Modern oncologic and operative outcomes for oesophageal cancer treated with curative intent.

The curative approach to oesophageal cancer carries significant risks and a cure is achieved in approximately 20 per cent. There has been a recent trend internationally to observe improved operative and oncological outcomes. This report audits modern outcomes from a high volume centre with a prospective database for the period 2004-08. 603 patients were referred and 310 (52%) were treated with curative intent. Adenocarcinoma represented 68% of the cohort, squamous cell cancer 30%. Of the 310 cases, 227 (73%) underwent surgery, 105 (46%) underwent surgery alone, and 122 (54%) had chemotherapy or combination chemotherapy and radiation therapy. The postoperative mortality rate was 1.7%. The median and 5-year survival of the 310 patients based on intention to treat was 36 months and 36%, respectively, and of the 181 patients undergoing R0 resection, 52 months and 42%, respectively. An in-hospital postoperative mortality rate of less than 2 per cent, and 5-year survival of between 35 and 42% is consistent with benchmarks from international series.

Fistulization in a locally advanced case of squamous cell carcinoma of the prostate.

Squamous cell carcinoma of the prostate gland is very rare, constituting 0.5%-1% of all prostatic malignancies. Though it has a similar clinical presentation to prostate cancer, the tumor is more aggressive, spreading to bone, liver and lung. The median survival time is approximately 14 months. Diagnosis is exclusively by histology. Therapeutic options may include radical surgery, radiotherapy, chemotherapy, hormonal therapy or a combination of these treatments. We present a case of locally advanced squamous cell carcinoma of the prostate and comment on its management and subsequent disease related complication.

Successful outcome of patients with relapsed/refractor Hodgkin lymphoma treated with high dose chemotherapy at the National Adult Bone Marrow Transplant Unit at St. James's Hospital.

Patients with Hodgkin lymphoma who relapse or are refractory to first line multi-agent chemotherapy can be successfully salvaged with high dose therapy (HDT) and autologous stem cell transplant (ASCT). Twenty-six patients with relapsed or refractory Hodgkin lymphoma have been treated with HDT and ASCT at St James Hospital between 2000 and 2005. At day 100 post HDT-ASCT, 23 patients were in complete remission. This group included all 6 patients transplanted at first relapse, 8 of 9 with advanced disease and 9 of 11 with primary refractory disease. Patients treated in first relapse had the best outcome with an overall and progression free survival of 100% (median, 37 months). Patients with primary refractory disease had the poorest outcome with an overall survival of 76% (median, 28 months). All patients with primary refractory disease responsive to salvage chemotherapy were in remission at a median of 28 months. The presence of chemosensitive disease prior to transplantation was the most important determinant of outcome. PET-CT imaging is useful to assess chemosensititvity prior to HDT and thus predict which patients will do well post HDT-ASCT. No patient died of treatment related toxicity. The outcome of this patient series compares favourably with international figures.

Hypoxia in prostate cancer: a powerful shield against tumour destruction?

Tumour hypoxia is progressively emerging as a common feature of prostate tumours associated with poor prognosis. While the molecular basis of disease progression is increasingly well documented, the potential role of hypoxia in these processes remains poorly evaluated. By dissecting the impact of hypoxia-inducible factor 1 alpha on molecular responses, this review provides evidence for a powerful protecting role of oxygen deprivation against oxidative stress injury, androgen deprivation, chemotherapeutic and radiation cytotoxicity. We propose hypoxia as a potent tumour-induced shield against destruction and suggest its targeting may need to be routinely addressed in the management of prostate cancer.

The tissue plasminogen activator gene promoter: a novel tool for radiogenic gene therapy of the prostate?

BACKGROUND: Radiation therapy is a treatment modality routinely used in cancer management so it is not unexpected that radiation-inducible promoters have emerged as an attractive tool for controlled gene therapy. The human tissue plasminogen activator gene promoter (t-PA) has been proposed as a candidate for radiogenic gene therapy, but has not been exploited to date. The purpose of this study was to evaluate the potential of this promoter to drive the expression of a reporter gene, the green fluorescent protein (GFP), in response to radiation exposure. METHODS: To investigate whether the promoter could be used for prostate cancer gene therapy, we initially transfected normal and malignant prostate cells. We then transfected HMEC-1 endothelial cells and ex vivo rat tail artery and monitored GFP levels using Western blotting following the delivery of single doses of ionizing radiation (2, 4, 6 Gy) to test whether the promoter could be used for vascular targeted gene therapy. RESULTS: The t-PA promoter induced GFP expression up to 6-fold in all cell types tested in response to radiation doses within the clinical range. CONCLUSIONS: These results suggest that the t-PA promoter may be incorporated into gene therapy strategies driving therapeutic transgenes in conjunction with radiation therapy.

Quality of life and survival in patients treated with radical chemoradiation alone for oesophageal cancer.

AIMS: To report cancer-specific and health-related quality-of-life outcomes in patients undergoing radical chemoradiation (CRT) alone for oesophageal cancer. MATERIALS AND METHODS: Between 1998 and 2005, 56 patients with oesophageal cancer received definitive radical CRT, due to local disease extent, poor general health, or patient choice. Data from European Organization for Research and Treatment of Cancer quality-of-life questionnaires QLQ-30 and QLQ-OES24 were collected prospectively. Questionnaires were completed at diagnosis, and at 3, 6 and 12 months after CRT where applicable. RESULTS: The median follow-up was 18 months. The median overall survival was 14 months, with a 51, 26 and 13% 1-, 3- and 5-year survival, respectively. At 12 months after treatment there was a significant improvement compared with before treatment with respect to dysphagia and pain. Global health scores were not significantly affected. CONCLUSIONS: Considering the relatively short long-term survival for this cohort of patients, maximising the quality of those final months should be very carefully borne in mind from the outset. The health-related quality-of-life data reported herein helps to establish benchmarks for larger evaluation within randomised clinical trials.

Radiation to control transgene expression in tumors.

Significant evidence has accumulated indicating that certain genes are induced by ionising radiation. An implication of this observation is that their promoter regions include radiation-responsive sequences. These sequences have been isolated in the promoter of several genes including Erg-1, p21/WAF-1, GADD45alpha and t-PA. The mechanism by which radiation induces gene expression remains unclear but involves putative binding sites for selected transcription factors and/or p53. Consensus CC(A/T)6GG sequences have been localized in the Erg-1 promoter and are referred to as serum response elements or CArG elements. The tandem combination of CArG elements has been shown to improve gene expression levels, with a 9-copy motif conferring maximum inducibility. The response of these genes to ionising radiation appears to follow a sigmoid relationship with time and dose. Therapeutic induction of suicide genes and significant cytotoxicity can be achieved at clinically relevant x-rays doses both in vitro and in vivo but was found to be cell-type dependent. Radiation-inducible gene therapy can be potentially enhanced by exploiting hypoxia through the inclusion of hypoxia-response element motifs in the expression cassette, the use of the anaerobic bacteria or the use of neutron irradiation. These results are encouraging and provide significant evidence that gene therapy targeted to the radiation field is a reasonably attractive therapeutic option and could help overcome hypoxic radioresistant tumors.

Achieving hypoxia-inducible gene expression in tumors.

Hypoxia is an inevitable feature of solid tumors and a common cause of treatment failure. Hypoxia acts as a trigger to genetic instability, apoptosis and possibly metastases. The adaptive response to cellular hypoxia involves the modulation of the synthesis of multiple proteins controlling processes such as glucose homeostasis, angiogenesis, vascular permeability and inflammation. The hypoxia responsive element (HRE) sequences isolated from oxygen-responsive genes have been shown to selectively induce gene expression in response to hypoxia when placed upstream of a promoter. The levels of induced gene expression were dependent on the number of HRE copies and the oxygen tension. Hypoxia-mediated cancer gene therapy strategies may represent a promising mean to significantly improve the efficacy of standard radiation therapy and chemotherapy approaches.

Feasibility and efficacy of a supervised exercise intervention in de-conditioned cancer survivors during the early survivorship phase: the PEACH trial.

PURPOSE: This study aims to evaluate the feasibility and efficacy of an 8-week supervised exercise program in de-conditioned cancer survivors within 2-6 months of chemotherapy completion. METHODS: Participants were randomly assigned to an 8-week, twice-weekly, supervised aerobic exercise training regime (n = 23) or a usual care group (n = 20). Feasibility was assessed by recruitment rate, program adherence and participant feedback. The primary outcome was aerobic fitness assessed by the Modified Bruce fitness test at baseline (0 weeks), post-intervention (8 weeks) and at 3-month follow-up. Secondary outcomes included physical activity, waist circumference, fatigue and quality of life. RESULTS: The recruitment rate was 81 % and adherence to the supervised exercise was 78.3 %. Meaningful differences in aerobic fitness between the exercise and usual care groups at both the 8-week [mean 3.0 mL kg(-1) min(-1) (95 % CI -1.1-7.0)] and 3-month follow-up [2.1 mL kg(-1) min(-1) (-2.3-6.6)] were found, although these differences did not achieve statistical significance (p values >0.14). Self-reported physical activity increased in the exercise group (EG) compared to the usual care group at both 8-week (p = 0.01) and 3-month follow-up (p = 0.03) and significant differences in favour of the EG were found for physical well-being at both the 8-week (p = 0.03) and 3-month follow-up (p = 0.04). Improvements in fatigue (p = 0.01), total quality of life plus fatigue (p = 0.04), and a composite physical functioning score (p = 0.01) at the 3-month follow-up were also found. CONCLUSION: The PEACH trial suggests that 8 weeks of supervised aerobic exercise training was feasible and may improve aerobic fitness, fatigue and quality of life in de-conditioned cancer survivors during the early survivorship phase. IMPLICATIONS FOR CANCER SURVIVORS: Exercise interventions commenced in the early survivorship phase appear safe, feasible and may lead to improvements in QOL and fatigue.

Comparison of two fractionation regimens in the multimodal therapy of cancer of the esophagus.

Multimodal therapy is increasingly utilized in the management of esophageal cancer. The optimum dose and fraction is unclear, and this retrospective analysis compared two radiation regimens in multimodality regimens where the chemotherapy arm and the type and magnitude of surgery was constant. Ninety-three consecutive patients with squamous cell carcinoma or adenocarcinoma of the esophagus were reviewed. Forty patients received the conventional unit regimen of 44 Gy in 22 daily fractions (2 Gy/fraction), and 40 patients received an increased dose per fraction (40 Gy in 15 daily fractions [2.67 Gy/fraction]). All patients received two courses of 5-fluorouracil and cisplatin and surgery was carried out within 8 weeks of completing therapy. The median overall survival in the group receiving the increased dose per fraction group was 25 months compared with 17 months in the conventional dose per fraction group (P=0.08). At 1, 3, and 5 years, 66%, 38%, and 38%, of patients in the increased dose per fraction group were alive, compared with 65%, 18%, and 15% in the conventional dose per fraction group (P=0.13), respectively. In the conventional dose per fraction group, two patients developed esophageal fistulae and one patient died postoperatively due to hemorrhage from an aorto-enteric fistula. There were no significant differences observed between treatment groups, but a trend toward improved efficacy appeared with the increased dose per fraction.

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer.

Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5' CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (P < 0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score > or =7 (P=0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in early-stage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

Primary thromboprophylaxis for cancer patients with central venous catheters--a reappraisal of the evidence.

Venous thromboembolism (VTE) is responsible for an estimated 25 000 deaths per annum in UK hospital practice. It is well established that many of these deaths could be prevented through the use of appropriate thromboprophylaxis. This issue is of particular relevance in oncology practice, where the risks of VTE and bleeding are both significantly higher than those observed in general medical patients. Cancer patients with in-dwelling central venous catheters (CVCs) are at particularly high risk of developing thrombotic complications. However, the literature has produced conflicting conclusions regarding the efficacy of using routine primary thromboprophylaxis in these patients. Indeed such is the level of confusion around this topic, that the most recent version of the American College of Chest Physicians (ACCP) guidelines published in 2004 actually reversed their previous recommendation (published in 2001). Nevertheless, minidose warfarin continues to be routinely used in many oncology centres in the UK. In this article, we have performed a systematic review of the published literature regarding the efficacy and the risks, associated with using thromboprophylaxis (either minidose warfarin or low-dose LMWH) in cancer patients with CVC. On the basis of this evidence, we conclude that there is no proven role for using such thromboprophylaxis. However, asymptomatic CVC-related venous thrombosis remains common, and further more highly powered studies of better design are needed in order to define whether specific subgroups of cancer patients might benefit from receiving thromboprophylaxis.

(18)FDG uptake during induction chemoradiation for oesophageal cancer fails to predict histomorphological tumour response.

To determine whether [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) could predict the pathological response in oesophageal cancer after only the first week of neoadjuvant chemoradiation. Thirty-two patients with localised oesophageal cancer had a pretreatment PET scan and a repeat after the first week of chemoradiation. The change in mean maximum standardised uptake value (SUV) and volume of metabolically active tissue (MTV) was compared with the tumour regression grade (TRG) in the final histology. Those who achieved a TRG of 1 and 2 were deemed responders and 3-5 nonresponders. In the responders (28%), the SUV fell from 12.6 (+/-6.3) to 8.1 (+/-2.9) after 1 week of chemoradiation (P=0.070). In nonresponders (72%), the results were 9.7 (+/-5.4) and 7.1 (+/-3.8), respectively (P=0.003). The MTV in responders fell from 36.6 (+/-22.7) to 22.3 (+/-10.4) cm(3) (P=0.180), while in nonresponders, this fell from 35.9 (+/-36.7) to 31.9 (+/-52.7) cm(3) (P=0.405). There were no significant differences between responders and nonresponders. The hypothesis that early repeat FDG-PET scanning may predict histomorphologic response was not proven. This may reflect an inflammatory effect of radiation that obscures tumour-specific metabolic changes at this time. This assessment may have limited application in predicting response to multimodal regimens for oesophageal cancer.

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer.

Multimodal therapy comprising neoadjuvant chemotherapy and radiation therapy prior to radical resection is increasingly utilized in gastroesophageal cancer. The achievement of a complete pathological response (pCR) or a major response is associated with an improved survival. However, up to 70% of patients show an incomplete or no response to the neoadjuvant regimen, and the identification of factors which predict a response would be of considerable clinical benefit. A retrospective analysis of a prospectively updated esophageal cancer database was performed. The predictive values of the following clinicopathological factors were investigated: age, sex, tobacco, alcohol, weight, clinical history, tumor type, site, length, width, morphology and differentiation. Statistical analysis was performed using Chi-square test with Pearson's test or Kruskal-Wallis test. One hundred and seventy-six patients were identified who had undergone neo-adjuvant chemoradiotherapy at St James's Hospital Dublin, between January 1990 and June 2003. A complete pathological response was seen in 40 cases (23%). There was a significant (P < 0.05) relationship between response to chemoradiotherapy and pretreatment tumor length. The median tumor length in the pCR group was 2 cm (1-5 cm) compared with 3 cm (2-7 cm) in non-responders (P < 0.05). Body weight, sex, tobacco or alcohol usage, tumor site, or differentiation were not predictive of response, although a trend (P = 0.08) was observed for squamous cell cancer compared with adenocarcinoma. Smaller tumor length was predictive of a greater response to chemotherapy and radiation therapy. This may reflect different tumor biology, perhaps with acquired resistance to treatment-induced apoptosis in the larger tumors. A simpler explanation is that the existing dose and treatment schedule for combination chemoradiotherapy is suboptimal in patients with larger tumors.

Signal transduction.

Ordered cell proliferation relies on a complex interplay between diverse cell types, interstitial stroma and organ vasculature. At a cellular level the response to growth stimuli is dependent on the bidirectional exchange of information between the cell membrane and nucleus. Specific regulatory molecules enable the transfer of growth signals and constitute the signal transduction pathways. In malignant disease deregulation of growth regulatory pathways is believed to contribute to the characteristic features of neoplasia, unrestricted cell proliferation, direct invasion of surrounding tissues and the formation of distant metastases. Many proto-oncogenes and oncogenes encode proteins that are strongly suspected to function in aberrant signal transduction (Table 1).

A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines.

The c-erbB-2 receptor tyrosine kinase proto-oncogene product is overexpressed in 20-30% of breast carcinomas and this has been shown to correlate with poor prognosis. Previous analysis of tumour-derived lines has demonstrated that although the c-erbB-2 gene is often amplified, overexpression can occur from a single-copy gene. Moreover, whether or not the gene is amplified, overexpressing cells produce 6- to 8-fold more mRNA per gene copy than low-expressing cells. In this paper, we examine the possible mechanisms causing this deregulation of c-erbB-2 mRNA accumulation. Nuclear run-on studies indicated that the extra mRNA accumulation was due to increased transcription of the gene in overexpressing cells. Promoter analyses using c-erbB-2 5' flanking sequences linked to CAT showed that the promoter is more active in overexpressing cells. Coupling promoter deletion functional studies with footprinting experiments, using nuclear extracts derived from both low and overexpressing cells, allowed the identification of a DNA-binding protein, OB2-1, which is considerably more abundant in a range of overexpressing lines. We discuss the possible role of OB2-1 in c-erbB-2 overexpression in breast tumour lines.

Targeting gene transcription: a new strategy to down-regulate c-erbB-2 expression in mammary carcinoma.

Overexpression of the c-erbB-2 proto-oncogene in mammary carcinoma is frequently associated with amplification of the c-erbB-2 gene, but it also occurs from single-copy gene. Studies in mammary-derived cell lines have shown that, whether or not the gene is amplified, there is a 6- to 8-fold increase in the accumulation of c-erbB-2 mRNA per gene copy in overexpressing cells. We have recently shown that this phenomenon is due to increased activity of the c-erbB-2 promoter mediated by the binding of a novel transcription factor, OB2-1, which is present at higher levels in overexpressing cells than in low expressors. OB2-1 activity therefore represents a novel therapeutic target for the down-regulation of c-erbB-2 levels in human cells. As a prototype for this strategy, we show here that the drug sodium aurothiomalate is able to inhibit the DNA-binding activity of OB2-1 in vitro and also to interfere with c-erbB-2 promoter activity in cell-based transfection assays. In addition, endogenous c-erbB-2 immunoreactivity was reduced in cells treated with aurothiomalate as compared with the levels observed in control cells.

Broadcast quality teleconferencing for oncology.

The National Cancer Institute (NCI) in Bethesda, Maryland has developed a broadcast-quality teleconferencing system known as the Telesynergy system to address the need to convey expert information between larger cancer centers and their remote counterparts. This system is available to "Partnerships in Science Program" partners across the U.S. Recently, it has been made available in Ireland under a "Memorandum of Understanding" among the Department of Health and Children of Ireland, the Department of Health and Social Services in Northern Ireland, and the NCI. The Telesynergy system is capable of transmitting not only broadcast-quality teleconferencing among several different sources, but also diagnostic-quality radiology and pathology images. Remote operated microscopes and video cameras allow biopsy specimens to be discussed and manipulated from several different locations. Smear preparations of blood, bone marrow, and other cytological specimens can be examined in detail by a remote operator. The system can also transmit conventional x-ray images and paper documents. The Telesynergy system ensures that each patient, regardless of location, will receive an expert assessment and be given optimal therapy. While the system is currently being developed in Ireland for use in oncology, it is hoped that other specialties can benefit from it in the future.