Laveniya Satgunaseelan - Academia.edu (original) (raw)

Papers by Laveniya Satgunaseelan

Research paper thumbnail of Abstract 210: Advancing knowledgebase representation of pediatric cancer variants through ClinGen/CIViC collaboration

Cancer Research, 2021

Childhood cancers are driven by unique profiles of somatic genetic alterations, with a significan... more Childhood cancers are driven by unique profiles of somatic genetic alterations, with a significant contribution from predisposing germline variants. Understanding the genomic landscape of pediatric cancers is complicated by their rarity, the heterogeneity of variation within a given disease, and the complex forms of structural variation they contain. Variants in childhood disease may differ from those in adult versions of the same cancer type, or may have different clinical significance. Currently, pediatric variants are underrepresented in cancer variant databases, and an urgent need exists for their publicly available expert curation. To address this, the Pediatric Cancer Taskforce (PCT) was formed within the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) (https://www.clinicalgenome.org/working-groups/somatic/). The PCT is a multi-institutional group of 39 members with broad experience in childhood cancer and variant curation, whose work con...

Research paper thumbnail of Modulation of immune response by head injury

Research paper thumbnail of P16 Expression Independent of Human Papillomavirus is Associated with Lower Stage and Longer Disease-Free Survival in Oral Cavity Squamous Cell Carcinoma

Pathology, Jan 28, 2016

There is limited information regarding the incidence of p16 expression, its association with huma... more There is limited information regarding the incidence of p16 expression, its association with human papillomavirus (HPV) and prognosis in oral cavity squamous cell carcinoma (OSCC). The role of p16 in OSCC is evaluated in 215 cases using tissue microarrays (TMAs). p16 immunohistochemistry and HPV in situ hybridisation were performed on TMAs following histopathology review of 215 patients with OSCC in the Sydney Head and Neck Cancer Institute database. Thirty-seven (17.2%) cases showed p16 expression without association with HPV. p16 expression significantly decreased with increasing pT category (p=0.002). p16 expression was associated with longer disease-specific survival on univariable analysis (p=0.044) but not on multivariable analysis adjusting for depth of invasion. Amongst patients receiving adjuvant radiotherapy, patients with p16 expression had significantly longer disease-free and overall survival. p16 expression was seen in early stage OSCCs and was associated with better s...

Research paper thumbnail of Role of the inflammatory process in traumatic brain damage

Inflammatory Diseases of the Central Nervous System, 2000

Research paper thumbnail of Atypical EWSR1 FISH signal patterns in bone and soft tissue tumours:- diagnostic experience with 135 cases

Histopathology, Jan 6, 2016

Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. ... more Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in situ hybridisation (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not classically associated with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfill the published diagnostic criteria for rearrangements. Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic workup. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% o...

Research paper thumbnail of A geographical comparison of p16 expression in squamous cell carcinoma (SCC) of the tongue

Research paper thumbnail of Perineural space infiltration by endosalpingiosis

Research paper thumbnail of Ng et al J Neurotrauma 2012

Research paper thumbnail of Semple et al J Neuroinflammation 2010

Background: The chemokine CCL2 (also known as monocyte chemoattractant protein-1, or MCP-1) is up... more Background: The chemokine CCL2 (also known as monocyte chemoattractant protein-1, or MCP-1) is upregulated in patients and rodent models of traumatic brain injury (TBI), contributing to post-traumatic neuroinflammation and degeneration by directing the infiltration of blood-derived macrophages into the injured brain. Our laboratory has previously reported that Ccl2-/-mice show reduced macrophage accumulation and tissue damage, corresponding to improved motor recovery, following experimental TBI. Surprisingly, Ccl2-deficient mice also exhibited delayed but exacerbated secretion of key proinflammatory cytokines in the injured cortex. Thus we sought to further characterise CCL2's potential ability to modulate immunoactivation of astrocytes in vitro. Methods: Primary astrocytes were isolated from neonatal wild-type and Ccl2-deficient mice. Established astrocyte cultures were stimulated with various concentrations of lipopolysaccharide (LPS) and interleukin (IL)-1β for up to 24 hours. Separate experiments involved pre-incubation with mouse recombinant (r)CCL2 prior to IL-1β stimulation in wild-type cells. Following stimulation, cytokine secretion was measured in culture supernatant by immunoassays, whilst cytokine gene expression was quantified by real-time reverse transcriptase polymerase chain reaction. Results: LPS (0.1-100 μg/ml; 8 h) induced the significantly greater secretion of five key cytokines and chemokines in Ccl2-/-astrocytes compared to wild-type cells. Consistently, IL-6 mRNA levels were 2-fold higher in Ccl2-deficient cells. IL-1β (10 and 50 ng/ml; 2-24 h) also resulted in exacerbated IL-6 production from Ccl2-/-cultures. Despite this, treatment of wild-type cultures with rCCL2 alone (50-500 ng/ml) did not induce cytokine/chemokine production by astrocytes. However, pre-incubation of wild-type astrocytes with rCCL2 (250 ng/ml, 12 h) prior to stimulation with IL-1β (10 ng/ml, 8 h) significantly reduced IL-6 protein and gene expression. Conclusions: Our data indicate that astrocytes are likely responsible for the exacerbated cytokine response seen in vivo post-injury in the absence of CCL2. Furthermore, evidence that CCL2 inhibits cytokine production by astrocytes following IL-1β stimulation, suggests a novel, immunomodulatory role for this chemokine in acute neuroinflammation. Further investigation is required to determine the physiological relevance of this phenomenon, which may have implications for therapeutics targeting CCL2-mediated leukocyte infiltration following TBI.

Research paper thumbnail of Yan et al Neuroscience 2013

The velocity of impact between an object and the human head is a critical factor influencing brai... more The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. We modified the standard WDIA model to produce impact velocities of 5.4, 5.85 and 6.15 m/s while keeping constant the weight and the drop height. Gradations in impact velocity produced progressive degrees of injury severity measured behaviourally, electrophysiologically and anatomically, with the former two methods showing greater sensitivity to changes in impact velocity. There were impact velocity-dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses; however axonal injury (demonstrated by immunohistochemistry for b-amyloid precursor protein and neurofilament heavychain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury.

Research paper thumbnail of Neurotherapeutics Proof 25.11.09

Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is... more Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults. The development of secondary brain injury represents a window of opportunity in which pharmaceutical compounds with neuroprotective properties could be administered. To establish effective treatments for TBI vic-tims, it is imperative that the complex molecular cascades contributing to secondary injury be fully elucidated. One pathway known to be activated in response to TBI is cellular and humoral inflammation. Neuroinflammation within the injured brain has long been considered to intensify the damage sustained following TBI. However, the accumulated findings from years of clinical and experimental research support the notion that the action of inflammation may differ in the acute and delayed phase after TBI, and that maintaining limited inflammation is essential for repair. This review addresses the role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression.

Research paper thumbnail of Semple et al 2010

Research paper thumbnail of Woodcock & Morganti-Kosmann Frontiers in Neurotrauma 2013

Research paper thumbnail of Paper Vivianne

Research paper thumbnail of Ziebell et al 2011

Research paper thumbnail of Yan et al J Neuroinflamm 2011

Background: The combination of diffuse brain injury with a hypoxic insult is associated with poor... more Background: The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles. Methods: Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O 2 /88% N 2 ) or normoxic (22% O 2 /78% N 2 ) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique. Results: TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels. Conclusion: Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.

Research paper thumbnail of 48. An Unusual Presentation of Angiomatoid Fibrous Histiocytoma (Afh)

Pathology, 2015

ABSTRACT AFH accounts for 0.3% of all soft tissue tumours and typically affects the extremities o... more ABSTRACT AFH accounts for 0.3% of all soft tissue tumours and typically affects the extremities of children and young adults. Classically, microscopically, fascicles and sheets of oval to spindle cells, pseudovascular spaces, haemorrhage and a fibrous pseudocapsule rimmed by a lymphocytic infiltrate are noted. However, some cases lack these typical features, often bearing a striking resemblance to organising haematoma. Recently, cytogenetic analysis of AFH has shown specific translocations involving the EWSR1 and FUS genes. We document a seventy-one year old man who presented with a recurrent lesion of the left triceps muscle, six years after surgical excision. The radiology, morphology and immunohistochemical profile (EMA, desmin negative) of the initial lesion were those of an organising haematoma. (The lesion was completely embedded). It's true nature was only revealed at recurrence, where characteristic histological and immunohistochemical features of AFH were noted, prompting cytogenetic evaluation of both lesions. The EWSR1 rearrangement was present in the initial and recurrent lesion. Therefore, whilst morphological and immunohistochemical evidence of AFH were not present initially, recent cytogenetic advances have enabled confirmation of AFH at that time. This case illustrates the utility of cytogenetic testing in the diagnosis of AFH where the lesion deviates from the classical histological appearance. This possibility should be considered in haematomas in the absence of a specific cause at any age. References 1. Bohman S, Goldblum JR, Rubin BP, et al. Angiomatoid fibrous histiocytoma: an expansion of the clinical and histological spectrum. Pathology 2014; 46: 199-204. 2. Thway K. Angiomatoid fibrous histiocytoma: A review with recent genetic findings. Arch Pathol Lab Med 2008; 132: 273-7.

Research paper thumbnail of THE ROLE OF p16 EXPRESSION IN ORAL SQUAMOUS CELL CARCINOMA

Pathology, 2015

Aims: To evaluate fat-soluble vitamin status and prothrombin time (PT) in children with cystic fi... more Aims: To evaluate fat-soluble vitamin status and prothrombin time (PT) in children with cystic fibrosis (CF) aged 18 years in NSW and to assess rates of deficiency from 2007-2010. Methods: A retrospective analysis of fat-soluble vitamin levels and PT in children aged 18 years who lived in NSW and attended any of the three paediatric CF centres from 2007-2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. Results: Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin test in the study period. The prevalence of vitamin D and E deficiency fell from 22.11% to 15.54% and 20.22% to 13.89%, respectively, from 2007-2010. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Vitamin K was measured infrequently. Prolonged PT was common. Low vitamin levels were associated with poor clinical status. Discussion: This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Testing of vitamin K-dependant factors needs consideration. Further studies are needed to continue monitoring rates of vitamin deficiency in the CF community.

Research paper thumbnail of Breast Implant-Associated Squamous Cell Carcinoma – a Rare Long Term Complication

Pathology, 2015

ABSTRACT We present a case of a 58-year-old female, who presented with pain and induration of her... more ABSTRACT We present a case of a 58-year-old female, who presented with pain and induration of her left breast in 2014, following the third surgical revision of her breast implants initially inserted in 1985. On histopathological review, a high grade epithelial malignancy was seen confined to the perimeter of the implant capsule, reminiscent of an infiltrating ductal carcinoma of the breast. Keratinisation and intercellular bridges were identified and the malignant cells showed strong diffuse staining with CK5/6 and p63, supportive of a diagnosis of breast implant-associated squamous cell carcinoma (SCC). She subsequently underwent a completion mastectomy, which showed no evidence of residual malignancy. Two cases of breast implant-associated SCC have been documented in the early 1990s. This case highlights the importance of recognising this entity as a long term complication of breast implants, and as a potential diagnostic pitfall in implant-associated malignancy. References 1. Paletta C, Paletta FX Jr, Paletta FX Sr. Squamous cell carcinoma following breast augmentation. Ann Plast Surg 1992; 29: 425-9. 2. Kitchen SB, Paletta CF, Shehadi SI, et al. Epithelialization of the lining of a breast implant capsule. Possible origin of squamous cell carcinoma associated with a breast implant capsule. Cancer 1994; 73: 1449-53.

Research paper thumbnail of A Case of Denosumab-Treated Multifocal Giant Cell Tumour – Pitfalls and Complications

Pathology, 2014

ABSTRACT Giant cell tumours account for 4-5% of all primary bone tumours and are usually unifocal... more ABSTRACT Giant cell tumours account for 4-5% of all primary bone tumours and are usually unifocal. Multifocal giant cell tumour (GCT) is a rare entity, accounting for less than 0.1% of all bone tumours. Denosumab, a RANK-L inhibitor, prevents osteoclast-mediated destruction and is currently being trialled as a possible alternative treatment to surgery. We report a case of a 23-year-old female with multifocal GCT treated with denosumab. The pathological and radiological features prior to, during, and following cessation of treatment with denosumab are described and illustrated. The fibro-osseous appearance of treated giant cell tumour, often devoid of osteoclast-type giant cells, is a potential pathological pitfall. Denosumab-treated giant cell tumour can be mistaken for other neoplasms, including osteosarcoma, emphasising the importance of clinical history and radiological findings in the interpretation of bone pathology. References 1. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2013. 2. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012; 18: 4415-24. 3. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2012; 14: 901-8.

Research paper thumbnail of Abstract 210: Advancing knowledgebase representation of pediatric cancer variants through ClinGen/CIViC collaboration

Cancer Research, 2021

Childhood cancers are driven by unique profiles of somatic genetic alterations, with a significan... more Childhood cancers are driven by unique profiles of somatic genetic alterations, with a significant contribution from predisposing germline variants. Understanding the genomic landscape of pediatric cancers is complicated by their rarity, the heterogeneity of variation within a given disease, and the complex forms of structural variation they contain. Variants in childhood disease may differ from those in adult versions of the same cancer type, or may have different clinical significance. Currently, pediatric variants are underrepresented in cancer variant databases, and an urgent need exists for their publicly available expert curation. To address this, the Pediatric Cancer Taskforce (PCT) was formed within the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) (https://www.clinicalgenome.org/working-groups/somatic/). The PCT is a multi-institutional group of 39 members with broad experience in childhood cancer and variant curation, whose work con...

Research paper thumbnail of Modulation of immune response by head injury

Research paper thumbnail of P16 Expression Independent of Human Papillomavirus is Associated with Lower Stage and Longer Disease-Free Survival in Oral Cavity Squamous Cell Carcinoma

Pathology, Jan 28, 2016

There is limited information regarding the incidence of p16 expression, its association with huma... more There is limited information regarding the incidence of p16 expression, its association with human papillomavirus (HPV) and prognosis in oral cavity squamous cell carcinoma (OSCC). The role of p16 in OSCC is evaluated in 215 cases using tissue microarrays (TMAs). p16 immunohistochemistry and HPV in situ hybridisation were performed on TMAs following histopathology review of 215 patients with OSCC in the Sydney Head and Neck Cancer Institute database. Thirty-seven (17.2%) cases showed p16 expression without association with HPV. p16 expression significantly decreased with increasing pT category (p=0.002). p16 expression was associated with longer disease-specific survival on univariable analysis (p=0.044) but not on multivariable analysis adjusting for depth of invasion. Amongst patients receiving adjuvant radiotherapy, patients with p16 expression had significantly longer disease-free and overall survival. p16 expression was seen in early stage OSCCs and was associated with better s...

Research paper thumbnail of Role of the inflammatory process in traumatic brain damage

Inflammatory Diseases of the Central Nervous System, 2000

Research paper thumbnail of Atypical EWSR1 FISH signal patterns in bone and soft tissue tumours:- diagnostic experience with 135 cases

Histopathology, Jan 6, 2016

Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. ... more Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in situ hybridisation (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not classically associated with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfill the published diagnostic criteria for rearrangements. Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic workup. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% o...

Research paper thumbnail of A geographical comparison of p16 expression in squamous cell carcinoma (SCC) of the tongue

Research paper thumbnail of Perineural space infiltration by endosalpingiosis

Research paper thumbnail of Ng et al J Neurotrauma 2012

Research paper thumbnail of Semple et al J Neuroinflammation 2010

Background: The chemokine CCL2 (also known as monocyte chemoattractant protein-1, or MCP-1) is up... more Background: The chemokine CCL2 (also known as monocyte chemoattractant protein-1, or MCP-1) is upregulated in patients and rodent models of traumatic brain injury (TBI), contributing to post-traumatic neuroinflammation and degeneration by directing the infiltration of blood-derived macrophages into the injured brain. Our laboratory has previously reported that Ccl2-/-mice show reduced macrophage accumulation and tissue damage, corresponding to improved motor recovery, following experimental TBI. Surprisingly, Ccl2-deficient mice also exhibited delayed but exacerbated secretion of key proinflammatory cytokines in the injured cortex. Thus we sought to further characterise CCL2's potential ability to modulate immunoactivation of astrocytes in vitro. Methods: Primary astrocytes were isolated from neonatal wild-type and Ccl2-deficient mice. Established astrocyte cultures were stimulated with various concentrations of lipopolysaccharide (LPS) and interleukin (IL)-1β for up to 24 hours. Separate experiments involved pre-incubation with mouse recombinant (r)CCL2 prior to IL-1β stimulation in wild-type cells. Following stimulation, cytokine secretion was measured in culture supernatant by immunoassays, whilst cytokine gene expression was quantified by real-time reverse transcriptase polymerase chain reaction. Results: LPS (0.1-100 μg/ml; 8 h) induced the significantly greater secretion of five key cytokines and chemokines in Ccl2-/-astrocytes compared to wild-type cells. Consistently, IL-6 mRNA levels were 2-fold higher in Ccl2-deficient cells. IL-1β (10 and 50 ng/ml; 2-24 h) also resulted in exacerbated IL-6 production from Ccl2-/-cultures. Despite this, treatment of wild-type cultures with rCCL2 alone (50-500 ng/ml) did not induce cytokine/chemokine production by astrocytes. However, pre-incubation of wild-type astrocytes with rCCL2 (250 ng/ml, 12 h) prior to stimulation with IL-1β (10 ng/ml, 8 h) significantly reduced IL-6 protein and gene expression. Conclusions: Our data indicate that astrocytes are likely responsible for the exacerbated cytokine response seen in vivo post-injury in the absence of CCL2. Furthermore, evidence that CCL2 inhibits cytokine production by astrocytes following IL-1β stimulation, suggests a novel, immunomodulatory role for this chemokine in acute neuroinflammation. Further investigation is required to determine the physiological relevance of this phenomenon, which may have implications for therapeutics targeting CCL2-mediated leukocyte infiltration following TBI.

Research paper thumbnail of Yan et al Neuroscience 2013

The velocity of impact between an object and the human head is a critical factor influencing brai... more The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. We modified the standard WDIA model to produce impact velocities of 5.4, 5.85 and 6.15 m/s while keeping constant the weight and the drop height. Gradations in impact velocity produced progressive degrees of injury severity measured behaviourally, electrophysiologically and anatomically, with the former two methods showing greater sensitivity to changes in impact velocity. There were impact velocity-dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses; however axonal injury (demonstrated by immunohistochemistry for b-amyloid precursor protein and neurofilament heavychain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury.

Research paper thumbnail of Neurotherapeutics Proof 25.11.09

Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is... more Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults. The development of secondary brain injury represents a window of opportunity in which pharmaceutical compounds with neuroprotective properties could be administered. To establish effective treatments for TBI vic-tims, it is imperative that the complex molecular cascades contributing to secondary injury be fully elucidated. One pathway known to be activated in response to TBI is cellular and humoral inflammation. Neuroinflammation within the injured brain has long been considered to intensify the damage sustained following TBI. However, the accumulated findings from years of clinical and experimental research support the notion that the action of inflammation may differ in the acute and delayed phase after TBI, and that maintaining limited inflammation is essential for repair. This review addresses the role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression.

Research paper thumbnail of Semple et al 2010

Research paper thumbnail of Woodcock & Morganti-Kosmann Frontiers in Neurotrauma 2013

Research paper thumbnail of Paper Vivianne

Research paper thumbnail of Ziebell et al 2011

Research paper thumbnail of Yan et al J Neuroinflamm 2011

Background: The combination of diffuse brain injury with a hypoxic insult is associated with poor... more Background: The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles. Methods: Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O 2 /88% N 2 ) or normoxic (22% O 2 /78% N 2 ) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique. Results: TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels. Conclusion: Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.

Research paper thumbnail of 48. An Unusual Presentation of Angiomatoid Fibrous Histiocytoma (Afh)

Pathology, 2015

ABSTRACT AFH accounts for 0.3% of all soft tissue tumours and typically affects the extremities o... more ABSTRACT AFH accounts for 0.3% of all soft tissue tumours and typically affects the extremities of children and young adults. Classically, microscopically, fascicles and sheets of oval to spindle cells, pseudovascular spaces, haemorrhage and a fibrous pseudocapsule rimmed by a lymphocytic infiltrate are noted. However, some cases lack these typical features, often bearing a striking resemblance to organising haematoma. Recently, cytogenetic analysis of AFH has shown specific translocations involving the EWSR1 and FUS genes. We document a seventy-one year old man who presented with a recurrent lesion of the left triceps muscle, six years after surgical excision. The radiology, morphology and immunohistochemical profile (EMA, desmin negative) of the initial lesion were those of an organising haematoma. (The lesion was completely embedded). It's true nature was only revealed at recurrence, where characteristic histological and immunohistochemical features of AFH were noted, prompting cytogenetic evaluation of both lesions. The EWSR1 rearrangement was present in the initial and recurrent lesion. Therefore, whilst morphological and immunohistochemical evidence of AFH were not present initially, recent cytogenetic advances have enabled confirmation of AFH at that time. This case illustrates the utility of cytogenetic testing in the diagnosis of AFH where the lesion deviates from the classical histological appearance. This possibility should be considered in haematomas in the absence of a specific cause at any age. References 1. Bohman S, Goldblum JR, Rubin BP, et al. Angiomatoid fibrous histiocytoma: an expansion of the clinical and histological spectrum. Pathology 2014; 46: 199-204. 2. Thway K. Angiomatoid fibrous histiocytoma: A review with recent genetic findings. Arch Pathol Lab Med 2008; 132: 273-7.

Research paper thumbnail of THE ROLE OF p16 EXPRESSION IN ORAL SQUAMOUS CELL CARCINOMA

Pathology, 2015

Aims: To evaluate fat-soluble vitamin status and prothrombin time (PT) in children with cystic fi... more Aims: To evaluate fat-soluble vitamin status and prothrombin time (PT) in children with cystic fibrosis (CF) aged 18 years in NSW and to assess rates of deficiency from 2007-2010. Methods: A retrospective analysis of fat-soluble vitamin levels and PT in children aged 18 years who lived in NSW and attended any of the three paediatric CF centres from 2007-2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. Results: Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin test in the study period. The prevalence of vitamin D and E deficiency fell from 22.11% to 15.54% and 20.22% to 13.89%, respectively, from 2007-2010. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Vitamin K was measured infrequently. Prolonged PT was common. Low vitamin levels were associated with poor clinical status. Discussion: This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Testing of vitamin K-dependant factors needs consideration. Further studies are needed to continue monitoring rates of vitamin deficiency in the CF community.

Research paper thumbnail of Breast Implant-Associated Squamous Cell Carcinoma – a Rare Long Term Complication

Pathology, 2015

ABSTRACT We present a case of a 58-year-old female, who presented with pain and induration of her... more ABSTRACT We present a case of a 58-year-old female, who presented with pain and induration of her left breast in 2014, following the third surgical revision of her breast implants initially inserted in 1985. On histopathological review, a high grade epithelial malignancy was seen confined to the perimeter of the implant capsule, reminiscent of an infiltrating ductal carcinoma of the breast. Keratinisation and intercellular bridges were identified and the malignant cells showed strong diffuse staining with CK5/6 and p63, supportive of a diagnosis of breast implant-associated squamous cell carcinoma (SCC). She subsequently underwent a completion mastectomy, which showed no evidence of residual malignancy. Two cases of breast implant-associated SCC have been documented in the early 1990s. This case highlights the importance of recognising this entity as a long term complication of breast implants, and as a potential diagnostic pitfall in implant-associated malignancy. References 1. Paletta C, Paletta FX Jr, Paletta FX Sr. Squamous cell carcinoma following breast augmentation. Ann Plast Surg 1992; 29: 425-9. 2. Kitchen SB, Paletta CF, Shehadi SI, et al. Epithelialization of the lining of a breast implant capsule. Possible origin of squamous cell carcinoma associated with a breast implant capsule. Cancer 1994; 73: 1449-53.

Research paper thumbnail of A Case of Denosumab-Treated Multifocal Giant Cell Tumour – Pitfalls and Complications

Pathology, 2014

ABSTRACT Giant cell tumours account for 4-5% of all primary bone tumours and are usually unifocal... more ABSTRACT Giant cell tumours account for 4-5% of all primary bone tumours and are usually unifocal. Multifocal giant cell tumour (GCT) is a rare entity, accounting for less than 0.1% of all bone tumours. Denosumab, a RANK-L inhibitor, prevents osteoclast-mediated destruction and is currently being trialled as a possible alternative treatment to surgery. We report a case of a 23-year-old female with multifocal GCT treated with denosumab. The pathological and radiological features prior to, during, and following cessation of treatment with denosumab are described and illustrated. The fibro-osseous appearance of treated giant cell tumour, often devoid of osteoclast-type giant cells, is a potential pathological pitfall. Denosumab-treated giant cell tumour can be mistaken for other neoplasms, including osteosarcoma, emphasising the importance of clinical history and radiological findings in the interpretation of bone pathology. References 1. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2013. 2. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012; 18: 4415-24. 3. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2012; 14: 901-8.