Shared acquired genomic changes in zebrafish and human T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover the genetic changes occurring in T-ALL, and those contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from four zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) with a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted our analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in > 3 zebrafish cancers and ≥ 4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with three zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies with aCGH results from 50 human T-ALL patients who failed induction, relapsed or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, nine recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution.

Heritable T-cell malignancy models established in a zebrafish phenotypic screen.

T-cell neoplasias are common in pediatric oncology, and include acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL). These cancers have worse prognoses than their B-cell counterparts, and their treatments carry significant morbidity. Although many pediatric malignancies have characteristic translocations, most T-lymphocyte-derived diseases lack cytogenetic hallmarks. Lacking these informative lesions, insight into their molecular pathogenesis is less complete. Although dysregulation of the NOTCH1 pathway occurs in a substantial fraction of cases, many other genetic lesions of T-cell malignancy have not yet been determined. To address this deficiency, we pioneered a phenotype-driven forward-genetic screen in zebrafish (Danio rerio). Using transgenic fish with T-lymphocyte-specific expression of enhanced green fluorescent protein (EGFP), we performed chemical mutagenesis, screened animals for GFP(+) tumors, and identified multiple lines with a heritable predisposition to T-cell malignancy. In each line, the patterns of infiltration and morphological appearance resembled human T-ALL and T-LBL. T-cell receptor analyses confirmed their clonality. Malignancies were transplantable and contained leukemia-initiating cells, like their human correlates. In summary, we have identified multiple zebrafish mutants that recapitulate human T-cell neoplasia and show heritable transmission. These vertebrate models provide new genetic platforms for the study of these important human cancers.

Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic Zebrafish.

The zebrafish has emerged as a powerful genetic model of cancer, but has been limited by the use of stable transgenic approaches to induce disease. Here, a co-injection strategy is described that capitalizes on both the numbers of embryos that can be microinjected and the ability of transgenes to segregate together and exert synergistic effects in forming tumors. Using this mosaic transgenic approach, gene pathways involved in tumor initiation and radiation sensitivity have been identified.

Prolonged survival with confirmed metastatic pulmonary ameloblastoma.

This report presents a living 94-year-old female with known metastatic pulmonary ameloblastoma diagnosed over 37 years ago. Initial treatment for the primary lesion of the anterior mandible was carried out 18 years before diagnosis of pulmonary lesions. Despite the presence of bilateral pulmonary metastases, the patient remains asymptomatic and received no treatment for these lesions. To our knowledge this case represents the longest survival time recorded after appearance of untreated metastatic disease.

The use of CO2 laser in the treatment of oral white patches: outcomes and factors affecting recurrence.

Laser therapy has been a favoured treatment regime for oral leukoplakia since the mid 1980s. There is no information in the literature regarding factors affecting outcomes in patients with oral leukoplakia. Forty-three patients (mean age 60.3+/-13.6 years) with 73 primary oral leukoplakia were assessed for outcome and factors affecting survival. Dysplastic lesions were found in the majority of patients. The male to female ratio was 1.7:1 with 74% ex- or current smokers, 27% consuming alcohol and 31% continuing to smoke after treatment. The mean observation time was 47.2+/-28.2 months (range 2-102 months). Disease-free survival was 55.4% at 3 years that dropped to 33.9% after 5 years. The malignant transformation rate was 7.3%. No significant prognostic factors were found on univariate analysis but alcohol consumption (P=0.034) and previous malignancy (P=0.018) were found to be significant prognostic indicators using multivariate analysis. Continuation to smoke approached significance (P=0.061). Similar disease-free survival and malignant transformation rates with minimal complications were found as compared to the literature. Recommendations for minimizing recurrence are presented. Long-term follow up and removal of aetiological factors, such as smoking and alcohol, are advised.

Factors affecting survival in patients with oral cancer: an Australian perspective.

Little is known regarding disease-specific cumulative survival and factors affecting survival in Australian populations with oral squamous cell carcinoma. Kaplan Meier and Cox proportional hazards models were used to determine survival factors in 116 consecutive patients treated surgically at a single institution. Overall 5-year disease-specific survival rate was 83.3%. Five-year disease-specific survival probability was 88.7%, 83.8%, 83.3% and 76.5% for stage I, II, III and IV, respectively. Univariate analysis revealed that local and regional recurrence, distant metastases, N stage, margin status, radiotherapy, perivascular spread and extra-capsular spread (ECS) significantly influenced survival. Significant multivariate factors included local and regional recurrence, positive margins, and ECS. Better survival rates were found than in previous, older Australian reports. Close observation for early recurrence and aggressive management of patients with recurrence, positive margins and ECS, is advised.

Percutaneous endoscopic gastrostomy in patients undergoing resection for oral tumors: a retrospective review of complications and outcomes.

PURPOSE: The use of a percutaneous endoscopic gastrostomy (PEG) in patients undergoing resection for oral tumors is not universal, and varying complication rates have been reported. This study reviews our experience with the use of a PEG as an adjunct in this setting. MATERIALS AND METHODS: The records of patients treated for oral tumors by oral and maxillofacial surgery were reviewed retrospectively. All patients undergoing resection for oral tumors and having a PEG were included. Patient age, gender, disease type, and stage, as well as type of operation, were recorded. Data obtained included the timing of PEG placement, duration of PEG use, and PEG complications. Patient weight and body mass index (BMI) were abstracted when recorded preoperatively and about 2 weeks and between 4 and 8 weeks postoperatively. Weight and BMI results were subjected to statistical analysis. RESULTS: Fifty PEGs were placed in 49 patients with oral tumors. The mean age of the patients was 61 years. More than 90% of tumors were squamous cell carcinomas. Most PEG tubes were placed at the time of resection by 1 surgeon and were retained for a mean duration of 114 days. A minor complication rate of 10% and a major complication rate of 8% were noted. Weight decreased significantly by 2.9% from preoperative level to week 2, but there was no other significant difference found between any other weight or BMI measurement. Incidental findings on PEG placement included Barrett's metaplasia in one patient and gastric adenocarcinoma in another. CONCLUSIONS: The use of PEG in patients with oral tumors at our institution was found to be effective in maintaining adequate nutrition, as assessed by weight and BMI, during recovery and convalescence. There is an acceptable low complication rate. Use of an experienced endoscopist and PEG placement at the time of resection are advocated.

Maintenance of mouth hygiene in patients with oral cancer in the immediate post-operative period.

BACKGROUND: Little has been written about mouth hygiene measures during the immediate postoperative phase in patients with oral cancer. Mouth hygiene not only involves the care and maintenance of the dentition and its related structures, but also the maintenance of surgical sites, reconstructive techniques such as free flaps and generally keeping the mouth clean, which may optimize healing potential and patient comfort. Ward conditions and novel methods of reconstruction require innovation and improvisation of routine methods of mouth and oral hygiene. METHODS: A review of techniques of mouth hygiene used during the immediate post-operative phase by our unit over the last nine years and a review of the literature. RESULTS: Various methods gained from our experience in treating patients with oral cancer at the Austin and Repatriation Medical Centre are documented. Most methods involve a combination of either chlorhexidine or normal saline mouth rinses and mechanical cleaning. CONCLUSIONS: There are many different methods of mouth care in patients who have had resection for oral tumours. It is important for dental practitioners, hygienists and allied health professionals, who may be involved with care of such patients to have an understanding of the methods that are available and appropriate for such patients.

Reconstructive techniques for the repair of oral and maxillofacial oncological procedures: what are they, how do they work and what do they look like?

BACKGROUND: There are many different ways to reconstruct the oral and maxillofacial region post tumour ablation. In the past, the resection of oral tumours had been associated with significant disfigurement and loss of function. Modern techniques aim to restore function and improve cosmetics. This paper aims to describe the techniques used in patients treated at the Austin and Repatriation Medical Centre and to answer the more common questions associated with reconstructive techniques. METHODS: A review of techniques of oral reconstruction used by our unit over the last nine years and a review of the literature. RESULTS: Various techniques of reconstruction gained from our experience in treating patients with oral cancer are documented. There are a variety of techniques including grafts, local flaps, regional flaps and free vascularized flaps. Metallic implants such as osseointegrated dental implants may also be used for dental rehabilitation. CONCLUSIONS: There are many different methods of reconstruction in patients who have had resection for oral tumours. It is important for general dental practitioners who may be involved with the care of such patients to have an understanding of the modern techniques of reconstruction that may be used.

Diabetic ketoacidosis secondary to dento-alveolar infection.

Diabetic ketoacidosis (DKA) is a medical emergency with a potentially fatal outcome if not recognized and treated appropriately. Infective processes are a common precipitant of DKA. We report two cases of dentoalveolar infections in patients with type I diabetes mellitus who presented with DKA. The management of such cases requires both specialist surgical and medical intervention.

Patterns of referral of patients undergoing surgical management for oral cancer.

BACKGROUND: Oral cancer is most often diagnosed by dentists or dental specialists. We were interested in analyzing demographic and referral data for a cohort of patients referred for the management of oral cancer to our unit. METHODS: A consecutive review of all patients treated by oral and maxillofacial surgery at the Austin and Repatriation Medical Centre over the last 10 years. Inclusion criteria included those patients with malignant oral and perioral disease that underwent surgical management. Exclusion criteria included those patients who did not have malignant oral disease, who did not have surgical management and those patients who were not treated by our unit as the primary surgeon. RESULTS: A total of 113 patients were identified. The mean age for presentation for the group was 61.6 years and the male to female ratio was 1.2:1. Approximately 70 per cent of patients were smokers or had smoked in the past. Over the last 10 years there has been a steady increase in referrals to our unit. Over half of all patients referred were from the Royal Dental Hospital of Melbourne while the majority of the remainder of the referrals were from private oral and maxillofacial surgeons. A significantly increased number of referrals from other sources were identified. Surveillance techniques that can be used in general dental practice are also described. CONCLUSIONS: A high proportion of referrals from dental sources highlights the importance of the dentist and dental specialist in the diagnosis and referral of patients with suspected oral cancer. Patients can either be referred to a dental hospital, private oral and maxillofacial surgeons or directly to a public hospital oral and maxillofacial surgery unit treating oral cancer, such as the one at the Austin and Repatriation Medical Centre.