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Background Giant cell tumour of bone (GCTOB) is a relatively uncommon, benign, but locally aggressive neoplasm. Denosumab is a fully human monoclonal antibody with inhibitory effects on receptor activator of nuclear factor kappa-B ligand that has shown early promise as a possible treatment adjuvant for GCTB. However, much is still unknown about its current indications, long-term effects, the potential risk for rapid relapse and its involvement in sarcomatous transformation. Methods We analysed the outcomes of 154 patients with GCTOB. We assessed clinical outcomes via local recurrence free-survival, metastatic free-survival and sarcomatous transformation between those treated without Denosumab and those with neo-adjuvant Denosumab. Our radiological and pathological outcomes were assessed through independent specialist reviews. Results Four (19.0%) patients of the neo-adjuvant group had local recurrence of disease versus 16 (12.0%) patients in the surgery alone group; this results in a 3.62 times increased likelihood of developing local recurrence (P = 0.030). The median time to local recurrence was shorter for the neo-adjuvant group (421.5 days versus 788.5 days) (P = 0.01). There was no difference between Denosumab and the surgery groups in terms of metastatic disease (P = 0.45). Two patients in our cohort with GCTOB developed sarcomatous transformation, both were treated with Denosumab. Conclusion Our use of Denosumab tended to be for those patients who had surgically difficult tumours to halt the progression and allow easier resections. Of concern we noted a trend towards increasing recurrence rates with the potential risk for rapid relapse. Furthermore, two cases experienced sarcomatous transformation, which is a growing area of concern within the literature.

BACKGROUND AND OBJECTIVES: Leiomyosarcoma of skin (LMS) can be sub-classified on pathology appearances as Dermal or Subcutaneous. The aim of this study was to provide treatment recommendations for these uncommon tumours. METHODS: A retrospective review of all patients with dermal and subcutaneous leiomyosarcoma managed at the Peter MacCallum Cancer Centre, Australia from January 2003 to December 2018 was performed. Eighty-three patients were identified (64 dermal leiomyosarcoma, 19 subcutaneous leiomyosarcoma). RESULTS: Subcutaneous leiomyosarcoma were larger (median size 14 mm dermal, 49 mm subcutaneous, P = 0.01). No patient with a dermal leiomyosarcoma developed metastatic disease compared to 4 of the 19 subcutaneous leiomyosarcoma (5-year overall survivals, 98% and 88%, respectively, P = 0.03). The most common site of metastasis was to the lung. No difference in risk of local recurrence was apparent (5-year recurrence-free survivals were 85% and 78%, respectively, P = 0.17). Adjuvant radiotherapy was used in 16 (25%) dermal leiomyosarcoma patients and 13 (68%) subcutaneous leiomyosarcoma patients (P

BACKGROUND: Retroperitoneal sarcomas are rare soft tissue tumours accounting for 10-15% of soft tissue sarcomas. Patient prognosis and treatment recommendations (including extent of surgery and neoadjuvant strategies) are determined by the pre-operative histopathological subtype and grade obtained from biopsy and thus it is important to understand the accuracy of biopsy in retroperitoneal masses. METHODS: This study presents a case series of primary retroperitoneal sarcomas managed at Peter MacCallum Cancer Centre (PMCC) between 2008 and 2019. Statistical analyses were performed to determine correlation between histopathology from percutaneous biopsy and surgical excision. RESULTS: A total of 117 patients who underwent percutaneous core biopsy and surgical excision of retroperitoneal sarcoma were included. Diagnostic accuracy varied with histopathological diagnosis, but overall precise concordance between biopsy and final histopathology was seen in 61% (κ = 0.57). Biopsy was most sensitive for identifying well-differentiated liposarcoma (WDLPS) (sensitivity 85%, 95% CI 0.06-0.96) and leiomyosarcoma (sensitivity 81%, 95% CI 0.54-0.96) and was least sensitive for identifying de-differentiated liposarcoma (DDLPS) (sensitivity 40%, 95% CI 0.25-0.56). Overall agreement between biopsy and final histopathology increased with use of PET/CT scan pre-biopsy and with use of fluorescence in situ hybridisation testing on biopsy, however, neither test improved recognition of de-differentiated components within WD/DDLPS on core biopsy. CONCLUSIONS: Pre-operative biopsy is important for clinical decision making in the treatment of retroperitoneal sarcoma. A significant portion of patients with a WDLPS will have a de-differentiated component identified at the time of resection that was not identified on initial biopsy.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a rare malignant tumour of mesenchymal origin, which was conceived following re-classification of malignant fibrous histiocytoma (MFH). The objective of this study is to determine prognostic factors for the outcome of UPS, following multi-modal treatment. METHODS: Data of UPS tumours from 1996 to 2016 were collected, totalling 266 unique UPS patients. Median follow-up was 7.8 years. All tumours were retrospectively analysed for prognostic factors of the disease, including local recurrence (LR) and metastatic disease (MD) at diagnosis, tumour size, grade, location and depth, patient age, adjuvant therapy and surgical margin. Overall survival (OS), post-treatment LR and metastatic-free survival were assessed as outcomes. RESULTS: The 5- and 10-year OS rates for all ages were 60% and 48%, respectively, with a median survival time of 10.1 years. Multivariate analysis revealed that the adverse prognostic factors associated with decreased OS were older age (P

Bone tumours encompass an extensive range of lesions present in the human skeletal structure. Despite the extreme rarity of bone sarcomas, bone tumours encompass a broad, heterogeneous list of tumour subtypes that have various, distinct clinical and pathological characteristics. In addition to primary mesenchymal lesions, the bone can also give rise to many other non-sarcomatous tumours, including tumours of haematopoietic origin and metastatic bone disease, and these therefore must also be included in the differential list. The diagnostic challenge for pathologists, therefore, is twofold: (1) these tumours are uncommon and infrequently encountered in clinical practice, which presents a challenge to inexperienced pathologists, and (2) the broad histological spectrum of bone tumours can cause diagnostic confusion. Accurate diagnosis is essential in prognostication of disease and ensuring appropriate treatment. For this reason, bone cancers are best managed in a multidisciplinary team at expert tertiary referral centres [1].

The pathologist’s approach to a soft tissue tumour firstly involves understanding the clinical and radiological situation. Knowledge of such features, in conjunction with pathological assessment, allows for consideration of the likely differential diagnoses. Factors that are considered include the age of the patient [Table 7.1] and the size and location of the tumour [Table 7.2]. It is also useful to know which tissue layer the tumour has arisen within—if it is superficial, lies within the subcutaneous fat, is deep to the deep fascia or is located intramuscularly. It is also important to obtain the patient’s past medical history, as some tumours have associations or may be part of a syndrome. Neurofibromatosis-1 (NF-1), for example, is a genetic syndrome that is associated with development of neurofibromas and malignant peripheral nerve sheath tumours (MPNST) [1–3]. Familial adenomatous polyposis (FAP) is another syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, that is associated with intra-abdominal desmoid fibromatosis [4–6]. Desmoid fibromatosis is also associated with pregnancy and often occurs within the abdominal wall in this patient population [7–9].

Sarcomas encompass a diverse, heterogeneous family of rare neoplasms arising from mesenchymal origin, accounting for only 1% of all malignant tumours [1]. This includes approximately 70 histopathological entities covering tumours of the bone, muscle, fat, vasculature and peripheral nervous system. Sarcomas are classified according to the tissue that they most closely resemble and can arise in almost any anatomical site within the body, adding to its diversity [2, 3]. Traditional classification based on these morphologic features alone is therefore insufficient in capturing the complexity of clinical behaviours encountered in practice [4]. The advent of ancillary tools such as immunohistochemistry (IHC), cytogenetics and molecular genetics has allowed stratification of sarcomas into more accurate entities that are reflective of their typical clinical characteristics [5, 6]. A better understanding of the molecular basis of bone and soft tissue tumours has widespread implications in improving patient management, including the diagnostic accuracy of sarcomas, prognostication of the disease and the development of more targeted therapies. This review will discuss the current molecular aberrations understood in sarcoma and their potential applications in sarcoma diagnosis, prognosis and treatment.

Immunohistochemistry (IHC) is an indispensable tool in the diagnosis of sarcomas. Sarcomas are a vast, diverse and complex group of neoplasms arising from mesenchymal origin. They present a diagnostic challenge as they are rare and have many overlapping appearances under the microscope. Accurate diagnosis of sarcomas is necessary for deciding management and prognostication of the disease. Historically, the categorisation of sarcomas has been based on their presumed line of differentiation [1, 2]. In some cases, the histomorphology is straightforward and distinct; however, in other cases, the histogenesis can be ambiguous, and further investigation is required to assist with the diagnosis [3]. To compound this, benign mesenchymal lesions and non-sarcomatous tumours are frequently encountered as differential diagnoses to sarcomas and thus present an additional diagnostic challenge [4]. The use of ancillary pathological techniques, therefore, is essential in the evaluation of mesenchymal tumour samples. IHC is a microscopy-based method that utilises immunological and biochemical principles to detect protein expression in tumour cells. Since its discovery in 1942, IHC has progressively improved through development of new antibodies. Nowadays, it has established itself as a valuable adjunctive step in the pathological diagnosis of surgical specimens of bone and soft tissue tumours.

Soft tissue sarcoma is an umbrella term which encompasses over 60 histological tumour types. Approximately 15% of soft tissue sarcomas arise in the retroperitoneum. This complex group of tumours poses unique management challenges due to their often large size, histological heterogeneity and complexity of anatomical relationships. This review discusses the management of retroperitoneal tumours including the need for preoperative diagnosis, the evidence for neoadjuvant radiotherapy, the role of multivisceral resection and the importance of a multidisciplinary team approach.

Background Obtaining a histological diagnosis is essential for appropriate management of pathological fractures. Computed tomography (CT) is an accurate method of obtaining diagnosis for musculoskeletal tumours. We analysed whether diagnostic accuracy was maintained in the evaluation of pathological fractures. Methods A retrospective review of 101 consecutive patients presenting to our tertiary musculoskeletal tumour centre with pathological fracture was performed. Patients underwent core needle biopsy under CT guidance of pathological fractures diagnosed by plain radiography and either CT or magnetic resonance imaging. The histopathology of the CT-guided biopsy was compared with the sample obtained from open biopsy or definitive surgery to determine diagnostic accuracy. Results The mean age at diagnosis was 52 ± 20 years (range: 18-85) in a cohort of 46 men and 55 women. Diagnostic accuracy of CT-guided biopsy was 82.18%. There were 65 malignant and 36 benign tumours with diagnostic accuracy of 86.15% and 80.56%, respectively. The positive predictive value for a malignant tumour was 98.21% whilst it was 93.1% for benign tumours. The femur (53 cases) and humerus (25 cases) were the commonest bones fractured. The most frequent diagnoses were metastasis (20.79%), giant cell tumour (17.82%), osteosarcoma (9.90%) and myeloma (9.90%). There were no complications of CT-guided biopsy. Conclusion Pathological fracture does not confound the diagnosis of musculoskeletal tumours. CT-guided biopsy is an accurate diagnostic tool in the evaluation of pathological fractures. Final diagnosis and management should be made in the context of appropriate anatomical and functional imaging using a multidisciplinary approach.

Paget's disease of the bone may predispose the development of malignant bone tumors such as osteosarcoma. Giant cell tumor (GCT) as a consequence of Paget's disease is rare. Bone GCT is characterized by rapid growth, the destruction of bone, extension to the surrounding soft tissue and abnormal bone turnover caused by an abnormality of the receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) pathway. Denosumab is a RANK-RANKL inhibitor, which is used to treat osteoporosis and bone GCT. In the current study, a 60-year-old male presented with severe pain located between the right thigh and the knee. The patient could not bear weight on the affected leg. The patient had suffered from Paget's disease for 15 years. The complications from Paget's disease included degenerative hip disease, for which the patient underwent a right total hip replacement. A right periacetabular lesion was identified and confirmed as Paget's disease-induced GCT by needle biopsy. A positron emission tomography (PET) scan revealed significant tumor metabolic activity. Subsequent to obtaining informed consent, the patient started treatment with denosumab. A total of 2.5 months after starting denosumab, a PET scan showed no residual pathological uptake at the site of the previously identified large PET avid tumor. After 1 year, the patient exhibited a satisfactory clinical improvement. In conclusion, treatment with denosumab markedly reduced the size of the hemi-pelvic GCT and led to a complete metabolic response.

This study aimed to compare the oncological results between unplanned excision (UE) and planned excision (PE) of malignant soft tissue tumor and to examine the impact of residual tumor (ReT) after UE. Nonmetastatic soft tissue sarcomas surgically treated in 1996–2012 were included in this study. Disease‐specific survival (DSS), metastasis‐free survival (MFS), and local‐recurrence‐free survival (LRFS) were stratified according to the tumor location and American Joint Committee on Cancer Classification 7th edition stage. Independent prognostic parameters were identified by Cox proportional hazard models. Two‐hundred and ninety PEs and 161 UEs were identified. Significant difference in oncological outcome was observed only for LRFS probability of retroperitoneal sarcomas (5‐year LRFS: 33.0% [UE] vs. 71.0% [PE], P = 0.018). Among the 142 UEs of extremity and trunk, ReT in re‐excision specimen were found in 75 cases (53%). UEs with ReT had significantly lower survival probabilities and a higher amputation rate than UEs without ReT (5‐year DSS: 68.8% vs. 92%, P

Purpose Distinguishing between enchondromas and low-grade (grade 1) chondrosarcomas can be challenging. The aim of this study was to investigate the role of Thallium-201 scintigraphy and Technetium-99 m pentavalent dimercaptosuccinic acid (Tc-99 m DMSA (V)) in the diagnosis and grading of chondrosarcomas. Methods 232 consecutive patients with pathologically proven cartilaginous tumours between the years 2000 and 2018 were evaluated. We included 197 patients (101 males and 96 females; median age 50 years; range 15–86 years) who underwent Thallium-201(n = 193) and/or Tc-99 m DMSA (V) scanning (n = 67). Increased uptake was defined as uptake greater than background. The reference standard was the histopathological assessment based on a grading system (grade 1–3). Data was analysed using multivariate modelling. Results There were 46 patients with enchondromas and 151 with chondrosarcomas. Of those, 64 (enchondroma n = 21, chondrosarcoma n = 43) underwent both Thallium-201 and Tc-99 m DMSA (V). Thallium-201 uptake had 7.92 times greater odds of grade 1 chondrosarcomas than enchondromas. Thallium-201 uptake was significantly associated with the odds of a higher grade chondrosarcoma (grade 2–3). DMSA (V) positivity was associated with 4.75 times the odds of a chondrosarcoma diagnosis over enchondroma (p = 0.024). DMSA (V) uptake revealed no association with chondrosarcoma grading. Conclusion Low-grade chondrosarcomas continue to pose a diagnostic dilemma. Thallium-201 scans may identify malignancy in benign appearing tumours as well as differentiate between low-grade and high-grade chondrosarcomas in said malignancies. DMSA (V) may be useful in distinguishing between benign and malignant entities as a whole.

To evaluate the validity of contrast enhanced dual energy CT using a lung perfusion algorithm in assessing for post-traumatic scaphoid proximal pole avascular necrosis. From Aug 2013 to Aug 2016, 18 patients (19 wrists, 16 males, 2 females, mean age 28 years) were assessed as high-risk for proximal pole scaphoid avascular necrosis by a single surgeon following a scaphoid fracture and were referred for contrast-enhanced dual energy CT. 8 wrists had specimens sent for correlative histological analysis and 11 were correlated with operative notes. Eight surgical specimens were sent to histology and showed a 100% correlation (8/8) with the DECT findings. The remaining 11 wrists that did not have a specimen sent had in-surgery findings that also correlated with DECT. A single case was discrepant (1/11) due to presence of an intra-osseous ganglion, which was reported as osteonecrosis on CT, but considered viable at surgery. No case was called viable on CT that proved to be necrotic at either surgery or histologically. Contrast-enhanced dual energy CT using a perfusion algorithm is an innovative and promising method in evaluating viability of the post-trauma proximal pole of scaphoid.

Multiple biomarkers are under evaluation to guide the use of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC), including programed death ligand 1 (PD-L1) tumor cell staining. We have developed a new approach that accurately quantifies PD-L1 status and identifies multiple mutations by using a single bronchoscopy specimen. A novel molecular marker was identified to detect the presence of malignant cells in radial endobronchial ultrasound bronchial brushings from NSCLC (n = 15) and benign (n = 13) nodules by quantitative real-time RT-PCR (RT-qPCR). The MMP9:TIMP3 transcript ratio was significantly increased in NSCLC and using receiver operating characteristic curve analysis accurately discriminated malignant and benign bronchoscopy specimens (area under the curve = 0.98; 95% CI, 0.93-1; P 0.0001). Utilizing the same specimens, PD-L1 expression and multiple oncogenic mutations were detected by RT-qPCR and next-generation sequencing. A second archive of snap-frozen squamous cell carcinoma (n = 40) and control (n = 20) biopsies with matching formalin-fixed, paraffin-embedded slides were used to compare PD-L1 status by immunohistochemistry and RT-qPCR. The biopsy cohort confirmed that the MMP-9:TIMP3 ratio was predictive of malignancy and demonstrated that PD-L1 transcript expression was concordant with PD-L1 tumor cell membrane staining in NSCLC (Spearman r = 0.636, P 0.0001). This rapid molecular approach can detect malignant cells and using the same single bronchoscopy specimen can generate high-quality unfixed nucleic acid that accurately quantify PD-L1 status and identify multiple oncogenic mutations.

Bone and soft-tissue sarcomas are rare and heterogeneous malignancies arising from tissues of mesenchymal origin. Treatment planning is informed by accurate diagnosis for which biopsy is the diagnostic standard. Biopsy in the setting of suspected malignancy is a technically challenging procedure that should only be performed at specialist institutions. Without the requisite expertise, they can compromise the viability of reconstructive procedures and may make necessary amputation to achieve adequate surgical margins. The risk of complications arising from the procedure must be minimized and therefore biopsy should always be preceded by imaging. There must be no attempt at biopsy or excision prior to referral if there is any suspicion of malignancy. Patients with suspected bone and soft-tissue tumours are best evaluated and treated at specialist sarcoma centres under the care of expert multidisciplinary teams. Prompt referral to a specialist sarcoma centre should always be made prior to biopsy for any suspicious mass that is painful, progressively increasing in size, greater than 5 cm in diameter, deep to deep fascia or recurs following inadvertent excision.

This study aimed to discuss the role medical imaging has on diagnosis of musculoskeletal desmoid tumours and to describe their radiological appearances on various imaging modalities. Imaging of histologically proven cases of desmoid tumours at St. Vincent's Hospital Melbourne were obtained via picture archiving communication system (PACS) and then assessed by two musculoskeletal radiologists. Suitable imagings were obtained from PACS. All imaging chosen was de-identified. Desmoid tumours can occur in many areas of the body. Imaging plays an important role in the diagnosis of these tumours and magnetic resonance imaging has been the gold standard for imaging and is the most accurate in terms of assessing tumour margins and involvement of surrounding structures.

Osteosarcoma is the most common primary bone cancer affecting adolescent and young adults. The majority of osteosarcomas occur sporadically, although increasing age is associated with a higher risk of secondary osteosarcoma. Common causes of secondary osteosarcoma include pre-existing Paget's disease and prior irradiation. Bone infarct-associated sarcoma (IAS) is a rare subset of secondary sarcoma with few reports to date. We present the case of a 28-year-old male who presented with IAS potentially related to previous steroid exposure from treated Hodgkin disease in childhood. He is currently undergoing neoadjuvant chemotherapy with consideration of a limb-sparing surgery after two cycles.

Background: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can ‘normalise' tumour vasculature, thereby improving oxygenation, remains unknown. Methods: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer 18F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design. Results: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r2=0.85; P

Soft tissue sarcoma is an umbrella term which encompasses over 60 histological tumour types. Approximately 15% of soft tissue sarcomas arise in the retroperitoneum. This complex group of tumours poses unique management challenges due to their often large size, histological heterogeneity and complexity of anatomical relationships. This review discusses the management of retroperitoneal tumours including the need for preoperative diagnosis, the evidence for neoadjuvant radiotherapy, the role of multivisceral resection and the importance of a multidisciplinary team approach.

Brenda Slavin (nee Stewart) was educated at Whalley Range High School, Manchester. Her family emigrated to South Africa in1948, cutting short her school certificate. Times were hard, and she was sent out to train and work as a secretary, but, in addition to shorthand and typing, she surreptitiously added Latin to her night school studies and, with this under her belt, was admitted to preclinical studies at Witwatersrand University. She was a good student and was stimulated by two teachers in particular, who shaped her future interests throughout life—Raymond Dart, of Australopithecus fame, and Sidney Brenner, a future Nobel laureate in biochemistry. She obtained an intercalated BSc in biochemistry in 1953. Her aim was that, with a bachelors degree, she could demonstrate and earn a little, to offset the costs of being a clinical student. A senior lecturer, an alumnus of her old school, recognised her talents, intervened, and advised her to go to Edinburgh for her clinical studies, lending her the initial money to make this change. In Edinburgh she met Gerry, a student in the same year, who was to become her husband of 57 years. They graduated in 1957, and, after house jobs in Edinburgh’s teaching hospitals, she accompanied him to the Bechuanaland protectorate for his national service. There, as a medical officer, she initially studied malnutrition among infants and schoolchildren in the Bamangwato reserve. She then undertook general duties in bush clinics and hospitals. …

Superficial myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly associated with infiltrative growth (tail sign) and local recurrence, but the impact of preoperative radiotherapy is uncertain.Eight consecutive superficial MFS and 10 superficial UPS cases treated with preoperative radiotherapy and surgery were reviewed. Pathological response, surgical margin and magnetic resonance imaging (MRI) were retrospectively evaluated. Oncological events were reported in a descriptive form.Pathologically, nearly-complete response was observed in six UPS cases. Tail sign was pathologically detected in 13 cases, eight of which remained viable. Among the eight cases with viable tail, three cases, including two with positive margin, locally recurred. No major discrepancy was observed between tail length on pre-treatment T1-weighted post-contrast, fat-saturated MRI and pathological tail length.Tail of superficial MFS and UPS can retain viability even after radiotherapy and cause local recurrence unless they respond to radiotherapy well. Wider resection including the tail on MRI is recommended.

Pluripotent stem cells are a potential source of autologous cells for cell and tissue regenerative therapies. They have the ability to renew indefinitely while retaining the capacity to differentiate into all cell types in the body. With developments in cell therapy and tissue engineering these cells may provide an option for treating tissue loss in organs which do not repair themselves. Limitations to clinical translation of pluripotent stem cells include poor cell survival and low cell engraftment in vivo and the risk of teratoma formation when the cells do survive through implantation. In this study, implantation of human induced-pluripotent stem (hiPS) cells, suspended in Matrigel, into an in vivo vascularized tissue engineering chamber in nude rats resulted in substantial engraftment of the cells into the highly vascularized rat tissues formed within the chamber. Differentiation of cells in the chamber environment was shown by teratoma formation, with all three germ lineages evident within 4 weeks. The rate of teratoma formation was higher with partially differentiated hiPS cells (as embryoid bodies) compared to undifferentiated hiPS cells (100% versus 60%). In conclusion, the in vivo vascularized tissue engineering chamber supports the survival through implantation of human iPS cells and their differentiated progeny, as well as a novel platform for rapid teratoma assay screening for pluripotency.

Summary The Royal College of Pathologists of Australasia is developing a series of protocols as an educational tool to assist pathologists in the reporting of relevant information for specific cancer specimens. The protocol for the management of soft tissue tumour resections has recently been released, and this document elaborates the relevant literature on which that protocol drew. Sarcoma is uncommon but is associated with significant morbidity and mortality, and its management is complex. Diagnostic errors are not uncommon and these can have disastrous effects on patient outcome. Sophisticated ancillary testing is often an important adjunct to diagnosis and prognostication. Referral to a specialist sarcoma unit is indicated for both adult and paediatric sarcoma.

Current cell-based treatment alternatives to organ transplantation for liver failure remain unsatisfactory. Hepatocytes have a strong tendency to dedifferentiate and apoptose when isolated and maintained in culture. In contrast, liver progenitor cells (LPCs) are robust, easy to culture and have been shown to replace damaged hepatocytes in liver disease. In this study we investigate whether isolated LPCs can survive and differentiate toward mature hepatocytes in vivo when implanted into a heterotopic mouse tissue engineering chamber model. Healthy Balb/c mice and those put on a choline-deficient ethionin-supplemented diet to induce chronic liver disease were implanted with a tissue engineering chamber based on the epigastric flow through pedicle model, containing either 1 × 10(6) LPCs suspended in Matrigel, or LPC-spheroids produced by preculture for 1 week in Matrigel. Four weeks after implantation the chamber contents were harvested. In all four groups, progenitor cells persisted in large numbers to 4 weeks and demonstrated evidence of considerable proliferation judged by Ki67-positive cells. Periodic acid Schiff staining demonstrated differentiation of some cells into mature hepatocytes. Constructs grown from LPC-spheroids demonstrated considerably greater LPC survival than those from LPCs that were grown as monolayers and implanted as dissociated cells. The combined use of LPC spheroids and the vascularized chamber model could be the basis for a viable alternative to current treatments for chronic liver failure.

Ewing sarcoma (ES) and osteosarcoma (OS) have different biological characteristics and respond differently to chemotherapy. We reviewed 18F-FDG PET imaging characteristics of ES and OS patients at baseline and following treatment to determine whether this biological variation is reflected in their imaging phenotype. A retrospective review of ES and OS patients treated with neoadjuvant chemotherapy and surgery was done, correlating PET results with histologic response to chemotherapy. Change in the maximum standardized uptake value (SUVmax) between baseline and post-treatment scanning was not significantly associated with histologic response for either ES or OS. Metabolic tumor volume (MTV) and the percentage of injected 18F-FDG dose (%ID) in the primary tumor were found to be different for ES and OS response subgroups. A 50% reduction in MTV (MTV2:1

The histological fate of abdominal dermis-fat grafts implanted into the temporomandibular joint (TMJ) following condylectomy was studied. 21 rabbits underwent left TMJ discectomies and condylectomies; 6 were controls (Group A; no graft used); 15 (Group B) had autogenous abdominal grafts transplanted into the left TMJ. Animals were killed after 4, 12 and 20 weeks. Specimens of the TMJ were histologically and histomorphometrically evaluated. At 4 weeks, fat necrosis was clear in all specimens. The dermis component survived and formed cysts with no necrosis. By 12 weeks, viable fat deposits appeared with no evidence of necrotic fat. At 20 weeks, large amounts of viable fat were present in Group B specimens. Group A had no fat, although the missing condyles regenerated. In the presence of viable fat, Group B showed little condyle regeneration 20 weeks after condylectomy. Non-vascularised fat grafts do not survive transplantation, but stimulate neoadipogenesis. The fate of the dermis component of the graft is independent of the fat component. Fat in the joint space disrupts the regeneration of a new condylar head. Neoadipogensis inhibits growth of new bone and cartilage. This has clinical implications for TMJ ankylosis management and preventing heterotopic bone formation around prosthetic joints.

Background: Comparative gene expression is commonly determined with reference to the expression of a housekeeping gene (HKG), the level of which is assumed to be unregulated. There are little data to date on the effect of disease on the expression of classic HKGs in hepatitis C virus (HCV)-infected human liver. Aims: To identity HKGs stable across a wide spectrum of disease in human HCV-infected liver. Methods: β-Actin, hypoxanthine phosphoribosyltransferase 1 (HPRT1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), splicing factor arginine/serine-rich 4, β-glucuronidase and 18S ribosomal RNA (18S rRNA) were measured by real-time polymerase chain reaction in liver biopsy tissue. Samples were categorised for inflammation, fibrosis and steatosis, and allocated into groups with mild or severe liver disease. Values were analysed using Spearman's rank correlation, NormFinder, BestKeeper and geNorm programs. Results: All genes performed well in the samples of patients with low disease activity, but HPRT1, β-actin, GAPDH and 18S rRNA ranked poorly in samples with severe fibrosis or inflammation. Conclusions: Our results indicate that liver disease affects the expression of common HKGs and that β-glucuronidase and splicing factor arginine/serine-rich 4 are the most stable HKGs from this group for studies of gene expression in HCV-infected human liver.

Sir,Epithelioid angiomyolipoma (EAML) is a rare variant of the classic angiomyolipoma (AML), a common benign tumour of the kidney. The 2004 World Health Organization Classification of Renal Neoplas...

A 17-year-old male presented with an expanding lump over the dorsal aspect of his hand. It was painful and tender with no history of trauma. X-rays revealed mottled, radiolucent bony lesion with the evidence of dorsal cortex destruction and prominent periosteal new bone along the metacarpal diaphysis. An MRI confirmed an expansile mass eroding the dorsal cortex of the third metacarpal shaft. The mass extended into the adjacent soft tissues. The mass was diagnosed as a giant cell tumour of the metacarpal diaphysis and managed by excisional curettage, phenolisation and cementation. Diaphyseal giant cell tumours, especially of the hand, are extremely rare.

Background/aims: To evaluate the association between demographical features, serum ALT and HBV DNA and the prevalence of significant fibrosis and inflammation on liver biopsy in patients with chronic hepatitis B. Methods: In this cross-sectional study of patients on St Vincent's Hospital HBV database, patients were classified into three groups on the basis of HBeAg status and HBV DNA level and the prevalence of significant (F2/3/4) fibrosis and (A2/3) inflammation in each group was established. Patients were also divided into HBeAg-positive and -negative groups and examined for the prevalence of significant fibrosis/inflammation in the strata of HBV DNA and ALT. Predictors of significant fibrosis and inflammation in HBeAg-positive and -negative patients were examined by logistic regression. Results: Three hundred and ninety four patients (HBeAg positive=198; HBeAg negative=196) with liver biopsy were identified. Fifty-eight percent of HBeAg-negative patients with HBV DNA >25 000 IU/ml had F2/3/4 fibrosis. HBV DNA and F2/3/4 were positively correlated in HBeAg-negative patients [odds ratio (OR) 1.42, P=0.001] but inversely correlated in HBeAg-positive patients (OR 0.71, P=0.03). HBV DNA was an independent predictor of significant fibrosis in HBeAg negative (P=0.03) but not HBeAg-positive patients. In HBeAg-positive patients, age was the only predictor of significant fibrosis (P=0.001) and ALT the only predictor of significant inflammation (P=0.003). In the whole cohort there was a close positive association between inflammation and fibrosis. Conclusion: Increasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis only in patients with HBeAg-negative CHB.

Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naive CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. Conclusion: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker. (HEPATOLOGY 2010)

Background: It has been hypothesised, mainly from studies with animal models of liver disease, that the transport of substrates for metabolic enzymes and their subsequent metabolism and elimination in hepatic bile or blood is co-ordinated, but there is little information on this process in diseased human liver. Methods: In this study we have measured by reverse transcription polymerase chain reaction (RT-PCR) major genes involved in drug metabolism from UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B4) and cytochrome P450 (CYP) families (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), transport (OATP-C, MRP2, MRP3, and MDR1) and major transcription factors (PXR, CAR, HNF1alpha, HNF4alpha, RXR, and AHR) involved in their regulation. Liver biopsy tissue from patients with viral hepatitis was scored for inflammation and fibrosis by the METAVIR system, and separated into groups with mild (A0-1; F0-1, n = 20) or severe (A2-3; F3-4, n = 19) liver disease. Correlation analysis (Spearman rank-test, P

Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed beta-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma cell lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased beta-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.

Bladder malignancy in the kidney transplant recipient is rare and compared with the general population tends to be of high grade and have an aggressive clinical course. In this report, we describe a case of urothelial carcinoma developing in a kidney transplant recipient 6 years after the diagnosis of polyomavirus nephropathy (PVN). BK virus (BKV) DNA was identified in urine and serum by PCR. The diffuse strong staining of SV40 T-antigen and p53 within both the in situ and invasive carcinoma suggest that BKV may play a role in the oncogenic pathway in this clinical setting.

Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (

OBJECTIVE: To describe tumour characteristics and clinical management of melanomas newly diagnosed in 1996 and in 2000--before and after publication of the clinical practice "Guidelines for the management of cutaneous melanoma" by the Australian Cancer Network (1997), and their endorsement by the National Health and Medical Research Council (NHMRC) and republication (1999). DESIGN AND SETTING: Survey of clinicians involved in the management of patients with melanoma sampled from the Victorian Cancer Registry. The Registry is notified of all cases of cancer diagnosed by pathology laboratories and hospitals in both the public and private health sectors in the state of Victoria. PATIENTS: People with a cutaneous melanoma newly diagnosed in 1996 and 2000. All invasive melanomas > 1.50 mm in thickness were included, and for each year random samples were selected of 100 each of invasive melanomas 0.76-1.50 mm in thickness, invasive melanomas < or = 0.75 mm, and in-situ melanomas, plus 50 melanomas of unknown thickness. MAIN OUTCOME MEASURES: Biopsy method, adequacy of pathology reporting, adequacy of definitive excision (compared with margins recommended by the Guidelines), and follow-up procedures. RESULTS: The use of partial biopsies increased between 1996 and 2000. Recommended margins of definitive excision were used in only 33.6% of cases. Margins were smaller than recommended for 36% of in-situ melanomas, risking recurrence of primary melanoma. Documented follow-up examinations for subsequent primary skin malignancy were uncommon (6%). CONCLUSIONS: Many aspects of the management of primary cutaneous melanoma appear not to meet the recommendations of the published Guidelines. Further studies to explore the reasons for failure to meet the Guideline recommendations are needed.

Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Pr1 (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Pr1 series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth. (Cancer Res 2006; 66(23): 11271-8)

Purpose The purpose of this study is to determine the effects of unilateral discectomy and condylectomy on the contralateral intact rabbit craniomandibular joint at the histological level. Materials and Methods Fifteen New Zealand white rabbits were used and divided into 3 groups. Three rabbits were used as controls (group A) whereby a sham operation was undertaken without breaching the joint space of the left craniomandibular joint (CMJ). In 6 rabbits (group B), the articular disc of the left CMJ was excised. The remaining 6 rabbits (group C) underwent surgical resection of the left condylar head at the level of the condylar neck. The resultant surgical defects were left to heal without any grafting and the incisions were closed with resorbable sutures. The rabbits were sacrificed at 4, 12, and 20 weeks after surgery and both the left and right CMJs were histologically prepared and examined under light microscopy. Results In the 4-week group, unilateral discectomy and condylectomy resulted in remodeling of the unoperated right CMJ with histological evidence of flattening of the condylar head which was more pronounced in the condylectomy group. In the 12-week group, the remodeling process in the unoperated right CMJ was less pronounced with most of the activity concentrated in the medial pole, especially in the condylectomy group. The 20-week group showed no obvious signs of remodeling in the unoperated right CMJs in both the discectomy and condylectomy groups. Evidence of condylar regeneration was seen in all groups in the left CMJ which had undergone condylectomy. No evidence of disc regeneration in the operated left CMJ was seen in any of the discectomy groups. Conclusions Unilateral discectomy and condylectomy have an early adverse effect on the structural integrity of the contralateral unoperated CMJ which appears to be short lived. The early remodeling effects on the unoperated right CMJ appear to be reversible as the operated left CMJ heals.

Purpose The purpose of this study is to determine the histological fate of the full thickness skin graft when placed into the temporomandibular joint using a rabbit model. Materials and Methods Fourteen New Zealand white rabbits were used and divided into 3 groups. Two rabbits were used as controls (Group A) whereby a sham operation was undertaken with an incision made and immediately repaired without breaching the joint space of the left craniomandibular joint (CMJ). In 6 rabbits (Group B), the joint capsule of the left CMJ was surgically breached but the articular disc was preserved and the wound was repaired. The remaining 6 rabbits (Group C) also had the left CMJ surgically exposed with preservation of the articular disc and the interpositional placement of a full thickness skin graft that was taken from the skin of their necks. All grafts were placed above the articular disc and head of condyle in the superior joint space and firmly secured to the surrounding tissues with nonresorbable sutures. The rabbits were sacrificed at 1, 3, and 5 months after surgery and the left CMJs were histologically prepared and examined under light microscopy. Results The condylar head in the regions where the disc was present appeared to closely resemble that of the control rabbits. However, where the disc was breached by inadvertent surgical trauma (Group B), the underlying condyle showed an irregular outline with increased fibrosis and a marked reduction in mature cartilage. In the subarticular bone there was increased osteoblast and osteoclast activity reflecting high bone activity indicative of a remodeling rather than a degenerative process. The interpositional skin grafts in all experimental animals (Group C) were found adjacent to the condyle on the lateral aspect rather than above the condylar head where it was originally sutured in place. Significant atrophy and reduction in the number and size of the skin appendages such as sweat glands and hair follicles was found within the grafted skin of all experimental animals (Group C) compared with normal skin. All the grafts showed evidence of epidermoid inclusion cysts. Conclusions The full thickness skin graft is not a suitable interpositional material for the TMJ because of the high risk of epidermoid cyst formation and the propensity for lateral displacement of the graft even when sutured into the appropriate intra-articular position.

Pigmented villonodular synovitis is a rare and benign but potentially locally aggressive disease that should be considered in younger patients who present with monoarticular joint symptoms and pathology. We present a 30-year-old Sudanese woman with a huge mass arising from the right hip joint. A multimodality radiological approach to investigation and diagnosis is demonstrated and discussed. Histopathological examination of the resected specimen confirmed the diagnosis of pigmented villonodular synovitis with the mass consisting of a proliferation of fibrohistiocytic cells, abundant haemosiderin, foamy histiocytes, and occasional giant cells. The patient made a good recovery, with mobility aided by arm crutches and a hip abduction brace.