. Deferiprone had no effect on proliferation or viability of cells that were not costimulated. In summary, deferiprone effectively suppressed active EAE disease and it inhibited T-cell function.

A rare case of recurrent secretory meningioma with malignant transformation.

A 72-year-old woman previously operated for a sphenoid-ridge meningioma, now presented with double vision. Histology showed a secretory meningioma with an epithelial-appearing, malignant component. Malignant transformation in a secretory meningioma is not known. This is the first report of such an occurrence.

Cervical spine metastasis from adrenal pheochromocytoma.

Metastatic tumours are the most common type of tumours in the spine of which only 10% occur in the cervical spine. We report a rare presentation of metastatic pheochromocytoma of the cervical spine which was successfully treated operatively. Adequate precautions should be taken during surgery as the tumour is very vascular. Radiotherapy is useful in the treatment of residual tumour.

Gorham's disease of skull base and cervical spine--confusing picture in a two year old.

The unusual presentation of Gorham's disease of skull base and cervical spine in a two-year-old female child with radiological signs mimicking those of raised intracranial pressure is discussed. The differential diagnosis consists of skull base tumours, meningitis, osteomyelitis of the base of skull, congenital hydrocephalaus and congenital syndromes involving the skull base. Pathologically it can be very difficult to differentiate it from lymphangioma of the bone. Difficulty in establishing the diagnosis is discussed along with failure of radiotherapy and palmidronate therapy to cause arrest of the disease process and failure of surgery to provide stabilisation. We describe the course of the disease in this child over the period of last eight years. To the best of our knowledge this is the youngest case of Gorham's described so far.

Intracranial non-Hodgkin's MALT lymphoma mimicking a large convexity meningioma.

Primary presentation of an intradural Non-Hodgkin's lymphoma is rare. Recently these B cell lymphomas of mucosa associated lymphoid tissue (MALT) have gained acceptance as an important pathological subtype and are distinguishable from other primary CNS lymphomas that exhibit aggressive behaviour. Over the past decade a number of these lesions have been reported to resemble a meningioma both intra-operatively and radiologically. The authors outline such a case of marginal zone B cell lymphoma that clinically and radiologically resembled a meningioma. This case illustrates the rare occurrence of low grade dural B cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions, if appropriate targeted therapy is to be administered.

Pronounced inhibitory effect of chlorcyclizine (CCZ) in experimental hepatocarcinoma.

Thepiperazine chlorcyclizine HCl (CCZ), possessing significant antimetabolic as well as virucidal and virustatic activities against the human immunodeficiency virus (HIV) and other retroviruses, was selected to determine its anticarcinogenic potential The anticancer activity of CCZ was evaluated against procarcinogen n-diethylnitrosamine (NDA)-initiated hepatocarcinogenesis, which was subsequently promoted by phenobarbital (PB) in male Sprague-Dawley rats. The anticancer efficacy of CCZ was monitored by estimating some potential markers of neoplastic and preneoplastic hepatic conditions, e.g., glutathione (GSH), glutathione-S-transferase (GST) and gamma-glutamyl transpeptidase (gammaGTP). CCZ exhibited antineoplastic activity on a long-term therapeutic basis. Furthermore, this drug restricted the exponential increase of the antioxidant markers in the hyperplastic nodule and the surrounding liver tissues in comparison with the carcinogen-controlled rats during the entire period of treatment. A decrease in the number of nodules was observed in the CCZ-treated group.

Twenty year review of histopathological findings in enucleated/eviscerated eyes.

BACKGROUND/AIMS: To evaluate the need for routine histopathological analysis of enucleated/eviscerated eyes and changes in indications for eye removal. METHODS: Retrospective review of all enucleation/evisceration histopathology reports over 20 years. Clinical history was correlated with pathological findings. Two 10 year periods (1984-93, 1994-2003) were compared to detect changes in indications for eye removal. RESULTS: In total, 285 histopathology results were traced from 1984 to 2003; 161 and 124 were evisceration and enucleation specimens, respectively. Glaucoma, malignant melanoma, trauma, and retinal detachment were the most frequent diagnoses 1984-1993. Ocular trauma was the most frequent diagnosis 1994-2003, followed by phthisis bulbi and endophthalmitis. Three cases were diagnosed as metastatic carcinoma; all were suspected preoperatively. A fourth case was a diagnostic surprise: adenocarcinoma found in an eye removed for pain and phthisis. Comparison of two 10 year periods showed a decrease in the number of enucleations/eviscerations, perhaps reflecting a decrease in the number of specimens sent. A preference for eviscerations was evident over the 20 years. CONCLUSION: The number of eyes removed and histologically analysed decreased in the period 1994 to 2003, perhaps because of better treatment options, allowing globe preservation. There was a significant shift in the diagnosis in the two time periods, and a preference for evisceration in both. Only one diagnostic surprise was discovered (0.35%). This study does not support the need to send all globes/contents for histopathological examination. However, because of the one unexpected finding, it is recommended where the examination is incomplete or the history of visual loss is unclear.

Management of Vascular Injuries in a Forward Hospital.

BACKGROUND: Management of vascular injuries poses a challenging problem under warlike conditions. Several authorities recommend limb revascularisation only within first 6-8 hours, as the outcome after delayed revascularisation is poor. METHODS: A retrospective analysis of 61 consecutive patients with vascular injury in a forward hospital over a 25- month period was carried out. RESULTS: Vascular injuries constituted 3.1% of all injuries. The mean injury to treatment delay (lag time) was 11 hours, and 10 patients received treatment after 12 hours. The overall amputation rate was 15%, but only 6.5% for those revascularised within 12 hours and 44% for those undergoing surgery after 12 hours (Chi-square 4.59, p < 0.05). Presence of associated fractures was associated with an adverse outcome (Chi-square 4.24, p < 0.05), as was ligation in comparison to revascularisation (Chi-square 7.86, p < 0.005). Popliteal injuries were associated with a high amputation rate. CONCLUSIONS: Failure to revascularise (ligation of artery), presence of associated fracture, and restoration of circulation beyond 12 hours are associated with a high amputation rate.

Outcome of periocular basal cell carcinoma managed by overnight paraffin section.

BACKGROUND: Surgical excision of periocular skin cancer allows for optimum control in terms of tumour recurrence. Although Mohs' technique gives the best outcome, it is not widely available. Processing paraffin sections is slower but histologically superior to Mohs' frozen sections. We report the results of using a standard paraffin section (non-Mohs') technique to confirm histological clearance. METHOD: A retrospective study between 1/6/95 and 1/6/99 of all consecutive patients who had excision of periocular cancer was performed. All patients had surgical excision of the tumour with a 3-mm margin. Rapid (24-hour) paraffin sections were done and reconstruction performed if histological clearance was confirmed. If tumour was still present, a further 3-mm margin was excised at the appropriate edge(s) before reconstruction took place. RESULTS: This study yielded 93 basal cell carcinomas (BCCs) of which 86 were of primary origin and 7 were recurrent tumours. The tumour characteristics were as follows: 88% nodular BCCs, 82% had a maximum surface measurement less than or equal to 10 mm, 39.8% were inner canthal and 49.5% were localised to the lower lid. In the 30 (35.4%) cases that required further excision based on the initial histological reports, tumour was seen in only four (11.4%) cases. Overall histological clearance for primary BCCs was achieved in 81/86 (94.2%) cases. There was only one late recurrence at 4 years and 5 months. Among recurrent BCCs, there was one recurrence (12.5%) and this was despite histological clearance having been reported. CONCLUSION: For primary BCCs the recurrence rate in this study was low and comparable to that following Mohs' technique. This approach, using routine pathological facilities, therefore offers a viable technique for managing periocular BCCs.