An exploration of the impact of ethanol diluent on breath alcohol concentration in patients receiving paclitaxel chemotherapy.

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.

The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

The impact of outpatient systemic anti-cancer treatment on patient costs and work practices.

BACKGROUND: There is extensive focus on the rising costs of healthcare. However, for patients undergoing cancer treatment, there are additional personal costs, which are poorly characterised. AIM: To qualify indirect costs during anti-cancer therapy in a designated Irish cancer centre. METHODS: An anonymous questionnaire collected demographic data, current work practice, and personal expenditure on regular and non-regular indirect costs during treatment. Differences between groups of interest were compared using the Mann-Whitney U test. RESULTS: In total, there were 151 responders of median age 58 years; 60 % were female and 74 % were not working. Breast cancer (29 %) was the most frequent diagnosis. Indirect costs totalled a median of €1138 (range €21.60-€7089.84) per patient, with median monthly outgoings of €354. The greatest median monthly costs were hair accessories (€400), transportation (€65), and complementary therapies (€55). The majority (74 %) of patients used a car and median monthly fuel expenditure was €31 (range €1.44-€463.32). Women spent more money during treatment (€1617) than men (€974, p = 0.00128). In addition, median monthly expenditure was greater for those less than 50 years old (€1621 vs €1105; p = 0.04236), those who lived greater than 25 km away (€2015 vs €1078; p = 0.00008) and those without a medical card (€2023 vs €961; p = 0.00024). CONCLUSION: This study highlights the need for greater awareness of indirect expenditures associated with systemic anti-cancer therapy in Ireland.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.

Chemotherapy induced peripheral neuropathy: the modified total neuropathy score in clinical practice.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, potentially reversible side effect of some chemotherapeutic agents. CIPN is associated with decreased balance, function and quality of life (QoL). This association has to date been under-investigated. AIMS: To profile patients presenting with CIPN using the modified Total Neuropathy Score (mTNS) in this cross-sectional study and to examine the relationship between CIPN (measured by mTNS) and indices of balance, quality of life (QoL) and function. METHODS: Patients receiving neurotoxic chemotherapy regimens were identified using hospital databases. Those who did not have a pre-existing neuropathy were invited to complete mTNS, Berg Balance Scale (BBS), timed up and go (TUG), and FACT-G QoL questionnaire. mTNS scores were profiled and also correlated with BBS, TUG and FACT-G using Spearmans correlation coefficient. RESULTS: A total of 29 patients undergoing neurotoxic chemotherapy regimens were tested. The patients mTNS scores ranged between 1 and 12 (median = 5), indicating that all patients had clinical evidence of neuropathy on mTNS. No significant correlations were found between mTNS and BERG (r = -0.29), TUG (r = 0.14), or FACT-G (r = 0.05). CONCLUSIONS: This study found a high prevalence of CIPN in patients treated with neurotoxic chemotherapy regimens. The mTNS provided a clinically applicable, sensitive screening tool for CIPN which could prove useful in clinical practice. mTNS did not correlate with BBS, TUG or FACT-G in this sample, possibly due to relatively mild levels of CIPN and consequent subtle impairments which were not adequately captured by gross functional assessments.

Cutaneous metastases from gastric carcinoma: an unusual presentation.

We report the case of a 71-year-old gentleman who intially developed cutaneous metastases from gastric carcinoma on his chin and cheek resembling sebaceous cysts.

Acute upper arm ischaemia: a rare presentation of non-Hodgkin's lymphoma.

Digital ischaemia has been sparsely reported in current literature. Its association with lymphomatous conditions has been described in even more exceptional occurrences. We present the first case of upper arm ischaemia associated with non-Hodgkin's lymphoma. A brief literature review of this rare phenomenon is also accompanied with it.

Patterns of participation of patients in cancer clinical trials in Ireland.

BACKGROUND: In the United States the overall participation in cancer clinical trials (CCT) is less than 3% [Avis et al. in J Clin Oncol 24:1860-1867 (2006); Lara et al. in J Clin Oncol 19:1728-1733 (2001)]. In Europe there is little data on participation in such trials. AIM: We aim to gather information on factors influencing CCT enrolment in Ireland. METHODS: From November 2005 to 28 February 2006 all consecutive patients considered for systemic therapy were assessed for eligibility re participation in available CCTs. RESULTS: A total of 290 patients were included. Overall 2.4% of patients were recruited to one of the available CCTs. The main reasons for failure of trial recruit were: no trial for cancer type (60%), no trial for stage (21%), ineligible by trial criteria (16.1%), patient declined (0.3%), and physician discretion (2.6%). Only one patient, who was otherwise eligible, declined entry into a clinical trial. CONCLUSIONS: Irish patients with cancer are very willing to participate in CCTs. Current levels of recruitment compare favourably with international levels.

Practical problems and resource implications with the use of warfarin for venous thromboembolism in patients with cancer.

BACKGROUND: Oral anticoagulants present multiple practical problems for patients undergoing chemotherapy. To assess the practice implications of anticoagulation therapy, a review was carried out. METHODS: A review of all patients with cancer treated with warfarin for venous thromboembolism (VTE) over a 1-year-period was carried out. Adverse events and therapeutic efficacy were assessed and the extra volume of work involved in monitoring was quantified. RESULTS: Fifty-five patients with cancer and VTE were treated with warfarin from 07/04 to 06/05. Twenty-one invasive interventions required disruption of anticoagulation. There were eight admissions for haemorrhage. Nine patients died while on warfarin. A total of 1,379 coagulation tests were performed. There were 382 extra dayward visits attributable to warfarin monitoring. On treatment, 13 patients (24%) were changed from warfarin therapy to low molecular weight heparin (LMWH). CONCLUSIONS: This study identifies and quantifies the extra resource utilization with warfarin therapy in patients undergoing chemotherapy.

Association between paclitaxel and necrotic pancreatitis.

To our knowledge this is the first reported case of paclitaxel associated necrotic pancreatitis requiring a pancreatic necrostomy. This was a near fatal complication associated with paclitaxel with a high resulting morbidity. Although this is a rare association physicians should be wary of the potential to develop severe pancreatitis in patients receiving this therapeautic agent. Monitoring of serum amylase during therapy is therefore warranted.

HIV infection among heroin users and area of residence.

The aim of this study was to develop a hypothesis to explain the link between HIV prevalence and area of residence. The study was conducted in two parts using two existing data sources. In Part 1, the bloodborne viral test status and test results of a sample of clients attending treatment in December 2001 in two areas of Dublin, an inner city area (Dublin 8) and a suburban area (Dublin 24), were extracted from the Bloodborne Viral Status Dataset created by Grogan. In Part 2 the characteristics of heroin users seeking treatment for the first time at treatment services in their respective areas of residence, Dublin 8 or Dublin 24, between 1997 and 2000 were examined, using data from the National Drug Treatment Reporting System. A higher proportion of heroin users in Dublin 8 had HIV and hepatitis C than did their counterparts in Dublin 24. The analysis suggests that heroin users in Dublin 8 were more likely both to have ever used cocaine and to have used heroin daily, than were those who lived in Dublin 24. Also, a higher proportion of injectors living in Dublin 8 used heroin and cocaine concurrently than did their counterparts in Dublin 24. In both samples, heroin users who lived in Dublin 8 were older than those who lived in Dublin 24. The findings led to a hypothesis:'The risk of acquiring HIV is associated with area of residence and may be linked to cocaine use.

Bloodborne virus infections among drug users in Ireland: a retrospective cross-sectional survey of screening, prevalence, incidence and hepatitis B immunisation uptake.

BACKGROUND: Injecting drug users are at high-risk of bloodborne virus infections including hepatitis C (HCV), hepatitis B (HBV) and HIV. AIMS: To document screening for and immunisation against bloodborne viruses and to determine the known prevalence and incidence of these infections. METHODS: A cross-sectional survey of clients attending 21 specialist addiction treatment clinics in one health board area in greater Dublin. Data collected on demographic characteristics, serology for HCV, HBV and HIV and immunisation against HBV. RESULTS: A total of 316 (88%) had been tested for anti-HCV antibody, 244 (68%) had been tested for anti hepatitis B core antibody (anti-HBc), 299 (84%) had been tested for hepatitis B surface antigen (HBsAg) and 307 (86%) had been tested for anti-HIV antibody. The prevalence of anti-HCV, anti-HBc, HBsAg, and anti-HIV were: 66%, 17%, 2% and 11% respectively. The incidence of HCV, HBV and HIV infections were: 24.5, 9.0 and 3.4 per hundred person years respectively. Eighty-one per cent of those in whom it was indicated, had started a targeted HBV immunisation programme in the clinics. CONCLUSION: The proportion of clients screened for HCV, HBV and HIV infection has increased since the introduction of a screening protocol in 1998. Targeted vaccination for opiate users against hepatitis B is more successful than previously shown in Ireland. The prevalence and incidence of bloodborne viruses remains high among opiate users attending addiction treatment services, despite an increase in availability of harm reduction interventions.

"Why are we working so hard?" A cross-sectional survey of factors influencing GP workload in the Eastern Regional Health Authority area.

There is increasing evidence to suggest that the subjective workload of GPs in Ireland is too heavy. The aims of this study, therefore, were to identify the social and demographic issues that GPs perceive as being implicated in determining their workload. A self-administered questionnaire, inviting GPs to score a series of factors according to the degree to which it increased their workload, was sent to one-quarter of GPs practising in the Eastern Regional Health Authority (ERHA) area. The response rate was 71%. Seventy-nine (60%) felt their workload was 'too heavy,' while 109 (85%) felt they could improve the quality of care they provide, if their workload was reduced. Access to OPD services (mean score = 7.31), access to other hospital services (mean score = 7.16), and the number of elderly patients (mean score = 6.28) were considered to be the most important factors in determining workload. This paper describes the factors that impact on self-perceived workload for GPs, factors which need to be considered when planning and funding future developments in primary care.

Physical interaction between p53 and primary response gene Egr-1.

The tumor suppressor p53 and primary response gene Egr-1 are nuclear transcription factors with regulatory roles in signal transduction pathways mediating cellular proliferation and growth arrest as well as the complex genetic programs controlling differentiation and programmed cell death. We identified a physical association between these regulatory proteins in vitro and in vivo. Recombinant p53 and Egr-1 fusion proteins complexed with in vitro translates of Egr-1 or p53, respectively, or with these respective proteins in cell lysates. This protein-protein interaction was detected in vivo by immunoprecipitation and Western blot analysis of serum-activated cellular lysates with high levels of induced Egr-1 and of human lung cancer cell lines with constitutive overexpression of Egr-1 and mutant p53. A p53 mutant at codon 154 did not bind Egr-1, while p53 proteins with point mutations at residues 156, 246, 247, and 273 associated with this zinc finger transcription factor. p53 bound full-length Egr-1 and an Egr-1 mutant with a deletion of the 5' transactivation region but did not associate with Egr-1 protein lacking an internal segment that included the first two zinc finger domains, suggesting that binding may require the presence of intact zinc finger motifs. A variant-sized Egr-1 protein expressed by lung fibroblast cell line MRC-9 was also bound by p53. The interaction of these regulatory proteins may alter multiple features of their biological activity especially with regard to the specificity of transcriptional control.

Biomarker assays in nipple aspirate fluid.

The noninvasive technique of nipple aspiration as a potential source of biomarkers of breast cancer risk was evaluated. The feasibility of performing mutagenesis assays, amplifying DNA, and performing protein electrophoresis on nipple aspirate fluid was explored. A tool was developed to measure the level of discomfort, if any, from this procedure. Twenty-five healthy women (20 premenopausal and 5 postmenopausal) were enrolled. Fluid was obtained using a modified breast pump. Premenopausal women were scheduled for four to six weekly aspirations, and postmenopausal women were scheduled for one to two weekly aspirations. Mutagenesis assays were performed using the Salmonella (Ames) assay. DNA amplification of several microsatellite regions was carried out using polymerase chain reaction. Protein was quantified, and two-dimensional protein electrophoresis was performed. Overall, fluid was obtained from 80% of the women, and the level of discomfort was minimal. Acid hydrolysis of one sample resulted in mutagenicity; all six nonhydrolyzed samples were not mutagenic. The ability to amplify DNA ranged from 34% to 96%, depending on length of the microsatellite region examined. The average protein concentration was 71 microg/mL. Two-dimensional protein electrophoresis was successfully performed on samples from two subjects. Nipple aspiration is a simple technique and is easily learned and well tolerated, which yields a reagent useful for a variety of investigations. This technique may facilitate the identification and application of biomarkers for future breast cancer risk assessment and chemopreventive protocols.

Coordinate regulation of cyclooxygenase-2 and TGF-beta1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors.

Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-beta1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-beta in RER adenocarcinomas is complex because of the increased mutation rate of TGF-beta type II receptors. Northern analysis showed abundant TGF-beta1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-beta1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-beta1 treatment caused a TGF-beta-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-beta1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence.