Young patients with colorectal cancer: How do they fare?

Background: Younger patients with colorectal cancer (CRC) have long been thought to have a poorer prognosis than older patients. Recent overseas reports, however, have disputed this. The aim of the present study was to conduct a review of data on patients with colorectal cancer collected over a 29-year period at Princess Alexandra Hospital (PAH) to ascertain the outcome of a younger subset of patients at this hospital. Methods: The PAH Colorectal Project records on 2495 patients with malignancies of the colon, rectum and anus who were treated and followed since 1971, were analysed to determine clinical presentation, treatment and outcome. A group of 61 patients with colo-rectal adenocarcinoma was identified who were aged less than 40 years at presentation. Their clinical data were then compared with the larger group of older patients. Results: There were 30 male and 31 female patients in the younger group. A positive family history was the most consistent risk factor, present in 34% of patients. Despite this, only one patient out of 61 had been diagnosed as a result of a screening programme. The Australian Clinico-Pathological Stage (ACPS), histology and distribution of tumours corresponded to that of the older patients. The overall 5-year survival among younger patients was 53%. The 5-year survival rates in younger patients were better than that for older patients for ACPS A and B, reaching statistical significance for both of these stages. Conclusions: Our results indicate that younger patients with colorectal cancer have the potential to do just as well as older ones. With the influence of a family history of colorectal cancer being very apparent in this group, greater emphasis should be placed on an adequate screening programme for them.

Broadsheet - Dendritic cells and their emerging clinical applications

Dendritic cells (DC) are now recognised as a unique leukocyte type, consisting of two or more subsets. The origins and functional inter-relationships of these cells are the subject of intense basic scientific investigation. They play important roles in initiating and directing immune responses, defending the host from pathogens and maintaining self tolerance. Fundamental studies are defining new molecules and mechanisms associated with DC function. The first methods for counting these rare blood cell populations are already providing interesting new clinical data. Indeed, abnormal DC function may contribute to deficiencies in the immune response against malignancies. Phase I trial data suggests that DC-based cancer vaccination protocols may contribute an important new biological approach to cancer therapy. Manipulation of DC to facilitate allogeneic transplantation and even to manage autoimmune disease are likely developments.

Primary fallopian tube carcinoma: the Queensland experience

The purpose of this study was to review the experience with fallopian tube carcinoma in Queensland and to compare it with previously published data. Thirty-six patients with primary fallopian tube carcinoma treated at the Queensland Gynaecological Cancer Center from 1988 to 1999 were reviewed in a retrospective clinicopathologic study. All patients had primary surgery and 31/36 received chemotherapy postoperatively. Abnormal vaginal bleeding (15/36) and abdominal pain (14/36) were the most common presenting symptoms at the time of diagnosis. Median follow-up was 70.3 months and the median overall survival was 68.1 months. Surgical stage I disease (P = 0.02) and the absence of residual tumor after operation (P = 0.03) were the only factors associated with improved survival. Twenty of the 36 patients (55%) presented with stage I disease and survival was 62.7% at 5 years. No patient with postoperative residual tumor survived. The majority of the patients with fallopian tube carcinoma present with stage I disease at diagnosis, but their survival probability is low compared with that of other early stage gynecological malignancies. If primary surgical debulking cannot achieve macroscopic tumor clearence, the chance of survival is extremely low.

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.

Hand-assisted laparoscopic adrenalectomy: An alternative minimal invasive surgical technique for the adrenal gland

Background: Presently the surgical approach to the adrenal gland is in a state of flux. While the traditional approach to the adrenal gland has been the open transabdominal technique, more recently laparoscopic approaches, particularly via the transabdominal route, have increasingly been utilized. However, laparoscopic intervention for the adrenal gland can be problematic in certain circumstances, particularly for large adrenal masses and in instances of adrenal malignancies. Methods: In this report we describe the use of hand-assisted laparoscopic adrenalectomy as an alternative minimal invasive surgical approach to the adrenal gland. Hand-assisted laparoscopic adrenalectomy using the HandPort system (Smith & Nephew, Sydney, Australia) was undertaken in three patients requiring adrenalectomy for mass lesions including one patient with Conn's syndrome. Results: In all three cases, surgery proceeded promptly and uneventfully. In the present paper, the details of the technique of hand-assisted adrenalectomy are described. This is the first report in the world literature of this new technique for the adrenal gland. Conclusions: Hand-assisted laparoscopic adrenalectomy is an easily performed technique, which can be completed within a short operative time span and which has the advantage of providing intraoperative tactile localization for the adrenal gland. It may be particularly applicable for large adrenal tumours, yet only involves the performance of a small abdominal incision. Postoperative recovery is comparable with that reported for the laparoscopic-only technique. Hand-assisted adrenalectomy is a new technique which has great potential and which warrants further evaluation.

Human peripheral blood V alpha 24(+) V beta 11(+) NKT cells expand following administration of alpha-galactosylceramide-pulsed dendritic cells

Background and Objectives We have undertaken the first clinical trial involving the administration of alpha-GalactosylCeramine (alpha-GalCer)-pulsed dendritic cells (DCs) to human subjects, to determine safety, optimal dose, optimal administration route and immunological effects. Materials and Methods Subjects (n = 4) with metastatic malignancy received two infusions of alpha-GalCer-pulsed DCs intravenously, and two infusions intradermally. The percentages of Valpha24 Vbeta11 NKT cells in peripheral blood (PB) were determined by three-colour flow cytometry and the PB NKT cell numbers were calculated using the total number of PB lymphocytes/ml determined by automated full-blood counts. Results No serious treatment related adverse events were observed during the study period. Administration of alpha-GalCer-pulsed DCs in vivo can significantly (P < 0.03) increase PB Valpha24(+) Vbeta11(+) NKT cell numbers above pretreatment baseline levels after the transient fall in the NKT numbers within 48 h. Conclusions Administration of alpha-GalCer-pulsed DCs is well tolerated, modulates PB Valpha24(+) Vbeta11(+) NKT cells and may have a role in the therapy of malignancies sensitive to activities of Valpha24(+) Vbeta11(+) NKT cells, or for autoimmune diseases.

Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells

Background: The response of hepatocellular carcinoma (HCC) to therapy is often disappointing and new modalities of treatment are clearly needed. Active immunotherapy based on the injection of autologous dendritic cells (DC) co-cultured ex vivo with tumor antigens has been used in pilot studies in various malignancies such as melanoma and lymphoma with encouraging results. Methods: In the present paper, the preparation and exposure of patient DC to autologous HCC antigens and re-injection in an attempt to elicit antitumor immune responses are described. Results: Therapy was given to two patients, one with hepatitis C and one with hepatitis B, who had large, multiple HCC and for whom no other therapy was available. No significant side-effects were observed. The clinical course was unchanged in one patient, who died a few months later. The other patient, whose initial prognosis was considered poor, is still alive and well more than 3 years later with evidence of slowing of tumor growth based on organ imaging. Conclusions: It is concluded that HCC may be a malignancy worthy of DC trials and sufficient details in the present paper are given for the protocol to be copied or modified. (C) 2002 Blackwell Publishing Asia Pty Ltd.

The current status of laser applications in dentistry

A range of lasers. is now available for use in dentistry. This paper summarizes key current and emerging applications, for lasers in clinical practice. A major diagnostic application of low power lasers is the detection of caries, using fluorescence elicited from hydroxyapatite or from bacterial by-products. Laser fluorescence is an effective method for detecting and quantifying incipient occlusal and cervical,carious lesions, and with further refinement could be used in the, same manner for proximal lesions. Photoactivated dye techniques have been developed which use low power lasers to elicit a photochemical reaction, Photoactivated dye techniques' can be used to disinfect root canals, periodontal pockets, cavity preparations and sites of peri-implantitis. Using similar principles, more powerful lasers tan be used for photodynamic therapy in the treatment of malignancies of the oral mucosa. Laser-driven photochemical reactions can also be used for tooth whitening. In combination with fluoride, laser irradiation can improve the resistance of tooth structure to demineralization, and this application is of particular benefit for susceptible sites in high caries risk patients. Laser technology for caries' removal, cavity preparation and soft tissue surgery is at a high state of refinement, having had several decades of development up to the present time. Used in conjunction with or as a replacement for traditional methods, it is expected that specific laser technologies will become an essential component of contemporary dental practice over the next decade.

Ex vivo analysis of T-cell responses to Epstein-Barr virus-encoded oncogene latent membrane protein 1 reveals highly conserved epitope sequences in virus isolates from diverse geographic regions

Epstein-Barr virus (EBV)-encoded oncogene latent membrane protein (LMP) 1, which is consistently expressed in multiple EBV-associated malignancies, has been proposed as a potential target antigen for any future vaccine designed to control these malignancies. However, the high degree of genetic variation in the LMP1 sequence has been considered a major impediment for its use as a potential immunotherapeutic target for the treatment of EBV-associated malignancies. In the present study, we have employed a highly efficient strategy, based on ex vivo functional assays, to conduct an extensive sequence-wide analysis of LMP1-specific T-cell responses in a large panel of healthy virus carriers of diverse ethnic origin and nasopharyngeal carcinoma patients. By comparing the frequencies of T cells specific for overlapping peptides spanning LMP1, we mapped a number of novel HLA class I- and class II-restricted LMP1 T-cell epitopes, including an epitope with dual HLA class I restriction. More importantly, extensive sequence analysis of LMP1 revealed that the majority of the T-cell epitopes were highly conserved in EBV isolates from Caucasian, Papua New Guinean, African, and Southeast Asian populations, while unique geographically constrained genetic variation was observed within one HLA A2 supertype-restricted epitope. These findings indicate that conserved LMP1 epitopes should be considered in designing epitope-based immunotherapeutic strategies against EBV-associated malignancies in different ethnic populations.

Matrix metalloproteinase-2 and-9 involvement in canine tumors

Matrix metalloproteinases (MMPs) are a family of enzymes implicated in the degradation and remodeling of extracellular matrix and in vascularization. They are also involved in pathologic processes such as tumor invasion and metastasis in experimental cancer models and in human malignancies. We used gelatin zymography and inummohistochemistry to determine whether MMP-2 and MMP-9 are present in canine tumors and normal tissues and whether MMP production correlates with clinicopathologic parameters of prognostic importance. High levels of pro-MMP-9, pro-MMP-2, and active MMP-2 were detected in most canine tumors. Significantly higher MMP levels were measured in canine tumors than in nontumors, malignancies had higher MMP levels than benign tumors, and sarcomas had higher active MMP-2 than carcinomas. Cartilaginous tumors produced higher MMP levels than did nonsarcomatous malignancies, benign tumors, and normal tissues, and significantly greater MMP-2 than osteosarcomas and fibrosarcomas. Pro-MMP-9 production correlated with the histologic grade of osteosarcomas. The 62-kd form of active MMP-2 was detected only in high-grade, p53-positive, metastatic malignancies. Zymography proved to be a sensitive and quantitative technique for the assessment of MMP presence but has the limitation of requiring fresh tissue; inummohistochemistry is qualitative and comparatively insensitive but could be of value in archival studies. MMP presence was shown in a range of canine tumors, and their link to tumor type and grade was demonstrated for the first time. This study will allow a substantially improved evaluation of veterinary cancer patients and provides baseline information necessary for the design of clinical trials targeting MMPs.

Epstein-Barr virus-associated Hodgkin's lymphoma

Survivors of Hodgkin's lymphoma (HL) frequently have many years to experience the long-term toxicities of combined modality therapies. Also, a significant proportion of HL patients will relapse or have refractory disease, and less than half of these patients will respond to current salvage strategies. 30–50% of HL cases are Epstein–Barr virus associated (EBV-positive HL). The virus is localized to the malignant cells and is clonal. EBV-positive HL is more frequent in childhood, in older adults (>45 years) and in mixed cellularity cases. The survival of EBV-positive HL in the elderly and the immunosuppressed is particularly poor. Despite improvements in our understanding of EBV-positive HL, the true contribution of EBV to the pathogenesis of HL remains unknown. Increased knowledge of the virus’ role in the basic biology of HL may generate novel therapeutic strategies for EBV-positive HL and the presence of EBV-latent antigens in the malignant HL cells may represent a target for cellular immunotherapy.

Induction of Therapeutic T-Cell Responses to Subdominant Tumor-associated Viral Oncogene after Immunization with Replication-incompetent Polyepitope Adenovirus Vaccine

The EBV-encoded latent membrane proteins (LMP1 and LMP2), which are expressed in various EBV-associated malignancies have been proposed as a potential target for CTL-based therapy. However, the precursor frequency for LMP-specific CTL is generally low, and immunotherapy based on these antigens is often compromised by the poor immunogenicity and potential threat from their oncogenic potential. Here we have developed a replication-incompetent adenoviral vaccine that encodes multiple HLA class I-restricted CTL epitopes from LMP1 and LMP2 as a polyepitope. Immunization with this polyepitope vaccine consistently generated strong LMP-specific CTL responses in HLA A2/K-b mice, which can be readily detected by both ex vivo and in vivo T-cell assays. Furthermore, a human CTL response to LMP antigens can be rapidly expanded after stimulation with this recombinant polyepitope vector. These expanded T cells displayed strong lysis of autologous target cells sensitized with LMP1 and/or LMP2 CTL epitopes. More importantly, this adenoviral vaccine was also successfully used to reverse the outgrowth of LMP1-expressing tumors in HLA A2/K-b mice. These studies demonstrate that a replication-incompetent adenovirus polyepitope vaccine is an excellent tool for the induction of a protective CTL response directed toward multiple LMP CTL epitopes restricted through common HLA class I alleles prevalent in different ethnic groups where EBV-associated malignancies are endemic.

Total glossectomy: Is it justified?

Background: The treatment of advanced malignancies of the tongue with total glossectomy is controversial. Methods: The present study retrospectively reviews 20 patients that had total glossectomy with or without laryngectomy performed at the Princess Alexandra Hospital (Woolloongabba, QLD, Australia) over the past 10 years. The clinicopathologic parameters, perioperative morbidity and mortality were assessed. Results: The 5 years disease free and disease specific survival rates were 34% and 38%, respectively. Ninety per cent of patients acquired independent oral feeding prior to discharge, while 57% of patients that had laryngeal preservation performed achieved satisfactory vocal rehabilitation. Conclusion: Total glossectomy is an oncologically sound surgical procedure that should only be performed in carefully selected patients with advanced malignancies affecting the tongue.

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is mutated in Wilms' tumours and other malignancies. WT1 is one of the earliest genes expressed during kidney development. WT1 proteins can activate and repress putative target genes in vitro, although the in vivo relevance of such target genes often remains unverified. To better understand the role of WT1 in tumorigenesis and kidney development, we need to identify downstream target genes. In this study, we have expression pro. led human embryonic kidney 293 cells stably transfected to allow inducible WT1 expression and mouse mesonephric M15 cells transfected with a WT1 antisense construct to abolish endogenous expression of all WT1 isoforms to identify WT1-responsive genes. The complementary overlap between the two cell lines revealed a pronounced repression of genes involved in cholesterol biosynthesis by WT1. This pathway is transcriptionally regulated by the sterol responsive element-binding proteins (SREBPs). Here, we provide evidence that the C-terminal end of the WT1 protein can directly interact with SREBP, suggesting that WT1 may modify the transcriptional function of SREBPs via a direct protein-protein interaction. Therefore, the tumour suppressor activities of WT1 may be achieved by repressing the mevalonate pathway, thereby controlling cellular proliferation and promoting terminal differentiation.